key: cord-293717-j4w6mq0f authors: meza, herbert tejada; lambea gil, álvaro; saldaña, agustín sancho; martínez-zabaleta, maite; juez, patricia de la riva; martínez, elena lópez-cancio; apilánez, maría castañón; isasi, maría herrera; enguita, juan marta; alfonso, mercedes de lera; arenillas, juan f; olaizola, jon segurola; fernández, juan josé timiraos; sánchez, joaquín; castellanos-rodrigo, mar; roel, alexia; menéndez, ignacio casado; freijo, mar; rodriguez, alain luna; portilla, enrique palacio; lópez, yésica jiménez; castro, emilio rodríguez; rivas, susana arias; garcía, javier tejada; rodríguez, iria beltrán; julián-villaverde, francisco; garcía, maria pilar moreno; trejo-gabriel-galán, josé maría; iñiguez, ana echavarría; juste, carlos tejero; lázaro, cristina pérez; moreno, javier marta; on behalf of the nordictus investigators, title: impact of covid-19 outbreak on ischemic stroke admissions and in-hospital mortality in north-west spain date: 2020-06-26 journal: int j stroke doi: 10.1177/1747493020938301 sha: doc_id: 293717 cord_uid: j4w6mq0f background and purpose: spain has been one of the countries heavily stricken by covid-19. but this epidemic has not affected all regions equally. we analyzed the impact of the covid-19 pandemic on hospital stroke admissions and in-hospital mortality in tertiary referral hospitals from north-west spain. methods: spanish multicenter retrospective observational study based on data from tertiary hospitals of the nordictus network. we recorded the number of patients admitted for ischemic stroke between 30 december 2019 and 3 may 2020, the number of ivt and evt procedures, and in-hospital mortality. results: in the study period, 2737 patients were admitted with ischemic stroke. there was a decrease in the weekly mean admitted patients during the pandemic (124 vs. 173, p<0.001). in-hospital mortality of stroke patients increased significantly (9.9% vs. 6.5%, p = 0.003), but there were no differences in the proportion of ivt (17.3% vs. 16.1%, p = 0.405) or evt (22% vs. 23%, p = 0.504). conclusion: we found a decrease in the number of ischemic stroke admissions and an increase in in-hospital mortality during the covid-19 epidemic in this large study from north-west spain. there were regional changes within the network, not fully explained by the severity of the pandemic in different regions. since the first reported case in early december 2019, severe acute respiratory coronavirus 2 (sars-cov-2) infection, known as coronavirus disease 2019 (covid-19), has become pandemic so rapidly that healthcare systems have been overwhelmed all around the world. [1] [2] [3] in spain, by 16th may, 231,350 cases and 27,650 deaths had been confirmed. 4 many extreme measures have been taken to contain the spread of the disease, such as locking down communities, which could have affected the optimal stroke care. spain has been one of the countries more heavily stricken by sars-cov-2, but this pandemic has not affected all regions equally. while some registered more than 3000 cases per day, others did not reach 120. in this context, there is general uncertainty in spain regarding the real impact of the covid-19 outbreak on hospital stroke admissions. moreover, the necessary measures taken by hospitals, aiming to increase healthcare professionals' protection, and government measures to protect at risk patients from unnecessary admission, may have jeopardized the quality of care provided to stroke patients. we aimed to analyze the impact of the covid-19 pandemic outbreak on hospital ischemic stroke admissions as well as the use of reperfusion therapies and inhospital mortality in tertiary referral hospitals from north-west spain. this spanish multicenter retrospective observational study was based on the nordictus network data. nordictus is a research and innovation network in cerebrovascular diseases that brings together all public hospitals with stroke units in north-west spain, with a global catchment area of 11.5 million inhabitants. according to its territorial division, the spanish state is divided into 17 autonomous communities (ac) and two autonomous cities, both groups being the highest or first-order political and administrative division in the country. ac are divided into 50 total provinces and nordictus covers 23, grouped in 8 ac represented in figure 1 , with the sars-cov-2 seroprevalence in each region by 14th may. sixteen of the 18 referral centers of the network offered their data. during pandemic, none of the participating regions changed its prehospital ischemic stroke care. epidemiological data of covid-19 cases were obtained from the ministry of health, consumer affairs and social welfare. it considers confirmed cases those who have a positive polymerase chain reaction for sars-cov-2. due to a change in the counting system in the ac of galicia, historical data from that administration were obtained from its regional department of health (conselleria de sanidade). 5, 6 study population we reviewed the data from tertiary hospitals of the nordictus network and recorded the number of patients admitted for ischemic stroke between 30 december 2019 and 3 may 2020. we grouped the cases in two periods, according to the setting of the state of emergency in spain (14 march 2020) and considering the start of the covid-19 period as the 11th week (w11) of 2020. we also recorded the number of intravenous (ivt) and endovascular treatments (evt), as well as wake-up strokes or unknown-onset time. finally, in-hospital mortality was recorded and analyzed as the key quality indicator of the stroke care process. sixteen centers from eight different spanish ac participated in this study. we used descriptive statistics to compare the incidence of stroke admissions before and after the setting of the state of emergency in spain, expressed in strokes per week (w) and the differences between the other study variables (ivt, evt, in-hospital mortality, and wake-up strokes or unknown-onset time) in those periods. qualitative variables are described using counts and percentages, and continuous quantitative variables as means with standard deviation and medians with interquartile ranges when necessary. comparisons between groups were made using chi-square tests for comparing categorical variables and the student test or mann-whitney u test for continuous variables; p values < 0.05 were considered statistically significant. statistical analysis was performed with spss statistics 20. the study was approved by the local ethics committee of each participating center. treatment of every data obtained in the registry was done following the spanish data protection law (data protection and digital rights guarantee act). in total, 2737 patients with ischemic stroke (male 1476, 53.5%; average age 73.5 years, sd ae 6.0) were attended to any of the hospitals participating in the study between 30 december 2019 and 3 may 2020. table 1 shows global and specific results for each hospital and grouped by regions. globally, there was a weekly average of 173 (iqr (interquartile range) 171.0-178.5) ischemic stroke admissions before the setting of the state of emergency against 124 (iqr 114.8-134.3) afterward (p < 0.001) ( table 1 ). this drop in stroke cases occurred progressively from week 11 (w11, 9-15th march), persisting over time despite the decrease in confirmed cases of covid-19, but it did not occur homogeneously in each hospital; the reduction was only significant in 6 out of 16 centers (table 1, figure 2 ). there were no differences in the proportion of ischemic stroke undergoing ivt (17.3% vs. 16.1%, p ¼ 0.405) or evt (22% vs. 23%, p ¼ 0.504) during the pandemic or in the proportion of wake-up/ unknown-onset strokes (39.4% vs. 39.1%, p ¼ 0.887). in-hospital mortality of stroke patients increased significantly during the covid-19 pandemic (6.5% vs. 9.9%, p ¼ 0.003) ( table 1 ). this study demonstrates a decrease in stroke admissions and an increase in stroke mortality during the covid-19 pandemic across 16 centers within the nordictus network including arago´n, asturias, cantabria, castilla y leo´n, euskadi, galicia, la rioja, and navarra in north-west spain. on 14 march 2020, the government of spain implemented extraordinary measures to control viral transmission, restricting free mobility over the entire country equally. this was reinforced from 31st march to 11th april, with essential workers the only ones allowed to leave their homes. these restrictions have been maintained until 4th may (w18). since then, there has been a gradual return to normal by stages and which has varied between provinces. to date, castilla y leo´n is among the territories which maintain the most restrictive measures in spain. a decrease in hospital admissions for ischemic stroke in europe is a situation that has already been referred to in different scientific media, 7-9 but just described in two regional studies. 10, 11 this is the first study of which we are aware describing this phenomenon in hospitals from different regions throughout a wide coverage area in this continent. we found a decrease in the absolute number of ischemic strokes admissions, and although this was observed in all of the hospitals participating in the study, it only reached statistical significance in 6 out of 16 centers. if we group them by ac, the proportion increases so that only three out of eight territories (cantabria, la rioja, and navarra; uni-provincial ac) did not show a significant decrease. the magnitude of the decrease varied markedly between study centers. this varied from a drop in ischemic stroke cases of more than 50%, in three most international journal of stroke, 0(0) affected hospitals compared to a drop of less than 10% drop in the three least affected hospitals (table 1) . in some cases, the variations were seen even despite being in the same ac and apparently with no correlation with the covid-19 cases per week curves for each region ( figure 2 ). one example is the steep decline observed in hospitals from asturias, which was less effected by covid-19 cases than other regions. possible explanations for the decrease in ischemic stroke admissions have been suggested. [10] [11] [12] these include changes in social behavior or attitude, minor non-disabling strokes staying at home, or admission to hospital isolation units where stroke might not be the major issue, or not enough attention being made to diagnose stroke. an argument against small strokes not being referred to hospital is our regional study from arago´n, one of the ac within the nordictus network, in which we did not find a higher proportion of patients with higher nihss or lower aspects compared to the pre-covid period. 10 others speak about a possible real decrease in the incidence of strokes due to a reduction of risk factors such as air pollution. 9, 13 the increase in mortality, above the usual values in our area, 14 could be explained by some of the previously described situations, or others such as fewer minor stroke admissions, increasing the proportion of severe ischemic strokes. it may also reflect an increase in stroke severity in patients with co-existent covid-19 infection. 15 some authors have described a decrease in the number of ivt and evt during this period. 11 we also found this, but with no change in the proportion of treatments performed, similar to the findings of zhao et al., who suggest the drop in the absolute number of ivt and evt cases merely reflects the decline in stroke admissions. 12 to the best of our knowledge, this study offers the biggest european sample to analyze the influence of covid-19 pandemic in ischemic stroke admissions. we found a decrease in the number of ischemic stroke admissions and an increase in in-hospital mortality. healthcare systems should be rapidly adapted to implement systems for covid-19 care, but also to ensure the usual and effective stroke care despite system reorganizations. since stroke is a life-threatening condition, it is important not to neglect the usual level of stroke care regardless of the difficult situation derived from the covid-19 pandemic. our study has some limitations. the main limitation is inherent to its retrospective, observational nature. besides, we did not investigate the incidence of virus infection among patients with stroke or whether it affected stroke outcomes. we did not obtain other stroke characteristics that could help to analyze the causes of the increasing mortality. second, although we analyzed data from sixteen hospitals with stroke units belonging to eight ac from the north of spain, some ischemic strokes in the region are not admitted to these hospitals but instead to small hospitals without stroke units. however, due to their role as reference centers and as the hospitals with the highest volume of stroke patients in the area, we believe our data give a valid representation of the impact of covid-19 in ischemic stroke over the whole region. finally, our results might not be extrapolated to other countries or regions with different stroke care protocols and different social and healthcare responses to the covid-19 pandemic. who declares covid-19 a pandemic covid-19 -navigating the uncharted covid-19: doctors are told not to perform cpr on patients in cardiac arrest datos agregados notificados por las xunta de galiza. datos de notifi-cacio´n de casos en galicia likely increase in the risk of death or disability from stroke during the covid-19 pandemic stroke care at the time of covid-19 outbreak express: covid-19 and stroke -a global world stroke organization perspective ischaemic stroke in the time of coronavirus disease impact of the covid-19 outbreak on acute stroke pathways -insights from the alsace region in france impact of the covid-19 epidemic on stroke care and potential solutions. stroke. epub ahead of print 20 the baffling case of ischemic stroke disappearance from the casualty department in the covid-19 era a set of care quality indicators for stroke management brain ischemic and hemorrhagic complications of covid-19 the author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: jf arenillas reports having received honoraria as speaker/consultant for the following companies: bi, pfizer, daiichi, bayer, amgen, and medtronic. e palacio portilla reports having received honoraria as speaker/consultant for the following companies: esteve, rovi, msd and amgen. the rest of the authors have no conflict of interests. the author(s) received no financial support for the research, authorship, and/or publication of this article. herbert tejada meza https://orcid.org/0000-0002-6506-1037 á lvaro lambea https://orcid.org/0000-0003-1785-9201 juan f arenillas https://orcid.org/0000-0001-7464-6101 jose´marı´a trejo-gabriel-gala´n https://orcid.org/0000-0001-9591-8452 key: cord-281716-e9fo38gy authors: gómez, l.; andrés, s.; sánchez, j.; alonso, j. m.; rey, j.; lópez, f.; jiménez, a. title: relationship between the treatment and the evolution of the clinical course in scouring merino lambs from “la serena” (southwest spain) date: 2008-05-31 journal: small ruminant research doi: 10.1016/j.smallrumres.2008.01.005 sha: doc_id: 281716 cord_uid: e9fo38gy abstract this work investigated the link between the type of treatment and the clinical evolution of lambs suffering from diarrhoea attributed to non-enterotoxigenic escherichia coli. two hundred and forty scouring lambs, and 25 healthy lambs selected as control, were used in this trial. the faecal samples from the scouring lambs were positive to non-enterotoxigenic e. coli. all the scouring lambs received supportive care and they were randomly allotted to two groups of 120 animals (treated group and untreated group). the lambs in the treated group were given two daily doses of 20mg/kg live weight spectinomycin for 3 days, while the other group of lambs (untreated group) did not receive any antibiotic. serum endotoxin was higher in the treated lambs. the combined infection of e. coli + proteus mirabilis was the most frequent microbiological result in the deceased treated lambs, while the only enteric pathogen isolated in the untreated lambs submitted to necroscopy was e. coli. the pathological findings most commonly recorded in the untreated lambs were suggestive of a generalized inflammatory process attributed to colibacilosis, while the lesions in the treated lambs might correspond to an enterotoxoemic process. the overproduction of p. mirabilis might be consequence of the antibiotic treatment and it would be the most probable cause of the endotoxemia, the high mortality rate and the pathological findings in the treated lambs. therefore, a supportive care without antibiotics does not lead to a poorer chance of survival in lambs with diarrhoea attributed to non-enterotoxigenic e. coli. diarrhoea in lambs is a complex, multi-factorial disease involving animal, environment, nutrition and infectious agents. several factors are able to predispose * corresponding author. tel.: +34 927257164; fax: +34 927257110. e-mail address: ajredon@unex.es (a. jiménez). to diarrhoea. flock size, type of facilities, type of breeding, lambing percentage, isolation of campylobacter jejuni, rotavirus spp., coronavirus spp. and salmonella spp. seem to be poorly correlated to lamb mortality. on the contrary, bad cleaning of the lambing areas, continuous lambing periods, accumulation of lambs in the pens, high content of fat, protein and lactose in milk, low serum gamma globulin and total protein in lambs and ewes, and cryptosporidium spp. infection are strongly 0921-4488/$ -see front matter © 2008 elsevier b.v. all rights reserved. doi:10. 1016/j.smallrumres.2008.01.005 linked to lamb mortality (muñoz et al., 1996; . it has been stated that some factors could affect the survival chance of the animals suffering from this disorder. the effect of endotoxemia is particularly important, as a relationship has been found between the presence of endotoxin in blood and the unfavourable prognosis of the scouring syndrome . this piece of research investigated the possible relationship among the type of treatment, the evolution of the clinical course and the severity of the pathological findings in lambs severely affected by diarrhoea. eighteen extensive sheep farms with previous history of high lamb losses attributed to scouring were randomly selected for this experiment. at the time of the trial all the flocks presented natural outbreaks of diarrhoea affecting lambs in the first 2 weeks of life, with a prevalence of 20-80%. the farms were located in the same geographical area (la serena, southwest spain) and they were managed under similar health, nutrition and husbandry practices. on each of the 18 farms, lambs were examined to identify "scouring lambs" with active diarrhoea, fever, tachypnea, dullness and a dehydration of 5-10%. the number of lambs selected in each farm was proportional to the prevalence of the scouring syndrome in the flock, with a total of 240 lambs with diarrhoea included in the study. at the time of the first physical examination samples of faeces were taken from the rectum of the lambs using sterile culture swabs (eurotubo ® , iasa, barcelona, spain). the scouring lambs received 400 ml of an intravenous ringer lactate solution (solución ringer lactato ® , braun, barcelona, spain) initially, and then they were rehydrated as many times as necessary. after 24 h, once the etiological diagnosis was known, half of the patients were treated with two daily doses of 20 mg/kg live weight spectinomycin for 3 days (spectamporcelet ® , ceva, barcelona, spain) and an oral dose of 0.07 mg/kg live weight halofuginone (halocur ® , intervet, spain) once a day for 3 days, while the rest of the animals only received halofuginone. all the animals were under veterinary supervision. experienced teams of observers monitored lambs at regular intervals to assess the outcome of treatment. during this period the lambs with unfavourable evolution were submitted to a final clinical examination and 2.5 ml blood were withdrawn from the jugular vein of each lamb into sterile clotting, edta and 3.2% trisodium citrate tubes (eurotubo ® , iasa, spain). at the same time, a certain number of healthy lambs in each farm, 25 in total (control group), were selected and sampled for comparison of the levels of endotoxin and fibrinogen in blood. then, the deceased lambs were submitted to necroscopy and further pathological and microbiological studies. blood samples were processed for serum and plasma separation. serum samples were assayed for endotoxin with the chromogenic lal test according to the manufacturer's instructions (chromogenic lal lysate test qcl 1000 ® , cambrex iberia products, barcelona, spain) by photometry (shimazdu uv 160 ® , pacisa, barcelona, spain). plasma fibrinogen was measured with a fibrinogen assay kit (thrombin 200, pacific hemostasis, huntersville, usa) in an automatic coagulometer (clot 1, pacisa, barcelona, spain). the lambs were examined post-mortem for gross evidence of disease and samples were taken from central nervous system (cns), lungs, liver, spleen, kidneys, abomasum, jejunum and mesenteric lymph glands for pathological and microbiological analysis. tissues for pathological study were fixed in 4% buffered formaldehyde solution by standard paraffinembedding methods. five micrometers thick sections were cut and treated with haematoxylin and eosin. the infectious agents involved in scouring were investigated by culture in appropriate media, immune assay and pcr. enteric bacteria were cultured on agar macconkey ® (oxoid, madrid, spain) and agar xlt4 ® (merck, barcelona, spain). blood agar was used for the anaerobiotic culture of clostridium spp. (blood agar ® , oxoid, spain). brucella agar was used for campylobacter spp. (modified brucella agar ® , oxoid, spain). the cultures were carried out according to the procedures of carter and chengappa (1990 rey et al. (2003) . this method was used to identify virulent e. coli genes (primers and pcr mixture, amersham biosciences, barcelona, spain). after checking the normality of the distribution of data, the differences between the concentrations of endotoxin and fibrinogen in the blood of the lambs in the control, the treated and the untreated groups were tested for statistical significance by using anova. contingency tables and chi-squared test were employed to evaluate the statistical significance of any differences for case fatality rates, finding of enteric pathogens table 1 number of animals in the experiment, case fatality rate, serum endotoxin and plasma fibrinogen levels (mean ± standard error) in the lambs from the treated and untreated groups number of lambs scouring (n = 240) control lambs (n = 25) treated lambs (n = 120) untreated lambs (n = 120) serum endotoxin level (ng/ml) 0.14 ± 0.01 a 0.48 ± 0.01 b 0.31 ± 0.12 c plasma fibrinogen level (mg/dl) 114 ± 15 a,* 801 ± 92 b 723 ± 65 b case fatality rate (%) 68.3 a 17.5 b a, b and c mean with different letters in each row are significantly different (p < 0.05, *p < 0.001). faecal cultures from all the scouring lambs in all the farms (n = 240) were positive for e. coli and most of them for cryptosporidium spp. however, pcr assays yielded negative results for enterotoxigenic or verotoxigenic e. coli strains and for rotavirus, coronavirus and salmonella. c. jejuni was isolated only in one farm. the results of case fatality rate (%), serum endotoxin level (ng/ml) and concentration of fibrinogen (mg/dl) in plasma in the different groups of lambs are displayed in table 1 . the first two parameters were significantly higher (p < 0.05) in the treated lambs. however, no difference was found for plasma fibrinogen level between the treated and the untreated group. the occurrence of the main pathological findings in the treated and untreated deceased lambs is shown in table 2 . the patients in both groups presented some common pathological findings, as catarrhal gastroenteritis and the typical reactivity pictures in the lymphoid organs, with enlargement and hyperplasia. nevertheless, certain lesions in other systems appeared with different incidence in the two groups. the results of the microbiological study from the samples obtained at the necroscopy revealed the presence of e. coli, proteus spp. and, scarcely, cryptosporidium spp. the frequency of mixed infections of e. coli and proteus spp. is indicated in table 2 . in this trial the main enteric pathogens in the scouring lambs were cryptosporidium spp. and e. coli. the role of these agents in the production of diarrhoea in young small ruminants has been stated in this region (muñoz et al., 1996) and worldwide (matthews, 1999) . the concentration of endotoxin in the lambs in the two groups of scouring lambs was significantly higher than in the control group (table 1) . the level of endotoxin in the serum of the control lambs was similar to that reported for healthy horses (barton and collatos, 1999) , human blood donors (nadhazi et al., 2002) and lambs . the lambs in the treated and untreated groups presented levels of serum endotoxin comparable to those found in horses affected by colic (barton and collatos, 1999) and in human patients suffering from septic shock (danner et al., 1991) . plasma fibrinogen is an acute phase hepatic protein. it is an indicator of occult inflammatory disorder in ruminants; the greater the magnitude of its increase, the greater the magnitude of inflammation (kramer, 2000) . the concentrations of fibrinogen in the treated and the untreated lambs were significantly higher than in the control lambs (table 1 ). this is indicative of a severe inflammatory process. many lambs in the two groups presented catarrhal gastroenteritis and enlargement of the lymphoid organs, as reported in lambs suffering from scouring syndromes related to the same aetiology (barker and van dreumel, 1985) . the pathological findings recorded with a significantly higher frequency in the untreated lambs ( table 2) were suggestive of a generalized inflammatory process attributed to colibacilosis, which is characterized by meningoencephalitis, interstitial pneumonia, perivascular hepatitis and interstitial nephritis (barker and van dreumel, 1985) . the pathological findings registered more commonly in the treated lambs (table 2 ) might correspond to an enterotoxemic process. the inflammation of the intestine attributed to e. coli would cause an ischemic injury to the digestive mucous barrier. in this instance, large quantities of endotoxin would be absorbed from the intestine, overwhelming the detoxifying ability of the liver and increasing the concentration of endotoxin in the peripheral circulation (king and gerring, 1988; haussman et al., 2000) . the presence of toxins in the organs would be responsible of the cell degeneration (haussman et al., 2000) , as suggested by the significantly higher concentration of endotoxin in the plasma of the treated lambs (table 1) . as indicated by the low frequency of isolation of cryptosporidium spp. in the lambs submitted to necroscopy, the treatment with halofuginone was highly effective, as it has been reported in calves (lefay et al., 2001) . the combined infection of e. coli + p. mirabilis had a higher incidence in the treated lambs (table 2) , while the only enteric pathogen isolated in the untreated lambs was e. coli. this finding might be associated to the effect of the antibiotic treatment. spectinomycin is a bacteriostatic antibiotic that inhibits protein synthesis in susceptible bacteria by binding to the 30s ribosomal unit (plumb, 1995) . the efficacy of antibiotic treatment against e. coli (hodgson et al., 1999) and the resistance of p. mirabilis against antibiotics in several circumstances (dance et al., 1987) have been reported. this could indicate that the treatment with spectinomycin could have limited the growing of e. coli in the patients from the treated group and it would have permitted the overproduction of p. mirabilis. p. mirabilis is able to produce endotoxin that can impair diverse biological functions through several mechanisms, as the alteration of platelet activity (saluk-juszczak et al., 2007) . in the treated lambs the concentration of endotoxin in serum was significantly higher than in the untreated group (table 1 ). this concentration was around 0.50 ng/ml, the point beyond survival chance is null ; while untreated lambs showed results below this limit. this could explain the significant difference in the mortality rate between the two groups (table 1 ). it could support as well the pathological findings of the spectinomycin-treated lambs lost by diarrhoea. the proliferation of p. mirabilis, the elevated endotoxin concentration, the higher mortality rate and the pathological findings in the treated group appeared to be related to the antibiotic treatment. therefore, it might be considered that, under the management and husbandry conditions of this trial, a supportive care without antibiotics would not lead to a poorer chance of survival in lambs with diarrhoea attributed to non-enterotoxigenic e. coli. another important benefit related to the reduction in the use of antibiotics would be the decrease of residues in meat. evaluation of some etiological factors predisposing to diarrhoea in lambs in the alimentary system tumor necrosis factor and interleukin-6 activity and endotoxin concentration in peritoneal fluid and blood in horses with acute abdominal disease enterobacteria a hospital outbreak caused by a chlorhexidine and antibiotic-resistant proteus mirabilis endotoxemia in human septic shock gel clot lal assay in the initial management of peritoneal dialysis with peritonitis: a retrospective study efficacy of a single dose of oral antibiotic given within two hours of birth in preventing watery mouth disease and illthriff in colostrums-deficient lambs evaluation of endotoxemia in the prognosis and treatment of scouring merino lambs detection of endotoxin in cases of equine colic normal haematology of cattle, sheep and goats efficacy of halofuginone lactate in the prevention of cryptosporidiosis in suckling calves g-stat 2.0 user's guide. department of biometry glaxo smithkline diseases of the goat role of enteric pathogens in the aetiology of neonatal diarrhoea in lambs and goat kids in spain plasma endotoxin level of healthy donors veterinary drug handbook serotypes, phage types and virulence genes of shiga-producing escherichia coli isolated from sheep in spain the effect of lipopolysaccharide from proteus mirabilis on the level of the stable end metabolic products of nitric oxide in blood platelets this work has been supported by the "department of education, science and technology, regional government" and "european funds for regional development" (project 2pr03b024). key: cord-343685-iq3njzoi authors: martin-olalla, j. m. title: age disaggregation of crude excess deaths during the 2020 spring covid-19 outbreak in spain and netherlands date: 2020-08-07 journal: nan doi: 10.1101/2020.08.06.20169326 sha: doc_id: 343685 cord_uid: iq3njzoi spanish and dutch official records of mortality and population during the 21st century are analyzed to determine the age specific crude death rate in the 2020 spring covid-19 outbreak. excess death rate increases exponentially with age showing a doubling time [5.0,5.6]a (spain) and [3.9,6.7]a (netherlands), roughing doubling every five years of increase in age.the effective infection fatality rate in spain also shows this doubling time. statistically significant mortality increase is noted above 45a (spain) and 60a (netherlands). a statistically significant increase of mortality is also noted in spain for the youngest age group. the illness designated covid-19 caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) caught worldwide attention since its identification in late 2019 [1] . spain is one of the european countries most impacted by the disease during the spring of 2020. confirmed covid-19 cases climbed up to several hundred thousands -some few thousands per one million population-and confirmed covid-19 deaths to some 28 000 or six hundred deaths per one million population. [2] lock-down measures came into effect on march 16 to help diminishing the outbreak. total excess deaths or crude excess deaths is a key quantity to understand the acute impact of a pandemic [3] . its determination sensibly requires a reference mortality or baseline and a time interval over which the excess is determined. baseline is determined from previous records of mortality. european national statistical institutes and eurostat are doing a great effort in disseminating weekly deaths in europe in the past years. this manuscript takes official records of weekly crude deaths in spain and netherlands during the 21st century and population records to ascertain the impact of the covid-19 in age specific death rates. in april 2020 eurostat set up "an exceptional temporary data collection on total week deaths in order to support the policy and research efforts related to covid-19" [4] . the data collection is disaggregated by sex, five year age group and nuts regions in several countries of the european union and elsewhere. data are provided by national statistical institutes on a voluntary basis. the 2020 weekly deaths still have the flag of "estimate". this manuscript will analyze the age disaggregation in spanish and dutch weekly death rate. the data set is not fully coherent. adding up deaths for every age group does not usually result in a number equal to the total number of weekly deaths included in the catalog. in 2020 total number of weekly deaths is larger than the sum of age grouped weekly deaths by 4 % (spain) and 3 % (netherlands). in a previous pre-print [5] the total (all-age) weekly crude death rate in spain was analyzed and a total excess equal to 1055 death per one million population from w10 to w21 in the year 2020 was reported. the 95 % confidence interval (ci) was [1023, 1087] . age group population values until january 1, 2019 for spain and netherlands were also collected from eurostat demo pjan table. this table disaggregates age year by year which allows to build up five year age groups matching to the weekly death data. linear interpolation was used to compute population a weekly basis. total population values for january 1,2020 can be collected from table ts00001 in eurostat. unluckily there is no age disaggregation. however these figure were obtained in spain from the table 31304 at the instituto nacional de estadística. for the dutch set the last two available shares of population for every age group were used to extrapolate the shares of population in 2020. eurostat requested the national statistical institutes the transmission of "a back series weekly deaths for as many years as possible, recommending as starting point the year 2000". in this manuscript spanish and dutch weekly 2 . cc-by-nc-nd 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 7, 2020. . https://doi.org/10.1101/2020.08.06.20169326 doi: medrxiv preprint deaths will be analyzed from 2001 on-wards. as eurostat points out "a long enough time series is necessary for temporal comparisons and statistical modelling". in age specific analysis the population n is assumed to be a blending, a mixture, or a multicomponent system composed of several age groups of size n i whose behaviour in relation to death is homogeneous under some circumstances. age specific weekly death rate [6] d i is nothing but the ratio between weekly deaths d i within a group i and its population n i . all age specific deaths sum up the total weekly deaths d = i d i . also considering the definition of age specific death rate this can be written as d = i n i × d i from which the total weekly death rate d = d/n can be obtained as d = x i d i where x i = n i /n is the shares of population by age group. total weekly death rate is then the weighted average of age specific death rates. figure 1 shows the age specific weekly crude death rate d i in spain for 19 age groups (color from a gradient palette) and the total weekly crude death rate d (orange). some interesting points must be remarked. first, in the figure it is clearly perceptible that higher age groups are equally spaced along the y-axis, which is logarithmic. therefore the age specific weekly death rates are distributed exponentially with age and follows the gompertz exponential law [7] d(a) ∝ 2 a/τ , where a is the age and τ is a characteristic age time for which d(a) doubles. this empirical law suggests the predominance of age specific contributions to the cause of death instead of external causes like wars, murders, plagues or the like. one could collapse the lines in figure 1 into a universal age-independent weekly death rate just by scaling weekly death rates with some exponential function whose characteristic time τ is obtained by fitting age specific weekly death rates. however no such scaling would fit to every age group. as an alternative it is useful to look for age specific baselines, which will model the behaviour of weekly death rate back in time. on the second hand and globally speaking, every age specific weekly death rate is decreasing with time in spain. just as an example a thin horizontal line at the level 0.3 % w −1 is plotted to highlight the evolution of the oldest age group. on the contrary the total weekly death rate stands still for nineteen years (see also ref. [5] ). this result can be understood considering two competing phenomena. first the improvements in the public health system which helps decreasing age specific death rates. second, the ageing of population helped by the decrease in fertility rates and by elder people being less prone to die. as a consequence death rates tend to increases simply because population tends to be elder and more prone to die even though at age specific smaller rates. for the specific set up in spain in the 3 . cc-by-nc-nd 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 7, 2020. . past 20 years the resulting total weekly death rate stands still. the ageing of population is perceptible in figure 1 by looking at total weekly death rate in the background of age specific weekly death rates. at the beginning of the 21st century d (orange line) matched to the seven to last age group, which is 60-64. in 2020 it matches to the six to last age group, 65-69. following the ideas in ref. [5] this work will analyze the cumulative weekly death rate from w10 to w21 which, in 2020 means from monday march 2, 2020 to sunday may 24, 2020. in this period of time weekly deaths exhibits an extremely large anomaly in spain (z− score equal to 16) and a moderate anomaly in netherlands (z ∼ 7). the data collection allows to compute deaths recorded in this elapsed time in the past years for every age group. scaling by the group population at the given year gives us the cumulative death rate in this period of time and year. figure 2 shows the results of this statistics grouped by age group and where age specific death rates are plotted against calendar year. every plot contains 19 data points per country. spanish data are displayed by solid blue circles. dutch results, by open black circles. notice that the death rates are shown in their normal scores -the score after sample average is removed and sample is scaled by sample standard deviation-so that every age specific y-axis extends equally. figure 2 also displays in a solid line the linear fitting from 2001 to 2019. the broken lines shows the 95 % confidence (prediction) interval for the residuals of the fit. this lines were extended until 2020 yielding the baseline or reference value of death rate for every age group and its confidence (prediction) interval. as discussed previously every age group displays decreasing values of observed death rates until 2020. it is easily perceived in the figure that every age group older than 45 years in spain showed an observed 2020 death rate outside the confidence interval of the normal behaviour in the previous 19 years. the death rate in 2020 is an outlier from a statistical point of view. the same happens in netherlands above age 55 a. it is unnecessary to collect every pearson's r 2 correlation coefficient or every p-value in these analyses: no age group sustains the null hypothesis of no relationship between age specific death rates and years. the largest recorded p-value is p = 0.0028 but usually p falls below 10 −5 . contrastingly the total death rate in spain and netherlands does sustain the null hypothesis (p = 0.48 and p = 0.87) at the standard level of confidence. it is also worthy to note that the youngest age group also exhibits an increase in 2020, which is equal in both countries. however it is only statistically significant in spain. it could be related to failures in the public health system amidst the strong stress lived in the spring of 2020 or to parents being reluctant to show up at hospital facilities. table 1 and table 2 summarizes the results displayed in figure 2 . the tables first lists the shares of population in 2020 x for every age group. then the observed cumulative death rates o in 2019 and 2020 for the observation period. next group of columns displays the results in figure 2 : first the predicted value or reference r for 2020 followed by the death rate excess e = o − r and three statistics related to it: the 95 % confidence interval, the p −score e/r and the z−score computed as the excess e divided by the standard deviation of the residuals. [8] if the ratio excess death to ci falls below 1 then the ci includes e = 0 suggesting that the excess is not statistically significant: in those cases p -scores and z−scores are not listed. for the sake of clarity the table then lists the excess age specific deaths e × x × n . finally in table 1 last two columns display the results from the nationwide seroprevalence study [9] s and the effective infection fatality rate ifr computed as e/s.[10] to the best of our knowledge there is not a seroprevalence study in netherlands yet. mimicking figure 2 one may think in plotting age specific cumulative death rates as a function of age group for every year in the collection. as an example first two columns of table 1 and table 2 shows a steadily progressive increase with age group. same happens for excess death rates and for ifr in table 1 which perceptibly doubles in every step above group 45-50. indeed such plots would have shown up the gompertz law in these magnitudes as observed in figure 3 (panels a, b and c) . age specific excess death rates (panel c) gives τ = 5.3 a (ci [5.0, 5.6]a) in spain and τ = 4.9 a (ci [3.9, 6.7]a) while ifr in spain shows τ = 5.2 a (ci [4.9, 5.6]a), as suggested by table 1 : the ifr doubles every step in the age group staircase climbing until 42 % for the most aged group. for age specific death rates (panels a and b) the analysis can be extended back to 2001. figure 4 shows the distribution of τ (y) in the past twenty years. errorbars display the confidence interval for τ (y). solid lines display the fitting τ versus y in the range 2001 to 2019 with broken lines showing the confidence interval. spanish characteristic times sustain the null hypothesis (p = 0.77) of non-relationship with calendar year. the observed value in 2020 is τ = 6.3 a, 7 % down from the reference τ = 6.8 a. dutch times do not sustain (p = 0.003). the observed value in 2020 is τ = 6.0 a, 4 % down the predicted value τ = 6.3 a. one of the most striking results is the anomaly observed for first age group -less than five years age-in table 1 and table 2 where it exhibits large p -score and z−score. somehow these scores may be biased by the model and is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 7, 2020. figure 2 ): the predicted value r and the excess e = o − r followed by 95 % confidence interval, p −score e/r and the z−score computed as the ratio e to the standard deviation of residuals; and the age specific total deaths (e − r) × x × n . last two columns shows the seroprevalence in the country [9] and the resulting effective age specific infection fatality rate ifr. figure 2 ): the predicted value r and the excess e = o − r followed by 95 % confidence interval, p −score e/r and the z−score computed as the ratio e to the standard deviation of residuals; and the age specific total deaths (e − r) × x × n . . cc-by-nc-nd 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 7, 2020. . https://doi.org/10.1101/2020.08.06.20169326 doi: medrxiv preprint might be unrealistic. nonetheless, panel d in figure 3 shows the ratio of observed age specific death rate in 2020 to observed age specific death rates in 2019 a magnitude which does not depend on modelling. in the panel the increase of mortality in elder groups is clear in spain (above 30 a) and netherlands (above 55 a) peaking at 80 a. the first age group usually gets high mortality rates compared to the following groups due to its specific fragility. this is noted in figure 1 by the lightest coloured age specific death rate in the middle of darker shades starting at 20 × 10 −6 w −1 . in figure 3 the relative increase for the first age group in spain (×1.4) matches to that observed at 60 a and the modelling shows o 20 well outside the predicted range of observations (see figure 2 ). it should also be taken into account that age specific death rate for the first age group matches to that of the 40-45 age group. if the latter is high enough to make its ratio (×1.2) relevant (making a 20 % of increase) then the former is high enough to make its ratio (×1.4) relevant (making a 40 % of increasing, and doubling the impact of the latter). it is out of the scope of this manuscript to address the cause of this striking anomaly. whether this is a direct impact of covid-19 in the youngest age group or an indirect impact due to poor public health responses or to parents reluctant to show up children at hospital for health. either way it is showing the well-known fragility of this age group. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 7, 2020. age specific excess death rates in spain and netherlands during the spring 2020 (w10 to w21) covid-19 outbreak follows gompertz exponential law with doubling times in the range [5.0, 5.6]a (spain) and [3.9, 6.7]a (netherlands) and roughing double every five years. same happens for the effective ifr in spain. this result is not far from the characteristic time observed for age specific death rates in the past twenty years which are 6.8 a (spain) and 6.0 a (netherlands). excess death for the eldest age group climbs to 1.8 % of the population of this group (spain) and 1.9 % (netherlands) which must be added to the usual 3.8 % (spain) and 4.7 % (netherlands) mortality rate for this group in this period of time. the youngest group age also shows the impact of the outbreak with a 40 % increase of mortality rate in spain relative to 2019 after a long standing decrease in the past twenty years. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 7, 2020. the author declares no conflict of interest. every piece of data in this work comes from public collection found in eurostat and the instituto nacional de estadística. a pandemic primer on excess mortality statistics and their comparability across countries this manuscript will print death rates as a number times 10 −6 where the number stands for the mortality per one million population. sometimes rates will be computed per capita and per some unit of time, like a number times 10 −6 a −1 which means per one million population and per year and not "per one million years notice that, however, figure 2 is scaled by the standard deviation of the sample the palette used in figure 1 is named "dense", from cmocean palettes by kristen thyng https://matplotlib. org/cmocean/.jmmo thanks national statistics institutes and eurostat for releasing public records of weekly deaths. jmmo knew of eurostat effort from a tweet posted by kiko llaneras https://twitter.com/kikollan/status/1288830168925188096 on july 30, 2020.this work was not founded. this work was performed using free software running on xubuntu 18.04.1lts. data bases have been imported into gnu octave-4.2.2 (https://www.gnu.org/software/octave/). pictures were developed thanks to gnuplot-5.2.2 (http://www.gnuplot.info/). the manuscript was typeset in gnu emacs-25.2.2 (https: //www.gnu.org/software/emacs/) assisted by auct e x(https://www.gnu.org/software/auctex/). data in pictures and in tables have been exported directly from octave.this project started on july 31, 2020. key: cord-316736-fz1yfhme authors: munoz-navarro, r.; cano-vindel, a.; schmitz, f.; cabello, r.; fernandez-berrocal, p. title: emotional distress and associated sociodemographic risk factors during the covid-19 outbreak in spain date: 2020-05-30 journal: nan doi: 10.1101/2020.05.30.20117457 sha: doc_id: 316736 cord_uid: fz1yfhme background spain is one of the countries that has been most affected by covid-19 disease. however, the emotional distress on the spanish population remains poorly understood. the aim of this study was to determine the presence of emotional disorders and related symptoms and to assess the influence of sociodemographic characteristics on this population. methods we conducted a cross-sectional survey using an online platform. participation was completely voluntary. sociodemographic variables were collected and symptoms of anxiety, depression, and panic were assessed through three questionnaires: generalized anxiety disorder-7 (gad-7), patient health questionnaire-9 (phq-9), and the patient health questionnaire-panic disorder (phq-pd). chi-squared statistics were applied to determine the influence of sociodemographic variables on symptom severity and diagnosis. results most respondents (n=1753) were female (76.8%), with a mean (sd) age of 40.4 (12.9) years; 39.1% were married and 39.5% held a high school degree. severe and moderate symptoms of anxiety and depression were high (6.5% and 14.3%; 9.9% and 12.9%, respectively) and more than one in four participants (25.7%) experienced a panic attack. a high proportion of participants met diagnostic criteria for emotional disorders: 15.3% for gad; 12.2% for mdd; and 17.2% for pd. significant risk factors were as follows: female, young adult, single, unemployed, and low income. conclusion due to limitations related to the study design (convenience sample), the findings of these study may not be applicable to the general population. nonetheless, the high prevalence of emotional symptoms and disorders in this sample suggests that mental health interventions are urgently needed in spain. emotional distress during the covid-19 outbreak in spain experiencing symptoms on most days as specified by one of the first two questions, plus symptoms on four other items. this algorithm was shown to have optimal sensitivity and specificity (.88 and .80) for the diagnosis of mdd in a spanish primary care sample (18) and presented also excelent psychometric properties (19) . the phq-pd is the module that assesses dsm-iv-based panic disorder (pd). we used the validated spanish-language version of this instrument (20), which can be used to screen for panic attacks in the last two weeks, and includes an algorithm for the diagnosis of pd. in this validation study, the screening question yielded a sensitivity score of .83 (specificity = .66) and the modified algorithm of the original version yielded a sensitivity of .77 (specificity = .72) which makes the phq-pd a very useful tool to asses for panic attacks and panic disorder. data stratified by the level of symptoms of depression, anxiety, and panic attacks as well as for the diagnosis (gad, mdd and pd) are presented as numbers and percentages. for symptom severity and diagnoses, chi-squared tests were applied to determine whether sociodemographic variables (gender, age, marital status, educational level, level of income, and employment situation) were differentially associated with levels of symptom severity and the proportion of diagnoses. the spss statistical software version 26.0 (ibm corp) was used to obtain z-values and standardized residuals, and post-hoc tests were performed using chi-squared tests on the squared residuals (df=1). bonferroni correction of the z-values was applied for value greater than +/-1.96 (α = .05). results were reported in the text as: (z-value; p-value). . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 30, 2020. . https://doi.org/10.1101/2020.05.30.20117457 doi: medrxiv preprint emotional distress during the covid-19 outbreak in spain participation was completely voluntary, the survey was anonymous, and confidentiality of all information provided was assured. before starting the survey, all participants were required to read the instructions and provide informed consent and could abandon the survey at any time, for any reason. the study was approved by the clinical research ethics committee of hospital university la fe of valencia. the confidentiality of personal data was protected under the spanish data protection law. table 1 ). ---insert table 1 here --p<.05), the 40-59 year age group (-2.7; p<.001) and finally by the group >=60 years of age (-3.2, p<.01) (see table 2 ). marital status was significant for depression (p<.001) and panic attacks (p<.01). the proportion of married people with inexistent depressive symptoms (5.7; p<.001) was significantly higher than in singles (-5.7; p<.001), with a lower proportion of moderate depressive symptoms (-5,6; p<.001), and less severe depressive symptoms (-2.1; p<.001) than singles (2.1; p<.001). the proportion of married people who experience a panic attach (-3.8; p<.001] was significantly less than that observed in the group of people living with an unmarried partner (3.6; p<.01) (see table 3 ). ---insert table 3 here ---educational level was significant for anxiety (p<.001), depression (p<.001) and panic attacks (p<.01). the proportion of people with a postgraduate degree with inexistent anxiety symptoms (2.6; p<.001) was higher than observed in university graduates (-2.2; p<.05). people with a high school degree presented low levels of mild symptoms (-3.1; p<.001]. postgraduate participants presented a lower proportion of moderate anxiety symptoms (-2.4; p<.01) compared to people with a high school degree (2.5; p<.01). finally, the highest proportion of severe anxiety symptoms was observed among . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. table 3 ). ---insert table 4 here ---income levels were significant for anxiety (p<.001), depression (p<.001) and panic attacks (p<.001). the proportion of people earning more than €60,000 presenting inexistent anxiety symptoms (3.2; p<.001) and mild anxiety symptoms (-2.3; p<.05) was significantly less than people earning between €36.000-60,000 (2.8; p<.01). the latter also presented a lower proportion of moderate anxiety symptoms (-3.9; p<.001) compared to people earning less than €12,000 (2.8; p<.01). finally, people earning €12,000-24,000 presented the highest proportion of severe anxiety symptoms (2.1; p<.001) compared to the lowest proportion observed in those earning €24,000-36,000 (2.2; p<.001). for depressive symptoms, the proportion of people earning < €12,000 with inexistent depressive symptoms (-2.7; p<.001) was less than in those earning €12,000-24,000 (-2.1; p<.01), people earning €36,000-60,000 (3.9; p<.001) and people earning more than €60,000 (2.6; p<.001). further, people earning < €12,000 presented the highest proportion of severe depressive symptoms (3.1; p<.001) compared to those earning between €36,000-60,000 (-2; p<.05) and more than €60,000 (-2.6; p<.001). people earning < €12,000 presented the highest proportion of panic attacks (3.2; p<.01) . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 30, 2020. . https://doi.org/10.1101/2020.05.30.20117457 doi: medrxiv preprint emotional distress during the covid-19 outbreak in spain compared to those earning between €12,000-24,000 (2.7; p<.05), between €24,000-36,000 (-2.1; p<.05) and more than €60,000 (-3; p<.001) (see table 4 ). ---insert table 5 here ---employment status was significant for anxiety (p<.001), depression (p<.001) and panic attacks (p<.01). retired participants presented the highest proportion of inexistent anxiety symptoms (2.6; p<.001) while individuals who had been laid off presented the highest proportion of mild anxiety symptoms (2.5; p<.05). part-time workers (2.2; p<.05) and unemployed not searching for work (2.5; p<.05) presented the highest proportion of moderate anxiety symptoms compared to full-time workers (-2.9; p<.01). no results were found in people that were laid-off (see table 5 ). proportion of people with mental health issues. the prevalence of anxiety and depressive symptoms and panic attacks was high, with 20.8% of participants presenting moderate to severe anxiety symptoms, 22.8% with moderate to severe depressive symptoms and a 25.7% presenting panic attacks. the prevalence of emotional disorders was also high, with 15.2% meeting diagnostic criteria for gad, 12.2% for mdd, and 17.2% for pd. as said, a very recent study conducted in a large sample (n=3480) in spain, reported symptoms of depression, anxiety and ptsd in a 18.7%, 21.6% and 15.8%, respectively (12). this prevalence was somehow higher that in our study, probably after the use of very brief tools like the gad-2 and the phq-2, with only two items, which can lead to some false positives (21) . in our study, the use of levels of symptoms and diagnostics algorithms may offer a more accurate prevalence. in this line, the national health survey, conducted by the spanish ministry of health, reported a prevalence of near 6.7% for anxiety and depression; a 9.1% and 9.2% for female and a 4% and 4.3% for male, respectively (22) . previous research on the prevalence of emotional disorders in the general population in spain has shown that the prevalence of anxiety and mood disorders is 6.2% and 4.4%, respectively (23,24) for panic disorders, one study found a prevalence of 0.8% in europe and 0.6% in spain (24). the prevalence rates observed in the current study are much higher than previous reports, probably because the prevalence in our study is based on screening tools rather than clinical interviews. a more recent study conducted by navarro-mateu et al. (25) in the spanish region of murcia presented prevalence rates for anxiety and mood disorders of 9.7% and 6.6%, respectively. those authors argued that the increase of prevalence was due to stressors such as socioeconomic risks. other studies have shown that the prevalence of emotional disorders rises in response to natural disasters (earthquakes) . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. in terms of the influence of sociodemographic factors, consistent with other published reports (28), we found that several factors were associated with an increased likelihood of presenting symptoms and/or being diagnosed with an emotional disorder: female sex, young age (18-25 years), single, low educational level, unemployed, and low income. our findings show that females appear to be more affected by the current pandemic than males, with a higher prevalence of gad and pd, a finding that is consistent with previous reports (29). nearly one-third of females (29.2%) in our survey reported experiencing a panic attacks, while moderate symptoms of anxiety and depression were also very high (15.8% and 14.6%, respectively) in among females. while no differences in mdd were observed between males and females, a surprisingly high percentage of female-19.8% and 16.5%-presented pd or gad, respectively. navarro-mateu et al. (2017) reported similar higher prevalence rates for women; although the prevalence in our study was considerably larger. we also found that young adults (age18-25) and adults (age 26-39) presented more emotional disorders (gad, mdd and pd) than older people. among young adults, the proportion presenting panic attacks (32.8%), moderate to severe depressive symptoms (36.5%), and moderate to severe anxiety symptoms (29%) were surprisingly high. although the increased prevalence of these disorders in young adults has been previously reported (30), the prevalence rate of emotional disorders in our sample was substantially higher. this finding suggests that it is imperative to implement preventive . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 30, 2020. . https://doi.org/10.1101/2020.05.30.20117457 doi: medrxiv preprint emotional distress during the covid-19 outbreak in spain measures in young adults (31). by contrast, elderly and retired people were the least affected of all the subgroups, perhaps due their experience with previous crises, which may have provided them with adequate coping mechanisms. severe depressive symptoms and pd were more prevalent in singles than in married people and those living with a non-married partner. interestingly, people living with a non-married partner presented higher rates of pd than married people. this could be explained by the fact than being married provides some security in affective and socioeconomic areas. for instance, a study conducted in a large spanish sample (>10,000 participants) examined the influence of gender and partner/marital status with respect to social instability, finding that a poorer mental health status was associated with poor stability among cohabiting women but not among married ones (32). this suggests that marriage can function as a protective factor for stability, especially in times of crisis, which may also explain why single people may be more affected. for level of education, our results indicate that a higher level of education was a protective factor against emotional disorders. we found that university graduates presented higher rates of anxiety than those with a postgraduate educational level, while a higher proportion of people with basic education presented depression and panic disorder compared to postgraduate participants. these findings are consistent with previous research showing that a low educational level may be a risk factor for mental health problems (28). however, it is important to consider that the present study, based on an online survey, was comprised of a large proportion of well-educated people who are also more skilled with new technologies. consequently, our findings may underestimate the true proportion of people in the general population currently suffering from psychological problems. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 30, 2020. . https://doi.org/10.1101/2020.05.30.20117457 doi: medrxiv preprint we also found that low income was a significant risk factor. a family income level of less than €24,000 per year was a risk factor for pd, gad, and mdd. indeed, severe depressive symptoms were more prevalent in people earning less than €12,000, accounting for 15.2% of that group. even more shocking was the high rate of panic attacks among people earning less than €12.000 (nearly 34%) or less than €24,000 finally, employment status was a predictor for emotional disorders, a finding that is related to income level. full-time workers and retired people were less affected by psychological problems than unemployed people, something consistent also with previous research (28). interestingly, no results were found in people that were laid-off, something that could have been expected. the main limitation of this study was the convenience sample, which was l comprised of volunteers through an online survey. overall, the sample was younger and more highly educated than the general population. consequently, the sample is not representative of the general population. in addition, people who were more affected by the crisis may have been more willing to participate in the study. given the likely . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 30, 2020. . https://doi.org/10.1101/2020.05.30.20117457 doi: medrxiv preprint emotional distress during the covid-19 outbreak in spain presence of self-selection effects, it is possible that prevalence rates are biased upwards. however, given the enormity of the potential health and socioeconomic threat posed by the virus, the high prevalence rates observed in this study certainly seem plausible, a finding that is further supported by previous research showing that quarantines can produce negative psychological consequences, including ptsd, confusion, and anger (7). potential stressors during quarantine include quarantine duration, fear of infection, frustration, and boredom, among others. future research should investigate these risk factors and the psychological resources like emotion regulation strategies that may be protective against the onset of emotional disorders (33). the findings of this study represent a call for action in spain and worldwide. our data show a major impact of this global health crisis on mental health and it seems probable that the resulting economic crisis may be even more harmful. as previous research has shown, the 2008 economic crisis had a severe negative impact on mental health in spain (25, 34, 35) . clearly, there is a need to implement preventive and treatment strategies as well as to reinforce health care services in times of crisis. indeed, primary care services should expect a rapid and significant increase in demand due to the increased prevalence of common mental health problems (34,36). unfortunately, the availability of evidence-based psychological treatments for emotional disorders in the primary care setting in spain and globally is scant (37). for this reason, we believe that is essential to reinforce primary care services to help patients with emotional disorders (38). also, preventive strategies (31) should be implemented worldwide in the general population to help address the mental health crisis currently facing the world (27). . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 30, 2020. we thank all the collaborators who kindly helped in the sample recruitment process. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 30, 2020. . more than €60,000 125 7.1 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 30, 2020. . differences in the determinants of posttraumatic stress disorder and depression after a mass traumatic event post-traumatic stress disorder following disasters: a systematic review the psychological distress and coping styles in the early stages of the 2019 coronavirus disease (covid-19) epidemic in the general mainland chinese population: a web-based survey mental health emotional distress during the covid-19 outbreak in spain primary care setting in spain a computerized version of the patient health questionnaire-4 as an ultra-brief screening tool to detect emotional disorders in primary care resumen metodológico. encuesta nac salud españa use of mental health services in europe: results from the european study of the epidemiology of mental disorders (esemed) project key: cord-146091-kpvxdhcu authors: sanchez-lorenzo, arturo; vaquero-mart'inez, javier; calb'o, josep; wild, martin; santurt'un, ana; lopez-bustins, joan-a.; vaquero, jose-m.; folini, doris; ant'on, manuel title: anomalous atmospheric circulation favored the spread of covid-19 in europe date: 2020-04-26 journal: nan doi: nan sha: doc_id: 146091 cord_uid: kpvxdhcu the current pandemic caused by the coronavirus sars-cov-2 is having negative health, social and economic consequences worldwide. in europe, the pandemic started to develop strongly at the end of february and beginning of march 2020. it has subsequently spread over the continent, with special virulence in northern italy and inland spain. in this study we show that an unusual persistent anticyclonic situation prevailing in southwestern europe during february 2020 (i.e. anomalously strong positive phase of the north atlantic and arctic oscillations) could have resulted in favorable conditions, in terms of air temperature and humidity, in italy and spain for a quicker spread of the virus compared with the rest of the european countries. it seems plausible that the strong atmospheric stability and associated dry conditions that dominated in these regions may have favored the virus's propagation, by short-range droplet transmission as well as likely by long-range aerosol (airborne) transmission. the world is currently undergoing a pandemic associated with the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), which is a new coronavirus first noticed in late 2019 in the hubei province, china 1,2 . the virus has a probable bat 3, 4 origin, and causes the ongoing coronavirus disease 2019 . although it is crucial to find a proper vaccine and medical treatment for this pandemic, it is also relevant to know the main factors controlling the transmission of the virus and disease, including the role of meteorological conditions in the spread of the virus. the world health organization (who) states that robust studies are needed to refine forecasting models and inform public health measures 5 . respiratory virus infections can be transmitted via direct and indirect contact, or by means of particles (droplets or aerosols) emitted after a cough or sneeze or during conversation by an infected person. the large particles (>5 μm diameter) are referred to as respiratory droplets and tend to settle down quickly on the ground, usually within one meter of distance. the small particles (<5 μm in diameter) are referred to as droplet nuclei and are related to an airborne transmission. these particles can remain suspended in the air for longer periods of time and can reach a longer distance from the origin 6 . these small aerosol particles are inhalable and can penetrate all the way down to the alveolar space in the lungs 7 , where cell receptors for some infectious respiratory viruses are located, including the angiotensin converting enzyme ii (ace2) used by sars-cov-2 to infect the individual 3 . airborne transmission has been suggested to play a key role in some diseases like tuberculosis or measles, and even in coronaviruses [8] [9] [10] . a recent study has described that the sars-cov-2 virus can remain viable at least up to 3 hours in airborne conditions 11 . respiratory droplets and aerosols loaded with pathogens can reach distances up to 7-8 meters under some specific conditions such as a turbulence gas cloud emitted after a cough of an infected person 12 . a study performed in wuhan, the capital of the hubei province, has shown that the sars-cov-2 virus could be found in several health care institutions, as well as in some crowded public areas of the city. it also highlights a potential resuspension of the infectious aerosols from the floors or other hard surfaces with the walking and movement of people 13 . another study has also shown evidence of potential airborne transmission in a health care institution 14 . recent studies have pointed out a main role of temperature and humidity in the spread of covid-19. warm conditions and wet atmospheres tend to reduce the transmission of the disease [15] [16] [17] [18] [19] [20] [21] [22] . for example, it has also been pointed out that the main first outbreaks worldwide occurred during periods with temperatures around 5-11ºc, never falling below 0ºc, and specific humidity of 3-6 g/kg aproximately 18 . the first major outbreak in europe was reported in northern italy in late february 2020. following that, several major cases have been reported in spain, switzerland and france in early march, with a subsequent spread over many parts of europe. at present (28 th march 2020) italy and spain are still the two main contributors of cases and deaths in the continent, with major health, political and socio-economic implications. the main hypothesis of this work is that the atmospheric circulation pattern in february 2020 has helped to shape the spatial pattern of the outbreak of the disease in europe. the main atmospheric circulation pattern during february 2020 was characterized by an anomalous anticyclonic system over the western mediterranean basin, centered between spain and italy, and lower pressures over northern europe centered over the northern sea and iceland ( figure 1 , figure s1 ). this spatial configuration represents the well-known north atlantic oscillation (nao) 23, 24 in its positive phase, which is the teleconnection pattern linked to dry conditions in southern europe whereas the opposite occurs in northern europe 25 . figure 2 and figure s2 show maps for february 2020 for several meteorological fields that provide clear evidence of the stable atmospheric circulation in southern europe, with a tendency towards very dry (i.e., lack of precipitation) and calm conditions. as suggested in an earlier analysis 18 , the sars-cov-2 virus seems to be transmitted most effectively in dry conditions with daily mean air temperatures between around 5ºc and 11ºc, which are the conditions shown in figure 2 for the major part of italy and spain. by contrast, northern europe has experienced mainly wet and windy conditions due to an anomalous strong westerly circulation that is linked to rainy conditions. these spatial patterns fit with the well-known climate features associated over europe during positive phases of the nao 26 . the arctic oscillation (ao), which is a teleconnection pattern very much linked to nao, showed in february 2020 the strongest positive value during 1950-2010 ( figure s3 ). the ao reflects the northern polar vortex variability at surface level 27 , and it consists of a lowpressure centre located over the norwegian sea and the arctic ocean and a high-pressure belt between 40 and 50ºn, forming an annular-like structure. positive values of the ao index mean a strong polar vortex, and the anomalous positive phase experienced during early 2020 has been linked with the recent ozone loss just registered over the arctic region 28 . we argue that this spatial configuration of the atmospheric circulation might have played a key role in the modulation of the early spread of the covid-19 outbreaks over europe. it is known that some cases were reported already in mid-january in france, with subsequent cases in germany and other countries 29 . thus, the sars-cov-2 virus was already in europe in early 2020, but it may only have started to extend rapidly when suitable atmospheric conditions for its spread were reached. it is possible that these proper conditions were met in february, mainly in italy and spain, due to the anticyclonic conditions previously mentioned. the link between the covid-19 spread and atmospheric circulation has been tested as follows. we have extracted the monthly anomalies of sea level pressure (slp) and 500 hpa geopotential height for february 2020 over each grid point of the 15 capitals of the european countries ( figure s4 ) with the highest number of covid-19 cases reported so far (see data and methods). figure 3 (top) shows that there is a statistically significant (r 2 =0.481, p<0.05) second order polynomial fit between the anomalies of the 500 hpa and the total cases per population. italy, spain, and switzerland, which are the only countries with more than 1,000 cases/million inhabitants in our dataset, clustered together in regions with very large positive anomalies of 500 hpa geopotential heights. for the total number of deaths the fit is also statistically significant for a second order polynomial regression (r 2 =0.50, p<0.05), and it shows clearly how italy and spain are out of scale compared to the rest of the european countries. similar results are obtained using slp fields (not shown). these results evidence that it seems plausible that the positive phase of the nao, and the atmospheric conditions associated with it, provided optimal conditions for the spread of the covid-19 in southern countries like spain and italy, where both the start and the most severe impacts of the outbreak in europe were located. to test this hypothesis further we have also analyzed the covid-19 and meteorological data within spain (see data and methods, figure s5 ). the results show that mean temperature and specific humidity variables have the strong relation with covid and fit with an exponential function ( figure 4 ). they indicate that lower mean temperatures (i.e., average of around 8-11ºc) and lower specific humidity (e.g., <6 g/kg) conditions are related to a higher number of cases and deaths in spain. nevertheless, it is worth mentioning that both meteorological variables are highly correlated (r 2 =0.838, p<0.05) and are not independent of each other. the temperatures as low as 8-10ºc are only reached in a few regions such as madrid, navarra, la rioja, aragon, castille and leon and castilla-la mancha. these areas are mainly located in inland spain where drier conditions were reported the weeks before the outbreak. the rest of spain experienced higher temperatures and consequently were out of the areas of higher potential for the spread of the virus, as reported so far in the literature [15] [16] [17] [18] [19] [20] [21] [22] . in addition, higher levels of humidity also limit the impact of the disease, and therefore the coastal areas seem to benefit from lower rates of infection. thus, in the southern regions of spain (all of them with more than 13ºc and higher levels of specific humidity) we found lower rates of infection and deceases. this is in line with the spatial pattern in italy, with the most (least) affected regions by covid-19 mainly located in the north (south). in contrast, when the whole of europe is considered on a country by country basis (see above and figure 3 ), we find the opposite, a clear gradient with more severity from north to south as commented previously. the spatial pattern of covid-19 described above has some intriguing resemblances with the 1918 influenza pandemic, which is the latest deadly pandemic in modern history of europe. the excess-mortality rates across europe in the 1918 flu also showed a clear northsouth gradient, with a higher mortality in southern european countries (i.e., portugal, spain or italy) as compared to northern regions, an aspect that is not explained by socio-economic or health factors 30 . in spain, a south-north gradient is also reported in the 1918 flu after controlling for demographic factors 31 . the central and northern regions of spain experienced higher rates of mortality, and this has been suggested to be linked to more favorable climate conditions for influenza transmission as compared to the southern regions 31 . interestingly, the slp anomalies of the months before the major wave of this pandemic (which occurred in october-november 1918) shows a clear south-north dipole with positive anomalies in southern europe centered over the mediterranean, and negative ones in northern europe ( figure s6 ). in other words, the nao was also in its positive phase just before the major outbreak of the 1918 influenza pandemic. this resembles the spatial patterns described above for the current covid-19 outbreak, both in terms of the spatial distribution of the mortality of the pandemic over europe as well as in prevailing atmospheric circulation conditions before the major outbreak. these intriguing coincidences need further research in order to better understand the spatial and temporal distribution of large respiratory-origin pandemics over europe. taking into account these results, we claim that the major initial outbreaks of covid-19 in europe (i.e., italy and spain) may be favored by an anomalous atmospheric circulation pattern in february, characterized by a positive phase of the nao and ao. taking into consideration current evidences in the literature, it seems that suitable conditions of air temperature and humidity were reached in northern italy and inland spain. indeed, meteorological conditions can affect the susceptibility of an infected host by altering the mucosal antiviral defense 32 and the stability and transmission of the virus 33 , as well as social contact patterns 34 . we also hypothesize that the anomalous meteorological conditions experienced in italy and spain promoted the airborne contagion both indoors and outdoors, in addition to the direct and indirect contact and short-range droplets, which helped to speed up the rates of effective reproductive number (r) of the virus ( figure s7 ). equally, the anticyclonic conditions, amplified in some areas by temperature inversions, may have reduced the dispersion of the virus outdoors. this stability and lack of precipitation can also produce more processes of suspension and resuspension of the infected aerosols indoors and, especially, outdoors, in a similar way as resuspension of anthropogenic pollutants in cities 35, 36 . equally, it is also suggested that high atmospheric pollutant concentrations can be positively related to increase fatalities related to respiratory virus infections 37, 38 and even covid-19 39 . this is a relevant issue as the main hotspot of covid-19 in italy is located in the po valley, one of the most polluted regions of europe, as well as the madrid region (the most affected region so far in spain) 40 . although the outbreak of a pandemic is controlled by a high number of biological, health, ncep/ncar 1 , era5 2 and era20c 3 atmospheric data are used in this manuscript. the maps and data have been retrieved by using the tools and websites referenced in the main text, and more details about the spatial and temporal resolution, vertical levels, assimilation schemes, etc. can be consulted in their references. in brief, an atmospheric reanalysis like those used here is a climate data assimilation project which aims to assimilate historical atmospheric observational data spanning an extended period, using a single consistent assimilation scheme throughout, with the aim of providing continuous gridded data for the whole globe. figure s4 . location of the 15 countries used in this study that provided cases and deaths of covid-19. figure s5 . location of the autonomous communities of spain, as well as the two autonomous cities of ceuta and melilla. the canary islands has not been included in this study due to its geographical location in tropical latitudes. figure s7 . schematic representation of particles emitted by a cough, with the large droplets settled down nearby (e.g., 1 m distance) and the smaller airborne particles spreading in suspension for longer time, and reaching longer distances, especially in dry and stable conditions as compared to wet environments. it is also possible that a resuspension of aerosol particles can eventually happen due to human activities (e.g., walking, cleaning, etc.) or air flows, which is enhanced under dry conditions due to the lack of precipitation. only statistically significant fields (p<0.05) are plotted as estimated by a student's t-test. map composed with the data and tools provided by the knmi climate explorer website (https://climexp.knmi.nl/start.cgi). the maps show a consistent picture of an intensification of the positive nao phase, which implies that in the future winter conditions as experienced over europe past february 2020 could become more common. clinical features of patients infected with 2019 novel coronavirus in wuhan , china a pneumonia outbreak associated with a new coronavirus of probable bat origin identifying sars-cov-2 related coronaviruses in malayan pangolins the role of particle size in aerosolised pathogen 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mortality burden of the 1918-1919 influenza pandemic in europe spatial-temporal excess mortality patterns of the 1918-1919 influenza pandemic in spain low ambient humidity impairs barrier function and innate resistance against influenza infection seasonality of respiratory viral infections a nice day for an infection? weather conditions and social contact patterns relevant to influenza transmission estimation of the contribution of road traffic emissions to particulate matter concentrations from field measurements: a review speciation and origin of pm10 and pm2.5 in spain environmental health : a global air pollution and case fatality of sars in the people ' s republic of china : an ecologic study the impact of ambient fi ne particles on in fl uenza transmission and the modi fi cation effects of temperature in china : a multi-city study exposure to air pollution and covid-19 mortality in the united states eea. air quality in europe -2019 report climate change 2013: the physical science basis. contribution of working group i to the fifth assess-ment report of the intergovernmental panel on climate change the ncep / ncar 40-year reanalysis project era5: fifth generation of ecmwf atmospheric reanalyses of the global climate influenza virus transmission is dependent on relative humidity and temperature the effects of weather and climate on the seasonality of influenza: what we know and what we need to know spread of sars-cov-2 coronavirus likely to be constrained by climate. medrxiv sanchez-lorenzo was supported by a fellowship ryc-2016-20784 funded by the ministry of science and innovation. javier vaquero-martinez was supported by a predoctoral fellowship (pd18029) from junta de extremadura and sgr 1362, catalan government) and the clices project this research was supported by the economy and infrastructure counselling of the junta of extremadura through grant gr18097 (co-financed by the european regional development fund) b conducted the analyses competing financial interests: the authors declare no competing financial interests corresponding author: arturo sanchez lorenzo key: cord-352717-g247rjh9 authors: guirao, b.; campa, j. l.; lópez-lambas, m. e. title: the assessment of the hsr impacts on spanish tourism: an approach based on multivariate panel data analysis date: 2016-12-31 journal: transportation research procedia doi: 10.1016/j.trpro.2016.12.027 sha: doc_id: 352717 cord_uid: g247rjh9 abstract literature review shows that little research has done so far to estimate how tourism indicators are affected by new high speed rail (hsr) lines. in 2012, a multivariate panel analysis developed by chen and haynes was applied to the chinese regions to quantify the hsr impact on tourism output. the chinese experience confirmed that, during the period 1999-2010, emerging high speed rail services did have significant positive impacts on boosting tourism in china. since them, no similar empirical tool has ever been tested in europe. the aim of this paper is to analyze and validate the suitability of this tool to assess empirically the effects of hsr on spanish tourism during the period 1999-2014, and to enhance the abovementioned model with a tourism database. with more than 20 years’ hsr experience, and operating the longest hsr network in europe (2,900 km), spain offers a good scenario for this model application because spanish tourism sector represents 10.2% of its gross domestic product (gdp). results clearly show that there is a direct linkage between the evolution of certain spanish tourism outputs and the construction of the hsr network. however, authorś recommendations include future new research on some variables limitations like the type of tourism output considered or the consideration of alternative explanatory indicators. in a climate of worldwide financial crisis, the exorbitant cost of building a new hsr line requires empirical evidence of its economic and social efficiency and this fact has generated a great debate in the scientific community (betancor and llobet, 2015; albalate and bel, 2015; albalate et al, 2015) . especially in countries with high tourism attractiveness, future hsr line projects need all possible benefits to be studied. tourism impacts on hsr could be considered as a benefit variable although we recognize that tourism is a complex phenomenon to analyze (sinclair and stabler, 1997; caccomo and solonandrasana, 2001) , a form of complementary demand for which the main components are transport, food, and accommodation (morley, 1992) . the link between tourism and transportation infrastructure has been widely analyze in the literature (khadaroo and seetanah, 2008) and there is a general feeling that an increase in the accessibility to the tourism destination usually leads to an increase in tourism demand. but hsr is a relatively new mode of transportation and represents a contemporary revolution in transportation technology which has been promoted only in some countries around the world. for that reason, although literature review shows how tourism has affected hsr demand (guirao and campa, 2015) , little research has done so far to empirically estimate the opposite effect: how tourism indicators are affected by new hsr lines, which is the main goal of this paper. the majority of published studies describe specific hsr experiences, mainly study cases (guirao and soler, 2008; bazin et al., 2011) and some observed hsr effects on tourism but, as it is described below, they do not lead to a general conclusion. using destination choice, delaplace et al. (2014) studied hsr impacts in paris and rome tourism. masson and petiot (2009) used an economic geographic model (krugman, 1991) , to discuss the influence of the southern european high speed rail (hsr) between perpignan (france) and barcelona (spain) on both tourism activity and economic development. using a non-empirical discussion, they argued that hsr can facilitate the development of tourism activities, and particularly business and urban tourism. with a similar methodology, using a gravitational model (the iso-tourist line from a time-space replacement concept) wang et al. (2012) studied in china the projected hsr effects on tourism: redistribution and transformation of the tourist market, market competition on a larger scale, and reallocation of the urban tourism centre. but the methodology developed by wang et al. was not empirical and did not allow the estimation of tourism ouput, like tourism demand or tourism revenue. apart from economic geography models and the choice destination approach, the existing literature on tourism demand is dominated by econometric models that tend to follow a single-equation panel data approach (lim, 1997; song and li, 2008; song and wong, 2003) . chen and haynes (2012) were the first to apply this methodology to hsr impact on tourism. through a multivariate panel analysis, they investigated the impact of chinese high-speed rail systems on the tourism industry, selecting only the numbers of incoming foreign tourists and tourism revenue as the dependent variables. the regional and geographic characteristics in the east and west, north and south of china vary substantially and the selected unit of their analysis was the provincial level, which includes 27 provinces and 4 municipalities. this experience confirmed that, during the period 1999-2010, emerging high speed rail services did have significant positive impacts on boosting tourism in china. in this context, the study of the suitability of the chen and haynes´s tool when applied to other european case studies seems to be the more reasonable first step towards the development of a systematic tool to evaluate the integral impact of hsr on the tourism industry. the man aim of this research lies in the first assessment of the dynamic panel data model tested in the chinese scenario when applied to a european country: spain. this paper is divided into the following parts: first, literature review in section 1; description and results of the model tested in china (section 2), application to the spanish case study (section 4); and finally, the main conclusions (section 4). the model proposed by chen and haynes (2012) is based on a multivariate panel analysis using the data from 1999 to 2010 at the provincial level. table 1 shows variables (and their main descriptive statistics) used by chen and haynes in their model. in relation to the dependent variables, the criteria used by authors to select the tourism output were focused on the availability of the related data base: number of foreign tourist arrivals (taf), number of oversea tourist arrivals (tat) and tourism revenue (tr). three different models, using the same structure and independent variables but different tourism output, were tested in order to quantify the impact of the hsr lines on china tourism. it is important to remark that domestic tourism demand data was not publicly available and was not considered in the research and this is an important drawback of the methodology. moreover, the numbers of total oversea tourist arrivals differs from the numbers of foreign tourist arrival in that the former not only includes the later, but also tourists from macau, hong kong and taiwan. fortunately, tourism revenue output includes revenues from total oversea tourist arrivals. in relation to explanatory variables (dependent variables), rail features are defined by three indicators: lengtht of the railway network (including conventional lines), rail traffic (ridership) and the presence of hsr lines in each province (dummy variable). a preliminary multicollinearity data analysis found that the correlations among two of these rail variables (rail length and ridership) were not low and this fact forced the authors to present two separated models per tourism output (see equations 1 and 2). in relation to the rest of independent variables, authors used two economic indicators: the annual nominal exchange rate (exc) from us dollar to rmb (renminbi, the legal tender of china) and the gross provincial product per capita (gpppc). some multidimensional features of local tourism are also collected: number of world heritage sites, number of scaled restaurants, number of museums, or number of public libraries (lib). impedance variables were also took into account as the number of accidental pollution releases or the dummy variable associated to the outbreak of sars (severe acute respiratory syndrome), originated in china in 2003. attracting dummy variables were also considered to control the influences of events, like the 2008 beijing olympic games and the 2010 shanghai expo respectively. finally, there is another additional variable in the model (called year, that does not appear in table 1 ), which finally collects the sequence of the observations (372 valid observations) and tries to measure time trends. equations 1 and 2 shows the structure of the models, which were implemented using a fixed effects (fe) formulation (to take into account the unobserved individual effects). the terms i and t denote tour destination provinces and time period respectively while y represents the dependent variables (foreign tourist arrivals, total overseas tourist arrivals or total overseas tourist revenue). consequently, three pairs of estimations were carried out by chen and haynes and the error term εit is the sum of the unobserved province-specific effects μi and the white noise error term υit. the results of the application of the six models (2 per tourism output) demonstrate the effectiveness of chen and haynes´ estimation. the adjusted r square of the 6 models range between 0.67 and 0.81, indicating that the selected variables can explain between 67 to 81 percent of variances of the different tourism outputs. equation 2 among the results obtained, surprisingly, the local site characteristics such as numbers of five stars hotels, high scale restaurants, world heritage sites and museums are not statistically significant in all the tested models. only the deterrent destination variable sars shows a strong significant but negative impact on all the tourism outputs while the number of pollutions is not statistically significant. on the other hand, the used origin variable, the exchange rate (exc), results a key determinant on tourism outputs together with the destination gross provincial product per capita (gpppc) variable. in relation to rail variables, and this is the main result obtained by chen and haynes, the key policy variable hsr is the most relevant, being statistically significant at 5% significance level. for instance, if the province has the hsr service, it is likely to have an additional 20 percent of foreign visitors, or 23 percent total oversea visitors, or 25 percent total oversea revenue in that year. with these findings, the authors confirm that hsr services do have a significant influence on promoting tourism but recognize the validity of previous hsr investments only in that particular time and spatial context. china results have encouraged authors of this paper to study the implementation of the multivariate panel data analysis to spain. immediately after, next section contains a demonstration and discussion of the modelling process and the results for the spanish case. the direct application of chen and haynes´s tool to the spanish case raises several difficulties, mainly associated to the adaptation of the statistical database to the variables used in the original model. in order to use similar criteria, a provincial level data base was considered and 47 provinces were selected (after removing those located on the spanish islands). the multivariate panel analysis was carried out taking into account the data base limitations and the period from 1999 to 2015 was selected for the study. in accordance with the original model, the dependent variables were focused on similar tourism demand indicators: number of foreign (non-resident in spain) tourists (tanr) and tourism revenue from not resident in spain tourists (tr). table 2 shows the list of variables (and their main descriptive statistics) introduced in the spanish models. rail variables were similar to the ones considered in china case study (rlen and rider) and, before designing the equations for the spanish case study, a preliminary multicollinearity data analysis found that the correlations among the explanatory variables rider and rlen were important (similarly to chen and haynes´s research). this fact forced the authors to present two separated models per output variable (rail ridership and rail network length). that means that four models have been designed and their results have been compared to the chinese findings. in the time period considered (1999) (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) no special impedance variables were took into account, like the chinese accidental pollution releases or the outbreak of diseases of sars. instead, three special dummy variables related to the promotion of big international cultural and sports events were introduced as attracting indicators: the forum 2004 held in barcelona (forum), the case of valencia and the america's cup in 2007 (amcup), and finally the case of the international exhibition in zaragoza held in 2008 (expoz). there is another additional variable in the model (called year), not linked to origin, destination or policy features, which finally collects the sequence of the observations and tries to measure time trends. in case of china, authors only used the annual nominal exchange rate (exc) from us dollar to rmb (renminbi), but this variable has been modified in the spain case study. according to the statistics of foreign tourism (instituto español de turismo, 2009), more than 75% of the spanish foreign tourism is coming from the european union and for that reason, our exchange variable has been defined as the difference between the provincial gdp and the european (eurozone) gdp, referring currency to year 1999. other modifications from the original model have to do with the type of hotels considered in the analysis: in spain, four star hotels are the most demanded ones for both domestic and foreign visitors (instituto español de turismo, 2015) , and for that reason the hotel variable (hotel) has included the number of 4 and 5 star hotels (china case study only included 5-star hotels). in relation to the unobserved individual effect in a panel model, four fixed effects model (fe) were developed, which consisted in statistical models that represents the observed quantities in terms of explanatory variables that are treated as if the quantities were nonrandom. table 3 shows the determinants of foreign tourism in spain obtained from model 1 (using rail network length) and a comparison with chen and haynes findings using the same tourism output. the tables 3-6 shows the determinants of tourism output in spain obtained from the model 1-4 (using rail ridership or rail length) and a comparison with chen and haynes results. the first finding, in the spanish case, is related to the local site characteristics such as numbers of five stars hotels, high scale restaurants, world heritage sites and museums. in china, these variables were not statistically significant in any of the designed models, while in spain, there are some indicators, like the hotel variable, which are statistically significant at 1% level. the coefficients of the hotel variable, considering the four models, range between 0.941 and 0.591. other local site characteristics, like museums or libraries reached high levels of significance, although their coefficients are much lower than hotel variable values. the insignificant results for the event variables are similar for the chinese and the spanish experience. the special events such as the 2008 beijing olympic game and the 2010 shanghai expo and number of pollution incidents are not statistically significant even at the 1% level. however, in china, the year dummy of 2003, which represents the epidemic of sars in that year, is highly statistically significant. the estimation makes sense since sars has a reasonably strong negative effect on foreign tourist arrivals in the spanish model no deterrent event variable was introduced and results are consistent with the chinese results. among all the explanatory variables, it is not surprising to find that the gross provincial product per capita (gpppc) variable has a significant impact on the number of foreign tourists, either in china or in spain. another key determinant is the exchange rate (exc), which represents the price level of tourism. in the case of china, a decrease of exc denotes the appreciation of rmb and a depreciation of us dollars, in other words, the price of a chinese tour rises. on the contrary, the increase of exc would indicate the decrease of tour price in china, which thus may further attract more international tourists. in relation to rail variables, while ridership and length are not really significant, the dummy indicator hsr plays an important role (being statistically significant at 1% significance level) in the foreign revenue models of china and spain. this result is the key finding of this paper, although coefficients obtained in spain are much lower than the ones obtained for china. in china, the highest coefficient is around 0.25, which can be interpreted as provinces with hsr services in that particular year are associated with approximate 25 percent additional tourism revenue than either year when they do not have the service or the provinces that do not have the services. in spain, the highest coefficient (see models 3 and 4) is 0.017, which means that provinces with hsr services in that particular year are associated with approximate 1.7 percent additional tourism revenue than either year when they do not have the service or the provinces that do not have the services. in conclusion, results shows how hsr in spain has affected positively to foreign tourism (especially revenue coming from foreign tourism), although his impact is not as important as the one registered in china. there are other explanatory variables in the model with identical significance but higher coefficients, like the gross provincial product or the number of hotels. in spain, hsr serves mainly domestic trips and one of the main drawbacks of the chen and haynes´s model is that it does not consider domestic tourists, and this percentage is quite high in europe. moreover, the hsr impacts on tourism in a country like china, where the alternative interurban transport network is less developed than in europe, are probably of a higher magnitude and easier to detect by an econometric model. further research is also needed on using variables related to the territorial distribution of the hsr lines and the services offered by the operating companies. in these commuter touristic relations, for example, most of the visitors do not use to stay at hotels and consequently, they are not registered as tourists by official statistics. in conclusion, the model needs a greater detail of data disaggregation together with a better understanding of the territorial distribution of the hsr lines through new explanatory variables. the hsr variable behavior is a key issue in this paper, being highly significant either in china or in spain, although coefficients obtained in spain are much lower than the ones obtained for china. results show how hsr in spain has affected positively to foreign tourism (especially revenue coming from foreign tourism), although his impact is not as important as the one registered in china. there are other explanatory variables in the model with identical significance but higher coefficients, like the gross provincial product or the number of hotels. in spain, hsr serves mainly domestic trips and one of the main drawbacks of the chen and haynes´s model is that it does not consider domestic tourists, and this percentage is quite high in europe. nevertheless, it must be highlighted that the most important tourism output considered in the spain case study (number of foreign tourists) is linked to the stay at hotels. due to the lack of other national data, like the number of visitors staying in apartments or in second residences, which have not been taken into account by the model, results should be interpreted with caution. their consideration as well as to deepen in the understanding of the existing impacts should be subject to further research with a new and ad-hoc data base elaboration. finally, the model needs a greater detail of data disaggregation together with a better understanding of the territorial distribution of the hsr lines and the type of hsr service offered by the operating companies. this paper only represents the first step towards a better understanding of the hsr impacts on the tourism industry. the economics and politics of high-speed rail. lessons from experiences abroad when supply travels far beyond demand: institutional and regulatory causes of oversupply in spain's transport infrastructure high speed railway, service innovations and urban and business tourism development tourism industry and high speed rail, is there a linkage: evidence from china's high speed rail development can high speed foster the choice of destination for tourism purpose impacts of the new high-speed service on small touristic cities: the case of toledo, in the sustainable city v. urban regeneration and sustainability. wessex institute of technology the role of transport infrastructure in international tourism development: a gravity model approach increasing returns and economic geography review of international tourism demand models can the high-speed reinforce tourism attractiveness? the case of the high-speed rail between perpignan (france) and barcelona (spain). in technovation a microeconomic theory of international tourism demand the choice of journey destination: a theoretical and empirical analysis the economics of tourism tourism demand modeling and forecasting-a review of recent research tourism demand modelling: a time varying parameter approach behavior of htr fuel elements in aquatic phases of repository host rock formations key: cord-354814-frlc6694 authors: sanchez-lorenzo, a.; vaquero-martinez, j.; calbo, j.; wild, m.; santurtun, a.; lopez-bustins, j.-a.; vaquero, j.-m.; folini, d.; anton, m. title: anomalous atmospheric circulation favored the spread of covid-19 in europe date: 2020-05-01 journal: nan doi: 10.1101/2020.04.25.20079590 sha: doc_id: 354814 cord_uid: frlc6694 the current pandemic caused by the coronavirus sars-cov-2 is having negative health, social and economic consequences worldwide. in europe, the pandemic started to develop strongly at the end of february and beginning of march 2020. it has subsequently spread over the continent, with special virulence in northern italy and inland spain. in this study we show that an unusual persistent anticyclonic situation prevailing in southwestern europe during february 2020 (i.e. anomalously strong positive phase of the north atlantic and arctic oscillations) could have resulted in favorable conditions, in terms of air temperature and humidity, in italy and spain for a quicker spread of the virus compared with the rest of the european countries. it seems plausible that the strong atmospheric stability and associated dry conditions that dominated in these regions may have favored the virus's propagation, by short-range droplet transmission as well as likely by long-range aerosol (airborne) transmission. the world is currently undergoing a pandemic associated with the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), which is a new coronavirus first noticed in late 2019 in the hubei province, china 1,2 . the virus has a probable bat 3, 4 respiratory virus infections can be transmitted via direct and indirect contact, or by means of particles (droplets or aerosols) emitted after a cough or sneeze or during conversation by an infected person. the large particles (>5 μm diameter) are referred to as respiratory droplets and tend to settle down quickly on the ground, usually within one meter of distance. the small particles (<5 μm in diameter) are referred to as droplet nuclei and are related to an airborne transmission. these particles can remain suspended in the air for longer periods of time and can reach a longer distance from the origin 6 . these small aerosol particles are inhalable and can penetrate all the way down to the alveolar space in the lungs 7 , where cell receptors for some infectious respiratory viruses are located, including . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint the angiotensin converting enzyme ii (ace2) used by sars-cov-2 to infect the individual 3 . airborne transmission has been suggested to play a key role in some diseases like tuberculosis or measles, and even in coronaviruses [8] [9] [10] . a recent study has described that the sars-cov-2 virus can remain viable at least up to 3 hours in airborne conditions 11 . respiratory droplets and aerosols loaded with pathogens can reach distances up to 7-8 meters under some specific conditions such as a turbulence gas cloud emitted after a cough of an infected person 12 . a study performed in wuhan, the capital of the hubei province, has shown that the sars-cov-2 virus could be found in several health care institutions, as well as in some crowded public areas of the city. it also highlights a potential resuspension of the infectious aerosols from the floors or other hard surfaces with the walking and movement of people 13 . another study has also shown evidence of potential airborne transmission in a health care institution 14 . recent studies have pointed out a main role of temperature and humidity in the spread of covid-19. warm conditions and wet atmospheres tend to reduce the transmission of the disease [15] [16] [17] [18] [19] [20] [21] [22] . for example, it has also been pointed out that the main first outbreaks worldwide occurred during periods with temperatures around 5-11ºc, never falling below 0ºc, and specific humidity of 3-6 g/kg aproximately 18 . the first major outbreak in europe was reported in northern italy in late february 2020. following that, several major cases have been reported in spain, switzerland and france in early march, with a subsequent spread over many parts of europe. at present (28 th march 2020) italy and spain are still the two main contributors of cases and deaths in the . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint continent, with major health, political and socio-economic implications. the main hypothesis of this work is that the atmospheric circulation pattern in february 2020 has helped to shape the spatial pattern of the outbreak of the disease in europe. the main atmospheric circulation pattern during february 2020 was characterized by an anomalous anticyclonic system over the western mediterranean basin, centered between spain and italy, and lower pressures over northern europe centered over the northern sea and iceland ( figure 1 , figure s1 ). this spatial configuration represents the well-known north atlantic oscillation (nao) 23,24 in its positive phase, which is the teleconnection pattern linked to dry conditions in southern europe whereas the opposite occurs in northern europe 25 . figure s2 show maps for february 2020 for several meteorological fields that provide clear evidence of the stable atmospheric circulation in southern europe, with a tendency towards very dry (i.e., lack of precipitation) and calm conditions. as suggested in an earlier analysis 18 , the sars-cov-2 virus seems to be transmitted most effectively in dry conditions with daily mean air temperatures between around 5ºc and 11ºc, which are the conditions shown in figure 2 for the major part of italy and spain. by contrast, northern europe has experienced mainly wet and windy conditions due to an anomalous strong westerly circulation that is linked to rainy conditions. these spatial patterns fit with the well-known climate features associated over europe during positive phases of the nao 26 . the arctic oscillation (ao), which is a teleconnection pattern very much linked to nao, . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 1, 2020. we argue that this spatial configuration of the atmospheric circulation might have played a key role in the modulation of the early spread of the covid-19 outbreaks over europe. it is known that some cases were reported already in mid-january in france, with subsequent cases in germany and other countries 29 . thus, the sars-cov-2 virus was already in europe in early 2020, but it may only have started to extend rapidly when suitable atmospheric conditions for its spread were reached. it is possible that these proper conditions were met in february, mainly in italy and spain, due to the anticyclonic conditions previously mentioned. the link between the covid-19 spread and atmospheric circulation has been tested as follows. we have extracted the monthly anomalies of sea level pressure (slp) and 500 hpa geopotential height for february 2020 over each grid point of the 15 capitals of the european countries ( figure s4 ) with the highest number of covid-19 cases reported so far (see data and methods). figure 3 (top) shows that there is a statistically significant . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint (r 2 =0.481, p<0.05) second order polynomial fit between the anomalies of the 500 hpa and the total cases per population. italy, spain, and switzerland, which are the only countries with more than 1,000 cases/million inhabitants in our dataset, clustered together in regions with very large positive anomalies of 500 hpa geopotential heights. for the total number of deaths the fit is also statistically significant for a second order polynomial regression (r 2 =0.50, p<0.05), and it shows clearly how italy and spain are out of scale compared to the rest of the european countries. similar results are obtained using slp fields (not shown). these results evidence that it seems plausible that the positive phase of the nao, and the atmospheric conditions associated with it, provided optimal conditions for the spread of the covid-19 in southern countries like spain and italy, where both the start and the most severe impacts of the outbreak in europe were located. to test this hypothesis further we have also analyzed the covid-19 and meteorological data within spain (see data and methods, figure s5 ). the results show that mean temperature and specific humidity variables have the strong relation with covid and fit with an exponential function ( figure 4 ). they indicate that lower mean temperatures (i.e., average of around 8-11ºc) and lower specific humidity (e.g., <6 g/kg) conditions are related to a higher number of cases and deaths in spain. nevertheless, it is worth mentioning that both meteorological variables are highly correlated (r 2 =0.838, p<0.05) and are not independent of each other. the temperatures as low as 8-10ºc are only reached in a few regions such as madrid, navarra, la rioja, aragon, castille and leon and castilla-la mancha. these areas are mainly located in inland spain where drier conditions were reported the weeks before the outbreak. the rest of spain experienced higher temperatures and consequently were out of the areas . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint of higher potential for the spread of the virus, as reported so far in the literature [15] [16] [17] [18] [19] [20] [21] [22] . in addition, higher levels of humidity also limit the impact of the disease, and therefore the coastal areas seem to benefit from lower rates of infection. thus, in the southern regions of spain (all of them with more than 13ºc and higher levels of specific humidity) we found lower rates of infection and deceases. this is in line with the spatial pattern in italy, with the most (least) affected regions by covid-19 mainly located in the north (south). in contrast, when the whole of europe is considered on a country by country basis (see above and figure 3 ), we find the opposite, a clear gradient with more severity from north to south as commented previously. the spatial pattern of covid-19 described above has some intriguing resemblances with the 1918 influenza pandemic, which is the latest deadly pandemic in modern history of europe. the excess-mortality rates across europe in the 1918 flu also showed a clear northsouth gradient, with a higher mortality in southern european countries (i.e., portugal, spain or italy) as compared to northern regions, an aspect that is not explained by socio-economic or health factors 30 . in spain, a south-north gradient is also reported in the 1918 flu after controlling for demographic factors 31 . the central and northern regions of spain experienced higher rates of mortality, and this has been suggested to be linked to more favorable climate conditions for influenza transmission as compared to the southern regions 31 . interestingly, the slp anomalies of the months before the major wave of this pandemic (which occurred in october-november 1918) shows a clear south-north dipole with positive anomalies in southern europe centered over the mediterranean, and negative ones in northern europe ( figure s6 ). in other words, the nao was also in its positive phase just before the major outbreak of the 1918 influenza pandemic. this resembles the spatial . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint patterns described above for the current covid-19 outbreak, both in terms of the spatial distribution of the mortality of the pandemic over europe as well as in prevailing atmospheric circulation conditions before the major outbreak. these intriguing coincidences need further research in order to better understand the spatial and temporal distribution of large respiratory-origin pandemics over europe. taking into account these results, we claim that the major initial outbreaks of covid-19 in is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. although the outbreak of a pandemic is controlled by a high number of biological, health, political, social, economic and environmental factors, with complex and non-linear interrelationships between them, the results of this study indicate that an anomalous atmospheric circulation may explain why the covid-19 outbreak in europe developed more easily (or faster) in the south-west (mainly north of italy and inland of spain). specifically, the extreme positive phase of the ao and nao during february 2020 could have modulated the beginning of the major outbreaks of covid-19 in europe. this detected anomalous atmospheric pattern, which produces dry conditions over southwestern europe, may have provided optimal meteorological conditions for the virus propagation. in the context of anthropogenic climate change, it has been shown that in future emissions scenarios a poleward expansion of the hadley cell is expected 41 , which in turn is in line with a tendency to increase the frequency of positive phases of the nao 42 ( figure s8 ). this should be taken into account for planning against future epidemics and pandemics that arise from respiratory viruses. interestingly, the conditions during the last major pandemic experienced in europe (the spanish flu in 1918), seem to resemble the current spatial pattern of affectation with more cases in the south of europe as compared to the north. equally, the dominant atmospheric situation was strongly affected by anticyclonic (cyclonic) conditions in the south (north) of . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. ncep/ncar 1 , era5 2 and era20c 3 atmospheric data are used in this manuscript. the maps and data have been retrieved by using the tools and websites referenced in the main text, and more details about the spatial and temporal resolution, vertical levels, assimilation schemes, etc. can be consulted in their references. in brief, an atmospheric reanalysis like those used here is a climate data assimilation project which aims to assimilate historical atmospheric observational data spanning an extended period, using a single consistent assimilation scheme throughout, with the aim of providing continuous gridded data for the whole globe. the artic oscillation (ao) index has been extracted from the climate prediction center of the national oceanic and atmospheric administration (noaa). the ao index is constructed by projecting the daily 1000 hpa height anomalies poleward of 20°n onto the loading pattern of the ao, this latter being defined as the leading mode of empirical orthogonal function (eof) analysis of monthly mean 1000 hpa height. more details and data: https://www.cpc.ncep.noaa.gov/products/precip/cwlink/daily_ao_index/ao.shtml. covid-19 data on country basis were obtained on march 26 th , 2020 from the website https://www.worldometers.info/coronavirus/, which it is mainly based on the data provided by the coronavirus covid-19 global cases by the center for systems science and engineering (csse) at the johns hopkins university. data from spain on regional scale . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. we have extracted the monthly anomalies of sea level pressure (slp) and 500 hpa geopotential height for february 2020 over each grid point of the 15 capitals of the european countries. we have selected the slp and 500 hpa fields in order to summarize the meteorological conditions over each location, as it is known that several meteorological variables can be involved in the transmission of respiratory viruses 4, 5 . with this approach we also avoid the lack of properly updated data for all potential meteorological variables involved in the covid-19 spread, which needs further research as soon as the pandemic ends and a more reliable and complete database of both covid-19 impact and meteorological data can be compiled 6 . for spain, several meteorological variables with high-quality records were obtained from the spanish meteorology agency (aemet) based on surface observations for each of the capital cities of the provinces inside each autonomous region. specifically, monthly averages for february 2020 of 2-m temperature, 2-m maximum temperature, 2-m minimum temperature (°c), air pressure (hpa), wind speed (km h −1 ), specific humidity (g kg -1 ), relative humidity (%), total precipitation (mm) and days of more than 1 mm of precipitation. an arithmetic average has been calculated for the autonomous regions with more than one province. we have checked coupled model intercomparison project phase 5 (cmip5) simulations for two future scenarios (rcp4.5 and rcp8.5) at the end of the 21th century. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 1, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint clinical features of patients infected with 2019 novel coronavirus in wuhan , china a pneumonia outbreak associated with a new coronavirus of probable bat origin identifying sars-cov-2 related coronaviruses in malayan pangolins the role of particle size in aerosolised pathogen transmission : a review covid-19): how covid-19 spreads recognition of aerosol transmission of infectious agents : a commentary evidence of airborne transmission of the severe acute respiratory syndrome virus aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 turbulent gas clouds and respiratory pathogen emissions: potential implications for reducing transmission of covid-19 aerodynamic characteristics and rna concentration of sars-cov-2 aerosol in wuhan hospitals during covid-19 outbreak transmission potential of sars-cov-2 in viral shedding observed at the university of the role of absolute humidity on transmission rates of the covid-19 outbreak role of temperature and humidity in the modulation of the doubling time of covid-19 cases. under rev the ncep / ncar 40-year reanalysis project era5: fifth generation of ecmwf atmospheric reanalyses of the global climate influenza virus transmission is dependent on relative humidity and temperature the effects of weather and climate on the seasonality of influenza: what we know and what we need to know . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 1, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review)the copyright holder for this preprint this version posted may 1, 2020. . https://doi.org/10.1101/2020.04.25.20079590 doi: medrxiv preprint key: cord-295543-nj4a640t authors: castañeda-babarro, arkaitz; arbillaga-etxarri, ane; gutiérrez-santamaría, borja; coca, aitor title: physical activity change during covid-19 confinement date: 2020-09-21 journal: int j environ res public health doi: 10.3390/ijerph17186878 sha: doc_id: 295543 cord_uid: nj4a640t background: the lockdown and social distancing caused by covid-19 may influence common health behavior. the unprecedent worldwide confinement, in which spain has been one of the most affected—with severe rules governing confinement—may have changed physical activity (pa) and sedentary habits due to prolonged stays at home. purpose: the aim of this study is to evaluate how self-reported pa and sedentary time (st) have changed during confinement in the spanish population. methods: 3800 healthy adults (age 18–64 years) residing in spain answered the international physical activity questionnaire short (ipaq-s) twice between 23 march and 1 april (confinement). data analysis was carried out taking into consideration meeting general pa recommendations before confinement, age and gender. results: self-reported pa decreased significantly during confinement in our sample. vigorous physical activities (vpa) and walking time decreased by 16.8% (p < 0.001) and 58.2% (p < 0.001), respectively, whereas st increased by 23.8% (p < 0.001). the percent of people fulfilling the 75 min/week of vpa recommendation decreased by 10.7% (p < 0.001) while the percent of people who reached 150 min/week of moderate activity barely changed (1.4%). the group that performed the most vpa before confinement showed the greatest decrease (30.5%, p < 0.001). men reduced time in vpa more than women (21% vs 9%, respectively) who even increased time in moderate pa by 11% (p < 0.05) and reported less increase in st than men (35% vs 25.3%, respectively). conclusion: the spanish adult population, especially young people, students and very active men, decreased daily self-reported pa and increased st during covid-19 confinement. on 11 march 2020, the world health organization (who) [1] declared a global pandemic caused by severe acute respiratory syndrome coronavirus (sars-covid-2), which has become a public health emergency of international concern. during its first phase of expansion outside china, italy and spain were the most affected countries reporting most cases and deaths. thus, they were the first nations to declare a state of emergency in europe. in spain it was declared on 17 march and the government ordered a lockdown to restrict travel and cancel non-essential services in order to stop the spread of coronavirus disease (covid-19) [2] . social distancing and confinement are fundamental in tackling the spread of coronavirus. however, the ongoing lockdown across the country has no precedent and it is unknown how this may affect the general population's health and wellbeing. in these circumstances, the sudden and stressful situation in addition to prolonged stays at home may imply a radical change in lifestyle behavior such as physical activity (pa), eating habits, alcohol consumption, mental health, quality of sleep, etc. [3] [4] [5] [6] [7] . likewise, there is a general concern about the negative health implications of inactivity and sedentary behavior [8] . the general recommendation for considering an adult to be physically active is to attain at least 150 min of moderate or 75 min of vigorous intensity activity per week or an equivalent combination of both [9] , and sedentary behavior is defined as any waking behavior practiced while lying down, reclining, sitting or standing, involving an energy expenditure ≤ 1.5 metabolic equivalents [10] . while the disease spreads around the world, healthy people are being requested to stay at home for prolonged periods of time and, as a consequence, covid-19 has radically modified the determining factors (individual, interpersonal, environmental, regional or national policies and global) [11] of both types of behavior thus, due to isolation and limitations in engaging in regular and common activities, fulfilling pa recommendations and reducing sedentary behavior during lockdown may pose a significant challenge, especially during the first weeks when the population has limited chances to find alternatives to ensure they remain active even at home. hence, although individuals were encouraged to remain physically active in their homes [12], the unprecedented confinement may give rise to two situations. (1) the active population may decrease their activity and (2) the inactive population may not be likely to increase their daily pa. despite the fact that lockdown has affected several countries, data are scarce about how people have changed their pa and sedentary behavioral patterns because of the specific cases of isolation in each country. therefore, the aim of this study was to analyze self-reported pa and sedentary behavior before and during lockdown caused by covid-19 in a spanish healthy adult population. healthy adults (age 18-64 years, age category defined by who) living in spain were asked to participate in this cross-sectional study. all the subjects were informed about the objective of the study and their free participation in it, being able to leave it whenever they wanted. ethics approval was obtained from the deusto university human ethics advisory group, and informed consent was obtained from participants. sociodemographic data (age, height, weight, gender, whether working and/or studying) and self-reported pa data were collected by questionnaires sent between 23 march and 1 april, just 10 days after the state of emergency was declared in spain. two questionnaires were sent together to be answered consecutively at the same time. the first collected retrospective data about habits during a normal week before lockdown, and the second asked about the following one or two weeks. the questionnaire used was the ipaq short version validated in spanish [13] . the ipaq short version asks about three specific types of activity undertaken during the previous 7 days in the four domains (leisure time, work, household activities and transport); items are structured to provide separate scores for walking, moderately intense and vigorously intense activities. the ipaq version also contains a question about the time spent on sedentary activity. the invitation to participate in the study was issued via social media, e-mail and mobile phone from the physical activity and sports sciences department, university of deusto. moreover, a national sports store (forumsport s.a.) and a biomechanical laboratory (custom4us) also sent the questionnaire to their customers by e-mail. the primary outcome was the change in time and intensity of self-reported pa and the sedentary time prior to the confinement situation and after it. the secondary outcome was the change in the percentage number of participants who fulfilled general pa recommendations according to age, gender, working status and baseline pa levels. a total of 4160 healthy subjects answered the questionnaire. a total of 360 were excluded due to exclusion criteria: not resident in spain (n = 16), age < 18 or ≥65 (n = 110) and extreme scores in vigorous, moderate and walking activities (≥6 h per day, 7 days a week). the exact number of participants excluded was as follows: n = 81 were excluded because the sum of the total active time was >6 h per day (vigorous + moderate + walking). within the pre-covid data, n = 17, n = 31 and n = 62 were excluded because they exercised > 180 min per session at a vigorous level of intensity, >180 at moderate intensity and >21 h (3 h per day, 7 days of week) walking, respectively. finally, within the during-covid data, n = 17, n = 9 and n = 17 were excluded because they exercised >180 min per session at vigorous intensity, >180 at moderate intensity and >21 h (3 h per day, 7 days of week) walking, respectively. a univariate analysis with paired t-tests was used to compare the differences in primary outcomes before and during confinement. furthermore, a chi 2 frequency test was used to assess secondary outcomes, which refer to the change in the percentage number of participants who fulfilled the amount of self-reported pa in the subgroups. a subgroup analysis was performed on different age groups (18-24, 25-34, 35-44, 45-54, 55-64) , gender (m, f), working status (students, active workers, people that study and work, those that reported they did nothing), and self-reported pa, categorized into vigorous activity groups (0-75, 75-150, 150-225, more than 225 min/week) and moderate activity groups (0-150, 150-300, 300-450, >450 min/week). the pa subgroup categories are based on world health organization (who) recommendations. we divided the data into different groups following in accordance with who recommendations for activity of moderate (150 min per week) and vigorous (75 min per week) intensity. within each of the two categories we divided the data into 4 groups as follows: (1) under the amount recommended (less than 150 min of moderate intensity or less than 75 min of vigorous intensity), (2) following recommendations (150 to 300 min of moderate intensity or 75 to 150 min of vigorous activity), (3) twice the amount recommended and (4) three times the amount recommended. this categorization was made to extrapolate the results to the amount of self-reported pa fulfilled by participants in the study, with α level set at 0.05. statistical analysis was performed using the spss data analysis version 23 (spss, inc., chicago, il, usa). table 1 shows the demographic characteristics of 3800 participants who were mostly male, (54%) active workers (78%) and aged 42.7 ± 10.4 years (mean ± sd). (5) data presented as mean ± sd, n (%) using the who stratification, we divided the sample into five bmi groups with n = 77 (2.1%) being the underweight group, n = 2621 (70.0%) normal; n = 897 (24.0%) overweight; n = 144 (3.8%) obese and n = 4 (0.1%) extremely obese (<18.5 kg/m 2 ; 18.5-24.9; 25-29.9; 30-39, 9 and ≥40 groups of bmi score, respectively). during confinement, the amount of time spent on moderate and vigorous activities by all the population decreased by 2.6% (p = 0.102) and 16.8% (p < 0.001), respectively. in addition, walking time was reduced by 58.2% (p < 0.001) whereas sedentary time increased by 23.8% (p < 0.001) ( table 2) . men reported a higher decrease in vigorous activities than women (21% and 9%, respectively) and both reduced walking time to a similar extent (58.5% men, 59.6% women) ( table 2 ). however, sedentary time was reported to have a higher increase in men (35%, p < 0.001) than in women (25.3%, p < 0.001) and accordingly, men significantly reduced moderate activities by 8.2% (p < 0.001) while women increased these activities by 11% (p < 0.05). the student group showed the highest decrease in moderate (16.1% p < 0.05), vigorous (24.3%, p < 0.001) and walking activities (66.9% p < 0.001), whereas unemployed or non-students were proved to be the most sedentary during confinement (47.7%, p < 0.001) ( table 2 ). the adult population (age 55-65 years) decreased the amount of time they spent on vigorous activities the most (22.1%) whereas for moderate activities and walking time it was the youngest subjects (18-24 years) who also evidenced the greatest increase in sedentary time (47.7% p < 0.001). regarding meeting pa recommendations, the number of subjects who failed to complete 75 minutes' activity of vigorous intensity per week before confinement increased by 10.7% (p < 0.001) during lockdown. (table 3 ). in addition, the most active population (>225 min/week of vigorous activity) decreased their activity significantly by 7.7% (p < 0.001). nevertheless, meeting 150 min of moderate activity per week barely changed (1.4%, p value 0.117). in the subgroup analysis, the most active subjects showed the highest decrease in vigorous activity time (30.5%, p < 0.001) ( table 2 ). however, the less active population increased the time they spent on these activities by 34% and this trend is also evidenced in the case of moderate activities. furthermore, walking time declined similarly for all self-reported pa levels, while in terms of sedentary time, the most active group reported the highest increase (40.3%, p < 0.001). self-reported pa decreased significantly during confinement in all the population, in which vigorous and walking activities declined the most and moderate activities barely changed. there were more inactive people who failed to fulfil the 75 min/week of vigorous activities during lockdown and sedentary time also increased considerably. the impact on active and sedentary behavior was particularly high in men, young people, students and the physically very active population. to our knowledge, there are limited previous studies that have analyzed the effect of confinement caused by a pandemic on self-reported pa. thus, it is difficult to assess whether the population we studied has reduced the amount of self-reported pa to a smaller or larger extent. the only available data we found about self-reported pa during confinement comes from activity trackers, where it has been shown that in europe the country with the greatest step count decrease recorded was spain, with 38% less, followed by italy with 25%. this reduction is similar to the falling trend in walking time shown in our study. in this regard, other studies carried out in similar lockdown situations (confinement during seasons with adverse weather conditions-cold winter or heat waves) also reported pa decrease during confinement, whereas sedentary time increased because poor or extreme weather becomes an environmental barrier to going outdoors [14] [15] [16] [17] . sedentary time increased considerably, most likely due to the exchange between common daily active behavior (walking, cycling or transport to work, etc.) and the prolonged stay at home. young people and students spent more time seated during confinement and this may be due to the forced e-learning which encourages sedentary behavior related to excessive time on screen-based activities [18] . likewise, according to the socioecological model [11] , in a comparable framework where social or environmental barriers promote an inactive lifestyle (social isolation, loneliness and, when season changes), more sedentary behavior and less time being spent on light, moderate and vigorous pa have been reported [19] [20] [21] . hence, an involuntary prolonged stay at home may encourage sedentary behavior as well as during confinement caused by covid-19. the most active subjects showed the highest decrease in vigorous activity time and this may be explained by two main reasons: the forced sudden inaccessibility to community resources (e.g., sports facilities, urban trails, parks, green spaces, etc.) and the lack of time to react during the first weeks of confinement to gather fitness resources, in order to continue engaging in regular activities at home. regarding moderate activities, our data showed that it barely changed in all the population and this could be attributed to the fact that some people may have been maintaining the minimum recommended time doing alternative activities at home. in this regard, the less active population increased vigorous and moderate activities during confinement, which could be related to the promotion of such activities by health institutions, fitness centers, the internet and television by posting daily online workout routines. to our knowledge, there are no scientific articles supporting the benefits of promoting pa established during confinement. some specific examples of such activities are spanish national television (morning workouts), the free online classes offered by several institutions and fitness centers (using online platforms such as zoom or google meet) and the recommendations made by health associations. our results showed that there are people who found new ways of being more active during this lockdown, which could become best practices in the future, should a pandemic of similar characteristics hit again. active behavior changed according to gender. both genders reduced walking time to a similar extent, although men reported a higher decrease in vigorous activities that may be related to the greater pa prevalence reported in women over the years. [22] [23] [24] [25] . in terms of sedentary behavior, sitting time increased more highly in men who also significantly reduced moderate activities, while women increased these activities. this could be attributed to the gender gap by historically demonstrated female inequality in household and child care tasks, in which men have shown a low level of involvement in spain [26] [27] [28] . regarding meeting pa recommendations, the global age-standardized prevalence among the inactive population was 27.5% in 2016 [23] . according to the eurobarometer (eurobarometer, 2014), 33.6% of the spanish adult population did not attain minimum levels of pa, and 36% spent most of the day sitting down (national health surveys in spain). in our population, our inactive population before confinement is lower (25.3% corresponding to 75 min/week vigorous pa) than that of the eurobarometer. that may be explained by the fact that the population recruited for the study was particularly more active as shown in the data for people undertaking >225 min/week of vigorous activities, and this could be attributed to the fact that the questionnaire was shared by institutions linked to sport, exercise and biomechanics. therefore, it is to be expected that we recruited a population that is commonly more active than the general population. a limitation of the current study is that we selected the ipaq short version instead of the ipaq-long one because of concerns that the length of the questionnaire would result in significant participant burden. in addition, although the questionnaire collects data about the last seven days, in our study we requested information beyond a week, which may be justified due to the unprecedented situation and the lack of time available to manage more appropriate study design and methods. in order to obtain as many participants as possible, sharing the questionnaire was sent to customers involved in sports and biomechanical issues in addition to being shared on social networks. therefore, a sampling selection bias may have occurred in the population analyzed due to their natural active habits. another limitation could be the cross-sectional design of the study since directionality of the associations cannot be established. finally, the way in which the data were collected in this study can be in itself considered a limitation, since participants reported data in a subjective way when answering self-rated questionnaires. on the other hand, one of the strong points of the study is that the questionnaire was sent just when the population started confinement (during the first two weeks), and so it is likely participants had their common activities in mind before confinement in a fresh and realistic way. to our knowledge, this is the first study carried out on a confined large sample size, which may be useful in designing different strategies in order for the confined population to reduce sedentarism and increase pa. in conclusion, healthy adults reduced daily self-reported pa and increased sedentary time during covid-19 confinement in spain. the impact was particularly high in men, young people, students and the very active population. strategies should thus be employed to increase pa and decrease sedentary behavior. in this study, we tried to ascertain the influence of confinement on the lifestyle of the population. this study may serve to show the effect of an extraordinary measure, such as confinement, on this lifestyle, as well as a greater awareness of the effect of confinement. moreover, the results may help design and target interventions aimed at increasing physical activity and reducing unhealthy levels of sedentary time associated with pandemic mitigation efforts. who director media briefing on covid-19. available online alcohol use and misuse during the covid-19 pandemic: a potential public health crisis? lancet public health 2020, 5, e259 a prospective study of holiday weight gain who mental health. mental health and psychosocial considerations during the covid-19 outbreak dealing with sleep problems during home confinement due to the covid-19 outbreak: practical recommendations from a task force of the european cbt-i academy physical exercise as therapy to fight against themental and physical consequences of covid-19 quarantine: special focus in older people a tale of two pandemics: how will covid-19 and global trends in physical inactivity and sedentary behavior affect one another? on behalf of sbrn terminology consensus project participants. sedentary behavior research network (sbrn)-terminology consensus project process and outcome correlates of physical activity: why are some people physically active and others not? validation of the international physical activity questionnaire-short among blacks the effect of season and weather on physical activity: a systematic review. public health physical activity levels of community-dwelling older adults are influenced by winter weather variables influence of seasonal variations on physical activity in older people living in mountainous agricultural areas comparison of summer and winter objectively measured physical activity and sedentary behavior in older adults: age, gene/environment susceptibility reykjavik study covid-19): the need to maintain regular physical activity while taking precautions associations between social isolation, loneliness, and objective physical activity in older men and women social isolation, loneliness, and health behaviors at older ages: longitudinal cohort study loneliness predicts reduced physical activity: cross-sectional & longitudinal analyses the active living gender's gap challenge: 2013-2017 eurobarometers physical inactivity data show constant higher prevalence in women with no progress towards global reduction goals worldwide trends in insufficient physical activity from 2001 to 2016: a pooled analysis of 358 population-based surveys with 1.9 million participants worldwide variability in physical inactivity a 51-country survey shifting the physical inactivity curve worldwide by closing the gender gap the gender revolution: a framework for understanding changing family and demographic behavior parentalidad y división del trabajo doméstico en españa el impacto de cuidar en la salud y la calidad de vida de las mujeres the authors gratefully acknowledge those who participated in this study and forumsport and custom4us for helping to disseminate the questionnaire. the authors declare no conflict of interest. key: cord-205189-4be24yda authors: asawa, parth; gaur, manas; roy, kaushik; sheth, amit title: covid-19 in spain and india: comparing policy implications by analyzing epidemiological and social media data date: 2020-10-26 journal: nan doi: nan sha: doc_id: 205189 cord_uid: 4be24yda the covid-19 pandemic has forced public health experts to develop contingent policies to stem the spread of infection, including measures such as partial/complete lockdowns. the effectiveness of these policies has varied with geography, population distribution, and effectiveness in implementation. consequently, some nations (e.g., taiwan, haiti) have been more successful than others (e.g., united states) in curbing the outbreak. a data-driven investigation into effective public health policies of a country would allow public health experts in other nations to decide future courses of action to control the outbreaks of disease and epidemics. we chose spain and india to present our analysis on regions that were similar in terms of certain factors: (1) population density, (2) unemployment rate, (3) tourism, and (4) quality of living. we posit that citizen ideology obtainable from twitter conversations can provide insights into conformity to policy and suitably reflect on future case predictions. a milestone when the curves show the number of new cases diverging from each other is used to define a time period to extract policy-related tweets while the concepts from a causality network of policy-dependent sub-events are used to generate concept clouds. the number of new cases is predicted using sentiment scores in a regression model. we see that the new case predictions reflects twitter sentiment, meaningfully tied to a trigger sub-event that enables policy-related findings for spain and india to be effectively compared. the covid-19 pandemic has seen several countries become epicenters for spread. spain was one such country; however, their policies were effective in curbing the initial outbreak of aaai fall 2020 symposium on ai for social good. copyright © 2020 for this paper by its authors. use permitted under creative commons license attribution 4.0 international (cc by 4.0). in march-may of 2020. this is arguably due to people and governments taking precautions to limit the population of people susceptible to the virus -masks, social distancing, lockdowns, business closures, etc from an early stage 1 . accordingly, the effectiveness of individual countries' policy responses to an epidemic or pandemic can be determined by how well citizens respond to those policies 2 . a person's conformity to a policy may be inferred from their ideologies mined through social media, such as twitter [van holm et al., 2020] . as shown in figure 1, over three months, spain recorded a decline of 97% in the number of new cases, whereas india has shown a 36% influx in new patients. is it possible to explore policy transfer from spain to india to curb the alarming covid-19 cases? could the number of infections be modeled using the twitter concepts about causal trigger sub-events in a causality network [helbing, ammoser, and kühnert, 2006] ? the reason we are conducting this study is there is limited prior research relating policy and changes in case counts, through social media analysis, for covid-19. we use twitter as the active platform for live information on the spread of covid-19. government policies, especially in developing nations, based on the epidemiological data, ignore the population-specific behaviors of culture, ideology, and politics that hinder these policies' implementation. for example, a large number of people in the us are opposed to wearing masks. to this end, we juxtapose spain and india's epidemiological data to identify a date when the curves show the number of new cases diverging from each other, and india started showing worsening conditions.although it could be argued that the differences we see in cases were due to travel from hotspots, it's important to note that india closed its borders by suspending all international flights starting march 22nd, in addition to taking steps to suspend inter-state travel by suspending domestic flights and domestic trains throughout the time frame of our analysis 3 . we recognized some critical policy-related concepts which are causally related in the covid-19 context. for instance, "settlement areas", "confinement to barracks", "mistrust of people", "loss of government authority" where x% refers to the share of covid-19 tests that came back as positive in a 7-day rolling average. bottom row: june 5th, spain 0.9% and india 6.7%, where x% refers to the share of covid-19 tests that came back as positive in a 7-day rolling average. causally follow announcement of "public policy". hence, we used the causality network of policy-related concepts identified by experts during severe acute respiratory syndrome (sars) to perform a knowledge-guided search on twitter [helbing, ammoser, and kühnert, 2006 ] (see figure 2) . we show kerala and mumbai's policy-related concept clouds. then we investigate the applicability of interventional policies in madrid and barcelona to kerala and mumbai. likewise, we observed a policy-level association between the canary islands and andhra pradesh as both regions have strong healthcare infrastructure. the main contributions of this work are thus investigating twitter conversations corresponding to explanatory causal trigger events, to form an ideological map of the population that provides insights into response to government policy (see methods). in turn, this is validated through the prediction of new cases using the sentiment scores of the twitter conversation (see regression analysis and explanatory events). finally, a comparison of policy and responses across similar regions in spain and india is discussed (see discussion and findings). [cowling et al., 2020] statistically analyzed the impact of policy on reducing the transmissibility rate of covid-19. the study was conducted on the epidemiological data of hong kong, and inferences were made using confidence intervals. our research aims to investigate the applicability of policies created by developed nations onto developing nations. such an exploration is not possible in cowling et al.'s study. further, cowling et al. provide statistical explanations on government policies' potency in hong kong rather than conceptual explanations, which is required to decide the "what next." while probing government policies' relevance from one nation to another, population-specific behaviors negatively affect cross-nation policy transfer. for instance, figure 2 : causality network of sub-events during sars pandemic by helbing et al.. we utilized this graph to represent sub-events within the covid-19 pandemic during extraction of the word cloud a likely source of infection in india was the tablighi jamaat movement, a religious gathering 4 , which became a coronavirus vector and was not taken into account in government policy or enforcement [sivaraman et al., 2020] . likewise, the return of migrant laborers to their home states in india and long weekend celebrations and parties in the united states led to an increase in covid-19 cases. as a result, policies such as reopening, contact tracing, and ensuring public compliance, which was effective in europe, are not directly applicable to india and the united states [hellewell et al., 2020] . it is essential to relate patterns in epidemiological data with evolving policy-related concepts and sentiment on social media to better study the likelihood of policy effectiveness [kalteh and rajabi, 2020] . other regression models that predict new cases do not consider social media information, which we posit is a significant predictor [shayak, sharma, and gaur, 2020] [prem et al., 2020] . in this research problem, we use multiple publicly available datasets and government resources, specific to spain and india (e.g., news reports, insights on epidemiological data). the first country dataset is a covid-19 dataset for spain data. the dataset is available here: link. it contains attributes including but not limited to: total # of cases, total # of hospitalizations, total # of patients in the icu, total # of recovered patients, and total # of new cases. the dataset was derived entirely from spain's ministry of health website and transformed into csv files. all of the data is available by province (the equivalent to states in the united states). the second dataset we use is a covid-19 dataset for india, available here 5 . this dataset contains attributes including but not limited to: # of confirmed cases per day, # of recovered per day, # of deaths per day, # of people in the icu, # of people on ventilators. the dataset was sourced from several sources, a list of which can be found here 6 . all of the data is available on a state-by-state level within india. after having the two datasets for identifying divergence points and initial identification of a problem, the final dataset we use is a dataset of twitter-ids, for our twitter social media analysis available here 7 . as stated in the dataset, "the repository contains an ongoing collection of tweets ids associated with the novel coronavirus covid-19 (sars-cov-2), which commenced on january 28, 2020. we used twitter's search api to gather historical tweets from the preceding seven days, leading to the first tweets in our dataset dating back to january 21, 2020." this dataset gives us access to the tweet id's pre-filtered concerning the coronavirus with keywords accessible here 8 . from this dataset, we hydrated 5, 075, 830 tweets from april 15 to may 15, of which 534 were geotagged from the state of kerala, and 7094, the state of mumbai. we want to analyze the differences between the spread of the virus in spain and india; however, the countries are too diverse to compare in their entirety. thus, we instead propose comparing the two countries on more granular scales, specifically by identifying pairs of states/regions (india/spain) that are similar on the following grounds: (1) population density, (2) unemployment rate, (3) tourism, and (4) quality of living, and examining the results. for this study, we restrict to the following two pairs of states/regions: (1) kerala and madrid, and (2) maharastra (mumbai city) and cataluña (barcelona region). on the data from these states/regions, we did visualizations of counts of new cases during april and may. this period was essential to assess the effectiveness of government policies in controlling the covid-19 pandemic. by creating pairs of states/regions from india and spain, we identified divergence points where india started showing worsening public health. figure 4 shows may 1st, 2020, as the divergence point for kerala and madrid. likewise, april 22nd, 2020, is the divergence point for mumbai and barcelona ( figure 5 ). once the relevant timeframe is defined, we extract tweets geotagged to the local indian regions, such as kerala and mumbai. it allows us to explore the people's responses towards government policies, which helps assess the rise in covid-19 cases. semantically understanding people's reactions from their twitter conversations is a challenging task for statistical natural language processing. hence, we utilize a hypothesized causal graph of policy-dependent subevents in helbing et al., which describes a series of activities occurring during a pandemic. some of the concepts described by helbing et al. are mistrust, church hospitals, mask distribution, mental health. we identify a set of relevant concepts that describe kerala and mumbai's tweets using a pre-trained multilingual conceptnet model from a sem-eval task [speer and lowry-duda, 2017] . we use the spacy parser to generate phrase embeddings of concepts and nouns extracted from tweets 9 . next, we perform a cosine similarity between the tweet vector and concept vector, with an empirically determined threshold of 0.45. the frequency of concept phrases was recorded and presented as people's responses in the given region during the given time frame. we begin by performing a preliminary visualization of the dataset. in figure 4 , we observe the new case counts in kerala scaled up by a factor of 100 (for trend visibility) compared to madrid's region. it seems that the data points remained reasonably close from the period of march 15th to may 1st, after which there is a second wave of covid-19 spread in kerala. in contrast, madrid remained relatively close to 0 for the rest of the period. this divergence from its previous relative similarity to madrid is a key feature we intend to explore using real-time conversations on twitter. through semantic analysis of kerala's tweets around the point of inflection, we recorded mentions of gatherings such as marriages and poor capacity of the health system, which are potential causes of the rise in new cases (see figure 6) . furthermore, people mentioned information on ways of transmission with no known source of origin, prompting the government to reinstate lockdown procedures. overextension of lockdown by the government developed a panic reaction among the individuals in kerala. the state also saw a lack of cooperation among authorities in affected regions, which contributed to a surge in cases. rumors circulated through misleading campaigns that developed uncertainty and fear upsetting people's livelihood in kerala, making them restless in critical containment zones. from april to may, people's responses to government policies showed expressions of social instability, unemployment, uncontrolled infection transmission, and circulation of rumors. in figure 5 , we observe the plots of daily new cases in maharashtra, whose case counts were almost all from mumbai and cataluña (spain, barcelona). first, it seems that the data points remained fairly close from march 15th to april 22nd, at which point the new cases in cataluña remained fairly close to 0 for the rest of the period. though the population density and social composition of mumbai are different from kerala, we recorded the use of similar concept phrases reflecting similar consequences of government policies. for instance, social instability, reaching out to catholic hospitals 10 (or church hospitals), seeking military aid during lockdown 11 , mental health, panic reaction, and people seeking therapy. compared to kerala, mumbai showed a significant rise in unemployment, which is relatively similar to the trend in unemployment in barcelona, and madrid 12 . the figure 3 : workflow detailing the approach described in this study to analyze citizen response to policies and generate explainable inferences on the epidemiological data, in addition to predicting future changes in the spread of an epidemic. situation of unemployment remained constant from april to may in kerala and mumbai. further, the concept of "general population behavior" describes the migrant population, which constituted 93% workforce in india, contributed to the rise in the covid-19 cases as people travelled back to and-barcelona-both-rank-in-the-bottom-10-of-best-cities-forjobs-following-coronavirus-crisis/ their homes for security. these external factors, which aren't recorded in epidemiological data but explain epidemiology patterns, should be incorporated in models like sir to better estimate the future patterns in the spread of disease [sivaraman et al., 2020]. as we can see, within both states, the topical content being discussed is relatively the same. in the time series curve, including april, we saw that the coronavirus cases had a steadily increasing number of new cases per day with a slight curvature. this indicates that the simifigure 6 : after the first wave of covid-19 spread in the month of march, the government of india instituted various policies, such as school closings, business closings, travel bans, over-extensions, which impacted public life, especially for daily wage families. hence, we see rise in the frequency of tweets concerning mental health, medical care, and unemployment. as a consequence of the policies, we observe emerging events such as rumors, churches becoming hospitals due to overloaded healthcare facilities, social instability, and mistrust (in rectangle black box). through citizen sensing around the point of inflection (figure 4 ) , we noticed a constant frequency of concepts such as poor public life and bad condition of the state, which reflected on the imperfection in policy implementation. larity in thinking over time compounded, possibly resulting in the eventual seemingly exponential growth in the spread of covid-19. we will next validate if these thinking patterns captured in twitter sentiments are a good predictor of new cases. we use multivariate linear regression (mvr) with tweet sentiment to predict future cases in kerala and mumbai's regions from mid-april to mid-may, over a month across different periods. to determine each tweet's sentiment, we use the flairnlp python library 13 . we combine sentiments of concepts (figure 6 and 7) identified from each tweet into daily sentiment values -from the period of april 16th to may 14th/15th. we then perform mvr using the features is described in materials sections and another with tweet sentiment. the first mvr model uses the past 30 days of new cases and recovered cases to predict the next 30, and the second mvr model also uses tweet sentiment to predict the next 30 days. we use a cumulative function on both new cases and recovered cases to better reflect the upward trend. we find that the regression error does indeed decrease when using the tweet sentiments. we specifically look at the differences in the rmse values and the adjusted r 2 for quantitative performance gains. further, we use periods of 3, 7, and 14 days from may 15th for the two mvr models, as these have been shown in [pavlicek, rehak, and kral, 2020] to be the periods of days with which covid-19 13 https://github.com/flairnlp/flair figure 7 : as we can see, within both states, the topical content being discussed is relatively the same. throughout the frame of the time series, including april, we saw that the trend in coronavirus cases had a steadily increasing number of new cases per day, or a positive second derivative. this indicates that the similarity in thinking over time compounded, possibly resulting in the eventual seemingly exponential growth in the spread of covid-19 that we witness. deaths show regularities (see table 1 and 2). previous literature suggests that the rmse uncertainty for this number of data points would be approximately 12.9% [faber, 1999] . a model's explainability is vital in such a high stakes application for humans to trust and understand its predictions. while the weights of a linear model lend themselves nicely to interpretation, they alone do not provide any insight into the type of events that may have triggered such conversation on twitter. for tweets with concepts of high sentiment score weight in the model, we use the causal graph [helbing, ammoser, and kühnert, 2006 ] built for the sars epidemic to provide explanatory sub-event triggers for those concepts. an example is shown in figure 2 , where the causal structure of sub-events that guided the extraction of twitter conversation is marked. the government can use this graphical explanation to shape its policy going forward. note that the dataset of mumbai tweets was 14 times more extensive than kerala, resulting in high rmse. we see a more noticeable difference in adjr 2 and rmse values for mumbai further in time from may 15th, than we do for kerala except for the 14 days. thus, we believe that this research can be explored further with potentially more statistically significant findings through access to larger datasets in this paper, we presented a methodology to determine crowd responses to governmental policies that can impact health and new case predictions in real-time, and evaluate those responses to provide direction for new public health policy. in broad terms, the method presented is the first visualization of the data to identify the features of interest, elicit time-frames of events upon which to focus analysis, and explain the pattern in epidemiological data with social network sentiment analysis. for our comparison of the effectiveness of policies in spain and india, we were able to identify a critical time-frame across multiple state/province pairs that proved to be a divergence point in the spread of the virus where spain appeared to be succeeding in containing the virus. in contrast, india seemed to be experiencing exponential growth. looking at the timelines of government lockdowns: after the 10th case, india took action on day 21 and spain on day 16. after the 1st death, india took action on day 13 and spain on day 29. finally, after the 100th case, india took action on day 13 and spain on day 10. we see that arguably, the nations took action on a similar timescale concerning the beginning of the spread. we posit, therefore, that the differences in responses to policies can be found in crowd ideology via twitter. looking at a few of the previously identified key phrases, we can see some examples of selected tweets that display concepts previously identified in the concept clouds, along with a timely response from authorities in spain: 2. medical care tweet (mumbai): "when the richest country has zero public health care in place and they need to hire in the middle of a pandemic" --spain used a royal decree to declare a 15-day national emergency back on march 15th [legido-quigley et al., 2020] . it dedicated significant investments to its healthcare system, quoted "it had allocated c2.8 billion to all regions for health services and created a new fund with c1 billion for priority health interventions." 3. social instability tweets (kerala and mumbai): (a) "if you get into a cyclical lockdown it will be devastating for economic activity because that would destroy trust."(b) "people will lose trust if the lockdown continues indefinitely. need to work out a way.#rahulshowstheway" --spain's civil guard dedicated time to compiling a report and evaluating possible scenarios of growing social unrest in conjunction with law enforcement agencies, coming up with different responses to rising crime rates or civil unrest. the report specifically noted that the spanish population has accepted the lockdown, "which started out as one of the strictest in europe" 15 . this is where real-time nlp analysis plays an instrumental role. identifying topical categories and sentiments associated with them through social network analyses like twitter provides an avenue to quantitatively and qualitatively evaluate and rank responses to different policies. for quantitative assessment, we considered intuitive model performance metrics, such as rmse and adjr 2 . qualitative inspection was performed by mapping the people's response to sub-events in sars's causality network. we project the identified causally triggered sub-events onto a concept cloud and analyze over two critical months post-initiation policies. even though a linear model is already interpretable in terms of weights, this type of explainability is of paramount importance to understand and trust the model predictions in such a high stakes application. this can give governments insight into whether they must make policies stricter, add more policies, or enforce policies differently than they are at the moment. real-time analysis of the social network and virus data can significantly change the course of health events and are a promising yet relatively unexplored tool for governments and policymakers to use. we have presented in this work a case study with two (state, region) pairs, specifically (mumbai, barcelona) and (kerala, madrid). we posit that this work can be extended to other (state, county) pairs. considering one pair such as andhra pradesh and the canary islands (see figure 8 )both of which are known to have strong healthcare systems relative to the rest of their countries -we can plot the time series visualization and analyze the divergence point. it's important to note that there other uncontrolled variables that make it hard to draw affirmative causal conclusions, and this is an important aspect we hope to consider in future work. the results from this preliminary work could be used to explain epidemiological models, specifically, the exo-sir (exogenous -susceptible, infected, recovered) model. exo-sir is built to model the disease's spread while taking into account exogenous factors (e.g., gathering, compliance to public policy). since our study identified concepts such as social instability, mistrust, and poor medicare as responses of the population against the instated policies, it could be considered potential exogenous factors influencing sir models. our future research may entail including government policies themselves as the exogenous impact on a sir population, and more accurately identifying and explaining the spread of a disease in a community by considering citizen response to policies. all the code and datasets for this study are available for the reproducibility of our results here. impact assessment of non-pharmaceutical interventions against coronavirus disease 2019 and influenza in hong kong: an observational study estimating the uncertainty in estimates of root mean square error of prediction: application to determining the size of an adequate test set in multivariate calibration disasters as extreme events and the importance of network interactions for disaster response management feasibility of controlling covid-19 outbreaks by isolation of cases and contacts. the lancet global health covid-19 and digital epidemiology the resilience of the spanish health system against the covid-19 pandemic. the lancet public health oscillatory dynamics in infectivity and death rates of covid-19 the effect of control strategies to reduce social mixing on outcomes of the covid-19 epidemic in wuhan, china: a modelling study a new delay differential equation model for covid-19 conceptnet at semeval-2017 task 2: extending word embeddings with multilingual relational knowledge the impact of political ideology on concern and behavior during covid-19 we would like to acknowledge dr. victor vicente palacios for his support in the spain data collection and its interpretation. also we would like to acknowledge mr. nirmal sivaraman and dr. sakthi balan of lnmiit-jaipur for their brain-storming and input into the direction of this research. we acknowledge partial support from the national science foundation (nsf) award 1761880: "spokes: medium: mid-west: collaborative: community-driven data engineering for substance abuse prevention in the rural midwest". any opinions, conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the nsf. key: cord-301527-i3xz1rfi authors: millán, javier; rodríguez, alejandro title: a serological survey of common feline pathogens in free-living european wildcats (felis silvestris) in central spain date: 2009-01-13 journal: eur doi: 10.1007/s10344-008-0246-z sha: doc_id: 301527 cord_uid: i3xz1rfi twenty-five serum samples of 22 free-living european wildcats (felis silvestris) captured from 1991 to 1993 in central spain were tested for evidence of exposure to seven feline pathogens. all the wildcats but one (95.4%) presented evidence of contact with at least one of the agents (mean = 2.2). contact with feline leukemia virus (felv) was detected in 81% of the wildcats (antibodies, 77%; antigen p27, 15%). antibodies to feline calicivirus (fcv, 80%), feline herpesvirus (fhv, 20%), feline parvovirus (fpv, 18%), and chlamydophila sp. (27%) were also detected. analyses were negative for feline immunodeficiency virus and feline coronavirus. the probability of having antibodies to fpv was inversely related with the concentration of serum cholesterol and with a morphometric index of body condition. similarity in the composition of antibodies against disease agents (number and identity of detected and undetected antibodies) was significantly higher in pairs of female wildcats than in pairs of males or heterosexual pairs, suggesting that females had a more homogeneous exposure to pathogens. seroprevalence for fhv was higher in males than in females. antibodies to fhv and chlamydophila sp. were more frequent in winter than in other seasons. in addition, the mean similarity of the pathogen community between pairs of serum samples was higher if both wildcats were caught during the same season than if they were not. mean similarity was lowest when serum samples obtained in winter were compared with those from spring or summer. the results suggest that some agents probably had a reservoir in domestic cats and may cause some undetected morbidity/mortality in the studied wildcat population, whereas others, such as felv and fcv, may be enzootic. the european wildcat (felis silvestris schreber 1777) is catalogued as vulnerable (iucn 2007) . the wildcat has a scattered distribution in europe, where it has disappeared from much of its original distribution area, resulting in severe fragmentation of its populations. the mediterranean area that includes the iberian peninsula represents one half of the distribution range of the species in europe (lozano et al. 2003) . according to garcía-perea (2002) , the wildcat population in spain could have declined and experienced considerable fragmentation. acknowledged threats are persecution, habitat loss, and hybridization with domestic cats. however, the importance of other factors of decline has been so far neglected. in particular, an increasing concern exists about the role of infectious diseases as a cause of decline of populations of some wild species (smith et al. 2006) . domestic cats are common in the dominant cultural landscapes of mediterranean europe, allowing for their interaction with wildlife and increasing the potential for disease transmission between domestic cats and wildcats. in fact, wildcats from a number of locations in northern europe host viruses commonly found in domestic cats (mcorist et al. 1991; artois and remond 1994; daniels et al. 1999; leutenegger et al. 1999; fromont et al. 2000) . contact with the pathogenic feline leukemia virus (felv) was detected in all these studies. fromont et al. (2000) also detected infections with the feline immunodeficiency virus (fiv). in contrast, račnik et al. (2008) failed to detect evidence of contact with felv and fiv in wildcats in slovenia. excepting a few parasitological studies (torres et al. 1989; rodríguez and carbonell 1998) , no information is available about the disease agents infecting the european wildcat in the iberian peninsula or other areas of the mediterranean region. fiv, felv, and other feline pathogens are known to infect domestic cats in spain (arjona et al. 2000; solano-gallego et al. 2006) . these disease agents might not only decrease the persistence of local wildcat populations through increased mortality but also in more subtle ways, e.g., altering the behavior or reducing the body condition and fitness of infected individuals (scott 1988) . furthermore, since the mechanisms of transmission between species of such disease agents are poorly known in the wild, wildcats could be involved in the epidemiology of infectious diseases that may pose a risk for sympatric rare endangered species, specially the iberian lynx (lynx pardinus), which have little contact with anthropic environments (delibes et al. 2000) . the aims of the present study were (1) to assess the seroprevalence against feline disease agents in free-living wildcats and (2) to examine whether prevalence, number of detected agents, and similarity between wildcats in the composition of the pathogens they were exposed to were related with sex, season, and body condition. we studied a wildcat population in a 110-km 2 area of eastern toledo mountains, southcentral spain (39°18′ n, 3°4 5′ w). the study area consists of a mosaic of mediterranean shrubland, cereal fields, and to a lesser extent, pastureland. major land uses other than agriculture are game and sheep and goat husbandry. there are no towns or other forms of urban use, but the area contains scattered farms (0.1 farm/km 2 ), most of them permanently inhabited, where free-roaming domestic cats and dogs are fairly common. around 30 buildings aggregate in a 60-ha spot near the eastern end of the study area; a few are used as holiday houses; the other are virtually abandoned. in the course of ecological studies, double-entrance box traps and padded no. 2 victor coil-spring traps (woodstream, lititz, pennsylvania) were placed during periods of 2-16 weeks across the study area. trapping took place from winter (january-march) to summer (july-september), between 1991 and 1993. twenty-two wildcats were caught and immobilized either with ketamine hydrochloride (ketolar©, parke-davis, spain) mixed with xylazine hydrochloride (rompún©, bayer, spain), or with tiletaminezolazepam (zoletil©, virbac, spain). wildcats were measured, weighed and classified as adults or juveniles (<1 year old), on the basis of tooth wear, as well as signs of pregnancy or current (milk) or past lactation (hairless areas around nipples). coat patterns, size, weight, and spatial behavior indicated these animals were not domestic or feral cats. our sample consisted of five adult males, 15 adult females, and two juvenile females. whole blood was obtained from venipuncture of the cephalic veins. samples were collected in serum separator tubes and allowed to clot. then, they were centrifuged at 2,000 rpm for 15 min, and the serum was removed. a fraction was subjected to biochemical analysis, and the rest was kept frozen at −20°c until examined for the presence of antibodies to disease agents. since three individuals were caught twice, 25 serum samples were obtained. for each wildcat, body condition was estimated in two ways: (1) the residual of a regression line of (log) body weight (g) against (log) head plus body length (mm), and (2) the concentration of total cholesterol (mg/dl) in the serum. in mammals, it is well known that the intake of animal proteins increases plasma total cholesterol (forsythe et al. 1980; sugano and roba 1993) . thus, we hypothesized that a higher concentration of serum cholesterol indicates a higher protein intake and a better condition. morphological and biochemical estimates of condition were statistically independent (r=0.373, p=0.106). serum samples were tested using enzyme-linked immunoassay (elisa) using commercial kits provided by ingenasa (madrid, spain) and evl-eurovet (madrid, spain) to the following disease agents: fiv (ingezim fiv©), felv (ingezim felv gp-70©), feline coronavirus (fcov; ingezim fcov©), feline calicivirus (fcv; f1008-ab02-feline calicivirus antibody elisa©), feline herpesvirus-1 (fhv; f107-ab02-feline herpesvirus antibody elisa©), and chlamydophila sp. (f1009-ab01-chlamydia antibody elisa©). presence of antibodies against feline parvovirus (fpv) were determined using a test for canine parvovirus (ingezim cpv©) using anti-cat igg as conjugate, following the recommendations of the manufacturer. finally, the presence of felv p27 was determined with elisa for antigen detection (ingezim felv-das©). each procedure incorporated positive and negative control sera according to the manufacturer's instructions. we explored the univariate effects of sex, season, and body condition on the presence of antibodies against each considered pathogen with logistic regression. then we fitted generalized linear models with poisson errors to examine the effect of the same predictors on the number of disease agents per individual. finally, we examined how similar the composition of pathogens was in each sample as a function of sex and season. for a given pair of serum samples a and b, we computed the simple matching coefficient (krebs 1998 where a is the number of pathogens that occur both in samples a and b, b is the number of antibodies in sample b but not in sample a, c is the number of antibodies in sample a but not in sample b, and d is the number of antibodies absent in both samples. we calculated this index of similarity in the identity of antibodies for all pairs of samples and compared the means of the simple matching coefficient between combinations of levels of sex and season with analysis of variance. all the wildcats but one (95.4%) presented evidences of contact with at least one of the pathogens (mean=2.2 pathogens/individual). four wildcats revealed antibodies for one agent (18.2%), 11 for two agents (50.0%), three for three agents (13.6%), two for four agents (9.1%), and one for five agents (4.5%). seroprevalences are shown in table 1 . exposure to felv and fcv was detected, respectively, in 81% and 80% of individuals. antibodies against fpv, fhv, and chlamydophila sp. were found in 20-30% of individuals. there was no evidence of contact with fiv or fcov (table 1) . antibodies against felv were detected in 17 wildcats. sera of two other individuals yielded an absorbance value between the positive and negative cutoffs. in addition, three wildcats resulted positive for antigen detection. one of them presented both antigen and antibodies. a second individual was sampled twice and presented antigen and antibodies only in the second sample, 1 year later. the third wildcat was also sampled twice, and in the first sampling, both tests were negative, but 2 weeks later, it presented antigenemia but not antibodies (see table 2 for these and other cases of seroconversion). the prevalence of fhv in males was four times higher than in females, and these sexual differences were marginally significant (table 3) . prevalence was similar in both sexes for other agents, except chamydophila sp. whose proportion in males was more than twice as high as in females, though differences were not significant. the seroprevalence of fhv in wildcats caught in winter was significantly higher than in samples obtained in other seasons (table 3 ). there was also a tendency for chamydophila sp. to decrease its prevalence from winter to summer, whereas we found lower variation in seasonal prevalence for other agents. in general, the probability of having contacted a disease agent showed a weak association with indices of body condition. however, the probability of having antibodies against fpv had a significant inverse relationship with the concentration of serum cholesterol (table 3) . a similar trend was found between this probability and the morphometric index of body condition. no apparent clinical signs were observed in any of the studied wildcats at the time of handling. poisson regression indicated that sex, season, and body condition did not explain a significant fraction of deviance in the number of types of antibodies found in serum samples. similarity in the composition of antibodies against disease agents (number and identity of detected and undetected antibodies) was significantly higher in pairs of female wildcats than in pairs of males or heterosexual pairs (one-way analysis of variance (anova), f 2,250 =4.27, p= 0.015; fig. 1 ). the mean (±se) simple matching coefficient in pairs of the same sex (0.67±0.02) was significantly higher than in wildcat pairs of different sex (0.60±0.02; t= 2.48, df=251, p=0.014). there was a seasonal pattern of seroprevalence to the different studied disease agents in the wildcat population of toledo mountains was either in the range of, or higher than, values previously reported in europe (artois and remond 1994; mcorist et al. 1991; daniels et al. 1999; leutenegger et al. 1999; fromont et al. 2000) . active infections by felv were demonstrated in the studies quoted above. the felv antigenemia detected in the present study was in the range of the data by fromont et al. (2000) , mcorist et al. (1991) , and daniels et al. (1999) but was lower than that observed by leutenegger et al. (1999) . our results may indicate that, as observed by mcorist et al. (1991) and in contrast with the observations in other wild felids (e.g. citino 1986), felv may be self-sustained in the studied wildcat population. however, transmission from domestic cats may also occur. feline leukemia virus is fatal in domestic cats, and mortality related to felv infection have been reported in a free-living cougar (puma concolor; jessup et al. 1993 ) and in a captive bobcat (lynx rufus; sleeman et al. 2001 ). similar cases have not been recorded in the european wildcat. for example, leutenegger et al. (1999) did not find clinical signs in felv-infected wildcats. as a rule, no evident signs were observed in the wildcats during this survey, either seropositive or infected. this may indicate that most of the wildcats may survive the infection. nevertheless, some undetected mortality due to feline leukemia may occur. eighteen percent of the wildcats presented antibodies against fpv. this value was higher than those reported by leutenegger et al. (1999) and ostrowski et al. (2003) by means of the immunofluorescence assay. feline parvovirus causes feline panleukopenia (fpl), and mortality due to this syndrome has been observed in other wild felids (e.g. code, sex, and age are given. all analyses were negative in these wildcats for fiv, fpv and fcov the g statistic indicates the results of logistic regressions (sex, df=1; season, df=2). the sign of the logit coefficient and its significance are shown for the effects of two indices of body condition (df=1) w/l residuals of the regression log-weight vs. log-length, chol serum cholesterol concentration in bobcat, wassmer et al. 1988; or cougar, roelke et al. 1993 ). this disease is markedly harmful in kittens (barker and parrish 2001) . thus, if wildcat kittens succumb often to fpl as observed in feral cats (van rensburg et al. 1987) , this disease may have a substantial impact on productivity and thus on population dynamics. we found a negative relationship between indices of wildcat condition and exposure to fpv. the analysis performed detects igg, thus indicating past infection. then, it is difficult to explain an effect of a past infection with wildcat condition at the time of sampling. since, as said above, fpl is especially harmful in young cats, some incorrect development due to the disease could promote a subsequent impaired condition. anyway, relatively poor condition in fpv-seropositive wildcats, together with the observed low seroprevalence, could be due to fpv-associated morbidity or mortality, although our results are inconclusive in this regard. it is not known whether fpv is self-sustained in the wildcat population or domestic cats act as a reservoir. this virus is extremely resistant and can survive for months in the environment (greene 1998) . therefore, in addition to direct contact with a virus-shedding carnivore, habitat contamination by domestic cat feces may be a source of infection (roelke et al. 1993) . additional difficulties to interpret the moderate fpv prevalence we found arise from potential specificity problems (ostrowski et al. 2003) , since the elisa test utilized here does not allow determining if wildcats were infected by the feline or the canine parvovirus strain. thus, not only domestic cats but also dogs and red foxes (vulpes vulpes) could serve as sources of infection for wildcats, as suggested for the iberian lynx (roelke et al. 2008) . we detected evidence of exposure to the three main agents involved in the feline respiratory syndrome (frs), i.e. fcv, fhv, and chlamydophila sp. contact with fcv and fhv was also detected by artois and remond (1994) , daniels et al. (1999) , leutenegger et al. (1999) , and ostrowski et al. (2003) , but the prevalences we found are markedly higher than those reported in these studies. as far as we know, we report here for the first time antibodies to chlamydophila sp. (or antigenically related agents) in a wild feline species. only paul-murphy et al. (1994) tested but failed to detect antibodies to chlamydial agents in cougars. again, it is unknown whether these agents are endemic in the studied wildcat population or wildcats became infected after contact with domestic cats. riley et al. (2004) found higher titers to fcv in bobcats from areas where domestic cats occurred, suggesting that fcv might have been endemic in domestic cats but not in bobcats. in contrast, roelke et al. (1993) believed that the virus may be present in florida panthers, with transmission similar to that in the domestic cat (a persistently infected motherto-offspring pathway). we believe that the moderate to high prevalence of disease agents related with frs suggests that (1) contacts between domestic and wildcats, the most feasible way of transmission of fhv and chlamydophila, are frequent, and (2) fcv may be endemic in this wildcat population, the most likely way of transmission being from mothers to kittens. the pathological significance of these agents to wildcats is unknown. in domestic cats, morbidity of frs is considerable, although mortality is low (greene 1998) . moderate or high seroprevalences suggest that this may be the case for wildcats, although some neonatal mortality may occur too. the present study failed to demonstrate wildcat contact with fiv and fcov. both agents seem to be infrequent in other european wildcat populations (mcorist et al. 1991; daniels et al. 1999; leutenegger et al. 1999; fromont et al. 2000) . fiv might not be present in the studied population, although fiv antibodies are more likely to be found in adult, male cats (sellon 1998) , and only five individuals belonging to this cohort were included in the present survey. the prevalence of fiv in domestic cat populations in spain is around 8% (solano-gallego et al. 2006; arjona et al. 2000) . thus, the occurrence of unrecorded fatal cases of feline immunodeficiency in european wildcats from spain cannot be discarded. the observed low seroprevalence to fcov may be due to a probable absence of the agent in the domestic cats of the study area. according to addie and jarret (1998) , fcov is more common in domestic cats in catteries than in pet cats kept singly or in feral or stray cats. the domestic cats inhabiting our study area can be better described as feral cats than household cats. we found a relatively high seroprevalence to fhv in winter. assuming that interbreeding may not be uncommon, we believe that transmission of fhv (and perhaps of other agents) may be enhanced during the annual population peak of wildcats and domestic cats in summer-autumn, which may explain a higher seroprevalence in the following winter. no season-related differences in prevalence of any of the studied agents was recorded in previous studies regarding wildcat (mcorist et al. 1991; daniels et al. 1999; leutenegger et al. 1999; fromont et al. 2000; ostrowski et al. 2003) or other wild felines (e.g., paul-murphy et al. 1994) . in red foxes from australia, robinson et al. (2005) observed that the seroprevalence to canine adenovirus presented the highest seroprevalence in winter-spring, suggesting that foxes became infected in the mating season more probably than prior to dispersal, which is in agreement with our hypothesis for fhv. related with this, the observed higher seroprevalence of fhv and chlamydophila sp. in wildcat males may be also related with higher rates of intra-and inter-species encounters because males tend to move more during the mating season (liberg, 1988) . we also observed a similar pattern of exposure to agents in wildcats sampled in spring and summer, whereas animals sampled in winter presented a different pattern. these results indicate that there are clear seasonal-related variations in the exposure to the agents. we hypothesize that, during winter, some mortality of wildcats may be related with the exposure to one or more of the studied agents. this fact could be linked with the higher seroprevalence to fhv and chlamydophila sp. in winter samples: selective mortality associated to these pathogens would explain why these agents showed lower seroprevalence in the following spring-summer. although both pathogens course with low mortality in adult domestic cats (gaskell and dawson 1998) , nothing is known about the clinical course of these infections in free-living wildcats. in some cases, a chronification of the disease in cats occurs, with clinical signs ranging from sneezing and nasal discharge to corneal edema and blindness (gaskell and dawson 1998) . the latter may be critical for survival in the wild, and some mortality related to these agents cannot be discarded. interestingly, the identity of agents to which females presented antibodies, as well as the identity of agents to which females were not exposed, were more consistent than the composition of infectious agents in males. in addition, the similarity in the results of tests for multiple agents in pairs of the same sex was significantly higher than in wildcat pairs of different sex. as far as we know, no similar findings have been previously reported for any wild species. this result, far from giving simple differences in seroprevalence among sexes, presents evidence of a different pattern of exposure among females and males to the studied agents. we suggest that, whereas the behavior of the females exposes them to a particular set of agents and prevents exposure to others, the behavior of males (with a higher movement pattern, especially among juveniles during dispersal and adults during mating) makes more unpredictable the type of disease agents they face. our study confirmed that wildcats in central spain were in contact with five of the studied common feline pathogens, some of which exhibited high seroprevalences. it has not been determined to what extent these agents pose a risk for wildcat populations, although a negative relationship between seroprevalence and condition was found for fpv. therefore, our results indirectly support the hypothesis that diseases may contribute to reduce individual fitness. in addition, during the period when wildcats were captured, the extremely endangered iberian lynx was still present in toledo mountains (rodríguez et al. 1996) and thus potentially exposed to the studied pathogens. since the causes of the marked regression of lynx populations in the last 30 years are multiple and have not been completely elucidated (rodríguez and delibes 2002) and very little is known about natural causes of mortality (ferreras et al. 1992; rodríguez and delibes 2004) , we believe that diseases might be considered as a potential contributing factor of decline in the toledo mountains lynx population during the 1980s. feline coronavirus infections. in: greene ce (ed) infectious diseases of dog and cat seroepidemiological survey of infection by feline leukemia virus and immunodeficiency virus in madrid and correlation with some clinical aspects viral diseases as a threat to free-living wild cats (felis silvestris) in continental europe infectious diseases of wild animals transient felv viraemia in a clouded leopard feline viruses in wildcats from scotland action plan for the conservation of the iberian lynx in europe (lynx pardinus). nature and environment series 111 rates and causes of mortality in a fragmented population of iberian lynx felis pardina temminck, 1824 effects of dietary protein and fat source on plasma cholesterol parameters, lcat activity and amino acid levels and on tissue lipid content of growing pigs prevalence and pathogenicity of retroviruses in wildcats in france felis silvestris schreber, 1775 feline respiratory disease. in: greene ce (ed) infectious diseases of dog and cat feline panleukopenia. in: greene ce (ed) infectious diseases of dog and cat felis silvestris feline leukemia virus infection and renal spirochetosis in free-ranging cougar (felis concolor) ecological methodology viral infections in free-living populations of the european wildcat spatial organisation and reproductive tactics in the domestic cat and other felids importance of scrub-pastureland mosaics for wild-living cats occurrence in a mediterranean area: implications for the conservation of the wildcat (felis silvestris) some viral and protozool diseases in the european wildcat (felis silvestris) a serologic survey of wild felids from central west saudi arabia serologic survey and serum biochemical reference ranges of the free-ranging mountain lion (felis concolor) in california viral infections in wild-living european wildcats in slovenia exposure to feline and canine pathogens in bobcats and gray foxes in urban and rural zones of a national park in california prevalence of serum antibodies to canine adenovirus and canine herpesvirus in the european red fox gastrointestinal parasites of the iberian lynx and other wild carnivores from central spain patterns and causes of non-natural mortality in the iberian lynx during a 40 year period of range contraction use of non-wildlife passages across a high speed railway by terrestrial vertebrates seroprevalence of infectious disease agents in free-ranging florida panthers (felis concolor coryi) exposure to disease agents in the endangered iberian lynx (lynx pardinus) the impact of infection and disease on animal populations: implications for conservation biology feline immunodeficiency virus infection. in: greene ce (ed) infectious diseases of dog and cat feline leukemia virus in a captive bobcat evidence for the role of infectious disease in species extinction and endangerment serological and molecular evidence of exposure to arthropod-borne organisms in cats from northeastern spain dietary protein and lipid metabolism: a multi functional effect contribución al conocimiento de la cestodofauna de felis silvestris schreber, 1776 (carnivora: felidae) en la península ibérica effects of feline panleucopaenia on the population characteristics of feral cats on marion island ecology of the bobcat in florida acknowledgments j. nicolás guzmán and giulia crema assisted with wildcat trapping and sample collection. we thank amparo gomis at inac (ciudad real, spain) for performing biochemical analyses, j. manuel pérez de la lastra at irec (ciudad real, spain) for laboratory assistance during sera analyses, and jacques delbecque (ingenasa) and silvia simón (eurovet veterinaria s.l.) for information and advice about immunoassay performance. field work was supported by the spanish ministry of transportation, and lab work as well as manuscript preparation was funded by grants from junta de andalucía to a. rodríguez. the trapping and sampling protocol followed the spanish laws of animal welfare in scientific research (real decreto 1201 /2005 . key: cord-308005-t0bf5nos authors: iglesias-sánchez, patricia p.; vaccaro witt, gustavo fabián; cabrera, francisco e.; jambrino-maldonado, carmen title: the contagion of sentiments during the covid-19 pandemic crisis: the case of isolation in spain date: 2020-08-14 journal: int j environ res public health doi: 10.3390/ijerph17165918 sha: doc_id: 308005 cord_uid: t0bf5nos this study examines how confinement measures established during the covid-19 pandemic crisis affected the emotions of the population. for this purpose, public sentiment on social media and digital ecosystems in spain is analyzed. we identified affective tones towards media and citizens published on social media focusing on six basic emotions: anger, fear, joy, sadness, disgust and uncertainty. the main contribution of this work is the evidence of contagious sentiments and, consequently, the possibility of using this new dimension of social media as a form of a “collective therapy”. this paper contributes to understanding the impact of confinement measures in a pandemic from the point of view of emotional health. this analysis provides a set of practical implications that can guide conceptual and empirical work in health crisis management with an alternative approach, especially useful for decision-making processes facing emergency responses and health crises, even in an unprecedented global health crisis such as the traumatic events caused by the covid-19 disease. undoubtedly, the world is dealing with a health crisis unparalleled in this era that underscores a negative side of globalization. the world health organization (who) declared the covid-19 global pandemic in march 2020. although this kind of respiratory disease had already caused both widespread death and cases of infections in wuhan (china) since 2019, the health crisis did not show its true dimensions in europe up until february and march 2020. from then on, the race to combat the virus escalated worldwide. spain was one of the countries most affected by covid-19, establishing a nationwide state of alarm on march 14, 2020. consequently, the social distancing, self-isolation and quarantine measures in spain were radical and without precedent; such as the strict stay-at-home instruction for most of the citizens lasting almost two months, and ending with a progressive de-confinement process starting in the first week of may 2020. during this confinement period, spanish residents relied on digital ecosystems for disseminating and sharing information from official sources such as the government and health officials; and from the media and other peers. rodin et al. compiled a list of information producers in the case of a public health crisis that includes international and national public health organizations, national governments, non-governmental organizations, activist groups, news media and citizens [1] . furthermore, the communication is public and can be viewed without the need for subscription to the data source or explicit permission from the sender of the communication. the communication does not come from an advertising campaign. the communication has not been generated by automatic procedural methods (bots, fake posts, among others). the data was collected in the period from march 9 to may 1, 2020; thus, covering the beginning, peak and early de-confinement stages of the covid-19 related measures in spain. the collected communications were anonymized, eliminating authorship data, location, source, images, hyperlinks and non-textual components, to leave only the text corpus. the corpus of communications was analyzed using the natural language analysis tools (anl) provided by the ibm watson analytics service [17] . then, the corpus was analyzed again for confirmation purposes using the interval majority aggregation operator (isma-owa) [18] , which is designed for decision making in social media with consistent data, leveraged by the combination of computational intelligence and big data techniques [19] . the objective of the natural language analysis was to represent the subjective emotional response of the population as an objective and quantitative time series. the emotional response time series obtained in this way were: anger, disgust, joy, fear, sadness and uncertainty. the study period ranged from march 9 to may 1, 2020; and was divided into three distinctive stages. stage 1 ranged from march 9 to march 28. this stage covered the events starting with the announcement of the suspension of school activities in the basque and madrid autonomous communities of spain, flight cancellations from italy, nationwide suspension of university activities, the decree of the national state of alarm and the progressive temporary closure of non-essential businesses. stage 2 ranged from march 29 to april 9. this stage covered the events during the peak of the social distancing, self-isolation and quarantine measures in spain. most of the population, as well as non-essential workers remained at home. finally, stage 3 ranged from april 10 to may 1. this stage covered the events after the social distancing peak, including the extension of the state of alarm, the slow but progressive lessening of confinement measurements, some of the non-essential workers returned to their jobs, children were permitted to play outside, as well as asymmetric de-confinement measures, depending on the needs of the spanish autonomous communities. we expected to see significant differences in the emotional response of the population between the confinement stages. to test this, we performed a non-parametric kruskal-wallis h test, considering the stages as the independent variable and the emotional responses as the dependent variables. the normality of the measurement distribution for all the emotional response variables per stage was verified using kolmogorov-smirnov and shapiro-wilk tests. to further improve the qualitative analysis of the quantitative data, we performed a hierarchical linear smooth kernel regression on the emotional response time series, using the epanechnikov quadratic kernel [20] . this approach helps to reduce the noise inherent to data collected from digital ecosystems and provides a graphical representation of the emotion's tendency. the first hierarchy level corresponded to the complete study period, while the second hierarchy level corresponded to the stages separately. finally, we calculated the frequency of the words comprising the complete corpus dataset and determined the emotion polarity (positive or negative) related to them. all the above-mentioned statistical analyses were executed in ibm spss 27 (ibm: armonk, ny, usa). furthermore, the computational algorithms and natural language analyses were implemented in python 3 (python software foundation: wilmington, de, usa), using the natural language toolkit (nltk) [21] . the text corpus contained a total of 80,091 communications that were obtained from twitter (82.1%), youtube (12.3%), instagram (4.2%), official press websites (0.4%) and internet forums (1.0%). a chart of the normalized distribution of communications per day is shown in figure 1 , where 100 represents the maximum amount of communications obtained in a single day. this figure shows an increasing trend in the number of communications during stage 1, followed by a progressive decline in the proportion of communications during stages 2 and 3. the text corpus contained a total of 80,091 communications that were obtained from twitter (82.1%), youtube (12.3%), instagram (4.2%), official press websites (0.4%) and internet forums (1.0%). a chart of the normalized distribution of communications per day is shown in figure 1 , where 100 represents the maximum amount of communications obtained in a single day. this figure shows an increasing trend in the number of communications during stage 1, followed by a progressive decline in the proportion of communications during stages 2 and 3. from a generalized point of view, the kruskal-wallis h test showed that there was a statistically significant difference in emotional response score related to anger (χ2(2) = 17.806, p = 0.000), fear (χ2(2) = 6.462, p = 0.040), sadness (χ2(2) = 6.878, p = 0.032) and uncertainty (χ2(2) = 7.786, p = 0.020). on the other hand, there were no significant differences in the emotional responses related to disgust (χ2(2) = 1.368, p = 0.505) and joy (χ2(2) = 3.229, p = 0.199). due to the inherent differences between social media platforms, we conducted the same analysis on the communications from twitter, youtube, instagram, official press websites and internet forums separately. these results obtained from twitter are analogous to the generalized approach, where the kruskal-wallis h test showed that there was a statistically significant difference in emotional response score related to anger, fear, sadness and uncertainty (p < 0.05); while there were no significant differences in the emotional responses related to disgust and joy (p > 0.05). this phenomenon can be traced back to the fact that twitter provided most of the open-access communications available for this study. in a similar way, the communications obtained from youtube showed that there was a statistically significant difference in emotional response score related to anger, fear and sadness (p < 0.05), but no significant differences in the emotional responses related to uncertainty, disgust and joy (p > 0.05). the communications obtained from the instagram social media platform and online forums only showed statistically significant differences in the emotional response related to anger (p < 0.05), but no significant differences in the emotional responses related to fear, sadness, uncertainty, disgust or joy (p > 0.05). on the other hand, the communications obtained from official press websites did not show significant differences in any the emotional response scores measured (p > 0.05 in all cases). due to the small number of communications provided by these sources, it is difficult to establish the causes for this behavior in the emotional response. however, it is important to note that, the nature of from a generalized point of view, the kruskal-wallis h test showed that there was a statistically significant difference in emotional response score related to anger (χ2(2) = 17.806, p = 0.000), fear (χ2(2) = 6.462, p = 0.040), sadness (χ2(2) = 6.878, p = 0.032) and uncertainty (χ2(2) = 7.786, p = 0.020). on the other hand, there were no significant differences in the emotional responses related to disgust (χ2(2) = 1.368, p = 0.505) and joy (χ2(2) = 3.229, p = 0.199). due to the inherent differences between social media platforms, we conducted the same analysis on the communications from twitter, youtube, instagram, official press websites and internet forums separately. these results obtained from twitter are analogous to the generalized approach, where the kruskal-wallis h test showed that there was a statistically significant difference in emotional response score related to anger, fear, sadness and uncertainty (p < 0.05); while there were no significant differences in the emotional responses related to disgust and joy (p > 0.05). this phenomenon can be traced back to the fact that twitter provided most of the open-access communications available for this study. in a similar way, the communications obtained from youtube showed that there was a statistically significant difference in emotional response score related to anger, fear and sadness (p < 0.05), but no significant differences in the emotional responses related to uncertainty, disgust and joy (p > 0.05). the communications obtained from the instagram social media platform and online forums only showed statistically significant differences in the emotional response related to anger (p < 0.05), but no significant differences in the emotional responses related to fear, sadness, uncertainty, disgust or joy (p > 0.05). on the other hand, the communications obtained from official press websites did not show significant differences in any the emotional response scores measured (p > 0.05 in all cases). due to the small number of communications provided by these sources, it is difficult to establish the causes for this behavior in the emotional response. however, it is important to note that, the nature of official press tends to exhibit a more neutral emotion; therefore, the communications around these topics focus around discussion of facts and less intense emotional opinions. the linear smooth kernel regression of the emotional response time series using the epanechnikov quadratic kernel is shown in figure 2 . the horizontal axis represents the number of days that passed from the start of the study (9 march 2020) and the vertical axis represents the strength of the emotion, normalized from 0 to 1; where 0 is the lowest emotional intensity and 1 is the highest emotional intensity. moreover, the continuous black line represents the first hierarchical level, and the dashed dotted lines represent the second hierarchical level. official press tends to exhibit a more neutral emotion; therefore, the communications around these topics focus around discussion of facts and less intense emotional opinions. the linear smooth kernel regression of the emotional response time series using the epanechnikov quadratic kernel is shown in figure 2 . the horizontal axis represents the number of days that passed from the start of the study (9 march 2020) and the vertical axis represents the strength of the emotion, normalized from 0 to 1; where 0 is the lowest emotional intensity and 1 is the highest emotional intensity. moreover, the continuous black line represents the first hierarchical level, and the dashed dotted lines represent the second hierarchical level. the ratio of communications in isolation increased coinciding with the declaration of the state of alarm in spain, this increment is slightly faster than that of general communications about the covid-19 disease. the frequency of the words and the emotion polarity associated with them is displayed in figure 3 . the frequency ratio between words is expressed as the relative word size. on the other hand, the color represents the polarity in a scale ranging from bright green (absolute positive) to the ratio of communications in isolation increased coinciding with the declaration of the state of alarm in spain, this increment is slightly faster than that of general communications about the covid-19 disease. the frequency of the words and the emotion polarity associated with them is displayed in figure 3 . the frequency ratio between words is expressed as the relative word size. on the other hand, the color represents the polarity in a scale ranging from bright green (absolute positive) to bright red (absolute negative); and where black represents a neutral emotion. the words in the spanish language that expressed the highest frequency, in other words, the highest presence, are "casa" (house), "coronavirus", "cuarentena" (quarantine), "gente" (people), "personas" (people), "salir" (go out) and "termine" (end). moreover, most of the words shown in figure 3 are displayed in red, thus, representing a mostly negative emotion polarity, with a mean polarity of −0.3557 and a standard deviation of 0.2438. the exceptions to this negative trend are the words "mundo" (world), "medidas" (measures), "comer" (to eat) and "mantener" (to maintain); which showed a neutral-positive trend. int. j. environ. res. public health 2020, 17, x 6 of 10 bright red (absolute negative); and where black represents a neutral emotion. the words in the spanish language that expressed the highest frequency, in other words, the highest presence, are "casa" (house), "coronavirus", "cuarentena" (quarantine), "gente" (people), "personas" (people), "salir" (go out) and "termine" (end). moreover, most of the words shown in figure 3 are displayed in red, thus, representing a mostly negative emotion polarity, with a mean polarity of -0.3557 and a standard deviation of 0.2438. the exceptions to this negative trend are the words "mundo" (world), "medidas" (measures), "comer" (to eat) and "mantener" (to maintain); which showed a neutral-positive trend. the amount of user-generated content and social-media communications related to the social distancing, self-isolation and quarantine measures in spain increased rapidly and steadily during stage 1 of the study period. this coincided with the declaration of the sanitary state of alarm and the first of isolation measurements. a slight first peak in the raw amount of communications during this stage occurred between march 9 and 12, triggered by the suspension of academic activities in madrid and the announcement of the isolation measurements, respectively. moreover, the days near the end of the stage 1, around march 22, reported the highest amount of communications; matching the discussion about the first extension of the state of alarm. the communications gathered from stage 2 were focused around two main discussion areas. firstly, people were talking about the causes and effects of isolation; and secondly, the social media flourished with interesting proposals to cope with the isolation and stress of not being allowed to leave home. on the other hand, there was an increase in the amount of communications criticizing the government-imposed isolation measurements. stage 3 was the longest of the three stages, and marked the progressive lessening of the confinement measurements. the communications posted in online ecosystems during stage 3 showed an increased interest in the economic effects of the confinement in spain. then again, social media conversations gradually declined along with the reduction of the confinement measures ( figure 1) . results suggest that the isolation measures in spain significantly affected the emotions of the population. this effect is more noticeable through the anger emotional response. the smooth kernel regression of the anger timeline ( figure 2 ) shows its highest peak around the beginning of stage 2, the amount of user-generated content and social-media communications related to the social distancing, self-isolation and quarantine measures in spain increased rapidly and steadily during stage 1 of the study period. this coincided with the declaration of the sanitary state of alarm and the first of isolation measurements. a slight first peak in the raw amount of communications during this stage occurred between march 9 and 12, triggered by the suspension of academic activities in madrid and the announcement of the isolation measurements, respectively. moreover, the days near the end of the stage 1, around march 22, reported the highest amount of communications; matching the discussion about the first extension of the state of alarm. the communications gathered from stage 2 were focused around two main discussion areas. firstly, people were talking about the causes and effects of isolation; and secondly, the social media flourished with interesting proposals to cope with the isolation and stress of not being allowed to leave home. on the other hand, there was an increase in the amount of communications criticizing the government-imposed isolation measurements. stage 3 was the longest of the three stages, and marked the progressive lessening of the confinement measurements. the communications posted in online ecosystems during stage 3 showed an increased interest in the economic effects of the confinement in spain. then again, social media conversations gradually declined along with the reduction of the confinement measures ( figure 1) . results suggest that the isolation measures in spain significantly affected the emotions of the population. this effect is more noticeable through the anger emotional response. the smooth kernel regression of the anger timeline ( figure 2 ) shows its highest peak around the beginning of stage 2, roughly around march 29. it is important to notice that results also suggest that the isolation measures did not affect the joy or the disgust emotional responses of the population. the smooth kernel regression of the joy timeline ( figure 2) shows a steady increase during stage 1 and a horizontal stabilization during stages 2 and 3. the results show that all the studied emotional responses have an important presence during the analyzed isolation period; apart from disgust, that registered a minimal presence. the highlights of the emotional responses are detailed in table 1 , alongside the date that is most closely related to each event. some of the countries most affected by covid-19 experienced a decrease in infection rates, e.g., germany, and others; that started to implement some measures in order to lessen the impact of isolation in the economy. a new procedure to count the covid-19 cases was implemented and suggested a possible decline in the number of real cases reported. children under 14 years of age were allowed to play outside for one hour per day. the spanish government declared a national state of alarm and launched an advertising campaign on social media using the hashtag #estevirusloparamosunidos (that means "we will stop this virus together") massive applause to recognize the contribution and courage of medical staff. international media harshly criticized the spanish government for their management of the health crisis. 10/04 the daily death toll is estimated to be around 700 deceased. slight increase of daily death toll. the social media coverage of isolation was extensive, and a broad array of topics were addressed, as shown in figure 3 . however, there are four main topic groups: firstly, those that are specifically focused on the covid-19 illness, mainly regarding deaths, treatments and infection rates. secondly, those concerning lockdown, including self-isolation, confinement, home, family and going out. thirdly, there are topics that show society's concerns due to the uncertainty of the situation and its consequences, such as money, work, hunger, help and world. lastly, there were other topics that could not be classified within the first three groups, such as gratitude, donations, personal protection equipment and solidarity. moreover, it should be noted that, when considering daily usage of twitter hashtags during the pandemic, some of the most widely used during the study period were #yomequedoencasa (i am staying at home) and #quedatencasa (stay at home) with the intention of urging people to stay at home. the effect of these kinds of conversations in social media can also be appreciated in figure 3 , as the frequency of words such as "cuarentena" (quarantine) and "casa" (home) are very high. furthermore, this also explains the prevalence of words such as "salir" (go out) "termine" (finish), since people were also discussing their desire for this situation to end. it should be noted that the emotional response timelines displayed in figure 2 suggest a pattern of polarization on the topic of isolation. many communications expressed personal experiences, sentiments and proposals to stay at home, even initiatives to support medical staff and other front-line professionals; especially during the first half of the study period, in other words, near the end of stage 2. on the other hand, during stage 3 the focus of the citizens shifted towards the effects of the confinement measures, and the possible negative consequences of the new normality. regarding the coexistence of feelings, it should be noted that there are some events that clearly show the synergies of feelings. for example, march 27 marks the beginning of widespread temporary employment regulations in spain, designed to mitigate the economic consequences of the covid-19 pandemic. the peaks of joy and sadness reflect the mixed feelings on this issue (figure 2 ). another example of synergism between joy and fear happened on april 26. on this date the government allowed children under 14 years old to play outside. this was an expected measure, but a large portion of the population was worried about a possible new peak in infections. moreover, during the first days of stage 1, both anger and fear displayed a slight peak in the second hierarchical level of analysis, in other words, the dotted lines in figure 2 . the death toll seems to be the main cause of this peak; nevertheless, this behavior shifted towards the end of stage 3, where people expressed their concerns about the new normality. the analysis of the emotional content in the context of isolation due to covid-19 provides valuable insights into how sentiments are affected by confinement measures and how they are expressed and spread on social media. previous literature has addressed this issue by focusing on economic and financial crisis impacts [6] and how media content studies have been applied in health crisis management, which have been observed more from the communication point of view and more specifically through a public relations lens [1, 4] . although some authors have already pointed out that feelings expressed in online conversations can be contagious both in a positive [9, 15] and a negative way [11] [12] [13] , this work covers the gap by analyzing the public's sentiments in digital ecosystems as a health issue. the emotional reactions detected were in line with the general sentiment captured by the analysis of thelwall et al. [8] and neubaum and krämer [10] . the commentaries featured in online conversations highlight the societal impact and health implications of the pandemic as well as their implications in the global health crisis. additionally, it coincides with thelwall et al. [8] that sentiment detection in social media is challenging and can provide an interesting insight into facing the crisis, especially for those institutions with competences in this field. in any event, there are a few literature works focused on monitoring sentiments in social media [9, [11] [12] [13] 15] but not many through a health lens [5, 7] while taking into account the usefulness of analysis in health crisis management by considering all the responsible actors. this research is limited to the analysis of communications freely available in digital ecosystems; therefore, we consider that further studies using public opinion surveys, which could deepen the understanding of the emotional responses of the population, are needed. furthermore, this research focused solely on the hardest stages of covid-19 isolation in spain; thus, we recommend this study be replicated for other countries. the social distancing, self-isolation and lockdown measures in spain significantly affected the emotions of the population. furthermore, the driver of these emotions evolved and shifted during the stages of the confinement. the results of this study provide a snapshot of the emotional response of the spanish population during the covid-19 isolation. likewise, a repository of emotional content of an unprecedented outbreak is provided. furthermore, it reveals that social media can be a form of "social therapy" and a suitable approach for health crisis communication. this research responds to the lack of research at the intersection of emotional responses during crisis situations and, particularly to those related to public health and social media. moreover, the findings of this study provide valuable insights based on the repository of emotional content of a traumatic event such as the covid-19. the findings of this research are useful for encouraging health institutions to improve the management of social media and digital ecosystems during a health crisis; and to polish 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the terms and conditions of the creative commons attribution (cc by) license the authors declare no conflict of interest. key: cord-283979-1dn7at6k authors: portillo, aránzazu; ruiz-arrondo, ignacio; oteo, josé a. title: arthropods as vectors of transmissible diseases in spain() date: 2018-12-14 journal: med clin (engl ed) doi: 10.1016/j.medcle.2018.10.008 sha: doc_id: 283979 cord_uid: 1dn7at6k different aspects related to globalization together with the great capacity of the arthropod vectors to adapt to a changing world favour the emergence and reemergence of numerous infectious diseases transmitted by them. diptera (mosquitoes and sandflies), ticks, fleas and lice, among others, cause a wide spectrum of diseases with relevance in public health. herein, arthropod-borne disease are reviewed, with special emphasis on the existing risk to contract them in spain according to different parameters, such as the presence of arthropod and the circulation or the possible circulation of the causative agents. infectious agents. most avs belong to insecta and arachnida classes (table 1) . to review the broad subject of arthropod vector-borne diseases (avbd) in spain is a complex task. just listing the arthropods that transmit diseases in our environment, such as dipterans (culicids and phlebotominae sand flies), fleas, lice, bed bugs and ticks, among others, and the diseases they transmit, or that they can transmit at any given time, would be a reason for one or several treatises. in any case, before discussing the subject, it should be remembered that the infections that they transmit are usually included in the socalled zoonoses. in this regard, the world organization for animal health estimates that at least 60% of infections that affect humans have a zoonotic origin 2 and, according to the pandemic emerging threats program of the american agency for international development, almost 75% of current threats also have this origin. 3 one of the many known routes for the acquisition of zoonoses, apart from direct contact with animals or their products, faecal-oral or respiratory routes, bites or scratches, the consumption of undercooked 2387-0206/© 2018 elsevier españa, s.l.u. all rights reserved. products or the intake of milk, is av transmission. 4 it is difficult to limit this issue to our country, since the setting is global and very dynamic, and diseases do not understand political borders. only a few months ago new threats appeared, such as the re-emergence of yellow fever in brazil or the epidemic of plague in madagascar. 5 however, in this review we will put the focus on avbd with greater risk to humans in our environment, without losing the "one health" perspective. avbd are subject to complex interactions (demographic, social and cultural changes, climate change, wars and famine or evolution of microorganisms) among which, undoubtedly, global transport systems and the consequent invasion of exotic species 6 stand out. generally speaking, travel, migration and globalization contribute to the emergence of infectious diseases. its importance has been debated for many years and, possibly, dates back to ancient times. 7 humans carry their usual microbiota, pathogens, ectoparasites and other possible vectors, the immunological history of past infections and vaccines, the genetic load (greater or lesser susceptibility), cultural preferences, behaviours, habits and customs, as well as luggage (pets, goods and others). 7 in the case of avbd, the equation for the appearance of a certain disease would be the following: the presence of competent vector arthropods plus susceptible population, together with the presence of reservoirs and/or intermediate hosts (sick people), could give result an epidemic. the introduction of the tiger mosquito (aedes albopictus) and the threat of its expansion could be a good example. it is thought that a. albopictus was introduced in europe in 1979 through albania, by the trade of used tyres, although the first publication on its introduction in the european continent dates back to 1990 in italy. 8 since then, a. albopictus has expanded throughout the mediterranean area. in spain, this aggressive mosquito is well established in catalonia, levante, in the coastal area of murcia and andalusia. it has also been detected in guipúzcoa, 9 and little by little it is introduced in other non-coastal areas such as aragon, extending through travel routes (for example, motorways). 10 the last detection was carried out in the community of madrid 11 (fig. 1) . a few months ago, the first specimens of this species were also identified in the north of portugal. this mosquito has been incriminated as a vector of numerous arboviruses in different parts of the world, including europe. a. albopictus, is the chikungunya virus vector. in this regard, most of the cases in europe are imported, although in the last two decades there have been different epidemic outbreaks in italy 12 and, recently, in france. 13 in spain, only imported cases have been reported. 14 this mosquito (next to aedes aegypti which, as will be detailed later, has been detected in a timely manner in europe) can act as a vector of the dengue virus and with less effectiveness of the zika virus. 15 in france, a. albopictus was responsible for the first autochthonous cases of dengue 16 and of those reported in the same country during the following years, one of them with a history of travel to madeira, where a large outbreak had been reported (more than a thousand cases) between 2012 and 2013. 17 in 2011, the occurrence of autochthonous cases of dengue in croatia were also attributed to a. albopictus, establishing the transmission by this mosquito in europe. 18 in spain we are only suffering from their annoying bites, for now. 19 table 2 shows arbovirus infection and table 3 shows other infections transmitted by dipterans worldwide, with the risk of transmission in spain. we have evaluated the risk of emergence and/or re-emergence of these diseases in spain according to the existing studies for each pathogen, the experience according to other diseases, previous immunity and other criteria, some of them subjective, that do not appear in the text. a. aegypti is the main zika vector and also a transmitter of yellow fever, dengue and chikungunya. in principle, this species is not a problem because it is not settled in europe, although it has been detected in some areas, such as in an airport in the netherlands and, more recently, in fuerteventura 20 (canary islands) (fig. 1) . in view of the zika epidemic in the americas, the ministry of health, social services and equality, in collaboration with the carlos iii health institute and the autonomous regions, has established a zika virus disease surveillance in spain. to date (last update in july 2017), 325 confirmed cases have been reported, all imported, except 4 congenital cases whose mothers were infected in the risk zone and 2 autochthonous cases of sexual transmission. 21 it should be noted that it is not necessary to resort to invasive or exotic species to refer to avbd. thus, anopheles atroparvus is present in spain, a good malaria vector. the official map of the distribution of this mosquito is not updated; however, although the risk of a malarial outbreak is low in our country, 22 recent events have involved this species in the two cases of autochthonous malaria registered in the north of the peninsula. 23 spain was an endemic country of malaria until 1964, when who declared it a the risk of emergence/re-emergence is calculated based on three factors: (a) presence of cases of the disease in humans in the last 5 years in europe, mediterranean, central and south american countries with a significant relationship with spain; (b) presence of the vector in spain; (c) pathogenicity of the virus for humans. each factor is scored with one point (presence in the first two factors and low pathogenicity in the third factor) or with zero points (absence in the first two factors and high pathogenicity in the third factor). the first two factors are added and the third is subtracted. the total score can range between 0 and 2, with 0 being: low risk; 1: moderate risk; 2: high risk. free zone. in europe, after the eradication of malaria, most cases are imported, although sporadic cases have recently been reported in many mediterranean countries such as france, italy, greece. 24 the emergence of autochthonous cases in greece between 2009 and 2017 has raised doubts about the real situation in europe as a malaria-free zone. 25 other diptera present in spain which we cannot ignore are phlebotominae sand flies. the species phlebotomus perniciosus and phlebotomus ariasi, are the competent vectors of the leishmaniasis agent (leishmania infantum). there are also other potential vectors of l. infantum in spain, as they are phlebotomus papatasi and phlebotomus sergenti. leishmaniasis is endemic throughout the mediterranean basin in europe and its geographic scope is spreading. usually, the epidemiology of leishmaniasis was linked to the rural habitat with the presence of dogs. the great epidemic outbreak of fuenlabrada with a high number of cases in an urban area, in which leishmaniasis was not common, showed the dangers of changing the urban model in spain. many houses were built in rural agricultural areas with gardens and peri-urban green spaces where wildlife was present. in these places the concentration of phlebotominae sand flies was high, and, in their environment, there were not only dogs but also other l. infantum reservoirs, such as hares and rabbits. this fact together with mild temperatures in recent years, decreasing the mortality of the vector, seems to be what caused the great outbreak. [26] [27] [28] undoubtedly, the presence of phlebotominae sand flies throughout the iberian peninsula is a great threat, since not only do they transmit leishmania, but they are also toscana virus vectors, which is causing numerous cases of meningoencephalitis in some areas of spain 29 and other phleboviruses such as the granada virus (without proven pathogenic power), the naples virus or the sicily virus. 30 another species of mosquito to which special attention is to be paid is culex pipiens. this species, which is distributed and well represented throughout the iberian peninsula, is capable of transmitting the west nile virus (wnv). west nile fever is becoming a serious problem in some areas of europe, as in greece, where there has been an outbreak with numerous neuroinvasive forms, 31 and in 2017 cases have been reported in france, italy, romania, hungary, croatia, serbia and austria. 32 in spain, according to the data from the situation report and wnv risk assessment, published in 2013, there are several species of mosquitoes capable of virus transmission. for example, culex modestus, culex perexiguus and culex theileri show a high vector competence, while c. pipiens and a. albopictus have a moderate vector competence. 33 the first human case of neuroinvasive disease due to wnv in our country was identified, retrospectively, in a patient diagnosed with meningitis in september 2004 who, in the days before the onset of symptoms, visited a village in badajoz, extremadura (spain). 34 in 2010, the ministry of the environment reported the detection of wnv in 36 equine farms in the provinces of cádiz, sevilla and málaga. 35 through this active surveillance, 15 suspected cases were investigated and two human cases of wnv meningoencephalitis were confirmed. 35 between 2011 and 2016, virus activity was detected in equines, suggesting that the virus is endemic in our country. 36 in addition, there was previous evidence about its circulation in birds that were considered for the development of a predictive virus circulation model in our country. 37 another factor that clearly influences infections transmitted by arthropod vectors is climate change. in 2017 the international conference on climate change and health was held in atlanta, which revolved around the idea that: "health is the human face of climate change". following this meeting, a special article was published in the new england journal of medicine which stated that the distribution of infectious diseases such as lyme borreliosis, rickettsiosis or west nile fever are expanding at the same rate as their avs. 38 we know that climate variations and extreme weather events have a profound impact on avbd. 39 mosquitoes and ticks are devoid of temperature regulation mechanisms and, for this reason, fluctuations in temperature greatly affect their reproduction and survival. 40 in our country, it is more than possible that the great increase in the number of ticks in recent years is due to the fact that winters, in general, are much milder than years ago. just to mention an example, ixodes ricinus, the tick that most frequently bites people in the north of spain, is very sensitive to climate warming. this, among other factors, is increasing its survival. 41 this species of tick transmits very prevalent diseases in europe, such as lyme disease or tickborne encephalitis, or others such as rickettsia monacensis infection, human anaplasmosis, and babesiosis. 42, 43 in spain, human cases of all of them have been described, except for tick-borne encephalitis. although there is a high suspicion of the circulation of the virus in spain, the molecular screening of hundreds of ticks has been carried out in our laboratory, with negative results. 43 in addition, other pathogens have been detected in i. ricinus specimens collected in spain, such as rickettsia helvetica, candidatus neoehrlichia mikurensis or borrelia miyamotoi, which leads us to be alert to the possible occurrence of human cases. [44] [45] [46] as a consequence of climate change, the hypothesis about the probable changes in the distribution of another species of tick, hyalomma marginatum, which is the crimean-congo hemorrhagic fever (cchf) vector in europe, has also been established. under warmer climate conditions, according to prediction models, it is expected that the distribution of this tick species will extend to new areas which were previously free of the vector. in relation to this issue, the epidemiology of mediterranean spotted fever seems clearly associated with climate change, especially with low rainfall values 47 and it has been shown that warming causes greater aggressiveness in its avs. table 4 shows the tick-borne diseases throughout the world, with the prediction of risk for spain (subjective assessments). to be able to show a perspective on the avbd, it is essential to monitor and identify microorganisms in vertebrates and arthropods, designing strategies before their transmission to humans. early detection and implementation of control strategies allow minimizing the impact on the population. between 1990 and 2010, 91% of emerging infections spread from a wild-type focal point. 2 occasionally, the infection is spread directly from reservoirs such as bats, rats or chimpanzees to domestic animals, which amplify the infection, or to people; other times, infection dissemination (spill-over) occurs through av such as ticks, fleas or mosquitoes. in any case, it is essential to carry out a surveillance and to know the microorganisms carried by av. a recent example in spain is the detection of cchfv in ticks of the species hyalomma lusitanicum collected in deer a few years ago 48 in the province of caceres and the explanation of one of the possible ways of the arrival of the virus to our country. 49 detection of the disease that appeared in 2016 as, to some extent, it was predictable. on september 1, 2016, the ministry of health issued a press release reporting the death of a man by cchf and the contagion of the nurse who had taken care of him in the icu of the vallecas hospital where he had been treated. the first two autochthonous cases of cchf in spain were confirmed 50 (fig. 2) . in the last cchfv situation report and transmission risk assessment in spain, 51 52 the diagnosis of tick-borne diseases is not always easy. we must bear in mind that a tick bite history is usually absent in at least half of the cases and that incubation periods can be very long. depending on the size of the tick, they can be very difficult to see (they can simulate a small mole), and their bite is painless. unless there is awareness or a high index of suspicion when faced with certain signs and/or clinical symptoms, who is going to think of a tickborne disease? it is clear, "what is not sought, is not found". 52 in 2018, who revised the list of emerging pathogens that could cause serious epidemics in the future and those that need to be investigated, including cchfv, ebola/marburg virus, zika virus, middle east respiratory syndrome coronavirus (mers-cov), severe acute respiratory syndrome coronavirus (sars-cov), lassa virus, nipah virus and rift valley fever virus. in addition, this year the list is completed with disease x, referring to an international epidemic that could be caused by a pathogen whose pathogenic potential and route of transmission is unknown at the moment. this list takes into account the transmissibility between humans, the severity of cases and the percentage of mortality, the difficulty of control and diagnosis and the context of public health and global expansion. in addition, there are other diseases that need more attention as soon as possible: hemorrhagic fevers by other arenaviruses, chikungunya virus, diseases by other highly pathogenic coronaviruses or by emerging enteroviruses and febrile syndrome with severe thrombocytopenia. 53 many of these diseases are avborne. high high debonel/tibola: dermacentor-borne necrosis, erythema and lymphadenopathy/tick-borne lymphadenopathy; lar: rickettsiosis associated with lymphangitis. a in spain, borrelia hispanica relapsing fever. the risk of emergence/re-emergence is calculated based on two factors: (a) presence of cases of the disease in humans in the last 5 years in europe, mediterranean countries and central and south american countries with a significant relationship with spain; (b) presence of the vector in spain. each factor is scored with one point (presence in the two factors) or zero points (absence in the two factors) and both are added. the total score can range between 0 and 2, with 0 being: low risk, 1: moderate risk and 2: high risk. another av that is said to have killed more people than all wars together is the body louse (human pediculus), transmitting exanthematic or epidemic typhus (rickettsia prowazekii), endemic recurrent fever (borrelia recurrentis) and the trench fever (bartonella quintana). body lice have been a serious public health problem until recently. they live in the seams of clothes and multiply in cold weather, lack of hygiene and war conditions. a person can be infested with thousands of lice, and each specimen is capable of biting an average of five times a day. it is said that body lice were one of the main problems during the russian revolution, where three million people affected by exanthematic typhus died. thus, vladimir ilyich lenin (1870-1924) stated: either socialism defeats the louse, or the louse will defeat socialism". here in spain, it was also a problem during the post-war period and was used as propaganda by franco's regime. we can ask ourselves: is there a risk of an epidemic or an epidemic outbreak of exanthematic typhus? it could happen, as it occurred in burundi in 1996, when a large epidemic affected more than one hundred thousand patients. 54 all the alarms went off when a red cross nurse was diagnosed after returning from work in the affected country. body lice are not seen on the body surface but live in the seams of clothing, in 20 ± 2 • c temperatures. parasitism by body lice should be suspected in persons with signs of scratching and lack of hygiene, more frequently in cold times of the year. at present, body lice have reappeared in refugee camps in europe, as in the second world war. in november 2015, the european center for disease prevention and control reported the emergence of 27 cases of recurrent fever due to body lice at different points along the route followed by refugees arriving in italy from the syrian war. 55 in western europe, although we have not experienced any epidemic since the post-war period, and the fact that the condition had been eradicated, occasionally, there are r. prowazekii and b. quintana infection reports in homeless people parasitized by lice 56 and cases of brill-zinsser disease have been described in people who have suffered from exanthematic typhus which could lead to an epidemic outbreak in certain conditions. 57 fleas are other bloodsucking insects of worldwide distribution with an impact in public health. rickettsia can be transmitted to humans by at least two species: the rat flea (xenopsilla cheopis), which is the endemic or murine typhus vector (caused by rickettsia typhi), and the cat flea (ctenocephalides felis), which is the key vector of rickettsia felis and, occasionally, of r. typhi. as far as we know, rickettsias are not transmitted by the human flea (pulex irritans). in europe, murine typhus is a common avbd in mediterranean countries such as greece, cyprus, croatia and spain, including the canary islands. 58 it develops as a non-specific febrile disease, with or without rash, which is often underdiagnosed. in clinical practice, murine typhus should be included in the differential diagnosis of any patient with fever of intermediate duration, that is, in a patient with fever (more than 38 • c) of more than 7 and less than 28 days of progression, without focality to guide the diagnosis, which remains without a diagnosis after an initial evaluation that includes a complete clinical history, physical examination, complete blood count, chest x-ray and biochemical blood and urine tests. 59 r. felis infection is another rickettsiosis with characteristics similar to murine typhus, of which cases have also been published in spain 60 and that should be considered in patients with fever and/or rash, with a history of contact with cats or flea bites. despite the fact that there have been no reports of autochthonous yersinia pestis infection transmitted by the rat flea (x. cheopis) in spain, there is an alert for travellers at the time of writing this manuscript due to an epidemic outbreak in madagascar that has affected several thousand people. 5 finally, we should remember the phrase written by hans zinsser in 1934 in his book entitled: rats, lice and history: "nothing in the world of living creatures remains constant. infectious diseases are constantly changing, new ones are in the process of development and the oldest ones are changing or disappearing". currently, ticks are considered the most dangerous avs in the world, because of their ease in moving from animals to people, because of their ubiquitous nature (they are present on all continents, including antarctica) and because of their capacity to agglutinate inside them a host of pathogenic microorganisms potentially transmissible through their hematophagous habits. the human tampering of ecosystems (deforestation, erosion of geographical limits to facilitate travel, etc.) or climate change are some of the factors that are favouring a greater contact between wild animals (with their ticks and the diseases they transmit) and people, facilitating the expansion of ticks to new previously unoccupied areas. diptera, ticks or other av may play the leading role in the next pandemic. therefore, anticipating the next public health crisis is in our hands. the authors declare no conflict of interest. biology of disease 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situación y evaluación del riesgo para españa de virus del nilo occidental. centro de coordinación de alertas y emergencias sanitarias (ccaes), ministerio de sanidad west nile virus in spain: report of the first diagnosed case (in spain) in a human with aseptic meningitis west nile fever outbreak in horses and humans epidemiology and spatio-temporal analysis of west nile virus in horses in spain between risk mapping of west nile virus circulation in spain preventive medicine for the planet and its peoples vector-borne diseases and climate change: a european perspective impact of regional climate change on human health driving forces for changes in geographical distribution of ixodes ricinus ticks in tick-borne rickettsioses in europe the risk of introducing tick-borne encephalitis and crimean-congo hemorrhagic fever into southwestern europe (iberian peninsula). in: virology ii -advanced issues role of birds in dispersal of etiologic agents of tick-borne zoonoses detection of tickborne 'candidatus neoehrlichia mikurensis' and anaplasma phagocytophilum in spain in 2013 borrelia miyamotoi: should this pathogen be considered for the diagnosis of tickborne infectious diseases in spain? boutonneuse fever and climate variability crimean-congo hemorrhagic fever virus in ticks, southwestern europe crimean-congo hemorrhagic fever virus in ticks from migratory birds autochthonous crimean-congo hemorrhagic fever in spain informe de situación y evaluación del riesgo de transmisión de fiebre hemorrágica de crimea-congo (fhcc) en españa. ministerio de sanidad fiebre hemorrágica de crimea-congo: «lo que no se busca no se encuentra list of blueprint priority diseases outbreak of epidemic typhus associated with trench fever in burundi rapid risk assessment: communicable disease risks associated with the movement of refugees in europe during the winter season ectoparasitism and vector-borne diseases in 930 homeless people from marseilles zinsser disease in moroccan man fever of intermediate duration: new times, new tools and change of spectrum cluster of cases of human rickettsia felis infection from southern europe (spain) diagnosed by pcr we wish to thank jorge garcía labeaga, of urbe ingeniería, for his collaboration in the preparation of fig. 1 . key: cord-308658-38f8ftmh authors: aleta, alberto; moreno, yamir title: evaluation of the potential incidence of covid-19 and effectiveness of contention measures in spain: a data-driven approach date: 2020-03-06 journal: nan doi: 10.1101/2020.03.01.20029801 sha: doc_id: 308658 cord_uid: 38f8ftmh our society is currently experiencing an unprecedented challenge, managing and containing an outbreak of a new coronavirus disease known as covid-19. while china were the outbreak started seems to have been able to contain the growth of the epidemic, different outbreaks are nowadays being detected in multiple countries. much is currently unknown about the natural history of the disease, such as a possible asymptomatic spreading or the role of age in both the susceptibility and mortality of the disease. nonetheless, authorities have to take action and implement contention measures, even if not everything is known. to facilitate this task, we have studied the effect of different containment strategies that can be put into effect. our work specifically refers to the situation in spain as of february 28th, 2020, where a few dozens of cases have been detected. we implemented an seir-metapopulation model that allows tracing explicitly the spatial spread of the disease through data-driven stochastic simulations. our results are in line with the most recent recommendations from the world health organization, namely, that the best strategy is the early detection and isolation of individuals with symptoms, followed by interventions and public recommendations aimed at reducing the transmissibility of the disease, which although not efficacious for disease eradication, would produce as a second-order effect a delay of several days in the raise of the number of infected cases the first report by the chinese authorities of the covid-19 outbreak appeared in december 31st, 2019. ever since then, the world health organization (who) and national public health authorities have been tracing and reporting on the evolution of the outbreak. as initially feared, and despite contention measures adopted in china, with a big city like wuhan being quarantined for weeks, the disease spread beyond mainland china. as of february 29th, 2020, there are 85,403 cases worldwide, of which 79,394 correspond to china [1] . additionally, 53 countries, including spain, have reported at least one case of covid-19. two months into the outbreak, much is still unknown about the natural history of the disease and the pathogen. important from the modeling perspective, for instance, it has been claimed that a large number of cases might have gone undetected by routinely screening passengers, due to the special characteristics of this disease [2] . admmitedly, several studies predict that only between 10% and 20% of the cases have been detected and reported [3] [4] [5] [6] . as with any other novel disease, governments, public health services and the scientific community have been working towards stopping the spreading of covid-19 as soon as possible and with the lowest possible impact on the population [4, [7] [8] [9] . from a scientific point of view, there are two course of actions that can be followed. on the one hand, new vaccines and pharmaceutical interventions need to be developed. this usually requires months of work. therefore, on the other hand, it is important to study the large-scale spatial spreading of the disease through mathematical and computational modeling, which allows evaluating "in-silicon" what-if-scenarios and potential contention measures to stop or delay the disease. this modeling effort is key, as it can contribute to maximize the effectiveness of any protection measures and gain time to develop new drugs or a vaccine to protect the population. here, we follow the modeling path and analyze, through a data-driven stochastic seir-metapopulation model, the temporal and spatial transmission of the covid-19 disease in spain as well as the expected impact of possible and customary contention measures. our model allows to implement and quantify the impact of several conventional measures in spain. these policies are mostly aimed at reducing the mobility of individuals, but we also include other plausible settings like a reduction in the time for case detection and isolation. our findings agree with previous results in the literature that have reported that a reduction as large as 90% in traffic flow has a limited effect on the spreading of the disease. important enough and at variance with such studies, the data-driven nature of this study and the available dataset allowed us to disentangle the impact of each transportation mode in several scenarios of mobility reduction in spain. we found that while shutting down completely any transportation means does not lead to a significant reduction in the incidence of the disease, in some contexts the arrival of the peak of the disease is delayed by several days, which could eventually be advantageous. altogether, we provide evidences supporting the adoption of a mixed strategy that combines some mobility restrictions with, mainly, the early identification of infected individuals and their isolation. these conclusions agree with the latest recommendations by the who [10]. we also highlight that although this study has been made with data from spain, our findings can also be valid for any other country given the ubiquity of mobility patterns worldwide. stochastic seir-metapopulation models are routinely used to study the temporal and spatial transmission of diseases like the covid-19. here, we made use of such class of models and implement a data-driven version that allows to obtain realistic estimates for the spatial incidence of the disease as well as its temporal dynamics. more specifically, in terms of time, we feed the model with the available data as of february 28th, 2020. spatially, we consider that each province (there are 52 in spain, see appendix b) is represented by a subpopulation. furthermore, metapopulation models are composed by two types of dynamics: the disease dynamics governed by the chosen compartmental model, seir in our case, and the mobility of the individuals across the subpopulations that make up the whole metapopulation system. the latter ingredient, the mobility, connects the subpopulations and allows the disease to spread from one subpopulation to another. in what follows, we describe these two components of our model. to model the mobility of individuals we use a data-driven approach. data-driven modeling, at variance with more theoretically inspired methods, has the advantage that it allows to directly implement and evaluate realistic contention measures, thus producing scalable and actionable what-if-scenarios. to this end, we have obtained the inter-province mobility flows provided by the ministry of development of spain [11] . therefore, the minimal spatial unit in our system is a province. using the information from the mobility matrices, that report the origin and destination (od) of individual movements, at each time-step, we sample the number of individuals on the move from each province and distribute them across the country according to the information contained in these od matrices. important enough, this dataset not only includes the total number of individuals going from province to province, but it also distinguishes the main transportation means used by the individuals, see figure 1 . this will allow us to gauge the effect of travel restrictions on different transportation modes. furthermore, given that the epidemic started abroad, it is important to determine in which province the disease is more likely to be seeded first. given the current global spread and incidence of the epidemic, we thus take into account that the three countries with more cases are china, south korea and italy and consider that the most plausible route for an infected individual to reach spain is by plane. thus, we collected the number of passengers coming from each country to each spanish airport in 2019 from the spanish air navigation manager aena [12] . then, we assigned each spanish airport to its corresponding province and ranked them according to their total number of operations with each country, see figure 2. it is worth noticing that the information provided by aena is already aggregated by country. thus, this ranking cannot take into account which airports are mostly connected to locations where the outbreak is currently concentrated − e.g., north of italy. nevertheless, the ranking constitutes a valid proxy, and a good starting point, to seed the disease. the dynamics of the disease is governed by an seir compartmental model. in this model, individuals are classified according to their health status: susceptible (s) if they are susceptible to catch the disease; exposed (e) if they have been infected but are still asymptomatic and cannot infect other individuals; infected (i) once the incubation period is over and the individuals show symptoms and could infect others, and removed (r) when they are either recovered or deceased. within each province, the transition between compartments results from the following rules, iterated at each time step, corresponding to 1 day: where r 0 is the reproduction number, t e is the mean incubation time, n i stands for the number of individuals in region i and i i accounts for the number of infected individuals in such region. e→i: exposed individuals become infected at a rate inversely proportional to the mean latent period, t e . i→r: infected individuals become removed at a rate inversely proportional to the mean infectious period, t i . . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. similarly, the width of the links is proportional to the number of individuals using that route. note that for multimodal travels the associated mode is the one that corresponds to the largest part of the trip, which explains why there are links from the islands to provinces without ports in the matrix corresponding to maritime trips. in what follows, we parameterize the model according to the latest estimates for the disease parameters [4, 13] , namely, r 0 = 2.5, and a generation time t g = t e + t i = 7.5 resulting from considering t e = 5.2 and t i = 2.3 (in appendix d we report that similar results are obtained for other values of t g , see figures 11, 12 and 13) . additionally, note that we have not explicitly included in the model the possibility of asymptomatic transmission, which should not be mistaken by transmission from undetected or unreported cases. asymptomatic spreading is still under scrutiny and the statistical evidences are scarce and not significant enough as to be taken by granted. in any case, including this possibility would be trivially possible in this kind of models. a. quantifying the spatial and temporal evolution of the disease incidence. one of the main characteristics of the covid19 disease is its long latency times. currently, the average incubation period has been reported to be 5.2 [13] . thus, before proceeding with the evaluating the impact of the disease, we . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. first compare the metapopulation model employed here with a classical sir-metapopulation framework. to do so, we use the random-walk effective distance where p (j|j) is the normalized flow matrix without row and column j, p(j) is the j-column of p with element j removed and δ is a dimensionless parameter that depends on the infection, recovery and mobility rates [14] . this quantity, defined for sir metapopulation models, gives us the expected time that it would take for the disease to reach each subpopulation of the system, also known as the hitting time. in figure 3 , we compare the hitting time obtained from stochastic simulations of the seir metapopulation model with the theoretical distances derived for the simplified sir model. we can see that the correlation is nearly perfect, implying that the spreading itself is quite similar in both models. however, we find that the hitting times in the seir implementation are at least two times larger than the theoretical ones for the sir scenario (on its turn, stochastic simulations of the sir model agree very well with the theoretical expectations for the model, see appendix c). thus, the addition of the latent state produces a substantial delay on the spreading of the epidemic. this is in line with the fact that the epidemic is thought to have started in mid-november or early december, however, a noticeable number of cases was only reported by early january. figure 4 shows the expected hitting time for each province when the disease starts from 5 different locations, as well as one case with seeds in multiple places, as obtained from the seir metapopulation model. as before, the hitting times might seem long, but this is due to the long latent periods of the disease, in agreement with the evolution of reported cases in mainland china. we also note that spanish major cities are expected to be affected by the outbreak in no more than 40 days −but often within 20 days− from the initial time in all the situations considered. indeed, to mimic the situation in the country as of february 28th, 2020, and to make projections about the evolution of the disease into the future, we considered the scenario in which the model is initialized with infected individuals in the capital of each region where there are cases of covid19: madrid, tenerife, barcelona, balearic islands, zaragoza, seville and valencia [15] . the results show that the spreading is much faster (note that the outer circle in the 5 individual provinces represents 60 days while in this case it represents only 40 days) in such a situation. complementarily to figure 4 , we present in figure 5 further results on the temporal and spatial evolution of the disease dynamics. here we have computed, through stochastic simulations of the model, the cumulative number of infected individuals within each region assuming that the disease propagates from barcelona by 10 initially infected individuals. the results align with the theoretical predictions, and highlight the close relationship that exists between the two biggest cities of spain (barcelona and madrid), even though they are relatively far geographically (around 620 kilometers through the shortest path by car). again, note that the relative slow speed of the epidemic agrees with what has been observed in china. finally, it is worth remarking that all of these quantities have been obtained assuming that no control measures are taken, which is not the current case as (detected) infected individuals are being isolated and monitored by the authorities. additionally, we also stress that it is difficult to assess whether this corresponds to a worst-case projection or not, given the many unknowns that can't be taken into account, such as inflow of infected subjects from abroad, the fraction of infectious individuals that have gone undetected, etc. however, as we show next, this data-driven modeling approach do allow to evaluate the effect of customary contention measures. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/10.1101/2020.03.01.20029801 doi: medrxiv preprint our data-driven model is particularly useful to get insights into mobility-mediated transmission dynamics and to evaluate possible countermeasures. next, we explore diverse containment measures that could be implemented aiming at stopping the large-scale spreading of the disease. first, we analyze the effect of imposing mobility restrictions by limiting traffic flow in the country. we consider six different scenarios that correspond to each transportation mode being shutdown plus another one in which a total reduction of 90% of the overall traffic is imposed. these measures are extreme and unless the situation gets really critical, would not be put into practice as they bear an economic cost that would be insurmountable. nonetheless, as we show below, however drastic they appear to be, these measures are useless when it comes to completely stop the disease from propagating. indeed, a significant reduction in the estimated incidence is only obtained when other actions are feasible. admittedly, in figure 6a it is observed that the previous measures have no effect on the final size of the epidemic. on the other hand, if we look at the time for the peak of the epidemic to arrive, figure 6b , we see some minor effects. in particular, although shutting down most modes of transportation have practically no effect, if all private cars were removed (i.e., they remain confined in their corresponding province), the peak of the epidemic would be delayed by about 7 days. the most effective of the above scenarios of mobility restriction corresponds to an unrealistic 90% reduction of the overall traffic, when the peak would be delayed over 20 days. this is in agreement with previous studies that have shown that the only sizable effect of travel restrictions is to delay the peak of the epidemic. for instance, it has been claimed that the travel restrictions in wuhan only delayed the peak of the epidemic by 3 days [4] . another possibility, instead of limiting the mobility of the overall population, is to be extremely vigilant so as to make it possible to isolate all the cases that start to appear quickly enough. to check the impact of this policy, we have simulated a scenario in which the average number of days that an individual is able to go unnoticed and infect others is reduced from 2.3 to 2, 1.5 and 1 days. in figure 7a , we observe that this strategy is much more effective than traffic restrictions. in particular, if we were able to reduce the time since symptoms' onset to isolation below 1.5 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. each set of measures indicates when they were applied: since the beginning of the epidemic, and after 100 or 1,000 cases are detected in the whole country. note that individuals who escape isolation remain infectious until they recover, and thus they could be thought of as asymptomatic spreaders. days, the epidemic is greatly reduced. as a matter of fact, it has been recently reported [13] that this average number of days went down in china from 4.4 days at the beginning of the outbreak to 2.6 days, which is one of the reasons invoked to explain why the epidemic has started to decline in mainland china. in our case, these numbers would be compatible with generation times of 10 or 12.5 (see figure 12 ). it is also reasonable to assume that this strategy is not easy to implement in full, either because some individuals could purportedly try to avoid isolation or due to the fact that many infected subjects have mild symptoms similar to a common flu and neither go to the doctor nor report their state. therefore, we have simulated a slightly different scenario in which individuals are isolated the same day of their symptoms' onset with a certain efficacy. that is, only a given percentage of the new cases is isolated, while the others are able to roam freely. this framework would also be compatible with having asymptomatic individuals who are able to spread the disease, something that is currently under debate and not yet statistically supported. the equivalence with such hypothetical natural history of the disease in our model is such because we do not apply the prescribed percentage to the total number of infected individuals, but only to those who have just developed symptoms, thus, those that escape will remain infectious as if they were asymptomatic until they recover. in figure 7b we show the effect that different percentages of new isolated cases would have on the size of the outbreak. being able to hospitalize all individuals, on average, in less than 1 day enables to effectively stop the disease. yet, the results also show that even if all infectious are not isolated, as long as more than 60% of the infected individuals are, the effect would be similar and the disease would be effectively eradicated. lastly, we analyzed the consequences of self-protection measures such as wearing masks, washing more frequently ones hands or avoiding crowded places. to mimic these contexts, we simply reduced the effectivity of the transmission by a certain fraction, and study the final size of the epidemic, see figure 8a . the results show that a large reduction of at least 60% is needed to contain the disease. interestingly, if we look at the time to the peak of the epidemic, represented in figure 8b , we observe that decreasing the transmission not only reduces the size of the outbreak but also delays the peak. hence, even if this strategy might not be sufficient to completely stop the propagation of the disease in all cases, it could certainly help for preparedness and other clinical responses by delaying the spreading. the exception is when the reduction is very large (in the figure, beyond 60%) as in these cases the peak might occur earlier because the disease dies out. in concluding, it is apparent from all the results obtained for the different scenarios that we have considered that the most cost-effective strategy would be the isolation or quarantine of detected infectious cases, as long as the efficacy of such measure is over 60%. important for the current debate about the natural history of the disease, this policy would also work if there is a fraction of asymptomatic but infectious individuals in the population. our results also show that from a practical point of view, a combination of all the analyzed contexts can have second order benefits. as already stressed, containment measures should not only be directed towards a full cutdown of the number of infected cases. their efficacy is also given by other factors, such as delaying, even if only by a few days, the spreading of the disease. such delays are always good for preparedness and to have more time for clinical research that can lead to new pharmacological treatments or vaccines. for instance, even if traffic restrictions are not effective on their own, they facilitate the control of the population and thus it would be easier to detect infected individuals and treat them. similarly, self-protection measures and other social-distancing practices delay the spreading of the disease, freeing resources that would allow for a better management of the epidemic, in turn leading to an increase of the efficacy of individual isolation. closing public places would, in practice, reduce the transmission, which again will lower the total number of infections and thus make them more manageable for the public health system. this also highlights the importance of having a coordinated response system, since simply adopting central measures like imposing mobility restrictions and closing public places is not effective in the middle-to-long term. our model has several limitations and some of them could actually be overcome in the near future. perhaps the most important one has to do with the inability of current large-scale epidemiological models to fully account for behavioral changes in the population when a disease is evolving. as it is the case for the spreading of covid-19, the information −and more often than desired, misinformation− travels faster than the disease. this produces undesired effects such as a collapse in the emergency rooms at hospitals, a proliferation of information sources that do not provide sensible advices in all cases, anticipated economic loses and, in general, uncoordinated responses. therefore, it is a pressing challenge to develop more realistic ways to incorporate in models like the one employed here all these risk-averse responses and reactions. another limitation of the current study includes the relatively low spatial resolution, which is essentially determined by the data availability. the results however indicate that the level of granularity used here is enough to capture mobility patterns and the effects of possible interventions. finally, we have not considered the temporal and spatial variability of disease parameters, nor other potentially important characteristics of the host population such as the existence of super spreaders or the age structure, which seems to play a relevant role for this disease, at least in what concerns the case fatality rate. we plan to investigate on all these issues in the near future. acknowledgments ym acknowledges partial support from the government of aragon, spain through grant e36-17r (fenol), and by mineco and feder funds (fis2017-87519-p). aa and ym acknowledge support from intesa sanpaolo innovation center. the funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. the inter-province flow matrices include the number of individuals that move from province to province in spain for several days of october 2017. the data also includes the main mode of transport used by those individuals, as well as other characteristics such as the period of the day when the travel started. in our case, we have collected the matrices from the last two weeks of october and averaged them. for a deeper discussion on the characteristics of these matrices we refer the reader to the original source (in spanish) [11] . the upper level of administrative division in spain is denominated comunidad autónoma. there are 15 of such "autonomous communities" in mainland spain, one in the islands of the mediterranean sea (balearic islands) and one for the islands in the atlantic ocean (canary islands). besides, there are two autonomous cities (ciudades autónomas) in the north of africa, ceuta and melilla. the next administrative division is the province (provincia). there are 47 provinces in mainland spain, 1 in the balearic islands and 2 in the canary islands, plus the two autonomous cities making up the 52 subpopulations considered in our model. the number of inhabitants of each province varies a lot, from over 5 millions in madrid and barcelona to less than 100,000 individuals in ceuta and melilla. we collected the number of inhabitants of each province from the data provided by the spanish statistical office [16] . there are 45 airports in spain (including the heliports in algeciras and ceuta), although the majority of them only have connections to other spanish airports or european airports. as with the provinces, the traffic in these airports varies widely, from over 50 million passengers in madrid and barcelona to less than 2,000 in albacete and huesca. the information regarding spanish airports is provided by the spanish air navigation manager (aena) [12] . . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/10.1101/2020.03.01.20029801 doi: medrxiv preprint to ensure that this quantity is able to predict correctly the spreading in our metapopulation, we first implement an sir model and study the effect of using a different number of seeds, figure 10 . regardless on the number of seeds, the correlation between the obtained values and the theoretical ones is really large. however, the actual value depends on the number of initial seeds. thus, without any modification this measure can help us determine the arrival order, i.e., to which provinces the disease should arrive first, but not the precise time. nonetheless, depending on the number of seeds, a small correction has to be applied. as it is not clear yet what are the final disease parameters that affect the predictions about the spreading of the coronavirus, we here provide quantitative evidences that the results reported in the main text still hold for other values of the generation time t g . a similar exercise could be done for r 0 , but we believe that the consensus around . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not peer-reviewed) the copyright holder for this preprint . the value used here (2.5) is higher than for other parameters like the serial interval. figures 11, 12 and 13 show results obtained for t g = 10 and t g = 12.5. as it can be seen, the previous conclusions hold, and in most of the cases, also quantitatively in terms of relative variation with respect to the scenario in which no measures are implemented. ministry of development of spain spanish air navigation manager regions with cases of covid19 as of 29/02 in spain spanish statistical office key: cord-023773-sqojhvwx authors: araújo-vila, noelia; fraiz-brea, jose antonio; de araújo, arthur filipe title: spanish economic-financial crisis: social and academic interest date: 2020-04-21 journal: j bus cycle res doi: 10.1007/s41549-020-00045-z sha: doc_id: 23773 cord_uid: sqojhvwx the present study analyses the interest of both experts and the general population in the economic-financial crisis that has affected spain up until 2019. to examine the interest of the general users, google searches were analysed through the google trends tool. meanwhile, the interest of scholars was assessed through the analysis of academic papers published on scopus, one of the most relevant peer reviewed literature database. to this end, a scopus search was made for papers containing the fragment “spanish financial crisis” on their tittles, abstracts, or keywords, which ensued a sample of 632 studies. findings show that the spanish financial crisis worries the general population as well as scholars. peaks in searches by general internet users take place in the years preceding the crisis (2004 and 2005) as well as throughout its duration (2008, 2010, and 2012). accordingly, the academic interest has also grown substantially up from 2008. the years preceding the beginning of the spanish financial crisis-2002-2007-are characterised by a cumulative economic imbalance. many countries had extremely negative checking account balances, while others achieved atypical surplus values, which led to a global financial crisis. some countries had loose monetary policies, and at the same time, a great amount of savings. this led to the inflation of assets' prices, especially real state, which came to be known as the real estate bubble (garcía 2005) . in spain, construction was financed by international loans. the instability in the construction industry led to high rates of indebtedness, which soon affected the country's whole economy. an excessive amount of money was being loaned to an industry that was no longer profitable. in this context, banks were increasingly uncertain about whether the debts would be liquidated. moreover, productivity problems tend to lead to future economic issues. in the years preceding the crisis, spain's gdp grew more than that of the united kingdom and the united states (eu-klem 2013) . this was already a sign that something was not right, or that, at the very least, the situation was temporary and unrealistic. a significant part of this growth was caused by the construction industry, which was responsible for 25% of the country's economic growth between 2000 and 2007. as garcía (2005) points out, this was caused by the increase in working hours and the intensive use of technological capital. the so-called real estate bubble led to the beginning of a global liquidity crisis in the banking system, which was intensified by the frequent trade of complex and structured financial products. initially, this crisis did not affect spain, as the national banks had focused on retail banking and refrained from selling structured mortgage products (alonso-almeida and bremser 2013). however, economic-financial problems brought about by the global recession increased the perceived risk and the real estate market's adjustment, which eventually reached spain as well (álvarez 2008) . the present work analyses the interest demonstrated by both the general population and economic scholars (and those from related areas) in the economic-financial crisis that affected spain up until the observed period (2019). naturally, the health crisis currently being faced by the whole world due to the outbreak of covid-19 is an even bigger problem, which is expected to have catastrophic consequences for many countries' economies, including spain. in this context, it is important to observe that the present research does not consider such phenomenon, which started after the data collection and analysis period. regarding the methodological steps carried out as part of this investigation, first the extant literature on the spanish financial crisis was systematically reviewed, which allowed the authors to understand the factors that led to this situation. then, to achieve this paper's objective, the interest of the general population was assessed through the analysis of google searches on the subject throughout the selected timeframe (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) (2016) (2017) (2018) (2019) . meanwhile, the interest of academics was examined through the analysis of scientific papers published on the scopus database during the same period. since the end of the twentieth century, spain had been one of the fastest growing and most successful economies in europe. immigration, low interest rates, and a recently liberalised and modernised economy had contributed to this great economic status (royo 2009 ). this condition, however, was interrupted in 2007, when the country started facing a severe economic recession. although the global economic crisis significantly contributed to this deceleration, domestic imbalances have also played an important role. in this context, 2007 is arguably the year when the financial crisis reached spain, along with many other european countries. in the spanish instance, the crisis was the result of a 5-year period of high liquidity in the financial market (álvarez 2008) . in other words, during this time, it was particularly easy to convert any financial asset into money with minimal loss. this is shown by the increase in monetary aggregates (adrian and shin 2008) noticed in this period, which led to an overcapacity of the financial system. this, in turn, led to a general state of distrust, in which neither employers nor families were willing to not take credit. the only cases in which credit was taken were those when people needed to renew their debts or cover their losses. naturally, as capitalist economies are based on credit, such situation would necessarily have a negative impact on the country's economy. along with this deterioration of economic conditions, a poor management of the situation by the bank of spain, the dependence on wholesale financing, and weaknesses in the regulatory framework, all contributed to this recession (royo 2013) . however, the key factor that led spain to the current crisis was the channelling of the financial sector into the real estate market (alvarez 2008; montalvo 2014; taylor 2009 ). the so-called system of perverse incentives, adopted as a temporary solution to fund construction activities, made the real estate market very attractive (montalvo 2014). for the families, buying a house started to look like a very attractive proposal. for the sake of comparison, in the united states, there is the "lease with the option of purchase" model, which became a very favourable option, even for those who could not afford the mortgage payments. moreover, if the prices happened to increase, which was expected, all parts would benefit from capital gains (case et al. 2012 ). on the other hand, if prices remained stable, one could simply stop paying the mortgage and lose the purchase option. in this case, the deal would effectively become a regular rent. another incentive was the barriers of entries, through which people could also request a loan (mayer et al. 2009 ). in spain, however, the scenario was quite different, as the financial product normally employed for the purpose of buying a house is the personal loan with mortgage. in such a deal, if one does not liquidate the debt, they must give back the house. nevertheless, the general belief was that there was an incredibly low chance of decrease in prices, which encouraged many families to buy houses anyway (garcía-montalvo 2006) . there was a whole chain of factors that encouraged this model of purchase. for example, bank workers needed to sell mortgages in order to hit sales targets and gain bonuses. therefore, they lowered the criteria for granting this type of loan (montalvo 2014) . moreover, all this housing construction and urbanisation methods did not take place in an institutional void (garcía 2010) . part of the problem was exactly the lack of spatial planning. more precisely, as observed by maldonado and pérez (2008) , specific plans for urban development either did not exist or were totally disregarded. the described scenario led the spanish construction industry to a great recession, which significantly affected the country's economy (kapelko et al. 2014) . the difficulty in liquidating loan payments was also linked to a decrease in the demand for finished buildings (both residential and non-residential), which resulted in a large amount of unsold real state (vergés 2011) . in sum, as concluded by stiglitz (2010: 21) spain allowed a massive real estate bubble to arise, and now faces an almost total collapse of this market. as opposed to the united states, however, spanish banks were more prepared to endure this trauma, due to the country's banking regulations. nevertheless, they country's economy had much greater losses. this led to a general distrust by bank clients, which, as concluded by carbó-valverde et al. (2013) , is an indicator of a significant negative impact of banks' activities in the economy. moreover, the bursting of the real estate bubble contributed directly and indirectly to almost 2.3 million job losses and a large private debt (garcía 2010) , which further aggravated the situation and forced the government to save banks by financing them with foreign savings. therefore, spain was one of the european countries where the late 2000′s global economic crisis had the most devastating outcomes. this happened due to internal factors that amplified the crisis' effects, especially the country's massive real estate bubble. the present study examined the interest of two distinct groups in the spanish financial crisis: 1. the general internet user; and 2. scholars and specialists in economy and related areas. the interest of the first group was assessed with the help of google trends, a tool that allows researchers to examine general trends in google searches. google searches were selected as an indicator of the general internet users' interest because google is the most popular web searcher in the world (ebizmba 2018). the interest of the second group was assessed through the examination of scientific papers published on scopus's database, which is one of the peer-reviewed literature databases with the highest number of citations and abstracts (andalial et al. 2010; bosman et al. 2006) . the analysis carried out through google trends encompassed searches made with the keywords "crisis española", "crisis financiera española", and "spanish financial crisis", made worldwide up from 2004 (year in which the tool started registering searches). this allowed the authors to verify whether the general internet user's interest in the topic increased up from 2008, the year after the beginning of the crisis. the analysis of articles published on scopus was a slightly more complex, due to the nature of the database. first, a search for papers containing the fragment "spanish financial crisis" in their tittles, abstracts, and keywords was made. the phrase in english was adopted for the search because most studies in the database are in in this language. a total of 632 works was found, from which 49% had been published between 2016 and 2019 (see table 1 ). researches on the topic started being published in a considerable amount from 2009-2010, following the beginning of the crisis. studies published in the 1990′s refer to previous financial crises, such as the one that took place between the 1970′s and the 1980′s, or even crises in previous centuries. scientific studies were also subjected to a content analysis, which considered their tittles, abstracts and keywords. qualitative content analysis is a method for analyzing text data and delve into their meaning by following systematic procedures (schreier 2012) . the term includes a series of different techniques to analyse texts (powers et al. 2010 ). more specifically, content analysis serves to "identify, analyse and inform patterns within the data" (braun and clarke 2006 p. 79) . it includes the codification and classification of textual units, which makes it very useful to explore big volumes of textual information and determine tendencies, patterns within the words employed, as well as relationships between their meanings (gbrich 2007) . qualitative analysis methods are not only a useful tool for generating knowledge, but also an effective vehicle for presenting and addressing meanings and findings (holloway and todres 2005; sandelowski 2010 ). to assure these methods' validities, researchers must clearly explain how the results were achieved (schreier 2012 ). in the case of content analysis, the preparation phase starts with the definition of the unit of analysis (guthrie et al. 2004) , to which researches must consider what they want to analyse (cavanagh 1997) . in the present investigation, the object of analysis was the academics' interest in the subject of the spanish financial crisis. in this context, the units of analysis were, as previously stated, the tittles, abstracts and keywords of scientific studies on this topic. content analysis may serve two main functions, the heuristic and the proofing function (bardin 2000) . naturally, the goal of the present study was not verifying any previously proposed hypothesis about the interest of academics in the spanish financial crisis, but simply exploring the trends and patterns in such interest through the analysis of published researches. therefore, within this investigation, the content analysis serves the heuristic function, as it enriches the exploratory attempt, increasing the likeliness of discovery. moreover, within the available content analysis techniques, the one adopted in the present study was the categorical content analysis, which consists in dismembering text units, or categories, according to pre-established criteria. in this context, the chosen total 632 studies registry of unit was the word-rather than the theme-which facilitated the systematic analysis of a big volume of texts. moreover, the main enumeration rule for coding, as it considers that the registry unit's relevance increases with its frequency of appearance. a quantitative summary of the content analysis' results is presented in table 1 . the google trends analysis indicated that searches for "crisis financiera española" were only made in spain. some related searched topics include "crisis", "crisis financiera", "finanzas", "españa" and "ciencia económica", which showed a consisted increase in searches from 2008. the terms also show two punctual peaks in searches in november 2004 and march 2005, which were indeed the highest search rates within the analysed period. these peaks are followed by april 2009 and september 2008 (fig. 1) . when considering searches for more generic terms, such as "crisis española", the number of countries from which searches were made increases. among the additional countries, the ones with the highest numbers are peru, ecuador, colombia, and argentina (all spanish speaking countries) (fig. 2) . related search terms include "crisis económica española", "la crisis económica", "crisis económica españa", "crisis política española" and "la economía española" all of which had a puntual increase in searches in 2008, and then consistently decreased, especially after 2014. for these terms, search peaks took place in september 2008, june 2012, november 2012, and may 2010 (fig. 3) . when considering the english term "spanish financial crisis", the peak in searches was in march 2004, followed by april 2005 and june 2012. up from 2014, the numbers decrease significantly (fig. 4) . related search terms that present a punctual increase include "spain financial crisis" and "spanish economic crisis". when considering searches for the more generic term "spanish crisis", the countries from which the most searches were made are spain, singapore, united kingdom, australia, nigeria and united states (fig. 5) . searches for this term had their peak in june 2012, followed by may 2010, and unlike in the previous cases, october 2017, which is particularly recent (fig. 6) . as mentioned in the methodology chapter, the search for papers published on scopus's database ensued 632 studies addressing the spanish financial crises since 1990, 96% of which have been published in the last decade. studies on the subject come from three main areas: social sciences (46.2%), economy, econometry, and finances (32.3%), and business, management, and accounting (30.7%)-it must be observed that the same paper can be classified into more than one area. most of the researches were published on journal papers (83.1%). the remaining documents include reviews (6.9%), book chapters (5.7%), and conference papers (2.1%). to delve deeper into the topic, it is important to know which items are more often addressed within these studies. to this end, a frequency analysis of the whole sample of keywords (n = 1,643) was carried out. results indicate that the most frequent research topics are spain, financial crisis, economic crisis, crisis, human, article, economic recession, and finances (table 2) . to analyse the topic even further, the works of the most proliferous authors in the field-kapelko, m., lara-rubio, j., navarro-galera, a. and perles-ribes, j.f.-were analysed. each of these authors published five studies within the last 5 years. the titles, abstracts and keywords of such studies were subjected to a content analysis (table 3) . results show that although the crisis took place over a decade ago, back in 2007/2008, it still attracts significant academic interest. moreover, this interest comes from different research areas, as the mentioned authors investigate areas as distinct as the public sector, the banking sector, the construction industry, and the tourism industry. the concepts analysed within those studies include inefficiency, financial sustainability, and all the effects of the economic and financial crisis worldwide, in the euro zone, and especially in spain. the construction industry was one of the most affected, as it depends on economic cycles. therefore, the situation initiated in 2007 has led to a significant drop in productivity. the country's economic situation had a great impact on the sector. on the other hand, part of the studies analysed focus on the public sector. these studies emphasize the need for financial transparency, especially on official websites. the solvency problems, risk premiums, and bank loans brought about by the financial crisis ultimately affected local governments, which must deal with the consequent increase in levels of (public) debt. the banking sector is also one of the most affected by the economic situation. one of the biggest problems for the sector is the risk of loyalty loss and abandonment by its clients. at last, studies analyse how this situation affects one of the star industries of the country: tourism. more specifically, they examined which types of tourist destinations (e.g., seaside, cities, etc.) have already overcome the crisis, as well as how the economic cycles have affected the tourism industry, namely its employment growth rates, since the beginning of the crisis (2007/2008) . studies also examined the opposite effect, that is, how tourism development affects the crisis, specially through the sale of vacation houses, which ultimately affects the construction industry. finally, analogous to the analysis carried out with the web searches, the published papers' origins were examined and the countries that show the greatest scientific interest in this topic were identified. as expected, the country from which the highest number of studies was published is spain, which accounts for 78.4% of studies. with significantly lower numbers, the following countries account for most of the remaining researches: united kingdom (5.8%), united states (5.7%), germany (3.0%), italy (2,2%), netherlands (1.7%), portugal (1.6%), france (1.4%), and poland (1.1%). next, with less than 1% each, comes sweden, australia, canada, chile, peru, austria, belgium, colombia, and denmark (fig. 7) . table 3 academic studies from the most proliferous authors on the spanish financial crisis transparency about sustainability in regional governments: the case of spain current crisis; demand for greater transparency in the public sector; sustainability in public administration; regional governments; websites; sustainability information in the beginning of the twenty-first century, a series of economic circumstances triggered a global economic-financial crisis. these circumstances included the contrast between countries with extreme deficits in their commercial balances and those enjoying atypical surplus values. in europe, one of the countries that suffered the most as a result of the crisis was spain. in the years preceding the beginning of the crisis, the country experienced several favourable economic circumstances, such as a higher gdp growth than that of global leaders, i.e., the united states, which eventually proved to be an illusion. in 2007, the economic boom came to an end, following the solvency crisis in the banking system and the decrease in the demand for products and services, especially houses. in this context, the construction industry was one of the most affected, and arguably one of the main factors responsible for amplifying the crisis effects in the country (due to the real estate bubble). to the present day, spain has not fully recovered, and the aftermath of the crisis still worries its population. it is particularly striking that, in the years preceding the crisis, there was already an uneasiness about it. this is evidenced by web searches on the topic, which begin to increase already in 2004. in fact, the peak in searches for "crisis financiera española" took place in november 2004, which was an omen of what was about to happen. moreover, searches related to the spanish economic crisis, spanish economy or simply the economic crisis have also been quite frequent, which indicates that the population is still worried and interested in this topic. once the crisis begins, peaks in searches are once again observed, especially between 2008 and 2012. when considering searches worldwide (for terms in english), the data shows that the interest in the topic starts decreasing in 2014. therefore, the peaks in interest from the general internet users take place in two specific moments: years before 2007, when some people already inferred that a crisis was about to come, and the fig. 7 countries that investigate the spanish financial crisis first years of crisis. it must be observed, as well, that although the topic is particularly related to one country, spain (which is evidenced by the fact that the majority of searches were made from this country), the analysis of searches in english shows that internet users from other countries are also interested in the situation. those include several european countries, such as united kingdom (in second place, immediately after spain), germany, italy, portugal, and france; but also countries from other continents, such as the united states (in third place), and with a significantly lower volume in searches, australia, canada, chile, peru, and colombia. regarding the academic world, the subject starts attracting a great deal of interest up from 2009/2010, when the crisis had already begun. the peak in number of published papers takes place in 2017 (114 works). however, the biggest growth is noticed between 2011 and 2013, when the number of studies practically doubled. in sum, academic studies show a continuous growth from 2011 to 2017. the most frequently addressed topics amongst the 632 analysed studies are the economic or financial crisis, the economic recession, unemployment, and the banking system. many studies share some of the same keywords, from which "spain" is by far the most frequent. the content analysis carried out on the works from the most proliferous authors within the topic indicates that construction is amongst the most addressed industries or sectors in researches related to the crisis. this is in line with previous literature on the subject, as addressed on the theoretical overview, the construction industry played a relevant role in amplifying the crisis' effects in spain and was also one of the most affected economic activities. other particularly affected area was the public sector, which was also one of the leading figures of the situation, due to the lack of a proactive attitude and preventive measures, and to its actions during the actual crisis. other authors focus on tourism, a key industry to the spanish economy, and one that was also affected by the crisis. finally, similarly to the general internet user's interest, academic interest in this subject does not come exclusively from spain, but also from other european countries, such as germany, italy, france, and portugal. moreover, studies also come from countries outside europe, such as the united states, peru, and chile. this data indicates that there is a coincidence regarding the countries that show high levels of social preoccupation on the subject, demonstrated by the web searches, and those that show particularly high academic interest. funding this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. transparency about sustainability in regional governments: the case of spain. convergencia-revista de ciencias sociales strategic responses of the spanish hospitality sector to the financial crisis la banca española ante la actual crisis financiera. estabilidad financiera scopus: la mayor base de datos de literatura científica arbitrada al alcance de los países subdesarrollados análise de conteúdo scopus reviewed and compared: the coverage and functionality of the 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the case of spain the end of growth in residential tourism destinations: steady state or sustainable development? the case of calpe dictionary of nursing theory and research after the fiesta: the spanish economy meets the global financial crisis how did the spanish financial system survive the first stage of the global crisis? governance what's in a name? qualitative description revisited qualitative content analysis in practice freefall: america, free markets, and the sinking of the world economy the financial crisis and the policy responses: an empirical analysis of what went wrong (no. w14631) the information asymmetry in the spanish real estate sector. crisis and stocks. observatorio inmobiliario y de la construcción key: cord-295358-8niqpwvc authors: santamaria, luis; hortal, joaquin title: chasing the ghost of infection past: identifying thresholds of change during the covid-19 infection in spain date: 2020-04-14 journal: nan doi: 10.1101/2020.04.09.20059345 sha: doc_id: 295358 cord_uid: 8niqpwvc covid-19 pandemic has spread worldwide rapidly from its first outbreak in china, with different impacts depending on the age and social structure of the populations, and the measures taken by each government. within europe, the first countries to be strongly affected have been italy and spain. in spain, infection has expanded in highly populated areas, resulting in one of the largest nationwide bursts so far by early april. we analyze the evolution of the growth curve of the epidemic in both the whole of spain and madrid autonomous region (the second largest conurbation in europe), based on the cumulative numbers of reported cases and deaths. we conducted segmented, linear regressions on log-transformed data to identify changes in the slope of these curves and/or sudden shifts in the number of cases (i.e. changes in the intercept) at fitted breaking points, and compared their results with a timeline including both key events of the epidemic and containment measures taken by the national and regional governments. results were largely consistent in the four curves analyzed (reported infections and deaths for spain and madrid, respectively), showing two major shifts in slopes (growth rates) at 14-15 and 26-29 march that resulted in 37-65% reductions of slope, and originated in infection on 4-5 and 16-18 march (for case detections) and 14-23 february and 5-6 march (for deaths). small upward shifts in the progress of the disease in madrid were not associated with significant changes in the intercept of the curve, and seem related with unevenness in case reporting. these results evidence an early deceleration in the spread of covid-19 coinciding with personal hygiene and social distancing recommendations, as well as the general awareness of the population; and a second, stronger decrease when harder isolation measures were enforced. the combination of both breakpoints seemingly led to the start of the contention of the disease outbreak by early april, the limit of our time series. this highlights the importance of adopting public health strategies that include disseminating basic knowledge on personal hygiene and reduced social contact at the onset of the epidemic, and the importance of early enforcement of hard contention measures for its subsequent contention. covid-19 infection has rapidly spread worldwide since its first outbreak in wuhan (china) in mid december 2019. the global number of confirmed cases has gone over one million on 3rd april 2020 (john hopkins university coronavirus resource center, see dong et al. 2020) , barely 3 months after its first report on 31st december. individuals infected with covid-19 remain asymptomatic for 5-6 days, while presenting enough viral load to be infective after 1-2 days of infection (linton et al. 2020 , lai et al. 2020 . severe cases require hospitalisation 3-15 days after the appearance of the first symptoms, which are similar to other infectious respiratory illnesses. this, together with the initial unawareness of the population, led to a high transmission rate of the infection, which spread rapidly to neighbouring countries, the middle east and europe, and then the rest of the world (see https://nextstrain.org/ncov). an increasing number of countries was progressively affected, and they responded differently depending on the who and local expert advice at the moment, the structure and resources of their public health systems, their r+d+i capacity (which determined the number of pcrs available for testing contagions from blood samples, among other things), and their ability to implement social distance measures. the diversity of policy responses, together with the preexisting differences in spatial aggregation, social behaviour and age structure of their populations, provide an unique array of test cases to understand how different levels and combinations of preventive quarantine and social-distancing measures affected the spread of the pandemic. covid-19 arrived to mainland spain in early february (first recorded hospitalisation dates back to 15th february; table s1 ). during the first 2-3 weeks of february, covid-19 infection reached spain at least three times, via uk and italy -as evidenced by the presence of three different genetic clusters identified by nextstrain (hadfield et al. 2018 ; last accessed 8th april). different from italy, where infections were concentrated in the north, the combination of these three introductions with early, unnoticed community transmission resulted in consecutive outbreaks in distant, highly populated areas of the basque country and navarra (north), madrid (center), catalonia (north east), andalusia (south) and valencia (east) (see timeline in figure 5 below, and table s1 ). the spatial structure of the spanish populations has played a role in the particularly rapid spread of the pandemic in some regions the country. its impact has been harsher in the big conurbations of madrid (around 6.4m people; second most populated metropolitan area of the eu, after paris) and barcelona (c. 5 .4m) -as well as in álava, navarra and la rioja (c. 1m in total), following the early infection of healthcare workers from txagorritxu hospital. balearic and canary archipelagos also received infections from the early onset of the pandemic, so it is reasonable to assume that by early march covid-19 infections were widely distributed throughout the whole country. several factors make spanish data one of the most fair accounts of the effects of the pandemic at the country and regional levels, together with italy and, specially, south korea. although the lack of enough tests that has been pervasive for most countries (except south korea), spain has achieved one of the highest infection test ratios per capita (clark et al. 2020) , thanks to the early mobilisation of most pcr machines available in universities and research centres for either covid-19 testing or covid-19 research. importantly, only cases testing positive in the pcr make it to the official statistics -and (similar to italy but different to other european countries) all deaths testing positive are registered as caused by covid-19 infection, including those associated with previous pathologies or happening outside hospitals (e.g. in private homes and nursing homes). these data provide an underestimation of the total population infected and the number of fatalities-due to the limited number of tests; although for the number of deaths this is partly compensated by the lethality associated to other pathologies that is attributed to covid-19 when pcrs render positive tests. however, the relatively homogeneous intensity of testing and the stability of criteria for disease attribution throughout the time period of this analysis probably result in unbiased estimators for the spread of the pandemic. it is therefore safe to assume that the number of reported cases of infection and the number of deaths are reasonably good proxies for the advance of the pandemic. here we characterize the growth curve of covid-19 infections in the whole of spain, from the onset of the pandemic in early february through the establishment of increasingly more restrictive social and governmental restrictions to mobility and personal contact. we also perform he analyses for the madrid autonomous region (madrid hereafter), a highly populated area with good public transportation and a high daily commuting rate, which represented the country's largest focus of the pandemic -as it represents a prime example of the spread of the virus in a large, mostly panmictic population through time, and the effect of social-distancing measures thereupon. the adoption of containment measures by the national and regional governments followed a sustained increment through time, from the recommendation of preventive measures in late february and early march, to increasingly stricter social-distancing measures on 9-10 march, to a nationwide lockdown announced on 13 march and enforced on 15 march, to the the closure of all non-essential economic activities on 31 march (see figure 5 below, and table s1 ). such sequence of measures was broadly discussed by experts, media and social media, with opinions ranging from qualifying them as exaggerated or unnecessary during the first weeks of the outbreak; to criticizing them as tardy of insufficient in the weeks that followed. two controversies have been particularly strong: (i) were preventive and soft socialdistancing measures useful, or should hard social-distancing measures have been introduced from the early moments (late february to early march)?, and (ii) did the mass events on the weekend of 7-8 march, coinciding with the international women's day demonstrations (over 300k attendants in the whole country, 120k in madrid) and premier football league matches (around 280k spectators in total and 72k in madrid, respectively) trigger the early spread of the pandemic in spain's largest cities, specially in madrid? bearing this temporal sequence in mind, we analyze the growth curves of the cumulative numbers of cases detected and the cumulative number of deaths for both the whole of spain and madrid, focusing specifically in the changes in the growth rate (i.e. the slope of log-transformed data) of these curves through time. based on this analysis, we seek to answer two questions: (1) how effective were the different social-distancing measures in reducing infection and mortality rates?; and (2) how significant were the effects of 7-8 march mass gatherings on the expansion of the epidemic, compared with other key events and control measures? data on the different events that marked the evolution of the pandemic in spain (e.g. first cases detected, large infection bouts, first deaths) or influenced its perception by the general public, as well as policy measures (e.g. preventive isolation, social-distancing, lockdowns) and putative key events (e.g. large gatherings associated to sport events, political demonstrations and party rallies), were gathered from official sources, national and international media, and scientific publications. whenever possible, and in all cases for policy measures, we confirmed their date and content from official documents and/or websites from international, national or regional institutions. we include a broad list of events in table s1 and selected the most relevant ones for the timeline shown, together with the results of the statistical analyses, in figure 5 's graphical summary. official data on the (i) cumulative number of cases, and (iii) cumulative number of deaths were obtained from the daily covid reports of the spanish ministry of health, as compiled by the worldometer coronavirus data service (for national data) and the covid data service of eldiario.es (for regional data). data were extracted at two levels of aggregation, for spain as a whole country, and for madrid autonomous region (i.e. comunidad autónoma de madrid). for the analyses we included data from the first day in which at least 10 cases or at least 1 death were measured; and extended the analyses to 22-24 days after the onset of social-distancing measures on 13-15/3/20, a period doubling the average infection-to-detection time (10.1 days; see next section), and equaling the average infection-to-death time (21 days; see next section). to estimate the infection date of reported cases, we calculated the infection-to-testing time by combining reported values of incubation time (mean = 5.0 days in lauer et al. 2020 ; median = 5.1 days in linton et al. 2020 ; mean = 6.4 days in lai et al. 2020) with time from illness onset to hospital admission for treatment and/or isolation (median = 3.3 days among living cases and 6.5 days among deceased; linton et al. 2020 ). hence, we used an infection-to-testing time of 9 days for living cases and 12 days for dead cases. based on the proportion of 36% deaths to 64% recoveries reported from 3/3/20 to 6/4/20 (for a total of 57,006 closed cases in spain), we estimated an average infection-to-testing time of 10.1 days -which, for simplicity, was we fitted a family of segmented (broken-line) regressions with no, one, two and three breaking points (models 1 to 4, with two, four, six and eight parameters respectively) and compared them using the their adjusted r 2 and goodness of fit. goodness-of-fit comparisons were based on two criteria: (i) the distribution of the residuals; (ii) the adjusted r 2 ; and (iii) a fstatistic comparing each model with the next level of restriction -that is, to the model with one breakpoint (hence, two parameters) less (hank et al. 2020). to ensure residuals' homoscedasticity, we used linear fits on log10-transformed data; similar results were, however, obtained using exponential fits on untransformed data (not shown). fitted breaking points provide objective information on the moment at which infection dynamics changed, while slopes provide information of the direction and magnitude of such . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/10. 1101 changes. when analyzing the data from madrid, we observed discontinuities that suggested that some breakpoints could involve a change in the intercept, rather than in the slope. this would imply a significant shift in values at a given day, followed by a continuous increase at the same growth rate that preceded such day -an scenario consistent, for example, with a sudden increase in infection rate during the mass gatherings of 7-8 march. to test for this possibility, we assessed the fit of an additional model with two breaking points, the first one involving a change in the intercept and the second one involving a change in the slope (model 5). for the whole of spain, the model with two breaking points (model 3) provided the best fit (table 1) . fitted breaking points were placed on day 17.9 (14/3/20, estimated infection on 4/3/20) and 30.5 (26/3/20, estimated infection on 16/03/20) (figure 1 ). the growth rate of the number of cases decreased by 49% (from 0.15 to 0.08) after the first breakpoint (14/3/20) and decreased again by another 54% (from 0.08 to 0.03) after the second breakpoint (26/3/20). is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/10. 1101 of infection is provided in the upper x-axis. filled points indicate sundays. broken vertical lines indicate the breaking points of the best fit (model 3), which is shown with a thicker line. the analyses performed on the number of cases from madrid are consistent with the results for the whole country. the model with two breaking points (model 3) provided the best fit (table 2) . fitted breaking points were placed on day 12.7 (14/3/20, estimated infection on 4/3/20) and 26.6 (28-29/3/20, estimated infection on 18-19/3/20) (figure 2 ). the growth rate of the number of cases decreased by 65% (from 0.18 to 0.06) after the first breakpoint (14/3/20) and decreased again by 59% (from 0.08 to 0.03) after the second breakpoint (18-19/3/20). an inspection of the values and fits ( figure 2) shows that the apparent jump in the number of cases detected on 9/3/20 (estimated infection on 28/02/20) was caused by the combination of a decrease during the weekend (7-8/3/20) and an increase the following monday -which kept the point in line with the previous and posterior values. indeed, the only fitted model that identified a change of slope (model 4, breaking point at day 9.0, i.e. on 10/3/20, estimated infection 29/2/20) showed a 19% decrease in the growth rate (from 0.18 to 0.15) at such point -although it provided a non-significant improvement in goodness-of-fit relative to a more-parsimonious model without such breaking point (model 3) . similarly, the model with two breaking points involving a change of intercept and a change of slope (model 5), which resulted in a 11% increase in the intercept (from 1.3 to 1.45) on day 7.1 (8/3/20, estimated infection 27/2/20), did not result in a significantly better fit compared to model 2 ( table 2 ). here it is worth noting that a similar 'decrease-and-jump' in the number of cases was observed one week before, from saturday 29/2/20 to monday 2/3/20, although dates before 1/3/20 were not included in the analysis owing to the low number of registered cases (below the ten-cases threshold). . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/10.1101/2020.04.09.20059345 doi: medrxiv preprint the model with three breaking points (model 4) provided the best fit (table 3) . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/10.1101/2020.04.09.20059345 doi: medrxiv preprint (table 4 ). fitted breaking points were placed on day 9.8 (15/3/20, estimated infection on 23/2/20) and 20.7 (26/3/20, estimated infection on 5/3/20) (figure 4) . the growth rate of the number of cases decreased by 56% (from 0.22 to 0.10) after the first breakpoint (15/3/20) and decreased again by 65% (from 0.10 to 0.03) after the second breakpoint (26/3/20). the model with one slope shift (on day 12.4, i.e. 17/3/20, estimated infection on 25/2/20) and one intercept shift (on day 8.2, i.e. 13/3/20, estimated infection on 21/2/20) showed a marginally significant improvement of goodness-of-fit relative to model 2 (0.10<p<0.05), but a worse fit (larger rss and adjusted r 2 ) than the model with two slopes shits (model 3). table 4 . results of segmented regressions with an increasing number of breaking points, fitted on the number of fatalities attributed to covid-19 infections in madrid region from 5/3/20 to 6/4/20. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/10.1101/2020.04.09.20059345 doi: medrxiv preprint the use of segmented regressions provided an objective procedure to identify thresholds of change during the evolution of covid-19 pandemic in the whole of spain, and the large conurbation of madrid. the results of the four variables analyzed, involving two different spatial extents (whole country and regional), and two different lag times (10 days for cases, 21 days for fatalities), showed a consistent temporal pattern ( figure 5 ) that can be divided into three consecutive phases : (1) a first phase, in the early moments of the epidemic, characterized by sudden (apparent) jumps in the number of infections, particularly conspicuous in madrid, which were not accompanied by increases in the infection rate. this phase coincided with the detection of the first cases, imported from abroad; and the two jumps in the number of infections were synchronous with specific events of group infections (at sport events and nursing homes, respectively; red points 4 and 7 in figure 5 ). owing to the lag times mentioned above, the effects of this phase become perceivable between march 1 and march 8. during this phase, however, breaking points signaling one (madrid) and two (spain) consecutive decreases in the growth rates of the number of deaths were identified (37-40% and 56% decreases in spain and madrid, respectively). these breaking points could not be linked to any specific event or policy measure, and were probably related to the improvement of clinical procedures (detection and hospital treatment) following the detection, hospitalization -and, in some cases, death of the first cases. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https: //doi.org/10.1101 //doi.org/10. /2020 (2) a second phase, 1-2 weeks later, showing a highly consistent pattern of decreases in the growth rates of both the number of cases and the number of fatalities (49-65% and 40-56% reductions, respectively) at both geographical extents (spain and madrid). this inflection point, detected in the four variables analyzed, corresponds to infections taking place in the first week of march, following the issuing of preventive isolation measures (blue points 3-4 in figure 5 ) and the increased awareness of the public opinion (as the perception of the increases in cases and deaths described in phase 1 emerged), but preceding the issuing of most social-distancing measures by the central and regional governments (blue points 5-7 in figure 5 ). owing to the lag times mentioned above, these decreases become perceivable between march 13-14 (for the number of cases) and march 26-27 (for the number of deaths). the perception of slowdown at march 13-14 was reinforced by the impact of the breaking points in the number of deaths detected during phase 1 (for infections taking place after february 23)underscoring the decoupling of cause and perception (see below). (3) a third phase, 2 weeks later, showing a consistent pattern of decrease in the growth rates of the number of cases detected at both spatial extents (54 and 59% reduction in spain and madrid, respectively), but no change in the growth rate of the number of deaths. this decrease coincides closely with the issuing of strong social-distancing measures (nationwide lockdown and border closure). owing to the 21-days lag time between infection and death, it is likely that the period of time analyzed (extending to 21 days after the lockdown) was insufficient to detect similar changes in the number of deaths. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/10. 1101 (red) or decreases (blue) in the slope (growth rate) or intercept (sudden increases in values) of the numbers of cases and/or deaths. this basic analysis of the growth rates of cases and fatalities evidences the effectiveness of the contention measures taken by spanish national and regional governments. the confinement of all population that could telework, the suspension of in-class teaching in schools and universities, and the closure of non-essential shops, bars and restaurants resulted in a marked downwards inflection in the curves of both infections and deaths. however, it is also remarkable the existence of an earlier breakpoint, corresponding to a decrease in the rate of infections in the first week of march. this breakpoint was the most consistent (present in the four variables) and the most supported (present in all but one models with one or more breakpoints), suggesting that this was the most important change of dynamic during the period of time analyzed. the dropdown in the rate of infections coincides with an increase of the awareness of the spanish population (due to the reporting of a rapidly increasing number of cases and deaths, i.e. the delayed perception of the events of phase 1) and the issuing of official recommendations for the prevention and treatment of covid infections, but precedes the legal enforcement of most social-distancing measures by the regional and central governments (see figure 5 , table s1 ). indeed, it takes place the week before the marked decrease in community mobility registered during the second week of march (from march 8 to march 15) in both madrid and the whole of spain (google 2020) . this suggests that a large proportion of the spanish population changed their behaviour due to the combination of increasing awareness and the dissemination of preventive hygienic and distancing measures by the government and the media -with recourse to the examples of china, south korea and italy. it seems therefore fair to argue that, during this week, the population responded swiftly to the voluntary prevention and distancing measures suggested by the authorities and the media, and these were effective to slow down the early spread of the pandemic. the results also indicate, however, that these measures were not enough to contain the spread of the virus -and the issuing of the first soft social-distancing measures by the regional governments had little impact upon it. the next breaking point, resulting in the strongest reduction if the growth rate of the number of cases, took place closely after the onset of the stronger measures of national lockdown and border closure. as in the previous phase, the population's response was swift and started already with the partial confinement measures, one week before (e.g. google 2020) -surpassing broadly the expectations of 69 experts who predicted a collapse of the health system on march 25 (catanzaro 2020; arenas et al. 2020; mitjà et al. 2020) . these stronger isolation policies were probably instrumental in flattening the curve of infections, though not sufficient to date to bring it to a complete halt. unfortunately, the data available to date does not allow assessing the effect of the further strengthening of the lockdown (i.e. closure of non-essential economic activities) enforced on 30-31 march, as compared with the previous measures. what our results fail to show is the expected effects of certain key events pinpointed by the media on the spread of covid-19 infections. the demonstrations and football matches of 7-8 march did not result in significant increases in neither infection rates nor in the number of infections (as reflected in the numbers of cases and fatalities). an inspection of the stallingand-jump of the numbers of cases and deaths in madrid, which triggered such public perception, indicates that they are inconsistent with it -since, given the lag times involved, their effects should have shown up 10 to 21 days later. the stalling-and-jump pattern, which can also be observed in the previous and and following weekends (1st and 15th march, for the number of cases and the number of deaths, respectively), is more likely related to the phase 1 infection bouts shown in figure 5 . alternatively, they could be caused by droppings in patient attendance to hospitals or case/fatality reporting during the weekend, with the subsequent increase in the following monday. with hindsight, it is clear that issuing strong social-distancing measures earlier would have increased their effectiveness, thereby saving more lives and reducing the collapse of the spanish health system (see e.g. the sir-based simulations of casares & kahn 2020). our analyses evidence, however, that the responses of the population, media and authorities was slowed down by the perceptual trap created by the prolonged infection-to-detection and infection-to-death lags. it is somehow ironic that the rapid increase in the infections during the last weeks of february (described in phase 1) was only perceivable two weeks later -and, while the increments in number of cases and deaths were attributed to concurrent events that were most likely unrelated, they triggered a swift response precisely at a moment when early containment measures were already starting to work. similarly, the results of early containment measures were perceived two weeks later, and attributed to a direct consequence of the national lockdown. fortunately, expert advice to the government was aware of this perceptual trap and insisted on the necessity of stronger social-distancing measures -which have been narrowly sufficient, to date, to reach the objective of flattening the curves. the spread and growth intensity of the covid-19 pandemic is being driven by international connectivity (coelho et al. 2020) , which resulted in repeated exposition of the highly interconnected european population. in the case of spain, this has been particularly important at international hubs such as madrid or barcelona, although contagions due to tourism and sport events also initiated the spread at least in málaga and valencia (southern and eastern coasts, respectively), spreading the disease and facilitating community transmission throughout the whole spanish territory (see table s1 ). this implies that the risk of new introductions from abroad will regain importance, should the objective of flattening the curve and taming the outbreak succeed in spain. our results, however, underscore the importance of the prolonged delays between infection and detection for the early (re)containment of the infection. though population awareness and widespread adoption of preventive measures will likely slow down the advance of the disease in the future, this does not diminish the importance of implementing a much more active and complete system of early detection. this represents a formidable challenge for spain, whose public health and r&d systems (the latter being instrumental for supporting testing efforts) were severely affected by the post-2008 austerity measures. the analyses described above are highly consistent, and they were not strongly affected by changes in the extension of the data series (as more data became available) or in the fitting procedures (untransformed vs log-transformed data). however, their validity is potentially constrained by a number of caveats. we used data on the number of reported cases -i.e. severe cases subject to testing. in general, tests were restricted to those requiring hospitalization or belonging to risk groups, thus underestimating total infection numbers. similarly, while at the beginning the number of deaths recorded in spain included all deaths of patients who tested positive or showed a compatible symptomatology, during the peak of the pandemic several regional governments failed to count all deaths outside hospitals if they were not tested either pre-or post-mortem. given the significant numbers of deaths happening in nurse homes and particular residences, this unevenness in the measurement of covid-related fatalities could have biased results, eventually flattening the curve. if such effect was significant, however, it should have resulted in changes in the intercept of the number of deaths' curve. given the lack of evidence for such changes, we believe that our results will stand out if new data coming from autopsies or re-evaluations is available in the future. at any rate, these limitations emphasize that, at present, we can only use the available data as proxies for the actual rates of infection spread and lethality. therefore, our results must be taken with due caution until more detailed studies surveying seroprevalence in the general populations (including a broad study launched by the spanish government as we write; mitchell 2020) are available. it is also important to note that the relationship of the growth rates and breakpoints in the analysed data with the timeline provided in figure 5 may be affected by both the variability in the time lags between the time of infection and the times of both diagnosis and death (see introduction), and the irregular reporting of both variables during weekends and among spanish regions -particularly at the onset of the outbreak. however, the use of cumulative curves smoothes out considerably these effects, and provides in robust estimates of both breaking points and growth rates. finally, the use of a family of models reaching a maximum of three breaking points, necessary to maintain model parsimony, may have also resulted in the lack of detection of additional breaking points. however, all models showed very high r 2 and adjusted r 2 values; and in three out of four models (all but the number of deaths in spain), fitting an additional breaking point only resulted in slight, non-significant improvements in model fit. we might have also missed breaking points in the early stages of the infection, when values are lower and data more noisy. indeed, heteroscedasticity in the original, untransformed data resulted in such a risk of underdetection; but using transformed data achieved homoscedasticity, and more breaking points were actually detected on earlier than on later dates. to summarize, our analyses detected three inflection points in the dynamics of the covid-19 pandemic in spain: a first phase of rapid infection, accompanied by a decrease in the mortality rate most likely related to early improvements in the detection and treatment of this novel disease; a second phase of early reduction in the infection rate, chronologically related to public response to voluntary prevention and social-distancing requests by the authorities; and a third phase of major reduction in the infection rate, following the onset of hard socialdistancing measures (nationwide lockdown and land border closure). it is also apparent that prolonged infection-to-detection and infection-to-death lags may have caused misperceptions of the impact of certain events (most notably, the 8th march demonstrations and sport events) and the effectiveness of certain measures, while being probably instrumental in triggering the widespread social response during phase 2 of the contagion. therefore, in addition to the control measures undertaken, a more effective communication strategy that bridges the perceptual gap described could be instrumental in engaging the population into the harsh actions still necessary to fight the pandemic more efficiently. the authors and their institutions did not receive at any time payment or services from a third party (government, commercial, private foundation, etc.) for any aspect of the submitted work. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/10. 1101 situación del covid-19 en españa a dynamic model of covid-19: contagion and implications of isolation enforcement el colapso que no fue how the uk got coronavirus testing wrong exponential phase of covid19 expansion is not driven by climate at global scale. medrxiv an interactive web-based dashboard to track covid-19 in real time coronavirus en españa (iii): 6 medidas ante el abismo coronavirus en españa (i): razones para actuar con urgencia y contundencia joint hypothesis testing using the f-statistic nextstrain: real-time tracking of pathogen evolution covid-19 community mobility report, 29/3/20 version incubation period and other epidemiological characteristics of 2019 novel coronavirus infections with right truncation: a statistical analysis of publicly available case data severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and coronavirus disease-2019 (covid-19): the epidemic and the challenges the incubation period of coronavirus disease 2019 (covid-19) from publicly reported confirmed cases: estimation and application spanish government plans to test 30,000 families to discover the spread of the global coronavirus pandemic and if containment can be lifted experts' request to the spanish government: move spain towards complete lockdown. the lancet covid-19 -a timeline of the coronavirus outbreak using a delay-adjusted case fatality ratio to estimate under-reporting estimates of the severity of covid-19 disease @coronasurveys team (2020) measuring icebergs: using different methods to estimate the number of covid-19 cases in portugal and spain the authors have nothing to disclose. key: cord-232959-jcnvnn2k authors: arnal, raquel p'erez; conesa, david; alvarez-napagao, sergio; suzumura, toyotaro; catala, mart'i; alvarez, enric; garcia-gasulla, dario title: private sources of mobility data under covid-19 date: 2020-07-14 journal: nan doi: nan sha: doc_id: 232959 cord_uid: jcnvnn2k the covid-19 pandemic is changing the world in unprecedented and unpredictable ways. human mobility is at the epicenter of that change, as the greatest facilitator for the spread of the virus. to study the change in mobility, to evaluate the efficiency of mobility restriction policies, and to facilitate a better response to possible future crisis, we need to properly understand all mobility data sources at our disposal. our work is dedicated to the study of private mobility sources, gathered and released by large technological companies. this data is of special interest because, unlike most public sources, it is focused on people, not transportation means. i.e., its unit of measurement is the closest thing to a person in a western society: a phone. furthermore, the sample of society they cover is large and representative. on the other hand, this sort of data is not directly accessible for anonymity reasons. thus, properly interpreting its patterns demands caution. aware of that, we set forth to explore the behavior and inter-relations of private sources of mobility data in the context of spain. this country represents a good experimental setting because of its large and fast pandemic peak, and for its implementation of a sustained, generalized lockdown. we find private mobility sources to be both correlated and complementary. using them, we evaluate the efficiency of implemented policies, and provide a insights into what new normal means in spain. the covid-19 pandemic is changing the world in unprecedented and unpredictable ways. human mobility is at the epicenter of that change, as the greatest facilitator for the spread of the virus. to study the change in mobility, to evaluate the efficiency of mobility restriction policies, and to facilitate a better response to possible future crisis, we need to properly understand all mobility data sources at our disposal. our work is dedicated to the study of private mobility sources, gathered and released by large technological companies. this data is of special interest because, unlike most public sources, it is focused on people, not transportation means. i.e., its unit of measurement is the closest thing to a person in a western society: a phone. furthermore, the sample of society they cover is large and representative. on the other hand, this sort of data is not directly accessible for anonymity reasons. thus, properly interpreting its patterns demands caution. aware of that, we set forth to explore the behavior and inter-relations of private sources of mobility data in the context of spain. this country represents a good experimental setting because of its large and fast pandemic peak, and for its implementation of a sustained, generalized lockdown. we find private mobility sources to be both correlated and complementary. using them, we evaluate the efficiency of implemented policies, and provide a insights into what new normal means in spain. covid-19 has produced an unprecedented change in mobility [1, 2] . governments have implemented restrictive measures to contain the pandemic, focused on reducing social contacts [3] . this is a direct effort towards controlling the covid-19 spread, at a stage where the test and trace strategy is impractical [4] . mobility restriction measures range from the closure of schools and large gatherings, to the complete lockdown of the population and economic hibernation. different countries have implemented different measures, varying their severity and duration [5] . lifting these restrictions will lead societies to a new normality, which is still unclear how much will resemble the old normality. at this point it seems likely that societies will transition to a new basal mobility structure [6] . one we need to analyze and understand the sooner the better. there are many public sources of mobility data which can be used to measure the physical distancing of population during the covid-19 crisis [7] [8] [9] . unfortunately, most of these sources provide limited insights, focusing on a movement modality (e.g., public transport occupancy, public bike system usage, road densities). an alternative to public data is the data provided by private technological entities, which have access to a high volume of information through applications installed in mobile phones [10] . even though the segment of population that has these applications installed is not a perfect reflection of society (e.g., young segments of society are over-represented while elders and kids are under-represented) it is large enough to provide reliable estimations. at the moment, data provided by private entities represents the most reliable public source of information to explore the big picture from the perspective of people [11] . such sources of data include the ones provided by google, facebook and apple, as described in section 2. the main issue when working with private data sources is the imperfect knowledge regarding its nature. for privacy preserving reasons, raw data is never provided. instead, data goes through heavy pre-processing and anonymization procedures [12] . additionally, the conditions under which data is collected are not fully transparent either, as baselines and contextual information are often missing. to partially overcome these issues, in this work we investigate the relation between the different private data sources, and how can they be used complementary to provide a better understanding of mobility. for our analysis, we focus on the case of spain. the covid-19 pandemics in spain, and the political measures taken to control its spread in the country, provide an appropriate experimental setup. spain implemented a complete and sudden lockdown on march 15, 2020, while the first mild restrictions were put in place less than a week before (progressive closure of schools and banning of large gatherings) [5] . after the pandemic peaked in april, spain gradually recovered mobility and services over the span of two months (may and june). we will study spain's demographics and consider the relation between restriction policies, social behavior and pandemic evolution. this could be helpful for reacting to future mobility crisis. we will also study its progression towards a new normality in comparison with the old one. this could be helpful for the adaptation of mobility policies to the new social setting. the rest of the paper is structured as follows. first, we describe the data used in this work in §2. then we review the social context of the study in §3, including both the timeline of implemented policies, and an overview of spain demographics. most of our analysis takes place in §4. this includes a general study of mobility trends for all regions and data sources ( §4.1), a discussion on the anomalies observed ( §4.2), an analysis on the daily trends ( §4.3) and some insights on the new normality ( §4.4). finally, we review our conclusions in §5. for this work we have considered the data published by the facebook data for good program (fdg) [13] , by the google mobility assessments [14] , and by apple [15] . at the time of our analysis apple only provided one single mobility metric, the number of direction requests made from the apple maps application. in practice, this measure was too different from the other sources as to be directly compared. also, while it was possible to assess the anonymization effect on the data for fdg and google, we have not been able to do the same for apple. for these reasons, we disregard apple data in this analysis. private mobility indices are typically provided at a certain level of aggregated granularity. with administrative level 1 being country, level 2 in spain corresponds to region (17 autonomous communities or cc.aa.), and level 3 to province (50 of them in spain). as we will see next, the google data is provided at level 2 (regions), while facebook data is provided at level 3 (province), a smaller geographical granularity. this will be aggregated to level 2 on our work. facebook data for good presents multiple data sets of mobility, all of them with a general description of how they are obtained. there are two main data sets of particular relevance for the purpose of this work: a remain-in-tile index and movementbetween-tiles index [16] . both are based on gps data from a sample of users that have activated the tracking system on their mobile phones, dividing the space in level 16 tiles (squares of roughly 500 × 500 m). the first one, remain-in-tile, provides the percentage of people that remains in the same tile, computed as the total ratio of mobiles providing signal which do not change of tile during a whole day. the second one, movement between tiles, estimates mobility by computing how many different tiles are visited by the sample of people, compared with the same number during the same day of the week previous to the pandemics (february 2020) [12] . for the rest of this work, we will use the remainin-tile index, as it provides a more pure measurement. notice the remain-in-tile is an absolute measure (e.g., it does not depend on a baseline). this makes it straightforward to interpret, and a good candidate for counting people who are following confinement, as long as the population who has accepted to be pinned represents a good sample of the population. the anonymization of data prevents us from evaluating the fit between the data sample and the overall population distribution. a certain amount of bias is to be expected, as the penetration of smartphone and facebook varies significantly among cohorts. as with google, the elder population and the younger population could be slightly underrepresented, which may entail a certain bias. nonetheless, the size of the sample lead us to believe that the data can provide a reliable picture. we assess facebook's sample size in two ways. first, by considering facebook market penetration in the smartphone market, which is around 50-60% [17] with smartphones being available for 70% of the population. the subsample with an activated tracking system only needs to be around 10% to have a sample of 4% of the total population. even 1% of the population would be a very large sample in any kind of poll. second, data of active facebook users is also available from facebook geoinsights maps and indicates that 1% is indeed the typical order of magnitude of the sample. the fact that facebook requires a minimum of 300 active users to provide data (for anonymity reasons) allows us to validate the size of the sample. for example, the province of spain with the smallest population is soria, with roughly 90,000 people. this province and has never pined less than 300 people for the whole period under study (i.e., there is data for soria for all days). this means that the sample in soria is always above 0.5% of the population. we have no reason to suspect a lower coverage on the other provinces of spain. facebook data is provided at level 3 (province) granularity. in order to compare with google data (which is only available at level 2), we need to aggregate it. any level 2 region is a sum of one or more level 3 provinces. to compute the level 2 data from level 3 values we use the average of provinces weighted by their population. by doing so we obtain the ratio of people that remain in tile at level 2 aggregation for facebook. on april 2, 2020, google released its covid-19 community mobility reports [14] . since then, google periodically releases anonymyzed mobility data 1 , organized in a set of categories (e.g., retail, recreation, groceries, pharmacies, parks, transit stations). this data is always provided at administrative level 2 granularity (region). in addition to those, google also releases a residential and a workplace measure, estimating how much time is spent at those places. in the case of residential, it is based on the average number of hours spent at the place of residence for each user within a geographic location. this data is collected from those users opting in to location history, and is processed using the same algorithms used for the detection of user location in google places, offering an accuracy of around 100m in urban areas [18] . google mobility reports releases relative information for every day of the week. that is, mobility with respect to a baseline: the first five weeks of the year, from january 3 to february 6. given the large number of users of google maps there is no doubt that the sample size of google is also large compared with any standard polling sample. however, the fact that google does not provide an absolute value in the way facebook does presents researchers with serious challenges. the most important is that the baseline can be indeed corrupted by local festivities or changes in the normal baseline due to large-scale celebrations. as we will see, lack of access to the baseline prevents the direct comparisons of regions, and even days, and can complicate its interpretaion. google's residential index, which indicates the estimated time spent at the residence, should strongly correlate with facebook's remain-in-tile. i.e., a large fraction of people remaining at home should increase both indices. their direct comparison should provide context for their interpretation, and insights on their applicability. the first cases covid-19 in spain were reported on january 31st, in the canary islands. for roughly a month, all detected cases were imported from other countries. the first cases of community transmission (i.e., source of contagion unknown) were diagnosed on the february 26. in march is where the scope of our analysis begins. the number cases reached 999 on the 9th. at this point a few several regional governments took the first generalized measures, with the closure of schools. this escalated until march at administrative level 2, spain is composed by 17 regions and two autonomous cities (ceuta and melilla). the latter are not included in the analysis because their distinct nature would require a separate study. even so, the 17 regions of spain differ significantly in socio-economic factors, as shown in table 1 . two regions (catalonia and madrid) include the largest metropolitan areas, and had the most covid-19 cases in absolute terms. the rest of regions can be categorized as being dense or sparse (as determined by the population density), and as having their population centered on urban areas or not (as determined by the percentage of people living in cities with 50k or more inhabitants). cantabria and aragon are examples of the most uncommon cases, the first being fairly dense, with population centered on small towns, and the second being sparse, with population centered on cities. extremadura is a prototypical sparse and rural region, while madrid is extremely dense and urban. in our analysis, we focus on facebook's remain in tile index, and on google's residential index. the former is scaled (multiplied by 50) to approximate google's scale and facilitate the interpretation of figures. we have no means to assess the relation between the scale of both indices, which is why we avoid interpreting the relative volume between indices. nonetheless, as we will see in figure 1 , our scale provides a good approximation. our first analysis is focused on the general mobility trend of spanish regions during the peak of the pandemic. for this, we focus on the three months around the peak of the pandemic in spain, as shown in figure 1 . these are march, april and may. in this period, mobility in spain went through at least first of all, let us remark the lack of significant differences among regions with regards to the general trend. all show the same overall behavior through time. mild differences exist in the degree of confinement, and on the recovery speed during deconfinement. madrid for example reaches a higher level of confinement and recovers mobility much slower than extremadura. the main distinctive factor of regions comes from the occurrence of periodic peaks in the data (sometimes upwards, sometimes downwards). we discuss those in detail on the following section. according to both mobility indicators, the spanish society assumed and implemented the general lockdown in a matter of 48 hours (from march 12 to march 14) . this level of mobility restrain was sustained for seven weeks. for reference, wuhan, the source of the pandemic, held its lockdown for approximately eight weeks [19] . spain mobility was minimized from march 15, with the declaration of the state of alarm, to may 2, with the approval of de-confinement measures (consecutive orange, red and orange bands in figure 1 ). after may 2, restrictions were gradually lifted, causing a progressive recovery of mobility that officially ended on june 21. within the seven lockdown weeks, two were under hard-lockdown. since restrictions were enforced by police, mobility in this two week is a good estimate of the maximum mobility restriction that can be held in spain while keeping essential services running. to further understand the role of the hardlockdown, we compute an estimate of its impact on mobility. we are interested in its effect when compared to mobility under regular lockdown. the regular lockdown includes five weeks of lockdown data (the last two of march and the last three of april) during which traveling to industry and construction workplaces was allowed. this sort of lockdown is assumed to have a less damaging effect on the economy, but it enables infection among co-workers. to compare mobility between both periods we measure the corresponding area under the curve. the higher the area, the higher the constraint. for each period, we normalize the area by the number of weeks. the results for all 17 regions are shown in figure 2 as a separate distribution for the google and facebook indices. in this case, facebook is the most interesting source, since it is an absolute measure and allows us to measure volume of people. this data indicates an increase between 10% and 15% in the people who stayed put. the relevance of that number for the containment of the pandemic is unknown to us. i.e., we do not know which would have been the evolution of the pandemic if hard-lockdown had not been implemented. one may argue that many [20] shifted two weeks early to approximate contagion date. more people would have been infected, since regular lockdown enables transmissions on the workplace. however, the number of detected cases did not show any change after hard-lockdown ended, it continued to decrease at a similar rate. one may also argue that the hard-lockdown had a psychological effect on society, boosting resiliency to confinement. looking at how mobility recovers right after hardlockdown is lifted, this seems to be a valid hypothesis. if that were the case, a state of alarm without hard-lockdown may have lost adherence faster. to observe the effect and timing of the policies implemented, we can compare it with the status of the pandemic. for that purpose we use the number of daily reported cases, plotting it against the mobility curves. to approximate the date of the contagion from the date of report, we shift this data two weeks early. this is motivated by current estimates [21] , which assert that the vast majority of covid-19 patients develop symptoms (if any) before day 14 after contagion. figure 3 shows this comparison, for the case of madrid [20] , the region with the most cases and the strongest lockdown adherence. in figure 3 we observe the beginning of the lock-down overlapping with the initial containment of the pandemic. that is, the number of contagions halts its exponential trend around the date of the state of alarm declaration. although we do not know the exact role of the state of alarm, it is shown to be a clearly correlated factor. the seven weeks of general lockdown coincide with the seven weeks of strongest pandemic rate reduction. that is the time it took the pandemic to reach a basal situation in the region, with less than 100 reported cases a day. according to this estimate, this situation may have been reached around the starting date of the de-confinement process. if all this was the case, the duration of the spanish lockdown (7 weeks) was a very good fit to the evolution of the pandemic. a shorter lockdown may have induced a significantly higher risk of relapse, and a longer one seems unnecessary in sight of the contagion numbers estimated to be taking place in early may. let us remark that during the crisis policy makers could only use current daily cases for their decision making. that is, without the 2 week shift we performed in figure 3 . the de-confinement process was therefore a bolder (and riskier) initiative than figure 3 illustrates. the general trend described in the previous section is explained by the different stages of confinement enforced by the spanish government. on top of this trend, we can see the occurrence of a number of peak values, happening periodically and on all regions. these peaks occur mostly on sundays (marked with grey vertical lines in figure 1 ), and to a lesser degree on fridays and saturdays. let us discuss sundays and fridays in detail, since saturdays seem to be a middle ground, transitioning between both. sunday peaks are anticorrelated in terms of relative mobility (google goes down) and absolute mobility (facebook goes up) . this means the number of people moving is small when compared to near-by days of confinement. it also means that the number of people moving is not so different from what it used to be, when compared to the same day of the week on normality. in other words, people were not moving much on sundays before the covid-19 crisis, and during it they were moving less. accordingly, even though the decrease on mobility on sundays is not as big as on other days of the week, it still accounts for the day of the week with less absolute mobility. that would make sundays the best candidates for the mobility of risk population. in contrast, friday peaks exhibit a rather different behavior. in this case, the relative mobility decreases sharply (google goes up), while the absolute mobility remains stable or decreases mildly (facebook goes flat or slightly up). this indicates fridays are the days with the most different mobility patterns with respect to the previous normality (relative change), which speaks of the high mobility taking place on a normal friday. on these days is when society is showing its biggest change, leveling mobility to the rest of the working week. that would make fridays the best candidates for communication and support (e.g., mental health assessment). let us remind the reader that these insights may be reinforced by the bias in the data, which favours the presence of the young segments of society. let us now conduct an experiment to validate the hypothesis that peaks are related to the relative or absolute nature of measures. we transform the facebook measure from an absolute one to a relative one, using as a baseline analogous remain in tile data, from february 24 to march 8, before the first regional restriction measures. this baseline is computed weekday-wise, like google's. the result is shown in figure 4 , together with the original facebook data, and the google measure. the first obvious change are sundays, which now peak downwards like google. in fact, our relative facebook measure perfectly aligns with google around weekends (friday to monday) during the whole lockdown. this may be caused by differences in the data (both data sources have different resolutions to measure movement), or by differences in the baselines given the daily consistency. understanding the nature of these peaks is important because of the effect these may have on certain metrics. as shown in figure 5 , pearson correlation between facebook's remain in tile and google's residential index varies significantly from month to month. on march, mobility exhibited a very clear trend as a result of the establishment of confinement measures. in this setting, the correlation between both indices is clear (around 0.9 pearson correlation on average), and the peaks are not disruptive enough as to alter it. on the other hand, mobility during april was stable, as the whole month was under lockdown. this entails an overall flat behavior of the indicators. a context in which the inverted peaks have a dramatic effect, destroying all correlation between indices. finally, may appears as a middle ground. there is a generalized mobility trend, which reduces the upsetting effect figure 4 : evolution of mobility according to facebook absolute change (blue), facebook relative change (green) and google (purple). facebook relative change has been divided by 100 to match the scale of the other two indices. the vertical bands (green, orange, red, orange, green) correspond to pre-confinement, state of alarm declaration and lockdown, hard-lockdown, lockdown and de-confinement stages. grey vertical lines are aligned with every sunday. of the peaks, but the trend is not strong enough as to completely overpower the noise. week days have an important role in the characterization of mobility. let us now study the same data, but this time from the perspective of days. to do so we plot the facebook and google mobility indices as two different axis. figure 6 provides two visualizations for the first three months of the pandemic in spain. on the top row, the color gradient shows the change through time, week by week. on the bottom row, week days are color coded to illustrate the differences between days. in these plots, horizontal axis show absolute change (the more to the right, the bigger number of people stay at home) while the vertical axis shows relative change (the more up, the more percentage of people stay at home with respect with normal instances of that day). the first visible thing in figure 6 is the correlation between both values, as all data is mostly gathered around the diagonal. the top row shows the evolution of mobility, starting from the axis origin (bottom left) and suddenly jumping to the top right quarter of the plot as lockdown is implemented. the last friday and saturday before the lockdown (second week of march) are the only days in the middle of that jump. during confinement (april) data is rather stable in that area, until the de-confinement measures (may) bring it down and left again, but this time in a slow manner. the visualization using both google and facebook as axis shows the clear correlation be-tween them. in general, as relative mobility increases/decreases, so does absolute mobility. however, this relation seems to be somewhat dependant on the day of the week. as shown on the bottom row of figure 6 , sundays have a rather different behavior in terms of relative mobility (it shows less affection in this metric) while friday represents the opposite (it shows more affection in relative mobility). this is a different visualization of the same phenomenon observed in the peaks of figure 1 and discussed in §4.2. on the second half of may, spain started to lift the confinement measures that had been in place in the country for two months [5] . the process was asymmetrical, with regions with better pandemic indicators (i.e., number of daily cases, number of available hospital beds, etc.) de-confining faster than others. detailed maps of the differential treatment of regions can be found in governmental sources [22] this process ended on june 21, when the state of alarm (and all mobility restrictions) was lifted. on that date, the whole country officially entered the new normality. figure 7 includes the last four weeks of state of alarm (but without a generalized lockdown), and the first one of new normality. to facilitate visualization we change zoom in and the axis scale with respect to figure 6 . nonetheless, to enable comparison with the rest of the period under study, in figure 8 we plot the same data using the scale used in figure 6 the progression of mobility towards the axes origin is still visible and this smaller scale as weeks go by (in color gradient), for both working days (monday to friday) and weekend days (saturday and sunday). to compare the new normality with the old one, we must focus on the google axis, since this is relative to a baseline (january 3 to february 6). on the weekends mobility is already at google baseline levels, with all values between -5 and 5 on the last week (the new normal one). in contrast, working days are showing a higher difference with respect to the baseline, with several values in the last week between 5 and 15 in the google axis. this indicates that the change implemented by the spanish society during the new normality is focused on working days, while weekends are back to how they were. the recovery of old normality is not homogeneous amount regions either. catalonia and madrid, the regions with the biggest metropolitan areas, clearly lag behind. asturias, navarre, la rioja, region of murcia, extremadura and galicia are way ahead. of those, only murcia has a population density above 100 (132 people/km 2 ), hinting a potential relation with this indicator. the lag of catalonia and madrid during the first 4 weeks is likely related with the fact that these regions were slightly behind in the removal of restriction measures. however, during the 5th and last week of data all regions were under the same conditions, and catalonia and madrid still exhibit higher levels of mobility reduction. this may be related with the role of large metropolitan areas, were it is harder to keep a safe distance, and with the fact that both regions reported the highfigure 6 . the data of this figure is zoomed in and split between working days and weekend days in figure 7 . est absolute volume of infections during the pandemic. both these factors are strong psychological enablers of self-responsibility, which may have an effect of adherence to mobility reduction during the new normality. in this work we consider the use of private data sources (google and facebook) for assessing the levels of mobility in a country like spain. by doing so, we draw conclusions on two fronts. first, on the behavior and particularities of private data sources. and second, on how mobility changed during the covid-19 pandemic in spain. regarding private data sources, we have shown the differences between using an absolute measure (like facebook) and a relative measure (like google). both of them have limitations when used in isolation. the former lacks a contextualization of its values, while the latter depends entirely on the baseline used. when used together, they provide a visualizing of mobility where consistent patterns can be easily identified (as presented later in this section). for specific purposes, using a single data source may suffice, as long as it fits the goal: • an absolute measure like facebook's can be very useful for epidemiologic purposes, as it provides an pure measurement of mobility. that includes estimating number of contacts in a society, modeling the spread of the virus, and measuring the impact of policies on absolute mobility. • a relative measure like google's can be very useful for socio-economic purposes, as it provides a contextualized measurement of mobility. that includes understanding the change caused by the new normality, and the economic impact of mobility restriction policies. on the second topic of this paper, the analysis of spanish mobility during the covid-19 pandemic, we extract several conclusions. on one hand, data shows a huge mobility containment, sustained for a month and a half (march 15 to may 1st, approximately), very close to its theoretical limit (as represented by mobility during the hard-lockdown). this duration was sufficient to contain the spread of the virus and bring infection numbers down to traceable scale. in hindsight, the policies implemented in spain seem appropriate and proportional to the severity of the situation. that being said, the role, timing and convenience of the hard-lockdown remains to be further discussed. our work shows a relatively modest contribution of this policy to mobility reduction. on the other hand, the hardlockdown may have had an effect on prolonging adherence. our work identifies mild differences between regions during the three months of restricted movement. certain regions had a stronger adherence to confinement than others, mostly in relative terms. this may be caused by regional differences in prepandemic mobility, which is used as baseline for the relative measurement. a similar artifact are the inverted peaks of weekends, where a relative measure spikes down and an absolute measure spikes up. as demonstrated, this the result of combining a measure relative to the weekday with an absolute measure. we also saw significant differences among days. weekends exhibit the highest volume of mobility reduction in absolute terms, even during the hardlockdown, when traveling to work was forbidden for all except essential services. at the same time, weekends have the smallest mobility reduction in relative terms, indicating that the effort society had to make in this regard with respect to its previous patterns was smaller. fridays and sundays are particularly relevant days, the first because it represents the biggest change from normal behavior, the second because it represents the biggest absolute decrease in mobility. these particularities could be exploited for the general good. finally, we analyzed the new normality by looking at the weeks of de-confinement, up until june 27, a week after the state of alarm was lifted on the whole of spain. in this period, we found saturdays and sundays to be already at pre-pandemic levels of mobility. in contrast, working days (monday to friday) still show significant differences. the new normality also shows differences between regions, particularly for working days. regions with large metropolitan areas exhibit a reduction in mobility between 4% and 14% after restrictions were lifted. indeed, the new normality is most new on urban working days. economic and social consequences of human mobility restrictions under covid-19 spread and dynamics of the covid-19 epidemic in italy: effects of emergency containment measures presence and mobility of the population during covid-19 outbreak and lockdown in italy the effect of human mobility and control measures on the covid-19 epidemic in china ecml covid dashboard the spread of awareness and its impact on epidemic outbreaks evolución del nivel de movilidad del conjunto de provincias openflights rolls out new maps, moves to github mobile phone data for informing public health actions across the covid-19 pandemic life cycle quantifying international human mobility patterns using facebook network data aggregated mobility data could help fight covid-19 protecting privacy in facebook mobility data during the covid-19 response facebook data for good public datasets wilson mobility trends reports facebook disaster maps: aggregate insights for crisis response & recovery estudio anual mobile en españa 2019 y tendencias google timeline accuracy assessment and error prediction china scrambles to curb rise in imported coronavirus cases, wuhan eases lockdown situación y evolución de la pandemia de covid-19 en españa the incubation period of coronavirus disease 2019 (covid-19) from publicly reported confirmed cases: estimation and application plan para la transición hacia una nueva normalidad we would like to thank facebook and google for releasing the data that made this work possible. we also appreciate the insights and support of amaç herdagdelen, alex pompe and alex dow on the interpretation of peaks. part of this work was done under the global data science project for covid-19. we would also like to thank daniel lópez-codina, sergio alonso, and clara prats for fruitful discussions. finally, part of this research has received funding from the european union's horizon 2020 programme under the sobigdata++ project, grant agreement num. 871042. key: cord-010300-z33hblvi authors: montoya, ana; gálvez, rosa; checa, rocío; sarquis, juliana; plaza, alexandra; barrera, juan pedro; marino, valentina; miró, guadalupe title: latest trends in l. infantum infection in dogs in spain, part ii: current clinical management and control according to a national survey of veterinary practitioners date: 2020-04-21 journal: parasit vectors doi: 10.1186/s13071-020-04080-8 sha: doc_id: 10300 cord_uid: z33hblvi background: canine leishmaniosis (canl) is a parasitic zoonotic disease, endemic in the mediterranean basin including spain. while knowledge about canl, its management, treatment, prevention and control mounts, it remains unclear whether all clinical veterinarians follow the same international recommendations, such as those of the leishvet group. this study was thus designed to assess recent trends in the clinical management of canl in veterinary clinics across spain through a questionnaire-based survey. results were compared with those of a prior national multicenter questionnaire administered by our research team in 2005. methods: a questionnaire consisting of 28 questions about canl was developed using google forms and distributed by email to 1428 veterinary clinics in spain. questions were designed to obtain data on common clinical signs, techniques and complementary exams used to diagnose the disease, and on its monitoring, treatment and control measures. data were collected in a database for statistical analysis. results: completed questionnaires were returned by 295 clinics. compared to the situation in 2005, responses indicate that clinical signs of canl have not changed significantly, cutaneous lesions being still the most prevalent sign observed by practitioners. quantitative serological techniques are considered an adequate approach to diagnosis, provided their results are supported by the findings of a thorough physical exam, as well as complementary tests (complete blood count, biochemical profile, plasma protein electrophoretogram and complete urinalysis). treatment protocols and check-ups follow international recommendations. finally, a multimodal approach is being endorsed to adequately control canl including preventive measures such as annual serological check-ups and the combination of repellents and vaccines. additionally, owners are being better informed about canl by veterinarians, which translates to the improved control of this zoonosis. conclusions: the clinical management of canl has recently undergone significant changes owing to improvements in clinical knowledge of the disease, more unified international criteria, improved diagnostic techniques and their adequate interpretation, as well as a greater awareness of the disease transmitted to owners. [image: see text] canine leishmaniosis (canl) is an important parasitic zoonotic disease caused by leishmania infantum, endemic in the mediterranean basin including spain. the disease is transmitted by female blood-feeding phlebotomine sand flies, and dogs (canis familiaris) are both its natural host and the major reservoir of infection for humans and other animals [1, 2] . the presence of l. infantum in felids and other animals has also been confirmed, although so far there are few data on these species despite being considered a potential secondary reservoir for the infection of humans and other animals [3] [4] [5] [6] [7] . the closest example is the largest outbreak of human leishmaniasis known in europe occurring in 2009 in the southwest of madrid [8] in which hares (lepus granatensis) and rabbits (oryctolagus cuniculus) were identified in xenodiagnostic and molecular diagnostic studies as reservoirs and held responsible for the transmission of human leishmaniosis [9, 10] . the epidemiological role of wildlife species has not yet been established [4, [11] [12] [13] yet several authors propose that these animals can act as sentinels as they indicate the risk of transmission to other animals (domestic and wild) or even to humans, highlighting the importance of the concept of "one health" for the control of leishmaniosis [14] [15] [16] . in spain, the seroprevalence of canl differs from one area to another, depending on environmental factors such as temperature, humidity, geographical location, density and dispersion of the vector [1, 17] . in cats, seroprevalence rates provided in numerous studies have not been negligible, yet significantly lower than those observed in the canine population [18] . the most important characteristic of canl is its extraordinary clinical polymorphism. this determines that a thorough assessment including medical history and physical examination are mandatory to confirm a causal relationship between leishmania infection and the clinical signs presented by the animal. the diagnostic techniques used are based on the detection of the parasite (cytology, culture, molecular techniques, etc.) and anti-l. infantum antibodies (serological techniques). however, complementary diagnostic tests such as blood tests (blood count and biochemical profile), urine tests (e.g. urinalysis, urine protein/creatinine ratio (upc)), ultrasound, etc. are required to identify the clinicopathological abnormalities associated with the disease and thus assess the general disease status of the animal and monitor its clinical progression after treatment [2, 19, 20] . with regard to the treatment of canl, progress has been limited. although treatment and clinical follow-up protocols have markedly advanced, there is currently no treatment capable of parasitological cure or of avoiding relapse. prevention is the best way to fight the disease, greatly helping to stop the spread of infection to other animals and humans. however, at present, no preventive measure offers 100% guarantee. thus, recommendations are adequate control of the vector, early diagnosis, and the treatment of sick dogs according to their clinical stage depending on their clinical signs [2, 21, 22] . the development and appearance of new vaccines for canl is a new strategy for the control of this important zoonosis [21, 23, 24] . knowledge about canl, its management, treatment, prevention and control is on the increase. however, it is unknown whether all clinical veterinarians follow the same international recommendations such as those of the leishvet group [2, 21] . consequently, the aim of the present study was determine how canl is clinically managed via a multicentre questionnaire completed by veterinarians throughout spain. results were then compared with those of a similar national multicentre questionnaire developed by our research team in 2005 [25] . this study is part ii of a larger investigation addressing the current situation of canl is spain. in part i, we mapped seroprevalences of infection in dogs across the country based on reported and our own more recent data, and also provided sand fly species distributions and addressed factors affecting their distribution and density. the questionnaire (additional file 1: text s1), consisting of 28 questions about canl clinical management, was developed through google forms. the items included were the same as in a previous national multicenter questionnaire developed by our research team in 2005 [25] . in this questionnaire, information is obtained about the characteristics of the veterinary clinics, the incidence and prevalence of l. infantum infection, the clinical signs observed, the diagnostic techniques and the complementary analyses used for the diagnosis of canl and its monitoring, treatment, disease progression, control measures, vaccination and information provided to the owner. responses were anonymous and it was assured by collecting email addresses that questionnaires were not completed by more than one veterinarian at the same veterinary clinic. email addresses were obtained through the association of spanish veterinarian specialists in small animals (avepa), the veterinary colleges of the different provinces and in a web search. all data were collected in a database (microsoft excel 2010) for statistical analysis. in addition to descriptive statistics of the survey responses, we analysed the data in an effort to understand possible associations between the incidence and progression of l. infantum infection and geographical area. differences were also explored in the responses regarding diagnostic techniques, management of leishmaniosis (treatment and follow-up) and prophylactic measures provided by veterinarians who indicated they used leishvet guidelines versus those who did not. for this purpose, we used the chi-square test (spss 21.0). significance was set at p ≤ 0.05. the questionnaire sent by email to 1428 veterinary clinics in spain was completed by 295 clinics/veterinarians. the geographical distribution of these clinics covering 43 of the 50 spanish provinces are shown in fig. 1 . according to the canl infection risk based on seroprevalences recorded in spain) (the number of veterinary clinics surveyed (n) is provided alongside seroprevalence) were: canary islands (n = 1; 0.4%), northern spain (n = 32; 11.6%), central spain (n = 114; 41.5%) and south and east spain (n = 128; 46.5%). in most veterinary clinics, the average number of veterinarians was 1-4 (81.7%), and 64.4% examined more than 10 animals per day. the different canine vector borne diseases (cvbd) diagnosed by veterinarians were leishmaniosis (92.5%; 273/295), ehrlichiosis (48.8%; 144/295), anaplasmosis (20.7%; 61/295), dirofilariosis (15.6%; 46/295), piroplasmosis (9.5%; 28/295), borreliosis (1%; 3/295) and ricketsiosis (0.7%; 2/295). the presence of some cvbd was associated with geographical distribution such as dirofilariosis (south of spain, east of spain and canary islands) and piroplasmosis (north of spain) while leishmaniosis, ehrlichiosis and anaplasmosis showed a homogenous distribution pattern across spain. borreliosis and ricketsiosis were not assessed due to insufficient data. with regard to the incidence of l. infantum infection, the perception of 50.2% of veterinarians was that it remains stable, while 34.9% believe its incidence has increased and 14.9% it has decreased. significant differences were also observed (χ 2 = 23.257, df = 6, p = 0.001) in the perceptions of veterinarians in different geographical areas: 65.6% of the veterinarians working in northern spain thought that canl is increasing in incidence while in other areas, veterinarians (49.2-57%) felt that canl infection has stabilized. few data about feline leishmaniosis (fell) were reported. twenty-four of 295 (8.1%) participants indicated that they had diagnosed at least one cat infected with l. infantum. no significant differences in fell were observed with respect to the geographical area (χ 2 = 1.050, df = 2, p = 0.592). the clinical signs of canl often observed by veterinarians were loss of weight, adenopathy, exfoliative dermatitis and renal disease (fig. 2 ). some veterinarians also described sporadic clinical signs: diarrhoea (n = 25), neurological signs (n = 5) and lameness (n = 18). only eight veterinarians described clinical signs in cats testing seropositive for l. infantum. the most common of these were: nodular cutaneous lesions, ulcerative lesions, and chronic nasal discharge. in two seropositive cats, a concomitant retrovirus infection was identified. the items of the questionnaire were designed to differentiate between (i) an etiological and immunological diagnosis (serology); and (ii) complementary diagnostic tests (laboratory findings) (fig. 3) . for an etiological diagnosis, 35.4-59.5% of veterinarians never used cytological tests [lymph node (35.4%), bone marrow (59.5%), cutaneous imprinting (53%)]. further, 58.4-66.4% also reported they did not carry out pcr techniques on bone marrow or lymph node aspirates, while a blood sample was used by c.25% of veterinarians sometimes or even systematically for a pcr diagnosis. also, some veterinarians used other biological samples such as hair, ear swabs for a pcr diagnosis. among the serological techniques used, quantitative methods such as ifat and elisa were used always or frequently by 66.7% and 61.8%, respectively. however, responses indicated that qualitative methods such as a rapid test were used as the first diagnostic tool by 70.5%. cbc and biochemical profiles were used frequently or systematically by c.94% of veterinarians, as well as serum electrophoretogram (89%). this was followed by urinalysis (58.9%) and upc (61.2%) used frequently or always, although 9.4% and 11.7% had never used upc and urianalysis, respectively, to assess canl infection status. additional proof such as an abdominal ultrasound was frequently used by 21% of veterinarians. besides, 63.9% of veterinarians diagnosed canl while conducting tests for other cvbds (fig. 4 ). more than 90% of veterinarians (54.4% always, 31.9% often and 9.6% sometimes) described they used meglumine antimoniate as treatment for canl. however, 31.9% and 23.6% stated they had never used the doses recommended by leishvet of 50 mg/kg/bid/28 d and 100 mg/kg/sid/28 d. miltefosine was used by around 80% of veterinarians (12.7% always, 31.8% often and 42.7% sometimes), and usually at the dose recommended by the manufacturer. allopurinol was used systemically practically by 100% of participants, the most common dose being 10 mg/kg bid. immunomodulators such as domperidone were often or sometimes added by 30.6% and 34.3% of veterinarians, respectively; and systematically used by 20.9%. regarding the use of impromune ® (bioibérica, spain), 50.6% reported they had never used it compared to 4.2% and 13.6% who did so systematically or often, respectively. finally, 95% of the survey respondents indicated they had never used autovaccine for the treatment of canl (fig. 5) . responses to questions about the frequency of followup of dogs with canl were: visits every 3 or 6 months respectively in 26.8% and 32.3%, and yearly in 5.2%. responses by 35.7% of veterinarians were that they only scheduled visits if there was clinical recurrence. survival and euthanasia figure 6 shows the survival rates of dogs with canl. few dogs (0-25%) showed a survival of less than 3 months, 6 months or 1 year. while 45.4%, 65.8% and 76.8% of the veterinarians surveyed considered that more than 50% of dogs have a survival rate of more than 1, 2 and 5 years, respectively. the reasons for euthanasia, both those recommended by the veterinarian or at the request of the owner are indicated in table 1 . among these, owners usually requested euthanasia because they lived with children, elderly or immunocompromised individuals, and veterinarians often recommended euthanasia when there was chronic renal disease or treatment intolerance. the surveyed practitioners recommended the following preventive measures: (i) annual serological analysis (80.4%); (ii) use of repellents against the vector (96.7%); (iii) avoiding going outdoors during hours of greater phlebotomus fly activity (66%); (iv) use of mosquito nets (32%); (v) use of domperidone (47.1%); and (vi) vaccination against l. infantum (87.6%). repellents most frequently recommended were: seresto ® (bayer animal-health, germany), advantix ® (bayer animalhealth, germany) and scalibor ® (msd, france) (fig. 7) . when asked about vaccines, 87.6% recommended this practice. however, when we asked about the type of vaccine, 22.1% and 69.4% said they frequently or systematically used canleish ® (virbac, france) and letifend ® (leti, spain), respectively ( table 2) . when we asked about the detection of antibodies against l. infantum before vaccination, 96.9% of the veterinarians said they obtained serology proof before primary vaccination (85.2% undertook rapid tests while 11.7% conducted a quantitative test (ifat or elisa), whereas this figure was 66.3% before re-vaccination (58.7% admitted they only used rapid tests, and 7.6% used quantitative tests). veterinarians considered that vaccination was safe, as associated clinical signs were not usually observed. the most common clinical signs reported were pain and erythema at the point of inoculation. one of the last questions was whether the veterinarians explained to owners the zoonotic impacts of canl. replies were 73.4% always, 12.7% often, 8.7% sometimes and 5.2% rarely. veterinarians surveyed mentioned they knew about the leishvet research group (64.9%) compared to 35.1% who have never heard about leishvet. of those who were aware of leishvet, 53.6% had heard of leishvet in a conference about canl, 17.8% via a veterinary laboratory, 8.9% via a veterinary journal, 7.1% via an internet search, 6.5% via their university and 5.9% via a colleague. when comparing which veterinarians followed leish-vet guideline recommendations on diagnostic tools, treatment and monitoring of sick dogs, preventative measures, and vaccination, significant differences were only detected in the use of abdominal ultrasound as a recommendation (χ 2 = 13.643, df = 4, p = 0.009). in this survey, we collected information about the clinical management of canl from 295 practitioners working in 43 spanish provinces. despite the large number of surveys sent (n = 1428), we consider that the number of veterinarians who answered was low. however, these results are more representative than those of our initial study in 2005 in which data were obtained from only 106 veterinarians across five spanish provinces [25] . moreover, in the 2005 study, the veterinarians surveyed worked only in areas showing a high endemicity of canl, while this time low endemicity areas were also surveyed as in the studies of bourdeau et al. [26] and le rutte et al. [27] . before asking about canl, a question was included about other cvbd, and many of the veterinarians indicated they mainly detected canl and ehrlichiosis. nevertheless, other cvbd (e.g. dirofilariosis and piroplasmosis) were also reported. according to previous epidemiological studies, the presence of some vector-borne diseases is associated with geographical distribution [28] [29] [30] [31] [32] [33] . indeed, in this survey, dirofilariosis (south of spain, east of spain and canary islands) and piroplasmosis (north of spain) were associated with this variable as suggested by others [29, [33] [34] [35] . according to these new results, canl seems to be the most widely cvbd distributed in spain. however, veterinarians working in areas showing a high or medium endemicity considered that the incidence of canl remains stable, while those working in low canl endemic areas indicated that cases of canl have increased. this perception is similar to that described in other european countries that were until recently free of canl, such as the uk or germany [36] [37] [38] [39] . the reason for this is unknown, but could be due to (i) the increased transfer of infected dogs from endemic areas, such as rehomed or hunting dogs; (ii) more dogs travelling overseas to leishmania-endemic areas (e.g. taken there by their owners on holiday); (iii) other non-vector routes of transmission such as vertical, venereal, blood transfusion or dog-to-dog [40] [41] [42] [43] which may be contributing to the spread of autochthonous cases. the reason could also be a combination of these factors. the clinical manifestations of canl vary from subclinical to severe disease. in the present study, weight loss, lymphadenomegaly and exfoliative dermatitis were frequently observed in agreement with the findings of other studies and surveys [25, 26, [44] [45] [46] [47] . while renal disease, vasculitis, ocular and join disease have been observed less frequently, these are indicators of a worse prognosis because they are clinical signs related to immunocomplex deposition [48] [49] [50] [51] [52] . additionally, other clinical signs have been sporadically observed such as neurological signs [53] [54] [55] [56] [57] or digestive disorders [58] [59] [60] . although these signs could due to canl, other diseases must be considered in the differential diagnosis. regarding the diagnosis questions, the present survey differentiated between an etiological diagnosis (microscopy observation and/or pcr), serology and complementary tests. it should be noted that more than 35% of the practitioners surveyed mentioned they had never performed an etiological diagnosis, and if this was done, the most common method used was pcr on blood samples or cytology on lymph node aspirates. cytology (5.3%) or pcr (3.9%) on bone marrow aspirates were infrequently used for an etiological diagnosis. similar results have been obtained in questionnaire surveys by other authors [26, 46] . however, according to the leishvet group, blood is one of the least sensitive biological samples, and the use of bone marrow or lymph node aspirates is strongly recommended [2, 61] . bourdeau et al. [26] suggested veterinarians could reject the more invasive techniques due to the extra costs and the fact they are time-consuming as in some cases it will be necessary to sedate the animal. other authors suggest a lack of referral laboratories close to veterinary practices surveyed as the reason for the reduced use of molecular techniques [62] . however, we found no difference in the approach used according to the location of the veterinary practice. quantitative serological diagnosis is essential in the diagnosis and monitoring of canl, and although many veterinarians used the ifat technique (66.7%) and quantitative elisa (51.8%) frequently or systematically, there were also many clinics that used rapid tests (70.5%) as the first diagnostic approach, in agreement with the results of similar surveys [25, 26, 63] . while a rapid test may help confirm clinically suspected cases as they show high specificity in sick dogs, the indirect fluorescent antibody test and the enzyme-linked immunosorbent assay are the most suitable serological tools according the leishvet group and oie [2, 64] , as confirmed by several authors [65] [66] [67] . in other surveys conducted in spain and other canl endemic countries (e.g. italy), ifat was considered the gold standard by veterinary practices surveyed [45] [46] [47] . according to the responses, almost all veterinarians used cbc and biochemical profiles to monitor infected dogs, and c.80% also used electrophoretograms. these rates are significantly higher than those of our previous survey [25] , and indicate the improved clinical management of canl as suggested by the leishvet group [2, 21] . regarding the use of urinalysis, ranges of 25.5-33.9% to 21.5-37.4% used urine strip and urinalysis, respectively. also, 27.2-34.0% frequently or systematically, respectively, determined the upc. this is important, as according to leishvet and iris guidelines, upc is a highly suitable biomarker for diagnosis of canl because immunocomplex deposits in the renal glomerulus may induce immune-mediated glomerulonephritis. in sick dogs, this serious kidney lesion causes proteinuria with or without azotemia and chronic renal disease or even nephrotic syndrome of worse prognosis [68, 69] . another important complementary diagnosis is abdominal ultrasound which was performed frequently during canl followup by 6.4-14.6% of the veterinarians surveyed. these diagnostic methods (upc and ultrasound) were not included in other surveys but the present responses suggest that veterinarians have access to this new information on the clinical management of canl via the leishvet guidelines, iris guidelines and specialized conferences [2, 21, 69, 70] . the leishvet guidelines suggest that canl therapy should be based on clinical staging (serological status, clinical signs and laboratory findings), and recommended regimens are the combination of allopurinol and meglumine antimoniate or miltefosine in dogs with disease stage ii or iii [2, 21] . the results of the present survey suggest veterinarians frequently use the combination of meglumine antimoniate and allopurinol, followed by miltefosine, in accordance with a previous questionnaire survey [47] . the long-term use of allopurinol, in combination with n-methylglucamine antimoniate or miltefosine, has proved to be effective for maintaining clinical and parasitological improvement and delaying relapses in treated dogs. miltefosine is better tolerated with regard to liver and kidney function. there is scarce information regarding possible toxicity of antimonials, and some authors have suggested possible kidney and liver secondary effects [71] [72] [73] . it is also true, however, that disease relapse occurs much earlier in dogs treated with miltefosine [73, 74] . therefore, although available data are controversial, miltefosine could be recommended for treatment of canine leishmaniosis patients with renal or liver disease, and/or when subcutaneous or parenteral therapy may not be administered or is not indicated [73] [74] [75] [76] . when veterinarians were asked about regimens of n-methylglucamine antimoniate, they indicated the 100 mg/kg/sid/28 d dose was more used than 50 mg/kg/ bid/28 d, although differences were not significant. this could be related to the fact that some owners prefer to inject their dogs once a day rather than twice. most veterinarians stated they used allopurinol in combination with leishmanicide drugs, as allopurinol has been shown to prevent recurrence [77] . likewise, it has been shown that dogs treated with allopurinol are not able to transmit the parasite to sand flies [78] . however, some dogs develop xanthinuria due to the inhibition of the enzyme xanthine oxidase, so it is strongly recommended to include frequent urinalysis and abdominal ultrasound for monitoring dogs under long term therapy with allopurinol [79] , and assess renal mineralisation and urolithiasis [80] . the veterinarians surveyed responded they used urinalysis (58.9-61.2%) and ultrasound (21%) as preventative of adverse urinary effects. avoiding sand fly bites is one of the best ways to stop the spread of l. infantum infection [22, 81] . results obtained in this survey indicate that veterinarians recommend the use of repellents against the vector (96.7%), mainly collars and spot-ons as in other studies [45, 62, 82] . other measures to avoid sand fly bites were not often recommended such as avoiding dogs going outside during hours of sand fly activity (from dusk to dawn) and using mosquito nets. these preventive measures have increased in comparison to the 2005 survey [25] . sixty-six percent of veterinarians recommended keeping dogs indoors during the risk period and 32% recommended the use of mosquito nets. lastly, another preventative measure recommended was vaccination. in the 2005 survey, 100% of veterinarians asked about vaccination answered that if there were a vaccine available, they would use it. in this survey, 87.6% replied they recommended vaccination as a preventative measure. further, it is remarkable that the most common vaccine used by veterinarians surveyed is let-ifend ® and not canileish ® . this lower use than initially expected could be because its percentage effectiveness is c.70% [83] . in addition, canileish ® needs to be given for primovaccination as three consecutive doses three weeks apart to develop an adequate immune response while letifend ® is a single dose even for primary vaccination. this vaccine is also a diva (differentiating infected from vaccinated animals) vaccine, allowing to discriminate vaccinated from infected dogs. for all these reasons, let-ifend ® is at the first-line vaccine option over canileish ® , as reflected in the results of other surveys [84] [85] [86] . when asked about adverse reactions associated with vaccination, while most veterinarians consider them safe enough, adverse reactions to vaccination are mentioned in the vaccineʼs summary of product characteristics (spc). in experimental trials by oliva et al. [24] and lemesre et al. [87] no signs of a local or systemic reaction were observed one week after vaccination [24, 87] . in contrast, lladró et al. [44] found, through a questionnaire completed by 45 practitioners in girona (ne spain), that 82% of veterinarians mentioned adverse reactions (local reaction, gastrointestinal signs, fever, apathy, vasovagal syncope and anaphylactic shock) potentially associated with vaccination [44] . further, to date, no dogs receiving letifend ® have shown any associated local or systemic adverse events [86, 88] . however, in our survey the appearance of clinical signs could be correlated with the vaccine used (canileish ® or letifend ® ). vaccine manufacturers recommend performing a serological test before vaccination. in this survey almost all veterinarians mentioned they undertook a pre-primovaccination test. however, a high percentage of veterinarians stated they never performed any test before revaccination so it cannot be known if a dog has been infected during the inter-vaccination period. this test is strictly necessary since vaccines do not protect 100% [83] . on the other hand, the results of the present survey indicate that more veterinarians carry out rapid tests before vaccination. although rapid tests have a good sensitivity and specificity, quantitative techniques are considered more sensitive. thus, a quantitative test is always recommended before vaccination to ensure the vaccination of healthy animals, as sometimes dogs with low antibody titres are not detected using qualitative techniques [83, 89] due to their lower sensitivity. current treatments and follow-up have allowed for a greater survival of dogs with canl compared to the results of the 2005 survey [25] , over 50% of dogs showing a survival longer than 5 years. however, in some cases, a veterinarian will recommend euthanasia for humanitarian reasons, especially when there is renal disease or other associated diseases. according to the present survey, an owner will usually request euthanasia when there are small children, or immunocompromised or elderly persons at home, and when a dog lives in a shelter. the educational role of veterinarians is essential to explain the life-cycle of the parasite and how other animals or people could acquire the infection, highlighting the importance of control and prevention measures [21, 22] . veterinarians also need to make owners aware that culling canl positive dogs is not an adequate disease control measure, as confirmed in studies conducted in brazil where culling seropositive dogs failed to reduce the incidence of canine or human leishmaniosis [90] [91] [92] . another aspect to consider is that the dog is not the only reservoir capable of transmitting l. infantum. several studies have shown that leishmania-competent vectors feed on cats naturally infected with l. infantum and through xenodiagnosis have confirmed that infected cats can transmit the infection to p. perniciosus and l. longipalpis [93] [94] [95] . however, in endemic areas of canl, subclinical feline infections are common, although clinical cases are so far exceptional [18, 96, 97] . indeed, in the present questionnaire, 8% cases of feline leishmaniosis were reported although these data are insufficient to reveal the role of cats as a possible reservoir as the veterinarians did not specify the diagnosis technique or clinical signs. the leishvet group is a scientific association focusing on offering a consensus statement on the clinical management of canl and standardizing criteria for its diagnosis and treatment. the results of the present survey indicate that around 65% of the surveyed practitioners knew about leishvet. this contradicts the data collected in the questionnaire of le rutte et al. 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psychodidae: phlebotominae) populations from endemic areas of american visceral leishmaniasis in northeastern brazil current status of l. infantum infection in stray cats in the madrid region (spain): implications for the recent outbreak of human leishmaniosis? parasites vectors implications of zoonotic and vector-borne parasites to free-roaming cats in central spain publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank all the veterinarians who participated in this survey. publication of this paper was sponsored by bayer animal health in the framework of the 15th cvbd ® world forum symposium. despite significant changes in the clinical management of canl, its incidence has not decreased in recent years, due to factors such as improved clinical knowledge of the disease on the part of veterinarians, better available diagnostic techniques and their adequate interpretation, as well as a greater awareness of owners of control measures available (repellents and vaccines). we should thus continue to well inform practitioners so that they can improve health education among dog owners. supplementary information accompanies this paper at https ://doi. org/10.1186/s1307 1-020-04080 -8.additional file 1: text s1. questionnaire that was distributed to veterinarians.abbreviations bid: twice a day; canl: canine leishmaniosis; cbc: complete blood count; cvbd: canine vector borne diseases; d: day; diva: differentiating infected from vaccinated animals; elisa: enzyme-linked immunosorbent assay; fell: feline leishmaniosis; ifat: indirect immunofluorescence antibody test; iris: international renal interest society; pcr: polymerase chain reaction; sid: once a day; upc: urine protein/creatinine ratio; vbd: vector borne diseases. am participated in the design of the questionnaire, performed the statistical analysis and drafted the manuscript. rg participated in the design of the questionnaire, collected questionnaires and drafted the manuscript. rc, jpb, vm and js participated in collecting questionnaires and database completion. ap participated in database completion and helped draft the manuscript. gm conceived and coordinated the study, participated in its design and drafted the manuscript. all authors read and approved the final manuscript. this study was funded in part by bayer animal health. data supporting the conclusions of this article are included within the article. not applicable. not applicable. the authors declare that they have no competing interests.received: 14 january 2020 accepted: 10 april 2020 key: cord-320134-823msjjc authors: knez, matjaz; jereb, borut; jadraque gago, eulalia; rosak-szyrocka, joanna; obrecht, matevz title: features influencing policy recommendations for the promotion of zero-emission vehicles in slovenia, spain, and poland date: 2020-08-29 journal: clean technol environ policy doi: 10.1007/s10098-020-01909-9 sha: doc_id: 320134 cord_uid: 823msjjc abstract: to make society more sustainable, cleaner transportation technologies, such as zero-emission vehicles and sustainable mobility, are being investigated, promoted, and supported by different policy measures. the emphasis of this paper is determining the zero-emission vehicle features that can influence specific policy recommendations; this understanding can boost zero-emission vehicle use as a potential cleaner transportation technology among different consumer segments in different eu member states. a customer-oriented study of over 1500 slovenians, spaniards, and poles revealed the most relevant zero-emission vehicle-purchasing features are: (a) vehicle price and (b) fuel economy. the percentage of potential zero-emission vehicle buyers is said to rise to 80% should the price of electric cars decrease and fuel price increase accordingly, i.e. by 30% and 50%, respectively. concerning the car price, slovenian and polish consumers’ preferences are similar, and 40% of them (and up to 85% of spaniards) would consider buying one if the price drops by 25%. women in all three studied countries are more interested in zero-emission vehicles than men are. different policies should be used in poland, where people are not as interested in zero-emission vehicles as spanish and slovenian consumers are. customer segmentation in all three groups pointed out that poland has the highest share (19%) of "no-green" consumers, whereas spain has the highest share (60%) of "go-green" consumers, i.e. consumers who would consider buying a zero-emission vehicle in the foreseeable future. graphic abstract: [image: see text] consumers are mostly very reluctant to let go of their standard of living related to their primary means of transportation and their strong feelings of independence associated with personal car use (anderson and stradling 2004) . it is, therefore, essential to promote zero-emission driving since transportation is a significant source of greenhouse gasses (ghgs) and other pollutants such as co, nox, pm, sox, and heavy metals baleta et al. 2019) . it contributes 14% of all global ghg emissions , mostly as a consequence of road transportation . alternative sustainable technologies, as such, are one possible solution, and transforming consumer habits and lifestyles are another (kramberger et al. 2014; cramton et al. 2018; mccollum et al. 2017; sopjani et al. 2018) . in this respect, unveiling the consumers' attitudes, preferences, and decision factors towards zero-emission vehicles (zevs) is necessary for the formulation of effective policy measures, the effective commercialization and promotion of zevs for post-fossil and more sustainable personal transportation (bockarjova and steg 2014; komiyama and kraines, 2008; fan et al. 2018 ) that has become "an embraced goal" of many countries around the world. it is believed that different zevs are a viable near-term transportation technology capable of providing more sustainable personal mobility, especially in cases of dispersed population, and hold many promises: from reducing dependence on imported petroleum to decreasing ghg emissions (rodrigues teixeira and sodre 2018; turcksin et al. 2013 ) as well as some other environmental concerns reflected in healthier living environments and reducing noise pollution. however, mainstream adoption has not yet been achieved regardless of the international, national, and local incentives, along with enticing promises to solve these severe problems. zevs have some technological weaknesses [e.g. range of electric vehicles (ev), hydrogen storage in hydrogen fuel cell vehicles (hfcv) (thesen and langhelle 2008) , energy losses]; they still cost more than petrol-powered vehicles do; they require new infrastructure to be established (national academy of sciences 2013; knez et al. 2019) ; and their environmental benefits are debatable, especially regarding the electricity mix for charging (ajanovic and haas 2019). these issues are sometimes identified as key barriers to greater zev commercialization. however, this is not necessarily true for all of them since over 95% of drivers use cars for daily trips/ rides for up to 50 km (knez and obrecht 2015) ; therefore, range or charging infrastructure is not the core problem of zevs for the majority of potential users. a review of studies from the previous decade on customer-oriented studies of zev and low-emission vehicle (lev) is summarized in table 1 . concerning the literature reviewed, it must be noted that the "social" barriers may pose as much of a problem as the "technical" ones in the development of zevs for the mainstream consumer market. although purchasing decisions have been thoroughly studied, the research was focused mostly separately on financial or performance features, carried out for levs, evs, gas-powered vehicles, etc., performed in one country only and without potential user segmentation. the authors have not found any study dealing with the impact of different financial as well as non-financial features on zev-purchasing intentions regarding different segments of potential users within different geographically distant but similarly developed countries. investigating the impact of financial and technical features of zev in three different eu member states (slovenia, spain, and poland) and examining their potential impact to use it for more efficient zev promotion policies were also the primary motivation for this survey. since it was assumed that differences occur among different segments, even inside each state, segmentation was also performed, studied, and discussed. to define and set an appropriate mix of measures within promotion policies for greater use of zevs, countries' specifics, consumer segmentation, and acceptance of different promotional measures must first be examined and well understood. this paper's objectives are, therefore, to achieve the following: • examine the impacts of key performance and financial features regarding zevs in slovenia, spain, and poland and cross-compare the most and least important features since vehicle purchasing or renewal varies regarding consumer behaviour, which is different in different geographic areas (andre et al. 2018 ); • evaluate the impact of fossil fuel potential price increase and zev potential price decrease on customers' demand and willingness to buy zevs (it is believed that zev demand varies in dependence with fossil fuel prices and the price of alternative powertrains); • identify three segments of potential zev users: "nogreens" (not interested in zevs); "go-with-the-flow greens" (the largest and most promising segment for car manufacturers); and "go-greens" (the segment with the highest environmental awareness, already interested in zevs and already considering buying or using one in the near future); • analyse the differences between slovenia, spain, and poland as eu member states in different geographical areas of the eu to propose the most appropriate promotional policies and measures for the greater implementation of zevs. approximately 480 km range of evs is good enough to be accepted by 90% of potential ev users. hevs are identified as a possible solution for users that need longer ranges diamond (2009) usa some common barriers to the adoption of zevs include lack of knowledge by potential consumers, high initial costs, and low-risk tolerance achterberg et al. (2010) netherland three most important features for purchasing new hybrid cars in netherland are environmental concern, and the related need to take care of nature, as well as trust in alternative technology van de velde et al. (2010) belgium men, higher educated people, people between 35 and 54 years old, and people with the most pro-environmental attitude are less affected by the message of sustainability, while the choice of this is more important when addressing women, people younger than 35 and older than 55 years, lower educated, and less pro-environmental people axsen et al. (2010) usa performance requirements of evs batteries are closer to being commercially viable than expected turrentine et al. (2011) usa research shows that customers doubt that zevs are powerful enough for highways or safe in different weather conditions and puddles and if they are actually any better for the environment than internal combustion vehicles egbue and long (2012) not specified the charging infrastructure is now one of the major challenges faced by evs, and the most promising benefit is the possibility of home charging, quiet ride, and low maintenance costs. non-financial features associated with energy can influence consumers' decisions, but in the case of financial benefits, they are more likely to focus on their knowledge of alternatives, preferences, and budget knez et al. (2014) slovenia the most relevant factor for purchasing a low-emission vehicle is the total vehicle price. low-emission vehicles are, surprisingly, also more attractive for the older population. people would choose low-emission vehicles mainly based on very low running costs rather than any environmental benefit krupa et al. (2014) usa the realization of expected contributions to sustainability ultimately falls on the consumers' willingness to purchase the new technology. climate change awareness also brings a greater willingness to consider buying evs barth et al. (2016) germany the most important feature related to the adoption of evs is the purchasing price, followed by the oil price yadav and pathak (2016) india environmental concern emerged as the most significant predictor of green purchase intention mccollum et al. (2017) not specified stronger price-based incentives and/or non-price-based measures may be needed to transform the global fleet of passenger vehicles, at least in the initial market phases of novel alternatives egbue et al. (2017) not specified it is also important that any engineering and technology background is identified in a potential user since they are more open to buying evs than the general public is andre et al. (2018) france (paris) consumer behaviour can be different in different geographic areas lina and wu (2018) china (beijing, shanghai, guangzhou, and shenzhen) attitude factors such as network externality, price acceptability, government subsidies, vehicle performance, environmental concerns, and demographic characteristics such as gender, age, and marital status have significant impact on respondents' willingness to purchase electric vehicles zhou et al. (2019) china taxation preference had better performance in incentivizing evs than the direct subsidy, which is contrary to current political discourses makarova et al. (2019) russia technological forecasts based on zev-related research are also crucial for top managers of industry-leading carmakers, who steer the automotive industry towards a transition to a more sustainable future amatulli et al. (2019) not specified the companies' communication strategies itself might be the trigger that induces customers to buy a green product the primary purpose of this study is, therefore, to present a valuable insight for sustainable transportation policymakers, car manufacturers deciding on their zev priorities, and for sustainable mobility developers. the remainder of the paper is structured as follows: in the following section, information on materials and methods including background information on the analysed countries, data gathering, and studied features for the analysis is given. in the result section, a descriptive analysis of non-financial and financial considerations is presented, followed by the impact of a potential oil price increase and zevs' price decrease. further potential zev users are segmented from no-greens to go-greens, and policy measures enabling zev expansion are cross-compared. the discussion is integrated into the results section to derive implications for policymakers as well as car manufacturers. a short conclusion completes the paper. the first step was the identification and selection of the countries included in the study. this study is a comparative analysis of purchasing intentions in slovenia, spain, and poland-three eu member states that differ regarding geographical location and regarding gross national income per capita (gni). slovenia, a country in central europe, and poland, a country in north-eastern europe, both are younger eu member states, and spain, a mediterranean country in south-western europe, that is also an older eu member state. we believe that the geographic location of countries affects people's habits; also, all three countries had totalitarian regimes before the transition to democracy, which is why we believe that transition and thinking about alternative mobility are similar and different from countries that have been democratic for a long time. the countries are quite comparable also regarding their per capita gross national income (gni) (in 2018 slovenia: €24,800; poland: €20,100, and spain: €27,700) (eurostat 2019a) . regarding the policy and market setting, we believe that slovenia and poland, which entered the eu simultaneously and adjusted their legislation to the european union later than spain (as an older eu member) did, can also affect the dynamic of people's perception and the adoption of alternative mobility solutions, which can also be reflected in various areas, such as the economy, education system, and the presence of environmental topics in the media, which affects the diversity of spain, which has been a member of the eu for a longer time. additionally, all three studied countries have quite similar population density (approximately 90 people/km 2 in spain, approximately 102 people/ km 2 in slovenia, and 120 people/km 2 in poland) (eurostat 2019b) with highly randomly dispersed populations in most of their regions (and throughout the whole of slovenia) in towns where public transport is far from ideal, which means that a high share of the population must take a car to work, school, and on their daily routines. the collected data consist of primary and secondary data. secondary data gathered with reviewing relevant literature, e.g. statements and results regarding zevs, were extracted from studies focused on evs, zevs, hfcvs, as well as levs. in the case of lev studies, we excluded results related to biofuels and natural/petroleum gas-powered vehicles. for the primary data collection, a pre-structured questionnaire derived from the research of borthwick and carreno (2012) on green taxes and green tax incentives and legislation was used and distributed in slovenia, spain, and poland. part of this questionnaire was identified to be potentially interesting for research on consumer behaviour and the importance of zev performance features on consumers' purchasing decisions. when using a standardized questionnaire, comparable results are obtained and allow (also long-term) monitoring of selected research issues and gathered data (also to analyse the time series). the research was conducted from 2015 to 2017. the data gathered were statistically analysed and cross-compared. this survey population covers people currently owning a vehicle, as well as those who currently do not own a car but have daily access to one if and when they need it. people younger than 18 years old and people with no driving licence or without the possibility of using a vehicle were excluded from the survey. the focus group was adults with driving licences, because others are presumably more interested in public transport than having a personal zev. the sample includes 817 participants from slovenia, 337 participants from spain, and 352 participants from poland, whose purchasing intentions and relevant zev performance features were studied. a total of 94% of study participants currently own/have access to a car in slovenia, and 91% do so in spain and poland. the age group from 18 to 24 years presumably does not own a car (or does so to a lesser extent); therefore, they may also have a different perspective on zevs and are potential users. the educational structure was also examined and was found to be similar in all the countries studied. the data gathered from slovenia, spain, and poland were all statistically analysed and cross-compared. key similarities and differences of the studied features influencing the purchasing intentions for zev in studied countries were additionally analysed and discussed. secondary data were collected using the compilation method, from numerous scientific and professional references focused on the current research topic. limitations of the study were identified as being the limited time frame (2017) and the potential subjectivity of answers (i.e. personal opinions). these can be dynamic and vary in time. the statistical sample may also not completely accurately reflect the whole population. the collected data were processed and analysed with spss statistical software. cluster analysis was used for data classification, carried out by dividing and synthesizing the data into groups. for data analysis, principle component factor analysis enrolled to limit situational variables (attributes) was adapted from borthwick and carreno (2012) and was divided into the seven broad features presented in table 2 . financial consideration related to changing petrol prices and potential changes in zev were also investigated as being of core importance for the future purchasing intentions by numerous authors (andre et al. 2018; barth et al. 2016; popp et al. 2009 ). the willingness to buy zevs differs significantly regarding various features. their technical limitations, such as occasionally insufficient charging infrastructure (for evs, hfcvs, etc.) or limited performance of some types of zev (e.g. ev range, the electric range for phevs and hevs, hydrogen storage, etc.), are often identified as significant barriers to zev commercialization. nevertheless, because more zevs with better performance are being launched on the market (evs with improved range, hfcvs with improved charging and hydrogen storage, etc.) each year as well as rapid installations of numerous charging stations (public and private), it can be forecast that zevs will boost already in 2020. two non-financial features are crucial when analysing purchasing intentions: "overall condition and mileage of vehicle (e.g. especially when consider buying a used vehicle)", and "safety features". other important features are body style (e.g. hatchback, coupe), fuel type/type of vehicle, vehicle size (exterior), and style/appearance/colour. research results for slovenia, spain, and poland are presented in fig. 1 . the results indicate that there are some differences among the studied countries, especially regarding fuel type and acceleration. fuel type is much more important for spanish consumers than for their polish and slovenian counterparts, and acceleration is much less important for slovenian buyers than for spanish and polish ones. table 3 shows the three most influential and three least influential "non-financial" features relevant to future car-purchasing decisions by country. these features are accompanied by the data of mean (m), standard deviation (sd), and standard error of the mean (sem). there are some similarities but even more differences. for example, "safety features" are considered to be a very important feature in all three countries. however, the interesting point revealed in this research is that women see safety more relevant than men do in all three studied countries (average grade for slovenia: women 6.33 and men 5.85; average grade for poland: women 6.28 and men 5.77; average grade for spain: 6.73 and men 6.45). while safety is of greater importance for women, it is interesting that they also cause fewer traffic accidents (topolsek 2007) . other factors differed: slovenia and spain both have "equipment levels" at third place and spain and poland have "style/appearance/colour" at third and second places, but no other significant similarities were recognized. "fuel type" was much more important for spain, and "overall condition and mileage of vehicle" was more important for slovenian and polish respondents. it can be speculated that this is a reflection that more used cars are sold on slovenian and polish markets; therefore, this feature is more important in these two countries. table 3 also proves that the more important non-financial features have a bit lower standard deviation than the less important ones do. the obtained data are therefore closer to the means and the standard error of the mean is lower. probably, respondents give more attention to more important features (according to the less important features) and are, therefore, more certain about their decision in a certain area (country). however, it is entirely possible for one distribution to have a larger standard deviation than another distribution, while each person in the distribution with the larger standard deviation is as or more certain of their position than the individuals in the distribution with the smaller standard deviation. the scale the authors use measures only importance, not how certain the respondent is about their reply. when it comes to financial features, there are visible similarities between slovenia and poland, where the three most influential features are "fuel economy", "the total price of the vehicle", and "maintenance/repair costs". "fuel economy" is also a priority in spain, and this feature is crucial, especially nowadays since oil prices are high and still increasing. "value for money" and "trade-in value" seem to be especially important in spain. "warranty" and "methods of payment" also have significantly higher grades in spain. these features indicate that spanish purchasers are different from their slovenian and polish counterparts and are much more interested in financial features correlating long-term security related to value for money. in contrast, similarities between slovenia and poland are evident. a less important feature in all three countries seems to be "annual road tax". the average grade for individual financial features was similar in slovenia and poland with clear differences among potential spanish zev buyers (fig. 2) . the three most important and three least important "financial" features of zevs are presented in table 4 . "total vehicle price" was found to be the most important financial feature for participants from slovenia and second most important for poland. for spaniards, "total vehicle price" was among the three least important features. in contrast, "annual road tax" and "methods of payment" are the least important features in all three countries. (however, "methods of payment" does have a much higher average grade in spain.) therefore, these two measures should not be enforced for the promotion of zevs because they appear to have a relatively small impact on purchasing decisions. the same conclusions as for table 3 can also be seen from the data in table 4 : standard deviations at most important features represent more concentrated values around the mean value than in case of least important, for which the values are more dispersed around the mean value. from fig. 2 and table 4 , it can be seen that the three observed markets have certain similarities and, more importantly, also differences that must be taken into account by government authorities when promoting low-emission vehicles and by car manufacturers and retailers when designing marketing strategies for such vehicles. t-tests (two-tailed tests with means paired) on the mean and standard deviation values of the above-described features in figs. 1 and 2 are represented in fig. 3 . a three-time t test on two sets of mean values for each non-financial feature in fig. 1 shows that data from slovenia and poland are not significantly different; a more significant difference is found between mean values between slovenia and spain, features differ from each other more than means and more than standard deviations in the case of non-financial features. in our opinion, these differences can be attributed to the subjectivity that affects customer preferences. moreover, the respondents were asked about the influence of petrol and diesel prices on their purchasing decisions. in this case, the analysed data for slovenia, spain, and poland reveal strong similarities among them. approximately 11 percent of all participants (12% in spain, 10% in slovenia, and 9% in poland) were already seriously considering buying zevs at current petrol prices. if petrol prices increased by 30%, approximately 59% of respondents (58% in slovenia, 62% in spain, and 55% in poland) would begin thinking about buying zevs, which is a rather high percentage, since a 30% increase in petrol prices over several years is not an unlikely situation. the cumulative results are presented in fig. 4 . in the period from december 30, 2008, to april 2014, petrol prices in slovenia increased by 83% (from €0.827/l to €1.514/l). after that, a slight decrease was noted, and in 2017 and 2018, petrol prices increased again within the eu, while in 2019 and 2020, they decreased during an opec "oil price war" and in response to the decreased consumption during the 2020 pandemic (approximately €1/l). zev sales slovenia spain poland fig. 4 dependence of increasing fuel prices on zev demand in slovenia, spain, and poland also increased significantly in the same period. increasing fuel prices are motivating people to start to considering buying zevs since their usage cost is not that dependent or even completely independent of oil prices (fig. 4) . it is also easier to guarantee competitive transportation costs with technologies that are powered by local resources where the eu is not dependent on foreign suppliers. this will probably gain importance in redesigning supply chains after the corona virus pandemic. another key finding of this study is that people are more interested in the total price of the car than in different taxes when buying one. a smaller percentage of respondents are already thinking about buying a zev despite their slightly higher prices compared to conventional vehicles. however, this research determined that if the prices of environmentally friendlier and (in the long run) economical alternative decreased (by different percentages), the percentage of people seriously thinking about purchasing such a vehicle would significantly increase. the results are presented in fig. 5 . in fig. 5 , it is once more indicated that respondents from slovenia and poland have more similar preferences about decreased prices of zev than spaniards do. data analysis shows that spanish consumers are even more interested in potential changes in zev prices (especially smaller changes up to 15%) and that the share of potential consumers prepared to consider a zev as a real alternative (if its price would decrease) is much higher than in slovenia and poland. one possible reason for this is that spain set ambitious targets for the future uptake of some zevs with the primary objective of supporting national and international policies for tackling climate change. in support of these targets, spain has provided financial support to stimulate both the development and market uptake of these types of vehicles (aea 2009). every population comprises different individuals with varying susceptibility levels of changing their behaviour (anable 2005; carreno and welsch 2009) ; potential zev buyers in slovenia, poland, and spain were segmented with cluster analysis. cluster analysis/segmentation was, therefore, undertaken to identify population segments within the slovene, spanish, and polish driving populations, resulting in three distinct segments with different perceptions of susceptibility to zevs, as presented in table 5 . based on their response regarding the importance of situational factors and strength of psychological constructs, the following groups/clusters were formed (adapted from borthwick and carreno 2012): • group one: 19% in slovenia, and 8% in spain), • group two: go-with-the-flow greens (42% in slovenia, 40% in poland, and 32% in spain), and • group three: go-greens (60% in spain, 40% in poland, and 38% in slovenia). slovenia spain poland table 5 diversification of different segments of study participants * the "go-with-the-flow greens" segment includes participants that are interested in environmental issues or consider zevs in the future but are not interested in environmental issues and consider buying a zev in the future as the "go-greens" are segments/clusters "no-greens" "go-with-theflow greens"* "go-greens" are you interested in environmental issues? have you considered buying a zev in the future? the people in the third group ("go-green") are very interested in buying a zev in the near future, and they are aware of their responsibility to reduce their environmental impact. "go-with-the-flow greens" are interested in environmental issues or have a positive opinion about zevs and are considering buying one because others are talking about it or considering purchasing zevs in the future. "no-greens" are not interested in buying a zev in the foreseeable future. information about vehicle emissions is also not a priority when deciding about buying another new or used vehicle. figure 6 shows that the share of women is much higher in "go-green" and "go-with-the-flow" segments than the share of men. the share of women in the "no-greens" group was approximately one-third that of men in slovenia and spain and approximately one-fifth in poland. this can be noted in all the studied countries; therefore, the authors have concluded that women have a greater interest in zevs. the results are presented in fig. 7 . differences between countries are significant: 20.7% of the polish population above 45 years of age can be defined as "no-greens", 5.5% in slovenia, and none in spain. the most important difference is that the ratio of "go-greens" is increasing with age in slovenia. the distribution of "go-greens" among different age groups in poland is very similar, but in spain, it is the opposite of slovenia since the ratio of "go-greens" is decreasing with age. in spain, the younger population shows a more substantial commitment to the "go-green" group, but at the same time, there are more undecided or undefined in the middle-aged group. still, there are no "no-greens" in spain in the age group of 45 years or more. the "go-with-the-flow" group (or "undecided") is presumably also the most susceptible to turning into "go-greens" or "no-greens". the share of the "go-withthe-flow" group also differs significantly in the studied countries. it is similar in different age groups in poland but is very different in slovenia and spain. the highest population share that has identified themselves as "gowith-the-flow green" was noted in spain for the age group of 45 years or more and the lowest in slovenia for the age group of 35-44 years. the higher importance of co 2 and other emissions was identified as the main reason for that. moreover, "go-with-the-flow greens" are also more concerned about noise emissions. furthermore, the effect of different measures that encourage people to purchase a zev was studied. table 6 shows that different measures would have different impacts in different countries (e.g. "parking charges partly based on carbon emissions" are much more important for spaniards than slovenians or poles). the studied measures reflect different possibilities for the promotion of zevs, focusing on rewarding them (e.g. with time-saving or pricing incentives). time-saving measures (e.g. "low-emission vehicle lane") were evaluated as less important in all three studied countries than pricing incentives (all other studied measures). according to the results in table 6 , various measures can differently influence people to purchase a zev. differences are also clearly seen among the studied countries. for example, the measure "vehicle scrappage scheme" was defined as the most important measure for the promotion of zevs by study participants from all three studied countries. however, the average result in slovenia was 5.9, in spain 5.8, and in poland 4.7, meaning that even though it is the most important measure, it will probably have a smaller impact in poland than in spain and slovenia. "low-emission vehicle lane" and "parking charges based on carbon emissions", in contrast, seem to be more important and potentially more influential in spain than in poland and slovenia. high average scores for many measures indicate that a multiple-measure customer-oriented approach must be used for efficient zev promotion. study participants from poland assigned a significantly lower average importance to all measures for the promotion of zevs, which could mean that the polish market is not yet as prepared for zevsand that environmental consciousness is lower than in slovenia and spain. there were some similarities in identifying the most important financial as well as non-financial features for purchasing zevs between slovenia, spain, and poland. similarities were most visible when comparing slovenia and poland, which might be supported by similarities in culture and lifestyle among both studied slavic countries. however, poles assigned significantly lower average importance to zev promotional policy measures than spanish and slovenian participants, which is also consistent with the zev sales, which have the lowest share in poland. one reason for this could also be seen in petroleum prices, which are on average lower in poland than in spain and slovenia. different studies, as well as the results of this study, reveal that there is no single measure that would dramatically increase the demand for zevs except a large decrease in zev prices. consumer behaviour can be different in different geographic areas (andre et al. 2018 ) and can also be non-rational (mccollum et al. 2017) . all three governments must be aware that universal measures do not exist and that they are not as effective as customer-oriented measures. while the results are not to be generalized to all eu member states, they provide valuable orientation for emerging research and policy directions. the national academy of sciences (2013) report knez (2017) , and knez and obrecht (2017) also pointed out that there is no consensus on which policy measures are most effective and influential for the customers' decision-making process. if the governments want to increase interest in purchasing zevs, they should adjust and adopt a variety of different measures. as proved by zhao et al. (2019) , the implemented incentive policy must also be dynamic and not static to achieve the best results, so measures should be adapted easily. zhao et al. also mentioned that the newly launched regulation in china is anticipated to have a huge impact on the development of chinese as well as global zev markets. however, the regulation likely faces the risk of losing this positive effect in approximately 5 years pan or even earlier; therefore, relevant policies should be modified before such a scenario occurs. taxation as well as policy measures impacting zev use and commercialization will thus also vary in the future and must be considered in long-term environmental policies. this comply to the finding that "annual road tax" is not an important issue when considering a new zev since it is a relatively small expense in comparison with, for example, the total vehicle price. regardless, many eu countries proudly promote zev with an annual road tax that is related to vehicle emissions. zhou et al. (2019) , for example, argue that the taxation preference had better performance in incentivizing evs than the direct subsidies, which is contrary to current political discourses. cleaner technology acceptance rate and susceptibility to policy measures differ regarding the attitudes and values towards zevs. defined groups of "go-greens" (with the highest share in spain), "go-with-the-flow greens", and "no-greens" (with the highest share in poland) have shown very small shares of women among "no-greens" in all three studied countries, especially in spain and poland. in contrast, men are distributed more equally. other studies (borthwick and carreno 2012; lina and wu 2018) also proved that demographics, attitudes, knowledge, values, and behaviour may influence potential intentions to buy environmentally sound products. it is also significant if an engineering and technology background is identified for a potential user since they are more open to buying electric vehicles, for example, than the general public is (egbue et al. 2017) , which might also be one of the reasons why "go-greens" are more open to zevs since we can assume that they are better informed about new clean technologies than other groups are. car drivers in all studied countries are more familiar with information about fuel economy and the direct financial consequences of driving than information about a car's environmental influences (e.g. carbon emissions). recent studies of cramton et al. (2018) and mccollum et al. (2017) also confirmed that in general, the public is more aware of clean technology financial features instead of environmental impacts. potential buyers of zevs are poorly aware of the meaning of "grams of co 2 per 100 kms"; therefore, the car manufacturers and retailers, as well as supporting policies for zev promotion, should focus on information about how much money could be saved by buying a zev. there are measures that were proven to be successful at limiting and reducing ghg emissions in the transportation sector. varbanov et al. (2018) also summarize that the ghg emissions eu-28, as well as the usa, have been showing a decreasing trend in recent years. even the growth rate of chinese ghg emissions has been slowing down; however, these reductions are not yet enough to reach climate targets. this paper would prove most successful if awareness of clean technology need is recognized by car manufacturers as well as policy decisionmakers. this is particularly relevant in 2020, when the focus and scope of green eu recovery plan challenged by restarting european automobile industry. technical limitations of some zev, such as insufficient charging infrastructure (for evs, hfcvs, etc.) or hydrogen storage and v2g concept development within smart communities, and similar, seem to loosen their impact with technological development and greater commercialization. both the eu and china are focused towards evs that are up to five times more efficient than internal combustion engines (duić 2015) and could, therefore, enable more sustainable transportation and efficient use of local resources simultaneously. evs will also need to deal with battery end-of-life solutions to comply with circular economy principle and the development of comprehensive models for electricity generation, charging, and storage (especially hfcvs) to power cleaner transportation alternatives. the life cycle perspective needs to be studied in detail when choosing future transportation technology priorities on the policy level (obrecht and denac, 2016) . this study provides a practical contribution to the understanding of different features influencing zev as a potential technology for cleaner future transportation and the development of supporting environmental policies in slovenia, poland, and spain. our main findings are that study participants from different countries identified different features as the most important for the promotion of zevs and these can determine future policy requirements for zev in european countries. there were also significant differences among segments with spain leading in gogreens and poland that seems to be less prepared for zev as well as genders since women are in all three studied countries more interested for zev than men. future research should therefore focus on integrating multiple variables that could boost or decrease interest in zev and therefore significantly impact country-specific policy recommendations, such as different geographical conditions (e.g. lowlands, alpine/mountain regions), population density, and climate conditions. special attention should be oriented towards differences among different regions (e.g. asia, america, and other eu member and non-member states) to see how different geographically specific and distant potential zev users see most potential policy measures as well as zev future. unknowing but supportive? predispositions, knowledge, and support for hydrogen technology in the netherlands market outlook to for battery electric vehicles and plugin 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theory of planned behaviour technology development for electric vehicles under new energy vehicle credit regulation in china: scenarios through 2030 impact of policy incentives on electric vehicles development: a system dynamics-based evolutionary game theoretical analysis publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-315248-hww7duvj authors: albaladejo, isabel p.; gonzález-martínez, maría isabel; martínez-garcía, maría pilar title: a double life cycle in tourism arrivals to spain: unit root tests with gradual change analysis date: 2020-12-31 journal: journal of destination marketing & management doi: 10.1016/j.jdmm.2020.100497 sha: doc_id: 315248 cord_uid: hww7duvj the tourism area life cycle (talc) theory by butler (1980) proposes an s-shaped growth trend for the evolution of the number of tourists to a specific tourist destination. according to the data on tourist arrivals in spain from 1946 to 2015, there may have been one or two life cycles. this paper sets out to test these hypotheses by unit root tests with gradual change. the results confirm that a double s-shaped or bilogistic curve is the long-run equilibrium, thereby validating the existence of two talcs in the evolution of spanish tourism. the two logistic curves overlap in the late 1970s and early 1980s. the first is characterized by the spanish tourism boom in the 1960s, while the second illustrates the intense growth from 1995 to 2007, a period of sustained world economic growth. the covid-19 pandemic outbreak has rocked the world's economies. the attempts to control the disease have led to restricting travels and meetings, and this has had deeply harmful effects for tourism, a strategic sector for the spanish economy. the resilience of the tourism industry in spain has been tested on several occasions: at the beginning of the 1980s, after the oil crisis; during the 1990s, after the gulf war (1990) (1991) and during the years following the great recession of 2008. now, when a new recession is feared, it has become necessary to know how tourism reacts to crises and how it recovers after the subsequent economic expansion. although our research is focused on the time before covid-19, some valuable insights into the future can be inferred. this paper offers a methodology to study tourism evolution over time. the proposed method is inspired in the tourism area life cycle (talc) theory proposed by butler (1980) , which advocates an s-shaped trend for the evolution of tourism. following this theory, the method used in the present paper allows for a non-linear trend for tourism evolution, with one or two s-shaped cycles. the paper shows that it has been successful in capturing slowdowns in the crises, as well as speedups during economic recoveries, in spanish tourism for the period 1946-2017. the literature on the talc theory has grown greatly since 1980 (butler, 2006a; 2006b) . several studies exist that propose more than one phase of s-shaped growth in tourism. some theoretical extensions note that mature destinations have passed through different consecutive life cycles (garay & cànoves, 2011; petrevska & collins-kreiner, 2017) . moreover, there are situations where choice or necessity may lead a destination to improve its traditional product or enlarge its market, or even abandon either of them in favor of a new start (baum, 1998) . this could be the case in many destinations after the covid-19 crisis. should this prove to be the case, the emergence of a new tourism life cycle will be witnessed. although the talc theory is widely accepted among tourism economists, to the best of the authors' knowledge the literature lacks econometric tests supporting it. in this paper a formal model is proposed, with one or two s-shaped tourism life cycles, that can be tested with real data. taking into account the logistic growth models by lundtorp and wanhill (2001) and albaladejo and martínez-garcía (2017) , this paper will show that the talc theory can be validated by testing whether a logistic or bilogistic growth trend is a long-run equilibrium path to tourism evolution. specifically, it is argued here that unit root tests with gradual change, as proposed by leybourne et al. (1998) and harvey and mills (2002) , are suitable to test the talc theory. these tests use the logistic smooth transition function to model structural changes, and they allow us to analyze persistence, taking into account the possibility of one or two phases of s-shaped growth. the ability to capture smooth transitions in economic variables makes unit root tests with gradual change very suitable tools to test persistence in tourism time series. the unit root tests that have usually been applied to tourism series, however, only take into account instantaneous structural changes (charles et al., 2019; lean & smyth, 2009; narayan, 2005a narayan, , 2005b perles et al., 2016 among others) , which do not allow s-shaped trends, as the talc theory defends. the present paper applies the proposed method to the time series data on international tourism arrivals in spain for the period 1946 to 2017. the empirical results show that the evolution of tourism in spain is favorable to the talc theory with two cycles. the long-run equilibrium path is estimated and dating of the stages of the tourism in spain is provided. the equilibrium path captures the 1960s development stage, the rejuvenation of the sector from the mid-1980s and the new development stage prior to the economic and financial crisis of 2008. in addition, our results indicate that, in the case of spain, the economic crises, such as the 1970s oil crisis or the 2008 economic recession, are related to the period of tourism stagnation in each of the cycles. the nonlinearity of the estimated trend brings to light that revivals after crises do not arise abruptly, but smoothly, gaining speed over time. the paper is organized as follows. section 2 provides a literature review of the talc theory and the most recent advances in the study of tourism evolution. section 3 presents an overview of tourism data for spain since 1946. the data reveal that several socioeconomic and historical events define two different stages in the temporal evolution of international tourism arrivals. section 4 explains the logistic and bilogistic models, showing their relationship with the unit root tests with smooth transitions. section 5 uses these unit root tests to analyze the validity of the logistic and bilogistic growth models in the case of spain. section 6 provides some conclusions. the talc theory, as proposed by butler (1980) , is one of the most widely accepted theories regarding the evolution of tourist destinations. the theory argues for the existence of an s-shaped life cycle in the development of destinations with six key stages from exploration to a final post-stagnation stage, where decline, rejuvenation or other intermediate solutions are possible (see fig. 1 ). each lifecycle stageexploration, involvement, development, consolidation and stagnationis characterized by a different growth rhythm and the upper limit of the curve is determined by the carrying capacity of the destination. the talc theory has been widely used as a conceptual framework for studying the evolution of tourism areas, giving rise to a large number of works where it has been applied, applauded, criticized, and complemented with other contents and methods. the relevance of this theory in tourism economics is highlighted by lagiewski (2006) , who presented a selection of 49 relevant works related to the talc theory. noteworthy also is the two-volume book edited by butler in 2006 (butler, 2006a , which provides an important collection of research papers using the talc theory. today, the references to the talc theory are still numerous, as a web search of the term talc confirms. many of these studies apply the talc theory to specific destinations, describing their changes over time and defining their stages. some studies show that the life cycle of the analyzed destinations matches the six stages defined by talc (cooper & jackson, 1989; douglas, 1997; ioannides, 1992; priestley & mundet, 1998; strapp, 1988; tooman, 1997; zhong et al., 2008) . other studies find that the assessed destination life cycle is not entirely represented by the six stages of the talc theory (getz, 1992; weaver, 2000) . some studies add a 'pre-tourism' stage (young, 1983) or discuss the possibility of alternative stages after stagnation (agarwal, 1994; hovinen, 2002) . many studies debate how to measure and identify the lifecycle stages (getz, 1992; lundtorp & wanhill, 2001) . many others show that internal and external factors of the destination can affect the shape of the tourism trend ( (agarwal, 1997) ; ioannides, 1992; zhong et al., 2008) . the talc theory has also been combined with several other theories to overcome or improve some limitations and weaknesses. chapman and light (2016) consider the destinations as a mosaic of different elements, each of which follow a life cycle according to the talc, but which all fit together. holmes and ali-knight (2017) propose an extension of the talc theory adding seven other different trajectories. kubickova and martin (2020) consider government involvement and destination competitiveness to explain destination development from supply and demand perspectives. there is a new research trend which combines the concepts of the theory of evolutionary economic geography within the evolution of tourism areas (brouder & eriksson, 2013; brouder & ioannides, 2014; ma & hassink, 2013) . this new approach supplements the talc model with concepts as path dependence, co-evolution, complexity, and generalized darwinism. path dependence focuses on the initial conditions and existing knowledge. in addition to policy measures or any other triggers, the emergence of tourism also depends on preexisting natural or cultural resources, adventurers' experience, location advantage, and economic base. moreover, the development of a tourism area is the outcome of the co-evolution of tourist sectors, tourist products and institutions. the adaptation ability of a tourist area to ever-changing circumstances is essential for avoiding the decline (generalized darwinism). some applications of these concepts to specific tourism resorts are ivars i baidal et al. (2013) , ma and hassink (2013) , and faisal et al. (2020) among others. a number of studies propose more than one phase of s-shaped growth in tourism destinations. baum (1998) presents some examples and proposes two theoretical extensions to the talc theory, acknowledging that there are situations where choice or necessity may lead a destination to abandon its traditional product and market in favor of an entirely fresh start. garay and cànoves (2011) assert that major destinations have a long history and have passed through different consecutive life cycles, boosted by different regulatory measures. they illustrate their theory with the example of catalonia. also, for the case of some mathematical models have also been proposed to represent the talc theory. lundtorp and wanhill (2001) , with data of passenger flows to bornholm from 1912 to 2001, find that the logistic growth model fits the first phases of the talc theory well. however, since the logistic model assumes a fixed tourism market ceiling, it fails to explain the post-stagnation stage, where rejuvenation, decline, or any other intermediate possibility may arise. albaladejo and martínez-garcía (2017) go further and propose a multilogistic growth model, which is characterized by a non-constant carrying capacity, to represent the superposition of several life cycles in the tourism performance of a destination. entrepreneurship or governments may induce a rise or decline in the tourism market ceiling by improving infrastructures, enlarging the variety of tourism services offered or implementing regulatory measures or, as has happened since the covid-19 outbreak, travel restrictions or capacity reductions. the new model by albaladejo and martínez-garcía (2017) takes into account how these economic and social measures modify the carrying capacity. moreover, the authors estimate the multi-cycle model with the same data as lundtorp and wanhill (2001) . they find that this model fits the data better than a simple logistic function. following these papers, the present paper proposes a methodology to validate the talc theory. the contribution of the paper to the literature is two-fold. firstly, it will show that the unit root tests with gradual change allow to test if a s-shaped trend (with one or two cycles) is a long-run equilibrium path. secondly, it will demonstrate that tourism in spain has followed a double cycle trend. spain began its way in the tourism sector at the final years of the nineteenth century when it appeared tentatively on the lists of peripheral tourist destinations as had greece and egypt (cirer-costa, 2017). since then, it has had a dynamic evolution influenced by several situations and has become a firmly consolidated tourism destination. according to data from the world tourism organization (unwto, 2019), in the 2018 ranking of countries, it was the world's second largest destination, surpassing the us and only behind france in international tourist arrivals (82.8 million), and only behind the us in receipts (us $73.8 billion). to study the evolution of spain as a tourism destination, this paper analyzes the arrivals of international tourists from 1946 to 2017. the statistical sources on tourism and passenger movement to spain, the spanish national statistics institute (ine) and the institute for tourist studies provide only estimates for the number of non-resident visitors from 1950 to the present, but pellejero-martínez (2002) gives the numbers of arrivals from 1946 to 1949. 1 prior to this, in the first three decades of the twentieth century, the number of foreign tourists to spain was already on the rise and tourism companies were already in existence (pack, 2008) . however, the spanish civil war (1936) (1937) (1938) (1939) brought about a decline in transport and accommodation infrastructures. the international isolation of spain after the end of the second world war (1939) (1940) (1941) (1942) (1943) (1944) (1945) also had profound negative effects on tourist arrivals. fig. 2 shows the numbers of international tourists arriving in spain from 1946 to 2017. as can be seen, international arrivals in spain have grown continuously since 1946, with several growth phases and even some years of decrease. the data in this figure show two different periods of intense growth. the first was driven by the tourism boom during the 1960s, and the second was characterized by an accelerated growth at the end of the 1990s and the first years of the 21st century. both periods of intense growth were followed by periods of deceleration, so two life cycles could better explain tourism evolution in spain. in what follows the historical and economic events during the period are presented. after the spanish civil war and the second world war, tourists began to arrive again although in very low numbers compared to previous years (pellejero-martínez, 2002) . spain was offering a sea and beach tourism at low prices compared to other mature mediterranean destinations like france and italy (pack, 2008) . in addition, in 1951 the ministry of information and tourism was created to coordinate all tourism activities and in 1953 a national tourism plan was proposed with the aims of promoting tourism, improving infrastructures and intensifying advertising abroad (pellejero-martínez, 2002) . in the second half of the 1950s, the number of tourists exceeded 3 million. the supply of accommodation also grew and was heavily regulated and controlled (pellejero-martínez, 2002) . tourism in spain was on the up. the 1960s were the tourism boom years in spain (pellejero-martínez, 2002; vallejo, 2002) . the 'stabilization plan' of 1959, which, among other changes, devalued the peseta by nearly one-third, had an almost immediate effect on the european tourists coming to spain for sun and beach tourism (sánchez-sánchez, 2001 ). the number of tourists grew from 5.4 million to over 20 million, and as a consequence, the number of hotel establishments multiplied by three and hotel beds by four (pellejero-martínez, 2002) . the tourism sector began to develop in spain. during the 1970s, the tourism sector in spain slowed down. it suffered sharp drops and rises. in 1973 the first oil crisis began which, together with the decline of franco's dictatorial regime (he died in 1975) , and the democratic transition in spain, led to a short period, from 1974-1976, where the number of tourists decreased. in 1977 the tourists were higher than in 1976, but this new growth lasted just two years (1977 and 1978) . the second oil crisis in 1979 was decisive in causing negative growth for two years, 1979 and 1980, but again in 1981 the tourists were more than in 1978. in the 1980s, spain seemed to start a period of rejuvenation in tourism. during the first years of the spanish democracy, which began with the constitution of 1978, the tourism model underwent some changes. the price of hotels was no longer fixed by the state; there was a decentralization of tourism policy to the autonomous communities that make up spain under the new constitution and, while not forgetting the importance of quantity, there was a certain interest in quality, competitiveness, diversification and sustainability in tourism (pellejero-martínez, 2002) . all this, together with the entry into the european economic community (1986), boosted tourism arrivals and spain experienced a period of light growth (1984) (1985) (1986) (1987) (1988) . from 1989 to 1995, the number of international tourists again fluctuated. the gulf war (1990 war ( -1991 , which led to an international economic slowdown, and the crisis in september 1992 and august 1993, which hit the european monetary system (due to the obstacles that european countries faced in trying to achieve their ultimate goal of full monetary union), contributed to falls in the number of tourists. but this crisis also meant in spain the devaluations of its national currency in 1992, 1994 and 1995, which had a positive effect on tourism in the subsequent years. additionally, in 1992, spain started a strategic policy aimed at boosting tourism competitiveness, plan futures, and entrepreneurs made significant investments in their facilities (zoreda & perelli, 2014) . expo 92 and the olympic games contributed significantly to spreading the image of spain worldwide. from 1995 to 2007, the number of international tourists grew continuously. spanish tourism experienced a second strong development period. it was a sun and beach destination with low prices appealing to many tourists. moreover, some geopolitical circumstances, like the yugoslav wars from 1991 to 2001 or the luxor massacre on 17 november 1997, moved tourists to spain. since 2013, due to the beneficial effects of the economic recovery in europe together with the impact of the arab spring, the number of international tourists has grown uninterruptedly. this seems to indicate that tourism in spain could be beginning a new growth cycle that has been truncated by the actual covid-19 crisis. according to albaladejo and martínez-garcía (2017) , several life cycles in tourism can be formally represented by a multilogistic growth model. previous historical reviews show that up to two life cycles could have taken place in spain during the period of time studied. this section presents the logistic and bilogistic growth models as particular cases of the multilogistic model, and the unit root tests with gradual changes as a suitable method to validate them. the logistic growth model (lundtorp & wanhill, 2001) is quite a good theoretical approximation of the s-shaped curve of the talc theory. however, since the logistic model assumes a fixed tourism market ceiling, it fails to explain the concatenation of more than one growth phase, as seems to have occurred in spain. albaladejo and martínez-garcía (2017) propose a multilogistic growth model, where the investment or innovation in the tourism sector boosts the addition of new logistic curves which superpose the old ones. this model allows a non-constant tourism carrying capacity. political measures or sociological and environmental factors can make this ceiling evolve to higher levels. the result is the superposition of several s-shaped curves which can be described by the following differential equations system: where t t is the number of tourists at time t, ṫ t is its temporal derivative, c t is the maximum level of tourist development and use (carrying capacity), whose temporal evolution ċ t is driven by u t , the variable which measures the effort (e.g. share of labor or capital) devoted to increasing c t . the parameters are γ, δ, φ > 0 and η ≥ 0. the parameter γ represents the intrinsic rate of tourism attraction, δ measures the productivity of an effort, u t ,φ are the returns to scale and η is the depreciation rate of the carrying capacity. equation (1) with a constant c t is the logistic growth model proposed by lundtorp and wanhill (2001) to represent the sinusoidal development of a tourist destination. this logistic curve generates the first five phases in the development of a resort described by the talc theory (fig. 1) . equation (2) was introduced by albaladejo and martínez-garcía (2017) to allow for the possibility of increases in the tourism carrying capacity. any capacity increment requires economic or human efforts, u t , in the form of investment in infrastructures, in accommodation or in r&d. albaladejo and martínez-garcía (2017) follow the growth models tradition (solow, 1956, if there are decreasing returns to scale, or rebelo, 1991, if there are constant returns to scale) to model carrying capacity increments. the growth of tourism carrying capacity c t , depends on u t , whose value is given by the entrepreneurship activity, government spending on infrastructures and services or tourism promotion polities. if depreciation η is nil and no investment is made (u t = 0 for all t), then the carrying capacity will remain constant at the level c. this is the case of the logistic model by lundtorp and wanhill (2001) . if this is so, the solution of differential equations (1) and (2) is where s t (γ, λ) is the logistic function given by: where λ is the turning point, that is, s t grows with t at an increasing speed if t ≤ λ, and, although growing also if t > λ, the speed reduces as t grows from λ. note that if t = λ, tourism occupation is 50% of its maximum level, c. moreover, if t = 0, the number of tourists given by (3) is the initial one t 0 and if t→ + ∞ the number of tourists approaches c, the maximum level of tourism exploitation if no investment in this sector (u t = 0 for all t). equation (3) models the transition between two levels of tourism t 0 and c. the parameter γ determines the speed of transition. if γ is close to zero, the transition is very smooth. as γ takes values farther from zero the transition is less smooth and the change becomes more abrupt. when it approaches infinity, the transition is instantaneous. this specification is . flexible enough to represent processes with instantaneous transition (γ→ + ∞) or without any change as limiting cases (γ→0). this sinusoidal curve (3) is represented in fig. 3 . in (3) it is assumed that the choice of the decision rule u t = 0 is made at time t = 0 and the planner (government/entrepreneurship) will always maintain this policy rule. however, if tourism promotion is one of the objectives of the planner, at a certain date t, they could decide to invest in increasing the tourism capacity. this could have been the case of the spanish plan futures in the 1990s, which may have encouraged the investments in infrastructures and tourism facilities renovation. if so, tourism carrying capacity increases from an initial level c 1 to a higher one, c 2 . inspired by the case of spain, this paper considers the following decision rule: where u is the net investment (deducting depreciation) on increasing tourism capacity from the date t up to the date when capacity reaches the new level c 2 . once this higher capacity is reached, investment vanishes. if this policy rule is adopted, two life cycles can concatenate, as depicted in fig. 4 , where the initial carrying capacity is c 1 and the final one is c 2 . as proved in albaladejo and martínez-garcía (2017) , the solution of this differential equation system is the bilogistic growth model: where s it (γ i , λ i ) are logistic functions: times λ 1 and λ 2 are the midpoints of two transitions. parameter γ i determines the speed of each transition, and γ 1 and γ 2 are allowed to differ. equation (6) models the transition between t 0 to c 1 and, finally, to c 2 . both models (3) and (6) could be a good approximation of the talc theory, with either one or two s-growth periods. the talc theory also has implications for the persistence in tourism time series: shocks to the tourism sector must be transitory around a non-linear trend represented by at least one s-shaped curve. the traditional approach to looking at the degree of persistence of a time series is to apply unit root tests. these tests have been widely used in empirical tourism literature to determine the transitory or permanent effects of economic crises or other types of shocks on tourism (charles et al., 2019; lean & smyth, 2009; narayan, 2005a narayan, , 2005b perles et al., 2016, among others) , and to examine the convergence hypothesis for tourism markets (lean & smyth, 2008; narayan, 2006; tang, 2011) . however, to the best of the authors' knowledge, they have never been applied to test the validity of the talc theory. besides this, most of them consider under the alternative a stationary process around either a linear trend or a linear trend with one or more abrupt breaks, neither of which allows an s-shaped evolution as the talc theory predicts. an increment in the carrying capacity means devoting efforts to tourism investment and a time lag is necessary to achieve the desired carrying capacity. moreover, a higher carrying capacity increases the growth rate of tourism arrivals, but, again, a time lag is necessary for the number of tourist to achieve the new limit. thus, tourism arrivals will not react instantaneously to an increment in the carrying capacity, so, the temporal evolution of a tourism series is likely to be better explained by a model that allows gradual rather than instantaneous adjustment. this paper proposes the use of unit root tests with gradual change, as suggested in leybourne et al. (1998) and harvey and mills (2002) , to test whether there have been one or two life cycles in spanish tourism. these procedures test whether a series is stationary around a deterministic component with one structural change (leybourne et al., 1998) or two structural changes (harvey & mills, 2002 ) which can occur gradually over time. both tests model changes using logistic smooth transition functions, allowing an s-shaped evolution of tourism arrivals (the test by leybourne-newbold-vougas) or a double s-shaped evolution (the harvey and mills test). therefore, these tests are suitable tools to test empirically the logistic and bilogistic growth model, respectively, and the talc as a whole. when using the leybourne et al. (1998) unit root test, model a is considered for the alternative hypothesis because it coincides with the logistic model proposed in (3). this specification contains no trend and involves an s-shaped transition in the deterministic mean. it follows that: 2 where α 0 is the intercept, υ t is a i(0) stochastic process with zero mean, and function s t is given in (4). parameter τ ∈ [0, 1] determines the timing of the transition midpoint λ = τz, where z is the sample size of the time series. when using the harvey and mills (2002) unit root test, model a is also considered for the alternative hypothesis. it contains no trend and involves a double transition in the mean only, as in the bilogistic growth model (6). this alternative hypothesis is the following equation: where α 0 is the intercept, υ t is a i(0) stochastic process with zero mean, (3) is the stochastic error term υ τ . a constant α 0 is also added to capture those seminal tourists prior to the start of the logistic growth. nevertheless, as is shown later, this constant is not significant in the case of spain. and functions s it (i = 1, 2) are given in (7). parameters τ i ∈ [0, 1] determine the timing of each transition midpoint λ i = τ i z, where z is the sample size of the time series. both unit root tests are conducted using the following two-step procedure employed by leybourne et al. (1998) . the first step is to estimate the deterministic component of the model considered under the alternative by nonlinear least squares (nls) and compute the resulting nls residuals. the second step is then to estimate the augmented dickey fuller (adf) equation with the nls residuals and calculate the t-statistic associated with the ordinary least squares estimate of the coefficient of lagged residuals in adf equation. critical values are tabulated in leybourne et al. (1998) and harvey and mills (2002) . a rejection of the null hypothesis of leybourne-newbold-vougas test would indicate that the time series for tourism would be stationary around a single s-shaped curve. a rejection of the null hypothesis of harley-mills test would indicate that the shocks to tourism are temporary, and that tourism arrivals in spain would probably be a stationary time series around a double s-shaped curve, providing empirical evidence in favor of two tourism area life cycles. if tourism in spain followed a single s-shaped curve, the leybourne-newbold-vougas test would be more powerful than the harvey and mills one. however, their results could be wrong if this were not the case, that is if spanish tourism followed a double s-shaped curve. note that the specification of the process under the alternative in each unit root test is sufficiently flexible to nest, as particular cases, a stationary process without structural changes, as well as a stationary process with instantaneous changes. an additional advantage of both procedures is that they do not require us to predetermine the timing of the different phases of the life cycle since they allow the speed and the midpoint of each transition to be determined endogenously. the econometric study analyzes the time series data on arrivals of international tourists in spain from 1946 to 2017, presented in section 3. the unit root tests suggested by harvey and mills (2002) and leybourne et al. (1998) are applied to examine the persistence of shocks to this time series, taking into account a possible s-shaped evolution in the number of tourists. the results show that only the harley-mills test rejects the null hypothesis. both unit root tests were carried out for different sampling periods and the conclusions are robust in terms of sample selection. establishing the beginning of the sample in 1946, each of the last five years of the period analyzed (2013, 2014, 2015, 2016 and 2017) were considered as the final year. table 1 presents the leybourne-newbold-vougas and the harley-mills tests for each of these five sample periods. the unit root null hypothesis is not rejected for any series at the 10% level when the leybourne-newbold-vougas test is employed. in contrast, the harley-mills test rejects at 1% when the sample period ends in 2013, at the 5% level when the sample period ends in 2014 and 2015, and at the 10% level with the sample up to 2016 or 2017. the analysis thus confirms that this spanish tourism demand series follows a stationary process around a bilogistic function, although this empirical evidence is weaker when the analysis period includes the last two years of the sample. note that since 2013 the positive effect of the economic recovery of europe together with the outbreak of the arab spring may have generated a new cycle until the 2020 covid-19 crisis. this extreme will not be confirmed until this crisis reaches an end and more up-to-date data are available. in addition to conducting unit root tests, it is interesting to estimate the implied model in order to fit the corresponding bilogistic function. for this estimation, only the period 1946-2015 was considered, which is the longest sampling period where the null hypothesis of unitary root is rejected at least at 5% against the alternative of stationary around a smooth double transition. 3 the model was estimated with autoregressive errors, whose order is determined by the maximum lag order required in the adf equation, i.e. ar(2) errors. the intercept turned out to be non-significant, so it is disregarded in the estimation. table 2 shows the results of the nls estimation. all of the estimated coefficients of the double logistic function were significant and the analysis confirms a double transition in the evolution of this tourism demand series. since the estimated transition speeds take similar values not far from zero, 0.182 and 0.226, the transition between different states occurs smoothly for time series data on arrivals of international tourists, showing evidence in favor of two s-shaped growth periods. the estimated transition midpoint fractions were 0.342 and 0.780 corresponding to years 1970 and 2000. this means that the first growth period is centered around 1970 and the second near to 2000. thus, the estimated bilogistic function is the sum of two similar logistic functions with the midpoints separated by 30 years. finally, note that the estimated autoregressive coefficients do not suggest i(1) behavior. indeed, the autoregressive roots are complex, suggesting cyclical behavior about a double smooth transition in the mean. therefore, there is empirical evidence for a double s-shaped dynamic. fig. 5 presents the estimated deterministic double smooth transition (bilogistic curve) and the actual values of the international tourists arrival series. in general, the data are well represented by this function, which clearly shows the two rapid increases in tourism demand, from the early 1960s and again from the late 1990s until the beginning of the great recession. to provide a clearer interpretation of the results, the two estimated logistic functions (s 1t and s 2t ) are shown in fig. 6 . this figure also identifies the five stages (in fig. 1 ) of the life cycle in each logistic function. the date of these stages is obtained following the lundtorp and wanhill (2001) procedure. the first logistic curve represents the tourism demand evolution of spain from 1946 until the 1980s, when a rejuvenation process, represented by the second logistic curve, began in the spanish tourism sector. the second curve starts to grow when the first one has reached about 80% of saturation, and thus two overlapping s-shaped curves are visible. since the stages of consolidation and stagnation of the first logistic curve overlap with the first stages of the second curve, the stagnation in the number of tourists in the eighties predicted by the first logistic curve is avoided before it occurs and is unobservable in the data. regarding the first logistic curve, the exploration stage goes to 1957, when tourists slowly start to come to spain again after the spanish civil war and the second world war. the involvement stage, which assumes some regularity in tourism, is achieved in the second half of the 1950s (more precisely, from 1957 to 1963, according to this study's estimations). the development stage starts in the early 1960s, when, as has been explained, spain experiences a tourism boom with an important and continuous growth. the growth rate drops in the seventies as a result of the 1970s oil crises, and the last stages of this first s-shaped curve begin. the consolidation and stagnation stages date from 1977 to the end of the eighties. both stages overlap the first stages of the second logistic curve. this second curve shows the change of tourism trend, due table 1 international tourists. unit root tests with gradual change. to the arrival of democracy in 1978 and the entry into the european economic community in 1986. after the gulf war in 1990 and the european monetary system crisis in 1992, the growth rate of tourists arrivals increases. spain starts to be seen as a well-defined tourist destination. this new development stage goes from 1995 to 2007, coinciding with a period of uninterrupted world economic growth. with the great recession of 2008 this period of strong growth ends and the stages of consolidation and stagnation of the second curve begin. to summarize, the results of this study are in accordance with the talc theory showing evidence in favor of a double s-shaped dynamic in the evolution of spanish tourism demand. since the harvey-mills unit roots test indicates that the bilogistic function is a long run equilibrium path, shocks to the tourism sector are transitory around a non-linear trend represented by two overlapping s-shaped curves. this paper proposes a method to test if the non-linear evolution defended by the talc theory is a long-run equilibrium path for tourism data series. the logistic and bilogistic models by lundtorp and wanhill (2001) and albaladejo and martínez-garcía (2017) are well accepted as mathematical approximations to the talc theory. the analysis has shown the relationship between these models and the unit root tests with smooth transition by leybourne et al. (1998) and harvey and mills (2002) . their flexibility to capture smooth transitions in economic variables, and their ability to represent the talc theory, make them both very suitable tools to test persistence in tourism time series. these unit root tests have been applied to analyze whether there is a single or a double life cycle in spanish tourism from 1946 to 2017. the results confirm that a double s-shaped trend constitutes a longrun equilibrium path for spanish tourism and deviations from it are due to transitory shocks. the double life cycle is the result of the superposition of two logistics curves that account for the whole spectrum of stages described by the talc theory: exploration, involvement, development, consolidation, and stagnation. the first estimated logistic trend goes from 1946 to the 1980s, including the 1960s tourism boom. the second estimated logistic curve overlaps the first one during the 1980s, which shows a rejuvenation of tourism in spain, and captures the new development stage from 1995 to 2007. the evolution of tourism in spain after the great recession suggests the possibility of the beginning of a new third phase of growth which has been truncated by the current covid-19 crisis. there is a noticeable link between spanish tourism and economic performance in europe: the main spanish tourism market. the two stages of intense growth in spanish tourism occur in periods of european economic prosperity, while the economic recessions suffered in europe slow down the spanish tourism growth rate. moreover, our results also show that the recovery after recessions follows a non-linear trend, very slow initially but reinforcing and gaining speed with time. this means that early investments after a crisis could be crucial to boost this reinforcement process. once tourism is activated the feedback forces boost its growth and the speed of growth increases. after the covid-19 crisis, the economy will sooner or later reactivate. people will gradually return to their normal behavior patterns. however, tourism will emerge at a measured pace, at least until a vaccine is available. people will not hurry to go back to their traditional holiday places and full beaches, as they used to. visitors will come back to tourism destinations in small numbers initially (those who feel healthy, young or safe). as the economy recovers and the disease scope decreases, visitor numbers will increase, starting a new tourism life cycle. those destinations that control the epidemic first and succeed in providing security to the visitors (by mean of the necessary investments) will be the first to benefit from the feed-back forces, and will gain visitors at a higher rate as time goes by. once the process starts, in the light of our analyses, we do not expect a quick and linear recovery, which table 2 international tourists. nls estimation . i.p. albaladejo et al. would produce a trend with the shape of a v. tourism evolution is nonlinear, so the recovery will be s-shaped. future research will be needed to confirm this prediction. the resort cycle revisited: implications for resorts the resort cycle and seaside tourism: an assessment of its applicability and validity the post stagnation stage for mature tourism areas: a mathematical modeling process taking the exit route: extending the tourism area life cycle model staying power: what influences micro-firm survival in tourism urban tourism and evolutionary economic geography: complexity and co-evolution in contested spaces the concept of a tourist area cycle of evolution: implications for management of resources the tourism area life cycle. applications and modifications. clevedon the tourism area life cycle exploring the tourist destination as a mosaic: the alternative lifecycles of the seaside amusement arcade sector in britain how resilient is la réunion in terms of international tourism attractiveness: an assessment from unit root tests with structural breaks from turbulence in mediterranean tourism destination life cycle: the isle of man case study applying the life cycle model to melanesia (re)creating spaces for tourism: spatial effects of the 2010/2011 christchurch earthquakes life cycles, stages and tourism history: the catalonia (spain) experience tourism planning and the destinations life cycle unit roots and double smooth transitions the event and festival life cycle-developing a new model for a new context revisiting the destination lifecycle model tourism development agents: the cypriot resort cycle the evolution of mass tourism destinations: new approaches beyond deterministic models in benidorm (spain). tourism management exploring the relationship between government and destination competitiveness: the talc model perspective the applications of the talc model: a literature survey are malaysia's tourism market converging? evidence from univariate and panel unit root tests with structural breaks asian financial crisis, avian flu and terrorist threats: are shocks to malaysian tourist arrivals permanent or transitory? unit roots and smooth transitions the resort life cycle theory. generating processes and estimation an evolutionary perspective on tourism area development testing the unit root hypothesis when the alternative is a trend break stationary process: an application to tourist arrivals in fiji the structure of tourist expenditure in fiji: evidence from unit root structural break tests are australia's tourism markets converging? tourism, modernization, and difference: a twentieth-century spanish paradigm la política turística en la españa del siglo xx: una visión general economic crisis and tourism competitiveness in spain: permanent effects or transitory shocks? a double life cycle: determining tourism development in macedonia the post-stagnation phase of the resort cycle long-run policy analysis and long-run growth el auge del turismo europeo en la españa de los años sesenta a contribution to the theory of economic growth the resort cycle and second homes old wine in new bottles: are malaysia's tourism markets converging? application of the lifecycle model in tourism annual report 2010 a year of recovery international tourism highlights economía e historia del turismo español del siglo xx a broad context model of destination development scenarios touristization of traditional maltese fishing-farming villages tourism development and tourism area life-cycle model: a case study of zhangjiajie national forest park los 20 años que han revolucionado el sector turístico español isabel p. albaladejo harley-mills leybourne-newbold-vougas 1946 -2017 .69* (9) note: *,**,*** denote significant at the 10%, 5% and 1% level respectively. numbers in brackets are the number of lags included in the adf regressions, which is determined by the schwarz information criterion, considering 10 as the maximum. key: cord-274532-i1g9ikdb authors: tobias, aurelio; valls, joan; satorra, pau; tebe, cristian title: covid19-tracker: a shiny app to produce comprehensive data visualization for sars-cov-2 epidemic in spain date: 2020-04-06 journal: nan doi: 10.1101/2020.04.01.20049684 sha: doc_id: 274532 cord_uid: i1g9ikdb data visualization is an essential tool for exploring and communicating findings in medical research, and especially in epidemiological surveillance. the covid19-tracker web application systematically produces daily updated data visualization and analysis of the sars-cov-2 epidemic in spain. it collects automatically daily data on covid-19 diagnosed cases, intensive care unit admissions, and mortality, from february 24th, 2020 onwards. two applications have already been developed; 1) to analyze data trends and estimating short-term projections; 2) to estimate the case fatality rate, and; 3) to assess the effect of the lockdown measures on the trends of incident data. the application may help for a better understanding of the sars-cov-2 epidemic data in spain. the first confirmed cases of sars-cov-2 in spain were identified in late february 2020 (1) . since then, spain became, by the end of march, the third most affected country worldwide after the united states and italy and recorded the second number of deaths due to the sars-cov-2 pandemic after italy (2) . since march 16 th , lockdown measures oriented on flattening the epidemic curve were in place in spain, restricting social contact, reducing public transport, and closing businesses, except for those essential to the country's supply chains (3) . however, this has not been enough to change the rising trend of the epidemic. for this reason, a more restrictive lockdown was suggested (4), and eventually undertaken by the spanish government on march 30 th (5) . data visualization is an important tool for exploring and communicating findings in medical research, and specially in epidemiological surveillance. it can help researchers and policy makers to identify and understand trends that could be overlooked if the data were reviewed in tabular form. we have developed a shiny app allows users to evaluate daily time-series data from a statistical standpoint. the covid19-tracker app systematically produces daily updated data visualization and analysis of sars-cov-2 epidemic data in spain. it is easy to use and fills a role in the tool space for visualization, analysis and exploration of epidemiological data during this particular scenario. the covid19-track app has been developed in rstudio using the shiny package (6) . shiny offers the ability to develop a graphical user interface (gui) that can be run locally or deployed online. last is particularly beneficial to show and communicate updated findings to a broad audience. the app has a friendly structure based on menus to shown data visualization for each of the analyses currently implemetned: projections, intervention, and methodology sections ( figure 1 ). . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/10.1101/2020.04.01.20049684 doi: medrxiv preprint 3 -projections displays a plot with trends for daily icu admissions and mortality since the epidemic began and estimates a 3-day projection. -intervention displayes and calculates the effect of the lockdown period on the trend of incident data on daily diagnosed cases, icu admissions, and mortality. -methodology shows the statistical details on the analyses implemented. the app has an automated process to update data and all analyses every time a user connects to the app. it is available online at the following link: https://ubidi.shinyapps.io/covid19/ and shortly free available on github as an r package. we collected daily data on covid-19 diagnosed cases, intensive care unit (icu) admissions, and mortality, from february 24th onwards. data is collected automatically every day daily from datadista github repository (7). this repository updates data according to the calendar and rate of publication of the spanish ministry of health/instituto de salud carlos iii (8) . data corresponding to the available number of icu beds in spain (year 2017) are also obtained from the datadista github repository (7). . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/10.1101/2020.04.01.20049684 doi: medrxiv preprint for the evaluation of the observed trends of the accumulated number of cases, we used a classical quasi-poisson regression model (9), allowing for over-dispersion and with a logarithmic link function, evaluating the existence of a quadratic effect. the two models are described as follows: model 2: log(e(ct))=β0+β1t+β2t 2 where t = 1, 2, …, t represents the time unit (from the first observed day until the last, t consecutive days in total), and it assumes that ct, the observed cases, are distributed following a quasi-poisson probability law. estimated parameters and their standard error are used to obtain the predictions in the observed period of time but also the short-term projections, computing 95% confidence interval (95%ci)or the expected number of cases. the analyses have been carried out using r version 3.6.3. this analysis is accessible on the projections menu, displaying short-term projections up to 3 days for covid19 diagnosed cases, icus, and mortality in a time-series plot ( figure 2 ). results are available nationwide by default, but also at the regional level, allowing a dropdown menu for this purpose. in addition, the produced graph is mouse-sensitive, showing the exact number of observed and predicted/projected cases for both models through the time-series. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/10.1101/2020.04.01.20049684 doi: medrxiv preprint to assess the effect of the lockdown on the trend of incident cases, admissions in icu intensive care units, and mortality, we used an interrupted time-series design (10) . the data is analyzed with quasi-poisson regression with an interaction model to estimate the change in trend: log(e(ct))=β0+β1t+β2lockdown+β3t * lockdown where t =1, 2, …, t represents the time unit (from the first observed day until the last, t consecutive days in total); and lockdown is a binary variable that identifies the periods before after the alarm status decree (0 = before mar 15 th , 2020; 1 = after mar 16 th , 2020). the analyses have been carried out using r, version 3.6.3. we should acknowledge that this is a descriptive analysis without predictive purposes. for an easy interpretation, and comparison of the effectiveness of lockdown measures between countries, a linear trend is assumed before and after the lockdown. the changes in the definition of diagnosed cases have not been taken into account, nor has the reduction in the susceptible population because of the lockdown. therefore, the incident cases are modelled directly instead of the incidence rate, assuming that the entire population is at risk. although not accounted for residual autocorrelation, the estimates are unbiased but possibly inefficient. this analysis is accessible on the intervention menu, displaying trends in a time-series plot before and after the lockdown for covid19 diagnosed cases, icus, and mortality ( figure 3 ). the daily percentage (%) mean increase and its 95%ci are also reported. results are available nationwide. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/10.1101/2020.04.01.20049684 doi: medrxiv preprint so far, the covid19-tracker app has been very well received online, with a large number of connections generating an outsized memory usage on our server ( figure 4 ). we are currently planning to improve the app by uploading shortly new applications for data visualization and analysis, which may help for a better understanding of the sars-cov-2 epidemic data in spain. moreover, the covid19-tracker app could also be extensible to data visualizations across other countries and geographical regions. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/10.1101/2020.04.01.20049684 doi: medrxiv preprint none . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/10.1101/2020.04.01.20049684 doi: medrxiv preprint covid-19 in europe: the italian lesson oxford martin school, the university of oxford, global change data lab real decreto 463/2020, de 14 de marzo, por el que se declara el estado de alarma para la gestión de la situación de crisis sanitaria ocasionada por el covid-19 experts' request to the spanish government: move spain towards complete lockdown. the lancet real decreto-ley 10/2020, de 29 de marzo, por el que se regula un permiso retribuido recuperable para las personas trabajadoras por cuenta ajena que no presten servicios esenciales, con el fin de reducir la movilidad de la población en el contexto de la lucha contra el covid-19 integrated development for r. rstudio, inc limpieza y normalización de las tablas de la situación diaria acumulada de la enfermedad por el coronavirus sars-cov-2 (covid-19) en españa en un formato accesible y reutilizable 2020 situación de covid-19 en españa 2020 comparison of different approaches to incidence prediction based on simple interpolation techniques interrupted time series regression for the evaluation of public health interventions: a tutorial . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint . https://doi.org/10.1101/2020.04.01.20049684 doi: medrxiv preprint key: cord-017158-w2tlq6ho authors: moriones, enrique; garcía-andrés, susana; navas-castillo, jesús title: recombination in the tylcv complex: a mechanism to increase genetic diversity. implications for plant resistance development date: 2007 journal: tomato yellow leaf curl virus disease doi: 10.1007/978-1-4020-4769-5_7 sha: doc_id: 17158 cord_uid: w2tlq6ho mutation, reassortment, and recombination are the major sources of genetic variation of plant viruses (garcía-arenal et al., 2001; worobey & holmes, 1999). during mixed infections, viruses can exchange genetic material through recombination or reassortment of segments (when the parental genomes are fragmented) if present in the same cell context of the host plant. hybrid progeny viruses might then arise, some of them with novel pathogenic characteristics and well adapted in the population that can cause new emerging diseases. genetic exchange provides organisms with a tool to combine sequences from different origins which might help them to quickly evolve (crameri et al., 1998). in many dna and rna viruses, genetic exchange is achieved through recombination (froissart et al., 2005; martin et al., 2005). as increasing numbers of viral sequences become available, recombinant viruses are recognized to be frequent in nature and clear evidence is found for recombination to play a key role in virus evolution (awadalla, 2003; chenault & melcher, 1994; moonan et al., 2000; padidam et al., 1999; revers et al., 1996; garcía-arenal et al., 2001; moreno et al., 2004). understanding the role of recombination in generating and eliminating variation in viral sequences is thus essential to understand virus evolution and adaptation to changing environments knowledge about the existence and frequency of recombination in a virus population might help understanding the extent at which genes are exchanged and new virus variants arise. this information is essential, for example, to predict durability of genetic resistance because new recombinant variants might be formed with increased fitness in host-resistant genotypes. determination of the extent and rate at which genetic rearrangement through recombination does occur in natural populations is also crucial if we use genome and genetic-mapping information to locate genes responsible of important phenotypes such as genes associated with virulence, transmission, or breakdown of resistance. therefore, better estimates of the rate of recombination will facilitate the development of more robust strategies for virus control (awadalla, 2003). mutation, reassortment, and recombination are the major sources of genetic variation of plant viruses (garcía-arenal et al., 2001; worobey & holmes, 1999) . during mixed infections, viruses can exchange genetic material through recombination or reassortment of segments (when the parental genomes are fragmented) if present in the same cell context of the host plant. hybrid progeny viruses might then arise, some of them with novel pathogenic characteristics and well adapted in the population that can cause new emerging diseases. genetic exchange provides organisms with a tool to combine sequences from different origins which might help them to quickly evolve (crameri et al., 1998) . in many dna and rna viruses, genetic exchange is achieved through recombination (froissart et al., 2005; martin et al., 2005) . as increasing numbers of viral sequences become available, recombinant viruses are recognized to be frequent in nature and clear evidence is found for recombination to play a key role in virus evolution (awadalla, 2003; chenault & melcher, 1994; moonan et al., 2000; padidam et al., 1999; revers et al., 1996; garcía-arenal et al., 2001; moreno et al., 2004) . understanding the role of recombination in generating and eliminating variation in viral sequences is thus essential to understand virus evolution and adaptation to changing environments (de wispelaere et al., 2005; vignuzzi et al., 2006; domingo, 2000; eigen, 1993) . knowledge about the existence and frequency of recombination in a virus population might help understanding the extent at which genes are exchanged and new virus variants arise. this information is essential, for example, to predict durability of genetic resistance because new recombinant variants might be formed with increased fitness in host-resistant genotypes. determination of the extent and rate at which genetic rearrangement through recombination does occur in natural populations is also crucial if we use genome and genetic-mapping information to locate genes responsible of important phenotypes such as genes associated with virulence, transmission, or breakdown of resistance. therefore, better estimates of the rate of recombination will facilitate the development of more robust strategies for virus control (awadalla, 2003) . recombination appears to be common among members of the family geminiviridae, which have single-stranded dna genomes (padidam et al., 1999) . in this group of viruses, more notably among members of the genus begomovirus, recombination seems to contribute greatly to the genetic diversification of viral populations (zhou et al., 1997; berrie et al., 2001; pita et al., 2001; chatchawankanphanich & maxwell, 2002; umaharan et al., 1998; moffat, 1999; harrison & robinson, 1999; sanz et al., 1999 sanz et al., , 2000 . replication of these viruses, in addition to a rolling circle replication (rcr) mechanism (saunders et al., 1991; stenger et al., 1991) , also involves a recombination-dependent replication (rdr) mechanism (jeske et al., 2001) . rdr provides geminiviruses with a tool by which damaged or incomplete dna could be recovered for productive infection by homologous recombination and converted into full-size genomic dna. the existence of this replication mechanism might explain in part the extent at which recombination occurs in geminivirus populations (jeske et al., 2001; preiss & jeske, 2003) . recombination in begomoviruses is found at the strain (hou & gilbertson, 1996; kirthi et al., 2002) , species (zhou et al., 1997; fondong et al., 2000; navas-castillo et al., 2000; sanz et al., 2000; martin et al., 2001; saunders et al., 2002; garcía-andrés et al., 2006) , genus (briddon et al., 1996; klute et al., 1996) , and family (saunders & stanley, 1999) levels. the potential of begomoviruses to generate genetic diversity through recombination can be relevant for their ecological fitness, because greater sequence heterogeneity provides a reservoir of virus variants in the population that enables rapid adaptation to changing environmental conditions. thus, begomoviruses like those in the tomato yellow leaf curl virus (tylcv) complex exploit gene flow provided by recombination as a mechanism to increase their evolutionary potential and local adaptation. the tomato yellow leaf curl disease (tylcd) causes severe damage to tomato production in many warm and temperate regions worldwide varma & malathi, 2003) . different virus species and strains of the same virus species have been associated with tylcd, among them, tylcv fauquet et al., 2003; stanley et al., 2005) . in this chapter, tylcd-associated viruses are referred to as "tylcv complex". recombination seems to have played an important role in the origin of viruses of the tylcv complex. two case studies are examined here in detail. the earliest evidence of naturally occurring recombination within the genus begomovirus was found when the genome of the mld strain of the monopartite virus tomato yellow leaf curl virus (tylcv-mld) was compared with the genome of the type strain of tylcv (navot et al., 1991) . the nucleotide sequences of the rep gene and the intergenic region (ir) of the type and mld strains of tylcv were only 87% and 78% identical, respectively, whereas the rest of the genome shared 98% nucleotide identity. harrison & robinson (1999) suggested that the rep-ir regions of both genomes were acquired from different parental viruses that could not be identified at that moment. however, when increasing number of begomovirus dna-a sequences became available, navas-castillo et al. (2000) were able to identify the existent viruses more related to such parents. these authors compared the sequences of nine isolates of the tylcv complex, three of the type strain of tylcv (the original isolate from israel, and isolates from the dominican republic and cuba), five of the tylcv-mld strain (the original mld isolate from israel, and isolates from spain, portugal, and japan), and one tylcv isolate from iran (now recognized as the ir strain of tylcv). when phylogenetic relationships between nucleotide sequences of these isolates were analyzed, changes in the topological position of certain isolates occurred depending on the part of the genome compared (ir and open reading frames -orfs -v1, v2 and c1-c4). detailed comparisons throughout the genome using plotsim-ilarity diagrams (wisconsin gcg software package) (devereux et al., 1984) clearly indicated that four regions (named i-iv in figure 1 ) were recognized for which differential distribution of nucleotide identity was observed. region iii comprised about 5′ half of the rep gene (orf c1), including the orf c4 and part of the ir; region i comprised most of the rest of the genome, and regions ii and iv were small regions separating region i from region iii ( figure 1 ). in these comparisons, the nucleotide sequences of the tylcv-mld isolates from spain, portugal, and japan on the one hand and those of the tylcv type strain isolates from israel, cuba, and dominican republic on the other, proved to be almost identical between them throughout the genome. also, when region i was analyzed, phylogenetic analyses revealed that all tylcv isolates grouped in a single clade related to tomato yellow leaf curl sardinia virus (tylcsv), another species of the tylcv complex causing the tylcd. however, when comparing sequences in region iii, significant changes occurred in the phylogenetic relationships of certain tylcv isolates. thus, based on sequences of this region most tylcv isolates grouped in a single clade related to tylcsv, but tylcv (type strain) and tylcv-ir isolates grouped separately, together with begomovirus isolates bangalore-2 and bangalore-4. these two latter viruses were considered at that moment to belong to the begomovirus species, tomato leaf curl virus (tolcv) , however now they are known to belong to the asian begomovirus species tomato leaf curl karnataka virus (tolckv) and tomato leaf curl bangalore virus (tolcbv), respectively (stanley et al., 2005) . therefore, the genomes of tylcv, tylcv-mld, and tylcv-ir begomovirus isolates reflect a modular composition, with genome fragments having diverse phylogenetic origins that were probably put together after successive recombination events. tomato yellow leaf curl sardinia virus (tylcsv) is another monopartite begomovirus species of the tylcv complex that comprises isolates infecting tomato in the mediterranean basin, both in southern europe and northern africa (noris et al., 1994; . in the tylcsv clade, at least three different types of sequences can be distinguished, represented by the type strain, originally described from sardinia (tylcsv), the sicily strain (tylcv-sic), and the spain strain (tylcv-es). through comparison of the genome of isolates of the type and sic strains from italy following a similar procedure to that described above for tylcv (i.e., search for topological changes in the phylogenetic trees, and analysis with plotsimi-larity diagrams), evidence was obtained for differences in the phylogenetic origin of the different genomic regions of these isolates probably as a result of recombination events. two regions could be distinguished when the genomes of these isolates were compared ( figure 2a ): region i, in which the percentage of nucleotide identity between tylcsv and tylcsv-sic is 96%, and region ii, which includes a shorter fragment that comprises part of the ir, and the 5′ end of orf c1, in which the percentage of nucleotide identity is significatively lower, about 64%. when nucleotide sequences in region i were phylogenetically analyzed, tylcsv type strain clustered in the tylcsv-clade, closely related to tylcsv-sic, tylcsv-es, and the rest of viruses of the tylcv complex ( figure 2b ). however, after comparison of nucleotide sequences in region ii, a significant topological change occurred in the position of the tylcsv type strain isolate ( figure 2c ). thus in this case, tylcsv type strain isolate did not group with isolates of the tylcv complex, but in a clade that comprised all the cassava-infecting begomoviruses from africa, being the closest related sequence that of an isolate of south african cassava mosaic virus (sacmv) ( figure 2c ). therefore, these results strongly suggested that the tylcsv-type strain resulted regions i and ii for which differential distribution of nucleotide identity is observed are indicated. positions of the open reading frames (orfs) and of the intergenic region (ir) are indicated at the top of the figure (a). phylogenetic relationships for viruses in the tylcv-complex and the dna a from a recombination exchange of genetic material occurred between tylcsv and african begomovirus ancestors. the above examples of putative recombinations involving begomoviruses of the tylcv complex from the middle east and the mediterranean basin seem to reflect exchange of genomic fragments with begomoviruses present in asia (e.g., india) and africa. therefore, it could be hypothesized that an ancestral "tylcv" evolved and generated new variants (species or strains) by exchanging genetic material through recombination with other begomoviruses in its travel accross different areas of the old world. because begomoviruses in the tylcv complex belong to a clade of begomoviruses of the old world that affect tomato, and this crop was introduced in this region from america only recently, several scenarios can be suggested. one possibility is that a number of tylcv-like viruses could have already existed in the wild or cultivated hosts of the old world before the introduction of tomato. when tomato was grown in different areas, it could have become infected with these preexisting viruses. alternatively, an ancestor of the begomoviruses of the tylcv complex infected tomato and, in its travel through the regions of asia, africa, and europe (regions in which tomato has become a major crop), different virus lineages evolved by acquisition of genomic fragments from other begomoviruses by genetic exchange through recombination. thus, emergence of new begomoviruses could have occurred which shared tomato as common host. as tomato has become a major crop, it could act as a bridge for begomoviruses between other local crops or wild reservoirs, favoring contact between viruses otherwise separated. spread of bemisia tabaci biotypes highly polyphagous like the biotype b could also have favored exchange of viruses between tomato and other cultivated or wild hosts and thus facilitating recombination to occur. evidently, it is reasonable that an intermediate situation between the two scenarios proposed is what occurred and probably is occurring. new information about viruses infecting wild and cultivated hosts in regions of the old world could provide some clues about the origin and evolution of this complex of viruses. in addition to the well-documented examples of recombination shown above, other examples that involved begomoviruses of the tylcv complex have also been reported in the literature. thus, an interspecific recombination has been described for begomoviruses infecting tomato in central sudan (idris & brown, 2005) . in this case, two recombinant fragments were identified in the genome of the isolate sd:gez:96 of tomato leaf curl sudan virus from gezira (tolcsdv-[sd:gez:96]) when compared with the isolate sd:96 from sudan of the gezira strain of tylcv (tylcv-gez[sd:96]). also, padidam et al. (1999) detected several other putative recombination events also involving viruses of the tylcv complex by employing a statistical technique for detecting gene conversion based on the program geneconv. their analyses, using 64 geminivirus dna a sequences, identified 420 statistically significant recombinant events, 36 of them being listed and identified. six of the listed recombination events involved tylcv or tylcsv, some of them between strains of the same species (e.g., tylcsv/tylcsv-sic) whereas others had as a partner a non-tylcv virus from africa or asia (e.g., tylcv/chayote yellow mosaic virus, tylcsv/indian cassava mosaic virus). surprisingly, geneconv identified as recombinant a fragment shared between a spanish isolate of tylcsv and bean dwarf mosaic virus, a begomovirus species from the new world. rybicki (1994) already pointed out that recombination is probably a powerful tool in the evolution of begomoviruses, not only in the long term but also in the short to medium term. in this sense, padidam et al. (1999) evaluated the hypothesis that recombination among begomoviruses is contributing to the increasing emergence of new species and suggested that such studies could facilitate understanding of how viruses could evolve in response to changes in the ecosystem. in the next sections of this chapter, we will present data that evidenced the extent at which recombination is contributing to the diversification and adaptation of begomoviruses of the tylcv complex during their colonization of southern spain (western mediterranean basin). emergence and spread of new recombinant viral species belonging to the tylcv complex is shown from field data. also evidences from laboratory experiments are provided that support frequent emergence of new recombinant virus variants during single host plant infection cycles, in mixed infections between tylcv and tylcsv. the two case studies described in the previous section are examples of ancient, and probably multiple, recombination events that contributed to the emergence of begomoviruses of the tylcv complex. but if located at the right place and the right time, it could be possible to be witness to the occurrence of such a recombination event and emergence of the new virus variant originated. this was the case during studies of the epidemics of begomoviruses of the tylcv complex that recently colonized southern spain. following are data that evidence the relevance of recombination in the rapid evolution of such a population for its adaptation to a novel environment. mixed infections can be frequent in nature associated with begomovirus epidemics. thus for example, in a recent survey for viruses associated to tylcd in epidemics in tomatoes of the western mediterranean basin (italy and spain), it was shown the presence of isolates of eight different virus variants of the tylcv complex occurring simultaneously in the epidemics (figure 3) figure 4 ). therefore, opportunities for genetic exchange are evident, and appearance of novel variants as a result of recombination events can be predicted. as mentioned before, begomovirus replication involves two mechanisms, a rcr (saunders et al., 1991; stenger et al., 1991) and a rdr (jeske et al., 2001; preiss & jeske, 2003) . recombinant variants can be produced through the latter mechanism if viruses coexist in the same cell. if viable and competitive, these de novo created recombinant viruses can emerge and perpetuate in the population during epidemics. recent introduction of begomoviruses into new areas provided an ideal model to analyze aspects of genetic adaptation and evolution of an invading virus population. this was the case of the colonization of southern spain by begomoviruses of the tylcv complex associated with tylcd, which is well documented . this case is an interesting example of invasion success following multiple introductions, similar to those reported for animal or plants (novak & mack, 2001; kolbe et al., 2004) , in which recombination is providing tools for biological adaptation. initial colonization with isolates of the es strain of tylcsv during the early 1990s, resulted in a relatively stable population in which reduced genetic diversity was observed, a typical result of a population bottleneck upon invasion of a new area (sánchez-campos et al., 2002) . this could have been detrimental for the success of the invader begomovirus population. however, subsequent introductions of isolates of the type and mld strains of tylcv morilla et al., 2003) resulted in novel sources of variation, and conditions for recombination to occur, thus providing to the begomovirus population tools to gain potential for local adaptation. this was the case of the novel recombinant variant named tomato yellow leaf curl málaga virus (tylcmalv) that . phylogenetic relationships for tomato yellow leaf curl disease (tylcd)-associated begomovirus isolates present in tomato samples randomly collected in italy (italics/bold letters) and spain (normal letters) between 1999 and 2003. relationships were inferred based on a sequence of about 300 nucleotides encompassing the intergenic region (ir) by neighbor-joining analysis. support for nodes in a bootstrap analysis with 1,000 replications is shown for figures over 500. horizontal branch lengths are drawn to scale with the bar indicating 0.1 nucleotide replacements per site. vertical distances are arbitrary. names of isolates refer to host species origin (t, tomato), sample number/year, field (fi means field i), and sampling region (sicily, sic, and sardinia, sar, in italy; málaga, mlg, almería, alm, and murcia, mur, in spain) . representative isolates are included of begomovirus species associated with tylcd in the mediterranean area, the type, sic and es strains of tomato yellow leaf curl sardinia virus (tylcsv), type (isolates from israel, spain, and italy) and mld strains of tomato yellow leaf curl virus (tylcv), tomato yellow leaf curl málaga virus (tylcmalv), and tomato yellow leaf curl axarquía virus (tylcaxv) (genbank accession numbers x61153, z28390, z25751, x15656, aj489258, dq144621, af071228, af271234, and ay227892, respectively) (boxed and bold letters). as outgroup, an isolate of tomato leaf curl virus (tolcv) was used (genbank s53251). emerged as a result of a genetic exchange between isolates of the es strain of tylcsv and of the mld strain of tylcv. this natural recombinant variant showed to be better adapted ecologically than either parental virus and spread rapidly in the population . recently, a novel recombinant between tylcsv-es and the type strain of tylcv was detected in the population, which also seemed to be well adapted ecologically (garcía-andrés et al., 2006) . therefore, recombination showed to be an important force driving the evolution of the population of these viruses for adaptation to the novel ecological conditions present in the invaded area. native species, acting as reservoirs, can play an important role in the emergence of plant virus epidemics (hull, 2002) . for begomoviruses, studies are available that indicate presence in wild reservoirs (funayama-noguchi, 2001; jovel et al., 2004; ooi et al., 1997; roye et al., 1997) . to evaluate the possible importance of wild reservoirs as sources of begomovirus genetic diversiy for epidemics, the begomovirus population present in the solanum nigrum l. plant community found in southern spain was examined. s. nigrum is a wild host widely distributed in the mediterranean area, which can survive for long periods (even for more than 2 years) thanks to the mild climatic conditions present. infections with controls tylcd-associated begomoviruses are known in this plant species (bedford et al., 1998; salati et al., 2002; sánchez-campos et al., 2000) . our studies indicated that this wild host is an excellent reservoir of variants of viruses of the tylcv complex for tylcd epidemics. in fact, phylogenetic reconstruction of sequences of begomoviruses obtained from s. nigrum plants sampled in the málaga region (southern spain) between 2000 and 2003 demonstrated the presence of isolates of all the tylcd-associated begomoviruses species and strains reported in spain ( figure 5) . moreover, mixed infections in single s. nigrum figure 5 . phylogenetic relationships among begomoviruses detected in plants of the population of the native reservoir solanum nigrum present in málaga (southern spain). relationships were inferred by neighbor-joining analysis of sequences comprising the intergenic region (ir) (about 300 nucleotides). support for nodes in a bootstrap analysis with 1,000 replicates is shown for figures over 700. vertical distances are arbitrary and branch lengths are drawn to scale; the bar indicates 0.05 nucleotides substitutions per site. begomovirus isolates are named according to indications of the geminiviridae study group of the international committee on taxonomy of viruses, giving the code of the country of origin, sample name, and year of collection (e.g., "es:sn8-1:00", in which "es" refers to spain, "sn8-1", to isolate 1 derived from the sample number 8 of s. nigrum, and "00" to the year 2000). representative begomoviruses included (boxed and bold letters) are the same as in figure 3 . as outgroup, an isolate of ageratum yellow vein virus (ayvv) was used (genbank x74516). (adapted from garcía-andrés et al., 2006.) plants were evident, as observed for example in sample sn8:00, in which tylcsv-like and tylcv-like sequences were detected (e.g., isolates es:sn8-1:00, es:sn8-2:00, respectively, figure 5) . therefore, s. nigrum plants can be an optimal niche for genetic exchanges to give rise to better-adapted recombinant begomoviruses. in fact, we demonstrated the presence in this host species of isolates of a new previously undescribed begomovirus of recombinant nature, named tomato yellow leaf curl axarquía virus, tylcaxv (e.g., isolate es:sn1:03, figure 5) . this virus variant was demonstrated to be the result from a genetic exchange between isolates of the es strain of tylcsv and of the type strain of tylcv (found coinfecting s. nigrum plants, figure 5) . novel pathogenic properties are demonstrated for tylcaxv that suggested enhanced ecological adaptation (garcía-andrés et al., 2006) . we concluded therefore that presence of mixed begomovirus infections in wild reservoirs can be a cause for alarm, because novel recombinants might arise with unpredictable consequences for epidemics of viruses of the tylcv complex. sequence analyses of field isolates have revealed substantial evidence for widespread occurrence of recombination amongst begomoviruses (padidam et al., 1999; sanz et al., 2000; berrie et al., 2001; pita et al., 2001; chatchawankanphanich & maxwell, 2002) . however, it remains unclear whether recombination represents a frequent phenomenon shaping begomovirus populations during a single host plant infection life cycle. we investigated this aspect for infections with tylcsv and tylcv as model system (garcía-andrés et al., 2007b) . these two viruses coinfect single plants in nature garcía-andrés et al., 2006) , and even could share single nuclei of an infected plant (morilla et al., 2004) , a prerequisite for recombination to occur. natural mixed infections were simulated in tomato and the frequency of recombinant genomes was evaluated at several times post coinfection. we found that recombinant-like molecules accumulated in the virus progeny of mixed-infected plants and rapidly constituted a significant proportion of the population (in most cases about 50% of the genomes analyzed, figure 6a ). we also found that parent tylcsv and recombinant variants generated de novo coexisted, suggesting that the latter fit well in the population and were not outcompeted. however, at least in the experimental conditions analyzed, tylcv was outcompeted, suggesting that it is less adapted to compete in planta with either tylcsv or the recombinants arisen. this was surprising because tylcv seems to be well adapted to compete during natural epidemics . therefore, other factors in addition to competitiveness in planta are associated with the success of a begomovirus variant in nature (transmission, host range, etc.). interestingly, only three types of recombinant variants could be recovered in the plant coinfected with tylcv and tylcsv during the 400-day infection cycle analyzed. therefore, constraints for recombination seemed to exist in these viral genomes. moreover, frequency of the different recombinant variants found in the population could vary with time but, at least in the experimental conditions used, one type predominated through the entire experiment (type iv, figure 6b ). although additional studies are needed to better understand the significance of recombination in single host infection cycles in this group of viruses, these data suggested that recombination seems to be a frequent phenomenon and could contribute significantly in generating genetic diversity and novel virus variants for local adaptation. given the importance of recombination in the molecular evolution of viruses promoting biological adaptation, understanding the frequency at which it occurs, mechanisms involved, and ecological features that control the rate of recombination, might help to predict the emergence of new viruses. this knowledge can be used to improve effectiveness and durability of current control procedures (bonnet et al., 2005; lewis-rogers et al., 2004) . efficient control of plant virus diseases is difficult, however the use of virus-resistant cultivars can provide an effective mean to limit the economic damage caused. although the use of resistance is the most desirable plant virus control strategy, it often fails because resistance-breaking virus genotypes appear and increase their frequency in the virus population (lecoq et al., 2004; garcía-arenal et al., 2001) . the durability of resistance is determined by the evolutionary potential of plant viruses (garcía-arenal & mcdonald, 2003) and recombination is one of the major forces driving virus evolution. in this regard, recombination events have been demonstrated to be associated with major changes in fitness and pathogenic characteristics of plant viruses, including expansion of their host range and increase in their virulence (fernández-cuartero et al., 1994; stenger et al., 1994; pita et al., 2001; zhou et al., 1997; gibbs et al., 2001; garcía-arenal & mcdonald, 2003; rest & mindell, 2003; garcía-andrés et al., 2006) . thus, recombination can accompany or even be at the origin of major changes during virus adaptation. in fact, recombination is known to be a potent mechanism to create more fit genotypes (bürger, 1999; hu et al., 2003) , that can help viruses to adapt to novel environmental conditions (dybdahl & storfer, 2003; lively & dybdahl, 2000; stavrinides & guttman, 2004; zhou et al., 1997) . therefore, the risk of break of a begomovirus resistance owe to the appearance and spread of better-adapted recombinant variants exists and should be considered to predict the durability of a resistance. the abundance of recombinant variants in a virus population should also be kept in mind for the evaluation of the potential impact of recombination in the use of transgenic plants expressing viral sequences (harrison, 2002; aaziz & tepfer, 1999b; tepfer, 2002; de wispelaere et al., 2005) . the virus-resistant transgenic plants (vrtps) hold the promise of enormous benefit for agriculture, however, questions concerning the potential ecological impact have been raised (tepfer, 2002) . numerous transgenic crops resistant to a wide range of viruses have been developed (beachy, 1997) , many of them based on the application of the concept of pathogen-derived resistance (sanford & johnston, 1985) . different virus sequences have been used for the development of virus-derived transgenic resistance, including genes encoding coat proteins, replicases, movement proteins, proteases, or helper components (lomonossoff, 1995) . however, it is important to examine vrtp carefully and take into account the risk of the deployment from the point of view of biosafety. interactions are possible in transgenic plants between products of the viral transgene (whether dna, rna, or protein) and an incoming virus, which can result in potential ecological risks like synergism, heteroencapsidation, or recombination (tepfer, 1993 (tepfer, , 2002 robinson, 1996; aaziz & tepfer, 1999a) . it has been demonstrated that recombination of a challenging virus with a transgene could have important biological consequences such as changes in virulence or host range (kiraly et al., 1998; frischmuth & stanley, 1998) . therefore, if as mentioned above rdr occurs during geminivirus multiplication within plants, transgenic constructs that provide information for symptom expression, host range, tissue and vector specificities should be avoided (jeske et al., 2001) . in this sense, it is a fortunate coincidence that the resistance strategy that uses defective interfering dnas as control elements was successful for geminiviruses (frischmuth & stanley, 1993; jeske et al., 2001) . this work was supported in part by grants agl2001-1857-c04-02 and agl2005-03101 from the ministerio de educación y ciencia, spain, and the european commission. s. garcía-andrés completed this research as part of her ph.d. degree and was recipient of a fellowship from the ministerio de educación y ciencia, spain. recombination between genomic rnas of two cucumoviruses under conditions of minimal selection pressure recombination in rna viruses and in virus-resistant transgenic plants complete nucleotide sequence of an infectious clone of a mild isolate of tomato yellow leaf curl virus (tylcv) the evolutionary genomics of pathogen recombination mechanisms and applications of pathogen-derived resistance in transgenic plants solanum nigrum: an indigenous weed reservoir for a tomato yellow leaf curl geminivirus in southern spain complete nucleotide sequence and host range of south african cassava mosaic virus: further evidence for recombinations amongst begomoviruses role of recombination in the evolution of natural populations of cucumber mosaic virus, a tripartite rna plant virus analysis of the nucleotide sequence of the 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begomovirus family geminiviridae mosaic evolution of the severe acute respiratory syndrome coronavirus recombinant beet curly top virus genomes exhibit both parental and novel pathogenic phenotypes replicational release of geminivirus genomes from tandemly repeated copies. evidence for rolling circle replication of a plant viral dna viral genes and transgenic plants risk assessment of virus-resistant transgenic plants distribution and diversity of geminiviruses in trinidad and tobago emerging geminivirus problems: a serious threat to crop production quasispecies diversity determines pathogenesis through cooperative interactions in a viral population evolutionary aspects of recombination in rna viruses evidence that dna-a of a geminivirus associated with severe cassava mosaic disease in uganda has arisen by interspecific recombination key: cord-027960-qzg2jsz6 authors: royo, sebastián title: from boom to bust: the economic crisis in spain 2008–2013 date: 2020-06-28 journal: why banks fail doi: 10.1057/978-1-137-53228-2_4 sha: doc_id: 27960 cord_uid: qzg2jsz6 this chapter analyzes the overall economic crisis that started in 2008 in spain. it is impossible to disentangle the 2008 banking crisis from the overall economic crisis that affected the country at the same time. this chapter looks at the performance of the spanish economy throughout the 1990s and the first decade of the twentieth century. it examines the reasons for the success of the spanish economy in the 1990s and provides an overview of the main causes of the 2008–2013 crisis and the governments’ responses. the economic crisis that hit the country in 2008 cannot be separated from the subsequent financial crisis. in order to contextualize the banking games that inform the next chapters and to understand the overall consequences that the economic crisis had on spanish banks and cajas , this chapter examines the economic crisis and analyzes its causes and consequences. yet again, the performance of the spanish banking system was deeply connected to the performance of the spanish economy, and progress in the banking sector was marred by the performance of the spanish economy at large. the economic crisis that started in 2008, part of the great recession that engulfed most countries, had profound consequences for the spanish banking system. this book will show that the financial crises were the result of a political bargain in which incentives and a lax regulatory framework favored developers, property owners, and bankers, thus confirming a central tenant: the crucial importance of domestic political institutions, the rules of the game, and the role of domestic players operating within those institutions. from: sebastián royo, "after austerity: lessons from the spanish experience," in towards a resilient eurozone: economic, monetary and fiscal policies, ed. john ryan (new york: peter lang, 2015) . the 2008 economic crisis, while not fully unexpected, came as a relative surprise given the strong performance of the spanish economy during the first years of the twentieth century. the overall pattern of spanish economic history has been described, crudely, as a graph shaped like an upside-down version of the letter 'v'. that is, the graph rises-bumpily at times, through 600 years under the romans, 700 years under or partly under the moors, and a century of empire-building-to the peak of spanish power in the sixteenth century. after that, the history of the nation goes downhill until the 1970s. a vast empire was gradually lost, leaving spain poor and powerless. and there was much political instability: spain suffered forty-three coup d'états between 1814 and 1923, a horrendous civil war between 1936 and 1939, followed by thirty-six years of dictatorship under generalísimo franco. 1 after franco's death in 1975, the graph turned upward again. king juan carlos, franco's heir, oversaw the return of democracy to the country. a negotiated transition period, which has been labeled as a model for other countries, paved the way for the elaboration of a new constitution, followed by the first free elections in almost forty years. these developments were followed by the progressive return of spain to the international arena-where they have been relatively isolated during the dictatorship. the following decade also witnessed the socialist party being elected to actual power in 1982, bringing a new aura of modernity to the country. the 1980s also witnessed spain's integration into nato (1982) and the european community (1986). the following two and a half decades were a period of phenomenal growth and modernization. indeed, before the global crisis that hit spain in the spring of 2008 the country had become one of europe's most successful economies. 2 while other european countries had been stuck in the mud, spain performed much better at reforming its welfare systems and labor markets, as well as improving flexibility and lowering unemployment. over the decade and a half that preceded the 2008 global financial crisis, the spanish economy seemed to had been able to break with the historical pattern of boom and bust, and the country's economic performance was nothing short of remarkable. yet all this came to a halt when the global financial crisis hit spain in 2008. as a result, spain is suffering one of the worst crises since the 1940s (royo 2013) . following the transition to democracy and the country's european integration, spain was, prior to the 2008 crisis, a model country. but then the (debt fueled) dream was shattered and the country's economy imploded after 2008. how did this happen? policy choices and the structure of decision making; the role of organized interest; the structure of the state; and institutional degeneration all played an important role in explaining the severity of the economic crisis in spain; as did the country's membership under an incomplete monetary union. the country had to face a triple crisis: financial, fiscal, and competitiveness. this chapter seeks to provide an overview of the country's evolution since the transition to democracy, and to explain its economic collapse after 2008 (see royo 2000 royo , 2008 royo , 2013 . the first section of the chapter outlines the main features of the spanish growth model, and the challenges that it faced. section two describes the scale of the shock it underwent from 2008 onward and analyzes the triple crisis in financial, fiscal, and competitiveness performance. the chapter concludes with brief lessons from the spanish experience. european integration was instrumental in the modernization of the country. indeed, before the global crisis that hit spain in the spring of 2008 the country had become one of europe's most successful economies (see table 4 .1). propped up by low interest rates and immigration, spain was (in 2008) in its fourteenth year of uninterrupted growth and it was benefiting from the longest cycle of continuing expansion of the spanish economy in modern history (only ireland in the euro zone has a better record), which contributed to the narrowing of per capita gdp with the eu. indeed, in 20 years per capita income grew 20 points, one point per year, to reach close to 90% of the eu15 average. with the eu25, spain already reached the average in 2008. the country grew on average 1.4 percentage points more than the eu since 1996. unemployment fell from 20% in the mid-1990s to 7.95% in the first half of 2007 (the lowest level since 1978), as spain became the second country in the eu (after germany with a much larger economy) creating the most jobs (an average of 600,000 per year over that decade). in 2006, the spanish economy grew a spectacular 3.9%, and 3.8% in 2007. as we have seen, economic growth contributed to per capita income growth and employment. indeed, the performance of the labor market was spectacular: between 1997 and 2007, 33% of all the total employment created in the eu-15 was created in spain. in 2006, the active population increased by 3.5%, the highest in the eu (led by new immigrants and the incorporation of women in the labor market, which increased from 59% in 1995 to 72% in 2006); and 772,000 new jobs were created. the economic success extended to spanish companies, which expanded beyond their traditional frontiers (guillén 2005) . in 2006, they spent a total of e140 billion on domestic and overseas acquisitions, putting the country third behind the uk and france in the eu. of this, e80 billion were to buy companies abroad (compared with the e65 billion spent by german companies). in 2006, spanish foreign direct investment (fdi) abroad increased 113%, reaching e71.5 billion (or the equivalent of 7.3% of gdp, compared with 3.7% in 2005). 4 in 2006 iberdrola, an electricity supplier purchased scottish power for $22.5 billion to create europe's third largest utility; banco santander, spain's largest bank, purchased britain's abbey national bank for $24 billion, ferrovial, a family construction group, concluded a takeover of the british baa (which operates the three main airports of the uk) for £10 billion; and telefonica bought o2, the uk mobile phone company. indeed, 2006 was a banner year for spanish firms: 72% of them increased their production and 75.1% their profits, 55.4% hired new employees, and 77.6% increased their investments. 5 the country's transformation was not only economic but also social. the spanish became more optimistic and self-confident (i.e., a harris poll showed that spaniards were more confident of their economic future than their european and american counterparts, and a poll by the center for sociological analysis showed that 80% were satisfied or very satisfied with their economic situation). spain became 'different' again and according to public opinion polls it had become the most popular country to work for europeans. 6 between 2000 and 2007, some 5 million immigrants (645,000 in 2004 and 500,000 in 2006) settled in spain (8.7% of the population compared with 3.7% in the eu15), making the country the biggest recipient of immigrants in the eu (they represented 10% of the contributors to the social security system). this was a radical departure for a country that used to be a net exporter of people, and more so because it was able to absorb these immigrants without falling prey (at least so far) to the social tensions that have plagued other european countries (although there have been isolated incidents of racial violence) (see calavita 2005) . 7 these immigrants contributed significantly to the economic success of the country in that decade because they boosted the aggregate performance of the economy: they raised the supply of labor, increased demand as they spent money, moderated wages, and put downward pressure on inflation, boosted output, allowed the labor market to avoid labor shortages, contributed to consumption, and increased more flexibility in the economy with their mobility and willingness to take on low-paid jobs in sectors such as construction and agriculture, in which the spanish were no longer interested. 8 indeed, an important factor in the per capita convergence surge with the eu after 2000 was the substantive revision of the spanish gdp data as a result of changes in the national accounts from 1995 to 2000. these changes represented an increase in gpd per capita of 4% in real terms (the equivalent of slovakia's gdp). this dramatic change was the result of the significant growth of the spanish population since 1998 as a result of the surge in immigration (for instance in 2003 population grew 2.1%). the key factor in this acceleration of convergence, given the negative behavior of productivity (if productivity had grown at the eu 6 according to the financial times, 17% of those polled selected spain as the country where they would prefer to work ahead of the uk (15%) and france (11%). see "españa vuelve a ser diferente," el país, february 19, 2007, and financial times, february 19, 2007. 7 calativa provides a detailed analysis of the immigration experience in spain and exposes the tensions associated with this development. she also highlights the shortcomings of governments' actions in regard to integration, and the impact of lack of integration on exclusion, criminalization, and radicalization. see 2005. 8 "immigrants boost british and spanish economies," financial times, tuesday, february 20, 2007, p. 3. average spain would have surpassed in 2007 the eu per capita average by 3 points), was the important increase in the participation rate, which was the result of the reduction in unemployment, and the increase in the activity rate (the proportion of people of working age who have a job or are actively seeking one) that followed the incorporation of female workers into the labor market and immigration growth. indeed between 2000 and 2004, the immigrant population has multiplied by threefold. as a matter of fact, most of the 772,000 new jobs created in spain in 2006 went to immigrants (about 60%). their motivation to work hard also opened the way for productivity improvements (which in 2006 experienced the largest increase since 1997, with a 0.8% raise). it is estimated that the contribution of immigrants to gdp had been of 0.8 percentage points in the four years to 2007. 9 immigration represented more than 50% of employment growth, and 78.6% of the demographic growth (as a result spain led the demographic growth of the european countries between 1995 and 2005 with a demographic advance of 10.7% compared with the eu15 average of 4.8%). 10 they also contributed to the huge increase in employment, which was one of the key reasons for the impressive economic expansion. indeed, between 1988 and 2006, employment contributed 3 percentage points to the 3.5% annual rise in spain's potential gdp (see table 4 .1). 11 what made this transformation possible? the modernization of the spanish economy in the two and half decades prior to 2008 had been intimately connected to the country's integration in the european union. indeed, european integration was a catalyst for the final conversion of the spanish economy into a modern western-type economy. yet, membership was not the only reason for this development. the economic liberalization, trade integration, and modernization of the spanish economy started in the 1950s and 1960s and spain became increasingly prosperous over the two decades prior to eu accession. however, one of the key consequences of its entry into europe was that it consolidated and deepened that development processes, and it accelerated the modernization of the country's economy. indeed, eu membership facilitated the micro-and macroeconomic reforms that successive spanish governments undertook throughout the 1980s and 1990s. spain also benefited extensively from european funds those two decades: approximately 150 billion euros from agricultural, regional development, training, and cohesion programs. moreover, european monetary union (emu) membership was also very positive for the country: it contributed to macroeconomic stability, it imposed fiscal discipline and central bank independence, and it lowered dramatically the cost of capital. one of the key benefits was the dramatic reduction in short-term and long-term nominal interest rates: from 13.3% and 11.7% in 1992, to 3.0% and 4.7% in 1999, and 2.2% and 3.4% in 2005. the lower costs of capital led to an important surge in investment from families (in housing and consumer goods) and businesses (in employment and capital goods). indeed, emu membership (and the stability pact) provided the country with unprecedented stability because it forced successive governments to implement responsible economic policies, which led to greater credibility and the improvement of the ratings of spain's public debt (and consequently to lower financing costs). another important factor to account for the country's economic success was the remarkable economic policy stability that followed the economic crisis of 1992-1993. indeed, there were few economic policy shifts throughout the 1990s and early 2000s, and this despite changes in government. between 1993 and 2009, there were only two ministers of finance, pedro solbes (from 1993 to 1996 , and from 2004 to 2009 ) and rodrigo rato (from 1996 to 2004 ; and the country only had three prime ministers (felipe gonzález, josé maría aznar, and josé luís rodríguez zapatero). this pattern was further reinforced by the ideological cohesiveness of the political parties in government and the strong control that party leaders exercise over the members of the cabinet and the parliament deputies. in addition, this stability was reinforced by the shared (and rare) agreement among conservative and socialist leaders regarding fiscal consolidation (the balance budget objective was established by law by the popular party), as well as the need to hold firm in the application of restrictive fiscal policies and the achievement of budgetary surpluses: as a result, a 7% budget deficit in 1993 became a 2.2% surplus in 2007, and public debt decreased from 68% of gdp in 1998 to 36.2% in 2007. finally, other factors that contributed to this success included the limited corruption and the fact that politics were fairly clean and relatively open; that spain had a flexible economy; and the success of spanish multinationals: there were eight firms in the financial times list of the world's largest multinationals in 2000, and 14 in 2008. 12 the challenges however, this economic success was marred by some glaring deficiencies that came to the fore in 2008 when the global financial crisis hit the country, because it was largely a "miracle" based on bricks and mortar. 13 the foundations of economic growth were fragile because the country had low productivity growth (productivity contributed only 0.5 percentage points to potential gdp between 1998 and 2006) and deteriorating external competitiveness. 14 over the decade that preceded the 2008 crisis spain did not address its fundamental challenge, its declining productivity, which only grew an average of 0.3% during that decade (0.7% in 2006), one whole point below the eu average, placing spain at the bottom of the eu and ahead of only italy and greece (the productivity of a spanish worker was the equivalent of 75% of a us one). the most productive activities (energy, industry, and financial services) contributed only 11% of gdp growth. 15 12 according to 2007 data from the world bank governance indicators (http://info. worldbank.org/governance/wgi/sc_chart.asp), spain was ranked in the 75-100th country's percentile ranks in control of corruption, government effectiveness, regulatory quality, rule of law, and voice and accountability. 13 according to martinez-mongay and maza lasierra, "the outstanding economic performance of spain in emu would be the result of a series of lucky shocks, including a large and persistent credit impulse and strong immigration, underpinned by some right policy choices. in the absence of new positive shocks, the resilience of the spanish economy to the financial crisis might be weaker than that exhibited in the early 2000s. the credit impulse has ended, fiscal consolidation has stopped, and the competitiveness gains of the nineties have gone long ago." see martinez-mongay and maza lasierra (2009 moreover, growth was largely based on low-intensity economic sectors, such as services and construction, which were not exposed to international competition. in 2006, most of the new jobs were created in low-productivity sectors such as construction (33%), services associated with housing such as sales and rentals (15%), and tourism and domestic service (30%). these sectors represented 75% of all the new jobs created in spain in 2006 (new manufacturing jobs, in contrast, represented only 5%). furthermore, the labor temporary rate reached 33.3% in 2007, and inflation was a recurrent problem (it closed 2006 with a 2.7% increase, but the average for that year was 3.6%), thus the inflation differential with the eu (almost 1 point) had not decreased, which reduced the competitiveness of spanish products abroad (and consequently spanish companies were losing market share abroad). 16 competitiveness was further hindered by a deep process of economic deindustrialization, low value added and complexity of exports, and low insertion in global value chains. in addition, family indebtedness reached a record 115% of disposable income in 2006, and the construction and housing sectors accounted for 18.5% of gdp (twice the eurozone average). house prices rose by 150% since 1998, and the average price of a square meter of residential property went up from 700 euros in 1997 to 2000 at the end of 2006, even though the housing stock had doubled. many wondered whether this bubble was sustainable. 17 the crisis that started in 2008 confirmed the worst fears, and the implosion of the housing bubble fueled corruption and bad practices in the cajas sector of the financial system. moreover, between 40 and 60% of the benefits of the largest spanish companies came from abroad. yet, in the years prior to the crisis this figure had decreased by approximately 10 percentage points, and there had been a decline in direct foreign investment of all types in the country, falling from a peak of 38.3 billion euros in 2000 to 16.6 billion euros in 2005. 18 states; imports were 25% higher than exports and spanish companies were losing market share in the world. hence, the trade deficit reached 9.5% in 2008. 19 while there was overall consensus that the country needed to improve its education system and invest in research and development to lift productivity, as well as modernize the public sector, and make the labor market more stable (i.e., reduce the temporary rate) and flexible, the government did not take the necessary actions to address these problems. spain spent only half of what the organization of european co-operation and development (oecd) countries spent on average on education; it lagged most of europe on investment in research and development (r&d); and it was ranked 29th by the unctad as an attractive location for research and development. finally, other observers noted that spain was failing to do more to integrate its immigrant population, and social divisions were beginning to emerge. 20 by the summer of 2008, the effects of the global crisis were evident in spain, and between 2008 and 2013 the country suffered one of the worst recession in modern history. this collapse was not wholly unexpected. the global liquidity freeze and the surge in commodities, food, and energy prices brought to the fore the unbalances in the spanish economy: the record current account deficit, persisting inflation, low productivity growth, dwindling competitiveness, increasing unitary labor costs, excess consumption, and low savings, had all set the ground for the current devastating economic crisis (see royo 2013) . as we have seen, the imbalances in the spanish economy came to the fore in 2007-2008 when the real estate market bubble burst and the international financial crisis hit spain (see table 4 .2). in just a few months the 'debt-fired dream of endless consumption' turned into a nightmare. by the summer of 2013, spain faced the worst economic recession in half a century. according to government statistics, 2009 was the worst year since there has been reliable data: gdp fell 3.7%, unemployment reached over four million people (eventually reaching over 27% in 2012, with more than 6 million people unemployed), and the public deficit reached a record 11.4% of gdp (up from 3.4% in 2008). consumer confidence was shattered, the implosion of the housing sector reached historic proportions, and the manufacturing sector was also suffering. initially, the zapatero government was reluctant to recognize the crisis, which was becoming evident as early as the summer of 2007, because of electoral considerations: the country had a general election in march 2008. and after the election, the zapatero government was afraid to admit that it had not been entirely truthful during the campaign. by 2007, there was increasing evidence that the model based on construction was already showing symptoms of exhaustion. yet, the spanish government not only refused to recognize that the international crisis was affecting the country, but also that in spain the crises would be aggravated by the very high levels of private indebtedness. as late as august 17, 2007, finance minister solbes predicted that 'the crisis would have a relative small effect' in the spanish economy. when it became impossible to deny what was evident, the government's initial reluctance to recognize and address the crisis was replaced by frenetic activism. the zapatero government introduced a succession of plans and measures to try to confront the economic crisis, and specifically to address the surge of unemployment (royo 2013 ) (see fig. 4.1) . the sharp deterioration of the labor market was caused by the economic crisis and the collapse of the real estate sector, and it was aggravated by a demographic growth pattern based on migratory inflows of labor: in 2007, there were 3.1 million immigrants in the country, of which 2.7 million were employed and 374,000 unemployed. in 2008, the number of immigrants increased by almost 400,000-3.5 million (representing 55% of the growth in the active population), but 580,000 of them were unemployed (and 2.9 million employed), an increase of 200,000. in the construction sector alone, unemployment increased 170% between the summer of 2007 and 2008. meanwhile, the manufacturing and service sectors (also battered by the global crisis, lower consumption, and lack of international competitiveness) proved unable to incorporate these workers. the pace of deterioration caught policy-makers by surprise. the zapatero government prepared budgets for 2008 and 2009 that were utterly unrealistic in the face of rapidly changing economic circumstances (as did all other advanced countries, the g-20 agreed on a plan for fiscal stimulus that would later prove relatively ineffective and dangerous for spain as it increased the country's debt). as a result, things continued to worsen over the new four years. the most significant decline was in consumer confidence, which was hammered by the financial convulsions, the dramatic increase in unemployment, and the scarcity of credit. as a result, household consumption, which represented 56% of gdp, fell 1% in the last quarter of 2009 for the first time in the last 15 years. according to the bank of spain, this decline in household consumption was even more important in contributing to the recession than the deceleration of residential investment, which had fallen 20%, driven down by worsening financial conditions, uncertainties, and the drop in residential prices. the government actions had limited effect stemming this hemorrhage, and their efficacy was inadequate. finally, the impact of the global economic crisis was felt well beyond the economic and financial realms. the crisis also had severe political consequences. spain followed in the path of many other european countries (including ireland, portugal, greece, and france) that saw their governments suffer the wrath of their voters and have been voted out of office. the socialist party (psoe) was re-elected in a general election on march 9, 2008. soon thereafter, economic conditions deteriorated sharply and the government's popularity declined rapidly. between march 2008 and march 2012, there were a number of electoral contests in spain at the local, regional, national, and european levels. at the national and european levels, the one common pattern was the outcome: the defeat of the socialist party and the victory of the popular party (pp). and at the regional and local levels the socialists suffered historical losses, losing control of regional government that they ruled for decades (notably, castilla-la mancha and extremadura), and even losing the election for the first time in one of its historical strongholds, andalusia (although they were able to reach a coalition with a smaller leftist party to stay in power). in the end, the economic crisis ignited a pattern of political polarization, instability, and fragmentation of the party system that crystallized in 2015 (following the pp's absolute majority) and lasts through today: as of fall of 2019, spain has had 4 general elections in 4 years. one of the most common misinterpretations regarding the crisis in southern europe was attributing it to mismanaged public finances. many policy-makers across europe, especially in the creditor countries (crucially germany), still insist today (2019) that the crisis was caused by irresponsible public borrowing, and this, in turn, led to misguided solutions. in fact, with very few exceptions, notably greece, that interpretation is incorrect. in spain, the crisis did not originate with mismanaged public finances. on the contrary, as late as 2011, spain's debt ratio was still well below the average for countries that adopted the euro as a common currency: while spain stood at less than 60% of gdp, greece stood at 160.8%, italy at 120%, portugal at 106.8%, ireland at 105%, belgium at 98.5%, and france at 86%. on the contrary, prior to 2007, spain seemed to be in an enviable fiscal position, even when compared with germany. 21 spain ran a budget surplus in 2005, 2006, and 2007 . it was only when the crisis hit the country and the real estate market collapsed that the fiscal position deteriorated markedly and the country experienced huge deficits. the problem in spain was the giant inflow of capital from the rest of europe; the consequence was rapid growth and significant inflation. in fact, the fiscal deficit was a result, not a cause, of spain's problems: when the global financial crisis hit spain and the real estate bubble burst, unemployment soared, and the budget went into deep deficit, caused partly by depressed revenues and partly by emergency spending to limit human costs. the government responded to the crisis with a massive e8 billion public works stimulus. this decision, combined with a dramatic fall in revenue, blew a hole in government accounts resulting in a large deficit. furthermore, the conditions for the crisis in spain were created by the excessive lending and borrowing of the private sector rather than the government. in other words, the problem was private debt and not public debt. spain experienced a problem of ever-growing private sector indebtedness, which was compounded by the reckless investments and loans of banks (including the overleveraged ones), both integral components of the bank bargains that we examine later in the book, that were aggravated by competitiveness and current account imbalances. in spain, the private sector debt (households and nonfinancial corporations) was 227.3% of gdp at the end of 2010; total debt increased from 337% of gdp in 2008 to 363% in mid-2011. yet, although spain entered the crisis in a relatively sound fiscal position, that position was not solid enough to withstand the effects of the crisis, especially being a member of a dysfunctional monetary union with no lender of last resort. the country's fiscal position deteriorated sharply-collapsing by more than 13% of gdp in just two years. looking at the deficit figures with the benefit of hindsight, it could be argued that spain's structural or cyclically adjusted deficit was much higher than its actual deficit. the fast pace of economic growth before the crisis inflated government revenues and lowered social expenditures in a way that masked the vulnerability hidden in spanish fiscal accounts. the problem is that it is very difficult to know the structural position of a country. the only way in which spain could have prevented the deficit disaster that followed would have been to run massive fiscal surpluses of 10% or higher during the years prior to the crisis in order to generate a positive net asset position of at least 20% of gdp. 22 this, for obvious reasons, would not have been politically feasible. there is another way to look at the crisis. many economists argue that the underlying problem in the euro area was the exchange rate system itself, namely, the fact that european countries locked themselves into an initial exchange rate. this decision meant, in fact, that they believed that their economies would converge in productivity (which would mean that the spaniards would, in effect, become more like the germans). if convergence was not possible, the alternative would be for people to move to higher productivity countries, thereby increasing their productivity levels by working in factories and companies there (or to create a full fiscal union to provide for permanent transfers, as argued by oca theory). time has shown that both expectations were unrealistic and, in fact, the opposite happened. the gap between german and spanish (including other peripheral country) productivity increased, rather than decreased, over the past decade and, as a result, germany developed a large surplus on its current account; while spain and the other periphery countries had large current account deficits that were financed by capital inflows. 23 in this regard, one could argue that the incentives introduced by emu worked exactly in the wrong way. capital inflows in the south made the structural reforms that would have been required to promote convergence less necessary, thus increasing divergence in productivity levels. in addition, adoption of the euro as a common currency fostered a false sense of security among private investors. during the years of euphoria following the launching of europe's economic and monetary union and prior to the onset of the financial crisis, private capital flowed freely into spain and, as a result as we have seen, the country ran current account deficits of close to 10% of gdp. in turn, these deficits helped finance large excesses of spending over income in the private sector. the result did not have to be negative. these capital inflows could have helped spain (and the other peripheral countries) invest, become more productive, and "catch up" with germany. unfortunately, in the case of spain, they largely led to a massive bubble in the real estate market, consumption, and unsustainable levels of borrowing. the bursting of that bubble contracted the country's real economy and it brought down the banks that gambled on loans to real estate developers and construction companies. at the same time, as noted above, the economic boom also generated large losses in external competitiveness that spain failed to address. successive spanish governments also missed the opportunity to reform institutions in their labor and product markets. as a result, costs and prices increased, which in turn led to a loss of competitiveness and large trade deficits. this unsustainable situation came to the fore when the financial shocks that followed the collapse of lehman brothers in the fall of 2007 brought "sudden stops" in lending across the world, leading to a collapse in private borrowing and spending, and a wave of fiscal crisis. a third problem had to do with the banks. as we will see in much greater detail later in the book, this problem was slow to develop. between 2008 and 2010, the spanish financial system, despite all its problems, was still one of the least affected by the crisis in europe. during that period, of the 40 financial institutions that received direct assistance from brussels, none was from spain. in december 2010, moody's ranked the spanish banking system as the third strongest of the eurozone, only behind finland and france, above the netherlands and germany, and well ahead of portugal, ireland, and greece. finally, santander and bbva had shown new strength with profits of e4.4 billion and e2.8 billion, respectively, during the first half of 2010. spanish regulators had put in place regulatory and supervisory frameworks, which initially shielded the spanish financial system from the direct effects of the global financial crisis. indeed, the bank of spain had imposed a regulatory framework that required higher provisioning, which provided cushions to spanish banks to initially absorb the losses caused by the onset of the global financial crisis. and there were no toxic assets in bank´s balance sheets. nevertheless, this success proved short-lived. in the summer of 2012, spanish financial institutions seemed to be on the brink of collapse and the crisis of the sector forced the european union in june (2012) to devise an emergency e100 billion rescue plan for the spanish banking sector (see chapter 1). when the crisis intensified, the financial system was not able to escape its dramatic effects. by september 2012, the problem with toxic real estate assets forced the government to intervene and nationalize eight financial institutions. altogether, by may 9, 2012, the reorganization of the banking sector involved e115 billion in public resources, including guarantees. as we will examine later in the book, there are a number of factors that help account for the deteriorating performance of the spanish banks after 2009. the first was the direct effect of the economic crisis. the deterioration in economic conditions had a severe impact on the bank balance sheets. the deep recession and record-high unemployment triggered successive waves of loan losses in the spanish mortgage market coupled with a rising share of nonperforming loans. like many other countries such as the united states, spain had a huge property bubble that burst. land prices increased 500% in spain between 1997 and 2007, the largest increase among the oecd countries. as a result of the collapse of the real estate sector had a profound effect in banks: five years after the crisis started, the quality of spanish banking assets continued to plummet. the bank of spain classified e180 billion euros as troubled assets at the end of 2011, and banks were sitting on e656 billion of mortgages of which 2.8% were classified as nonperforming. a second factor was concern over the country's sovereign debt. as mentioned before, the crisis in spain did not originate with mismanaged public finances. the crisis has largely been a problem of ever-growing private sector debt, compounded by reckless bank investments and loans, particularly from the cajas , as well as aggravated by competitiveness and current account imbalances. to place the problem in perspective, the gross debt of household increased dramatically in the decade prior to the crisis, and by 2009 it was 20 percentage points higher than the eurozone average (86% of gdp versus 66%). but the austerity policies implemented since may 2010 aggravated the fiscal position of the country. the ratio of spain's debt to its economy was 36% before the crisis and reached 84% in 2013. in sum, spain fell into the "doom loop" that had already afflicted greece or portugal and led to their bailout. the sustainability of the spanish government debt was affecting spanish banks (including bbva and santander) because they had been some of the biggest buyers of government debt in the wake of the ecb long-term refinancing operation liquidity infusions (the percentage of government bond owned by domestic banks reached 30% in mid-2012). again, the doom loop was a result of emu weakness, namely the lack of a banking union with a centralized eu funded mechanism to bail out banks. spanish banks were also suffering the consequences of their dependence on wholesale funding for liquidity since the crisis started, and, in particular, their dependence on international wholesale financing, as 40% of their balance depends on funding from international markets, particularly from the ecb. borrowing from the ecb reached e82 billion in 2012, and spanish banks had increased their ecb borrowings by more than six times since june 2011, to the highest level in absolute terms among euro area banking systems as of april 2012. the crisis also exposed weaknesses in the policy and regulatory framework, part of the banking bargains that we will examine later in the book. the most evident sign of failure was the fact that the country had already adopted five financial reforms in three years and had implemented three rounds of bank mergers. the results of these reforms were questionable at best. the fact that spain had five reforms in less than three years, instead of one that really fixed the problem, says it all. they had been perceived largely as "too little and too late," and they failed to sway investors' confidence in the spanish financial sector. finally, the financial crisis can also be blamed on the actions (and inactions) of the bank of spain, one of the key actors involved in the bank bargains. at the beginning of the crisis, the bank of spain's policies were all praised and were taken as model by other countries. time, however, tempered that praise and the bank of spain was criticized for its actions and decisions (or lack thereof) during the crisis. spanish central bankers chose the path of least resistance: alerting about the risks but failing to act decisively. the economic crisis that started in spain 2008 was largely a problem of ever-growing private sector debt, aggravated by competitiveness and current account imbalances, and compounded by reckless bank investments and loans, particularly from the cajas , which by over-lending freely to property developers and mortgages contributed to a real estate property bubble. this outcome was a result of the political bargains at the heart of the game of bank bargains focus of this book. the bubble contributed to hide the fundamental structural problems of the spanish economy outlined in the previous sections and had an effect in policy choices because no government was willing to burst the bubble and risk suffering the wreath of voters. furthermore, cheap credit also had inflationary effects that contributed to competitiveness losses and record balance of payment deficits. therefore, three dimensions of the crisis (financial, fiscal, and competitiveness) are interlinked in their origins. the crisis exposed the underbelly of the financial sector and showed that many banks (particularly the cajas ) were not just suffering liquidity problems but risked insolvency, which led to the eu financial bailout of june 2012. the bailout had onerous conditions attached and it limited national economic autonomy (see dellepiane and hardiman 2011) . finally, the financial and fiscal crises were made worse by the incomplete institutional structure of emu and by bad policy choices at the eu level (excess austerity and refusal to act as a lender of last resort for sovereigns by the ecb) (royo 2013) . in the end, the crisis exposed the weaknesses of the country's economic model. indeed, despite the previous two decades' significant progress and achievements, the spanish economy still faced serious competitive and fiscal challenges. unfortunately, the economic success the country prior to the crisis fostered a sense of complacency, which allowed for a delay in the adoption of the necessary structural reforms. and this was not a surprise as the spanish economy was living on borrowed time, despite all the significant progress, and the country still had considerable ground to cover, given the existing income and productivity differentials, to catch up with the richer eu countries and to improve the competitiveness of its economy (see royo 2013) . the sudden collapse of the spanish economy came as a shock. yet, in retrospect it should not have been such a surprise. the policies choices and political bargains taken during the previous decades led to an unsustainable bubble in private sector borrowing that was bound to burst. moreover, as we will examine on chapter 7, the institutional degeneration that led to systemic corruption and contributed to the implosion of parts of the financial sector made the crisis almost unavoidable. as we have seen, much of spain growth during the 2000s was based on the domestic sector and particularly on an unsustainable reliance on construction. as we will later in the book, this outcome was part of a political bargain in which tax incentives and a lax regulatory framework favored developers, property owners, and bankers (particularly cajas ). the particular regulation of the cajas proved fatally flawed, as it provided incentives that favored local and regional government actors' access to finance at the expense of an environment that would have provided a stable and efficient banking system. on the contrary, it led to a form of crony capitalism spanish style, in which they invested massively in the construction sector in search of rapid growth and larger market share. these decisions proved fatal once the real estate bubble burst, and they led to the nationalization of several cajas , including bankia, and the financial bailout from the european union. membership in the european single currency was not the panacea that everyone expected to be, thus confirming the crucial importance of domestic political institutions and how domestic players operate within those institutions. in spain, the adoption of the euro led to a sharp reduction in real interest rates that contributed to the credit boom and the real estate bubble. however, it also altered economic governance decisions. successive spanish governments largely ignored the implications of emu membership and failed to implement the necessary structural reforms to ensure the sustainability of fiscal policies and to control unitary labor costs. these decisions led to a continuing erosion of competitiveness (and a record current account deficit), and a huge fiscal deficit when the country was hit by the global financial crisis. indeed, the experience of the country shows that eu and emu membership had not led to the implementation of the structural reforms necessary to address these challenges. on the contrary, emu contributed to the economic boom, thus facilitating the postponement of necessary economic reforms. this challenge however is not a problem of european institutions, but of national policies. the process of economic reforms has to be a domestic process led by domestic actors willing to carry them out. the spanish case serves as an important reminder that in the context of a monetary union, countries only control fiscal policies and relative labor costs. spain proved to be weak at both. it failed to develop an appropriate adjustment strategy to succeed within the single currency, and it ignored the imperative that domestic policy choices have to be consistent with the international constraints imposed by euro membership. on the contrary, in spain domestic policies and the imperatives of participating in a multinational currency union stood in uneasy relationship to one another. the crisis was the tipping point that brought this inconsistency to the fore, which led to the worst economic crisis in spanish modern history (before covid-19). next we turn to the elements of domestic bargains that underline the financial crisis. immigrants at the margins ucd geary institute discussion series chapters the rise of spanish multinationals competitiveness and growth in emu: the role of the external sector in the adjustment of the spanish economy from social democracy to neoliberalism royo, sebastián. lessons from the economic crises in spain after austerity: lessons from the spanish experience key: cord-290967-u0xx47dl authors: caja, g.; díaz-medina, e.; salama, a. a. k.; salama, o. a. e.; el-shafie, m. h.; el-metwaly, h. a.; ayadi, m.; aljumaah, r. s.; alshaikh, m. a.; yahyahoui, m. h.; seddik, m. m.; hammadi, m.; khorchani, t.; amann, o.; cabrera, s. title: comparison of visual and electronic devices for individual identification of dromedary camels under different farming conditions date: 2016-08-17 journal: j anim sci doi: 10.2527/jas.2016-0472 sha: doc_id: 290967 cord_uid: u0xx47dl the camel industry uses traditional (i.e., iron brands and ear tags) and modern (i.e., microchips) identification (id) systems without having performance results of reference. previously iron-branded (n = 45; 1 yr) and microchipped (n = 59; 7 yr) camels showed problems of healing (8.6% of brands) and reading (only 42.9% of brands and 69.5% of microchips were readable), which made their use inadvisable. with the aim of proposing suitable id systems for different farming conditions, an on-field study was performed using a total of 528 dromedaries at 4 different locations (egypt, n = 83; spain, n = 304; saudi arabia, n = 90; and tunisia, n = 51). the id devices tested were visual (button ear tags, 28.5 mm diameter, n = 178; double flag ear tags, 50 by 15 mm, n = 83; both made of polyurethane) and electronic (ear tags, n = 90, and rumen boluses, n = 555). electronic ear tags were polyurethane-loop type (75 by 9 mm) with a container in which a 22-mm transponder of full-duplex technology was lodged. electronic boluses of 7 types, varying in dimensions (50 to 76 mm length, 11 to 21 mm width, and 12.7 to 82.1 g weight) and specific gravity (sg; 1.49 to 3.86) and each of them containing a 31-mm transponder of half-duplex technology, were all administered to the dromedaries at the beginning of the study. when a low-sg bolus was lost, a high-sg bolus was readministered. readability rates of each id system were evaluated during 1 to 3 yr, according to device and location, and yearly values were estimated for comparison. on a yearly basis, visual ear tag readability was not fully satisfactory; it was lower for rectangular ear tags (66.3%) than for button ear tags (80.9%). yearly readability of electronic ear tags was 93.7%. bolus readability dramatically varied according to their sg; the sg < 2.0 boluses were fully lost after 8 mo. in contrast, the sg > 3.0 boluses were efficiently retained (99.6 to 100%) at all locations. in conclusion, according to the expected long lifespan of camels, low id performances were observed for iron brands, injectable microchips, and ear tags (visual and electronic), making their use inadvisable as unique id systems in camels. the high readability of dense electronic boluses recommended their use as a permanent id device of reference in camels. worldwide, there are 27 million of the old world camels (fao, 2015) , where near 90% of them are dromedaries (camelus dromedarius l.) or arabian camels, spreading all over the arid flat lands between the 0 and 40°n (from the canary islands to rajasthan) and the 20 and 30°s (australian deserts) parallels. camels are culturally reverenced and economically appreciated by their strategic values (i.e., milk, meat, draft, manure, hair, and hides), but there are also some concerns related to their overgrazing (el-keblawy et al., 2009 ) and feral herds (dennis et al., 2010) and to endemic (fassi-fehri, 1987 ) and emergent diseases (e.g., middle east respiratory syndrome coronavirus; chu et al., 2014) . dromedaries show a long lifespan (approximately 30 yr) and few distinctive coat traits, making a necessity to use the artificial marks for individual identification (id). traditional camel id is based on the use of clan or family symbols ("wasm" or "lealama" in arabic) engraved by red iron brands on visible body sites (e.g., cheek, neck, thigh). however, branding is questioned today for welfare reasons and is inadequate for modern id and traceability standards. modernization of livestock farms led to the adoption of id devices (caja et al., 2004) such as visual (e.g., brands, tattoos, ear tags, and collars) and electronic (e.g., injectables, ear tags, and boluses). despite the sedentarization of herds and the creation of intensive dairy farms (faye et al., 2012) , little attention has been paid to camel id and traceability. camels are absent from the terrestrial animal health code of the world organization for animal health (oie, 2016) , the codex alimentarius (who-fao, 2016) , or the guidelines of icar (2016). camel id is only regulated in the emirate of abu dhabi based on the use of radio-frequency identification (rfid) injectable transponders or microchips (adfca, 2010) . to our knowledge, however, there are no studies evaluating the performance of different id devices in camels. therefore, the aim of this research was to compare the performances of using visual vs. electronic camel id systems in a wide range of geographical locations and different farming conditions. animal care and experimental procedures used in this study were approved by the ethical committee on animal and human experimentation (reference 3189) of the university autonoma of barcelona and followed the guidelines for animal performance recording of the spanish committee of animal electronic identification (mapa, 2007) and of icar (2016) evaluation of the id systems was conducted under a randomized incomplete block design performed at 4 locations using a total of 528 dromedaries of different breeds, ages, and farming conditions (stabled or grazing). these locations were 1) egypt (maghrebi breed, n = 83), 2), spain (canarian breed, n = 304), 3) saudi arabia (maghatir breed, n = 37, and majaheem breed, n = 53), and 4) tunisia (maghrebi breed, n = 51). all farms were located between the 28 and 34°n parallels, where the camel is habitual, and followed similar production cycles with natural mating and calving during the winter season. location number 1 (egypt). the camel farm was located at the camel experimental station of the animal production research institute in marsa matrouh (matrouh governorate, egypt) where 83 maghrebi female dairy camels averaging 5.7 ± 0.5 yr (range 1.1 to 13.8 yr) and 461 ± 13 kg bw (range 248 to 691 kg bw) and in different physiological stages (open, pregnant, and lactating) were used. they were stabled in loose stalls on sand-bedded pens and fed berseem clover hay (1 to 2.5 kg/d), rice straw (1 to 2.0 kg/d), saltbush (1 to 2.0 kg/d), and concentrate (0.5 to 3.5 kg/d) according to their requirements (wilson, 1989) . water was freely available in water troughs. lactating camels were milked twice a day by hand after camel-calf stimulation. location number 2 (spain). the camel farm was located at the oasis park-museo del campo majorero (la lajita, fuerteventura, canary islands, spain) where 296 canarian dromedaries of different ages (newborn, suckling, growing, and adult), physiological stages (open, pregnant, and lactating), gender (males, females, and castrates), and uses (camel rides and dairy camels) were used. all camels were stabled in loose stalls on sand-bedded pens and fed alfalfa hay (1 to 2.5 kg/d), palm fronds (1 to 1.5 kg/d), thornless acacia branches (acacia salicina lindl.; 1 to 2.0 kg/d), and concentrate (0.5 to 3.5 kg/d) according to their requirements (wilson, 1989) . water and mineral blocks were freely available. lactating camels suckled their calves for 1 yr and were machine milked once a day using a 2-stall tunnel milking parlor with a portable bucket machine. a total of 90 dairy camels aged 1 to 15 yr, located at the al-watania agri farm (al jouf, saudi arabia; n = 50) and the camel and rangeland research center (al jouf, saudi arabia; n = 40), of 2 breeds (maghatir or bright, n = 37, and majaheem or dark, n = 53) and in different physiological stages (open, pregnant, and lactating) were used. milking and growing camels were in loose stalls on sand-bedded pens, and dry and pregnant camels were under free-rangeland grazing conditions. yearling camels were fed alfalfa hay (1 to 2 kg/d), concentrate (1.0 kg/d), and barley straw ad libitum. lactating camels were fed alfalfa hay (2 to 5 kg/d), barley straw and corn stalks (2 to 7 kg/d), and concentrate (0.5 to 2 kg/d) according to their requirements (wilson, 1989) . water and mineral blocks were freely available inside the pens. lactating camels suckled their calves for 6 mo and were machine milked twice a day using a 10-stall tunnel and low milk pipeline (al-watania agri farm) and a 2-stall tunnel with a portable bucket machine (camel and rangeland research center) milking parlors. location number 4 (tunisia). the camel farm was located at the laboratory of animal husbandry and wildlife of the arid regions institute in medénine (tunisia) where a total of 51 maghrebi dairy dromedaries (adult females 7 to 15 yr, n = 50, and yearling, n = 1) were used. adult camels grazed during the day on saline rangelands and were sheltered during the night on sand-bedded pens and fed barley straw. lactating camels suckled their calves for 6 mo and were fed concentrate at a flat rate of 4 kg/d (as fed) during the lactation period and were machine milked twice a day using a single milking stall and a portable bucket machine. the yearling camel was fattened with concentrate (1.5 kg/d) and barley straw ad libitum and was slaughtered 8 mo after identification. water and mineral blocks were freely available in the shelter. previous identification. forty-five adult maghrebi camels (age > 7 yr) from location number 1 (egypt) showed red iron brands (1 to 3 digits, 20 cm high) on the left thigh, which had been made by the technical personnel of the camel experimental station of the animal production research institute 1 yr before the beginning of the study. these camels were used to assess the readability of the brand under on-farm conditions. on the other hand, 59 adult castrated male canarian camels (age 10 to 15 yr) from location number 2 (spain), daily used for camel rides and previously injected (i.e., 7 yr before the beginning of the study) with glass-encapsulated rfid microchips, 12.0 by 2.1 mm, of full-duplex b technology according to iso 11784:1996 (radio frequency identification of animals -code structure; iso, 1996a) and iso 11785:1996 (radio frequency identification of animals -technical concept; iso, 1996b), were also used to assess the readability of the microchips. the injections were performed subcutaneously in the left side of the neck (at the halfway point between the ears and the withers) by the veterinarian of the oasis park-museo del campo majorero according to the guidelines of the world small animal veterinary association (2016) for horses and camelids. serial numbers of the injected microchips ranged from 982 009100063248 to 982 009100969093 (azasa-allflex, madrid, spain). visual ear tags. two types of visual ear tags (vet) inserted in the left ear were used for camel visual id: one was at location number 1 (vet1; n = 83; egypt) and the other was at location number 2 (vet2; n = 304; spain). the vet1 consisted of 2 rectangular flags of polyurethane (50 by 15 mm, 3 g; hasco tag co., dayton, ky), which were laser recorded with 3 digit numbers. the vet2 consisted of polyurethane double button ear tags (28.5 mm button diameter, 20.5 by 5.5 mm pin length by diameter, and 3.5 g total weight; azasa-allflex) and were laser recorded with an alphanumeric code consisted of 2 letters of the spanish province (i.e., gc for gran canaria) followed by a serial code of 4 numbers and 2 letters (e.g., gc 3854 ab). electronic ear tags. plastic-loop type electronic ear tags (eet) were applied in the left ear of 90 dromedaries at the al-watania agri farm at the beginning of the study at location number 3 (saudi arabia). they consisted of white polyurethane (75.0 by 9.0 mm, length by width) with a pin-lock closing system (17.0 mm pin and 10.0 by 9.0 mm lock) and a container (31.0 by 9.0 mm) intended to lodge a glass encapsulated transponder of 22 by 4 mm and full-duplex b technology (set-tag; shearwell data ltd., minehead, somerset, uk). the total weight of the eet was 2.5 g. serial numbers of the microchips ranged from 940 000002204916 to 940 000002363335 (shearwell data ltd.). electronic rumen boluses. seven types of electronic rumen boluses (erb; n = 555) varying in features were applied to all camels at all location sites. the erb consisted of cylindrical capsules of different dimensions, made of several nontoxic and nonporous materials to reach different specific gravities (sg). features of bolus types (erb1 to erb7) are shown in table 1 , where different ranges of capsule dimensions (50.0 to 76.4 mm length, 11.2 to 21.1 mm width, and 12.7 to 82.1 g weight) and sg (1.49 to 3.86) can be identified. similar sizes and sg ranges of rumen boluses were previously used by caja et al. (1999) , ghirardi et al. (2006a,b) , and carné et al. (2011) for assessing their readability in small and large domestic ruminants. it is worthwhile mentioning that when a low-sg bolus was lost, a high-sg bolus was readministered. a random sample of 10 boluses of each type was collected to measure their physical features under laboratory conditions using a precision weighing scale (0.01 g accuracy; bp 3100 p; sartorius ag, göttingen, germany) and a digital caliper (0.03 mm accuracy; shaodong feiyue hardware tools factory, yiwu, china). the sg of each bolus was measured according to the archimedes principle by contrasting the weight of the bolus with the weight of its volume of displaced distilled water, similarly to ghirardi et al. (2006a) . boluses were applied by trained operators according to the procedure described by caja et al. (1999) and carné et al. (2009a) , using livestock balling guns (datamars trazabilidad sl, barcelona, spain) adapted to each bolus type. the full set of boluses (erb1 to erb7) was tested at locations number 1 and 2 in camels of all ages (newborn to adult) under intensive conditions to assess the ease of administration and the bolus readability at the mid-term (3 yr) duration. at locations number 3 and 4, only boluses of type erb6 and erb5, respectively, were administered to adult camels to confirm their retention at the mid term (3 yr) in adult camels under grazing conditions. low-sg boluses were designed to be lost with the aim of determining the threshold of bolus features to be retained in camels. all boluses contained a 31 by 3.8 mm glass encapsulated transponder of half-duplex technology (ri-trp-rr2b-06; the animal registration and identification system [tiris], almelo, the netherlands) that worked at a low frequency (134.2 khz) in agreement with the current standards of the international organization for standardization (iso) on animal electronic id (iso, 1996a (iso, ,b, 2009 ). visual devices. readability of each digit of the previous iron brands was made by sight at the beginning of the study at location number 1 (egypt), and the results were manually recorded. readability of the alphanumeric code of vet (vet1 and vet2) at locations number 1 (egypt) and 2 (spain) was also assessed by sight and the id codes were manually recorded after 1 yr of insertion. when retained, the readable ear tags were not broken or seriously damaged. any official ear tag lost at location number 2 (spain) was replaced by veterinary officers only at the annual blood sampling campaign for camel tuberculosis. no replacement was done at the other location sites. electronic devices. readability of all rfid or electronic id devices (i.e., microchips, eet, and erb) was performed using full-iso handheld transceivers, connected to a 70-cm-long stick antenna (gasiso; datamars trazabilidad sl) that is able to read iso rfid transponders of half-duplex and full-duplex b technologies at a minimum distance of 12 and 20 cm for ear tags and boluses, respectively, as established by european commission regulations ec 21/2004 (ec, 2004 and ec 933/2008 (ec, 2008b) on this issue. gesreader 2s (rumitag, esplugues de llobregat, barcelona, spain) handheld readers were used in at locations number 1 (egypt), 3 (saudi arabia), and 4 (tunisia), whereas the gesreader 3 (datamars trazabilidad sl) was used at location number 2 (spain). microchips previously injected at location number 2 were individually read at the beginning of the study while the camels were restrained in a sitting-down position. readability of eet and erb was evaluated under static conditions using the above-indicated handheld transceivers and stick antennas while the camels were in a standing position and restrained in a raceway (locations number 1, 2, and 4) or inside the milking parlor (location number 3). the time required for reading each id device type was recorded at locations number 2 and 3 using an electronic chronometer (geonaute trt´l 100; decathlon, alcobendas, spain). periodical readings of rfid devices were performed at different time intervals according to the location sites: d 0, 1, 2, 7, 14, 21, 30, 60, 120, 150, 180, and 210 ; at 2-mo intervals until yr 1.5; and finally at 3 yr at location number 1. similar time intervals were used at locations number 2, 3, and 4 from 0 to 180 d and later every 6 mo until yr 3. each device was read immediately before and after administration to check for breakages or electronic failures that might happen during administration as well as, in the case of erb, to ensure the proper location of the bolus in the forestomachs (c1 compartment of camel) before releasing the animal. the readability rate of id devices was assessed by the ability of each type of device to be read under static conditions at each time point and at the end of the study; the actual readability was expressed as r (%) = (number of readable devices/number of applied devices) × 100. obtained r values were compared on a yearly basis (seroussi et al., 2011) , whereas the yearly readability rate (r y ; %) was estimated by the expression r y = (r/100) 1/y × 100, in which y is the duration of the study in years (e.g., from table 2 : r y = 94.935% for r = 69.5% after 7 yr). no aging effects or reidentification are considered in this expression, so the actual values of readability in the long term would be lower in practice than those estimated. the losses, electronic failures, and readability of id devices were analyzed with the catmod procedure of sas (version 9.4; sas inst. inc., cary, nc) on the basis of the categorical nature of these variables. a logit model with an estimation method of maximum likelihood (cox, 1970) was used to evaluate the effects of each type of id device. a log-rank test of equality across strata (i.e., type of ear tags or id rumen boluses) was performed with the lifetest procedure of sas. for the analysis of data acquired by the erb, the procedure phreg (proportional hazard regression) for survival data of sas was considered preferable to the logit model to avoid the possible bias produced by the different number of animals monitored until the end of the study in addition to introducing the effects of the location sites and bolus features (i.e., size and sg). such analysis permitted the comparison of the longitudinal readability and the estimates of readability of the erb throughout the entire period of study, without excluding censored data (data from animals that left the study before a device failed), as previously performed by carné et al. (2009a) . furthermore, the 1 calculated as readability (r) = (number of readable devices/number of applied devices) × 100. 2 estimated as 100 − r y , in which r y is the yearly readability rate = (r/100) 1/y × 100, in which y is the duration of the study in years. 3 estimated values of r, after 10 and 25 yr, respectively, using the corresponding values of r y previously calculated. table 1. readability data were compared on a yearly basis. the differences between means were declared significant at p < 0.05, unless otherwise indicated. a total of 528 camels were finally identified in the 4 locations using 5 different id systems (i.e., iron brands, injectable microchips, vet and eet, and erb). the total number of id devices applied and their long-term performance at all locations are summarized in table 2 . hot-iron brands. the previously iron-branded camels at location number 1 (egypt) showed signs of healing problems in 8.6% of brands on the thigh, where most of them formed some kind of keloid (aberrant epidermal hyperplasia developed during the healing process) at the brand site, which, consequently, resulted in only 42.9% of brand digits being fully readable (table 2) . injected microchips. the camels identified with rfid microchips at location number 2 (spain), already injected 7 yr before the beginning of our study, showed a low readability (69.5%; table 2 ) but equivalent to 94.9% of yearly readability. moreover, they showed some difficulties for locating the injection site and reading with the gesreader 3 transceiver (datamars trazabilidad sl) used. no detailed information was available on the precise injection site of the microchips in the neck of our camels and we needed 26 ± 4 s, on average, to locate and read them. no relevant migration was estimated from the injection site; all the microchips were located in the middle of the neck. visual ear tags. readabilities of vet devices measured at locations number 1 (egypt) and 2 (spain) after 1 yr were lower in vet1 (rectangular) ear tags than in vet2 (button) ear tags (66.3 vs. 80.9%, respectively; p = 0.011; table 2 ); the annual losses were very high (33.7 and 19.1%, respectively). both vet1 and vet2 were hard to read in camels because of the height of the camels and their biting and kicking behavior. moreover, most ear tag losses were associated with breakages of the ear tissue (occasionally of the whole ear) or the ear tag, usually as a consequence of their behavior of fighting for dominance. electronic ear tags. readability of plastic-loop eet applied at location number 3 (saudi arabia) measured in our study after 3 yr was 82.2% (table 2) , which, on the yearly basis, is equivalent to 93.7%. this value was similar to the readability of vet2 (button, p = 0.793) and greater than that of vet1 (rectangular, p = 0.018) in our camels and, in fact, supported the convenience of using small and light ear tags in camels. the estimated eet yearly losses at location number 3 (saudi arabia) were 6.3% (table 2) , which were lower than the above-reported mean values of vet but within the range of losses previously observed for injected rfid microchips. on the other hand, with regard to reading time, the eet at location number 3 (saudi arabia) were read 65% faster (9 ± 1 s) than the injected rfid microchips at location number 2 (spain). electronic rumen boluses. administration of erb was done easily and safely (i.e., no injuries or casualties) when performed by trained operators in yearling and adult camels using balling guns adapted to the size of the bolus and the age of the camels. the best restraining positions for bolus administration were standing up and sitting down for young and adult camels, respectively, and assistance was required in all cases. boluses were mostly swallowed at the first attempt (95%) after being gently released at the end of the tongue (torus linguae) and when the mouth was maintained firmly closed until the involuntary deglutition reflex took place. although time for bolus swallowing was not measured, we noted that erb were swallowed faster if previously warmed to body temperature. nevertheless, 2 erb at location number 2 (spain; 0.7%) were blocked in the neck of young suckling camels during administration (erb2, 1 wk of age and 24 kg bw, and erb6, 3 mo of age and 70 kg bw) by operators with little experience. although the erb6 (large) was easily unblocked by gently pushing with an esophageal probe in the 3-mo-old camel calf, we were unable to remove the erb2 (small) with veterinary assistance in the case of a 1-wk-old calf, where the bolus was located in the trachea and causing asphyxia. necropsy reports of culled adult camels at location number 2 (spain) and the yearling fattened camel slaughtered at location number 4 (tunisia) revealed that the erb were properly located in the c1 compartment of the camel forestomachs, without causing damages or signs of alteration of the mucosa. in 3 cases, however, the erb were located at the water sacs of the c1 compartment. no relevant changes in health or apparent intake and behavior were observed in our camels as a consequence of the administration of the different erb types used at different location sites and under different feeding and farming conditions. as shown in table 2 , readability of erb widely varied according to bolus type (0 to 100%); the erb1 (small) and erb3 (large) were not retained at all (regurgitated) in the camel forestomachs, whereas the rest of the erb showed a high final retention (98.1 to 100%), in all cases agreeing with the international committee for animal recording (2016) recommen-dation (>98%). according to bolus features (table 1) , the lost bolus types were those with the lowest weights and sg values, which were regurgitated. results of the predicted yearly readability of erb at all location sites by using the cox's proportional-hazards regression model for survival data (table 3 ; fig. 1 ) revealed that sg was the most critical factor (χ 2 = 562.9, p < 0.001) for the retention of erb in the camel forestomach and its mid-and long-term readability. as shown in fig. 1 , the estimated readability values were >98% for sg > 3.0 boluses (erb2, erb4, erb5, erb6, and erb7), whereas it dramatically dropped early after administration (at d 7, approximately 70%; at d 30, approximately 40%; and at d 365, approximately 0%) for sg < 1.5 boluses (erb1 and erb3). bolus size (χ 2 = 188.9, p < 0.001) and location site (χ 2 = 61.1, p < 0.001) were also significant factors for erb readability, but their inclusion in the model explained less than 25% of the effects. differences between actual (table 2 ) and estimated (table 3) values of yearly readability for erb were moderate, ranging from −2.6 to 0.3%. these observations were mainly due to the high number of erb being monitored until the end of the study (positively censored). the estimated values of readability for low-sg (erb1 and erb3; sg from 1.49 to 1.51) and high-sg (erb2, erb4, erb5, erb6, and erb7; sg from 3.10 to 3.86) boluses markedly differed (p < 0.001). similar to the observed case of the actual data, no differences within sg < 2.0 or sg > 3.0 bolus groups were detected (p = 0.895). on average, the time required for reading the camels identified with erb at location number 2 (spain) was 12 ± 5 s, which was 14 s (54%) shorter and 3 s (33%) longer, respectively, than the above-indicated reading times for injected rfid microchips and eet using similar reading procedures. nevertheless, reading difficulties were observed using the gesreader 2s (rumitag) transceiver in pregnant camels at the end of pregnancy at locations number 1 (egypt, n = 1) and 3 (saudi arabia, n = 5). all boluses were again readable after parturition. the paper is based on observational and experimental data obtained from commercial camel herds. the main limitation of our experiment in extracting causal relationships is because all treatments were not possible at all locations due to differences in farm conditions and in available facilities. this is the case of iron brands, which were applied before starting the experiment in egypt and are not currently allowed in some countries due to welfare regulations. on the other hand, having the concern of residues in camel meat for human consumption, we considered a unique opportunity to report the mid-term performances of microchips already injected by a veterinarian in a group of riding dromedaries in spain. moreover, the unsatisfactory readability results observed for both iron brands and microchips motivated the interest for testing alternative id systems. time differences between types of id devices were standardized on a yearly basis for comparison, and differences between means were separated by using a logit model with an estimation method of maximum likelihood. a more detailed analysis of the relation between treatments and id performances was therefore not possible, but the explanation of the results was completed with relevant literature data and local experts' knowledge about dromedary husbandry. hot-iron brands. low readability results similar to ours (table 2) were reported by aurich et al. (2013) in horses, where breed-specific symbols of iron brands were readable in 84% of the horses, whereas the double-digit individual branding number was readtable 3 . predicted yearly readability of electronic rumen boluses (erb) by the cox proportional-hazards regression for survival data from all the experiments and taking into account the specific gravity and size of the boluses readability estimates, % 0 ± 0 c 99.9 ± 0.1 a 0 ± 0 c 99.6 ± 0.2 a 97.4 ± 1.1 b 99.1 ± 0.5 a 99.7 ± 0.2 a a-c within a row, values with different superscripts differ (p < 0.05). 1 bolus details are shown in table 1 . rumen bolus contained a half-duplex glass encapsulated transponder (31.0 by 3.8 mm; datamars trazabilidad sl, barcelona, spain). 2 small are <60 mm long and large are >60 mm long. able in only less than 39% of the horses. the risk of skin lesions by branding, which is equivalent to thirddegree thermal injuries , and the associated pain, as reported in iron-branded steers (schwartzkopf-genswein et al., 1997) , together with the low readability values makes the generalized use of iron branding inadvisable for camel id. although iron branding is a traditional method for the permanent id of livestock, the use of this method is currently banned in many countries (e.g., denmark, germany, netherland, scotland), due to animal welfare concerns (erber et al., 2012) . whatever the case, no iron branding should be applied without the appropriate analgesia. injected microchips. the time it took to find the microchips in the middle of the neck in our results agreed with that reported by stein et al. (2003) in equids injected before 4 to 5 yr. besides, small-sized microchips (11.4 by 2.2 mm), similar to those injected in our camels, were applied in the neck of horses (between poll and withers into the nuchal ligament or into musculature according to the european regulation ec 504/2008 (ec, 2008a) by konermann (1991) and wulf et al. (2013) , who reported 89.5 to 100% readability during short-term studies (9 and 6 mo, respectively). no long-term studies have been made in camels or horses using microchips in the neck, but løken et al. (2011) injected small-sized microchips (13.5 by 2.2 and 13.9 by 2.2 mm; glass-or polymer-encapsulated) in the ear (ear base or ear lobe) of testing bulls in a 8to 30-mo study and reported, on average, 92.3% readability. no differences between glass-and polymerencapsulated microchips were detected by løken et al. (2011) . the use of longer glass-encapsulated transponders (23 or 32 by 3.8 mm) in suitable body sites (ear scutulum and armpit) of fattening calves slaughtered at 8 to 12 mo by conill et al. (2000) showed 93.0 to 98.5% readability, which differed according to body site and transponder size. when comparing our results of microchip readability of the long term (7 yr) in camels with short and mid term (0.5 to 2.1 yr) in horses and cattle, it is clear that the values of estimated yearly losses by using the seroussi et al. (2011) expression in our camels (5.1%; table 2 ) were consistent and within the range of those previously calculated in horses (0 to 13.7%) and cattle (1.8 to 8.4%). a main concern related to the injection of rfid microchips in the neck of camels is the difficulties of recovery at slaughter and their possible presence in the meat as a residue and hazard object (i.e., glass capsule and electronic components). the world small animal veterinary association (2016) strongly recommended that any microchipped food-producing animal should carry an external id to indicate that a microchip is present (i.e., to be recognized and recovered at slaughter) and in some cases their use may not be permitted. conill et al. (2000) reported recovery times of approximately 1 min at the slaughterhouse when 23 and 32 mm transponders were injected in the ear base and armpit of fattening calves. the smaller size of rfid microchips used in camels (i.e., 12 to 15 mm, as in horses and pets), the uncertainty of their presence (i.e., high losses), and location difficulties (i.e., short reading distance) will compromise the safety of camel meat (i.e., neck) for consumers, making it not fully recommendable in the camel industry. visual ear tags. there are few researches reporting vet readability in livestock, and their performances dramatically vary according to the species and the exploitation conditions. edwards et al. (2001) studied the inflammatory reaction after the insertion of different ear tag types in sheep (i.e., metal loop, plastic loop, single or double plastic flags, etc.) and reported that metalloop tags produced more severe lesions that persisted longer than other ear tag types, therefore making their use inadvisable. fosgate et al. (2006) reported 87.6% of annual losses of plastic vet in a study on domestic water buffalo that lasted 3 yr under extensive conditions, with the overall median ear-tag retention being 272 d and the final retention zero, and they concluded that ear tags were inadequate for the long-term id of buffaloes under extensive conditions. in the case of goats, carné et al. (2009a) reported vet losses varying between 6.0 and 17.1% for official and unofficial (i.e., tip-tag ear tags) plastic vet in a 3-yr study. moreover, carné et al. (2009b) reported that goat breed is also key for vet retention (i.e., ear length differences), where the annual losses varied between 1.4 and 17.1% in 4 u.s. goat breeds under semi-intensive farming conditions. table 1 . losses of official vet in sheep (ghirardi et al., 2006b) and in fattening calves (conill et al., 2000) ranged from 3.3 to 11.4%, respectively. mean annual losses of 3 different plastic official vet, measured in a study that lasted 3.2 yr in dairy cattle under intensive conditions (seroussi et al., 2011) , varied between 11 and 20%, makes visual ear tag losses greater than expected according to the international committee for animal recording (2016) requirements (losses <2%). when data from buffaloes was not taken into account, the overall annual losses for vet ranged between 2.0 and 20.0% (i.e., cattle and goats), which are lower than the values observed in our camels (19.1 to 33.7%; table 2 ). unlike the regulations indicated above for cattle, sheep, or goats, there are no specific regulations for official camel ear tag design. however, despite not expecting high retention rates for vet, our results suggest that button ear tags should be preferable to flag ear tags for camel id in practice. electronic ear tags. there is controversy in the literature on comparing the performances between eet and vet, as reported by babot et al. (2006) in pigs and carné et al. (2009a carné et al. ( , 2010 in goats. nevertheless, eet are considered less damaging for the ear than vet due to their optimized design (edwards et al., 2001) . it should be stressed that ear tag weight must be limited when applied in young animals (caja et al., 1997) , due to the low strength of the thin ear tissue, which, as a consequence, reduces the reading distance (i.e., smaller antenna) and dynamic reading efficiency of the eet. there are few data reporting eet readability in livestock. caja et al. (2014) reviewed the state of the art of different id devices in goats and reported 92.9% readability (range between 79.8 to 100%) for eet in goats under different conditions. on the other hand, the fast readability of eet in our results was mainly a consequence of the easy location by sight as well as the fact that camels were not afraid of the stick antenna when gently approached from the back of the head. electronic rumen boluses. we did not expect side effects of erb administration as we followed the procedures described by caja et al. (1999) and carné et al. (2009b) in large and small ruminants. nevertheless, previous complete training and administration skills were considered key for implementing erb in the camel industry. antonini et al. (2006) reported that bolus administration did not affect, at the mid term, the productive performance or produce specific lesions in the reticulorumen mucosa of cattle of different ages. moreover, martín et al. (2006) and castro et al. (2010) reported that bolus administration did not affect the intake and digestive performances of adult goats as well as the growth and the forestomach development of milk fed kids, respectively. the positive relationship between erb readability in the forestomachs of camels and the bolus sg was expected. in fact, other authors previously stressed the key role of the sg (i.e., >3.0) for the retention of boluses in the reticulorumen of cattle (ghirardi et al., 2006a) , sheep (ghirardi et al., 2006b; hentz et al., 2014) , and goats (carné et al., 2011) . the difficulties in reading the erb observed when using the gesreader 2s (rumitag) transceiver in pregnant camels at the end of pregnancy at locations number 1 (egypt) and 3 (saudi arabia) was explained by the limited reading distance of the transceiver. this leads us to recommend the use of the gesreader 3 (datamars trazabilidad sl) or other available transceivers with a greater reading distance in camels. according to our results, for a camel productive life of 25 yr, the estimated readability of the studied id systems would vary between 0 and 100%, with the adequately designed erb (i.e., sg > 3.0) being the only system agreeing with the international committee for animal recording (2016) requirement (yearly losses < 2%). the highest values of predicted yearly readability by the cox's proportional hazards survival analysis, warranting the permanent id of dromedaries in the long term, were obtained with the erb2, erb4, erb6, and erb7 (99.1 to 99.9%). the greater number of camels used in the case of erb2 and erb6 made the decision of choice more robust with regard to their use in practice. comparatively, less than 60% of ear-tagged or microchipped camels would be identifiable after 10 yr and less than 30% after 25 yr, clearly showing the advantages of using erb. agreeing with our conclusion, moreki et al. (2012) reported that boluses were the most tamperproof and highly retained id device in a study comparing different methods for cattle id (i.e., vet, eet, and electronic boluses) under range-extensive conditions in botswana. additionally, hentz et al. (2014) stated that boluses have advantages over ear tags in warm and hot climates (e.g., brazil), as the internal devices (i.e., forestomach) reduce the risks of ear tag losses, tissue damage, and lesions on the ear. nevertheless, the above-mentioned erb4 to erb7 had large dimensions (66.0 to 68.0 mm length and 16.9 to 21.1 mm diameter), which made their use inadvisable in young suckling camels. therefore, these types of boluses should be used in camel calves older than 3 mo and heavier than 90 kg bw. the age is important for safe bolus administration, which depends on the anatomical development of the pharynx and esophagus and on the dimensions (length and diameter) of the erb used (carné et al., 2009a) . despite the administration of erb being possible during wk 1 of life, our advice for identifying young suckling camels is to administer small-sized boluses, such as the erb2, when the calves have passed the perinatal period and look vigorous (e.g., after 1 to 2 wk of age and >50 kg bw). for weaners and adult camels, any of the erb4 to erb7 are recommended for the long-term id under extensive and intensive conditions. for the first time, the performances of visual and electronic id devices have been studied in dromedary camels under a wide range of locations and different farming conditions. results and conclusions would be useful to farmers and administration bodies in assessing which are the most suitable devices for camel id in practice. no iron branding or injected microchips are recommended for the id of camels due to readability and to welfare and meat safety concerns, respectively. additionally, the low id performances reported for the long term makes their use inadvisable as a reference system for the camel industry. the use of vet as a single id device is also not recommended for the permanent id of camels due to the high losses and elevated risk of ear breakages. whatever the case, small-sized ear tags (e.g., button shape) or plastic-loop ear tags (e.g., eet) would be preferable to ear tags with large flags. the high readability of dense and adequately designed erb in the long term and under different farming conditions makes their use the most recommendable as the id device of reference for the permanent identification of camels. nevertheless, like required by international regulations in other livestock species, the use of a second visual id device might be suggested for an easy management in large farms of dairy dromedaries, although further studies are needed to confirm this recommendation. regulation no. 4. the animal identification and registration system for the emirate of abu dhabi in vivo mechanical and in vitro electromagnetic side-effects of a ruminal transponder in cattle readability of branding symbols in horses and histomorphological alterations at the branding site comparison of visual and electronic identification devices in pigs: on-farm performances state of the art on electronic identification of sheep and goat using passive transponders state-of-art of electronic identification techniques and applications in goats development of a ceramic bolus for the permanent electronic identification of sheep, goat and cattle diversity of animal identification techniques: from 'fire age' to 'electronic age longterm performance of visual and electronic identification devices in dairy goats modeling the retention of rumen boluses for the electronic identification of goats readability of visual and electronic leg tags versus rumen boluses and electronic ear tags for the permanent identification of dairy goats extended field test on the use of visual ear tags and electronic boluses for the identification of different goat breeds in the united states effects of mini-bolus used for the electronic identification of milk fed kids on the growth performance and development of the reticulorumen mers coronaviruses in dromedary camels effects of injection position and transponder size on the performances of passive injectable transponders used for the electronic identification of cattle the analysis of binary data feral camels in the australian rangelands establishing a system for the identification and registration of ovine and caprine animals and amending regulation (ec) no 1782/2003 and directives 92/102/eec and 64/432/eec implementing council directives 90/426/eec and 90/427/ eec as regards methods for the identification of equidae amending the annex to council regulation (ec) no 21/2004 as regards the means of identification of animals and the content of the movement documents a comparison of commonly used ear tags on the ear damage of sheep camel grazing affects species diversity and community structure in the deserts of the uae physiological and behavioural responses of young horses to hot iron branding and microchip implantation diseases of camels integrated impact of climate change and socioeconomic development on the evolution of camel farming systems food and agricultural organization of the united nations (fao). 2015. faostat ear-tag retention and identification methods for extensively managed water buffalo (bubalus bubalis) in trinidad evaluation of the retention of electronic identification boluses in the forestomachs of cattle retention of different sizes of electronic identification boluses in the forestomachs of sheep international committee for animal recording (icar). 2016. icar recording guidelines. international agreement of recording practices automatic electronic identification systems for farm animals. the commission of the european communities, dg telecommunications, information industries and innovation subcutaneous electronic identification in cattle: a field study intake behaviour and digestive effects of electronic identification with ruminal bolus in adult goats identificación electrónica animal: experiencias del mapa cattle identification and traceability in botswana behavior of cattle during hot-iron and freeze branding and the effects on subsequent handling ease long-term survival of flag eartags on an israeli dairy farm evaluation of microchip migration in horses, donkeys, and mules the nutritional requirements of camel world health organization -food and agricultural organization of the united nations (who-fao) terrestrial animal health code. chapter 4.1. general principles on identification and traceability of live animals reduced-size microchips for identification of horses: response to implantation and readability during a six-month period key: cord-274778-wds40e6i authors: tejedor, santiago; cervi, laura; tusa, fernanda; portales, marta; zabotina, margarita title: information on the covid-19 pandemic in daily newspapers’ front pages: case study of spain and italy date: 2020-08-31 journal: int j environ res public health doi: 10.3390/ijerph17176330 sha: doc_id: 274778 cord_uid: wds40e6i spain and italy are amongst the european countries where the covid-19 pandemic has produced its major impact and where lockdown measures have been the harshest. this research aims at understanding how the corona crisis has been represented in spanish and italian media, focusing on reference newspapers. the study analyzes 72 front pages of el país and el mundo in spain and italy’s corriere della sera and la repubblica, collecting 710 news items and 3456 data evidences employing a mixed method (both qualitative and quantitative) based on content analysis and hemerographic analysis. results show a predominance of informative journalistic genres (especially brief and news), while the visual framing emerging from the photographic choice, tend to foster humanization through an emotional representation of the pandemic. politicians are the most represented actors, showing a high degree of politicization of the crisis. spain and italy, with 238,564 and 231,732 confirmed cases, respectively, are amongst the european countries where the covid-19 pandemic has produced its major impact and where lockdown measures have been the harshest. due to the reduced mobility and the imposed lockdown, the internet has proved to play a decisive role in terms of media consumption during the quarantine. social networks have occupied the first position among online platforms most frequently consulted by citizens. according to twitter, the information on the pandemic as well as the conversations related to the topic have caused a 23% boost in total active daily users, reaching the general level of 164 million users per trimester. news check-up has experienced a prominent growth at that stage. specifically, the peak of media consumption coincided with the first measures of social distancing and has increased in correspondence with governmental communications. these data should be interpreted within the current crisis of journalism and the crisis of media credibility. a recent survey of 27 countries by ipsos global advisor [1] shows how citizens are rather skeptical towards the information they receive from the media, especially when it comes to online press. in spain, 41% of the surveyed trust in television, whereas 39% expressed their preference for traditional media, such as printed press. making reference to the intentions, the research claims that half of the total number of the surveyed believe that printed papers have "good intentions" as opposed to 66% considering that online newspapers and web pages are the ones with "the worst intentions" [1] . based on the trust placed on the printed media-as the most credible and rigorous media-this research analyzes a total of 72 front pages of the main daily newspapers in spain and italy (36 each) . the research considers the daily newspaper's front page as a fundamental element that synthetizes and prioritizes the contents that the particular medium treats as the most important. at the same time, the front page maintains a direct relation to the digital version of the medium, somehow setting the agenda. in other words, the front page serves a privileged space for public identity construction [2] . the study, carried out between 24 february and 4 april 2020, collected 710 pandemic-related news pieces and 3456 data evidences, aimed at answering the following research questions: • how has the covid-19 pandemic been covered on the front pages of spain and italy's main daily newspapers? • what types of journalistic genres have been used? • what types of political or social figures and institutions appear the most? • what role has been assigned to an image/photograph in the coronavirus-related information items of the front page? the covid-19 crisis has posed new challenges to journalism. media play a fundamental role in framing a crisis, since providing the right information from a reliable source is the key issue in this type of pandemic. the world health organization (who) has used the term "infodemic" to define the overabundance of information introduced by coronavirus and to warn the citizens against the risks caused by this information excess, that contain a great amount of hoaxes and rumors. as sylvie briand, director of infectious hazards management at who's health emergencies program notices, this phenomenon is not new "but the difference now with social media is that this phenomenon is amplified, it goes faster and further, like the viruses that travel with people and go faster and further". the role of social media in spreading misleading health information is not new [3] , but the covid-19 crisis has shown the critical impact of this new information environment [4] . many studies have focused on and are still focusing on how the disintermediated role of social media may foster misinformation: scholars studying iran [5] and spain [6] , stress how social media spread rumors, others [7] try to analyze the structure of this infodemic, or concentrate on the effect of media exposure [8] . within this social media euphoria, very few studies have focused on legacy media, intended as the mass media that predominated prior to the information age-particularly print media, radio broadcasting, and television-even if reality is showing that legacy media still plays an important role [9] . a study [7] noticed how cnn has recently anticipated a rumor about the possible lockdown of lombardy (a region in northern italy) to prevent the pandemic, publishing the news hours before the official communication from the italian prime minister. as a result, people overcrowded trains and airports to escape from lombardy toward the southern regions before the lockdown was in place, disrupting the government initiative, aimed to contain the epidemic and potentially increasing contagion. other literature [10] stresses the importance of looking at mainstream media coverage pointing out the importance of a high quality scientific journalism [11] . the analysis of the printed daily newspapers' front pages has been object of recurrent studies for the last 50 years. starting with the classical works [12] [13] [14] [15] [16] [17] [18] [19] up to the contemporary researches [20] [21] [22] [23] , various studies have dealt with content analysis of that essential element of the printed press [24, 25] . other studies followed them, concentrating on the comparison between the front pages in printed and digital editions of a medium [26] . as previously highlighted, daily newspaper's front pages are considered to be the most important page, displaying informative priorities and editorial position in relation to current issues [27] . other studies [28] single out three core elements of a daily newspaper's front page: headlines, or visual linguistic set; texts, or visual paralinguistic set and images, or visual non-linguistic set. in this context, the importance of media and information literacy, seen as the citizens' ability to access, use, assess, and create responsible and ethical content [29] , has become crucial. media and information literacy refers to the vital role that information and media possess in the everyday life of a person, therefore this skill represents an indispensable component to exercise freedom of expression and information. in this vein, numerous studies [29] [30] [31] [32] stress the significance of a digital literacy development that would exceed studying merely technical or instrumental aspects to embrace the issues of the critical use of media. the research, based on previous studies [33] , analyzes a total of 710 news items extracted from 72 front pages of the four main daily newspapers of spain and italy (36 per country). el país and el mundo of spain alongside with corriere della sera and la repubblica of italy were chosen, based on their relevance and the availability of their front pages. the analysis has been carried out through the use of a template chart consisting of 15 parameters and 64 categories that were obtained mainly in inductive form. the study, possessing descriptive and explanatory character, employs a mixed method (both qualitative and quantitative) based on content analysis and complemented by direct observation and hemerographic analysis as the main techniques. the first technique focused on the analysis of various elements that constitute the front page designs by means of a template chart elaborated during the research process. subsequently, we implemented a hemerographic analysis of texts, headlines and images. the data were processed through descriptive statistics planning with spss software. the analytical chart has considered all the elements displayed in table 1 . coronavirus-related information occupies 71% of the front pages. precisely, 506 news items out of the total 710 focus on topics related to the covid-19 pandemic. as for the main journalistic genres, (see figure 1 ), we can observe brief as the most common. this journalistic genre, characterized by its conciseness and brevity, has been defined as brief, a summarized piece of news that solely reflects the most relevant data of the information, missing profound insight and context. the total of pandemic-related units possess the form of short pieces, that could oscillate between 1 or 5 lines. coronavirus-related information occupies 71% of the front pages. precisely, 506 news items out of the total 710 focus on topics related to the covid-19 pandemic. as for the main journalistic genres, (see figure 1 ), we can observe brief as the most common. this journalistic genre, characterized by its conciseness and brevity, has been defined as brief, a summarized piece of news that solely reflects the most relevant data of the information, missing profound insight and context. the total of pandemic-related units possess the form of short pieces, that could oscillate between 1 or 5 lines. news occupies the second position in the list of types of the texts about coronavirus at the analyzed front pages. the informative approach towards, in other words, dominates the representation of the crisis. the effort of the daily newspapers to inform their readers on the characteristics, impact and spread of the virus has been detected. nonetheless, it is worth mentioning that opinion articles (with a total number of 81 counted units) surpass other informative journalistic genres. moreover, the importance of the editorial photo with a total number of 38 units, solely accompanied by the footnote, demonstrates a comprehensive approach to the topic through the communicative value of the image. the location of news items at the daily newspapers' front pages can be considered another element of high value when it comes to the detection of importance of each topic. in this sense the studies grant more value to the upper part and the right part from the reader's standpoint. the right part is the most valuable of the odd-numbered page and the left part is the most important for the even-numbered pages. concretely, projecting an imaginary v onto the open double page, the higher the position on the v, the more value the piece has (both in terms of editorial and advertising rates). accordingly, results show that news about coronavirus appear mostly located in the upper part, but in the left zone (see figure 2 ). in this way, it is possible to point out that the newspapers place the news in an important area of their front pages. in addition, in second position, with a total of 81 news items, is the upper right-hand area. in this way, it is possible to point out that the news have been progressively occupying the areas of greatest visual impact of the front page. however, this set of news items is very close to the 147 news items on the pandemic that appear at the bottom of the front page, i.e., the one of least importance. a total of 76 appear at the bottom left and 71 at the bottom right. therefore, the distribution of the news on covid-19 between the two areas marked by the horizontal division of the first page (top/bottom) is very tight. news occupies the second position in the list of types of the texts about coronavirus at the analyzed front pages. the informative approach towards, in other words, dominates the representation of the crisis. the effort of the daily newspapers to inform their readers on the characteristics, impact and spread of the virus has been detected. nonetheless, it is worth mentioning that opinion articles (with a total number of 81 counted units) surpass other informative journalistic genres. moreover, the importance of the editorial photo with a total number of 38 units, solely accompanied by the footnote, demonstrates a comprehensive approach to the topic through the communicative value of the image. the location of news items at the daily newspapers' front pages can be considered another element of high value when it comes to the detection of importance of each topic. in this sense the studies grant more value to the upper part and the right part from the reader's standpoint. the right part is the most valuable of the odd-numbered page and the left part is the most important for the even-numbered pages. concretely, projecting an imaginary v onto the open double page, the higher the position on the v, the more value the piece has (both in terms of editorial and advertising rates). accordingly, results show that news about coronavirus appear mostly located in the upper part, but in the left zone (see figure 2 ). in this way, it is possible to point out that the newspapers place the news in an important area of their front pages. in addition, in second position, with a total of 81 news items, is the upper right-hand area. in this way, it is possible to point out that the news have been progressively occupying the areas of greatest visual impact of the front page. however, this set of news items is very close to the 147 news items on the pandemic that appear at the bottom of the front page, i.e., the one of least importance. a total of 76 appear at the bottom left and 71 at the bottom right. therefore, the distribution of the news on covid-19 between the two areas marked by the horizontal division of the first page (top/bottom) is very tight. figure 3 displays the main entities mentioned in the stories, that is to say institution or entities most recurrently mentioned or displayed. of the information, 46% mentions geographical scenarios (europe, madrid, milan, etc.). in this sense, there is a tendency to depersonalize the information and to extrapolate it to wider scenarios or territories. this aspect is important insofar as the subject is the element of the sentence that carries out the action contained in it. in 22% of the cases the front page news referred to national entities of non-political nature (the hospital, the emergency unit, the laboratory, the intensive care unit, the sports center, the cultural center, etc.). in particular, there is a notable reference to entities linked to hospitals and healthcare scenarios. national political entities (government, trade unions, spokespersons, minister of health, etc.) occupy the third position in the rank of entities linked to the news, with 19%. political entities from abroad (the who, the european union, the european parliament, etc.), with 9%, and non-political entities from abroad (especially universities, research groups or the media), with 4%, respectively, completed the list of entities. figure 3 displays the main entities mentioned in the stories, that is to say institution or entities most recurrently mentioned or displayed. of the information, 46% mentions geographical scenarios (europe, madrid, milan, etc.). in this sense, there is a tendency to depersonalize the information and to extrapolate it to wider scenarios or territories. this aspect is important insofar as the subject is the element of the sentence that carries out the action contained in it. in 22% of the cases the front page news referred to national entities of non-political nature (the hospital, the emergency unit, the laboratory, the intensive care unit, the sports center, the cultural center, etc.). figure 3 displays the main entities mentioned in the stories, that is to say institution or entities most recurrently mentioned or displayed. of the information, 46% mentions geographical scenarios (europe, madrid, milan, etc.). in this sense, there is a tendency to depersonalize the information and to extrapolate it to wider scenarios or territories. this aspect is important insofar as the subject is the element of the sentence that carries out the action contained in it. in 22% of the cases the front page news referred to national entities of non-political nature (the hospital, the emergency unit, the laboratory, the intensive care unit, the sports center, the cultural center, etc.). in particular, there is a notable reference to entities linked to hospitals and healthcare scenarios. national political entities (government, trade unions, spokespersons, minister of health, etc.) occupy the third position in the rank of entities linked to the news, with 19%. political entities from abroad (the who, the european union, the european parliament, etc.), with 9%, and non-political entities from abroad (especially universities, research groups or the media), with 4%, respectively, completed the list of entities. in particular, there is a notable reference to entities linked to hospitals and healthcare scenarios. national political entities (government, trade unions, spokespersons, minister of health, etc.) occupy the third position in the rank of entities linked to the news, with 19%. political entities from abroad (the who, the european union, the european parliament, etc.), with 9%, and non-political entities from abroad (especially universities, research groups or the media), with 4%, respectively, completed the list of entities. figure 4 details which kind of people are mostly mentioned within the main characters in the information on covid-19. interestingly, national political figures are the most numerous group with 28% of the total, stressing how the crisis is highly politicized. in second place, we find anonymous citizens who are protagonists in 27% of news items on the front page. if political figures normally make it to the front pages, within the covid-19 crisis, anonymous people have become co-protagonists of the front pages. public figures from different countries (with 14%) making statements about the pandemic outnumbered those affected by or suffering from the virus (with 11%) and international political figures (with 10%). finally, health personnel, who have generated important recognition and ovations, have only been the protagonists of 6% of the front page news about the virus, while researchers and scientists (with 4%) occupy the last place in percentage of presence in the front pages. headlines are also of great importance. their location on the page, and the type and size of the title contributes to underlining the importance of the information among the set of pieces selected to appear on that page. in relation to this (see figure 5 ), the study has identified a predominance (160) of appellative headlines, focused on drawing the reader's attention. for this reason, the headlines tend to be non-verbal and have very atomized structures that seek to convey to the reader news about a subject he or she already knows. as an example, figure 6 shows the headlines from italian la repubblica: "tutti a casa" (everybody is at home) and "chiude l'italia" (italy closes) to announce the lockdown measures. headlines are also of great importance. their location on the page, and the type and size of the title contributes to underlining the importance of the information among the set of pieces selected to appear on that page. in relation to this (see figure 5 ), the study has identified a predominance (160) of appellative headlines, focused on drawing the reader's attention. for this reason, the headlines tend to be non-verbal and have very atomized structures that seek to convey to the reader news about a subject he or she already knows. as an example, figure 6 shows the headlines from italian la repubblica: "tutti a casa" (everybody is at home) and "chiude l'italia" (italy closes) to announce the lockdown measures. headlines are also of great importance. their location on the page, and the type and size of the title contributes to underlining the importance of the information among the set of pieces selected to appear on that page. in relation to this (see figure 5 ), the study has identified a predominance (160) of appellative headlines, focused on drawing the reader's attention. for this reason, the headlines tend to be non-verbal and have very atomized structures that seek to convey to the reader news about a subject he or she already knows. as an example, figure 6 shows the headlines from italian la repubblica: "tutti a casa" (everybody is at home) and "chiude l'italia" (italy closes) to announce the lockdown measures. and generally opt for the structure of subject, verb and predicate, enunciating a topic related to the pandemic trying to answer the "what" and the "who" of such information. the expressive ones, which have an evocative function on an event known to the reader, are the scarcest (only 57 have been counted). this reduced number emphasizes the existence of a commitment among the media analyzed to avoid sensationalist headlines or those that seek only to externalize moods. another classification of headlines focuses on speech acts. in relation to these, as shown by figure 7 , the headlines with textual quotations-which reproduce, between quotation marks, the declaration of one of the protagonists of the information-predominate (67 in total). the majority presence of this type of headlines denotes an interest of the media in presenting the information from a personalized standpoint, thus, bringing the stories closer to the subjects that have generated them. indirectly quoted headlines (30) and partially direct headlines (24) accumulate a smaller number of cases. by analyzing the types of verbs used (see figure 8 ), a predominance of strong interpretative verbs, characterized by highlighting the intensity of an action, is detected (43 in total), followed by weak interpretive verbs (a total of 31) which, although with less intensity, denote a willingness of the journalist to give more intensity to an action. the narrative ones, which are more neutral, add up to the continuity of the news about covid-19 on the front pages of the media, both in italy and spain, justifies this tendency towards headlines of an appellative nature that allude to facts that are familiar to the citizens. the informative headlines, with a total of 112 units, are the most conventional and generally opt for the structure of subject, verb and predicate, enunciating a topic related to the pandemic trying to answer the "what" and the "who" of such information. the expressive ones, which have an evocative function on an event known to the reader, are the scarcest (only 57 have been counted). this reduced number emphasizes the existence of a commitment among the media analyzed to avoid sensationalist headlines or those that seek only to externalize moods. another classification of headlines focuses on speech acts. in relation to these, as shown by figure 7 , the headlines with textual quotations-which reproduce, between quotation marks, the declaration of one of the protagonists of the information-predominate (67 in total). the majority presence of this type of headlines denotes an interest of the media in presenting the information from a personalized standpoint, thus, bringing the stories closer to the subjects that have generated them. indirectly quoted headlines (30) and partially direct headlines (24) accumulate a smaller number of cases. and generally opt for the structure of subject, verb and predicate, enunciating a topic related to the pandemic trying to answer the "what" and the "who" of such information. the expressive ones, which have an evocative function on an event known to the reader, are the scarcest (only 57 have been counted). this reduced number emphasizes the existence of a commitment among the media analyzed to avoid sensationalist headlines or those that seek only to externalize moods. another classification of headlines focuses on speech acts. in relation to these, as shown by figure 7 , the headlines with textual quotations-which reproduce, between quotation marks, the declaration of one of the protagonists of the information-predominate (67 in total). the majority presence of this type of headlines denotes an interest of the media in presenting the information from a personalized standpoint, thus, bringing the stories closer to the subjects that have generated them. indirectly quoted headlines (30) and partially direct headlines (24) accumulate a smaller number of cases. by analyzing the types of verbs used (see figure 8 ), a predominance of strong interpretative verbs, characterized by highlighting the intensity of an action, is detected (43 in total), followed by weak interpretive verbs (a total of 31) which, although with less intensity, denote a willingness of the journalist to give more intensity to an action. the narrative ones, which are more neutral, add up to by analyzing the types of verbs used (see figure 8 ), a predominance of strong interpretative verbs, characterized by highlighting the intensity of an action, is detected (43 in total), followed by weak interpretive verbs (a total of 31) which, although with less intensity, denote a willingness of the journalist to give more intensity to an action. the narrative ones, which are more neutral, add up to a total of 19; while the perlocutionary ones, which incorporate an effect that is intended to be achieved by means of an action, are the least numerous, with 18 units counted. a total of 19; while the perlocutionary ones, which incorporate an effect that is intended to be achieved by means of an action, are the least numerous, with 18 units counted. out of all the pieces about the covid-19 crisis, 177, that is to say 35% of the total content on the pandemic, has some kind of photographic accompaniment. only 2 are in black and white, and in 8 have an artistic quality. the reduced number of photographs on the pandemic on the covers is striking, although it could be justified by the difficulty of obtaining images or doing so from a variety of themes that would allow for dynamism and renovation of the covers. regarding the characters that appear in the photographs, public figures such as pope francis, or celebrities, like sportsmen or writers have taken over the front pages (28.85%). the second leading role is played by anonymous citizens who appear in everyday scenes, with a total of 24%, and national politicians account for 19%. only 3% have images of people affected by or patients who have contracted coronavirus. international political figures account for 8% of the total. finally, health personnel only appear in 14% of the photographs and scientists and researchers in 3%. the visual framing also shows a certain level of both spectacularization (with the presence of celebrities) and politicization of the crisis, while health workers and scientists that actually are on the frontline of the fight against the virus are less visible. by comparing italian and spanish news outlets, we can observe how covid-19 occupies the majority of the information in both countries. nonetheless, while in spain it occupies 62% of the front page; in italy covid-19 related pieces cover a striking 80% of the information (see figure 9 ). italy was the first european country severely hit by the pandemic, so it makes sense to state that this unpleasant surprise somehow engulfed media attention. with regard to the information that presents a predominance of numeric data, the number of pieces is very low in both countries. spain, with 9%, and italy, with 2%, reinforce the scarcity of information focused only on figures or percentages. this might seem surprising, due to the overwhelming amount of data information (statistics, evolution of case numbers, etc.) we have received during the pandemic, nonetheless it confirms the interpretative role assumed by the printed press: while on line media can offer on line updating, the printed press offers a more interpretative vision of facts. figure 10 displays the main entities portrayed in the information. geographical names, that is to say cities or regions, are the most numerous in the information on covid-19 (51% in italy and 38% in spain), followed by national institutions not linked to politics, which, with 21% in italy and 24% in spain, show the prominence that this type of institution has acquired in the framework of this crisis. political institutions are those that occupy the third place with 16% of the total in italy and 25% out of all the pieces about the covid-19 crisis, 177, that is to say 35% of the total content on the pandemic, has some kind of photographic accompaniment. only 2 are in black and white, and in 8 have an artistic quality. the reduced number of photographs on the pandemic on the covers is striking, although it could be justified by the difficulty of obtaining images or doing so from a variety of themes that would allow for dynamism and renovation of the covers. regarding the characters that appear in the photographs, public figures such as pope francis, or celebrities, like sportsmen or writers have taken over the front pages (28.85%). the second leading role is played by anonymous citizens who appear in everyday scenes, with a total of 24%, and national politicians account for 19%. only 3% have images of people affected by or patients who have contracted coronavirus. international political figures account for 8% of the total. finally, health personnel only appear in 14% of the photographs and scientists and researchers in 3%. the visual framing also shows a certain level of both spectacularization (with the presence of celebrities) and politicization of the crisis, while health workers and scientists that actually are on the frontline of the fight against the virus are less visible. by comparing italian and spanish news outlets, we can observe how covid-19 occupies the majority of the information in both countries. nonetheless, while in spain it occupies 62% of the front page; in italy covid-19 related pieces cover a striking 80% of the information (see figure 9 ). italy was the first european country severely hit by the pandemic, so it makes sense to state that this unpleasant surprise somehow engulfed media attention. int. j. environ. res. public health 2020, 17, x for peer review 9 of 16 the characters that appear in the information correspond to very diverse profiles. national political figures are the most numerous, with 26% in italy and 37% in spain (see figure 11 ). this aspect contrasts with the reduced presence of institutions, as mentioned above. thus, it is possible to with regard to the information that presents a predominance of numeric data, the number of pieces is very low in both countries. spain, with 9%, and italy, with 2%, reinforce the scarcity of information focused only on figures or percentages. this might seem surprising, due to the overwhelming amount of data information (statistics, evolution of case numbers, etc.) we have received during the pandemic, nonetheless it confirms the interpretative role assumed by the printed press: while on line media can offer on line updating, the printed press offers a more interpretative vision of facts. figure 10 displays the main entities portrayed in the information. geographical names, that is to say cities or regions, are the most numerous in the information on covid-19 (51% in italy and 38% in spain), followed by national institutions not linked to politics, which, with 21% in italy and 24% in spain, show the prominence that this type of institution has acquired in the framework of this crisis. political institutions are those that occupy the third place with 16% of the total in italy and 25% in spain. the characters that appear in the information correspond to very diverse profiles. national political figures are the most numerous, with 26% in italy and 37% in spain (see figure 11 ). this aspect contrasts with the reduced presence of institutions, as mentioned above. thus, it is possible to point out that politics is personalized as party politics through the representation of figures of the different parties of the country that complies with the seminal findings of hallin and mancini [41] . the characters that appear in the information correspond to very diverse profiles. national political figures are the most numerous, with 26% in italy and 37% in spain (see figure 11 ). this aspect contrasts with the reduced presence of institutions, as mentioned above. thus, it is possible to [41] . in italy, citizens account for 30% of the total number of items; in spain, they account for only 17%. these differences are equally visible in the presence of researchers or scientists, which in italy is 9% and in spain reaches 26%. the main characters that appear in the photographs on the covers, displayed by figure 12 , show important differences between the two countries. celebrities or public figures are the ones that absorb the most attention, with 26% of the total in italy and 30% in spain. this aspect emphasizes the importance given to this type of profile in the information and awareness of the pandemic. citizens, with 16% in italy and 28% in spain, would be in second place. there is, therefore, a prominent role in italy, citizens account for 30% of the total number of items; in spain, they account for only 17%. these differences are equally visible in the presence of researchers or scientists, which in italy is 9% and in spain reaches 26%. the main characters that appear in the photographs on the covers, displayed by figure 12 , show important differences between the two countries. celebrities or public figures are the ones that absorb the most attention, with 26% of the total in italy and 30% in spain. this aspect emphasizes the importance given to this type of profile in the information and awareness of the pandemic. citizens, with 16% in italy and 28% in spain, would be in second place. there is, therefore, a prominent role for anonymous people. national politicians, with 24% and 17%, respectively, would be in third place. patients (with 4% and 3%) and researchers or scientists (with 2% and 3%) hardly appear in the cover images. even if health centers are not the most prominent settings in pictures, we observed how, when looking at the physical spaces represented in the news, summed up in figure 13 , we can observe similarities and differences. first, while italian newspapers offer an emotional representation of the crisis by granting an enormous importance to the representation of empty spaces (such as squares or symbolical touristic spots, like the trevi fountain in rome, that in a normal situation would be crowded), spanish news outlets completely avoid this option, that only account for 2% of the total pictures. in both cases, however, urban spaces are the most recurrent (with 27% in italy and 52% in spain). in addition, although their importance is not prominent, the spaces related to political life (congress, etc.) with 10% in italy and 22% in spain, have a significant presence in the cover photographs. health centers or health camps, with 19% and 12%, are other places that appear next to citizens' homes (with 19% and 10%, respectively). even if health centers are not the most prominent settings in pictures, we observed how, when portrayed, these spaces are emotionally charged to dramatize the tragedy. figure 14 shows two examples of spanish newspapers el mundo y el país showing coffins of victims in the middle of the crisis. even if health centers are not the most prominent settings in pictures, we observed how, when portrayed, these spaces are emotionally charged to dramatize the tragedy. figure the covid-19 crisis has been a shocking reality that took most countries by surprise. italy and spain have been amongst the first in europe to be hit by the pandemic. thus, observing media behavior is especially interesting. to answer our research questions, we can state that the covid-19 crisis has been covered mainly in an informative way: the analysis of the two main newspapers in spain and italy allows to observe a predominance of informative journalistic genres. in particular, the predominant genre is the brief, short news items, which lack contextual information, and do not offer in depth information to the readership. however, the choice of images, that is to say the visual framing of the stories, seems to suggest an emotional turn. in other words, even if the predominance of informative genres, together with the the covid-19 crisis has been a shocking reality that took most countries by surprise. italy and spain have been amongst the first in europe to be hit by the pandemic. thus, observing media behavior is especially interesting. to answer our research questions, we can state that the covid-19 crisis has been covered mainly in an informative way: the analysis of the two main newspapers in spain and italy allows to observe a predominance of informative journalistic genres. in particular, the predominant genre is the brief, short news items, which lack contextual information, and do not offer in depth information to the readership. however, the choice of images, that is to say the visual framing of the stories, seems to suggest an emotional turn. in other words, even if the predominance of informative genres, together with the avoidance of openly emotional headlines might suggest that the analyzed newspapers have avoided sensationalism, both the mentioned visual framing and the increased presence of anonymous citizens and celebrities among the subjects, can be interpreted as an attempt to humanize the information pieces, emotionally charging them. in particular, it is important to stress out the high level of politicization of the crisis: politicians have been the most recurrent actors both in the information and in the pictures. this, as seen, seems contradictory to the scarce presence of institutions. this result, however, should not be of surprise since, as already pointed out by hallin and mancini [41] , both spain and italy belong to the polarized pluralist model, in which party politics is predominant to institutional politics. moreover, both countries are characterized by high intensity political polarization, therefore the management of the crisis has been the source of harsh political conflicts between government and opposition, that has been reflected by the media. concretely, spanish media outlets are the ones that give a more political vision of the crisis. accordingly, we observed a trend to objectify the different news actions and events through the use of geographical entities. the use of physical enclaves (italy, spain, milan or madrid, for example) lead to a simplification or generalization of reality that can bias the reading and interpretation of what has happened. in the same vein, it is important to stress that both health personnel and researchers directly involved in the fight against the virus, have a negligible presence both in pictures and information. in conclusion, we can sum up that the protagonists of the pandemic are not those affected, or involved in the fight, but rather anonymous citizens, and especially celebrities and politicians. these results cannot be discussed without taking into consideration the general framework of the social responsibility theory. as pointed out by mcquail in his seminal work [42] , media should accept and fulfil certain obligations to the society and should meet high professional standards of accuracy, truth, objectivity and balance. therefore, journalists and professionals should be accountable to the society reflecting and respecting diversity, pluralism as well as diverse points of view and rights of reply. applying these criteria to the specific field of health communication, defined by sixsmith et al. [43] as the study and use of communication strategies to inform and influence individual and community decision that enhance health, encompassing health promotion, health protection, disease prevention and treatment, we see how media are pivotal to the overall achievement of the objectives and aims of public health. in this sense, media practitioners and their organizations should be in charge of delivering rigorous health information, aimed at creating awareness about people's health, to prevent diseases and encourage healthy living. one of the main requirements of good health journalism [44] , thus, is to present evidence-based news with proper perspective, and without giving rise to sensationalism or alarm. as pointed out by many studies [45, 46] journalism training, in order to cope with these new challenges, should lay special emphasis on these aspects, providing not only specific health journalism training, but developing specific media and information literacy training devoted to health issues. acknowledging the geographical limitations, our study allows a series of conclusions to be drawn, which, from a diagnostic perspective, may help both scholars and journalism practitioners and deepen on the behavior and reaction capacity of newspapers in front of important and tragic events such as planetary pandemic. from a scholarly perspective, our work is embedded in a stream of literature that considers media to play a crucial role in framing public debates and shaping public perceptions by selecting which issues are reported and how they are represented [20] [21] [22] [23] . even if, as said, our results are limited to spain and italy, we have shown that printed newspapers avoid the massive use of data or percentages, leaving live updates to on line media, concentrating on more informative and interpretative pieces. this, on the one hand suggest they still play a crucial role in molding public opinion by offering more interpretative content [9] , on the other they directly and indirectly interact with digital media, in charge of giving more live information. for this reason, our results suggest that legacy media should still be examined to see how they influence/are influenced in their interaction with online media. in addition, we have pointed how in both countries the pandemic has been highly politicized. this result, stressing out the salience of the political factor in representing the pandemic, underlines the need for more comparative research, analyzing media portrayal in different contexts and how different media, embedded in different political and cultural contexts, have reacted. in particular, the current corona crisis, having a global reach and effect, could be an ideal occasion to compare media behavior in different countries to observe the existence of similarities and differences, and to which extent different political cultures and political systems modify media reactions to a pandemic, following and proving hallin and mancini's model [41] . in addition, even if reference newspapers seem to opt for an informative approach, their visual framing and the choice of images (i.e., empty places) emotionally charges the information. in this sense, besides the need for more comparative research to prove that this is a global trend, from a practical standpoint, our results align with the findings of previous studies [45, 46] , stressing the need to promote media and information literacy, not only among citizens, but also among media professionals. as demonstrated, both the predominance of short news items, which lack contextual information, and the visual framing can make the process of processing the essence of information messages difficult, making the susceptibility of many people to misinformation as risky as susceptibility to the virus itself. thus, as previously pointed out, in order to achieve rigorous and responsible health information, journalism training should not only provide specific health journalism training, rather media and information literacy skills should be developed in this field. in the same vein, media and information literacy campaigns geared towards citizenship should focus specifically on health issues, since, as the current crisis has showed, health is one of the most sensitive topic when it comes to quality information to avoid the risk of misinformation. accordingly, the current corona crisis underlines the necessity of a reform of science communication. this pandemic has underlined that the media often does not offer rigorous scientific information, prioritizing a (possibly) misleading humanization of news. first, media professionals should be trained and help to implement fact-checking functions, particularly to debunk fake news, misinformation and disinformation on health subjects. moreover, a renewed cooperation and a greater communication between media, health experts, academia and policy makers is essential for improving quality of health news. for 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communication and its role in the prevention and control of communicable diseases in europe: current evidence, practice and future developments health communication: the responsibility of the media in nigeria. spec tejedor calvo, s. analysis of journalism and communication studies in europe's top ranked universities: competencies, aims and courses análisis de los estudios de periodismo y comunicación en las principales universidades del mundo. competencias, objetivos y asignaturas this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license key: cord-307846-t8ejmq71 authors: ugolini, francesca; massetti, luciano; calaza-martínez, pedro; cariñanos, paloma; dobbs, cynnamon; ostoic, silvija krajter; marin, ana marija; pearlmutter, david; saaroni, hadas; šaulienė, ingrida; simoneti, maja; verlič, andrej; vuletić, dijana; sanesi, giovanni title: effects of the covid-19 pandemic on the use and perceptions of urban green space: an international exploratory study date: 2020-10-16 journal: urban for urban green doi: 10.1016/j.ufug.2020.126888 sha: doc_id: 307846 cord_uid: t8ejmq71 urban green space (ugs) is an essential element in the urban environment, providing multiple ecosystem services as well as beneficial effects on physical and mental health. in a time of societal crisis these effects may be amplified, but ensuring that they are maintained requires effective planning and management – which is a complex challenge given the rapid changes in modern society and the need for continual adaptation. this study aims to identify the drivers that normally attract visitors to ugs, and to assess the effects of social isolation on the usage and perception of ugs during the covid-19 pandemic. we conducted an online survey during the period in which restrictive measures were imposed in response to the pandemic (march-may 2020), in croatia, israel, italy, lithuania, slovenia and spain. results showed that urban residents normally have a need for accessible ugs, mainly for physical exercise, relaxing and observing nature. the reduction in ugs visitation during the containment period was related to distinct changes in the motivations of those who did visit, with a relative increase in "necessary activities" such as taking the dog out, and a reduction in activities that could be considered non-essential or high-risk such as meeting people or observing nature. behavioral changes related to proximity were also observed, with an increase in people walking to small urban gardens nearby (e.g. in italy) or tree-lined streets (e.g. in spain, israel), and people traveling by car to green areas outside the city (e.g. in lithuania). what the respondents missed the most about ugs during the pandemic was "spending time outdoors" and "meeting other people" – highlighting that during the covid-19 isolation, ugs was important for providing places of solace and respite, and for allowing exercise and relaxation. respondents expressed the need for urban greenery even when legally mandated access was limited – and many proposed concrete suggestions for improved urban planning that integrates green spaces of different sizes within the fabric of cities and neighborhoods, so that all residents have access to ugs. in a world of increasing urbanization and with more than half of the population living in cities, urban green space (ugs) is a crucial element for urban transformation and the sustainability of cities (andersson et al., 2015) . prominent tendencies and movements in urbanism, such as landscape urbanism (waldheim, 2016) , ecological urbanism (mostafavi and doherty, 2016) , ecological landscape urbanism (steiner, 2011) and ecosystem urbanism (rueda, 2019) emphasize that prioritizing nature and ecological considerations can improve the quality of life in citiesand that ugs is the key. ugs directly and indirectly promotes a better quality of life (sanesi et al., 2011) , as it can provide refuge from an increasingly stressful everyday lifestyle j o u r n a l p r e -p r o o f (van der berg et al., 2010) , encourage social cohesion (zijlema et al., 2017) , stimulate physical activity (hunter et al., 2015) , improve health (van den bosch and sang, 2017) and even enhance a person's wellbeing and mental state (nath et al., 2018; tsai et al., 2018) . ugs includes a diversity of biophysical structures and their ecological processes, which combine to support the city's "green infrastructure" and provide multiple "ecosystem services": namely provisioning services, regulating services and cultural services (haines-young and potschin, 2018) . the european commission (ec, 2013) has highlighted the importance of integrating these divergent approaches to service provision in cities, and transforming the traditional concept of isolated ugs (parks and gardens) into a comprehensive vision of green infrastructure. this vision is also reinforced in the eu biodiversity strategy 2030 (ec, 2020) and new green deal (ngd) (ec, 2019) . the intended optimization of es that this implies is seen as a necessary response to the rapid changes in lifestyle that modern urban society is experiencing, as the role and functions of ugs are shifting to adapt to new demands and human needs (derkzen et al., 2017) . ugs represents an urban design resource which is not only aesthetic, but fully functionaland one that must be utilized and nurtured in accordance with the holistic and comprehensive concept of green infrastructure, integrating the perceptions and preferences of citizens in planning proposals and management of this resource in the future (ryan, 2011) . human perceptions and preferences towards nature are believed to be either innate (e.g. evolutionary theories such as "biophilia" by wilson (1984) , or attention restoration theory by kaplan & kaplan (1989) ), or learned (according to cultural theories)in the latter case being shaped by social, cultural and personal characteristics (tveit et al., 2019) . in many studies carried out on the attitudes that people have toward ugs, significant differences have been found between various localities (de la barrera et al., 2016; riechers et al., 2019) and countries (schipperijin et al., 2010; bertram and rehdanz. 2015) indicating that cultural background as well as environmental factors can condition the expectations and behavior of a particular population. there is much more to be learned about how these perceptions and usage patterns may change in response to external events. research on how a global event of great magnitude may be perceived differently in different j o u r n a l p r e -p r o o f geographical contexts is not frequent. given the worldwide health emergency caused by the pandemic, it is of great interest to explore whether and how citizens' behavior and perceptions of ugs in different places may have changed, above and beyond the ways in which the particular areas were affected by the pandemic and the social restrictions that were imposed. while several major epidemics have occurred throughout the world in recent decades (e.g. sars, mers), the covid-19 pandemic has already had a global impact which is unprecedented in its scope and scale. as governments around the world have responded to the public health threat by imposing social distancing protocols, economic shutdowns and various forms of home quarantine, it has been hypothesized that these measures may have fundamentally changed the relation between humans and public spaces, in terms of use and perception. the purpose of this study was to explore, from an international perspective, the ways in which human behavior, perceptions and attitudes toward ugs may have changed due to restrictions imposed by the containment of the covid-19 outbreak in different countries, in comparison to the period prior to the restrictions. in addition, the study aimed to evaluate citizens' satisfaction with ugs in their locality and elicit constructive recommendations for improvement. the study was conducted in croatia, israel, italy, lithuania, slovenia, and spain. these countries constitute a diverse range of societies and cultures, each with norms and customs that might influence the use and perception of ugseven, and perhaps especially, during the emergency situation triggered by the covid-19 pandemic. the measures implemented to contain the covid-19 outbreak in the six countries studied began on different days, and with different levels of restrictions (supplementary materials (sm) table 1 ). italy was the first country to adopt restrictive measures at a national level. initially (between the 9 th and 20 th of march 2020), sports activities and walking outdoors were allowed, even though public gatherings were prohibited. but the rapid increase in positive cases led the ministry of health to ban any kind of physical exercise or walking j o u r n a l p r e -p r o o f farther than 200 m from home, and going outdoors was allowed only for essential reasons. similar restrictions were imposed on march 22 in israel, only allowing movement 100 m away from home. a few days after the outbreak in italy, spain began recording a dramatic increase in positive cases and on the basis of the italian experience, imposed on march 14 the strictest level of limitationsaccording to which going outside was allowed only for essential activities, and thus the frequentation of ugs was banned. in slovenia, croatia and lithuania, outdoor activities were allowed throughout the period but with strong warnings to keep distance from other people (other than family or close relatives) and to avoid gatherings even between a few people. these restrictions lasted until april 18 in slovenia (where some outdoor activities were allowed), until april 27 in lithuania, and until the beginning of may in the other countries. in italy, although with regional distinctions, vegetable gardening was generally allowed from the 20 th of april. (see further details in sm table 1 ). at the beginning of the isolation period in italy (march 2020), an online questionnaire (using google forms) was developed for distribution to the general public. respondents were asked for informed consent prior to their participation in the survey. a link was provided with information on the researchers conducting the survey, what data would be collected, how the data would be stored, analyzed and reported, and respondents' rights regarding the provided data. participation was voluntary, and participants had the right to leave the questionnaire at any point. the questionnaire was divided into nine sections and contained between 30 and 45 questions, depending on whether respondents self-identified as those who usually visit ugs ("ugs visitors") or those who do not ("non-ugs visitors") and on whether they visited or not ugs during the covid-19 pandemic. the results presented below refer to sections 1-5 (see the structure of the questionnaire in sm table 2 ) and consider responses to an open question (which was included in all countries except slovenia) on the relationship between urbanization, people and nature. the questionnaire was originally developed as an initial exploration in italy, where it was pre-tested by 10 people of different ages and education levels in order to ensure the clarity of the questions and overall j o u r n a l p r e -p r o o f structure. the preliminary version was corrected based on the suggestions and feedback, and then translated from italian into english and into other languages. data collection was concurrent in most countries, starting on the 12 th of april and ending on the 4 th of may 2020 (sm -table 3 ) when a relaxation of restrictive measures to contain the covid-19 outbreak was declared in most countries. restrictions on ugs visitation during the pandemic were largely similar in most countries, despite stricter limitations in italy, spain and israel. in each country, non-probability samples were obtained through an unrestricted self-selected survey (fricker, 2008) . distribution of the online questionnaire initially started through the authors' networks of professional and personal contacts, by email and through social media (facebook, whatsapp, etc.) or posts on websites. participants were kindly asked to fill in the questionnaire and distribute further to their contacts. thus, the distribution proceeded according to a snowball effect, and did not allow for personal identification of individual respondents. the datasets were analyzed by performing descriptive statistics, while logistic regression analysis was used to compare differences among countries. we transformed each item in the questionnaire into a binary variable according to the indicated preference by the respondent (y/n) and calculated the odds ratio (or) and 95% confidence interval (ci) of the association of each item and nationality of the respondents, considering the countries with the highest score for that item as the reference group. the level of significance was set to p<0.05. differences within each country were also investigated by the chi-square test between pairwise options. the same test was also used for comparisons between two datasets (e.g. attitudes of ugs visitors before and during covid-19 restrictions). statistical analyses were performed using r software (https://www.r-project.org/) and particularly the odds ratio (or) package. it should be noted that due to the sample type (purposive sampling) and mode of administration (internet survey), conclusions could be made only for the sampled population. textual responses were analyzed separately. if text provided under the option "other" expressed a concept that was analogous to one of the predefined choices, the answer was coded with that choice, and if a concept that was different from the predefined options was indicated by several respondents, we assigned a common code to those responses to allow further comparative analysis. for the open-ended question, respondents were invited to share "thoughts about urbanization and the relationship between people and nature in the city" which were analyzed using text mining. text mining is a computer-based technique that extracts information from large data sets (feldman and sanger, 2007; fuller et al. 2011) . all responses to open-ended questions were translated into english in order to unify them in a single dataset. the analysis was performed using statistica (release 12, statsoft, inc. 1984 -2014 . the preliminary phase consisted of filtering the text in order to reduce the presence of insignificant words, and words with the same meaning were combined. "indexing" produced a draft list of words that could be further "cleaned" by combining further synonyms and deleting more words. the program computed the raw frequencies of word occurrences, enumerating the number of times that a given word occurs in each text unit. the list of frequencies was used to create a matrix of all the words, which indicates the concurrent presence of words in the same text units. exploratory analysis of the word matrix was done to find the most relevant words and connections between them from the perspective of the respondents. two approaches were applied: correlation analysis (with mapping of p-values to visualize the results), and principal component analysis (pca) . in order to derive the content of the text units with much greater detail, we also performed content analysis (krippendorff, 2004) and thematic analysis (braun and clarke, 2006) . collected data (n=2560) were checked for consistency, and records that were missing essential information were excluded (n=20). the final sample thus consisted of 2540 responses distributed over the six countries, ranging from 230 respondents in israel to 657 in spain. the majority of the respondents in all countries were female (see sm table 4) , with especially high percentages in lithuania (84%), croatia (76%) and slovenia (74%) (α<0.005). respondents were mostly adults in the age range of 30-69 years old, with some differences between countries: the dominant age groups j o u r n a l p r e -p r o o f in spain were 50-59 and 60-69 and in slovenia 40-49 and 50-59, while in other countries the proportions of respondents were more evenly distributed between 40 and 69. in israel, younger respondents (20-29) were also well represented (sm figure 1 ). the majority of respondents in most of the national samples had completed some form of higher education, most notably in lithuania, israel, slovenia, and spain (sm figure 2a ). the italian and croatian samples also included some respondents (on average 25%) whose educational level was listed as a high school diploma (α<0.005). the large majority were employed in a public or private company (α<0.005) (sm figure 2b ), while israel counted the highest percentage of students (22%). most respondents (table 1) reported living in large towns or cities with more than 100,000 inhabitants. the percentage was highest in croatia (74%), and exceeded 50% in every country except italy (45%). if we consider all the respondents living in urban areas, the largest proportions were found in croatia and lithuania (93% and 88%, respectively), followed by italy, israel, spain and slovenia. respondents were firstly asked whether they generally (pre-pandemic) tended to visit or spend significant periods of time in ugs in the place where they live. most respondents (85-95% depending on country) stated that they do visit ugs frequently (table 2) . despite croatia and slovenia showing different percentages of respondents living in urbanized contexts, both recorded the highest rates of visitation, especially among those living in urban areas, with a score significantly different from italy, lithuania, or spain. in italy and lithuania, respondents from large towns and cities were also much more frequent visitors of ugs than those living in small towns and villages or in rural areasthough this was not the case in israel, croatia and slovenia. j o u r n a l p r e -p r o o f table 2 . percentage of ugs visitation in the place of residence and percentage of visitation within each category of place of residence. statistical differences between countries are identified by the odds-ratio test, taking as reference the country with the highest percentage. different lowercase letters in italics indicate that or were significantly different (p<0.05), ns means no difference. significant differences between town size within the same country were identified by the chi-square test and differences are indicated by capital letters at α<0.05. regarding the habits of ugs visitors (sm table 6 ). most respondents declared that they reach the ugs by foot, despite some differences among countries (table 5b ). for instance in slovenia, the percentage was significantly higher than in italy, croatia, and lithuania. private cars were selected as a means of transportation to ugs by lithuanians, significantly more than italians, slovenians, spaniards and israelis. croatians and slovenians tend to use bikes to visit ugs more than spaniards, israelis, and lithuanians, while some italians go by motorcycle. on the other hand, the option of public transportation was only selected by a small minority, though higher in italy than in croatia, slovenia or israel. regarding the type of ugs visited (table 5c ), in all countries except slovenia most respondents indicated visiting an urban park. the largest proportion of visitors to urban parks was in italy (57%), slightly higher than in croatia (55%) and significantly higher than in lithuania, spain, israel and slovenia. urban gardens were most frequented by israelis (15%), with percentages relatively lower among italians and spaniards and near-zero among lithuanians, croatians and slovenians. in slovenia, over half of the respondents (52%) selected green area outside the town; which included forest, as slovenians listed this term separately. riverbanks were frequented by 16% of spanish respondents and j o u r n a l p r e -p r o o f slightly less by respondents from other countries (except israel, with only 4%)while the option of treelined was largely selected by lithuanians (8%). in all countries, most respondents declared that they visit a green space more than once a week (table 5d) , with the largest majorities in slovenia and spain. italy also recorded the highest percentage for the option several times a month as compared to other countries, whereas slovenia recorded the highest percentages of respondents visiting a ugs once a month. few respondents, ranging from 0% in slovenia to 7% in lithuania, declared going to ugs less than once a month. and significantly more than israel, italy or croatiawith an even greater difference from lithuania. however, the option of relaxing was also frequently selected, especially in slovenia, italy and croatia, and this was the main reason mentioned for visiting a green space in lithuania (34%). observing nature, going out with children and walking the dog were selected as secondary options. in particular, observing nature was selected mainly by italians, significantly more than croatians and slovenians. respondents from the latter countries more often selected walking the dog than those from lithuania, italy, spain or israeland lithuanians selected taking the kids outdoors more than spaniards, slovenians, italians or israelis. meeting people was scarcely selected, though registering more as a priority for croatians, israelis and slovenians than for italians, lithuanians or spaniards. respondents were asked whether or not they had visited any ugs during the period of covid-19 containment measures. those who used to visit some type of ugs before the pandemic (ugs visitors) generally continued to do so (table 3) significant differences between the two categories (ugs visitors vs. non-ugs visitors) were identified by the chi-square test. differences are indicated by * at α< 0.05, ** at < 0.01 and *** at α< 0.005. regarding the pre-pandemic ugs visitors, who represent the large majority in all countries, significant differences were observed during the containment period in the distance traveled to ugs with respect to the pre-covid situation (fig. 1 ). in general, there was a tendency to visit green spaces at closer distances (< 200 m) in israel, italy and spain, although the differences were only significant in spain (α<0.01). however, in croatia, italy, lithuania and spain the percentage of respondents traveling farther was slightly higher than the percentage of those going shorter distances (α<0.05) (sm j o u r n a l p r e -p r o o f fig. 1 percentage of variation in the distance traveled to ugs during the containment period relative to the pre-pandemic period, among ugs visitors. significant differences between the two situations (before vs. during covid-19) were identified by the chi-square test. differences are indicated by * at α< 0.05, ** at α < 0.01 and *** at α< 0.005. the or cross-analysis comparing travel distance with place of residence (large city, small town, rural etc.), showed significant correlations in israel, italy, lithuania and slovenia (sm -table 8 ). people living in a village or a rural area in israel were more likely to travel more than 500 meters to visit a green area than those living in a large town or city. italy and lithuania showed opposite results, with people living in big towns or cities more likely than people living in small towns (or in villages/rural areas, in italy) to travel over 500 meters. the latter trend was also found in slovenia, particularly among people living in villages or rural areas, who preferred travelling shorter distances than urbanites. the most commonly reported way of reaching ugs in all countries during the containment period was on foot (α<0.05). israel showed the highest percentage, while croatia and lithuania had significantly lower percentages (sm -table 7b ). bicycle travel was mostly selected by slovenians, to a considerably greater extent than israelis and spaniards, while the car was mainly a choice of lithuanians. very few differences within countries were observed between visitor behavior before and during the covid-19 containment in terms of the preferred means of transportation ( figure 2 ). the only statistically significant difference was a decrease in car use in israel (-7%, α<0.05), which was similar to an increase of israelis reaching the green j o u r n a l p r e -p r o o f area on foot when compared to the pre-pandemic behavior. an even larger increase (of 10%, though not statistically significant) in going on foot was seen in italy. fig. 2 . percentage of variation in the means of transportation used by ugs visitors during the containment period relative to the pre-pandemic period. significant differences between the two situations (before vs. during covid-19) were identified by the chi-square test. differences are indicated by * at α< 0.05, ** at α < 0.01 and *** at α< 0.005. regarding the type of green space visited during the pandemic containment period, the majority of respondents in most countries chose urban parks, though to a lesser extent than before (sm table 7c ). the main exceptions were in slovenia (α<0.05) where green areas outside the town were preferred by a large margin, and in italy where the margin was narrower. in fact a relative increase in travel to green areas outside the respondents' place of residence was seen in several other countries as well, reaching 7% (α<0.05) in croatia-where there was a 15% reduction in visitation to urban parks (α<0.01)and smaller percentages in israel, lithuania and spain (figure 3 ). in italy there was a similar reduction of 12% (α<0.05) in frequentation of urban parks, and in spain there was a significant 4% increase in visitors of tree-lined streets (α<0.05)a preference also noticed in israel and croatia. urban gardens were also increasingly appreciated, especially by italiansas compared with croatians, lithuanians, and slovenians. figure 3 . percentage of variation in the type of ugs reached by ugs visitors during the containment period relative to the pre-pandemic period. significant differences between the two situations (before vs. during covid-19) were identified by the chi-square test. differences are indicated by * at α< 0.05, ** at α < 0.01 and *** at α< 0.005. excluding the option "i have not gone", which was mainly selected option by respondents in italy and spain (64% in both countries), the main motivation to visit a green area in many countries was to do physical exercise (indicated as walking or running) followed by relaxing, which was particularly common in lithuania (sm table 7d ). the motivations showing a large decline during the containment (fig. 4) were those that could increase the risk of contagion, such as meeting people, and those we might consider "non-essential", such as observing naturewhich was less selected in every country (reduction by 6-8%), but was still one of the top motivations for lithuanians (sm -table 7d ). physical exercise was the most frequently mentioned motivation during the pandemic in every country except spain and lithuania, most notably in italy, israel and croatia. finally, taking the dog out increased in relative importance in every single country, most significantly in spain (where it rose by over 8%). taking the kids outdoors was most cited by croatians. j o u r n a l p r e -p r o o f figure 4 . percentage of variation in the reasons given for visiting ugs during the containment period (among those who did so) relative to the pre-pandemic period, by ugs visitors. significant differences between the two situations (before vs. during were identified by the chi-square test. differences are indicated by * at α< 0.05, ** at α < 0.01 and *** at α< 0.005. surprisingly, respondents who visited ugs during the covid-19 pandemic declared that they did it quite often (sm -table 7e) , with the option of more than once a week selected by a majority in nearly every country (reaching 93% in slovenia). only in spain once a week was selected more frequently (43% vs. 41%), and italy was the country with the highest proportion of respondents (19%) declaring that they only went out oncemoderately higher than croatia (15%), lithuania (14%) and israel, and much higher than slovenia and spain. when respondents were asked if the ugs visited during the period of containment was the same as the one they visited pre-pandemic, the majority in all countries (except croatia) answered that it indeed was (sm table 9 ). the percentage of those who declared that their visitation changed to a different ugs ranged from 52% in croatia to 10% in slovenia. in an open-ended question (sm -table 10 ), the majority of these respondents in israel, italy and in spain wrote that their main reason was to stay closer to home (presumably following the rules set by local legislation)while in lithuania and slovenia (and by a small margin also croatia) the main rationale given was to avoid people. another consideration that was linked to the local j o u r n a l p r e -p r o o f restrictions was the non-accessibility of ugs in italy and in spain, for the simple reason that they were closed (25% in both countries). respondents were also asked about their perceptions regarding ugs during the period of home quarantine, specifically: a) the possibility of seeing some outdoor "greenery" from the window of their residence, b) the extent to which they "miss" accessing green areas directly, and c) what particular activities related to ugs they miss the most (sm -table 13 ). in terms of a "green view" from the window (table 13a) , the great majority of respondents reported being able to see some form of ugswith highest percentages lacking any such view found in lithuania (17%), italy (14%) and spain (14%). overall the most commonly reported views were of private gardens (ranging from 38% in israel to 20% in spain), with the notable exception of slovenia, where respondents instead referred to natural landscape (34%) or other (52%), represented mostly by a generic green space near buildings, vegetable gardens and playgrounds (45%, 26 and 16% respectively within other). also, the possibility of seeing tree-lined streets was prominently mentioned in spain (32%), israel (28%) and croatia (28%). in response to the question "during the period of closure, how much do you miss going to a green area?", over half of the lithuanians (and nearly half of the slovenians) declared that they did not miss ugs at all, or if so just a little. these cases were exceptional, however, as a clear majority reported missing ugs a lot in italy (64%), spain (64%) and israel (62%)and this was also the top response in croatia (35%) and even in slovenia (30%), where the distribution of responses was especially wide (table 13b) . regarding the aspects of ugs that respondents missed the most (table 13c) , there was considerable variation among countries but several significant patterns do emerge. first of all, respondents from most countries prioritized spending time outdoors, which was the top response in italy (29%) and israel (23%) and nearly so in lithuania (23%) and croatia (22%). in slovenia, on the other hand, this sentiment was not expressed at all; instead meeting other people was missed the most (40%), which was also the top response in croatia (25%) and among the top responses in israel (20%). for spaniards, exercising outdoors was the activity most missed (40%), followed by observing nature (20%)both of which were also missed in israel j o u r n a l p r e -p r o o f (21% and 19% respectively) and the latter in italy (19%). finally, it may be noted that lithuanian respondents missed, above all else, breathing fresh air (28%). the extent to which citizens missed ugs depended on their frequency of visitation. those who never went out during the pandemic missed the ugs the most (sm -table 14) , and this relationship also occurred with the group who did visit ugs during the isolationas visitors who went to ugs more frequently (e.g. more than once a week) missed ugs less than the other groups (sm -table 15 ). respondents missed visiting ugs, although those who could see natural landscape missed it only to a minor extent (sm -table 16 ). finally, the questionnaire respondents were asked for an open-ended reflection on the relationship between urbanization, people and nature. a total of 2280 valid responses were collected, in which the automated text mining identified a total of 59 significant words as the most commonly used by the respondents (sm table 17 ). the five most used terms were "green area" (1791 counts), "city" (603 counts), "nature" (544 counts), "trees" (434 counts) and "human" (289 counts). the correlation analysis of the word matrix (sm fig. 3 ) showed how "green areas" were conceptually linked to other key terms such as "awareness", "city", "greenery", as well as "lack" and "urbanization". moreover, the word "city" was frequently used together with the words "nature" and "trees," and the word "man" was often connected to "health," "nature" and "trees". another perspective was offered by the pca analysis, conducted on the same word matrix: thirteen components were selected explaining 80% of the word matrix variability (sm table 18 ). the most relevant association (p1) was between "green areas", "trees" and "citizens" (39% variability explained). associated to such words were several terms from p2: "nature", "man" and "to create" (13% variability explained). the concepts of "urban" and "life" appeared from p3, and "health", "quality" and "urbanization" from p4. thematic analysis of the entire body of text, identifying text units by their content within the respondent's answer for a total of 2367 valid text units, allowed us to identify 39 individual concepts which were grouped into nine categories, on the basis of the objective and conceptual meaning derived from the original text (sm -table 19 ). these categories were further grouped into three macro-categories, in which 60% of the individual concepts were assigned to the macro-category governance, 23% to awareness and 16% to benefits and services. the concepts associated with the macro-category of governance were the most mentioned in all countriesmost prominently in croatia (accounting there for 92% of the total), followed by lithuania j o u r n a l p r e -p r o o f (74%) and by italy, spain and israel with 50% each (see table 20 in sm for a comparison of the five countries; the slovenian survey did not include this open question). within governance, the greatest number of concepts were related to the category of planning (40%)including tangible recommendations such as the need to "increase the quantity of green surfaces," "adopt approaches to urban planning which integrate green space and tree plantations into new neighborhoods," and "reduce paving and building." an additional 14% of all the individual concepts were related to the category of management, such as "maintenance of green areas" and "quality of management." respondents showed a certain level of awareness of the importance of green areas, emphasizing environmental consciousness, and to a somewhat lesser extent also expressed the need to educate adults and children to care for the environment. indeed, under awareness, the majority of texts referred to consciousness (16%), a term that identifies the text units expressing respondents' own personal awareness in relation to the importance of urban greenery, including have a greater contact with nature and respect for nature. minor categories included education (6%) and valuation (1%), which included concepts that express the importance of recognizing the added value of green areas. texts indicated respondents' awareness either in general terms or with special emphasis on specific benefits (11%)mostly related to health and well-being and psychological state. this study was motivated by the social isolation that was imposed during the covid-19 pandemic in 2020. findings from our online survey in six european countries highlighted some of the changes in behavior and attitude related to the visitation of urban green space that resulted from this altered reality. the samples in croatia, israel, italy, slovenia, lithuania, and spain were all overwhelmingly urban, with most respondents living in large cities (table 1 ). this is highly reflective of the european population overall, and it indicates that most people cannot take ugs for granted. the results demonstrate how adults not only share this need, but they are willing, in general, to travel long distances within or beyond the city to access ugs. in order for ugs to be accessible to the population, they need to be created and maintained within the urban fabric, which is often densely built and characterized by competing land uses. in terms of the reasons that urban dwellers have this need for ugs, it was clearly seen from pre-pandemic results that the most sought-after activities in ugs were physical exercise and relaxing (sm -table) . this was the case for all countries, though italians and lithuanians in particular also expressed an appreciation for nature observation. the use of ugs for running, walking and outdoor sports has been widely studied and found to depend on numerous interconnected variables and aspects of the urban fabricincluding built density and green surface area, pedestrian access, safety and protection from traffic and crime (sreetheran and van den bosch, 2014) . taking children outdoors and walking the dog were also commonly cited activities, the latter also associated with physical exercise (christian et al., 2016) . a key objective of the survey was to discern changes in ugs visitation after the covid-19 restrictions were enacted. in italy and spain, the two largest countries in the survey and the two hardest hit by the pandemic, nearly two-thirds of those who previously visited ugs on a regular basis responded that they simply stopped going (sm table 7) . while this can easily be attributed to the government restrictions on personal mobility during the period of containment, 36% of respondents in each of these two countries did continue making their way to some ugs. this indicates that the need for greenery and open air certainly did not disappear with the legal restrictions to access to such places. the reduced visitation was in fact not evenly distributed among different population groups; for example a larger reduction was seen among female respondents (sm -table 21 )many of whom may have been put off by other duties or the insecurity of parks that were relatively deserted (sreetheran and van den bosch, 2014) . while the restrictions may not have changed people's basic need for ugs, they did lead to an increase in the diversity of ugs that were accessedwith some traveling out of town, and others relying more on tree-lined streets and urban gardens (fig. 3 , sm table 7 ). this finding points to a possible dichotomy in which limitations on regular access to parks could result in trends toward either more localized or more longdistance travel (sm -table 22 ), both of which have environmental implications. the evidence for this dichotomy is also suggested by changes in the modes of transportation used for reaching ugs. while in most countries such changes were not pronounced, a significant reduction in the use of private cars was registered in israel, accompanied by an increase among those arriving on footand in an especially striking result, and one that could have tangible implications for ugs planning, pertains to the stated motivations for changing one's behavior. a strong reduction was seen among people going to ugs for reasons that could be seen as non-essential, such as observing nature or which could pose a risk for possible contagion, such as meeting people (fig. 4) . this is significant because it shows that parks and other ugs have essential functions that are fundamentally different from other types of public places like shops or restaurants. while ugs can indeed serve as centers of public gathering, they can also be vital for the opposite reasonto serve as places where people can find respite and isolation within the crowded city. all of these findings have implications for the design, management, and indeed the appreciation of ugs. when respondents were asked how much they missed ugs, the response was clear, with the large majority missing ugs to a large extent ugs (sm -table 13 ). however this feeling depended on their frequency of visitation, with deeper feelings expressed by those who never went to ugs or went just once during the pandemic (sm table 15 ). the view of greenery from peoples' windows played only a minor role, although those who could see natural landscapes missed ugs only to a minor extent, likely because such views induced a perception of freedom or sense of exploration (sm -table 16 ). regarding what they missed the most during the period of home quarantine, respondents in most countries prioritized the simple idea of spending time outdoorsand while this might seem like a fairly straightforward reaction to the circumstances of being confined to one's home for an extended period, it should be stressed that the question referred specifically to green space, and not to outdoor areas in general. this could be an indicator of the special biophilic importance that greenery has for city dwellers, above and beyond the need for open space such as may be found in a public square that is relatively devoid of vegetation. in this sense, parks and tree-lined streets may once again be seen as having added value not just as public open spaces for gathering, but alsoas indicated during the time of the pandemicplaces of personal refuge within the city (fig. 3) . this in no way diminishes the tremendous value of large public parks, and in fact urban parks were the most selected type of ugs during the pandemic. what many respondents missed most during the pandemic was park-related activity like exercising outdoors and meeting other people (sm -table 13 ); in other words, parks are seen as vital places. in some cases (e.g. israel and italy), observing nature and breathing fresh air j o u r n a l p r e -p r o o f were also highly missed. these findings express the wide range of needs fulfilled by ugsfrom the physical to the cognitive and emotional, and from the tangible to the ethereal. when it came to expressing their general feelings about the relationship between people and nature in the context of urbanization, most respondents focused on tangible issues related to the planning and management of ugs. many focused on design and planning decisions made by local actors, such as increasing the spatial extent of green areas and improving residents' access to them. this reflects a forward-looking, action-oriented attitude on the part of many respondents within the survey sample. it also reflects the large percentage of respondents with higher education (see supplementary material) and presumably with a high level of knowledge or interest in the topic, as demonstrated by the familiarity with specific definitions and laws related to the management of urban green (as expressed in individual textual responses). a concurrent theme, appearing through the selected options of ugs and the responses to the open-ended questions, is related to the importance for urban green infrastructure to be well articulated and inclusive of different types of greenery. in order to create resilient cities, urban planning and design should consider a diverse mix including large parks which can offer spacious open-air green settings, which are useful for visitation (even without large gatherings) of ugs during times of pandemic, together with smaller pocket parks and gardenswhich can guarantee, as much as possible, that all residents will have access to ugs within walking distance from their home. from this perspective, it becomes important to foster the multiple services that different types of ugs provide in the city and to re-think urban policy and planning to respond to new behaviors and needs that have arisen from the covid-19 pandemic (honey-rosés et al. 2020) . for instance, the rise of pedestrian movement and green mobility observed in some countries should be accompanied by the provision of streets, sidewalks and biking trails that are shaded with healthy, appropriately selected and well nurtured trees, connecting green spaces throughout the city through vital green corridors. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. j o u r n a l p r e -p r o o f conceptualization, methodology, formal analysis, writing-original draft preparation formal analysis, writing-original draft preparation; pedro calaza-martínez: investigation, data curation, writing-original draft preparation; paloma cariñanos: investigation, data curation, writing-original draft preparation silvija krajter ostoic: investigation, data curation, writing-original draft preparation ana marija marin: investigation, data curation; david pearlmutter: investigation, data curation, writing -review & editing writing-original draft preparation, ingrida šaulienė: investigation, data curation, writing-original draft preparation writing-original draft preparation; andrej verlič: 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mediators we would like to thank all the people and organizations who promoted and distributed the survey in the six countries, as well as all survey respondents.in croatia, this work has been supported in part by the croatian science foundation under the project uip-2017-05-1986. cd was supported by fondecyt 11190295. in spain a special thank to the spanish association of parks and public gardens. key: cord-325077-j77wbcr3 authors: prado-gascó, vicente; gómez-domínguez, maría t.; soto-rubio, ana; díaz-rodríguez, luis; navarro-mateu, diego title: stay at home and teach: a comparative study of psychosocial risks between spain and mexico during the pandemic date: 2020-09-30 journal: front psychol doi: 10.3389/fpsyg.2020.566900 sha: doc_id: 325077 cord_uid: j77wbcr3 context: the emergency situation caused by coronavirus disease 2019 (covid-19) has affected different facets of society. although much of the attention is focused on the health sector, other sectors such as education have also experienced profound transformations and impacts. this sector is usually highly affected by psychosocial risks, and this could be aggravated during the current health emergency. psychosocial risks may cause health problems, lack of motivation, and a decrease of effectiveness at work, which in turn affect the quality of teaching. despite their importance, there are hardly any studies that analyze psychosocial risks of non-university teachers during a health emergency such as that caused by covid-19. objectives: the aim of this study was to analyze the perception of covid-19 and the psychosocial risks of non-university teachers comparing spain and mexico during the state of alarm caused by covid-19. methods: data were collected from 421 non-university teachers (80.2% women; 56.3% from mexico, 43.7% from spain) aged 24–60 (m = 39.32, sd = 10.21) via a self-completed questionnaire during the pandemic from march to april 2020. results: data analysis suggests that inequity is the most important risk, followed by work overload. teachers appear to be moderately satisfied with the information on covid-19 and the measures taken, while their satisfaction with the available resources is lower. when comparing the two countries, significant differences can be observed in every risk considered except for social support, with lower levels in mexican teachers compared to spanish ones. in the case of the perception of covid-19 and its impact, the perception in general of levels of information, measures, and resources is better among mexican teachers than among spanish ones, who present higher scores of the impact of the health emergency. conclusion: the results underline the importance of the professional’s perception of resources during a health emergency, which could prevent to some extent burnout and possible alterations associated with it. the measures taken by the responsible entities and the provision of information do affect teachers not only directly but also indirectly by making them more vulnerable to psychosocial risks that could affect their health and professional performance, thus affecting students as well. on january 09, 2020, the china center for disease control and prevention (china cdc) reported that a novel coronavirus had been detected as the causative agent for 15 of the 59 cases of pneumonia (european centre for disease prevention and control, 2020c; holmes, 2020) . on january 30, 2020, the world health organization (who) declared this first outbreak of novel coronavirus a "public health emergency of international concern" (world health organization, 2020a). on march 11, 2020, the director general of the who declared coronavirus disease 2019 (covid-19) a global pandemic (european centre for disease prevention and control, 2020d; world health organization, 2020b). as of march 25, 2020, all european union (eu)/european economic area (eea) countries and more than 150 countries worldwide are affected (world health organization, 2020a ,world health organization, 2020b . as of april 15, 2020, many eu/eea countries started to adjust their response measures (i.e., gradual opening of school, small shops, and other businesses, etc.) (european centre for disease prevention and control, 2020a) . data from the eu/eea show that around 20-30% of diagnosed covid-19 cases are hospitalized, and 4% have severe illness. hospitalization rates are higher for those aged 60 years and above and for those with other underlying health conditions (european centre for disease prevention and control, 2020b) . since december 31, 2019, and as of may 23, 2020, 5,175,476 cases of covid-19 have been reported, including 338,039 deaths (european centre for disease prevention and control, 2020b) . as this is a new virus, no vaccine is currently available; it may be many months or even more than a year before a vaccine has been tested and is ready for use in humans (european centre for disease prevention and control, 2020d) . main global data on cases and death are shown in table 1 . as can be seen in table 1 , spain and mexico are among the most affected countries, with spain ranking third in europe in terms of deaths reported by covid-19, and mexico ranking third in terms of deaths reported by covid-19 in the americas. on one hand, in spain, the situation has been particularly complicated. as of may 23, 2020, there have been 234,824 confirmed cases in spain, and 28,628 have died according to official data from the european centre for disease prevention and control (ecdc) (european centre for disease prevention and control, 2020d). the first positive diagnosis was confirmed on january 31, 2020 (linde, 2020) , while the first death occurred on february 13 in the city of valencia (caparrós, 2020) . in view of the rapid spread of the virus, since march 14, the spanish government has decreed a state of alarm (boletín oficial del estado, 2020), restricting the mobility of citizens to certain cases, such as the purchase of food and medicines or visits to medical centers or the workplace. all face-to-face teaching activities have been interrupted in spain since march 16, after the state of alarm was decreed (boletín oficial del estado, 2020), although some communities such as madrid or la rioja imposed this measure on their schools a few days earlier. in total, some 10 million students from all educational stages are currently following their academic year at a distance (faro de vigo, 2020) . a large number of teachers took on the tasks of distance teaching without being previously trained for them, nor having specific resources for all this in many cases. this whole situation of stress caused by the pandemic, together with changes in the usual working conditions, could negatively affect not only the psychosocial risks of teachers but also its main consequences such as burnout. on the other hand, in the case of mexico, the first positive diagnosis was confirmed on february 27 in mexico city (british broadcasting corporation, 2020) , almost a month after in spain. on march 30, a "health emergency due to force majeure" was declared as a result of the evolution of confirmed cases and deaths from the disease in the country, which led to the implementation of additional actions for its prevention and control (secretaría de salud, gobierno de méxico, 2020). currently, there have been 62,527 cases, of which 42,725 have been discharged and 6,989 have died, according to official data from the mexican government and ecdc (european centre for disease prevention and control, 2020d; secretaría de salud, gobierno de méxico, 2020) . despite the fact that spain is one of the countries most affected by the pandemic in europe, and mexico in america, we could say that the phase in which both countries are in this sense is different, since at the moment, it seems that spain has reached its peak long before mexico, with the former being in a phase of decreasing new cases, while the latter seems to be in the middle of a phase of increasing new cases. of the total number of cases of 824) , only 10,863 have been recorded in the last 14 days, while of the total number of cases in mexico (62,527), 31,005 have been recorded in the last 14 days, i.e., the figure has practically doubled in the last 2 weeks (as of may 23, 2020) (european centre for disease prevention and control, 2020d). the pandemic caused by covid-19 generates a series of impacts in all spheres of society, posing a challenge in practically all areas. during the pandemic, the population has had to adapt to a number of situations where uncertainty, fear, and, in many cases, pain have been present. these effects may translate into a range of emotional reactions (such as distress or psychiatric conditions), unhealthy behaviors (such as excessive substance use), and non-compliance with public health directives (such as home confinement and vaccination) in people who contract the disease and in the general population (pfefferbaum, 2020) . one of the many sectors that has had to adapt to this new situation and the demands that it entails is that of education. teachers at all levels of education have tried to maintain their fundamental role and continue to carry out their teaching duties, despite the uncertainty of the situation, the difficulties related to their own health and that of their loved ones, the lack of resources (material and knowledge), and the huge amount of extra work that adaptation to teach from home entails, including helping their students to cope to this situation. in particular, nonuniversity teachers (primary and secondary education), aware of the fundamental importance of learning for the development and future school performance of their students, have faced this situation by providing, in most cases, distance education, even if resources were often not available and uncertainty about the situation has always been present. in this context, the factors that are normally important for the good professional performance and well-being of teachers become even more relevant. among them are the so-called psychosocial risks. cox and griffiths (2005) define psychosocial risks at work as aspects regarding work design as well as the social, organizational, and management contexts of work that could potentially cause physical or psychological harm. psychosocial risks and work-related stress are among the most challenging issues in occupational safety and health, impacting significantly on the health of individuals, organizations, and national economies (bailey et al., 2015; bergh et al., 2018) . psychosocial risks arise from poor work design, organization, and management, as well as a poor social context of work, and they may result in negative psychological, physical, and social outcomes such as work-related stress, burnout, or depression (european centre for disease prevention and control, 2020d). more specifically, psychosocial risks have been shown to be related to low job satisfaction (guadix et al., 2015) , health problems (bergh et al., 2018) , work accidents (fornell et al., 2018) , work-related stress (junne et al., 2018) , and burnout (maslach et al., 2001; elshaer et al., 2018) . psychosocial risks are closely related to work-related stress, which has been associated with a reduction in social interaction and the ability to concentrate at work, an increase in physiological pain and cardiovascular problems, and a higher incidence of mental illness such as depression and anxiety (nielsen et al., 2020) . in this same vein, the right management of psychosocial risk helps to prevent accidents and absenteeism (maslach, 2017) , to increase productivity (bakker and demerouti, 2017; bakker and wang, 2019) and to promote well-being at the workplace (hammer et al., 2019) . among the different theoretical models that exist to explain the appearance of occupational stress, karasek (1979) model is the one with the most theoretical and empirical support and it is the one that currently has the most influence and attention. it explains work-related stress according to the imbalance between psychological demands at work (e.g., workload, role conflicts, interpersonal conflicts, job insecurity,. . .) and the control level or resources that the employee has. according to this model, the employee health or well-being depends on the balance of the work demands and the resources that the employees have. when the demands are higher than the resources, it can create a feeling of work-related stress in the employee. in addition, the chronic work-related stress can cause burnout syndrome, being able to appear as several physical or psychosomatic symptomatology. thus, an excess of demands will produce a negative consequence in the employee, as higher burnout; however, having enough resources benefits the employee, decreasing the probability of having higher burnout (hatch et al., 2018) . among the different psychosocial risks, the following stand out because of their importance in relation to the crisis situation and the theoretical reference model: (a) role conflict: this is the situation in which a worker cannot simultaneously satisfy the contradictory role expectations in which he or she is involved. there is role conflict when a worker is being given work tasks without enough resources to complete them and receiving contradictory requests from different people. previous research has shown that problematic levels of distress were 53% more likely for workers reporting role conflict (johannessen et al., 2013) . having to teach from your own home often can bring some role conflict, since familiar conciliation might get more challenging for those teachers who also have to perform other roles, such as being parents, partners, and caregivers in general. (b) lack of organizational justice: lack of organizational justice refers to the extent to which employees perceive they are treated unfairly in their workplace and the perception of the absence of reciprocity in social exchanges (moorman, 1991; kobayashi and kondo, 2019) . low organizational justice is known to be a potential risk factor for poor physical and psychological health among employees (fujishiro and heaney, 2009; kobayashi and kondo, 2019) . (c) workload: it assesses quantitative and qualitative workload. quantitative workload refers to the amount of activities to be performed in a given period of time, while qualitative workload refers to the difficulty of the task and the volume of information to be processed in relation to the time available (gil-monte, 2016). a high workload has been associated with low levels of well-being and higher risks of health problems (pace et al., 2019) . in general, the adaptation to the current pandemic situation requires an extra load of work that teachers (and family and students) have to deal with. (d) interpersonal conflicts: it assesses the frequency with which workers perceive conflicts coming from the school management, colleagues, students, or relatives of the students. interpersonal conflicts have been associated to health problems, particularly to depression (kubik et al., 2018) . in the context of the covid-19 pandemic, uncertainty has often made it difficult to reach an agreement between school, families, students, and teachers about the best way to proceed, which new measures to take in order to adapt, and for how long this measures should be maintained. (e) emotional work: it refers to the effort, planning, and control necessary to express the organizationally desirable emotions during interpersonal transactions (morris and feldman, 1996; ortiz et al., 2012) . previous research has shown that problematic levels of distress were 38% more likely for workers reporting high emotional work (johannessen et al., 2013) . in the context of a pandemic, an extra burden of negative emotions in teachers (such as worry, uncertainty, and fear) would be expected. (f) job insecurity: the perceived threat of losing one's current job in the near future (heaney et al., 1994) , or that the employer did not comply with his or her obligations or promises (breach of psychological contract) (vander elst et al., 2016) , can have equally serious consequences as actual job loss (de witte, 1999) . particularly, job insecurity is considered a stressor that affects negatively the physical, psychological, and social health of the employee (cheng and chan, 2008; de witte et al., 2015; de witte et al., 2016; selenko et al., 2017) . on the other hand, as the karasek model points out, one of the most important resources to cope with psychosocial risk factors is the social support at work. social support at work is defined as the social climate in the work context involving the relationship between the supervisor and coworkers (karasek and theorell, 1990) . it involves both social-emotional and instrumental support. the former refers to the degree of social and emotional integration between coworkers and the supervisor, while instrumental support refers to the collaboration between coworkers and the supervisor to carry out work tasks (martín-arribas, 2007 ). an important potential source of social support is the emotional support of family, friends, and colleagues, which is particularly difficult to have on a confinement situation such as that originated by the covid-19 pandemic. social support and resilience protect individuals from threats to their mental and physical health by reducing or balancing the negative effects of the stressful events they experience in life (woodhead et al., 2016; sun et al., 2017) . as previously stated, a large number of demands and low resources produce a series of negative consequences for workers (karasek, 1979) , of which psychosomatic health problems and burnout syndrome are the most important due to their prevalence and associated consequences. the term psychosomatic refers to all those alterations in which mental processes influence areas of the organism (montiel et al., 2016) . among the most common are various types of symptoms affecting multiple organs and systems. examples of these are back pain, tension headaches, sleep problems, chronic fatigue, heartburn, tension diarrhea, or heart palpitations (jaradat et al., 2016) . burnout syndrome is defined as a prolonged response to chronic emotional and interpersonal stressors at work and is defined by the three dimensions of burnout, cynicism, and inefficiency (maslach et al., 2001) . the prevalence of burnout in education oscillates between 11 and 35.5% depending on the country and the study considered (ratto et al., 2015; villaverde et al., 2019) . a eurofound study (aumayr-pintar et al., 2020) showed that, in portugal, 15% of educational professionals had a moderate risk of burnout, and the employees with burnout syndrome increased from 8 to 15% between 2008 and 2013. in addition, their study (king et al., 2018) with school counselors in australia found that 45% of the sample experiences burnout. given this prevalence in recent years, the study of burnout in the education sector has become increasingly important (kim and burić, 2019; mclean et al., 2019a; schonfeld et al., 2019) . most researches pointed out the importance of burnout on teachers (kaur and singh, 2014; yerdelen et al., 2016; schonfeld et al., 2019) , considering it as a risk for teachers that can negatively affect effective teaching (travers, 2017) , their interaction with their students (travers, 2017) , and their motivation for the job (mclean et al., 2019b) , resulting in absenteeism (makhdoom et al., 2019) , depression (martínez-monteagudo et al., 2019), insomnia (gu et al., 2020) , or a decrease in the capacity to give support to the students (zapf et al., 1999; jennings and greenberg, 2009) . despite the impact of pandemics on the health and wellbeing of citizens, and more specifically of workers, and their clear influence on working conditions, or more specifically on their psychosocial risks, there are hardly any studies that have addressed the effect of a pandemic on psychosocial risks. there are even fewer studies comparing these types of factors during a pandemic in spanish-speaking countries. although there are studies carried out within the framework of different crises, allowing for contextualization of stress situations, these do not focus on the specific case of a pandemic like the one we are facing due to covid-19. this situation is even more limited if we consider the impact on teachers. likewise, the few studies traditionally available have been carried out retrospectively, ignoring their perception of the pandemic, as well as the associated psychosocial risks during the times of greatest severity. after conducting a review of the literature, we were unable to observe any studies focused on teachers that analyzed the psychosocial risks of this group and their perception of the pandemic comparing two spanish-speaking countries at different phases or moments of the pandemic. therefore, the study presented here aims to fill this gap in the literature by offering a first approach to the perception of covid-19 by teachers and its relationship with psychosocial risks, comparing data from spain and mexico. the main aim of this study was to analyze the perception of non-university teachers regarding measures and resources implemented by institutions and governments and its impact on their daily work. also, to analyze the psychosocial risks of these professionals and its relation to the sanitary emergency caused by covid-19 comparing two spanish-speaking countries, spain and mexico, at a moment where the two countries were at different phases of the pandemic. data were collected from a sample of 421 non-university teachers (80.2% women and 19.8% men; 56.3% from mexico and 43.7% from spain) aged 24-60 years (m = 39.32, sd = 10.21) via a selfcompleted questionnaire during the covid-19 pandemic from march to april 2020. from spain, participants were aged 24-60 (m = 40.17, sd = 8.46), 71.1% of whom were women and 28.9% were men. from mexico, participants were aged 20-64 (m = 38.72, sd = 811.28), 86.6% of whom were women and 13.4% were men. at the beginning of the study, the research team contacted different associations and institutions of education in order to reach non-university teachers and invite them via e-mail to participate in the study. in the online invitation, teachers were informed about the purpose of the study and also about how their anonymity and confidentiality were guaranteed. the time cost of completing the questionnaire was 35 min. the eligibility criteria for participants were as follows. inclusion criteria: (a) to be a teacher in an institution other than university. (b) to be actively working during the moment of assessment. (c) to have signed the informed consent document and confidentiality agreement within the framework of the principles of the declaration of helsinki. the research included the variables and measurement instruments: different questionnaires were used to measure demands, resources, and consequences: the unipsico battery (gil-monte, 2016), the burnout assessment tool (bat) (schaufeli et al., 2019) , and the job insecurity scale (vander elst et al., 2014) . the demand factors include: taken from unipsico battery (gil-monte, 2016). role conflict is the situation in which a worker cannot simultaneously satisfy the contradictory role expectations in which he or she is involved. the scale is composed of five items (e.g., "i receive incompatible demands from two or more people"). participants are asked to score the frequency with which they have experienced the situation described in each statement on a likert-type scale from 0 to 4 (0 = never; 4 = very frequently: every day), with higher scores indicating higher levels of role conflict (scores above 1.6 are considered high, whereas scores equal to or below 0.81 are considered low). the scale has obtained adequate psychometric properties in previous studies and in the present research (total sample: α = 0.84; mexico: α = 0.80; spain: α = 0.84). extracted from unipsico battery (gil-monte, 2016). lack of organizational justice is defined as the perception of the absence of reciprocity in social exchanges. the scale is made up of five items (e.g., "i give up my skin at work compared to what i receive in return"). the response format is on a likert-type scale from 0 to 4 (0 = never; 4 = very frequently: every day), with higher scores indicating higher lack of organizational justice (scores above 2.4 are considered high, whereas scores equal to or below 1.6 are considered low). the scale has obtained adequate psychometric properties in previous studies and in the present research (total sample: α = 0.83; mexico: α = 0.74; spain: α = 0.89). taken from unipsico battery (gil-monte, 2016). it assesses quantitative and qualitative workload on a likert-type scale from 0 to 4 (0 = never; 4 = very frequently: every day). quantitative workload refers to the amount of activities to be performed in a given period of time, while qualitative workload refers to the difficulty of the task and the volume of information to be processed in relation to the time available. it consists of six items, three quantitative (e.g., "is it possible for you to work at a relaxed pace?") and three qualitative (e.g., "when you are working, do you encounter particularly hard situations?"), with higher scores indicating higher workload (scores above 2.17 are considered high, whereas scores equal to or below 1.51 are considered low). the scale has obtained adequate psychometric properties in previous studies and in the present research (total sample: α = 0.76; mexico: α = 0.62; spain: α = 0.80). extracted from unipsico battery (gil-monte, 2016). it assesses the frequency (0 = never; 4 = very frequently: every day) that workers perceive conflicts coming from the hospital management, colleagues, patients, and relatives of the patient. the scale consists of six items (e.g., "how often do you have conflicts with your colleagues?"), with higher scores indicating higher interpersonal conflicts (scores above 1 are considered high, whereas scores equal to or below 0.6 are considered low). the scale has obtained adequate psychometric properties in previous studies and in the present research (total sample: α = 0.60; mexico: α = 0.58; spain: α = 0.57). it was measured using the job insecurity scale (vander elst et al., 2014) . it consists of five items (e.g., "i feel insecure about the future of my job") designed to measure quantitative job insecurity (i.e., insecurity to lose the job as such). respondents were asked to rate these items on a 5-point likert-type scale, ranging from 1 ("strongly disagree") to 5 ("strongly agree"), with higher scores indicating higher levels of job insecurity. the scale has obtained adequate psychometric properties in previous studies and in the present research (total sample: α = 0.87; mexico: α = 0.76; spain: α = 0.91). the resource factors include: extracted from unipsico battery (gil-monte, 2016). this is defined as the availability of help from other people. it evaluates the social support offered by your head of studies, the management of the center, and by your colleagues, in all cases in the form of emotional support and technical support. it consists of six items (e.g., "how often do your colleagues help you when problems arise at work?"). this was answered on a 4-pont likerttype scale (0 = never; 4 = very frequently: every day), with higher scores indicating higher social support at work (scores above 2.83 are considered high, whereas scores equal to or below 2 are considered low). the scale has obtained adequate psychometric properties in previous studies and in the present research (total sample: α = 0.88; mexico: α = 0.88; spain: α = 0.89). the consequence factors include: included in the unipsico battery (gil-monte, 2016). it assesses the frequency of occurrence of psychosomatic problems related to the perception of sources of stress at work. it consists of nine items related to different systems of the organism (e.g., "have you been worried that, without making any effort, your breathing would be cut off?"). it was answered on a 4-pont likert-type scale (0 = never; 4 = very frequently: every day), with higher scores indicating higher psychosomatic problems (scores above 1.67 are considered high, whereas scores equal to or below 0.89 are considered low). the scale has obtained adequate psychometric properties in previous studies and in the present research (total sample: α = 0.90; mexico: α = 0.90; spain: α = 0.90). it was assessed using the reduced version of the bat (schaufeli et al., 2019) . it consists of 12 items that evaluate four scales: (european centre for disease prevention and control, 2020c) exhaustion (e.g., "at work, i feel mentally exhausted"), mental distance (e.g., "at work, i have trouble staying focused"), emotional impairment (e.g., "i don't recognize myself in the way i react emotionally at work"), and cognitive impairment (e.g., "i make mistakes in my work because i have my mind on other things"). participants are asked to score the frequency that they have experienced the situation described in each statement on a likert-type scale from 0 to 4 (0 = never; 4 = very frequently: every day), with higher scores indicating higher levels of burnout. the instrument has obtained adequate psychometric properties in previous studies and in the present research (total sample: α = 0.91; mexico: α = 0.89; spain: α = 0.91). this is an ad hoc questionnaire of 13 items constructed to measure different aspects related to the health emergency caused by the covid-19. the aspects considered are: available resources (provided by the health center, regional government, and national government, e.g., "i feel that my center has put sufficient resources to deal with covid-19 in my daily work"), information {provided by the health center, regional government, and national government, e.g., "i consider that from the regional government [e.g., state of sinaloa (mexico)/or autonomous community (spain)] i have been given enough information to deal with covid-19 in my daily work"}, measures (taken by the health center, regional government, and national government, e.g., "i believe that sufficient measures have been taken by the national government to address covid-19 in my daily work"), and impact on work (workload, labor conflicts, work-related stress, and workrelated concerns and fears, e.g., "the covid-19 has increased my workload"). the subjects score on a likert-type scale his or her level of agreement or disagreement with the statements (1 = totally disagree, 5 = totally agree). scores range from 1 to 5, with higher levels indicating greater satisfaction with the resources available, information, and measures taken, as well as higher levels of impact on work. the scale has obtained adequate psychometric properties ( a descriptive statistical analysis was performed for all study variables, as well as correlations and mean comparison analysis. all analyses were carried out using the statistical package spss (statistical package for the social sciences, version 25, armonk, ny, united states: ibm corp.). sociodemographic from the total sample of 421 non-university teachers, 237 were from mexico and 184 from spain. the great majority worked in a public institute (84.8%); 32% taught in kindergarten, as it can be seen in table 2 , regarding psychosocial risks, that teachers in spain present medium levels on all of the psychosocial risks, whereas teachers in mexico present medium levels on lack of organizational justices and of social support and low levels on the rest of psychosocial risks. as it can be seen in table 3 , during the pandemic, teachers in spain rated the resources, information available, and measures taken by the government and the hospital below the mean value of the answer scale, which points to a tendency to consider resources, information, and measures as insufficient. the highest scores from teachers in spain are regarding the impact of covid-19 on their jobs, although the scores in this case are also below the medium value of the answer scale. teachers in mexico, on the other hand, rated the resources and information available and the measures taken by government and the hospital above the mean value of the answer scale, which points to a tendency to consider resources, information, and measures as sufficient. the lowest score for teachers in mexico is the impact of covid-19 on their jobs. analysis of the mean comparison among the variables of the study was carried out between data from teachers in spain and mexico (table 4 ). in general, it seems that the pandemic has a greater effect in the case of spain, since there are statistically significant differences in all dimensions except social support, with higher levels of risk and consequences in the spanish case. likewise, there is greater satisfaction with the available information, resources, and measures in the mexican case than in the spanish case, and finally, there seems to be a greater impact of the pandemic on the work and life of teachers in the spanish case in comparison with the mexican case. the results of the correlation analysis among the variables are shown in table 5 . as it can be seen, almost all the variables are very strongly related. the only correlation that is not statistically significant is between the impact of covid-19 in the workplace and social support. when focusing on correlations among the variables in teachers from spain and mexico separately, the situation slightly changes ( table 6 ). in the case of teachers in spain, many of the psychosocial risks correlate between them, except for job insecurity that does not appear related to any of the resting variables. also, from the covid-19-related measures, information and measures are related with a higher number of psychosocial risks, whereas impact is less related to the rest of the variables (psychosocial risks as well as the resting covid-19-related measures). on the other hand, in the case of teachers in mexico, variables are also very strongly related between them, although lack of organizational justice and job insecurity are less related to the rest of the variables. also, in contrast with the case of spain, impact appears related with the rest of the covid-19-related measures. the current crisis caused by the coronavirus is a challenge not only in the health field but also in all spheres of society. in this context, professionals at all levels have had to adapt to new working conditions, in addition to dealing with the pandemic in their personal lives and as members of the community. among them, teachers of preschool and primary and secondary education have had to assume their important role in the best possible way, with limited means and resources and with the uncertainty of the moment and with the enormous responsibility that comes with educating and training children and adolescents, helping them to cope with the crisis and often providing relief as much as possible with homework and how to take school home (boletín oficial del estado, 2020; faro de vigo, 2020) . considering that teachers are vulnerable to burnout and job stress (zapf et al., 1999; jennings and greenberg, 2009; kaur and singh, 2014; yerdelen et al., 2016; travers, 2017; makhdoom et al., 2019; martínez-monteagudo et al., 2019; mclean et al., 2019b; schonfeld et al., 2019; gu et al., 2020) , and therefore the negative consequences these can have on their health and professional performance (bergh et al., 2018; fornell et al., 2018; junne et al., 2018; european centre for disease prevention and control, 2020d) , it is essential to study how psychosocial risks affect this group at a time of such vulnerability and general demand as the present. the literature on social risks to teachers in a pandemic context is extremely limited; however, it is critical to study the extent to which factors related to teachers' well-being may be affected during a health crisis such as the current one in order to ensure the well-being of teachers and, in turn, the children and adolescents in their care. this study has sought to explore the extent to which teachers are affected by psychosocial risks during the pandemic and how these risks relate to teachers' perceptions of the pandemic in terms of resources, measures, information, and impact. at the same time, it compares data of teachers in mexico with data of teachers in spain, two countries heavily affected by the pandemic and yet at very different stages of its development: spain in the midst of a drop in cases, mexico in the midst of a rise (european centre for disease prevention and control, 2020d) . at the time of collecting the data, the coronavirus crisis was at its peak in spain, while in mexico, it was in a more initial phase. this facilitates the interpretation of some of the data found. the main results of the study show, on the one hand, that teachers in spain as well as teachers in mexico inform about perceiving lack of organizational justice during the pandemic but, at the same time, to perceive social support. teachers in spain, however, also inform about role conflict, workload, interpersonal conflict, psychosomatic problems, and burnout. these data go in line with previous literature about the social risks that teachers are exposed to (zapf et al., 1999; jennings and greenberg, 2009; kaur and singh, 2014; yerdelen et al., 2016; travers, 2017; makhdoom et al., 2019; martínez-monteagudo et al., 2019; mclean et al., 2019b; schonfeld et al., 2019; gu et al., 2020) . regarding resources and information available about covid-19, the impact of covid-19 on their jobs, as well as measures taken by responsible entities (national and regional government, as well as work center), data from teachers in spain point to a perception of insufficient resources, information, and measures and to a perception of a moderatehigh impact of covid-19 on their jobs. regarding teachers in mexico, data point to a perception of sufficient resources, information, and measures taken by responsible entities, as well as to a perception of a moderate impact of covid-19 on their jobs. when specifically comparing data from teachers in spain and mexico, the results highlight a difference between teachers in both countries: spanish teachers present more role conflict, lack of organizational justice, workload, interpersonal conflicts, job insecurity, psychosomatic problems, and burnout than teachers in mexico. at the same time, teachers in spain inform about less resources, information, and measures than teachers in mexico, but also about a bigger impact of covid-19 on their jobs, than teachers in mexico. the fact that teachers in spain are more affected by psychosocial risks during the pandemic and are more burned out by work could be due, on the one hand, to the phase of the pandemic at the time of data collection, as the pandemic situation was more severe in spain at the time that the study was conducted. however, it could also be due to the fact that teachers in spain perceive fewer resources, information, and measures taken by responsible institutions, which could in turn worsen some of the psychosocial risks and even be a direct risk factor for burnout. specifically, in terms of the relationship between psychosocial risk factors and covid-19-related measures, these appear to be closely related, although it is true that in the case of teachers in spain, the relationship between covid-19related measures and social risks is clearer than in the case of teachers in mexico. of the covid-19-related measures, the least related to psychosocial risks is the impact of covid-19 on work, while of the psychosocial risks, the least related to the rest of the psychosocial risks and to covid-19-related measures is job insecurity. these data indicate that teachers' perception of the measures taken by the responsible entities, as well as the perception of sufficient information and resources, could influence the psychosocial risks to which these professionals are exposed. as mentioned above, some of the differences are due, on the one hand, to the phase of the pandemic in which both countries were and, on the other hand, to the perception of resources by teachers to face the pandemic and the challenges it poses in their professional life. one of the main limitations of this study is that it presents an analysis of relationships between variables that does not allow for the establishment of causal relationships between them. furthermore, it is a cross-sectional study that does not allow for observing the evolution of the data as the pandemic caused by covid-19 progresses. future studies could make new measurements of the variables when the different phases of the pandemic have passed, which would allow the comparison of the variables taking into account the evolution of the health crisis, as well as the evolution of the psychosocial risks of teachers and the possible development of pathologies that, based on the scientific literature, have been related to the burnout and psychosocial risks described here. despite its limitations, this study shows data collected in a context never before seen, where data on psychosocial risks are not collected a posteriori but in the midst of a pandemic crisis. our data speak of a greater general attrition of teachers in spain, which indicates that the pandemic may indeed be related to greater sources of stress and psychosocial risks. at the same time, data from the present study underline the importance of the perception of resources by professionals, which could prevent to some extent the burnout and the possible alterations associated with it. it is difficult to carry out this type of study in these contexts for a number of reasons, but we believe that it is important to have data to support the fact that the measures taken by the responsible entities and the provision of information affect teachers not only directly but also indirectly by making them more vulnerable to psychosocial risks that could affect their health and professional performance, thus affecting students as well. if this is important in any context, it becomes even more important in a context where the emotional toll on society is more evident than ever. some of the main practical applications of this research would be to know the psychosocial risks during a pandemic in non-university teachers to discover the perception of resources, information, and measures adopted by the different public and private entities to deal with covid-19, as well as to know the impact that this perception has had on the daily work of non-university teachers. these results can help make a difference between building resilience and developing burnout. any data that can clarify the relationships between the variables will be data that will benefit teachers, their students, and society in general. the results obtained in the present study allow to advance and consolidate the research on psychosocial risks during a pandemic while enabling the development of policies for action to improve teachers' coping with a pandemic and occupational health, which in turn will impact the outcomes of their work and society as a whole. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher. ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. the patients/participants provided their written informed consent to participate in this study. vp-g made a substantial contribution to the concept and design of the work, as well as on analysis and interpretation of data, drafted the article and revised it critically for important intellectual content, approved the version to be published, and participated sufficiently in the work to take public responsibility for appropriate portions of the content. mg-d made a substantial contribution to the concept of the work and acquisition of data, revised the article, approved the version to be published, and participated sufficiently in the work to take public responsibility for appropriate portions of the content. as-r made a substantial contribution to the concept or design of the work and on interpretation of data, drafted the article and revised it critically for important intellectual content, approved the version to be published, and participated sufficiently in the work to take public responsibility for appropriate portions of the content. ld-r made a substantial contribution to the design of the work and the acquisition of data, revised the article critically for important intellectual content, approved the version to be published, and participated sufficiently in the work to take public responsibility for appropriate portions of the content. dn-m made a substantial contribution to the concept and design of the work and acquisition of data, drafted the article and revised it critically for important intellectual content, approved the version to be published, and participated sufficiently in the work to take public responsibility for appropriate portions of the content. all authors contributed to the article and approved the submitted version. burnout in the workplace: a review of the data and policy responses in the eu. eurofound a national standard for psychosocial safety climate (psc): psc 41 as the benchmark for low risk of job strain and depressive symptoms job 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development of an instrument we would like to thank all the teachers who have voluntarily participated in this study even though they had a high workload and stress as a result of the health emergency caused by covid-19. we would also like to thank the reviewers and the editor of the journal for their valuable contributions to this paper. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 prado-gascó, gómez-domínguez, soto-rubio, díaz-rodríguez and navarro-mateu. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-355935-psnqrdo2 authors: paez, antonio; lopez, fernando a.; menezes, tatiane; cavalcanti, renata; pitta, maira galdino da rocha title: a spatio‐temporal analysis of the environmental correlates of covid‐19 incidence in spain date: 2020-06-08 journal: geogr anal doi: 10.1111/gean.12241 sha: doc_id: 355935 cord_uid: psnqrdo2 the novel sars‐cov2 has disrupted health systems and the economy, and public health interventions to slow its spread have been costly. how and when to ease restrictions to movement hinges in part on whether sars‐cov2 will display seasonality due to variations in temperature, humidity, and hours of sunshine. here, we address this question by means of a spatio‐temporal analysis in spain of the incidence of covid‐19, the disease caused by the virus. use of spatial seemingly unrelated regressions (sur) allows us to model the incidence of reported cases of the disease per 100,000 population as an interregional contagion process, in addition to a function of temperature, humidity, and sunshine. in the analysis we also control for gdp per capita, percentage of older adults in the population, population density, and presence of mass transit systems. the results support the hypothesis that incidence of the disease is lower at higher temperatures and higher levels of humidity. sunshine, in contrast, displays a positive association with incidence of the disease. our control variables also yield interesting insights. higher incidence is associated with higher gdp per capita and presence of mass transit systems in the province; in contrast, population density and percentage of older adults display negative associations with incidence of covid‐19. from a small outbreak linked to a live animal market at the end of 2019 to a global pandemic in a matter of weeks, the sars-cov2 virus and covid-19, the disease it causes, have threatened to overrun health systems around the world. in efforts to contain the spread of the disease, numerous governments in many regions and nations have either recommended or mandated social distancing measures, and as of this writing, millions of people in five continents shelter in place. there are encouraging signs that these measures have mitigated the spread of the virus (e.g., lancastle 2020; lewnard and lo 2020; wilder-smith and freedman 2020) . even so, this has come at a high cost, and the consequences for all spheres of economic, social, and cultural life have been dire (e.g., fernandes 2020; luo and tsang 2020) . as a result, there is a sense of urgency to anticipate the progression of the pandemic, in order to plan for progressive lifting of restrictions to movement and social contact (e.g., kissler et al. 2020) . needless to say, this has become a delicate, and politically charged, balancing act between public health and the economy (gong et al. 2020) . a salient question in the debate about how and when to ease social distancing measures is whether the virus will display seasonal variations. existing research on similar pathogens suggests that the virus could be more stable and potentially easier to transmit in conditions of low temperature and low humidity. while this is encouraging, it is important to keep in mind that "not all seasonal respiratory viruses experience the same spatiotemporal patterns" (de ángel solá et al. 2020, sec. 4) . this urges caution when extrapolating from known viruses. the evidence in this respect is as yet inconclusive, and although easing restrictions as the weather warms may appear tempting, doing so prematurely could well undo weeks or possibly months of costly measures. it is not surprising, given the stakes involved, that this issue has already triggered a lively debate. the current state of knowledge was well-summarized by the national academy of sciences, engineering, and medicine in the u.s. in a recent report (see national academies of sciences, engineering and medicine 2020). engaged by the office of the executive for guidance on this matter, this organization concluded that: "[some] limited data support a potential waning of cases in warmer and more humid seasons, yet none are without major limitations… additional studies as the sars-cov2 pandemic unfolds could shed more light on the effects of climate on transmission" (p. 6). to further complicate matters, much of the relevant work has yet to be peer-reviewed (see for instance the challenge of harbert, cunningham, and tessler 2020; to araujo and naimi 2020) . with the above considerations in mind, our objective with this paper is to investigate the influence of environmental factors, concretely temperature, humidity, and sunshine, on the progression of the pandemic. we adopt a population health approach, and report results from a spatio-temporal model of the incidence of covid-19 in the coterminous provinces in spain, one of the countries hardest hit by the pandemic. we combine data on reported cases of the disease with metereological information, to create a spatio-temporal dataset covering a period of 30 days. we then join this dataset with provincial-level economic and demographic information to act as controls to our key environmental variables. these data are analyzed using a spatial seemingly unrelated regressions (sur) approach, which allows us to model incidence of covid-19 as a contagion process. the results of this research provide evidence of the effect of temperature, humidity, and sunshine on the incidence of covid-19. the clearest result with respect to these variables is a lower incidence of covid-19 at higher temperatures and levels of humidity, while the opposite happens with respect to hours of sunshine. our control variables also provide some intriguing insights. higher incidence is associated with higher gdp per capita and presence of mass transit systems in the province; in contrast, population density and percentage of older adults display negative associations with incidence of covid-19. the results of this analysis provide support to the hypothesis of seasonality of the novel sars-cov2, and should be of interest to public health officials and policy makers grappling with the question of the trajectory of the pandemic. please note that this paper is prepared as a reproducible research document. the source r markdown document, as well as all data and code needed to reproduce/review/extend the analysis can be obtained from a public repository. 1 the global emergence of infectious diseases is mostly driven by environmental, ecological, and socio-economic factors (jones et al. 2008 ). in the case of sars-cov2, the ecological factors include the interaction between humans and wildlife. once transmission of a disease begins to happen between humans, socio-economic and environmental factors become increasingly important. as noted in the introduction, the focus of the paper is on environmental variables, concretely three related to meteorological conditions: temperature, humidity, and sunshine. much of what is known about the potential seasonality of sars-cov2 is a result of research on other pathogens. earlier, diverse studies have shown the effect of temperature and humidity on the incidence of influenza (e.g., mäkainen et al. 2009; jaakkola et al. 2014; kudo et al. 2019) . jaakkola et al. (2014) , for example, found that a decrease of temperature and absolute humidity precedes the onset of symptoms of influenza a and b viruses by 3 days in places where the temperature is low. after the 2002-2004 outbreak of sars, researchers also began to investigate the relationship between these factors and sars-cov (casanova et al. 2010; chan et al. 2011 ). casanova et al. (2010 , for instance, used surrogates to find that virus inactivation was likely more rapid at higher temperatures; in terms of humidity, these researchers reported that survival of the virus was lower at moderate relative humidity levels. chan et al. (2011) also found that viability of the virus that causes sars is also lost at higher temperatures (> 38 • c) and relative humidity superior to 95%. whether results from laboratory experiments will hold when the virus circulates in the community remains uncertain. at a global scale, de ángel solá et al. (2020) see less risk from sars-cov2 in the caribean basin; on the other hand, coelho et al. (2020) warn that at least during the exponential phase, expansion of the virus is not driven by climate. similarly, whereas araujo and naimi (2020) argue that spread of sars-cov2 will likely be constrained by climate, harbert, cunningham, and tessler (2020) remain unconvinced that spatial modelling can currently discriminate the distribution of the disease on the basis of climate, at least in the united states. yao et al. (2020) , examined data from china and came to the conclusion that neither temperature nor ultraviolet indices had an association with transmission of covid-19. this is despite previous research that has linked less exposure to uvb radiation to higher prevalence and severity of acute respiratory tract infections (zittermann et al. 2016; dabrowska-leonik et al. 2018; dinlen et al. 2016; mathyssen et al. 2017; esposito and lelii 2015; jat 2017; moriyama, hugentobler, and iwasaki 2020) . in addition to the environmental variables above, from a population health perspective it is also important to account for potential socio-economic and demographic confounders. to account for population-level factors, the first variable that we consider is gdp per capita. much has been written about globalization and the spread of infectious disease 2 . the growth in global connections has presented a challenge to spatial approaches in the initial stages of disease management, when the cause of a disease may still be unclear but the plane has already departed (zhou and coleman 2016) . in reference to the earlier outbreak of sars, van wagner (2008) chronicles how toronto's status as a global city turned out to be a vulnerability in this respect. in our case, we think of gdp per capita as a marker of a region's relative position in a network of global cities, and its potential to be further ahead in the trajectory of the pandemic. furthermore, wealthier regions also tend to concentrate more activities that produce non-traded goods, including building and construction (hallet 2002) . therefore, it is possible that wealthier regions remain relatively more active even during a lockdown. on the other hand, we cannot discount the possibility that less wealthy regions have a higher proportion of workers in manual occupations who cannot telework, and therefore have more difficulties complying with shelterin-place orders. secondly, we consider percentage of older adults (over 65) in a region. early evidence regarding covid-19 suggests that the case rate mortality is higher at older ages (e.g., the novel coronavirus pneumonia emergency response epidemiology team 2020). however, it is not clear that a relatively large population of older adults necessarily translates into higher transmission rates of the infection. the tool of choice in containing the spread of the disease has been social distancing. in this respect, the evidence from the field of transportation is that older adults tend to travel less frequently, for shorter distances, and have higher rates of immobility than most everyone, except the youngest members of the public (e.g., roorda et al. 2010; morency et al. 2011; sikder and pinjari 2012) . in other words, many older adults are, whether by preference or otherwise, already in a form of social isolation. social distancing during the pandemic may actually reinforce that condition for them, as suggested by the analysis of age-structured social contact in india, china, and italy of singh and adhikari (2020). since the age-structured matrix of social contact in spain is similar to italy (see prem, cook, and jit 2017) , our expectation is that populations with higher percentages of older adults will tend to have lower levels of social contact and hence of incidence. population density is also relevant since it directly affects the contact patterns and contact rates between individuals in a population (hu, nigmatulina, and eckhoff 2013) . the evidence available suggests a positive relationship between the transmission of covid-19 and population density (e.g., cumulative incidence in urban areas like nyc). for this reason, we anticipate a positive relationship between population density and the incidence of the disease. the last variable that we consider as a control is the presence of mass transit systems in a province. every province in spain offers some form of public transportation, but only five provinces have higher order systems of mass mobility (e.g., metro or subway), namely barcelona, madrid, sevilla, valencia, and bizkaia. public transportation has been hypothesized to relate to the spread of contagious disease by some researchers using agent-based approaches and simulation (e.g., perez and dragicevic 2009; wang et al. 2010) , and while we find scant evidence of a link in the literature, the idea is intuitively appealing. after all, unlike the isolation that a car offers to travellers, most mass transit system are cauldrons of social contact. the first reported case of covid-19 in spain was on january 31st, 2020, when a german tourist in the canary islands tested positive for the virus. after this case, it was still a few weeks before the first domestic case was reported, on february 27th in sevilla province (andalusia). in a short period of time, as testing started to ramp up, it became clear that an outbreak was flaring. by march 11th the world health organization (who) declared covid-19 officially a pandemic. this declaration marked a turning point for the public in spain too. as of march 13th, the number of cases of covid-19 reported in spain was 4,473, with a majority of cases (1,990) concentrated in madrid: these numbers were at the time the worst outbreak in europe after italy. in response to the situation, on march 13th the spanish national government declared a state of emergency, to go into effect on saturday march 14th. as part of the state of emergency restrictions to most activities were imposed, with the exception of essential services (e.g., food, health) and some economic subsectors of industry and construction. a few days later, on march 17th, spain closed its lands borders to allow entry only to returnee nationals and permanent residents. the lockdown was further hardened between march 30th and april 12th (including the easter weekend of april 10th-12th) and during this period only essential activities were allowed. during this period, there was a dramatic reduction in overall mobility, both within provinces as between. 3 our dataset includes information about the daily number of cases of covid-19 reported in spain at the provincial level (nuts3 in eurostat terminology) for the period between march 13th and april 11th, inclusive. for our purposes, we consider positive cases reported, but exclude symptomatic cases diagnosed by a doctor without a polymerase chain reaction (pcr) test. the spanish national government publishes periodic updates at the regional level (nuts2) and the information is also released at the provincial level as part of a collaborative project by geovoluntarios.com, 4 providencialdata19, 5 and esri españa (see datadista, 2020) . this information is compiled from several sources, mainly the official web pages of the spanish regional goverments, as documented in centro de datos covid-19. 6 we consider two sets of explanatory variables. the first one, and the focus of this research, are the three environmental variables, collected from official sources (i.g., aemet, the state meteorology agency, and mapa, the ministry of agriculture, fisheries, and food). the second set provides some relevant controls as discussed above, and are also collected from official sources, namely ine, the national statistics institute. table 1 shows the descriptive statistics and the provenance of the data used in this research. the spatial and temporal coverage of the data is as follows. our dataset begins on march 13, which is the first date when every province had reported at least one case of covid-19, and continues until april 11, for a period of 30 days. the unit of analysis is the province. provinces in spain are the equivalent of states, and are embedded in autonomous communities. as an example, cataluña is an autonomous community and consists of four provinces, namely barcelona, gerona, lerida, and tarragona. the size of the provinces is relatively large, as seen in table 1 . the smallest province is 1,978.12 km 2 (this is smaller than rhode island in the u.s.) and the largest province is 21,767.93 km 2 (slightly smaller than new jersey in the u.s.). while this is a relatively large degree of spatial aggregation, reporting on covid-19 is not yet consistent at smaller geographies, or cases are not reported at that level at all. an important aspect of working with environmental data such as temperature, humidity, and hours of sunshine, is the incubation period of the disease. lauer et al. (2020) report for the case of covid-19 a median incubation period of 5.7 days (with a confidence interval between 4.9 to 7.8 days). the vast majority of cases (95%) develop symptoms between 2.6 days (ci, 2.1 to 3.7 days) and 12.5 days (ci, 8.2 to 17.7 days). for this reason, we judge it best to use lagged values of the environmental variables. we test different time lags as follows. we consider a lagged 8-day average, from date-minus-12 to date-minus-5 days (hereafter lag8). secondly, we consider a lagged 11-day average, from date-minus-12 to date-minus-2 days (hereafter lag11). finally, to account for the likely duration of incubation, we consider a lagged 11-day weighted average, from date-minus-12 to date-minus-2 days (hereafter lag11w). the weights for this variable are calculated using the parameters of the log-normal distribution reported by lauer et al. (2020) , that is, a log-mean of 1.621 and a log-standard deviation of 0.418. with these weights, the environmental variables at date-minus-2 and date-minus-12 days are weighted as 0.041 and 0.009 respectively, whereas the environmental variables at date-minus-5 days are weighted as 0.194. these weights have the effect of changing the contribution of daily values to the lagged moving average. for instance, the temperature at date-minus-4-days is weighted more heavily than the temperature at date-minus-10-days, as a closer approximation of the conditions at the most likely time of contagion before the disease became manifest. the seemingly unrelated regression equations model (sur hereafter) is a multivariate econometric model used in different fields when the structure of the data consists of cross-sections for different time periods. the basis of this approach is well-known since the initial works of zellner (1962) , and has become a popular methodology included in several econometrics textbook (e.g., greene 2000) . to our knowledge, anselin (1988) was the first author to discuss sur from a spatial perspective, in the context of spatio-temporal analysis. in his landmark text, anselin discussed a model made of "an equation for each time period, which is estimated for a cross section of spatial units" (p. 141). from this milestone, a large body of research has developed to extend the classical sur into a spatial framework (e.g., rey and montouri 1999; lauridsen et al. 2010; le gallo and dall'erba 2006; lópez, martínez-ortiz, and cegarra-navarro 2017) . the classical sur model without spatial effects (from here, sur-sim) is a stack of equations as follows: where y t = (y 1t , … , y nt ) is a n × 1 vector, and in our case y st is the incidence ratio in the province s (s = 1, …, n) the day t (t = 1, …, t); x t is a n × k t matrix of the k t independent variables, with associated vector of coefficients β t ,; β t = (β 1t , … , β nt ) is a vector of coefficients and ϵ t = (ϵ 1t , … , ϵ nt ) is the vector of residuals. a key feature of the sur model is the temporal dependence structure among the vectors of residuals, namely: note that this specification is very flexible, in that it allows changes in the coefficients β it in order to modulate the effect of the independent variables on y t . this flexibility can be reduced and it is posible to impose restrictions considering some β coefficients as being constant over time. in this case, we can reformulate the coefficients expression β t = (β 1 , … , β r−1 , β r , β r+1 , … , β nt ) to restrict the first r coefficients to be constant across equations. this is equivalent to specifying some effects to be invariant over time. equation (1) can be rewriten in compact form: where y is now a vector of dimension nt × 1, x is a block-diagonal matrix nt × k (with k = ∑ t k t ) and ε is an nt × 1 vector. using the kronecker product notation (⊗), the error matrix structure is expressed concisely as: as is the case with cross-sectional data, it is possible to test the residuals of model (3) for spatial autocorrelation, and several tests have been developed to test the null hypothesis of spatial independence (see lópez, mur, and angulo 2014) . when the null hypothesis is rejected, several alternative specifications have been proposed to include spatial effects (anselin 1988) . in this paper we consider a spatial sur model that incorporates a spatial lag of the dependent variable as an explanatory factor. spatial analytical approaches have been used to understand contagion-difussion processes in the case of infectious disease in general (e.g., cliff, haggett, and smallman-raynor 1998) and the 2003-2004 sars outbreak in particular (e.g., meng et al. 2005; cao et al. 2010 ). while we are mindful of the same caveat that the novel sars-cov2 may not follow the patterns of previous diseases, there is still evidence from the united states that covid-19 displays spatial patterns that are consistent with a diffusion process (desjardins, hohl, and delmelle, 2020) . for this reason, the spatial lag model is appropriate to model incidence of covid-19 geographically, since it accounts for potential spatial patterns that result from a process of contagion, as explained next. the stack expresion for the sur model with a spatially lagged dependent variable (sur-slm) is as follows: this specification assumes that outcome (y st ) at location s and time t is partially determined by the weighted average (wy st ) of the outcome in neighboring provinces, with neighborhood defined by matrix w of spatial weights. in other words, the spatially lagged dependent variable represents a process of contagion, where the disease in neighboring provinces can spillover in a spatial way. the coefficients of the spatially lagged variable are estimated for each time period ρ t and identify the intensity and the sign of the contagion effect. it is possible test the null hypothesis of identical levels of spatial dependence (ρ i = ρ j , ∀i, j). the correspond wald test is available in the r package spsur. the sur-slm model can be estimated using maximum likelihood (lópez, mur, and angulo 2014) or instrumental variables (mínguez, lópez, and mur 2019) . a note regarding the interpretation of the model is in order. it is well-known that coefficients in linear regression models are partial derivatives of the dependent variable with respect to the independent variables, and therefore directly give the marginal effects or rates of change. spatially lagged models, however, are no longer linear. the intuition behind the non-linearity is that the spatial lag expands the information set to include information from neighbouring regions: in other words, the value of an explanatory variable in a spatial unit can have influence in other spatial units via the spatial lag. this makes interpretation of the coefficients less straightforward but also richer (golgher and voss 2016) . the results of lesage and pace (2009) for cross-sectional spatial lag models can be extended to the spatial sur framework. note that, according to elhorst (2014) , the partial derivatives have the following interpretation: if an explanatory variable (x k ) in a particular province changes, not only the incidence rate in that province changes, also incidence rates in other provinces change via the contagion effect. therefore, a change in x k in a particular province has a direct effect on that province, but also an indirect effect on neighbouring provinces. in this way, the ith diagonal element of the matrix of partial derivatives represents the (5) direct effect on the ith province, whereas the non-diagonal elements of ith row of the matrix of partial derivatives represent the indirect effects on other provinces. in order to obtain a global indicator, the direct effect is calculated as the mean of the diagonal elements and captures the average change in incidence ratio caused by the change in x k . likewise, a global indicator of the indirect effects is calculated as the mean of the non-diagonal elements. the total effect is the sum of direct and indirect effects. finally, note that if ρ k = 0, the indirect effects are 0 and the direct effects are equal to β k t. fig. 1 shows the geographical variation in the incidence of covid-19 in spain, as well as the temporal progression of the disease in weekly averages. our analysis begins on march 13. albeit still low, the highest incidence at this early date was in the provice of álava, in the north of spain. álava is not the most populous province, with a population of only 331,549, but it has the highest gdp per capita of all provinces. vitoria, its main city, is the capital of the basque country and has been the focus of efforts, along with san sebastian and bilbao, to develop a "global basque city" (meijers, hoekstra, and aguado 2008) . the other early focus of the pandemic in spain was madrid, which is the most populous province in the country and has the second highest gdp per capita after álava. the early outbreaks in these two provinces can be traced throughout the progression of the pandemic over time, although by the end of the period under study, other provinces had matched and even surpased their incidence rates, including segovia and soria to the north of madrid, and ciudad real and albacete to the south. fig. 2 shows the distribution of the environmental variables in spain. for ease of visualization we aggregate the provinces by autonomous community. each box-and-whisker in the figure represents the distribution of the variable for a community over the 30-day period. in the plot, the communities have been sorted by latitude, so that principado de asturias is the northernmost community, and andalucia the southernmost. as seen in the figure, there is a relatively wide range of values both within and between provinces over the 30-day period examined. the top panel of the figure shows the distribution of mean temperatures. the lowest mean temperature for a community on any given day was approximately 3 • c, and the highest about 20 • c, for a range of approximately 17 • . likewise, there is a great deal of variability in humidity, as seen in the middle panel of the figure, where the lowest mean humidity for any community is approximately 48% and the highest is close to 100%. finally, the bottom panel displays mean daily hours of sunshine in the community. this variable displays the most variability within communities over time, but remains relatively constant across communities. it is important to note that these are summaries by community, and the actual values of these variables for the provinces display somewhat more variability. fig. 3 includes three maps that display the spatial variation of our control variables, namely gdp per capita, percentage of older adults in province, population density, and presence of mass transit systems. as seen there, gdp per capita is higher in madrid and the northeast part of the country, mainly in pais vasco and cataluña. percentage of older adults is somewhat more checkered, with high values in madrid and other provinces in the center-west part of the country, but also in some provinces in the north. outside of provinces with major cities (e.g., madrid; bizkaia and gipuzkoa in pais vasco; pontevedra in galicia), population density tends to be higher in provinces along the mediterranean coast. the final panel in the figure shows the five provinces in the country that have higher order mass transit systems (e.g., metro). fig. 4 shows the distribution of daily simple correlations of incidence of covid-19 with the independent variables (with the exception of transit, which is a categorical variable). these correlations are calculated after log-transforming all variables. as previously discussed, the environmental variables have a temporal lag and were calculated using different time windows. it can be seen in the figure that temperature (in its three forms) has the highest simple correlation with incidence of covid-19. after temperature, gdp per capita has the highest positive correlation with the dependent variable. the distribution of these correlations is also quite tight over the 30-day period of the study. hours of sunshine tends to have a moderately high correlation with incidence of covid-19, but the distribution of these correlations is more spread, and in some cases strays into negative values. a similar thing happens with humidity, which also tends to display more day to day variation in the correlation with the dependent variable. the percentage of older adults shows a relatively tight distribution of day-to-day correlations, and autonomous communities in spain (sorted from north to south) value is negative. population density, in contrast, tends to be negative, but is relatively spread, and on some days, the simple correlation between density and incidence of covid-19 is weakly positive. overall for the period under examination, the pairwise correlations between these variables and incidence are significant at p < 0.05, with the exception of the three sunshine_hours variables. correlation analysis in the preceding section provides some insights about the potential associations between incidence of covid-19 and the various environmental and control variables. in this section we estimate three spatial sur models to test the differences between the various temporal lags and weighting schemes for the environmental variables. accordingly, we define three models: model 1, which is estimated using the lagged 8-day averages of the environmental variables (lag8); model 2, which is estimated using the lagged 11-day averages of the environmental variables (lag11); and finally, model 3, which is estimated using the lagged 11-day weighted averages of the environmental variables (lag11w). to implement the sur approach, we must define a matrix of spatial weights w. in this case, we consider neighborhoods based on adjacency, based on the well-known queen criterion (two provinces are adjacent if they share a boundary or touch at a vertex). the analysis is of the coterminous provinces. 7 for estimation, we log-transform the dependent and quantitative independent variables. the only variable that is not transformed is the categorical variable for transit systems. a log-log transformation is appropriate to capture non-linear relationships between variables and provides a straightforward interpretation of the coefficients as percentage change. furthermore, we introduce restrictions so that the coefficients of two of our control variables are constant over time, namely gdp per capita and percentage of older adults. we do not see an a priori reason to let those two variables vary across equations, and the correlation analysis in fig. 4 also suggest little temporal variation. in contrast, we let the spatial autocorrelation parameter, as well as the parameters of the rest of the independent variables (including the constant) to vary over time. 8 this will be useful to detect whether there are behavioral adaptations at the population level over the course of the period examined. as an example of behavioral adaptations, the effect of density might weaken over time, in the measure that the effects of the lockdown are felt: at full compliance with the lockdown, with people practicing social avoidance, density might matter less than other factors. after estimation, we compare the goodness of fit of the three sur models. fig. 5 shows the equation-level coefficient of determination r 2 , one for each time period/day. as well, the overall coefficient of determination for the system is reported for each model pooled-r 2 . the general trend is identical for the three models, with the goodness-of-fit improving over time and plateuing around a value of r 2 of 0.55. model 1 (lag8) performs somewhat better in the first few equations/days, when the goodness-of-fit is relatively poor, and then again in the last few equations/ variable correlation days. model 3 (lag11w), in contrast, does not perform well towards the end of the study period. the most balanced model in terms of equation-level goodness-of-fit appears to be model 1 (lag8), and this impression is further supported by a slightly higher value of the pooled-r 2 . the analysis using a lagged moving average of the environmental variables is generally in line with the incubation period reported by lauer et al. (2020) , although the results do not support the use of a weighted average. for the remainder of the paper, we will adopt model 1 (lag8) as our best model. in the following section we discuss the results of the analysis in more depth. table 2 presents a summary of the results of model 1 (lag8). recall that two coefficients were constrained and are estimated only for the first equation of the system, and thus are assumed to be constant over time. these are the coefficients corresponding to gdp per capita (p ≤ 0.10) and percentage of older adults (p ≤ 0.05). the sign of the coefficient for gdp per capita is positive, which indicates that wealthier regions tend to have a higher incidence of covid-19. this is in line with the idea that the epidemic started earlier in wealthier places due to their connections to a globalized world. the sign of the coefficient for percentage of older adults, on the other hand, is negative. as previously discussed, the level of social contact of older adults even under normal circumstances tends to be lower than for younger people. as a consequence, places with larger populations of older adults appear to have a natural level of social distancing in place. it is important to note that this does not detract from evidence that older adults are more vulnerable individually and in institutional settings, where their case mortality rates are perhaps the highest of all age groups. instead, this result indicates that their presence in the community at large tends to depress transmission of the virus. of the two other control variables, the coefficient of population density is significant at p ≤ 0.05 in 12, at p ≤ 0.10 in 3 equations, and not significant in 15. the coefficient for transit notes: significance: this is the number of coefficients with p-values as indicated. non-constrained: coefficient was allowed to vary across equations. constrained: coefficient as constant across equations. is significant at p ≤ 0.10 in 20 equations, and of those, significant at p ≤ 0.05 in 18 equations. the next four variables are environmental factors. the coefficient for humidity is significant at p ≤ 0.19 in 20 equations, and of those, significant at p ≤ 0.05 in 15 equations. of the environmental variables, temperature is the only variable that has significant coefficients in every equation at p ≤ 0.05. finally, sunshine has significant coefficients at p ≤ 0.05 in 24 equations. to better understand the results, we proceed to plot the coefficients in their temporal sequence. at this point it is worth recalling that the state of emergency went into effect on march 14. in the following figures, the periods of time indicated in yellow starting on march 14 correspond to the state of emergency, with only essential travel and selected industrial activities allowed; the period of time in orange was the stricter lockdown when only essential travel was allowed. we begin our discussion with the evolution of the spatial autocorrelation coefficient (ρ) in fig. 6 (left panel) . we notice that the magnitude of the spatial autocorrelation coefficient ρ declines over the period under analysis, and is not significant for some days. this is an interesting result: immediately prior to the declaration of the state of emergency, there appears to have been a strong inter-provincial contagion effect. keeping in mind that the incubation period ranges between 2 and 12 days with a median of 5, it is reasonable to expect that the effect of the lockdown will be observed with some delay. indeed, as seen in the figure, the autocorrelation coefficient remains high for several days, then begins to decline around march 23, and continues to weaken over time. at the end of the period under examination, the strength of this effect is much diminished and we would expect that under full compliance with strict lockdown conditions (meaning no inter-provincial mobility) the spatial contagion effect would be zero-as seems to be the case. the intercept (right panel in fig. 6) is indicative of the variation of the incidence of covid-19, other things being equal. here we see that at the incidence declines somewhat immediately after the state of emergency, only to begin increasing again over time. then, the incidence declines again after the stricter lockdown and rebounds to a higher level by april 11. figure 6 . temporal evolution of the spatial autocorrelation coefficient (rho) and the intercept of the model; dots are the point estimates and vertical lines are 95% confidence intervals. in yellow is the period after the declaration of the state of emergency, and in orange is the period when only essential activities were allowed. fig. 7 shows the temporal evolution of the coefficients for the two control variables that were not fixed over time, that is, log (density) (left panel) and transit (right panel). in section "background" we had anticipated a positive sign for the coefficient of density, and indeed, at the beginning of the period the coefficient is positive, albeit not significant, and then remains mostly non-significant for the earlier part of the lockdown. we are somewhat surprised by the way this coefficient turns significant and negative in the later part of the lockdown, after april 1st. this effect, we surmise, is the result of risk compensation, a situation where people adapt their behavior according to the perceived level of risk, becoming more careful when the perceived risk is higher and viceversa (e.g., noland 1995; phillips, fyhri, and sagberg 2011; richens, imrie, and copas 2000) . consequently, residents in high density regions may perceive the risk of infection as being higher, and adapt their behavior accordingly-while the opposite may be true of residents in low density regions. the coefficient for transit is positive, as expected, but with very wide confidence intervals, and in fact not significant in the earlier part of the period. the evolution of the coefficients for the three environmental variables is shown in fig. 8 . despite a mostly positive simple correlation with incidence (see fig. 4 ) once that we control for other factors, humidity has a negative association with incidence of . this is in line with the literature that describes the lower viability and transmission of different viruses at higher levels of humidity. the coefficients for temperature (topright panel) are consistently negative and this variable is, besides the intercept, the only one with significant coefficients in all equations. the range of variation of this coefficient during the period examined is approximately between −1 and −2, although it is important to recall that these values should not be interpreted directly as effects; more on this below. finally the plot for the coefficients associated with hours of sunshine (bottom panel) is more ambiguous: prior to the lockdown, the coefficient was negative, but not significant. however, five days into the lockdown, the coefficient becomes significant and positive. this result stands in contrast to previous findings regarding influenza, where more hours of sunlight reduced the strength and duration of epidemic durations (yu et al. 2013) . a difference with previous studies is the temporal scale of the analysis: where yu et al. (2013) use monthly averages, we use daily data for a much shorter period of time. the positive sign of sunshine may well be another instance of behavioral adaptations, whereby compliance with lockdown orders weakens on sunny days. the preceding discussion helps to establish the inferential contributions of the analysis, and indicate which variables display significant statistical associations with incidence of covid-19. the remaining question is, what are the implications. as discussed in section "methods: the spatial sur model" the effect of a variable is not clear from its coefficient alone, since a change to a variable in a province influences, via the contagion effect, its neighbors. for this reason, the appropriate way to estimate the effects is to calculate both the own effect and the effect due to contagion, or in other words the direct and indirect effects, respectively. the total effect is the sum of the two. a summary of the effects appears in table 3 . all effects in the table are interpreted as percentage change in the incidence of covid-19 as a consequence of a one percent change in the variable. the exception to this is figure 8 . temporal evolution of coefficient for the environmental variables; dots are the point estimates and vertical lines are 95% confidence intervals. in yellow is the period after the declaration of the state of emergency, and in orange is the period when only essential activities were allowed. transit (which was not log-transformed). this variable instead represents the percentage change in incidence between provinces without and with mass transit systems. two variables had temporally constrained coefficients. the estimated effect of gdp per capita is to increase the incidence of covid-19 by 0.449% for each percent increase of this variable (in €1,000 s). in our view, this is a measure of inertia, as provinces with higher gdp per capita where among the first to see exponential growth in the pandemic. percentage of older adults has a negative effect, and each percent increase in this variable is associated with a relatively small reduction of the incidence of approximately 0.67%. the temporal variation of the effects for the rest of the variables is shown in fig. 9 . the largest positive direct effect is transit, and the largest direct negative effects are temperature and humidity. the direct effects of these variables are as follows: for each percent point increase in temperature, there is between a 1% and 2% reduction in the incidence of the disease. this effect is compounded via contagion, as seen in the central panel in the figure, and the indirect effect can further reduce the incidence by up to 0.75%. the effect of humidity is also to reduce the incidence: each percent point of increase in humidity is associated with a reduction of up to 2% in incidence. with the addition of the indirect effect, the total effect of a 1% increase in humidity is to reduce incidence by up to 3%. as seen in the figure, the indirect (i.e., contagion) effects are stronger at the before and at the beginning of the lockdown period. nonetheless, by the end of the period under study, the indirect effects have weakened considerably. what do these effects mean? under a situation of lockdown, inter-regional contagion is reduced, as expected, and the total effects of the variables tend towards their direct effects. in the first few days covered by our analysis the total effect of all variables is greater due to the spatial contagion effect. contagion makes analysis and intervention more complex: the contagion effect essentially acts like a multiplier, whereby developments in each province spill over to their neighbors. once the contagion effect has been tamed, each province can be "treated" independently from its neighbors. it is important, before concluding our discussion, to highlight some limitations of this study. first, the analysis was conducted mostly under a situation of lockdown, and therefore, besides first days of the period examined, one must exercise caution when trying to extrapolate the findings to a situations without lockdown. secondly, it is well known that there is in many countries substantial underreporting of cases of covid-19 due to limited testing. in this case we do not suspect systematic provincial bias in reporting, and as long as the underreporting is consistent across units of analysis, we do not expect biased results; it is still important, however, to remain aware that the number of true cases is likely higher. finally, we defined neighborhoods based on adjacency. it would be interesting to compare adjacency to other connectivity criteria, for instance based on domestic transportation instrastructure and services. we flag this as a matter for future research. in this paper we presented a spatio-temporal analysis of incidence of covid-19 in spain. the analysis covers a 30-day period that begins immediately before the state of emergency was declared in the country. the focus of the research has been on the environmental correlates of incidence of the disease. there is a need for more empirical evidence, as policy makers, public health practitioners, and the public begin planning for the months ahead at this early stage of the pandemic. our results offer strong support for the hypothesis that incidence of covid-19 at the population level is lower at higher temperatures and levels of humidity: the estimated effect is a reduction in the neighborhood of 3% in incidence per each 1% increase in temperature, and a 3% reduction in incidence per 1% increase in humidity under conditions of contagion. these reductions are lower when contagion has ceased (i.e., due to lockdown conditions). the question here seems to be whether these environmental variables can yield a bigger reduction of more cases, or a smaller reduction of fewer cases. our control variables also offer some interesting insights. in particular, there is evidence of behavioral adaptations during lockdown in the form of risk compensation (density) and compliance with the lockdown (sunshine). these results offer a cautionary tale with regards to the effectiveness of the lockdown in more dense areas, and also the implications for compliance with stay-at-home orders as the northern hemisphere moves towards summer and more hours of sunshine during the day. if risk compensation is a factor, then efforts should be made to reduce or eliminate risk compensation in less densely populated regions. a key aspect of the analysis using spatial sur models is that we were able to model incidence of covid-19 as an interregional contagion process. here, we find that the strength of the contagion effect was dramatically reduced by the lockdown. needless to say, the analysis presented here is at the level of population health. for this reason, the analysis does not make any claims with respect to the effect of ultraviolet light on the virus, but rather about transmission of the virus in the population. for example, the analysis does not imply that the virus moves less effectively in places where more people live in close proximity to each other, but rather that humans are more contagious when they feel safe in less dense regions. similarly, more sunshine does not mean that the virus thrives, but rather that humans are more contagious to each other when their behavior adapts to this environmental condition. some directions for future research include investigating other modelling frameworks, such as geographically and temporally weighted regression and/or space-time conditional autoregressive models. in addition, the environmental variables examined here relate to meteorological conditions only, and did not include other environmental factors that may incide in the transmission of the virus, such as pollution. these other factors should be incorporated in future studies. (bivand, pebesma, and gomez-rubio 2013) , spsur (angulo et al. 2020 ) tidyverse (wickham et al. 2019) , units (pebesma, mailund, and hiebert 2016) . notes 1 https://github.com/paezh a/covid 19-envir onmen tal-corre lates. 2 as the globe and mail, canada's paper of record, put it in relation to the sars outbreak in 2003: "globalization means that if someone in china sneezes, someone in toronto may one day catch a cold" (editorial, march 28, 2003, p. a18) 3 https://www.mitma.gob.es/minis terio/ covid-19/evolu cion-movil idad-big-data/movil idad-provi ncial. 4 https://www.geovo lunta rios.org/. 5 https://www.datos covid.es/pages/ provi denci aldata19. 6 https://www.datos covid.es/pages/ sobre-la-inici ativa. 7 as a check for robustness, we also tested the rook criterion (two provinces are adjacent if they share a boundary, but not if they only touch at a vertex), and included the three islands in the sample. in this case we made an allowance for adjacency between the two islands in the autonomous community of canarias in the pacific (las palmas and santa cruz de tenerife), and assumed that islas baleares in the mediterranean are adjacent to three provinces in pais catalans (i.e., barcelona, tarragona, and castello) the results (which can be consulted in the source r markdown document) are robust to the specification of w. 8 we conducted sensitivity analysis letting all parameters vary over time, and while the results are qualitatively similar, the resulting models are less parsimonious. these results are available in the source r markdown document. rticles: article formats for r markdown. software manual spsur: spatial seemingly unrelated regression models. software manual spatial econometrics: methods and models, studies in operational regional science spread of sars-cov-2 coronavirus likely to be constrained by climate ggthemes: extra themes, scales and geoms for 'ggplot2'. software manual gridextra: miscellaneous functions for "grid weathering the pandemic: how 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supplementation in respiratory diseases -evidence from rct. polish archives of internal medicine cold temperature and low humidity are associated with increased occurrence of respiratory tract infections strategic planning for city networks: the emergence of a basque global city? understanding the spatial diffusion process of severe acute respiratory syndrome in beijing robust standard error estimators for panel models: a unifying approach ml versus iv estimates of spatial sur models: evidence from the case of airbnb in madrid urban area distance traveled in three canadian cities: spatial analysis from the perspective of vulnerable population segments rapid expert consultation on sars-cov-2 survival in relation to temperature and humidity and potential for seasonality for the covid-19 pandemic perceived risk and modal choice-risk compensation in transportation system simple features for r: standardized support for spatial vector data an agent-based approach for modeling dynamics of contagious disease spread risk compensation and bicycle helmets projecting social contact matrices in 152 countries using contact surveys and demographic data us regional income convergence: a spatial econometric perspective condoms and seat belts: the parallels and the lessons aemet: obtain climatic and meteorological data from spanish meteorological agency (aemet). software manual trip generation of vulnerable populations in three canadian cities: a spatial ordered probit approach immobility levels and mobility preferences of the elderly in the united states evidence from 2009 national household travel survey the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19)-china, 2020 toward a dialectical understanding of networked disease in the global city: vulnerability, connectivity, topologies use of gis and agent-based modeling to simulate the spread of influenza welcome to the tidyverse isolation, quarantine, social distancing and community containment: pivotal role for old-style public health measures in the novel coronavirus (2019-ncov) outbreak knitr: a comprehensive tool for reproducible research in r dynamic documents with r and knitr no association of covid-19 transmission with temperature or uv radiation in chinese cities characterization of regional influenza seasonality patterns in china and implications for vaccination strategies: spatio-temporal modeling of surveillance data an efficient method of estimating seemingly unrelated regressions and tests for aggregation bias accelerated contagion and response: understanding the relationships among globalization, time, and disease kableextra: construct complex table with 'kable' and pipe syntax. software manual märz winfried (2016) vitamin d and airway infections: a european perspective key: cord-273494-cl60qmu3 authors: campa, juan luis; lópez-lambas, maría eugenia; guirao, begoña title: high speed rail effects on tourism: spanish empirical evidence derived from china's modelling experience date: 2016-12-31 journal: journal of transport geography doi: 10.1016/j.jtrangeo.2016.09.012 sha: doc_id: 273494 cord_uid: cl60qmu3 abstract china and spain are currently among the top tourist destinations, coming third and fourth place in the 2014 world ranking of tourist arrivals, behind france and the us. tourism is crucial for the economies of spain and china, and both countries have the longest high speed rail (hsr) networks in the world. what role has hsr infrastructure played in the development of tourism in both countries? little research has been done to date, even in europe, to estimate empirically how tourism indicators are affected by new hsr lines. in 2012 a multivariate panel analysis by chen and haynes was applied to 27 chinese regions, and confirmed that emerging high speed rail services (during the period 1999–2010) had significant positive impacts on boosting tourism in china. no similar empirical tool has ever been tested in europe. the aim of this paper is to analyse and validate this tool when applied to the spanish context, and to develop a comparative analysis with the chinese case study. the methodology is applied to 47 spanish provinces during the period 1999–2015, and the results clearly reveal a positive but lower-value link (compared to china) between the increase in certain tourism outputs (foreign arrivals and revenues) and hsr network construction. however, further research is needed into the model's limitations, namely the availability of suitable tourism indicators in the official databases, the hsr explanatory variables considered, and the ability to detect “circular cause-effects” between hsr and tourism. due to the recent climate of financial instability, the discussion of evaluation methodologies for high-speed rail (hsr) projects is now a key issue for transport planners, both in countries without hsr and in those with long experience in hsr operation. the transport project evaluation methodologies and public sector investment assessment in the literature review follow two main frameworks: broad cba (cost benefit analysis) and multi-criteria analysis (mca). both methodologies must consider all the economic activities that are reinforced by hsr, among other variables. cba methodologies are most frequently used in the literature for estimating hsr profitability (coto-millan et al., 2007; de rus and nombela, 2007; betancor and llobet, 2015) , although in the last ten years mca has become more widespread as a method for evaluating transport projects, and offers the possibility of including indirect and long-term hsr impacts (guirao and campa, 2015) . macharis and bernardin (2015) reported that -after a more general category-passenger transport (such as hsr rail) and notably mobility management are the public administrations' most common types of transport project decisions handled by mca. within the cba methodologies, de rus and nombela (2007) were the first to calculate the required minimum level of demand at which investment in hsr could be considered profitable from a social perspective. they used real costs of construction, maintenance and rolling stock for european hsr lines currently in operation, in addition to potential time savings, standard time values and predicted growth in demand. although this approach has been generally accepted by the scientific community, the wider economic benefits of high speed are clearly hard to gauge, as they are swamped by manynot inconsiderableexternal factors such as territorial impacts. territorial impacts may lead directly to social and economic benefits, and despite the problems of estimating and analysis, some attempts have been made to study them, especially in the case of spain (gutierrez, 2001; ureña et al., 2009; ortega et al., 2012) . in this context, the tourism impact of hsr implementation has recently emerged as an important issue in the scientific literature, as it represents a possible benefit variable to support new investment in hsr lines. however tourism is a complex phenomenon (sinclair and stabler, 1997; caccomo and solonandrasana, 2001) , as it is a form of complementary demand for which the main components are transport, food, and accommodation (morley, 1992) , making it very difficult to separate the effects of transport on tourism from other territorial effects. the literature review described in section 2 shows how tourism has affected hsr demand. little research has been done so far, even in europe, to estimate empirically the opposite effect: how tourism indicators are affected by new hsr lines. many authors agree that the expansion of hsr networks and services brings new opportunities to cities, metropolitan areas, coastal and mountain regions, and other types of tourist destinations in europe. it also reinforces the expectations of local tourism stakeholders by improving the attractiveness of places for visitors, although no systematic patterns have been observed. most of the published studies describe specific hsr experiences (case studies) and some observed hsr effects on tourism, but do not lead to a general conclusion. china is one of the scenarios that has focused the highest number of methodologies to assess the impact of hsr on tourism (wang et al., 2012; chen and haynes, 2012; chen and haynes, 2015) . today, china has the world's longest hsr network (with over 19,000 km of track in service in january 2016), more than the rest of the world's high-speed rail tracks combined. when the chinese government began construction of hsr in 2004, the main objective was to promote economic growth through four north-south and four west-east hsr trunk lines. since the completion of a few sectional mainline projects, the impact of hsr on tourism demand has increasingly come under the spotlight, given its political significance for regional economic growth. using a multivariate panel analysis, chen and haynes were the first to investigate the impact of a high-speed rail system on the tourism industry, selecting only the numbers of incoming foreign tourists and tourism revenue as the dependent variables. the results of this research confirmed that the fledgling high-speed rail services significantly boosted tourism in china between 1999 and 2010, and that provinces with high-speed rail services were likely to have approximately 20% more foreign arrivals and 25% higher tourism revenues than provinces without these systems. concurrently with chen and haynes's first empirical works on hsr impacts on china's tourism industry, the research of wang et al. (2012) demonstrated that the chinese hsr system affected tourism demand by redistributing tourism centres and transforming the tourist market. however, this research methodology was not empirical so did not contribute to understanding the impact of hsr on tourism; chen and haynes were thus the first to address this issue in the literature. the most logical first step in the search for a new and systematic tool to evaluate the integral impact of hsr on the tourism industry would therefore appear to be to establish the suitability of applying the chinese experience to other european case studies. spain, with over 20 years of hsr experience, and operating the longest hsr network in europe(3100 km), is a good scenario for the analysis and application of this panel data model, as tourism is one of the country's key industries, accounting for 10.9% of its gross domestic product (gdp) for the year 2014 (ine, 2016a) . this paper contributes to the limited existing literature by analysing the empirical impact of a hsr network on tourism indicators. the added value of this research lies in the fact that it is the first assessment of the multivariate panel data model tested in the chinese scenario when applied to a european country: spain. the paper is divided into the following sections: section 2 contains a review of the literature on tourism and hsr. section 3 gives an explanatory description of the tourism sector in china and spain. section 4 includes the model equations, the application to the spanish case and a discussion of the results obtained compared to china. section 5 presents a study of the city of toledo (spain) at the local level to analyse in greater detail the "circular and cumulative causation" between hsr and the evolution of tourism indicators. finally, the main conclusions are summarised in section 6. the link between tourism and transportation infrastructure has been widely analysed in the literature (chew, 1987; martin and witt, 1988; abeyratne, 1993; seetanah, 2007, 2008) . there is a general consensus that an increase in accessibility to the tourism destination usually leads to an increase in tourism demand (della corte et al., 2013) , and is a critical factor in the overall number of tourists a destination receives. once the tourist has arrived at the destination, local transportation is also an important issue as it facilitates tourist mobility, although it has received less attention. there is practically no literature on empirical methodologies to assess the effects of new hsr lines on tourism. high-speed rail (hsr) is a relatively new mode of transportation in the contemporary transportation technology revolution, and has been promoted in various countries around the world (albalate and bel, 2012) . in contrast, the extensive literature on the link between air transportation and tourism (dobruszkes and mondou, 2013) has produced evidence of the significant effect of low-cost airlines on tourist outcomes (rey et al., 2011) . most of the published studies in the literature on the tourism effects of hsr describe specific hsr experiences (study cases) and some observed hsr effects on tourism, but do not point to a systemic methodology or a general conclusion (guirao and soler, 2008; bazin et al., 2011) . in hsr commuting relations it is important to take account of the fact that the possibility of returning within the same day can reduce the average length of the visitors' stay. this type of hsr service is quite common in some european countries such as france and spain (see ureña et al., 2009) , and may affect the interpretation of the main statistical tourism outputs (tourism revenues, number of overstays, etc.). for example, bazin et al. (2011) studied the impact of hsr on urban and business tourism in french cities connected to paris such as lyon, just 2 h away from paris by tgv (train à grande vitesse), and discovered that the daily expenditure of business tourists may be up to four times greater than that of leisure travellers. bazin et al. (2011) pointed out that business tourism can be a key strategic orientation for cities and large urban areas, but the possibility of returning within the same day affects the average length of the tourists' stay. guirao and soler (2008) used a survey approach to examine the impact of tourism in toledo on traffic from the new madrid-toledo line. commuters and tourists were the main users of the line and tourism accounted for over 30% of weekday hsr ridership. apart from these isolated case studies applied to hsr, we can distinguish three types of tools that are generally used to study the impact of transportation on the tourism industry: the choice destination approach, economic geography models, and econometric models to estimate tourism demand. the choice destination approach is based on rugg's model. rugg (1973) was the first to introduce a time constraint, the modification of the budget due to the transportation cost between alternative destinations, and the modification of the time constraint resulting from including the time cost between alternative destinations. assuming that tourists usually have a fixed holiday budget, prideaux (2000) developed a model to demonstrate the dynamic relationship between holiday expenditure categories and the tourists' point of origin. the first approach to study the effects of hsr on tourist destination choice was developed by delaplace et al. (2014) in paris and rome. the data collected from a survey of tourists in both cities were used for a quantitative analysis using regression models. the results showed that hsr influenced destination choice in different ways in the two cities, with tourism in paris being more dependent on hsr. this interesting contribution was continued by pagliara et al. (2014 pagliara et al. ( , 2015 using madrid as a case study, and also based on a revealed preference survey. the preliminary results showed that the spanish hsr system appeared to have a significant effect on tourists' decision to visit other cities connected to madrid, but the choice of madrid as a tourist destination (as in rome) was not influenced by the presence of hsr. although these results are quite illustrative, the notion that destination choice may be influenced by hsr does not prove that the construction of a new line will automatically increase total tourism demand or tourist sector revenues at the destination (accommodation, restaurants, museums and so on). economic geography models, like the core-periphery model introduced by krugman (1991) , have also played an important role. krugman (1991) showed that a change in transport cost induces a change in the intensity of spatial competition, which in turn influences the location of firms. masson and petiot (2009) used krugman's core-periphery model to explore the influence of the southern european high-speed railway line (hsr) between perpignan (france) and barcelona (spain) on both tourism activity and economic development. using krugman's theory (through a theoretical rather than an empirical discussion), they argued that hsr can facilitate the development of tourism activities, and particularly business and urban tourism. crampon (1966) first introduced the gravitational model into tourism research, and the only application of this approach to a hsr scenario dates from 2012: the projected effects (not validated) of chinese hsr on tourism were examined by applying the iso-tourist line from a time-space replacement concept (wang et al., 2012) . they forecasted the effects of the hsr network on three aspects: the redistribution and transformation of the tourist market, market competition on a larger scale, and the reallocation of the urban tourism centre. however, the results obtained by wang et al. were not empirical, and it is therefore important to quantify the increase in tourism demand in order to assess the influence of the new infrastructure. in addition to economic geography models and the choice destination approach, the existing literature on tourism demand is dominated by econometric models that tend to follow a single-equation time-series approach (lim, 1997; song and li, 2008; song and wong, 2003) . the only approach of this type applied to hsr corridors was developed by chen and haynes (2012) . through a multivariate panel analysis, they investigated the impact of chinese high-speed rail systems on the tourism industry, selecting only the numbers of incoming foreign tourists and tourism revenue as the dependent variables. chen and haynes classified their independent variables into three groups: "policy variables" (all related to rail infrastructure and ridership), "origin variables" (related to the economic relation between foreign countries of origin and destinations) and "destination variables" (local site features or special events at the destination). although the model does not consider domestic tourism (this data was not publicly available in china at the provincial level), the results of the research confirmed that policy variables have major significance in the model. the study concluded that during the period between 1999 and 2010, chinese provinces with high-speed rail services were likely to have approximately 20% more foreign arrivals and 25% higher tourism revenues than provinces without these systems. the authors empirically demonstrated that the presence of hsr services in each province boosted tourism in china more significantly than other local variables such as the number of world heritage sites or museums. in 2015, a variation of this original model was developed by chen and haynes over the period 1997-2012, but using a panel of 21 source countries for tourism in china instead of provincial data. other explanatory variables such as network density or number of stations were added in the equations and produced similar results, particularly for the network density variable. although this type of model is fairly dependent on the availability of a solid database, and despite the fact that the chinese context is quite different from the european one, the results obtained and the consistency of the model structure used by haynes and chen have encouraged the authors of this paper to extrapolate the methodology to the spanish case study. the chinese scenario is among the most sustained attempts to systematize the study of hsr impact on tourism (see also wang et al., 2012) and in the literature, the transfer of this methodology to the european scenario could be an important step towards obtaining extrapolated results. section 3 below examines the main figures representing the structure of tourism in china and spain in order to understand and discuss the results of applying the model to the spanish case study in section 4. spain is one of the most popular tourist destinations worldwide, occupying fourth place in 2014 in the world ranking of tourist arrivals, behind france, the us and china (unwto, 2015) . while spain has traditionally been a tourist country, international tourism arrivals in china started to grow after the open door policy was implemented in 1979. from 1980 to 2014, china's inbound tourist arrivals and tourism revenues grew at an average annual rate of 9.6 and 11% respectively (calculated with data from the national tourism administration of china nta, 2002 . currently ranking as the world's third most popular tourist destination, china is expected to attract 130 million tourists annually by 2020, taking it to number one (unwto, 2015) . the physical environment positively influences the choice of spain for tourism. the country has 108 days per year of temperatures above 25°c, and 2451 h of sunshineequivalent to 6.7 h of sun a day. it boasts 8000 km of coastline, and the highest number of blue flag beaches in the world. this is why leisure and holidays (84%) are the main motivations for the majority of arrivals. moreover, 24% of spanish territory is classified as a protected area (third in the european ranking) and it has a total of 45 world heritage monuments and sites, the third highest in the world. unlike spain, where "sun and beach" holidays are the main motivation for the majority of arrivals, tourist resources in china fall into two main groups: natural sites, and historical and cultural sites. china has 50 world heritage sites to date; of these 35 are cultural sites, 11 are natural sites, and 4 are cultural and natural (mixed) sites, ranking second in the world after italy (51 world heritage sites). most are located in coastal regions, which are also the hub of chinese economic power. china's mounting economic growth since 1978 has caused increasing disparity between the coastal and inland areas in almost all the major economic indicators (pedroni and yao, 2006) . in spite of the concentration of tourist resources in the coastal areas, the country's vast extension (9,597,000 km 2 versus 505,000 km 2 of spain) means the distances between them are higher than in spain, and aviation and hsr lines are the main transportation infrastructures on which foreign tourism is based. china's vast extension also means that seasonal weather conditions vary widely from region to region (with temperatures as low as −40°c in the north and as high as 40°c in the south), with major climate shifts limiting tourism during certain months of the year. another issue influencing tourism demand is the high level of air pollution in china's major urban and industrialised areas, which may aggravate visitors' bronchial, sinus or asthmatic conditions. there is scientific evidence (beckena et al., 2016) of the damage to destinations and risk perception that urban air pollution is causing to china's inbound tourism. the origin countries of foreign tourism in both spain and china are predominantly the neighbouring states. in case of spain, united kingdom (19.40%), germany (16.87%), france (11.16%) and italy (5.4%) accounted for more than 42% of tourist arrivals in 2014 (ine, 2016b) . eu residents provide 71% of international arrivals, in addition to a notable contingent of us (4.80%) and russian (2.98%) tourists. spain also receives tourists with a high degree of loyalty to the destination, measured as the number of times international tourists have visited the country on previous occasions: in 2012 the official frontur report from the instituto turístico español (ite, 2013a) showed that 80.2% of visitors claimed to have visited spain before. in 2014, 26.3608 million foreigners visited china, of whom the largest groupa total of 16.3313 millionwere asian (61.95%) (national bureau of statistics of china, 2015), most from south korea (25.6%). the second largest share was from europe, which contributed 5.5143 million visitors, accounting for 20.90% of the total. while the numbers of asian visitors is currently growing, the european market, headed by russia, has been declining since 2013. in third position was the us market, with a total of 2.7603 million visitors (10.5%). most visitors came to china for sightseeing or leisure activities, while the second largest group comprised those attending conferences and business meetings, accounting for 20.69%. domestic tourism also reveals differences between spain and china. in 2014, spain registered a balanced split between non-resident (51%) and resident (49%) tourists, while domestic tourism in china represented over 90% of total visitors (national bureau of statistics of china, 2016). there are also significant differences in the evolution of these figures: in spain, the balance of non-resident and resident tourists has remained stable, with a slight increase in the number of foreign visitors. the number of domestic tourists in china was 3611 million in 2014, with a 200% increase in the period 2004-2014 (1102 million in 2004) due to the country's vast population and rising standard of living, particularly in the last 30 years. it should be noted that in most official national databases the number of foreign and domestic tourists is linked only to hotel stays (overnights), meaning that the total domestic visitors in both cases (china and spain) has been undervalued, as there is no information on the number of tourists staying in apartments or second homes. in terms of the territorial distribution of hsr ( fig. 1 ) and its relation with the main local tourist destinations, spain's network is structurally radial, with the centre located in madrid. it has been extended mainly towards the more populated eastern and southern cities (barcelona, valencia, malaga, seville), most of which are located in the coastal area with high tourist attractiveness. china's network is concentrated mainly in the coastal area (where all the major economic indicators are higher), with four north-south lines, two of which are fully operative (beijing-harbin; beijing-shanghai) and the rest still in only partial operation (beijing-guangzhou-shenzhen-hong kong; hangzhou-fuzhou-shenzhen). these four lines cover most of the tourist destinations (beijing, hong kong and shanghai) or can be used as transport links to other remote destinations. there are also two east-west lines which are still only partially operated (qingdao-taiyuan; shanghai-wuhan-chengdu). the key issue in the interurban transport system when comparing china to spain concerns road infrastructure and conventional trains. although china has invested heavily in transport infrastructure in the last twenty years, spain had more than double the density of high-capacity roads (0.030 km/km 2 ) than china (0.012 km/km 2 ) in 2015. if hsr is considered together with conventional interurban rail lines, this figure is even slightly higher (0.031 versus 0.012). this partly explains why the impact of hsr on the current transport system could be even higher in china than in spain. accessibility to the main tourist destinations in spain before hsr started operation in 1992 was already guaranteed at a medium-high quality level. at the urban level, europe has a longstanding tradition of using and operating public transport, and spanish public transit is of significantly higher quality than its chinese counterpart, particularly in medium and small sized cities. while transport and tourism infrastructure in spain is balanced between inland and coastal provinces, many inland destinations in china have natural resources that could potentially represent a regional competitive advantage were they endowed with the necessary infrastructure conditions, but have had difficulty in drawing both domestic and international visitors away from the popular coastal gateways (jackson, 2006) . although the chinese tourism sector is currently experiencing one of its highest ever levels of growth, public strategies to improve quality levels in the tourism offer are new and being implemented at great speed. spain, in its traditional role as a "beach holiday" country, has developed innovative tourism policies by promoting inland areas of the country and diversifying into other spheres such as rural and urban tourism, gastronomy, shopping and health tourism (oecd, 2016). there is even a spanish rural tourism promotion plan for 2014, which is already producing results, and a shopping tourism plan focused on asian markets. a new health tourism cluster has also been created, and is promoted internationally through the combined efforts of several ministries and the private sector. other areas of diversification include golf tourism, ecotourism and religious tourism. spain can therefore be said to have a greater density of tourist destinations per km 2 , in addition to a wider diversification of tourism activities than china. this latter point is interesting from a territorial point of view, as hsr rail is not a permeable transport infrastructure (like roads), and the "city to city" link conditions the type of tourism itinerary. the density of transport infrastructure is also higher in spain, thereby increasing the accessibility to tourist destinations and supporting the hsr system by using hsr stations as useful intermodal nodes. the following section describes the application of a multivariate panel data analysis to spain at the provincial level to explain the evolution of several tourism indicators, using hsr among other destination variables. the results are compared to those obtained in the chinese case study using the same methodology, and the final analysis is supported by the tourism data provided in this section. spain, with more than 20 years of hsr experience and 3100 km of track in service, offers a good opportunity to apply the chen and haynes model (2012), even though the direct application of this methodology to the spanish case poses several difficulties, mainly concerning the adaptation of the statistical database to the variables used in the chinese case study. the proposed model is based on a multivariate panel analysis at the provincial level. spain is administratively divided into 17 regions and 50 provinces, and all the provinces were considered (except those located outside the iberian peninsula), in the period from 1999 to 2015. as the first hsr line started operation in 1992 (madrid-seville branch) and was the only one (table 1) for over ten years, this period covers most of the spanish hsr experience. fig. 1 differences between the spanish and chinese hsr networks, and shows the extension of both countries. the criteria used to select the tourism output (the dependent variable) in china focused on the availability of the related database: number of foreign tourist arrivals (taf) and tourism revenue (tr). two different modelsusing the same structure but a different tourism outputwere tested in order to quantify the impact of hsr lines on tourism in china. it should be noted that data (at the provincial level) for domestic tourism demand was not publicly available so was not considered in the research. table 2 shows the independent variables (and their main descriptive statistics) used by chen and haynes in their model. they are classified into "policy variables", "origin variables" and "destination variables". the policy variables are all related to rail transportation features such as: • passenger rail ridership (rider), measured in 10,000 people per year, introduced to capture the impact of the generic passenger railway system, including both normal and high speed trains. • length of railway (rlen), introduced as an alternative to reflect the impact of railway investment, as no actual investment data is available at the provincial level. • a hsr dummy variable (hsr) equal to one for the year and province that has a hsr service, and zero otherwise. this variable is perhaps the most relevant data to measure hsr effects, as there were no itemised statistics available per line and province. origin and destination variables are always present in demand transport models together with impedance variables (travel time or distance). as origin variables the authors use only the annual nominal exchange rate (exc) from the us dollar to the rmb (renminbi), the chinese legal tender. a long list of destination variables is given in table 2 , which can be perfectly extrapolated to case studies in other countries (hotels, number of world heritage sites, museums, and others). although this model does not consider trip features such as travel time or distance, it does take into account impedance variables such as the number of accidental pollution leaks (pollution) or the dummy variable associated to the outbreak of sars (severe acute respiratory syndrome) which originated in china in 2003. two special event dummy variables (bjolympic, shexpo) were also introduced to monitor the influence of the 2008 beijing olympic games and the 2010 shanghai expo respectively. in accordance with this approach, tourism output (the dependent variable) in spain focused on similar tourism demand variables, bearing in mind that the spanish national institute of statistics (ine) uses the term "number of tourists" rather than "tourist arrivals" to quantify the tourists visiting each province, and calculates the figures from the data for overnight stays provided by hotels. unlike china, data on domestic tourism demand is publicly available in spain at the provincial level, so the tourism output variables selected in the spanish case study were: foreign tourists, domestic tourists and revenues from foreign tourism. in table 3 these variables are referred to as: tanr (number of non-resident tourists), tar (number of resident tourist) and tr (tourism revenue from non-resident tourists in spain). three different models using the same structure but different tourism outputs were tested in order to quantify the impact of hsr lines on spanish tourism. the following policy variables (all related to rail transportation features) were used in the spanish case study: rlen quantifies the national rail length (including the conventional rail network), rider is the total rail ridership (including conventional rail traffic) and hsr (dummy variable) is the hsr presence at the provincial level. it was more difficult to design the origin variables. as only foreign tourism was considered in the chinese study, the authors used the annual nominal exchange rate (exc) from the us dollar to the rmb (renminbi). according to statistics from ine (ine, 2016b), in 2014 more than 71% of foreign tourism in spain came from the european union. our exchange variable is therefore defined as the difference between the provincial and european (eurozone) gdp, referring to 1999 currency to avoid the effect of inflation. the origin of domestic tourism is more difficult to determine, and no origin variable related to gdp was used. table 3 shows the rest of the independent variables (and their main descriptive statistics) added to the spanish models. apart from the local economic variable used in the chinese case studythe gross provincial product per capita (gpppc) -, significant efforts were made to collect the same multidimensional features of local tourism used in the original model: number of world heritage sites (whs), starred restaurants (resta), museums (museum) and public libraries (lib). art galleries are included in the museum database. in the spanish case, 4-star hotels are the most popular with both domestic and foreign visitors (ine, 2016b) , so the hotel variable (hotel) included the number of 4-and 5star hotels (unlike the chinese case study). in the time period considered (1999) (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) , no special impedance variables were taken into account, such as accidental pollution leaks or the outbreak of sars in china. it was decided to overlook these variables as no comparable cases have occurred in spain, and owing to the high degree of loyalty of visitors to spain (spanish institute of tourism, 2012). instead, three special dummy variables relating to major international cultural and sporting events were introduced as attracting indicators: the forum 2004 in barcelona (forum), the america's cup in valencia in 2007 (amcup), and the international exhibition in zaragoza in 2008 (expoz). these events have been recognised for their relevance in the research work of renau (2010) in spain. there is another additional variable in the model (called year), not linked to origin, destination or policy features, which groups the sequence of observations and measures time trends. before designing the equations for the spanish case study, the preliminary multicollinearity data analysis found high correlations between the explanatory variables rider and rlen. as in chen and haynes' research, this led the authors to present two separate models per output variable. eqs. 1 and 2 show the general structure of the multivariate analysis using panel data. subindices i and t denote destination provinces and time period respectively, while y represents the dependent variables (number of domestic tourists, number of foreign tourists and total foreign tourist revenue). a fixed effects model (fe) was developed for the unobserved individual effect in a panel model, consisting of a statistical model that represents the observed quantities in terms of explanatory variables that are treated as if the quantities were non-random. table 4 shows the determinants of the number of foreign tourists in spain compared with the results of chen and haynes (2012) . model 1 considers rail ridership as a policy variable, while model 2 uses network length. this multivariate analysis methodology is repeated again in table 5 to study the determinants of foreign tourism revenue in spain (model 3 with ridership, model 4 with length). table 6 shows the results for the output "number of domestic tourists" obtained from two multivariate analysis applied to the spanish panel data, one using the independent variable rlen and the other using rider. in the case of foreign tourism (models 1, 2, 3 and 4), the first finding in the spanish study concerns local site characteristics such as the number of 5-star hotels, starred restaurants, world heritage sites and museums. these variables were not statistically significant in china in any of the models designed, while in spain some indicators such as the hotel variable are statistically significant at the 1% level. the hotel variable coefficients in the four models range between 0.941 and 0.591. other local site characteristics such as museums and libraries show high levels of significance, although their coefficients are much lower than for the hotel variables. these results are consistent with the spanish offer at the destination: not only "beach and sun" attractions, but a greater diversification of areas such as rural and urban tourism, gastronomy, shopping, museums, health tourism, eco-tourism and others, all concentrated in the same physical location or within an easily accessible radius of influence using the transport system. our table 4 determinants of the number of foreign tourists in spain. comparison with chen and haynes' results (2012 explanation is that in spain the "destination" variables benefit from reinforcement and favourable complementarity, in addition to the fact that the country has a higher density of tourist destinations per km 2 compared to china. the reason the hotel coefficient is higher in spain than in china is probably due to the convenience for tourists of being able to choose between a range of different four-and five-star hotel chains at the destination, and to the way these hotels are linked to a range of other tourist attractions. the insignificant results for the event variables are similar for the chinese and the spanish experience. special events such as the 2008 beijing olympic games and the 2010 shanghai expo, and the number of pollution incidents are not statistically significant even at the 1% level. however, the dummy year of 2003 in chinarepresenting that year's sars epidemicis highly statistically significant. this is to be expected since sars had a fairly strong negative effect on foreign tourist arrivals. no deterrent event variable was introduced in the spanish model, and the results for the special events are consistent with the chinese ones. among all the explanatory variables, it is not surprising to find that the gross provincial product per capita (gpppc) variable has a significant impact on the number of foreign tourists in both china and spain. in china, the elasticities are 0.459 and 0.495, which can be interpreted as a 1% increase in the gpppc, associated to an increase of around 0.46 to 0.5% in foreign tourist arrivals. in spain, the level of significance of the variable is even higher (1%) for foreign tourism output, and the coefficients are higher, which supports the idea that visitors appreciate not only the presence of "sun and beach" at the destination but also the socioeconomic environment. in contrast, the gross provincial product per capita is not significant for the spanish revenue output models, which may mean that tourist expenditure in spain is not dependent on the price levels in the province (in richer provinces hotels and restaurants tend to be more expensive). another key determinant is the exchange rate (exc), which represents the price level of tourism in comparison with the countries of origin. in both china and spain the positive sign of this coefficient indicates that when the price levels in the destination are lower than in the origin countries, the number of visitors increases. this coefficient was higher in the chinese than in the spanish case study, indicating that tourism in spain is less sensitive to price levels. another argument that supports this idea is that most tourists in spain come from other eu nations (71% in 2014), and the differences in these price levels are less pronounced. the low sensitivity to price levels is reinforced by the fact that spain tends to welcome tourists with a high degree of loyalty to the destination. in the revenue models (in both china and spain), the exchange rate is less significant as a variable than the gross provincial product per capita (gpppc), and is unimportant in terms of significance. while ridership and length are not significant among railway variables, the dummy indicator hsr plays an important role in the chinese and spanish foreign tourism models, especially in the case of tourism revenues. the hsr variable is statistically significant at the 1% significance level in the chinese and spanish revenue models (table 5) , but only 5% significant in the demand models (number of foreign tourists) ( table 4 ). these results are the key findings of this paper, and indicate that spanish provinces with hsr receive more foreign tourists and more revenues than provinces without this service. nevertheless, the hsr coefficients for spain are much lower than for china, showing that the effect of hsr is much higher in china than in spain. the highest coefficient in the revenue models in china is around 0.25, implying that figures in parentheses are standard deviation. ***,**,* denote coefficients significant at the 1%, 5% and 10% statistical level respectively. provinces with hsr services were likely to have approximately 25% more tourism revenues than provinces without. in spain, the highest coefficient (see models 3 and 4 in table 4 ) is 0.017, indicating that provinces with hsr services were likely to have 1.7% more tourism revenues. the highest hsr coefficient in china in foreign tourism demand models (models 1 and 2, table 4 ) is around 0.201, suggesting that provinces with hsr services were likely to have 20.1% more tourists, while this percentage is only 1.3% in spain. these results can be explained by the fact that, as mentioned in section 3, distances between tourist destinations are greater in china than in spain, and the transport alternative to hsr is a lower density network (high-capacity roads and conventional trains). accessibility to the main tourist destinations in spain before hsr started operation in 1992 was already guaranteed at a mediumhigh quality level, and the impact of hsr on tourism indicators is thus less important. in the case of domestic tourists (models 5 and 6) and local site features -as in the case of foreign tourists-, the only significant variables are the number of hotels and the number of libraries (this latter with a low coefficient). neither the variable whs or museum is statistically significant, highlighting the importance of spanish coastal destinations for this type of tourism. in support of this argument, data from the familitur report (ite, 2013b) revealed that the three major destinations for domestic tourism were andalusia, catalonia and the region of valencia, accounting for almost 50% of visitor share. these three regions have a considerable extension of coastline, and the temperatures are excellent for "sun and beach" tourism. the only significant event variable is expozaragoza in 2008, with a high significance (1%). nevertheless, as in the foreign tourism models, the value of the coefficient (between 0.003 and 0.005) reveals its low real impact on the domestic tourist sector. the economic explanatory variable gpppc has the highest significances (lower than 1% in both rider and rlen models), and high coefficients (0.214 and 0.215 respectively). this finding underlines the considerable importance of tourism for the spanish provincial economy and its significant and positive role for regional economic growth, as noted by previous studies (cortés-jiménes, 2008) . in relation to policy variables, neither ridership nor the length and existence of hsr are significant, (not even at 10% significance). according to the familitur report (ite, 2013b), in 2012 the private car represented over 84% of the modal split in domestic tourist trips, indicating that the improvement in the speed and comfort of the rail network is not sufficient on its own to modify the mobility patterns of spanish families. this may be explained by the higher costs perceived by travellers in comparison with the private car when more than one person is travelling (which is very common in family tourism patterns). in conclusion, the results show that hsr in spain has positively affected foreign tourism outputs (especially revenues), although its impact is not as important as in china. there is no clear evidence of its effect on domestic tourism. hsr impacts on tourism in a country like china, where the alternative interurban transport network is less developed than in europe, are of a higher magnitude and easier to detect with an econometric model. further research is required on the use of hsr variables, which need to describe not only the existence of lines at the provincial level, but also the connectivity and territorial distribution of the hsr network, and the service conditions offered by the operating companies (fares, timetables and frequency). for example, in spain and france, some hsr lines are used by commuters, and in some cases tourism is an important trip purpose. none of these commuter visitors stay in hotels, and therefore do not appear as tourists in the official statistics. in conclusion, the model would benefit from a greater level of data disaggregation and a better understanding of the territorial distribution of hsr lines through new explanatory variables relating hsr operating conditions, and including new tourism outputs based on overstays in hotels and number of visitors to the main tourism attractions, or disaggregated revenues per sector (restaurants, museums and others). apart from the abovementioned drawbacks of the methodology applied to both china and spain, there is another issue arising from this research. after applying the model to the spanish case, it still remains to be clarified whether hsr development and tourism have a simultaneous effect and whether this system is really endogenous. although a "circular and cumulative causation" between hsr demand and tourism demand is always expected in these territorial systems, it is essential to separate any crossover effects, or at least identify which has the greater impact (hsr on tourism indicators, or tourism on hsr demand). in the next section a simple empirical analysis of endogeneity is applied to a specific spanish destination (toledo), in order to demonstrate by example that this separation can be achieved and derived from empirical data. in order to test endogeneity between hsr demand and tourism indicators, we selected toledo, a mid-sized tourist city in central spain with almost 78,000 inhabitants, as a case study. toledo is located 70 km south of madrid and has been linked to madrid by a hsr line since november 2005. it was declared a world heritage site by the unesco in 1986 for its extensive cultural and monumental heritage, and the historical coexistence of christian, muslim and jewish cultures. before construction work started on the new line, rail traffic in the previous conventional line was not insignificant (over 800,000 passengers in 2002), and rose to over 1,300,000 passengers in this decade, as shown in fig. 2 . the madrid-toledo hsr line is successful in terms of traffic, not only due to the hsr link to madrid and its attractiveness to tourists, but also because of the type of service provided by the operating company. since 2005, toledo has enjoyed avant services with over ten daily hsr shuttles (30 min' travel time), and is also favoured by the availability of monthly tickets which are economically highly advantageous compared to ordinary one-way tickets. if the schedules are compatible with work timetables, this frequency enables their use for commuting, with the result that over 60% of users of the madrid-toledo hsr line have been found to be commuters. the first indicator we quantified was the evolution of the number of tourists in toledo, drawing on tourism data provided by the spanish national statistical institute (ine), covering 50 provinces and a limited number of tourist points within a time span of 15 years (1998) (1999) (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) ). data at the provincial level were used to calibrate the multivariate regression model in section 3, but more detailed data are available as toledo is considered a tourist point by the ine. in both database sources, the "number of tourists" indicator is calculated by the ine using only the results of the survey of hotel occupancy, so this analysis must take into account that visitors to these cities who do not spend at least one night at the destination are still not registered as "tourists". in the case of toledo the number of tourists comprises two thirds of the visitors at the provincial level, and disaggregation between resident and non-resident tourists in spain has only been available from 2005 in the tourist point ine database. in addition to the evolution of the number of tourists in toledo, we studied other indicators such as the number of museum visitors (htickets sold) and its evolution before and after the implementation of the new hsr line. as the church of santo tométhe home of the famous painting "the burial of the count of orgaz"is one of the most visited museums in the city, we recorded the data for tickets sold per year. fig. 2a also shows the number of tourists and overnight stays in toledo (before and after the inauguration of hsr services in 2005) together with the evolution of rail passengers and the main museum visitors. an average of 26% of tourists are non-resident in spain. there was a sharp rise in the number of travellers after the opening of the hsr line. bearing in mind that commuters account for 60% of hsr traffic, the increase in both the number of tourists and number of visitors to the santo tomé museum is much more limited and appears to be more a result of other factors, revealing no clear evidence of the influence of hsr on these tourism variables. fig. 2b shows the evolution of the number of resident and non-resident tourists in the province of toledo for 2000-2013 (the period 2000-2005 is not covered at this disaggregation level by the ine's urban database of tourist points). there is no appreciable influence of hsr on residents, while a slight positive influence can be observed on non-residents. this is consistent with the results of the model applied to spain in section 4: foreign tourism in spain is more positively affected by hsr than domestic tourism, although the spanish financial crisis (which started in 2005) may have influenced this fact. the fall in all the variables since 2008, with a greater impact on the number of visitors to the santo tomé museum than on the number of travellers or the number of visitors, can be explained by the spanish financial and socioeconomic climate after 2005. this data context highlights the difficulties of assessing the influence of hsr on tourism indicators, but reveals that its influence may even be negligible for some types of tourism. in the case of toledo, the road infrastructure between madrid and toledo is perfectly covered by both a free dual carriageway (a-42) and a toll motorway (ap-41), while regular bus services offer frequencies of 30 min and travel times of 60 min (hsr travel time is 30 min with a frequency of 60 min). there are multiple alternatives to hsr. in order to find more empirical evidence on "circular and cumulative causation", we also analysed the evolution of the number of restaurant licenses in the city of toledo from 2000 (530 licenses) to 2013 (800 licenses), which revealed that the annual growth rate was fairly continuous regardless of the opening of the hsr line. additionally, it is difficult to assess in the short term whether hsr contributes to improving the image of a tourist city. apart from the madrid-seville line, most spanish hsr lines have been in operation for under ten years, which is too soon to analyse or model this kind of indirect effect. toledo was an important spanish tourism destination before 2005, despite its lack of hsr. in any case, the improvement of the image of a tourist city in the long run will be seen in the increase in most of the tourism outputs and revenues. after studying the local case of toledo, we can state that within this "cause-effect" relation the effect of tourism on hsr demand may be much more important than the effect of hsr infrastructure on tourism indicators. evidently, tourism will always be an object of trip generation, but when a tourism destination already has a high rate of transport accessibility, a new mode does not add a large number of new tourists but produces a new transport modal split in the access to destination. this example shows how this cause-effect relation may be totally unbalanced towards the benefits of hsr demand. in other destinations, this fact will depend on the alternative transport modes for accessing the tourist destination and the type of tourism affected -resident or nonresident-as they clearly behave in a different way. lastly, local strategies to promote tourism are also important. toledo is clearly a cultural destination, but gastronomy, and rural and ecotourism have also been publicly promoted at the provincial level in recent years. hsr is only one of the possible "gateways to the destination", but depending on the country and the province concerned, this can either be the optimal gateway, or simply a complement to other existing ones. the literature review shows how tourism has affected hsr demand, although little research has been done to date to empirically estimate the opposite effect of hsr on tourism indicators. chen and haynes were the first to study this impact through a multivariate panel analysis, obtaining positive results and showing that in the period between 1999 and 2010, fledgling high-speed rail services significantly boosted tourism in china. the analysis considered only foreign rather than domestic tourism due to the lack of data available at the provincial level. the most effective first step for obtaining a systematic tool to evaluate the integral impact of hsr on the tourism industry is to conduct a detailed study of the applicability of the chinese experience. with spain and china coming top of the rankings for the most visited tourist countries (along with france and the us) and the longest hsr networks in operation, spain can be considered the most suitable country for validating this tool. the tourism structure in both china and spain was studied in order to define the main differences and gain a greater understanding of the modelling results, and the following key issues were identified: tourism motivations, levels of transport accessibility to tourism destinations, weather limitations, evolution of domestic tourism and public strategies to promote tourism. the authors have made considerable efforts to adapt the spanish database to the variables defined in the chinese analysis, introducing new variables when necessary and eliminating any that are not applicable to the spanish scenario. six different models were designed using the following dependent variables: number of foreign visitors, number of domestic visitors and foreign revenue. for each dependent variable, two equations were defined (one using ridership and other railway length). the rail variables (the key issue in this research) show that while ridership and length are not really significant, the hsr dummy variable plays a clear positive role in the increase in both the number of foreign tourist arrivals and revenues, and is highly significant with a positive sign. nevertheless, the coefficients obtained for spain are surprisingly low compared to china, and reveal that spanish provinces with hsr receive about 1.3% more tourists and 1.7% more revenues (20.1% and 25.0% respectively for china). these differences are explained by the greater distances between tourist destinations in china, combined with the fact that the transport alternative to hsr is a lower density network (high-capacity roads and conventional trains). accessibility to the main tourist destinations in spain before hsr started operation in 1992 was already guaranteed at a medium-high quality level, and hsr impact on tourism indicators is thus less important. in the case of domestic tourism, neither ridership nor the length and existence of hsr are significant, (not even at 10% significance). it can therefore be concluded that the improvement in the speed and comfort of the journey implied by hsr is not sufficient on its own to modify the mobility patterns of spanish residents (in 2012 the private car represented over 84% of the modal split in domestic tourist trips), and that the higher costs perceived by travellers in comparison with the private car is crucial in determining domestic mobility patterns. another interesting finding deriving from the modelling is the differing significance of the destination variables (number of hotels, museums and libraries) that positively influence foreign tourism in spain but not in china, suggesting that the reinforcement and favourable complementarity of the "destination" variables are especially good public strategies to promote tourism. combined with a higher density of tourist destinations per km 2 and greater accessibility to them, this defines a different scenario for spain, in which hsr plays a secondary role. notwithstanding the limitations of the tourism databases (focused mainly on hotel occupancy), further research is required on the use of hsr variables, which should describein addition to the existence of lines at the provincial levelthe connectivity and territorial distribution of the hsr network, and the service conditions offered by the operating companies (fares, timetables and frequency). the model's ability to analyse "circular and cumulative causation" between hsr and tourism has also been discussed as a drawback of the methodology used in this research. although a cause-effect analysis would require a longer-term database series than available at present (over 20 years of hsr operation), this approach could be a first step towards improving the modelling. in order to clarify this issue, the authors have completed their research with a local case study (toledo, spain) with more disaggregated data to demonstrate how the effect of hsr on tourism indicators is ultimately less important than the impact of tourism on hsr demand. for some countries and cities, tourism can represent a real priority and a source of income, and the validated 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high-speed trains and tourists: what is the link? evidence from the french and spanish capitals high speed rail and the tourism market: evidence from the madrid case study regional income divergence in china the role of the transport system in destination development two decades of "show-urbanism" in spain: the big events as a tool for the urban change effect of low-cost airlines on tourism in spain. a dynamic panel data model the choice of journey destination: a theoretical and empirical analysis tourism demand modeling and forecasting -a review of recent research tourism demand modelling: a time varying parameter approach the high-speed rail challenge for big intermediate cities: a national, regional and local perspective effects of the high speed rail network on china's regional tourism development key: cord-028308-50pck13g authors: almeida, alejandro; galiano, aida; golpe, antonio a.; martín, juan m. title: regional unemployment and cyclical sensitivity in spain date: 2020-07-02 journal: lett spat resour sci doi: 10.1007/s12076-020-00252-3 sha: doc_id: 28308 cord_uid: 50pck13g unemployment has been routinely used as a measure of the economic cycle. in addition, regional unemployment rates are characterized by, among other factors, their relation to the national unemployment rate. in this regard, the literature on regional sensitivity to the economic cycle has analyzed how fluctuations in the national unemployment rate affect the regions. in recent years, due to the great impact of past crises, the development of new econometric techniques and the possible arrival of new crises, the debate on how sensitive regions are to the economic cycle has reopened. in spain, this debate is necessary since unemployment rates are very high and display a great deal of heterogeneity. we analyzed regional unemployment rates in spain between 1978 and 2018 through a recently developed dynamic spatial econometric model with common factors and found that some regions are more sensitive than others to the economic cycle. the results seem to show that in spain, the sensitivity to the economic cycle displays a geographical pattern where the most sensitive regions are those located on the mediterranean coast. specifically, we find that the sensitivity to the economic cycle of unemployment is not determined by the fact that regions have high or low unemployment; it seems that geographical location plays an important role. these results can be useful for the national and regional governments when they implement countercyclical policies. many studies since the 1960s have researched the topic of the cyclical sensitivity of the unemployment rate. in the beginning, this literature paid attention to the common component, which is dominant in explaining movements in regional unemployment rates (martin 1997) . the idea to link the regional to the national unemployment rate and to estimate this relationship for each individual region dates back to thirlwall (1966) and brechling (1967) , in what is known as the regional cyclical sensitivity literature. recently, vega and elhorst (2016) bring the cyclical sensitivity literature back to the analysis of regional disparities by considering in their methodology serial dynamics, spatial dependence and common factors. traditionally, dynamic panel data models only accounts for spatial dependence (also called weak spatial dependence) which is an observed correlation across space because of local interactions between regions generating spillover effects. this new model also allows to account for common factors (also known as strong spatial dependence) that is an observed correlation across space as a result of shared factors such a aggregated economic fluctuations, where outcomes change together as these factors change. this modeling opens a new line of interest for analyzing unemployment among regions considering the presence of common factor and ensuring, that way, unbiased results. briefly, the literature on regional unemployment disparities identifies four stylized facts that defines regional unemployment disparities: (1) regional unemployment rates are strongly correlated over time, (2) regional unemployment rate behaves in parallel to the national unemployment rate, (3) are correlated across space and (4) display heterogeneity among regions. focusing on spain, there are large differences in the unemployment rate among regions (bande et al. 2008; cuéllar-martín et al. 2019 ) becoming more persistent over time, and bigger after the last economic crisis (jimeno and bentolila 1998; albulescu and tiwari 2018) . so that, it is necessary to pay attention to these differences and address them in terms of cyclical sensitivity. thus, analyzing regional unemployment rate disparities, the dependence between different regions and the relation to the national rate simultaneously is a requirement to implement appropriate policies. the last economic recession in spain after 2009, reinforced this need, so that many studies had focused on analyzing the regional disparity in unemployment rates since that economic crisis. nowadays, this necessity reappears due to the dramatic effects produced in the spanish economy and its labor market because of the covid-19 pandemic (mckibbin and fernando 2020) . in this line, one of the articles that has focused on the analysis of the reactions of regional unemployment to changes in the economic cycle for spain is bande et al. (2008) . this paper concludes that there is a positive relationship between the regional dispersion of unemployment and the economic cycle, which guarantees that fluctuations in the economic situation of the country directly affect to regional unemployment. since that study, many papers have focused on analyzing the reason for these disparities, assuming that unemployment is sensitive to the economic cycle. for example, a group of papers make the analysis of regional cyclical sensibility based on dividing regions with high and low unemployment (bande and karanassou 2009; sala and trivín 2014) . other block of researches focuses on doing spatial analyses of unemployment disparities to find clusters of similar behaviors (cuéllar-martín et al. 2019) . finally, some papers have focused on looking for regional characteristics that motivate regional differences (lópez-bazo and motellón 2013; melguizo 2017) . however, none of the articles have analyzed trends of regional unemployment while simultaneously considering that regional unemployment rates are persistent, heterogeneous, parallel to the national rate and spatially dependent. according to vega and elhorst (2016) , isolated analysis can potentially lead to biased results, since series dynamics, spatial dependence and common factors are more likely to be interdependent. to the best of our knowledge, this paper is the first to simultaneously analyze, for the spanish case, the persistence, heterogeneity, spatial dependence and heterogeneity in economic cycle sensitivity of regional unemployment. the main objective of this work is to provide new evidence about how spanish regions react to economic fluctuations as a requirement to implement appropriate policies. the economic and labor implication due to public and private containment measures against the covid-19 pandemic, such as school, shops and factory closures, travel restrictions and quarantines, with the corresponding cut in domestic demand, (baldwin and tomiura 2020) make this knowledge to be crucial. as a result, heterogeneous behaviors will reveal the necessity to introduce regional perspectives against future economic fluctuations. our paper contribute to the literature as follow. as the main contribution, we use vega and elhorst (2016) methodology to simultaneously consider all components of the stylized fact that defines the disparities in regional unemployment rates. another contribution is that we show evidence that sensitivity has a geographic pattern since we find that the regions located on the mediterranean coast are the most sensitive and that as we go inland and northwest, this sensitivity decreases. this pattern reveals, moreover, that regions with higher unemployment rates are not the most sensitive. our results are in line with the new side of the literature indicating that the regional-specific unemployment rate is not important at all in the unemployment trend but that geographical factors do matter (cuéllar-martín et al. 2019) . in this vein, camacho et al. (2018) also find a geographical pattern in the propagation of economic crisis and the way the unemployment rate reacts to recessions. the data used in this work, extracted from de la fuente (2019), 1 are the annual unemployment rates for the 15 autonomous communities of spain from 1978 to 2018 and the annual spanish unemployment rate, treated as a common factor following bailey et al. (2016) . 2 regional unemployment rates tend to have some specific characteristics. in particular, many works have found that regional unemployment is characterized by being correlated in time, in space and with the national rate. figure 1 shows the evolution over time of regional unemployment rates for the 15 autonomous communities of spain analyzed together with the national rate. this figure shows how, in general, the regional and national unemployment rates have a similar trend throughout the analyzed period. some special situations can be observed where, despite behaving similarly to the national rate, the regional rate is always higher than the national unemployment rate, as in the case in andalucia or extremadura. on the other hand, la rioja and navarra always seem to stay below the national rate. in addition, this unemployment rate is relatively stable over time, except in different periods of economic growth and downturns. specifically, three major economic crises can be distinguished in spain (cancelo 2004; gadea et al. 2012; camacho et al. 2018) : the first in 1983-1985, the second in 1991-1994 and the third and most recent in 2008-2014. several conclusions can be drawn by observing fig. 1 . first, all crises seem to have a strong national component, since regional rates fluctuate similarly to the national rate. second, there is clear heterogeneity in the trends to analyze the spatial distribution of unemployment rates and to determine the possible correlation in space, fig. 2 maps unemployment rates over the period analyzed every eight years (1978, 1986, 1994, 2002, 2010 and 2018) . a clear north/ south contrast that has been accentuated in recent years, in addition, shows a pattern of spatial correlation, where neighboring regions have similar rates. to test that space matters in our case study, we have estimated global spatial autocorrelation through the moran's i statistic from 1978 to 2018. the results of these tests show that, for most of the years, the null hypothesis (absence of global spatial autocorrelation) is rejected. 34 our methodological strategy involves the application of the recently developed model by vega and elhorst (2016) , which simultaneously accounts for serial dynamics, spatial dependence and common factors; their study also shows how not simultaneously including these effects for the regional unemployment rate can produce biased results. we use the cd test (pesaran 2004 ) in its local version (moscone and tosetti 2009, eq.22) to test for the presence of cross-sectional dependence in our panel data. if the null hypothesis is rejected, we can corroborate the existence of cross-sectional dependence. this test is carried out by specifying the relationship matrix of the 15 spanish regions (w). the result of this test applied to the data shows the presence of cross-sectional dependence in regional unemployment rates (z = 29.987 with p value = 0.000). this outcome is highly statistically significant, indicating that crosssectional dependence needs to be accounted for. for this purpose, we have used a row-normalized binary contiguity matrix, which is an nxn matrix describing the arrangement of the regions in space, with 1 if two regions are neighbors and 0 if not. we use this alternative based on the empirical results explained in vega and elhorst (2014) and elhorst (2017) where they find that this specification outperforms the other alternatives. we tried first and second order binary contiguity matrix. however, second order binary contiguity seems not to reflect well the relations between the spanish regions since having 15 regions the average number of links in each region is 8.667. this result implies that, for example, andalusia, a region located in the far south of spain, would have spillovers with aragon located in the far north of spain. on the other hand, to determine if the nature of this spatial dependence is weak or strong (in other words, if it is due or not to the presence of common factors), we apply the -test exponent of bailey et al. (2016) . 5 this test can take values between 0 and 1, where values below 0.5 indicate the presence of weak spatial dependence and values equal to 1 indicate the presence of strong spatial dependence. the result of this test applied to the data gives = 1.003 6 and std. err. = 0.034 which points to the presence of strong spatial dependence, common factors needs to be accounted for. our target model is the one proposed by vega and elhorst (2016) that reads as follows: where u t is a column vector with one observation of the dependent variable (unemployment) for every unit (i) at every point at time (t). u t−1 , wu t and wu t−1 are vectors of temporal, spatial and spatiotemporal lags, respectively, with , and autoregressive coefficients. w is the row-normalized binary contiguity matrix. u n t and u n t−1 are the unemployment rates of the whole country at times t and t − 1 , and 1 and 2 column vectors with unit-specified coefficients of response to the common factors. represent the spatial fixed effect added to the model and t is the nx1 vector independently and identically distributed error term with zero mean and constant variance 2 . the parameter of the region's sensitivity to the economic cycle ( ) can be estimated by dividing the elements of 1 by 1 − or by dividing the elements of 2 by − − . this model allows us to simultaneously measure the four remarkable stylized facts that often arise from analyzing the evolution of regional unemployment rates. first, the presence of time correlation of the regional unemployment rates by incorporating the regional unemployment rate lagged in time as well as in time and space and the common factor (the national unemployment rate) lagged in time. second, the model allows us to account for the presence of spatial dependence by adding the spatial lag and the spatiotemporal lag. third this model includes the common factor and its lag in time, which allows for the estimation of an individual sensitivity parameter for each region and fourth we include spatial fixed effects which allow us to account for spatial heterogeneity. (1) u t = u t−1 + wu t + wu t−1 + 1 u n t + 2 u n t−1 + + t 5 a xtcse2 stata routine have been used (ditzen 2019) 6 values above the upper bound of the interval (0,1] may occur when not all the asymptotic properties are fully met (bailey et al. 2016 ). however, since the hypothesis = 1 cannot be rejected we can conclude that estimated lies within the interval. similar results can be also found in vega and elhorst (2016) . we begin by estimating the basic dynamic spatial panel data model with regional fixed effects and without including common factors (model a), and we apply both tests (cd local test and test) to the residuals of the model. these results are shown in table 1 , column a, where it can be seen that the residuals of the model continue to point to the presence of strong spatial dependence, with = 0.920 and std. err. = 0.048 . however, the local cd test points to the fact that weak spatial dependence is no longer present ( z = −0.838 and p value = 0.402 ), because the null hypothesis of spatial independence between neighboring regions cannot be rejected. results shows a highly and very significant temporal, spatial and spatiotemporal lag ( = 0.891 , = 0.825 and = −0.739). next, we estimate the model proposed by vega and elhorst (2016) incorporating common factors (model b). 7 through this model, it seems that both the local spatial dependence ( z = 1.196, p value = 0.232 ) and the presence of common factors ( = 0.255 , std. err. = 0.055 ) appear to have been effectively covered. 8 as seen in column b, the serially lagged unemployment rate ( = 0.929 ) is highly significant, reflecting the strong correlation of unemployment rates over time. in addition, the spatially lagged coefficient ( = 0.165 ) is positive and significant, reflecting the presence of spatial dependence between regions, and the lagged spatial autoregressive coefficient seems to be significant and negative. 7 we have also estimated the two-stage approach developed by bailey et al. (2016) . an lr test comparing both models shows that the simultaneous model fits the data better and the brechling-thirwall type of cyclical sensitivity estimated seems to show long-lasting problems (brechling 1967; domazlicky 1980) where regions with estimates greater than one are those with unemployment rates persistently higher that national average. 8 the model also seems to be stationary and stable since + + < 1 model b seems to have perfectly covered the presence of spatial dependence and common factors based on the results provided by the test. by introducing common factors, the model correctly cover the difference between spatial dependence and common factors. the and could have been overestimated in model a due to the absence of common factors. 9 another way to account for the presence of common factors would have been to add a time-period fixed effects to the model too. however, this would be similar to the inclusion of common factors at time t with the unit-specific coefficients replaced by a time dummy with a common coefficient. 10 in table 2 , we show the result of the coefficients of response to the national unemployment rate estimated for each of the regions ( ). both coefficients ( 1 in t and 2 in t-1) are highly significant. the estimation of the economic cycle sensitivity parameters is shown in the last two columns ( 1 , 2). 11 the regions most sensitive to the economic cycle appear to be comunidad valenciana, andalucia, region de murcia and cataluña, each with parameters greater than 1.100. it seems that regions located on the mediterranean coast share a common pattern. these communities are characterized by being the most touristy in spain, which may be a possible explanation. among the least sensitive communities, we find galicia, navarra and castilla y leon, each with parameters below 0.700. to show the spatial distribution of the sensitivity of the regions, fig. 3 shows in four shades of gray the intensity of the economic cycle sensitivity of each region ( 2 ). 12 it seems that spain has a specific sensitivity pattern where the most sensitive regions are those located on the mediterranean coast and sensitivity decreases as we move inland to the northwest. particularly, the economic cycle sensitivity of the regions in spain can be divided into four groups, from the most sensitive (in darker colors) to the least sensitive (in lighter colors). the first includes the four regions most sensitive to the economic cycle of spain, which are also those located on the mediterranean coast (andalucia, region de murcia, comunidad valenciana and barcelona). the second group, formed by extremadura and castilla-la mancha, are also regions that are sensitive to the economic cycle, although less so than the previous group; this second group is composed of regions located in the southern interior and neighboring the most sensitive regions. the third group is formed by regions that are not sensitive to the economic cycle and that are located in the northern interior of spain, away from the most sensitive regions. finally, the fourth group is formed by the least sensitive regions of spain, galicia and navarra. these results seem to point to the fact that when crises and recoveries appear, the regions located on the mediterranean coast are the ones most affected because they are the most sensitive. in recent years, there has been a growing interest among academics, practitioners and policy makers in finding a pattern in spanish regional unemployment trends. this interest emerges from the need to know how unemployment in each region 10 results of this model (with log-likelihood function value of − 753.298) are quite similar with parameter = 0.896 ( std. err. = 0.018 ), = 0.230 ( std. err. = 0.046 ) and = −0.179 ( std. err. = 0.051) 11 we calculate the parameters according to the procedure proposed in vega and elhorst (2016) . the standard errors are calculated using formulas for the sum and quotient of random variables (mood et al. 1974, pg. 178-181) . 12 we map parameter 2 since it is based on the relative strength of both internal and external habit of persistence (korniotis 2010). will react ahead of the increasingly common occurrence of recession phases. in this context, the literature documents that unemployment is persistent, heterogeneous, spatially dependent and parallel to the national rate, but these effects have never been analyzed simultaneously. in our paper, by applying the methodology proposed by vega and elhorst (2016) , the persistence, heterogeneity, spatial dependence and economic cycle sensitivity of spanish regional unemployment are analyzed simultaneously. furthermore, this methodology allows us to estimate heterogeneous coefficients of response to aggregate fluctuations. the findings show that there is a high persistence of unemployment in spain, that there is spatial dependence and that regions show different sensitivities to the economic cycle. although the first findings are in line with the previous literature, the main contribution of this article is to uncover the geographical pattern of sensitivity to the economic cycle. we find that the economic cycle sensitivity of unemployment is not determined by the fact that regions have high or low unemployment; it seems that geographical location plays an important role. specifically, the regions that have greater economic cycle sensitivity are located on the mediterranean coast and include regions with very different unemployment rates. however, what these regions do have in common is that they are areas very focused on the tourism sector, which can be taken as a possible explanation. the findings are related to melguizo (2017) who shows that regions with a more developed service sector suffer more variations in unemployment rates, and to camacho et al. (2018) who find a similar pattern in how crises and recoveries begin and end in spain. both findings are in line with the regional heterogeneity we observe, since they reveal that some regions suffer more from the effects of business cycle whereas other regions are less affected by economic contingencies. consequently, the application of national inflexible policies may difficult actions devoted to smooth cyclical swing of regional economic activity. therefore, that, as main find, we consider that this regional behaviour is indicating the necessity to apply differentiated employment policies when national economy face a crisis. nowadays, this find become into a crucial due to the employment destruction our regions are suffering because of the economic and labour impact caused by the restrictive measures against the covid-19 pandemic. on the one hand, with the pattern in the trend of regional economic cycle sensitivity that this paper finds, the national government can distribute resources in an efficient way to react to future recessions or to recoveries from past crises. on the other hand, regional policies can be adapted to each geographical area depending on its sensitivity, and regional cooperation is needed since spatial dependence points to the presence of possible spillovers. conflict of interest the authors declare that they have no conflict of interest. unemployment persistence in eu countries: new evidence using bounded unit root tests a two-stage approach to spatio-temporal analysis with strong and weak cross-sectional dependence thinking ahead about the trade impact of covid-19 regional unemployment in spain: disparities, business cycle and wage setting labour market flexibility and regional unemployment rate dynamics: spain 1980-1995 trends and cycles in british regional unemployment regional business cycle phases in spain el ciclo del empleo en españa: un análisis regional an empirical analysis of natural and cyclical unemployment at the provincial level in spain series largas de algunos agregados económicos y demográficos regionales: actualización de regdata hasta xtcse2: sata module to estimate the exponent of cross-sectional dependence in large panels regional business cycles: a survey spatial panel data analysis cycles inside cycles: spanish regional aggregation regional unemployment persistence (spain, 1976-1994) estimating panel models with internal and external habit formation the regional distribution of unemployment: what do micro-data tell us? regional unemployment disparities and their dynamics the global macroeconomic impacts of covid-19: seven scenarios an analysis of okun's law for the spanish provinces introduction to the theory of statistics a review and comparison of tests of cross-section independence in panels general diagnostic tests for cross-sectional dependence in panels labour market dynamics in spanish regions: evaluating asymmetries in troublesome times regional unemployment as a cyclical phenomenon 1. scott modelling regional labour market dynamics in space and time a regional unemployment model simultaneously accounting for serial dynamics, spatial dependence and common factors publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-316050-mqrx003q authors: seabra, claudia; reis, pedro; abrantes, josé luís title: the influence of terrorism in tourism arrivals: a longitudinal approach in a mediterranean country date: 2020-01-31 journal: annals of tourism research doi: 10.1016/j.annals.2019.102811 sha: doc_id: 316050 cord_uid: mqrx003q abstract this longitudinal study examines the impact that terrorist attacks within a representative group of european countries can have on the tourism demand of a south european country with no record of terrorism attacks. in order to analyze the connections between terrorist attacks and tourists' arrivals, occurred between 2002 and the end of 2016, an unrestricted vector autoregressive model was used for multivariate time series analysis. the main results show that terrorist attacks have a strong impact on tourist arrivals and confirm the existence of terrorism spillover, namely the substitution and generalization effects phenomena. terrorism has become an important and recurring topic in the public discourse over the last decades due to the increased frequency of terrorist attacks witnessed (national consortium for the study of terrorism and responses to terrorism, 2019). since the beginning of the century, and particularly over the last 10 years, several developed and stable countries have witnessed high levels of terrorist events (lanouar & goaied, 2019) . new york, united states (2001) , madrid and barcelona, spain (2004 , london and manchester, united kingdom (2005, 2017) , tuusula, finland (2007) , apeldoorn, netherlands (2009 ), utoya, norway (2011 ), paris and nice, france (2015 , brussels, belgium (2016) , sousse, tunisia (2015) , berlin, germany (2016) , istanbul, turkey (2016 , christchurch, new zealand (2019), colombo, sri lanka (2019) were some of the places that have experienced terrorist attacks, but the list goes on (national consortium for the study of terrorism and responses to terrorism, 2019). revolutionary and destructive groups carry out attacks all over the world every single day, transforming terrorism into a constant in modern life (coca-stefaniak & morrison, 2018) . according to the "prospect theory" (tversky & kahneman, 1992) , tourists are rational consumers who, when confronted with two different options, tend to choose the option that will bring them more potential gains and lower risk (seabra, kastenholz, abrantes, & reis, 2018) . when tourists perceive the existence of any risk of terrorism, they become more careful as they plan their travel and tend to adopt risk-reducing strategies (fuchs & reichel, 2011) . tourists are sensitive to terrorism threats and can be flexible in their destination choices (neumayer & plümper, 2016) , so they will avoid destinations they believe to be connected with that sort of threat (rittichainuwat & chakraborty, 2009 turning into a single market, which leads to the standardization of consumer lifestyles and the rising of "global consumers" (hollensen, 2011) . tourism is one of the most global economic activities and is, therefore, vulnerable to risks that affect any other global business (fennell, 2017) . the world has become interdependent and tourism crises in one part of the world can have strong repercussions on other locations (lanouar & goaied, 2019; ritchie, 2004) . when tourists realize that a destination is unsafe, they replace it with others they consider safer and, in doing so, may damage entire regions that are affected by violence or that tourists consider threatened by terrorism (beirman, 2003; gu & martin, 1992; lutz & lutz, 2018; mansfeld, 1996; sönmez, 1998) . this fact draws attention to the spatial patterns of terrorism impacts caused by spillover effect on destinations/regions (öcal & yildirim, 2010) . the topic of terrorism spillover effects has produced a considerable amount of literature (veréb, nobre, & farhangmehr, 2018) . the decline in tourists' arrivals and receipts caused by terrorism is well documented in several countries and regions since the 90s and has affected countries like spain (enders & sandler, 1991) , european countries ( (enders, sandler, & parise, 1992; radić, dragičević, & sotošek, 2018) , the mediterranean region (drakos & kutan, 2003) , non-democratic countries and africa (blomberg, hess, & orphanides, 2004) , the usa (bonham, edmonds, & mak, 2006; goodrich, 2002) , israel (eckstein & tsiddon, 2004; fleisher & buccola, 2002; morag, 2006; pizam & fleischer, 2002) , italy (greenbaum & hultquist, 2006) , nepal (baral, baral, & nigel, 2004) , ireland (o'connor, stafford, & gallagher, 2008) , fiji and kenya (fletcher & morakabati, 2008) , nigeria (adora, 2010) ; turkey (feridun, 2011; ozsoy & sahin, 2006) , pakistan (raza & jawaid, 2013) , the middle east (bassil, 2014) , the caribbean (lutz & lutz, 2018) , tunisia (lanouar & goaied, 2019) , and worlwide (liu & pratt, 2017; llorca-vivero, 2008; neumayer & plümper, 2016) . despite all past research conducted on the impacts of terrorism on tourism industry, and bearing in mind recent disturbing events, many sectors are calling for further in-depth analysis of this issue (almuhrzi, scott, & alroiyami, 2017; saha & yap, 2014) . people have to learn how to deal with the changes that this new global terrorism context is bringing to tourism (veréb et al., 2018) and it is crucial to find ways to cope with the disruption in tourist flows in the wake of terrorism events (cohen & cohen, 2012) . more investigation is required on the impact that terrorism may have on tourist arrivals and it will have to take into account the changes that are affecting the spatial patterns of tourism flows and, specifically, the spillover effects of terrorism (neumayer, 2004; prideaux, 2005) . while most empirical studies report the negative spillover effects on tourism demand and receipts caused by the substitution effect affecting countries and regions suffering from terrorism activity, there is no study, to our knowledge, dealing with the effects those events have on a safe country with no record of terrorism attacks. portugal is currently one of the most popular european tourist destinations (world tourism organization, 2018) and has no history of terrorist attacks ever (national consortium for the study of terrorism and responses to terrorism, 2019). the country is considered the third most peaceful country in the world by global peace index (institute for economics & peace, 2018) and clearly benefits from this safe tourist destination image. the main goal of this study is to analyze the influence that terrorist attacks carried out in a representative group of european countries can have on a safe country. this particular study will focus on portuguese tourism demand and will take into account the possible consequences of the so-called spillover effect, particularly the substitution and generalization effects. this paper begins with an outline of the current literature available on tourism consumer behavior regarding terrorism risk and the spillover effects caused by terror. the literature review was used to develop the study's conceptual framework. discussion on the research methodology was the next logical step. using a longitudinal study, this work uses an unrestricted vector autoregressive model to test the conceptual framework. arguments about theoretical and management implications are discussed in the last part of the article. the results of this study demonstrate the existence of the so-called substitution effect caused by terrorism events and add information to the existing literature about the spatial spillover effects of terrorism on tourism activity. it was also possible to create a tour-terror index allowing managers to observe the potential impacts of attacks on tourists' arrivals and receipts in different regions. the definition of terrorism is troublesome. according to previous research (lutz & lutz, 2018) terrorism is conceptualized, in the global terrorism database, as "the threatened or actual use of illegal force and violence by a non-state actor to attain a political, economic, religious, or social goal through fear, coercion, or intimidation" (national consortium for the study of terrorism and responses to terrorism, 2019). terrorism attacks generally "appear to be random and dispersed in order to create tension in the widest possible audience" (öcal & yildirim, 2010, p. 481) . tourism demand, as previously established, is particularly sensitive to terrorist attacks, since tourists' choices value safety, tranquility and peace (araña & león, 2008) . past research has repeatedly proved the strong exposure of tourism industry to terrorism and violence and showed that tourism is one of the economic sectors that are most vulnerable to this threat (araña & leon, 2008; avraham, 2015; lanouar & goaied, 2019; saha & yap, 2014) . several studies have proved its negative impacts on tourism activity as a whole in the short and long term (araña & león, 2008; baker, 2014; liu & pratt, 2017; pizam & smith, 2000; sönmez, 1998) . this is mainly because of the effects that terrorist threats have on tourists' decision-making process (neumayer, 2004; pizam & fleischer, 2002; ritchie, 2004; seabra, abrantes, & kastenholz, 2014; seabra et al., 2018; sönmez, apostolopoulos, & tarlow, 1999; sönmez & graefe, 1998) . safety is clearly one of tourists' main concerns. it is a basic human need. as such, it affects human behavior in general and consumer behavior in particular (isaac & velden, 2018) . when people travel, they do not want to feel exposed to situations that will threaten their integrity. tourists are concerned with travelling to a destination where they will be able to fulfill their desires with as little complications and threats to their safety as possible (seabra, dolnicar, abrantes, & kastenholz, 2013) . safety on vacation and leisure is an expected requirement for any visitor in any destination (baker, 2014) . therefore, stability is one of the key factors for the development of tourism industry (almuhrzi, scott, & alroiyami, 2017) . if some event disrupts this balance and causes a risk perception among tourists, it can have both a powerful and negative impact on demand. risk perception relates to the uncertainty of consequences and potential loss (dholakia, 2001) and is associated with a large number of factors that may influence tourists' decision making. since the first studies on leisure and travelling, seven types of risk perceptions have been considered (rohel & fesenmaier, 1992) : i) psychological: how travel will affect one's own self-image; ii) social: impacts on social image; iii) financial: the value of money; iv) time: the cost of the time wasted while planning and travelling; v) physical: impacts on physical and psychological wellbeing; vi) satisfaction: probability of experiencing some kind of dissatisfaction with the trip or one of its components; and vii) functional: associated with bad trip organization and malfunction of tourist equipment or transportation. those risks are associated with three travel dimensions: vacation risk, physical-equipment risk and destination risk. focusing specifically on the risk factors connected with tourism destinations, subsequent research drew attention to more specific issues such as: i) health: factors that may cause physical danger, injury or sickness (baker, 2014; jonas, mansfeld, paz, & potasman, 2011) ; ii) communication: language and communication barriers that may hinder the connections with locals or service providers (reisinger & mavondo, 2005) ; iii) natural disasters: the exposure to natural hazards (becken & hughey, 2013; pearlman & melnik, 2008) ; iv) crime: several forms of criminality and physical violence (brunt, mawby, & hambly, 2000; chesney-lind & lind, 1986; dimanche & leptic, 1999; michalko, 2004) ; v) political instability and violence (fletcher & morakabati, 2008; ioannides & apostolopoulos, 1999; saha & yap, 2014; sönmez, 1998; yap & saha, 2013) ; and vi) terrorism: probability of being involved in a terrorist attack (baker, 2014; lanouar & goaied, 2019; saha & yap, 2014; seabra et al., 2014) . terrorism and political instability are the threats that tourists fear the most (sönmez, 1998) . in fact, the younger generations rank "war, terrorism and political tension" as their top concerns (coca-stefaniak & morrison, 2018) . previous research reports that terrorism and political instability are "particularly intimidating risks due to the uncontrollable, involuntary and random nature of the potential harm involved in visiting destinations struck by such incidents" (kapuściński & richards, 2016, p. 235 ; see also cavleck, 2002; heng, 2006) . that way, the perceived risk of terrorism is more effective and will influence tourists' behaviors and decision-making, regardless of their country of origin or of their cultural background (seabra et al., 2018) . feridun (2011) suggests the existence of a negative causal effect of terrorism on tourism. raza and jawaid (2013) also proved the unidirectional causal relationship between terrorism and tourism. in their opinion, there is a unique direction of causality that goes from terrorism to tourism. the changes in tourists' decision making caused by perceived risks of terrorist attacks are mainly due to the so-called memory effect. memory effect means any feeling, apprehension, or panic that lead individuals to change their usual behaviors (shin, 2017) . people create a memory effect after experiencing or after hearing about devastating events that have occurred in a certain place. terrorist events can give rise to a great sensitivity between the tourists' initial memory of a destination andthe posterior image of such destination. this leaves a persistent recollection or memory effect (baggio & sainaghi, 2011) . past attacks directly influence tourist arrivals in the affected countries due to those negative memories. consequently, tourists will replace their usual leisure destinations with other places they consider safer (lutz & lutz, 2018) . eventually they will return to their favorite destinations and this is the reason why this memory effect is not permanent, although its effects may last for quite a long time as stated in previous research (baggio & sainaghi, 2011) . tourists show a high preference for more stable and peaceful geographic areas (araña & león, 2008; neumayer, 2004; reisinger & mavondo, 2005) since their main goal is to relax in an insouciant holiday environment (neumayer, 2004) . they have a big range of destinations available and, normally, they do not even consider travelling to places located near sites where risky incidents have occurred. they choose alternative destinations with similar characteristics but with a more stable environment (neumayer, 2004) . this has some negative economic impacts not only on the affected destinations (lanouar & goaied, 2019; sönmez et al., 1999) , but also on other nearby places. this is due to the spatial spillover effects (isaac & velden, 2018; walters & beirman, 2017 ) that will affect several destinations and entire regions (radić et al., 2018) . according to the institute for peace economics (institute for economics & peace, 2016), the contribution of the tourism sector to gross domestic product in 2015 was twice larger in countries where there had been no occurrence of terrorist attacks targeting tourists. between 2008 and 2014, tourism average contribution to gross domestic product growth reached 3.6% in countries that had experienced no terrorist attacks against tourists. in countries where attacks deliberately targeted tourists, it amounted to 1.9% only. nowadays, safety is one of tourists' major concerns when they have to choose their travel destination (world tourism organization, 2018). spatial spillover effects of terrorism on tourism activity: generalization and substitution effects spillover effect, a term which comes from economics, refers to the positive or negative externalities that an economic activity can have on any element not directly associated with that given activity. in tourism, spillover effects are closely related to a spatial perspective. it refers to the inadvertent effects that the tourism industry of a certain region has on tourism flows to other regions. positive spillover effects occur when a region benefits from their neighbors' tourism growth, while the opposite can occur when a destination is affected by negative factors occurred in neighboring regions (yang & wong, 2012) . previous research on the spillover effects found the existence of two major impacts of terrorism on tourism industry: the generalization and the substitution effects. the "generalization effect" refers to the cognitive biases of tourists who tend to generalize the perceived image of a given destination to a whole region (saha & yap, 2014) . the generalization effect may cause completely safe countries to witness strong drops in their tourism arrivals and revenues as a result of insecurity episodes in nearby countries (enders et al., 1992) . empirical evidence showed that perceptions of terrorist threats, war, political instability, and violence in one country tend to make tourists assume that entire regions are risky (sönmez, 1998; walters & beirman, 2017) . although some studies have shown that neighboring countries can sometimes benefit from being considered immediate substitutes, it has also been proved that there is always a negative impact on tourist demand in the region where the incident has occurred (gu & martin, 1992) . mansfeld (1996) proved that tourists who had experienced terrorist events during the arab-israeli conflicts transferred their fear of terrorism to the middle east as a whole. this spillover effect resulted in a negative contagion effect in that region but, on the other hand, had a positive impact on the tourist activity of the mediterranean area. neighboring countries, or countries that share identical characteristics, gain tourists in the same proportion as the less safe countries lose visitors. the different patterns of substitution that affect destinations are commonly represented by concentric rings. the "inner ring" that includes more unstable destinations like egypt, israel, jordan, lebanon, and syria was replaced by an "outer ring" composed of more peacefull and terrorism-free countries, such as cyprus, greece and turkey (mansfeld, 1996) . wahab (1996) drew attention to the fact that intraregional tourists may be more sensitive to this effect since they seek more peaceful destinations located near places considered to be of higher risk. in his study, he claimed the existence of a positive spillover effect in the case of egypt. however, an interregional tourist may also generalize conflict to an entire region, which may explain the decline in tourist arrivals in iraq's neighboring countries during the gulf war (sönmez, 1998) . during that period, middle east and eastern mediterranean countries experienced a big decline in tourist arrivals. cyprus, for example, experienced a drop of 3.38 million visitors in 1990 and of 2.94 million in 1991 as a result of the perceived risk of terrorism and political instability (goodrich, 2002) . drakos and kutan (2003) stated that any terrorist or violence event taking place in a particular middle eastern and north african destination will naturally affect tourist's perceptions of another country in that region (drakos & kutan, 2003) . some years later, kozak and his colleagues also concluded that tourists form overall negative images of entire regions due to terrorism acts (north america and the middle east), health issues (severe acute respiratory syndrome in asia) and political conflicts (africa). tourists change their travel plans when they realize the existence of any potential threat or risk. they assume that incidents that take place in a specific country will affect its neighboring countries as well. this assumption results in a global devastating impact on the region (kozak, crotts, & law, 2007) . recently, more empirical evidence supported findings that random terrorism acts perpetrated in some countries have an impact on nearby areas not directly subject to such attacks. this was true for kenya, africa (masinde, buigut, & mung'atu, 2016) and jordan because the violent uprisings in neighboring countries have deeply affected the image of the whole geographic area (liu, schroeder, pennington-gray, & farajat, 2016) . the "substitution effect" in tourism refers to customers' tendency to replace one destination with another, due to a number of factors that include changes in the elasticity of demand, shifts in price, a desire to try new products or experiences (tribe, 1995) or because of risk perception (prideaux, 2005) . using an unrestricted vector autoregressive model to analyze monthly data for spain covering a period of time between 1970 and 1988, enders and sandler (1991) identified negative unidirectional causality between terrorism attacks perpetrated by the separatist basque group eta and tourism activity in the country. the authors concluded that the biggest drop in tourists' arrivals occurred three months after the attacks and that a typical transnational terrorist incident can prevent about 1400 tourists from visiting a certain country (enders & sandler, 1991) . enders et al. (1992) , a year later, studied a large sample of european countries between 1974 and 1988 and determined that tourism reactions occurred mostly within a period of six to nine months after the incident and that there was clear evidence of the replacement of those destinations with others located in different regions (enders et al., 1992) . gu and martin (1992) analyzed the substitution effect based on tourist arrivals at orlando airport between 1971 and 1984. the authors concluded that there was a direct correlation between the increase in terrorist attacks in the middle east and in europe and the number of arrivals recorded at that airport (gu & martin, 1992) . during their analysis conducted on three mediterranean countries -greece, israel and turkey -, using italy as a control variable, drakos and kutan (2003) tested the cross-country effects of terrorism on tourism in the mediterranean region between 1991 and 2000. they concluded that the intensity of terrorism events, measured according to the location (urban vs rural) and the number of fatal casualties, led to shifts in tourist visits that caused positive and negative spillover. the country where the attack took place registered drops in tourist arrivals, while other nearby countries experienced an increase in their visitors. their empirical results revealed that israeli and turkish tourism industries are more sensitive to terrorism than their greek counterpart (drakos & kutan, 2003) . a study conducted on tourism flows after 9/11 in the united states and in hawaii reinforced the findings of earlier studies that showed the existence of that substitution effect. tourists change their travel plans instead of canceling them, giving priority to safer domestic destinations they perceive as less risky. the study results indicate that united states citizens replaced international destinations with hawaii balancing the significant drop of foreign arrivals that followed the 9/11 events (bonham et al., 2006) . focusing on the same period, araña and león (2008) used a discrete choice approach to assess the impact those worldwide events had on the way tourists evaluate the qualities of alternative and competing destinations located in the mediterranean area. the authors concluded that countries with higher proportion of islamic population, such as tunisia and turkey, suffered a more severe negative impact on their competitive value than other destinations, such as canary islands and the balearics, where this proportion was lower (araña & león, 2008) . using two estimation techniques, neumayer (2004) tested the impact of various forms of political violence on tourism. the cross-country analysis provides empirical evidence for intraregional, negative spillover and cross-regional substitution effects for countries where human rights are violated or where there is evidence of conflicts and other politically motivated violent events. the author concluded that tourists choose alternative destinations with similar characteristics but that are more stable (neumayer, 2004) . while examining the effects of terrorism on tourism activity in turkey, yaya (2009) found strong evidence that terrorism events in the country have affected the industry and that the madrid bombings had a positive effect on tourist arrivals in turkey. this happened because tourists perceive those two countries as close substitutes for one another (yaya, 2009) . other studies concluded that while some countries experience a negative indirect effect, terrorist attacks increase tourism demand in other neighboring countries that are known for their low or moderate risk level (saha & yap, 2014) . this is the case of dubai, for instance, that represents a safe regional alternative to lebanon or syria, two former popular tourism destinations destroyed by war (clancy, 2012) . a study dealing with the reactions of german tourists to unanticipated shocks and the respective impacts on risk perception and tourism destination selection analyzed several terrorism episodes: 9/11 (2001), egypt (1997), tunisia (2002), morocco (2003) and indonesia (2003) . the findings proved that those shocks heavily affected islamic countries and provided a temporary substitution effect in favor of (southern) european countries (ahlfeldt, franke, & maennig, 2015) . neumayer and plümper (2016) apply a model to explain tourists' arrivals using a lagged dependent variable and other lagged independent variables representing terrorist attacks proxies. using a spatial dyadic approach, the authors concluded that terrorist attacks on tourist destinations in a given country reduce tourist flows due to a substitution effect that is visible at several levels: i) from the countries in which the attacks took place and other similar source markets to a different destination or country; and ii) from the same tourism source market to other similar destinations (neumayer & plümper, 2016) . as stated, to this day there has been no record of terrorist events in portugal. other european countries such as luxembourg, monaco, lithuania, andorra, malta, montenegro, san marino, and slovenia are safe countries as well. however, none of these countries kept a record of tourism arrivals or receipts. with a large international recognition and several tourism awards granted to its many regions, cities and destinations, portugal has been one of the countries with the best performances in tourism. the country has experienced an average annual growth of 11% in tourists' arrivals since 2010 (world tourism organization, 2018) . in 2017, portugal received > 14.5 million international tourists and 9.3 million domestic tourists. the arrivals had a massive impact on tourism receipts that have been growing in a sustained way over these last few years and amounted to > 17 billion american dollars in 2017 (instituto nacional de estatística, 2019; world tourism organization, 2018). this growth is directly connected to the strategic positioning of the "destination portugal" brand that, in recent years, has brought portugal and other specific portuguese destinations several international awards. over the last years, portugal has won several international awards at the world travel awards: i) portugal "world's best tourist destination" (for the 3rd year in a row); (ii) lisbon "world's best citybreak destination"; iii) madeira "the best insular destination" (for the 4th year in a row); iv) sintra-monte da lua parks "the best example of heritage recovery"; v) portugal "the best european and world golf destination" (for the 5th year in a row); vi) "turismo de portugal" considered the world's best tourism organization, among many others. the image of portugal as a safe tourism destination has led to an exponential increase in tourist arrivals. in fact, portugal was the third safest country in the world in 2017 (institute for economics & peace, 2018) and is currently a huge european tourist attraction. portugal was the country chosen for this study because of its importance and potential and especially because it is regarded as a safe country with no record of terrorist events since ever. in the next subsections, sample and data will be presented. data includes tourists' arrivals in portugal, sorted by region of origin, and the number of terrorist attacks that have occurred in the selected european countries, from 2002 to the end of 2016. the main database that supports this study was built upon two different time series sub-databases: i) tourism arrivals in portugal between 2002 and 2016 and ii) the terrorism events occurred worldwide during the same time period. the first sub-database was obtained from the portuguese public statistical entity (instituto nacional de estatística, 2019). data provided information about the number of tourists who stayed in any accommodation facility in portugal, between 2002 and the end of 2016, sorted by region of origin. a reasonable medium-term time series is required if the analysis applies lagged variables (bell & jones, 2015) to achieve significant results. the number of guests has significantly increased, surpassing 21 million tourists in 2016 (see fig. 1 ). the compound annual growth rate from 2002 to 2016 was 4.78%, and the number of tourists doubled during that period. over the last 5 years, tourists coming from europe have exceeded the number of domestic tourists. these results reveal the increasing dynamics of the portuguese tourist sector and reflect the country's good and stable political, economic, and social environment. data collected regarding tourists' arrivals included all contributing countries and showed that the most representative emission markets in portugal are: europethe united kingdom, spain, france, and germany; africa -angola; america -brazil, the united states, and canada; asia -china and japan (instituto nacional de estatística, 2019). the second sub-database, obtained from global terrorism database (national consortium for the study of terrorism and responses to terrorism, 2019), gathers information about terrorist attacks per country and other aggregate geographic areas between 2002 and 2016 (see table 1 ). terrorist attacks, according to global terrorism database, are violent incidents triggered by bombing or explosion, arm attacks, assassination, and facility/infrastructure attack caused by terrorist organizations or individuals in a domestic c. seabra, et al. annals of tourism research 80 (2020) 102811 as well as in a transnational and international context. for each global terrorism database incident, information is provided on the date and location of the incident, the weapons used and the nature of the target, the number of casualties, and, when identifiable, the group or individual responsible for the attack (national consortium for the study of terrorism and responses to terrorism, 2019). table 1 provides information about the number of terrorist attacks sorted by country, considering also the injuries and fatalities caused by the events. the main criterion to select the considered countries was the number of terrorist attacks they have experienced between 2005 and 2016. the selected countries represent the biggest terrorist targets for each european region, as seen in table 1 (highlighted in light gray). however, some representative countries were selected to avoid multicollinearity. those were countries with the highest rate of terrorist attacks and that had some potential connection with portugal (social, economic or tourist connections). the importance of those countries as emissive markets was also taken into consideration. keeping in mind the tourism regions considered by world tourism organization (world tourism organization, 2018), the sample includes the united kingdom, for northern europe; the western europe sample includes france and germany; the central/eastern europe sample incorporates russia -russia and ukraine attacks are highly correlated, so this tourism market was an obvious choiceand lastly israel, greece, and spain were part of the southern/mediterranean europe sample. israel was chosen over turkey considering that turkey is strongly correlated with germany that represents an important tourist market for portugal. in addition to being the countries with a higher incidence of terrorist attacks, france, england, germany, greece, and spain are countries that, along with portugal, belong to the european union. they also have ancient and strong foreign commercial relations with portugal (base de dados portugal contemporâneo, 2019a). the first three countries considered are destinations chosen by many portuguese emigrants. therefore, strong communities have been created over the years and strong social relationships were established between different generations of families living both in their home countries and in the different host countries (base de dados portugal contemporâneo, 2019b). those are, furthermore, the most relevant emission markets to portugal. as for central/eastern europe, russia was the country that registered the higher number of attacks. portuguese relationships with russia date back to 1739 (russian federation, 2019) and those relationships are strengthened by commercial links (oil and gas imports) (belyi, 2003) . currently, a large number of russian tourists choose portugal as their tourism destination. they represent an important asset for tourism due to their number and to their high purchasing power. as far as the south /mediterranean region is concerned israel is, along with spain and greece, the country that has experienced more terrorist attacks. portugal established diplomatic relations with israel in 1977 and those relations were reinforced in 1992 with the signing of cultural, economic, industrial, technical, and scientific cooperation agreements (república portuguesa, 2019). the main goal of this study is to analyze the potential connections between terrorist attacks in specific european countries and tourist arrivals in portugal. the countries' political and economic stability, safety and security can be advantages that may attract tourists who have proven to be loyal to destinations that have recently been targeted by terrorist attacks. this study follows the procedure applied by neumayer and plümper (2016) when they used lagged dependent variables. the information about the number of terrorist attacks occurred in a certain country was also taken into account to provide an explanation on tourist arrivals per country of origin. the conceptual autoregressive model has two distinctive independent variables' groups. (1) one is related with the one-lag period and the two-lag period of the first differences (t -t −1 period) of the dependent variable values tourist arrivals from any continent or an autoregressive variable. the second, (2) is related with the first differences (t -t −1 period) of the one-lag period values of attacks perpetrated against the 7 selected countries, as described in fig. 2 . then, evidence was collected to prove that all the series were non-stationary at levels (time periods) using kendall's tau statistic indicator, also known as dickey-fuller test (gujarati, 2009 ). ordinary least squares cannot be trusted because they may cause 21 58 5 28 9 22 47 23 66 55 86 165 141 192 139 1057 1179 6 76 77 sweden 0 0 0 3 1 0 1 1 3 1 2 0 5 36 16 69 8 5 united kingdom 21 23 5 25 6 20 39 22 57 47 54 137 103 114 104 777 1033 84 western europe 40 13 14 36 39 23 24 18 5 22 70 14 31 103 83 535 1515 greece 11 12 4 6 23 15 53 115 49 11 22 53 26 31 31 462 56 76 israel 75 38 19 43 77 53 134 36 14 51 65 37 293 58 50 1043 3511 814 italy 7 15 3 6 4 41 21 31 24 23 11 37 21 3 0 1 5 4 1 3 226 2132 238 turkey 5 19 27 41 40 29 32 13 20 51 169 42 94 421 540 1543 6507 2159 310 268 155 260 282 215 563 425 436 399 604 496 1572 1501 spurious (non-sense) regressions. therefore, differencing the series to make them stationary can be a solution, but it could cause the loss of important long run relationships between levels (gujarati, 2009 ). co-integration tests were also performed and led to negative results. thus, and in accordance with previous works, it became clear that an unrestricted vector autoregressive model, using first difference variables would be the best solution (esso, 2010; gospodinov & pesavento, 2013; toda & yamamoto, 1995) to resolve potential non-stationarity series problems (shin, 2017) . the unrestricted vector autoregressive model method resembles simultaneous-equation modeling as it considers several endogenous variables together. nevertheless, each endogenous variable is explained by its lagged values or past lagged values. the first difference between the variables and their respective lagged values were used towards non-co-integration and non-stationarity at levels (statacorp, 2013) . the unrestricted vector autoregressive model assumed that all the attacks against the respective countries were exogenous variables in the model. it also considered that there were no or few relationships among them and that the aim would be to study one-way causality relationship between attacks and tourists' arrivals in portugal and not the opposite. since there may be a time lag (one or two-year delay effect) in the impact caused by the terrorist attacks on tourists' arrivals, this study opts to use a one period and a two-period time lag. the study also includes post estimation robustness tests for autocorrelation (lagrange-multiplier test) (statacorp, 2013) and residual distribution tests, like the jarque-bera test (lutkepohl, 2005) . fig. 2 shows the specification models used in the estimation. a granger causality test is used (asteriou & hall, 2015; zivot & wang, 2007) , suggesting that there is short run causality between the significant independent variables and the dependent variable. tourists' arrivals are an endogenous variable because its value is determined within the model. the terrorists' attacks against countries are exogenous variables, since their value is determined outside the model. in other words, they do not depend on tourist arrivals. there is no correlation between terrorist attacks and the error term whose data represents relevant input to the model. the objective of the analysis is to use terrorists' attacks as determinant variables. this is in line with the methodology used by neumayer and plümper (2016) in which terrorist attacks are exogenous variables that explain the arrivals of western tourists to islamic countries. table 2 demonstrates the descriptive statistics of all variables and table 3 shows the results of the model. data clearly suggests that tourists' arrivals from any country to portugal reflect the impact of a certain memory effect. hence, the first difference of the lagged autoregressive variable is statistically significant with a 0.1% alpha for every equation. the granger causality test applied to the model, and to its respective sub models, one for each dependent variable, demonstrates the existence of unidirectional causal relationship between terrorist attacks and tourist arrivals in this country. the second autoregressive lagged dependent variable has an important impact on tourist arrivals from portugal, europe, africa, and america, but, in contrast, exerts negative impact on the addition of more tourists. tourist arrivals from asia are positively related with the attacks perpetrated in greece, france and in the united kingdom; however, attacks perpetrated in spain move those specific tourists away from portugal and force them to look for other destinations. portuguese domestic tourists appear to be more sensitive to attacks committed in france, spain, and greece. in this case, there is a positive correlation, even if in the case of spain, the level of significance is slightly over 5%. terrorist attacks perpetrated in israel, the united kingdom, greece, germany, and france directly influence tourist arrivals from europe. in contrast, terrorist attacks perpetrated in spain and russia contribute to dislocate tourists from portugal to other regions. all variables are significant at the 0.1% level. even though there is evidence that all variables concerning tourists from africa are significant at the 0.1% level, the coefficient direction changes in the case of israel, russia, spain, and greece. in fact, only terrorist attacks that took place in israel and greece affect negatively tourist arrivals from africa in portugal, while attacks perpetrated in other countries positively influence arrivals in the country. as far as tourists from america are concerned, it seems that attacks in russia, israel and spain move them away from portugal and force them to choose other destinations, while attacks in france, germany and greece bring those tourists to portugal. tourists from oceania are negatively sensitive to attacks committed in russia and spain. a phenomenon that involves extremely sensitive reaction to terrorist attacks makes tourists replace a destination with other safer countries. post estimation tests to the models revealed the absence of auto-correlation after using the lagrange multiplier test, as null hypothesis of zero autocorrelation could not be rejected and as the null hypothesis under jarque-bera statistic of residuals' normality (statacorp, 2013) could not be rejected either. despite the importance granted to the effects of terrorism on tourism and in spite of a considerable amount of research conducted on such issue, there have been recent calls for new research on the topic, especially on the consequences that this phenomenon can exert on economy and tourism activity (almuhrzi, scott, & alroiyami, 2017; saha & yap, 2014) . this paper represents an effort to close this gap by establishing the connections between terrorist events in some regions and tourist arrivals in other regions. the study takes into account previous literature on spillover effects, specifically those that trigger the substitution and generalization effects that make tourists reject and replace destinations considered unsafe with others they consider safer (gu & martin, 1992; neumayer, 2004) . whereas past research analyzes terrorism negative spillover effects on tourism demand, the present study focuses on the effects that terrorism events have on the tourists' arrivals in a safe country that has no record of terrorism attacks. portugal is one of the european tourism destinations that have experienced a higher growth in tourism demand and receipts over the last decades. according to the institute for economics and peace, portugal is one of the world's most peaceful countries (institute for economics & peace, 2018) and has no record of terrorism events (national consortium for the study of terrorism and responses to terrorism, note: + p < 0,1; * p < .05; ** p < .01; *** p < .001; d first difference; l, l2 lags of respective variable; first number in the table is the variable coefficient and the second one in the same column is the z statistics. these are the significant values c. seabra, et al. annals of tourism research 80 (2020) 102811 2019). the present study demonstrates that terrorist attacks in other countries have an impact on the demand for portuguese tourist accommodations. in turn, the results also show that instability in other countries can have consequences for portuguese tourism arrivals confirming the existence of spillover effect. as far as the effects of terrorist attacks on tourists' arrivals in portugal are concerned, this study allowed the uncovering of interesting results. terrorist events perpetrated in the united kingdom, greece, and france positively affect tourist arrivals from asia. attacks perpetrated in spain, on the contrary, have a negative contribution to tourists' arrivals from asia. in the cases of france and greece, this occurs probably because they are both mediterranean destinations similar to portugal. this result confirms the existence of the substitution effect as well as the presence of the generalization effect (mansfeld, 1996) . asian countries have a strong historic, economic and even social connection with the united kingdom. natives of those countries are well aware of the attacks committed in the united kingdom through media coverage or through personal information provided by emigrants residing in the country. on the other hand, for asian tourists, spain and portugal belong to the same iberian territory since they are located in the same geographical and risk area. this belief confirms the existence of the generalization effect (enders & sandler, 1991) . terrorist attacks in france, greece and spain strongly affect portuguese domestic tourism. these are important tourism destinations to portuguese tourists. these results confirm earlier research on unsafety effects and prove that during unsafety times tourists do not stop travelling; alternatively, they choose domestic destinations they consider much safer (bonham et al., 2006) . terrorist events perpetrated in the united kingdom, france, germany, greece, and israel positively affect tourist arrivals in portugal from european countries. on the other hand, terrorist attacks occurred in russia and spain exert a negative impact on tourists' arrivals from europe. this happens possibly because those countries are geographically located in the center of europe. accordingly, european tourists will choose peripheral countries. this assumption is in accordance with the results obtained by mansfeld (1996) . the united kingdom, france and germany are also important emissive markets to portugal. that means that tourists who come from those parts of the world can feel safer in portugal than in their own countries. since they are intraregional tourists, they have enough information to know which countries are the safest (wahab, 1996) . in the cases of tourist destination such as greece or israel, the substitution effect involves portugal, probably because the three markets share the same emissive tourist markets. spain and portugal are neighboring countries. terrorist attacks in spain have severe impacts on tourists who come to portugal from asia, oceania, america, and from other european countries. however, tourists coming from africa, namely from angola, a portuguese-speaking african country (palop) and member of the community of portuguese speaking countries (cplp), or from portugal are unbiased and, thus, do not feel that effect. for those tourists, spain and portugal are two different and unrelated nations, even though they are both iberian countries. the overall findings show the existence of the so-called generalization effect (drakos & kutan, 2003; enders et al., 1992; kozak et al., 2007; liu et al., 2016; masinde et al., 2016) : a safe country like portugal with no terrorist events can suffer from the impact of episodes of insecurity that took place in spain, a neighboring country. such impact will affect tourism demand. moreover, this work confirms that the generalization effect that over-assumes the similarities of neighboring countries enhances the causal relationship between terrorist attacks and tourist arrivals (feridun, 2011; raza & jawaid, 2013) . the attacks perpetrated in russia do not produce changes in the destination choices of tourists coming from european traditional markets and tourists remain faithful to traditional destinations like spain, france, italy, greece, and tunisia, among others. in consequence, there is a decrease in tourists' arrivals in portugal. the attacks committed in the united kingdom, russia, spain, france, and in germany have a positive impact on the increase in tourists from africa who choose portugal as their destination. on the other hand, terrorist incidents in greece and israel seem to have a negative impact on their choice. these results may be due to the cultural and economic proximity of most african countries and specifically of angola, which is portugal's most important african market. terrorist attacks in greece and israel are responsible for the decrease in african tourists' arrivals, probably because instead of coming to portugal they rather choose high level shopping tourism destinations such as italy, france, the united kingdom, and germany. terrorism in greece, germany, and france positively affects tourist arrivals from america, while terrorist events occurred in israel, russia and spain will have a negative effect on the number of american tourists who choose portugal as their destination. the substitution effect is, once again, clear as far as greece is concerned since that destination is quite similar to portugal. germany and france are important markets for brazilian, north american and canadian tourists. however, due to the attacks in germany and france, those tourists decide to come to portugal instead. tourists from america are well aware of the repeated and regular instability and unsafety felt in russia and israel, so any negative event in those countries will force them to choose other traditional or domestic destinations. these findings are in close accordance with previous research conducted by pizam and fleischer (2002) . the influence of the memory effect is clear when past tourist arrivals influence current tourist arrivals. this occurs in all the models except in the case of tourist arrivals from oceania. this means people want to relive pleasant past experiences and return to destinations where they had spent enjoyable moments. this positive feeling reinforces the role played by memory effect when time comes to choose a destination. therefore, the present study reinforces the work carried out by baggio and sainaghi (2011) . asian, european, african, american, and portuguese tourists' experiences in portugal will have a strong and positive impact on the flow of tourists who will choose to visit the country in the coming years. this paper provides a number of theoretical contributions to tourism literature and helps explain the factors that may influence tourist flows. evidence collected show that tourist arrivals and the demand for tourist accommodation depend on international markets and, more specifically, on the existence of terrorist attacks in other countries. these assumptions confirm the existence of c. seabra, et al. annals of tourism research 80 (2020) 102811 "global consumers" (hollensen, 2011) . this study clearly demonstrates the existence of the so-called substitution effect caused by terrorism events. tourists choose destinations perceived as safer instead of places they see as potential terrorist targets, as stated in previous studies (e.g. ahlfeldt et al., 2015; araña & león, 2008; bonham et al., 2006; drakos & kutan, 2003; enders et al., 1992; enders & sandler, 1991; gu & martin, 1992; neumayer, 2004; neumayer & plümper, 2016; yaya, 2009 ). secondly, it was possible to confirm the existence of a one-year consumer short memory effect. the increase in tourist arrivals recorded during a certain year-long period has a direct impact on the increase of tourist arrivals that will occur in the following years. this result may be related with the positive image created by tourists' word of mouth or through the repetition effect. however, a longer, two-year memory effect shows different results. tourist arrivals from portugal, europe, africa, and america in a two-year lag reveal an opposite impact on the arrival of tourists in portuguese destinations, confirming the findings of the study conducted by enders and sandler (1991) . this study also contributes to add information to the existing literature that analyzes the effect of terrorist attacks on tourist arrivals according to their geographical origin. the results unveiled by this study allow public and private tourism organizations to create new predictive models or to update those already in motion, by adding new variables to improve their efficiency and increase the knowledge needed to understand and anticipate international tourist behaviors, specifically those that are related with the existence of terrorist attacks in other european regions. moreover, using the theoretical background provided by this paper, it was possible to create an index -tour-terror -that allows managers to observe the potential impacts of attacks perpetrated in a given region on the economy of recipient countries and that will lead to an increase or to a decrease in tourist arrivals. those fluctuations are related with the tourists' characteristics such as their cultural, social, and economic origin. these features may differ from the residents' usual standards but also from those of the average tourist who usually visits the country. accordingly, the tour-terror index determinants of a country may include independent variables like: i) the level of change in tourism demand and supply due to terrorist attacks; ii) the tourist price level structure; iii) tourists' purchasing power parity; iv) the duration of the stay; v) tourist accommodation capacity; vi) the capacity of other related facilities; and vii) human labor capacity. managers should face the fact that terrorist attacks provoke a substitution effect on destination choice behaviors. tourists will replace destinations considered unsafe due to terrorist threats with others considered safer. the physical distance of the tourists' home countries and their cultural and socio-economic traits influence this replacement behavior. in addition, managers must take into account that the substitution effect occurs between the european countries located in central areas and those located in peripheral areas. when terrorist attacks occur in the center of europe, tourists avoid those regions and choose peripheral destinations like portugal. evidence also made it clear that the opposite effect also happens. given the randomness of terrorist attacks, tourism managers should be prepared to alter quickly their marketing strategy, namely their market targeting strategies and promotion campaigns to prevent substitution effect. these specific practical implications are particularly important to tourist companies located in portugal. tourists from angola, brazil, the united states, and canada have proven to be very profitable since they stay longer and purchase high level and luxury products. for that reason, portuguese companies should make them their main target. the first limitation refers to the research settings, namely the fact that the study only considers one country and a 15-year time lag. more countries or bigger regions and a longer 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effects in tourism flows do political instability, terrorism, and corruption have deterring effects on tourism development even in the presence of unesco heritage? a crosscountry panel estimate terrorism and tourism: the case of turkey vector autoregressive models for multivariate time series she is doing her post-phd on "terrorism and the eu28: impact on citizens and organizations" in novasbe. her research interests are: 1) safety and terrorism, and 2) tourism. email: cseabra@uc pedro reis is a professor at polytechnic institute of viseu. pedro develops his research in: 1) finance, 2) accounting josé luís abrantes develops his research in: 1) marketing, 2) tourism, and 3) pedagogy key: cord-168710-a5pst4gf authors: jalilian, abdollah; mateu, jorge title: a hierarchical spatio-temporal model to analyze relative risk variations of covid-19: a focus on spain, italy and germany date: 2020-09-28 journal: nan doi: nan sha: doc_id: 168710 cord_uid: a5pst4gf the novel coronavirus disease (covid-19) has spread rapidly across the world in a short period of time and with a heterogeneous pattern. understanding the underlying temporal and spatial dynamics in the spread of covid-19 can result in informed and timely public health policies. in this paper, we use a spatio-temporal stochastic model to explain the temporal and spatial variations in the daily number of new confirmed cases in spain, italy and germany from late february to mid september 2020. using a hierarchical bayesian framework, we found that the temporal trend of the epidemic in the three countries rapidly reached their peaks and slowly started to decline at the beginning of april and then increased and reached their second maximum in august. however decline and increase of the temporal trend seems to be sharper in spain and smoother in germany. the spatial heterogeneity of the relative risk of covid-19 in spain is also more pronounced than italy and germany. started from wuhan, the capital of hubei province, china in december 2019, the outbreak of 2019 novel coronavirus disease has spread rapidly across more than 200 countries, areas or territories in a short period of time with so far over 4.4 million confirmed cases and 296 thousand confirmed deaths (world health organization, 2020) . the spread of covid-19 across and within countries has not followed a homogeneous pattern (giuliani et al., 2020) . the causes of this heterogeneity are not yet clearly identified, but different countries have different levels of national capacity based on their abilities in prevention, detection, response strategies, enabling function, and operational readiness (kandel et al., 2020) . besides, different countries have implemented different levels of rigorous quarantine and control measures to prevent and contain the epidemic, which affect the population movement and hence the spread pattern of covid-19. given the highly contagious nature of covid-19, the spatial pattern of the spread of the disease changes rapidly over time. thus, understanding the spatio-temporal dynamics of the spread of covid-19 in different countries is undoubtedly critical. the spatial or geographical distribution of relative location of incidence (new cases) of covid-19 in a country is important in the analyses of the disease risk across the country. in disease mapping studies, the spatial domain of interest is partitioned into a number of contiguous smaller areas, usually defined by administrative divisions such as provinces, counties, municipalities, towns or census tracts, and the aim of the study is to estimate the relative risk of each area at different times (lee, 2011; lawson, 2018) . spatio-temporal models are then required to explain and predict the evolution of incidence and risk of the disease in both space and time simultaneously (anderson and ryan, 2017) . estimation of area-specific risks over time provides information on the disease burden in specific areas and identifies areas with elevated risk levels (hot spots). in addition, identifying the changes in the spatial patterns of the disease risk over time may result in detecting either regional or global trends, and contributes to make informed and timely public health resource allocation (wakefield, 2007) . to account for the underlying temporal and spatial autocorrelation structure in the spread of covid-19, available data on the daily number of new cases and deaths in different countries/regions have already been analyzed in a considerable number of studies. for example, kang et al. (2020) used moran's i spatial statistic with various definitions of neighbors and observed a significant spatial association of covid-19 in daily number of new cases in provinces of mainland china. gayawan et al. (2020) used a zero-inflated poisson model for the daily number of new covid-19 cases in the african continent and found that the pandemic varies geographically across africa with notable high incidence in neighboring countries. briz-redón and serrano-aroca (2020) conducted a spatio-temporal analysis for exploring the effect of daily temperature on the accumulated number of covid-19 cases in the provinces of spain. they found no evidence suggesting a relationship between the temperature and the prevalence of covid-19 in spain. gross et al. (2020) studied the spatio-temporal spread of covid-19 in china and compare it to other global regions and concluded that human mobility/migration from hubei and the spread of covid-19 are highly related. danon et al. (2020) combined 2011 census data to capture population sizes and population movement in england and wales with parameter estimates from the outbreak in china and found that the covid-19 outbreak is going to peak around 4 months after the start of person-to-person transmission. using linear regression, multilayer perceptron and vector autoregression, sujath et al. (2020) modeled and forecasted the spread of covid-19 cases in india. as pointed out in alamo et al. (2020) , there are many national and international organizations that provide open data on the number of confirmed cases and deaths. however, these data often suffer from incompleteness and inaccuracy, which are considerable limitations for any analyses and modeling conducted on the available data on covid-19 (langousis and carsteanu, 2020) . we highlight that we are yet in the center of the pandemic crisis and due to the public health problem, and also to the severe economical situation, we do not have access to all sources of data. thus reseachers know only a portion of all the elements related to covid-19. in addition, data on many relevant variables such as population movement and interaction and the impact of quarantine and social distancing policies are not either available or accurately measured. combined with the unknown nature of the new covid-19 virus, any analysis such as the present study only provides an approximate and imprecise description of the underlying spatio-temporal dynamic of the pandemic. nevertheless, having a vague idea is better than having no idea, and the results should be interpreted with caution. currently, a wealth of studies have appeared in the very recent literature. many of them follow the compartmental models in epidemiology, partition the population into subpopulations (compartments) of susceptible (s), exposed (e), infectious (i) and recovered (r), and fit several variations of the classical deterministic sir and seir epidemiological models (peng et al., 2020; roda et al., 2020; bastos and cajueiro, 2020) . we believe that considering stochastic components is important, if not essential, to explain the complexity and heterogeneity of the spread of covid-19 over time and space. for this reason, in the present work we propose a spatio-temporal stochastic modeling approach that is able to account for the spatial, temporal and interactions effects, together with possible deterministic covariates. we acknowledge that the proposed model in its current form requires development and refinements as more information becomes available, but at the stage of the pandemic we are now, it can provide a reasonable modeling framework for the spatio-temporal spread of covid-19. this is illustrated by modeling the daily number of new confirmed cases in spain, italy and germany from late february to mid august 2020. the r code for implementing the proposed model can be made available upon request. we also provide a shiny web application (chang et al., 2020 ) based on the model discussed in this paper at https://ajalilian.shinyapps.io/shinyapp/. the structure of the paper is the following. the open data resources used in this study are introduced in section 2. a model for the daily number of regional cases is considered in section 3. as described in section 4, this model explains the spatio-temporal variations in the relative risk of each country in terms of a number of temporal, spatial and spatio-temporal random effects. the results of fitting the considered model to the number of daily confirmed cases in spain, italy and germany are given in section 5. the paper concludes in section 6 with a few last remarks. governmental and non-governmental organizations across the world are collecting and reporting regional, national and global data on the daily number of confirmed cases, deaths and recovered patients and provide open data resources. incompleteness, inconsistency, inaccuracy and ambiguity of these open data are among limitations of any analysis, modeling and forecasting based on the data (alamo et al., 2020) . particularly, the number of cases mainly consist of cases confirmed by a laboratory test and do not include infected asymptomatic cases and infected symptomatic cases without a positive laboratory test. in this study, we focus on the daily number of confirmed cases in spain, italy and germany and used the following open data resources. italy: data on the daily accumulated number of confirmed cases in the 20 regions of italy are reported by the civil protection department (dipartimento della protezione civile), a national organization in italy that deals with the prediction, prevention and management of emergency events. these data are available at the github repository https://github.com/ pcm-dpc/covid-19 and are being constantly updated every day at 18:00. germany: the robert koch institute, a federal government agency and research institute responsible for disease control and prevention, collects data and publishes official daily situation reports on covid-19 in germany. data on the daily accumulated number of confirmed cases in the 16 federal states of germany extracted from the situation reports of the robert koch institute are available at the github repository https: //github.com/jgehrcke/covid-19-germany-gae and are being updated on a daily basis. table 1 summarizes the number of regions, study period and country-wide daily incidence rate of the data for each country. data on distribution population of the considered countries are extracted from the gridded population of the world, version 4 (gpwv4), which provides estimates of the number of persons per pixel (1 degree resolution) for the year 2020 (center international earth science information network (ciesin) columbia university, 2018). these data are consistent with national censuses and population registers. 3 modeling daily regional counts suppose that a country, the spatial domain of interest, is partitioned into regions a 1 , . . . , a m , defined by administrative divisions such as states, provinces, counties, etc (see table 1 ). let y it denote the number of new covid-19 cases in region the expected number of new cases is given by e it = p i it , where p i is the population of region a i and it is the incidence rate of covid-19 in region a i at time t. under the null model of spatial and temporal homogeneity of the incidence rate it = 0 and provides an estimate for e it , where is an estimate of the country-wide homogeneous daily incidence rate (waller et al., 1997) . the estimated daily incidence rate per million population (10 6 0 ) so far is around 68, 46 and 29 for spain, italy and germany, respectively (see table 1 ). 3.2 distribution of daily regional counts consul and jain (1973) introduced a generalization of the poisson distribution, which is a suitable model to most unimodal or reverse j-shaped counting distributions. given nonnegative random rates λ it , i = 1, . . . , m, t = 1, . . . , t , we assume that y it 's are independent random variables following the generalized poisson distribution with and the parameterization (zamani and ismail, 2012 ) thus ϕ is the dispersion parameter and the case ϕ = 0 represents the ordinary poisson distribution (no dispersion) with here, parameter α controls the shape (power) of the relation between the conditional variance of y it |λ it and its conditional mean. for example, the relation between (zamani and ismail, 2012) . the underlying random rates λ it , i = 1, . . . , m, t = 1, . . . , t , account for the extra variability (overdispersion), which may represent unmeasured confounders and model misspecification (wakefield, 2007) . variations of the random rate λ it relative to the expected number of cases e it provide useful information about the spatio-temporal risk of covid-19 in the whole spatial domain of interest during the study period. in disease mapping literature, the nonnegative random quantities are called the area-specific relative risks at time t (lawson, 2018, section 5.1.4). obviously eθ it = 1 and which means that the temporal and spatial correlation structure of the underlying random rates λ it determine the spatio-temporal correlations between θ it 's. temporal correlation ar(2) ζ i spatial correlation due to distance between regions gmrf ξ i spatial correlation due to neighborhood relation between regions bym by ignoring these correlations, the standardized incidence ratio θ it = y it / e it provides a naive estimate for the relative risks (lee, 2011) . however, in a model-based approach the variations of the relative risks are often related to regional and/or temporal observed covariates and the correlation between θ it 's are explained in terms of regional and/or temporal random effects using, for example, a log linear model (wakefield, 2007; lee, 2011; lawson, 2018) . in the present study, we consider the log linear model where µ is the intercept and d i is the population density of region a i , i.e. the population of a i , p i , divided by the area of a i . the population density is standardized to have mean 0 and variance 1 and β is its regression coefficient. moreover, η it is a zero mean random effect which represents spatio-temporal variations in relative risks due to temporal and spatial trend and correlation. among many different possibilities, we assume that η it takes the additive form where δ i represents the temporal trend, ε t accounts for temporal correlation and ζ i and ξ i explain spatial correlation due to spatial distance and neighborhood relations among regions a 1 , . . . , a m , respectively (see table 2 ). the latent (stochastic) temporal trend δ t is expected to be a smooth function of t. since the second order random walk (rw2) model is appropriate for representing smooth curves (fahrmeir and kneib, 2008) , δ = (δ 1 , . . . , δ t ) is assumed to follow a rw2 model, i.e., where 2 , . . . , t −1 are independent and identically distributed (i.i.d.) zero mean gaussian random variables with variance 1/τ δ . here the precision parameter τ δ > 0 acts as a smoothing parameter enforcing small or allowing for large variations in δ t (fahrmeir and kneib, 2008) . to account for temporal correlation, we assume that ε t follows a stationary autoregressive model of order 2, ar(2); i.e., ε t = ψ 1 (1 − ψ 2 )ε t−1 + ψ 2 ε t−2 + t , t = 2, . . . , t, where −1 < ψ 1 < 1 and −1 < ψ 2 < 1 are the first and second partial autocorrelations of ε t and 2 , . . . , t are i.i.d. zero mean gaussian random variables with variance 1/τ ε . on the other hand, to account for spatial correlation, we assume that ζ = (ζ 1 , . . . , ζ m ) follows a gaussian markov random field (gmrf). more specifically, we assume that ζ is a zero mean gaussian random vector with the structured covariance matrix where i m is the m × m identity matrix, 0 ≤ ω < 1 and e max is the largest eigenvalue of the m × m symmetric positive definite matrix c = [c ii ]. the entry c ii of matrix c represents to what extend the regions a i and a i are interconnected. for example, c ii can be related to a data on commuting or population movement between regions a i and a i . in absence of most recent and reliable movement data between the regions of spain, italy and germany, we set c ii to be the euclidean distance between the centroids of a i and a i . in addition to interconnectivity and correlations due to spatial distance, the neighbourhood structure of regions a 1 , . . . , a m may induce spatial correlation among relative risks of regions because neighbouring regions often tend to have similar relative risks. to include spatial correlation due to neighborhood structure of regions in the model, we assume that ξ = (ξ 1 , . . . , ξ m ) follows a scaled version of the besag-york-mollié (bym) model (besag et al., 1991) ; i.e., ξ is a zero mean gaussian random vector with (riebler et al., 2016) here q − denotes the generalized inverse of the m × m spatial precision matrix q = [q ii ] with entries where n i is the number of neighbors of region a i and i ∼ i means that regions a i and a i share a common border. the parameter τ ξ > 0 represents the marginal precision and 0 ≤ φ ≤ 1 indicates the proportion of the marginal variance explained by the neighborhood structure of regions (riebler et al., 2016) . in a bayesian framework, it is necessary to specify prior distributions for all unknown parameters of the considered model. the gaussian prior with mean zero and variance 10 6 is considered as a non-informative prior for the dispersion parameter of generalized poisson distribution, log ϕ, and for the parameters of the log linear model for the relative risks µ, β, log τ δ , log τ ε , log τ ζ , log τ ξ , log ω 1−ω , 1−ψ1 and log 1+ψ2 1−ψ2 . the prior distribution for the α parameter of the generalized poisson distribution is considered to be a gaussian distribution with mean 1.5 and variance 10 6 . table 3 summarizes the model parameters and their necessary transformation for imposing the non-informative gaussian priors. since all random effects of the model are gaussian, the integrated nested laplace approximation (inla) method (rue et al., 2009) can be used for deterministic fast approximation of posterior probability distributions of the model parameters and latent random effects (martins et al., 2013; lindgren et al., 2015) . the r-inla package, an r interface to the inla program and available at www.r-inla.org, is used for the implementation of the bayesian computations in the present work. the r code can be made available upon request. the initial values for all parameters in the inla numerical computations are set to be the mean of their corresponding prior distribution. the initial value of α is chosen to be one (see table 3 ). for count data y it and in a bayesian framework, a probabilistic forecast is a posterior predictive distribution on z + . it is expected to generate values that are consistent with the observations (calibration) and concentrated around their means (sharpness) as much as possible (czado et al., 2009) . following a leave-one-out cross-validation approach, let be the event of observing all count values except the one for region a i at time t. dawid (1984) proposed the cross-validated probability integral transform (pit) for calibration checks. thus, pit it is simply the value that the predictive distribution function of y it attains at the observation point y it . the conditional predictive ordinate (cpo) is another bayesian model diagnostic. small values of cpo it (y it ) indicate possible outliers, high-leverage and influential observations (pettit, 1990) . for count data, czado et al. (2009) suggested a nonrandomized yet uniform version of the pit with which is equivalent to the mean pit can then be comparing with the standard uniform distribution for calibration. for example, a histogram with heights table 4 presents the bayesian estimates (posterior means) for every parameter of the considered model fitted to the daily number of new covid-19 cases in spain, italy and germany. the corresponding 95% credible intervals of the model parameters are also reported in parentheses. comparing the estimated parameters among different countries, it can be seen that the dispersion parameter ϕ of the generalized poisson distribution for italy is higher than spain and germany, but its shape parameter α is around 1.5 for the three countries, which implies that the variance of the daily counts in each region is approximately a quadratic function of their mean. the coefficient of the population density is not significantly different from zero for spain and italy, but is positive for germany which indicates that regions with higher population density have larger relative risks. the precision parameters of the temporal random effects imply that the temporal trend δ t has at least 35 times larger contribution (smaller precision) than ε t which represents temporal correlation. the opposite signs of ψ 1 and ψ 2 indicate rough oscillations in ε t . the spatial random effect ζ i has larger contribution (smaller precision) than ξ i in the total variations of the relative risks only in spain, while for italy and germany it is the opposite. this could be a result of large euclidean distance between spain continental european territory from two archipelagos territories, which is affecting the considered covariance structure of ζ i . in summary, the higher contribution (lower precision) in the total variations of the relative risks for spain, italy and germany is due to the temporal trend, spatial correlation and finally temporal correlation, respectively. this may hint that spatial correlations have a greater impact on the relative risks of covid-19 than temporal correlations. the bayesian estimates and 95% credible intervals for the temporal trend δ t , t = 1, . . . , t , are shown in figure 1 . these plots can be interpreted as a smoothed temporal trend of the relative risk in the whole country. in fact, figure 1 suggests that the covid-19 epidemic in all three countries rapidly reached their peaks and slowly started to decline at the beginning of april and then increased and reached its maximum in august. in addition, the second wave of the epidemic seems to be stronger in spain and germany shows a more smoother trend during the study period. figure 2 shows the the posterior means of the spatial random effects ζ i and ξ i , i = 1, . . . , m, on the corresponding map of each country. the plot illustrates spatial heterogeneity of the relative risk of covid-19 across regions in each country, particularly in spain. regions with positive (negative) ζ i + ξ i values are expected to have elevated (lower) relative risks than the the baseline country-wide risk during the study period. in order to see how the estimated relative risks under the fitted model are in agreement with the observed data, figure 3 shows the spatially accumulated daily number of cases m i=1 y it , t = 1, . . . , t , and their expected values under the fitted model, namely the posterior mean and 95% credible interval of m i=1 e it θ it , t = 1, . . . , t . except some discrepancies for spain and italy, the observed values are inside the 95% credible intervals and close to the expected values under the fitted model. figure 3 in addition shows 4-days ahead forecasts of the total daily number of new cases at the end of study period of each country. finally, histograms of the normalized pit values described in section 4.4 are obtained using j = 20 from the fitted models and plotted in figure 4 . the normalized pit values for the fitted models to data do not show a clear visible pattern and the histograms seems to be close to the standard uniform distribution. the above results and more details on observed and predicated values from the fitted model are also provided in an interactive shiny web application at https://ajalilian.shinyapps.io/shinyapp/. there are some limitations in the analyses and modeling of data on the number of new cases of covid-19, including data incompleteness and inaccuracy, unavailability or inaccuracy of relevant variables such as population movement and interaction, as well as the unknown nature of the new covid-19 virus. nevertheless, understanding the underlying spatial and temporal dynamics of the spread of covid-19 can result in detecting regional or global trends and to further make informed and timely public health policies such as resource allocation. in this study, we used a spatio-temporal model to explain the spatial and temporal variations of the relative risk of the disease in spain, italy and germany. despite data limitations and the complexity and uncertainty in the spread of covid-19, the model was able to grasp the temporal and spatial trends in the data. however, the posterior predictive checks using the normalized probability integral transform (pit) showed that there is room for the model improvements. obliviously, there are many relevant information and covariates that can be considered in our modeling framework and improve the model's predictive capabilities. one good possibility would be considering most recent and accurate human mobility amongst regions. we would expect our model would benefit from this information, which right now can not be accessed. moreover, the considered spatio-temporal model in this paper is one instance among many possibilities. for example, one possibility is to include a random effect term in the model that represents variations due to joint spatio-temporal correlations; e.g., a separable sptaio-temporal covariance structure. however, the considered model was adequate and no joint spatio-temporal random effect term was considered to avoid increasing the model's complexity. we focused here on a stochastic spatio-temporal model as a good alternative to existing deterministic compartmental models in epidemiology to explain the spatio-temporal dynamics in the spread of covid-19. however, it should be emphasized that one step forward would be considering a combination of a deterministic compartmental model in terms of differential equations for the number of susceptible, exposed, infectious and recovered cases with our sort of stochastic modeling approach. this is a clear novelty and a direction for future research. open data resources for fighting covid-19 a comparison of spatio-temporal disease mapping approaches including an application to ischaemic heart disease in new south wales, australia modeling and forecasting the covid-19 pandemic in brazil bayesian image restoration, with two applications in spatial statistics a spatio-temporal analysis for exploring the effect of temperature on covid-19 early evolution in spain. science of the total environment gridded population of the world, version 4 (gpwv4): population count, revision 11 shiny: web application framework for r a generalization of the poisson distribution predictive model assessment for count data a spatial model of covid-19 transmission in england and wales: early spread and peak timing present position and potential developments: some personal views statistical theory the prequential approach on the identification of trend and correlation in temporal and spatial regression the spatio-temporal epidemic dynamics of covid-19 outbreak in africa modelling and predicting the spatio-temporal spread of coronavirus disease 2019 (covid-19) in italy health security capacities in the context of covid-19 outbreak: an analysis of international health regulations annual report data from 182 countries. the lancet spatial epidemic dynamics of the covid-19 outbreak in china undersampling in action and at scale: application to the covid-19 pandemic bayesian disease mapping: hierarchical modeling in spatial epidemiology a comparison of conditional autoregressive models used in bayesian disease mapping. spatial and spatio-temporal epidemiology bayesian spatial modelling with r-inla bayesian computing with inla: new features epidemic analysis of covid-19 in china by dynamical modeling the conditional predictive ordinate for the normal distribution an intuitive bayesian spatial model for disease mapping that accounts for scaling. statistical methods in medical research approximate bayesian inference for latent gaussian models by using integrated nested laplace approximations a machine learning forecasting model for covid-19 pandemic in india disease mapping and spatial regression with count data hierarchical spatio-temporal mapping of disease rates coronavirus disease (covid-19) outbreak functional form for the generalized poisson regression model the authors declare that they have no conflict of interest. key: cord-284017-1fz90e3k authors: henríquez, josefa; almorox, eduardo gonzalo; garcia-goñi, manuel; paolucci, francesco title: the first months of the covid-19 pandemic in spain date: 2020-08-27 journal: health policy technol doi: 10.1016/j.hlpt.2020.08.013 sha: doc_id: 284017 cord_uid: 1fz90e3k background: : the covid-19 outbreak has led to an unprecedented crisis in spain. after italy, the spread of the virus was quick, and spain became the second epicenter in europe by number of cases and deceased. to tackle the outbreak and contain the spread, the spanish authorities undertook exceptional measures based on a generalized lockdown by which the majority of the economic activity ceased for several weeks. objectives: : the goal of this paper is to examine the spread of covid-19 in spain from february to may 2020, as well as the public policies and technologies used to contain the evolution of the pandemic. in particular it aims to assess the effectivity of the policies applied within the different autonomous communities. cases and deaths are presented until august as well as the main changes in containment and mitigation measures. methods: : data was collected from various official sources, including government reports, press releases and datasets provided by national and international level institutions. results: : we show that the main measure to contain the spread of the pandemic was a stringent confinement policy enforced through fines. it resulted in a substantial reduction in the mobility and the economic activity. at a regional level, the negative consequences of the crisis affected differently across regions. the covid-19 outbreak has led to an unprecedented crisis in spain. after italy, the spread of the virus was quick, and spain became the second epicenter in europe by number of cases and deceased. although the first case diagnosed with covid-19 was registered at the end of january, the spanish health authorities did not undertake measures until one month later, moment when a systematic and exponential increase in registered cases and deceases was observed. to tackle with the outbreak and contain the spread, the management of public health policies were centralized within the ministry of health and the authorities undertook exceptional measures based on a generalized lockdown by which the majority of the economic activity ceased for several weeks. in this paper we describe and analyze the spread of covid-19 in spain and the policies and technologies used through the course of the unfolding of the pandemic. our focus consists of assessing the patterns within regions departments, autonomous communities (ac), to understand how the pandemic evolved across different parts of the country. this question is particularly relevant for the spanish case given the highly decentralized nature of the health system where ac manage most public health policies and are provided with different health resources. these different resource allocations across ac prior to the crisis could have been key determinants to understand the spread and impact of the virus throughout different parts of the country. we do so by exploiting official sources of epidemiological information and assessing the trends across ac. in particular, we study several indicators that include: registered cases, recovered, deceased, hospitalizations, icu cases by age and gender and comorbidity patterns. further, we pay special attention to the outcomes of the different policies and technologies. in particular, we evaluate the effectiveness of lockdown measures by comparing the evolution of a stringency index during the different stages of the pandemic and mobility. the rest of the paper is structured as follows. section 2 provides an overview of spain and its health care system. section 3 describes the main epidemiological trends. section 4 presents the series of policies put in place. section 5 outlines the health system response. section 6 shows some economic and financial spillovers of the virus. section 7 concludes. at the end of the document the references can be found. in 2019, spain's population was 47 million people, distributed among the 17 acs that further divide into provinces. the health system is organized via a national health system typology, "sistema nacional de salud" (in spanish), and provides universal healthcare through 13,122 primary care facilities of general practitioners (gp), and 466 hospitals (1) . acs are the main managers of the health system coordinating the provider networks and purchasing resources. further, the ministry of health, dependent on central government, mainly acts in stewardship and coordination with the ac through the interterritorial council of the national health service. table 1 contains an overview of the demographics and health system characteristics of spain, which we use as aid in contextualizing the epidemiological trends of covid-19 and changes in health resources. spain's life expectancy (83.4) is the highest amongst in the european countries and it is well above the average of oecd nations (80.7). as an ageing country, the share of population over 65 exceeds other oecd countries (19.3 vs 17. 2) as well as the old age dependency ratio 1 (0.293 vs 0.264). alongside this longevity, spain presents a significant rate of morbidity having a 62.3% of older than 65 with two or more chronic conditions and a 7.2% of diabetes prevalence (also higher than the 6.4 average in oecd countries). [insert table 1 here] in a universal system, free at the point of use 2 , the funding of the health system plays a key role. as a result of the 2008 financial crisis, over the period 2008-17 the health budget shrank (2) . these reductions resulted in decreases from 73.9% to 70.8% of the average participation in funding of the portion related to government compulsory schemes. at the same time, private expenditure on health, especially out of pocket spending rose, reaching 23.6% currently. the existing proportion of health expenditure as a fraction of the gdp (8.9%) is around oecd numbers (8.8%), and higher than in 2008 (8.3%), while per capita healthcare expenditure of 3,428 usd (ppp) in 2018, was below the oecd average of 3,994. in terms of health and long-term care resources such as doctors, nurses and beds per 1,000 population, spain falls above oecd levelsespecially regarding nurses and hospital beds. concerning long term care resources, despite not ranking among the top countries, spain has more beds in long term care residences than italy (18.6), and falls slightly above oecd average (43.1). 1 ratio between those in working age with respect to those 65 and above 2 there are some exceptions such as pharmaceuticals. table 2 shows the differences in health resources across the acs. andalucía is the biggest ac by population whilst the autonomous city of melilla presents the highest population density. other big acs by population are madrid and cataluña. cataluña, is also on top regarding number of hospitals and beds but not in the number icu beds, key to treat covid-19 severe patients, or primary care facilities important for tracking early cases. [insert table 2 here] the covid-19 outbreak has modified the existing decentralized organization of health system. since the declaration of the state of alarm (14 th of march), the main tasks and policies to tackle the crisis were temporarily centralized around the ministry of health. these included centralized purchase of necessary goods and services in order to meet three main purposes (according to the ministry): reinforcement of the ac purchasing processes, allocation of resources among the population and professionals and organization of the production at national and international level. only once the outbreak is under control its effects and the state of alarm will conclude (21 st of june). this implies that the acs, at different speeds, will be regaining their competences in health. the ministry of health is the authority that sets and manages the protocol for reporting information related to covid-19. using a notification form, the ac report to two bodies under the ministry of health: the national center of epidemiology (centro nacional de epidemiologia, cne) and the center for coordination of alerts and sanitary emergencies (centro de coordinación de alertas y emergencias sanitarias, ccae). another key institution, in charge of the management and release of the epidemiological information is the charles iii institute of health (instituto de salud carlos iii, isciii). the isciii, gathers the information through the national network of epidemiological surveillance (renave). the isciii is the official source of information and we will use it in the paper. until may, the isciii released daily information at regional level regarding confirmed cases (through different testing methods), hospitalizations as well as referrals to intensive care units (icu), deceased and recovered cases. since then, and currently, daily data only on daily cases is being released, and is available to download in an interactive website (3) . further the isciii elaborates reports with relevant breakdowns of the information (i.e. demographic, clinical and epidemiological risk history characteristics). two main caveats in the data must be mentioned. first, in the initial stages of the pandemic, there was misalignment in the criteria applied by acs to classify new and hospitalized cases. since the 15 th of april, a unified criterion was implemented to account for the number of confirmed cases. these criteria included positive cases under different testing methods (e.g. pcr and antibodies tests) (4). second, data since the 20 th of may is under review, and since then the same information as before hasn't been released. for this reason, we use information until may to capture the complete range of epidemiological indicators, while we update the data until august, capturing daily cases (the currently available information). there are other types of information available that are relevant for the purposes of this paper. in particular, information on existing health resources, reported by the ministry of health and information on new measures to mitigate the contagion. the first confirmed case of covid-19 in spain was reported on the 31 st of january. it was an imported case corresponding to a german tourist visiting the island of la gomera (canary islands). after a month the number of confirmed cases increased to 100. [insert figure 1 here] seroprevalence study (5) detected initially that around 5% of the spanish population had antibodies, with a variability among regions and provinces ranging from 0.4% to 14%. this would mean that around 2.3 million individuals got the virus, while official numbers (subject to underestimations due to testing criteria and the nature of the illness where people can be asymptomatic, among others) are around 230,000. figure 2 presents several snapshots of the fatality rates during the outbreak at province level. these data are released independently by different regional governments and collected by montera24 3 . the data used for the calculation of fatality rates are also affected by the change in the methodology mentioned above so are updated to the last record available before the change in the methodology. during the first half of april fatality rates reached their peak affecting several provinces located in the east of the country. a month after the worse parts belonged to provinces from ac of cataluña, extremadura, asturias, castilla-leon and madrid. indeed, deaths in the peak of the pandemic have been proved to be significantly above (around twice) the reported by the ministry of health compared to deaths registered in the daily mortality monitoring system (6) and those informed by the national institute of statistics (7), compared to the same dates in the previous year. [insert figure 2 here] the cases of hospitalisations and referrals to intense care units (icu) have spread differently between different age ranges. as shown by figures 3 and 4 , the most affected groups have been individuals older than 60 years old which have been classified as risky population. in addition, especially in patients within the former age range, there has been a significant gender gap in hospitalisations where men have shown higher number of hospitalisations and icu referrals. interestingly the trends remain in parallel between genders for individuals younger than 40 years old. the epidemiologic information concerning diseases that may be related to covid-19 is presented at aggregate level without differentiation between acs in figure 5 . despite registering a lower number of hospitalisations, women registered a higher of daily cases than men in several diseases that included cardiovascular, diabetes and respiratory. yet, trends across genders are fairly similar. amongst all diseases, the base disease and associated risk is the comorbidity that presents more registered cases. [insert figure 5 here] to address the spread of the virus, typically countries will put in place measures to contain and mitigate the spread and also, due to the consequences those policies on the economy. as the peak of the pandemic has passed, it is necessary to cover two parts of the policies, their phase in, and their phase out. after who's notification of the existence of covid-19, spain was quick to follow the advised instructions of the international organism in terms of epidemiological protocols and spread of information to the public. press releases showed a confident approach by the authorities but also, a non-alarming one. an example is a press note from the 23rd of january arguing for reduced risk as spain had no close links to the epicenter in china (wuhan had no directs flights to from spain, or china not being a frequented vacation destination). figure 6 describes the full timeline of policies implemented to contain the spread of the virus. until the middle of february, only minor measures where implemented, and at the end of the month, the government opted to inform those with symptoms to stay home (28-02). some regional restriction where put in place after. since then, activities, gathering, sporting events started their suspension. the 9 th of march, schools and universities were closed when community outbreak was declared, following the 10 th of march, a flight ban to italy was imposed. it was only on the 14 th of march, when 7,658 cases had been recorded and 285 reported deaths, spain declared the state of alarm, limiting all people movement, with exception of grocery shopping, pharmacy and others. this came nearly a week after italy imposed a nationwide lockdown (the 9 th of march), but at a comparable number of cases (7, 985) , and around 3 times less deaths (724). despite this, cases continued an upward trend, and tightening of the lockdown was issued on the 29 th of march, where all non-essential activities where stopped. [insert figure 6 here] to assess the efficacy of the measures, figure 7 shows the containment measure stringency index (8) , which captures eight policy indicators on containment and closure policies (e.g. school closures and restrictions in movement) compared to the daily new cases (until august). it is observed how the measures started to grow in terms of containment while the pandemic was unraveling and stayed at their maximum from the start of april. in consequence, cases declined, and have remained low for may and june. it has become evident that after the spanish bumpy start, the restrictive measures that moved fast into extreme draconian ones paid the dividends. [insert figure 7 here] several determinants can be related to the success of the measures, aside the broadness of the containment measures. two other key ones relate to the enforcement of the measure and their outcomes (e.g. mobility). regarding the first, the state of alarm allowed punishable measures to be imposed, with fines ranging between €601 and up to €10,400. the ministry of internal affairs (25 th of april) informed that 741,407 fines had been issued since (9) . moreover, as in other countries, drones have been operated by police forces to monitor the measures imposed (e.g. lockdown) and to inform individuals out in public about hygiene measures. this further reflects on the mobility of the spanish population. figure 8 plots the percentage of mobility of the population per ac respect to the reference period 14-20 february. it can be observed how mobility was significantly reduced during the first week of the state of alarm, and was kept low during the lockdown period. [insert figure 8 here] regional effects of the lockdown have been highlighted in amuedo-dorantes and co-authors (10) , which show that regions that where at early stages of the contagion and were affected early on by confinement measures, reduced mortality rates. on the same basis, orea and álvarez (11)) using a spatial econometric approach simulate different scenarios to assess the effectiveness of the lockdown measures. their results suggest that the lockdown reduced the covid-19 cases in about 80% especially in provinces close to the outbreaks. also, they conclude that the effectiveness of the lockdown could have improved by 12.8% if the measures would have been implemented a week before. the reduced number in daily cases among others implied that gradually the country phased out the restrictions (see figure 9 ). as of monday, 13th of april, working restrictions to non-essential workers were lifted, and thousands (12) of workers returned to work, while citizens were still obliged to stay home until the 26 th of april. two further policies were put in place: first, allowing minors (younger than 14) to go outside, and second, in different timeslots, for those 14 years and older to exercise outside. [insert figure 9 here] the government has since agreed on a "plan of return to the new normality". different to how the state of alarm happened, applicable for the whole of spain, this plan will occur per ac in a process of co-governance with the ministry of health. some criteria have been put out by the ministry of health, but also, due to the fact that the government is in minority, political pressures from the ac will play an important role. when measures started to be consistently at lower levels, cases have started to slowly go up, and have now increased quite significantly to levels of april. moreover, mobility has increased substantially, and currently, probably due to the summer period, it is higher than in the reference period. this correlates too with the increases in cases observed. shutting down the economy, has meant that the government, to reduce the catastrophic impacts in businesses and individuals in terms of finances, have implemented several policies to push money into the country. legally, this have been published through several royal decrees. figure 10 shows the timeline of the four main decrees that aimed at addressing the economic impact of covid-19, and the two main restrictions imposed: declaration of the state of alarm and the closure of non-essential activities. [insert figure 10 the decree 18/2020 expanded measures related to an unemployment figure, temporary employment regulation known as erte, to protect employment, ranging from an extension of this figure due to major circumstances, and allowing those with erte to not contribute to social security. additionally, and not strictly related to covid-19 but highly influenced, was the implementation of the minimum vital income. the royal decree 24/2020, aimed at reactivating employment, protecting autonomous work and the competitiveness of the industrial sector. to address the needs associated to covid-19, spain had to unravel an extraordinary response in regard to its health system, putting to the forefront technology interventions. the pandemic, has also had spillover effects on non-covid19 related health care and health problems which are necessary to address to comprehend the full picture of the efforts and impacts. initially, spain was not equipped to deal with the rapid surge in cases. as mentioned, not only the organization of the system (e.g. decentralized), had to be modified, but the delivery of care (e.g. telemedicine), and its capacity had to be increased significantly in all major areas. this ranged from testing (availability of pcr and rapid tests, as well as labs to analyze them), beds (in existing and new facilities, and of different levels of severitygeneral ward and icu), ventilators, medical staff to personal protective equipment (ppe). two main changes with respect to the delivery of care occurred: a move towards telemedicine, and the use of phoneapps to provide information about the illness. first, several private initiatives towards telemedicine, in the form of apps and in supplementary insurance plans added this type of consults and experienced a growth of their use (13) . public use of telemedicine has been locally promoted, for example, the "hazlo" project, for the cardiac rehabilitation unit of the ramón and cajal university hospital (isciii and ramon y cajal university hospital) is a good example, while other types of consultations in the public system have been done through phone calls. second, the severity of the spread required information and services to alleviate calls to emergency rooms. phone apps where a key tool to provide information, self-diagnostic and monitoring of symptoms (e.g. apps like "stopcovid19" in cataluña, "coronamadrid app" for madrid or "asistencia covid-19" in canarias, cantabria, castilla-la mancha, extremadura, and asturias). in the pais vasco, "covid19.eus", aimed additionally at prevention, follow up to possible cases in their homes, and analysis of the concentration of cases. capacity of the system was quickly upscaled. one area of specific importance was testing. as the emergency unraveled, to contain the spread testing had to be increased and testing criteria evolved. testing widely has become the cornerstone of the health policy specially, to be able to lift restrictions. to achieve that objective, the country has increased labs available and processing capacity and purchased significant amount of materials. a key actor in this regards, dependent on the ministry of health, is the national center of microbiology (centro nacional de microbiología), which has assessed testing facilities and performed testing analysis. a key component has been the use of technology. specifically, the use of robots (currently, 4) in different institutions to automatize testing. this has been paired with the purchase of swabs (pcrs) and antibodies tests that have been distributed. table 3 shows the testing criteria. in can be observed that a reduction of the initial restrictions in place occurred over time. [insert table 3 (14) 4 . this has set the processing capacity around 47,000 daily pcr tests. since reporting started, on the 13th of april, the median days from symptoms to diagnostics was 5 days (2-9 range), while on the report of the 15 th of july, this number had been reduced to 3 (1-5). nevertheless, the regions vary in their testing agility, as outlier is melilla, with 15 days, and a range of 3-26, until the 30 th of july, while this value dropped to 4 on the 6 th of august (3). 4 news on the mentioned date with respect to tracing, the task has been given to the acs and a protocol has been elaborated by the ministry of health on that regards. as the regions have the autonomy to decide their tracing strategy, there is variation in the way they do so. a notable case that has been criticized is madrid, that hired a private company to do the tracing (15) . tracing, as of the first report (15th july), managed to reach 1 (0-3) close contact. until the 6 th of august, the mean number of close contacts traced was 4 (1-5). again, there is variance between the regions, as the highest median number of contacts identified per case in canarias is 9 , while the lowest is castilla la mancha with provisional hospitals had to be opened. notable cases are ifema (feria de madrid) (21st march) that could have accommodated, if necessary, up to 5,000 beds (and up to 800 icu beds) although it had a maximum of about 1,200 simultaneous patients; and in catalonia, fira de barcelona, which opened ready to admit 300 patients although potentially they could have been increased to 1,000. before the 29 th of march, icu beds totaled 4,405 (1). as observed in table 4 , where the new icu and total beds are presented, an increase of 72% has been experienced to a total of 7,577 as of march 29 th . despite some of the ac, previous to the virus, having the highest regional number of icu beds (e.g. madrid, 704), the sharp increase in cases saturated the capacity. the ac that increased in the greatest percentage its icu capacity was país vasco (207.3%), followed by murcia (192.7%), and madrid and catalonia (145% and 115.6%, respectively). [insert table 4 here] a key resource to treat serious patients are ventilators (invasive and non-invasive types). there is no data regarding pre-covid-19 availability of ventilators to offer relevant comparisons. nevertheless, since data has been made public (30 th [insert figure 11 here] in an effort to increase work safety, the country had to significantly increase the delivery of ppe to the acs. by means of centralized purchasing, and a public formula for distribution based on population size and epidemiological data, the ac receive masks (see figure 11 for the distribution over time compared to ), being madrid (more than 12.9 million) and catalonia (more than 10 million) the cas receiving the highest amount. as of 19 th of may, a new system was implemented combining the petition of the acs and the ministries calculation to meet a "reservoir amount" of masks. we must note that this does not consider the material purchased individually by each ac. to deal with the human resource shortages that covid-19 infection of medical staff and the general spread of the virus put in the system, a series of conditions previously in place related to contracting of medical staff, retirement, resident doctors, and graduation of health professionals had to be relaxed. the ministry of health informed that to the 2nd of april, it had increased the available for-hire health professionals to an extra 80,000. the second group of measures has consisted of cross-regional hiring process of health professionals from regions with less demand of covid cases to regions with higher levels of demand as for example madrid or catalonia. the outbreak and focus on covid-19 has resulted in a quick transformation in healthcare processes and structures that have produced spillover effects on the delivery of other medical service, and health aspects. one important aspect is related to waiting times. latest reports (december 2019) (19) , demonstrated an increase before and due to the pandemic effect on shifting the focus to treat covid-19 patients, they will suffer an increase. one specifically critical health service relates to transplants. the national transplant organization has released information stating that there has been a 82% decrease in donors and 85% decrease in transplants compared to the same period of the previous year (20) . there is also record of a decreased participation in mandatory immunization programs during the first months of the pandemic (21) . in short, many non-urgent health services were avoided by the population or postponed by the health services during the pandemic and will have to catch up when possible. in addition, other types of measures were implemented. pané-mena and pascual (22) list three types of measures implemented on specialist services that included coordination and crisis management measures, support measures refocusing some services exclusively to covid-19 related cases and referring other series to other centers and logistic measures based on tackling with the lack of devices and materials to provide a suitable healthcare. the economy of spain has suffered increased hardship due to the pandemic. gdp has contracted by -18.5 in the second quarter of 2020, and is currently in technical recession (23) , falling close to the worst projects of the international organizations by the spanish bank, between 16% and 21,8% (26) . moreover, the ibex-35 stock, has decreased significantly since january, with the lowest value being registered after the declaration of the state of alarm ( figure 12 ). since then, the evolution has been positive, while still below levels of mid-february. the most significant increase was produced when the announcement of the credit loans for the tourist sector was made in mid-june (27) , as this sector represents an important part of the spanish economy, that in 2019 accounted for 12.3% of the gdp, and 2.62 million jobs (28) . [insert figure 12 here] unemployment rates in spain have gone up to 15.33% in the second quarter of 2020 from 13.78% in the last quarter of 2019 (29) . in spite of this negative evolution, the unemployment rate is still much lower than in the first quarter of 2013, during the earlier economic crisis, when it reached the peak of 26.94%. however, this number does not consider those workers that have been subject to the temporary regulation of employment "erte" (for its name in spanish) (suspension of work or reduction in hours). at the same time, in the last months, the labor market has changed drastically, as full time job placements have gone down 17.7 percentage points (23) . as a result, the affiliation to social security decreased in the month of july in the amount of -747,657 individuals (most of them men, 53%) (30) . whether the economic impact of the pandemic is as large as estimated or even greater, will depend on the speed at which economic activity returns to normal, and on the existence of a possible resurgence or second wave that would bring the economy to a standstill again, before a preventive vaccine or cure for covid-19 becomes available. spain was one of the first countries to be hardly hit by covid-19 in terms of cases and deaths. data shows that the country overcome the peak of the spread and intensity of the virus, greatly aided by the very stringent confinement policies that lasted for nearly 2 months, aided by strict enforcement which implied fines reached all-time peak, and resulted in a significant decrease of mobility. having been an early epicenter, it struck the health system by surprise. the virus showed that the health system was not ready to confront a strain of this magnitude. nevertheless, the country managed to be quick in changing the necessary health system structures and increasing its resources to deal with the surge in cases. this encompassed from re-arranging the decentralized health system to a temporarily higher degree of centralization, to the significant roll out of ppe, beds, and medical staff to confront the emergency while it was unravelling. despite the measures to tackle with covid-19 have been centralized by the ministry of health and implemented homogeneously across the country, we have shown that the pandemic has had a different impact across spanish provinces. this situation has led to a relaxation of lockdown measures on a case-by-case basis. under this system, in order to lift mobility restrictions, ac have been required to submit bi-weekly reports to the health ministry to assess the suitability of their epidemic situation and more particularly their incidence rates. in some cases, provinces within the same ac showed different degrees of severity associated with the incidence rates. this was the case, for instance of the castilla león provinces closer to madrid (e.g. ávila, segovia), which took longer to increase their mobility compared to others located more to the north. the current debate in terms of public health consists of how to design measures to contain the new wave of cases that are arising in different ac. these measures need to promote the primary care delivered in general practices. primary care plays a core role in prevention and detection of early cases. to enhance the quality of their delivery it is necessary to improve the set of resources available in the current gp premises as well as incentivize the promotion of gp staff. further, they need to increase their capacity to conduct tests. to this extent, there has been a generalized increase of tests in all ac. another key area to address public health measures consists of the redefinition in the organization of long-term care services. two thirds of covid registered deceased in spain occurred in a care home (31) . these figures show deficiencies in the provision of long-term care under an epidemic crisis. to this extent, the implementation of coordinated protocols with a common framework as well as measures to increase the integration between long-term and primary care, may be two main elements to consider. . the data compiled correspond to the cumulative cases up to 15 th of may 6 . deaths are recorded as a person that has tested positive to covid-19 and has passed away. cases correspond to those with positive pcr tests. confirmed cases do not come from the sum of hospitalized, recovered and deceased, as they are not mutually exclusive. deceased and recovered could have been hospitalized and therefore be in the two groups. estadística de centros sanitarios de atención especializada situación de covid-19 en españa la inmunidad de la población española experimenta un leve incremento con una tasa del 5,21% en la segunda ronda del ene-covid19 sistema de monitoreo de la mortalidad diaria estadística experimental -estimación de defunciones semanales durante el brote de covid-19 (edes) oxford covid-19 government response tracker, blavatnik school of government tantas multas propuestas en el confinamiento como impuestas en 4 años de la ley mordaza timing is everything when fighting a pandemic: covid-19 mortality in spain how effective has the spanish lockdown been to battle covid-19? a spatial analysis of the coronavirus propagation across provinces notas de prensa el coronavirus impulsa la telemedicina en españa el 12% de los contagiados por coronavirus son trabajadores sanitarios informe sobre la situación de covid-19 en personal sanitario en españa sistema de información sobre listas de espera en el sistema nacional de salud. situación a 31 de diciembre de covid-19: impacto en la actividad de donación y transplantes covid-19 caida de las vacunaciones el desafio de la covid-19 para la atencióon especializada contabilidad nacional trimestral de españa: principales agregados cntr (avance) economic forecast for spain perspectivas económicas de la ocde macroeconomic projections for the spanish economy (2020-2022): the banco de españas contribution to the eurosystems el plan de sanchez para ayudar al turismo se basa en créditos a empresas primer trimestre 2020 sanidad estima en 27.359 los fallecimientos en residencias durante la epidemia, más de dos tercios con coronavirus población por comunidades y ciudades autónomas demography and population data extensión superficial de las comunidades autónomas y provincias, por zonas altimétricas health at a glance long-term care resources and utilisation: beds in residential long-term care facilities ciudades autónomas y provincias de colegiación, situación laboral y sexo mapa de recursos sociales y sanitarios renave; cne; cnm (isciii). informe. situación de covid-19 en españa a autonómica viajeros-km el mapa de la ocupación de las uci precios historicos ibex35 ministerio de educacion y formación. covid-19 key: cord-281961-5mdiwzvc authors: de las heras-pedrosa, carlos; sánchez-núñez, pablo; peláez, josé ignacio title: sentiment analysis and emotion understanding during the covid-19 pandemic in spain and its impact on digital ecosystems date: 2020-07-31 journal: int j environ res public health doi: 10.3390/ijerph17155542 sha: doc_id: 281961 cord_uid: 5mdiwzvc covid-19 has changed our lives forever. the world we knew until now has been transformed and nowadays we live in a completely new scenario in a perpetual restructuring transition, in which the way we live, relate, and communicate with others has been altered permanently. within this context, risk communication is playing a decisive role when informing, transmitting, and channeling the flow of information in society. covid-19 has posed a real pandemic risk management challenge in terms of impact, preparedness, response, and mitigation by governments, health organizations, non-governmental organizations (ngos), mass media, and stakeholders. in this study, we monitored the digital ecosystems during march and april 2020, and we obtained a sample of 106,261 communications through the analysis of apis and web scraping techniques. this study examines how social media has affected risk communication in uncertain contexts and its impact on the emotions and sentiments derived from the semantic analysis in spanish society during the covid-19 pandemic. the outbreak of the coronavirus disease was first reported by the wuhan municipal health and safety commission (hubei province, china) on 31 december 2019. one month later, the emergency committee of the international health regulations [1] declared the new coronavirus outbreak as a public health emergency of international importance (phei) at its meeting on 30 january 2020 [2] . five months after the official announcement, the virus has infected more than 6, 193 ,548 people worldwide and killed around 372,479 people [3], bringing catastrophic consequences for society [4] , completely collapsing health systems in different countries [5] and generating a strong economic recession worldwide [6] . throughout the history of mankind, societies have been faced with crises of various kinds and of very diverse natures, such as civil conflicts, financial crises, crises caused by the management and export of energy resources or emergencies caused by the impact of diseases and epidemics, among others [7] . it is only necessary to recall some of the events of the past 20th century to be able to appreciate how figure 1 shows the trend in reported cases of covid-19, deaths, and recoveries patients between 25 february 2020 and 29 may 2020. it is verified that the highest level of cases by coronavirus was on 31 march 2020 and deceased people on april 1. after these days, the curve of new infections and deaths trended downward and recovered people were increasing. face masks were a problem, especially at the beginning of the pandemic. initially, they were not available to the general population, so they were only used for those most at risk of infection, such as health care, security forces, and the military. the government of spain was responsible for the purchase and distribution of face masks to the autonomous communities. figure 2 shows the distribution of face masks carried out by the government between march 10 and may 29. madrid and catalonia, with the highest number of infections from covid-19, were where most face masks were distributed. face masks were a problem, especially at the beginning of the pandemic. initially, they were not available to the general population, so they were only used for those most at risk of infection, such as health care, security forces, and the military. the government of spain was responsible for the purchase and distribution of face masks to the autonomous communities. figure 2 shows the distribution of face masks carried out by the government between 10 march and 29 may. madrid and catalonia, with the highest number of infections from covid-19, were where most face masks were distributed. int. j. environ. res. public health 2020, 17, x 3 of 22 figure 1 shows the trend in reported cases of covid-19, deaths, and recoveries patients between 25 february 2020 and 29 may 2020. it is verified that the highest level of cases by coronavirus was on 31 march 2020 and deceased people on april 1. after these days, the curve of new infections and deaths trended downward and recovered people were increasing. face masks were a problem, especially at the beginning of the pandemic. initially, they were not available to the general population, so they were only used for those most at risk of infection, such as health care, security forces, and the military. the government of spain was responsible for the purchase and distribution of face masks to the autonomous communities. figure 2 shows the distribution of face masks carried out by the government between march 10 and may 29. madrid and catalonia, with the highest number of infections from covid-19, were where most face masks were distributed. this research work represents a pioneering challenge in the field of risk communication research. during the months of march and april 2020, various digital ecosystems were analyzed, and a sample of 106,261 communications was obtained through the analysis of apis and web scraping techniques. the study analyzes, through social media, how risk communication management has masks that the spanish government has distributed to each autonomous community from march 10 to may 29 [24] . the communication makes explicit reference to the covid-19 pandemic in spain. the communication is public and can be viewed without the need for a subscription to the data source or explicit permission from the sender of the communication. the author's reported age, when available, was over 18 years old as of the start of the end of the study (30 april 2020). the communication is written in spanish. on the other hand, the exclusion criteria were: • the communication does not come from an advertising campaign. the communication has not been generated by automatic procedural methods (bots, fake posts, among others). one of the most usual problems that we must deal with when using information from digital ecosystems is detecting spammers, fake information generated by bots, which tries to influence or modify the perceived opinion on existing information. to detect and discard this type of information we have implemented different types of algorithms based on support vector machine (svm) techniques which can detect the patterns of this kind of communications, such as the age of the account (in days), the number of comments from the account, follower/following ratio, and the ratio of messages containing urls. to prevent the effect of spammers, in this work we implemented and applied filters previously defined and tested in other scientific works [27, 28] . the emotion information from each communication was extracted employing the natural language analysis tools provided by the ibm watson analytics service [29] . the emotional intensity was measured in a 0 to 1 scale, where 0 represents the complete absence of this emotion; and 1 represents an absolute high intensity of the emotion. in total, this study measured the emotional intensity of four primal emotions-anger, fear, disgust, and sadness. to detect and measure the primary emotions in this study we used the services provided by the ibm watson system. watson is a cognitive computing platform that combines a deepqa architecture, with ai algorithms and big data to solve questions in the domain of natural language. this platform offers a wide range of services including discovery, knowledge studio, language translator, natural language classifier/understanding, and personality insights among others. watson has an overall precision of 97% in natural language processing and has been widely compared with other systems, as well as with humans, and in both cases, it has obtained very satisfactory results. for this reason, this system has been widely used in different scientific works where it has further proved its capabilities on natural language processing (nlp) tasks [30] [31] [32] [33] [34] [35] . in this work, we made use of the natural language understanding service from the ibm watson platform which, given an input text, provides an analysis of syntactic characteristics as well as information on categories, concepts, emotions, entities, keywords, metadata, relationships, and semantic roles. the reliability of the resultant emotion information was tested using the interval majority aggregation operator (isma-owa) [36] , which is designed for decision making in social media with consistent data, leveraged by the combination of computational intelligence and big data techniques [37] . to obtain representative results, when analyzing with information extracted from digital ecosystems, it is important to ensure a correct representation of such information and its quality. when people express opinions in communications, they do not do so in numerical value with a fixed scale, they use natural language expressions such as "this is great" or "this is not so good", so we employed the intervalar representation proposed in [36, 38] instead of a numerical scale. the main advantage of this approach is that intervals represent the information within communication in a way that is more similar to the way people express themselves in digital ecosystems, thus reducing the loss of information associated with forcing linguistic data to a hard-numerical scale. furthermore, regarding information quality, an important aspect that we must consider when assessing the validity of this information is to ensure that such information has been expressed with knowledge of the topic at hand and not at random. another advantage of the usage of an intervalar representation of digital ecosystem data is the availability of consistency indices that can be applied to the matrices obtained from communications to detect inconsistencies derived from uninformed opinions. for this purpose, in this work, we employed the ci+ index defined in [39] . the frequency of the words comprising the sample of communications was calculated using a natural language processing algorithm implemented in python 3, using the natural language toolkit (nltk) [40] . moreover, the emotion polarity (positive or negative) was measured using a multilayer perceptron model, trained to classify the emotional weight of written communications [38, 41] . the python nltk library is an open-source programming library for working with natural language data which incorporate functions that allow for the determination of the frequency of words in a text while discarding stop-words, that is words that are very common to a language but do not convey any significant information such as "the", "a" and "very". furthermore, the nltk library serves as a pre-processing tool to use other artificial intelligence tools such as artificial neural networks such as the multi-layered perceptron that we used in this work to detect the polarity of communications. a multi-layered perceptron (mlp) is a widely used artificial neural network architecture that utilizes a technique known as supervised training to learn how to differentiate data that is not linearly separable. in this case, we trained our mpl with a set of communications created by the spanish society for natural language processing (sepln) which contains over 100,000 natural language texts tagged with the polarity of each communication, that is, each communication contained metadata that indicated if the message was positive or negative. there are other techniques for natural language sentiment analysis, such as naïve bayes, or support vector machines, but we opted for the mlp approach since it can learn complex relationships and it does not enforce any sort of constraint concerning the input data [42] . to further improve the qualitative analysis, the above-mentioned information regarding the volume of communications, the frequency of words and the emotion expressed by each communication was contrasted to determine the information pathways between mass media, government, political parties, employers' confederation, non-governmental organizations (ngos), trade unions, the world health organization (who), among others. this approach provides a graphical representation of the information fluxes about the covid-19 disease in spain. for the analysis of the messages emitted by the spanish government, a content analysis of all press releases during the period of study was carried out. messages were classified as positive, neutral, or negative by selecting the most significant words from them. the frequency of repetition of these words was another objective of this content analysis. the result has been shown through a word cloud representative of the emotions and feelings expressed by the government in its press releases. the analysis of content permits inferences to be reproduced based on specific characteristics identified in the messages [43, 44] . this type of analysis allows for the discovery of tendencies and the revelation of differences in content communication. likewise, this allows the comparison of messages and means of communication, and the identification of intentions, appeals. to this effect, value and frequency analysis were used [45] . since the beginning of the pandemic, the structure organized by the government has involved relations between the spanish government (the health alert coordination center, which is part of the ministry of health) and the governments of the autonomous communities, the national epidemiology center, the national microbiology center and the international organization's world health organization (who), the european disease control center and the european commission [46] . to raise awareness and inform public opinion, the spanish government designed a communication strategy articulated in four actions that had the use of the mass media as channels of transmission of covid-19 information as a main objective: (a) weekly appearances of the president of the government. (b) daily press conferences chaired jointly by the following ministers: minister of health, who is responsible for the state of alarm decreed in the country; minister of defense, who is responsible for the military forces; minister of the interior, who is responsible for the state security forces and minister of transport. all of them were accompanied by experts in each of the areas. the ministers sent out a political message and the experts went into detail about the actions being taken. with a press conference format, online questions from the main spanish and foreign media were admitted. however, this format underwent the first modification after the second week being responsible for the press conferences the so-called "technical committee for monitoring the coronavirus pandemic in spain" consisting only of experts of the different ministries. on 25 april, there was a new restructuring of the press conferences, leaving only the director of the health alert and emergency coordination centre of the ministry of health as the health expert. this last change is censored by the communications media. (c) press release. after the appearance at a press conference, the communication department of the ministry of health sent a press release to all the media. (d) interviews with ministers. another of the government's actions was to make its cabinet available to the media for interviews. to reinforce the previous actions, on march 15 , the state government launched the advertising campaign #estevirusloparamosunidos. this campaign is adapted for television, press, radio, outdoor advertising, and social networks. in a public health crisis like the one spain is experiencing, a transparent and empathetic communication style would generate citizen confidence and would be more effective if politicians and experts unanimously tried to stimulate the population to take a positive stance towards the pandemic and the health and economic alert measures imposed by the government. although the generation of trust must be essential in a crisis, the analysis carried out shows the public's distrust of scientific experts and government representatives for a variety of reasons such as access to conflicting sources of information, contradictions in scientific reasoning, changes in decision-making and, above all, political confrontations. trust and credibility, demonstrated through empathy, experience, honesty, and transparency, are essential elements of public health crisis communication [18] . figure 4 analyzes the messages transmitted by the ministry of health in its press releases between march and april. in green, the positive messages were determined, in black the neutral ones and in red the negative ones. the word size indicates the frequency of repetition in the press releases. as can be seen in the word cloud, the negative word "covid" is the most used by the government in its communications. this is followed at a distance by "coronavirus" and "health crisis" with a dark red color that indicates their use in negative messages, but also in neutral tones. "social networks" is a neutral term used mainly to explain the social network campaigns implemented by the government. it is followed by "patients" and "nursing home". however, the most remarkable thing about this word cloud is its words in the green. the communication made by the communication office of the ministry of health has always wanted to give a positive view in all their messages, with "government" as the most used word, followed by "face masks", "ministry of health" or "test". this could indicate a lack of transparency about the situation the country was going through. none of these press releases refer to either the infected or the dead. attempts are made to give a protagonist role, at times, to all the actions carried out by the government. in spain, the decreed state of alarm requires the total confinement of the population. royal decree-law 10/2020, of 29 march 2020 [47] , establishes the minimum essential services of first necessity such as all those necessary for the supply of food to the population. the minimum distance was made to be one and a half meters. except for these cases, the rest of the population must carry out their work by teleworking, and if this work is not possible, the government approved royal decree-law 8/2020 of 17 march on extraordinary urgent measures to cope with the economic and social impact of covid-19 [48] , which regulates emergency procedures to combat the economic and social impact of the pandemic, denominated as the temporary employment regulation file (terf). the number of workers affected by the terf was two million on 3 april [49] . the high number of terf requests blocks the administration from responding to the citizens with a decrease of the collection of these aids and the decapitalization of these workers in some cases without the possibility of paying the rents of their houses or simply buying the necessary food for the family. non-governmental organizations and food banks have a crucial role to supply the neediest in the population. during confinement, the media are not left out. their workers follow their work from their homes. on televisions, these measures cause programs to be suspended and replaced by new programming offering coronavirus specials. these programs have a structure of news, interviews with experts or politicians, discussion programs or talk shows where covid-19 and the situation that citizens are experiencing are analyzed. due to the uncertainty of the situation and the isolation in their homes, citizens are consuming more television. thus, the month of march and later april became the months with the highest television audience in spanish history. march data show an average consumption of 282 min per person per day (4 h and 42 min). the average number of people who had watched tv for at least one minute a day was 369 min (6 h and 9 min) [50] . the progression in the television audience continued in the month of april with numbers never seen in the conventional spanish television with 302 min (5 h and 2 min) and 395 min (6 h and 35 min) respectively. in addition to television coverage, 33.6 million spaniards consumed this medium daily, representing 74.2% of the population [51] . the serious effects on the economy caused by the crisis determine that new actors acquire an active role in communication by modifying the initial panorama organized by the government. political parties, the confederation of employers and trade unions are configured as sources of information. these new stakeholders also offer interviews to the communication media, organize press conferences, and finally communicate with citizens directly through social media (see figure 1) . therefore, the stakeholder structure created by the government is increased by other social actors who have their own opinion on the management of the pandemic. all of them have in common the use of the media to convey their messages to the citizens, converting these media as the main interlocutors with the population. the high consumption of television makes it the main means of information used by citizens. public and private televisions in spain broadcast the press conferences of the different stakeholders and the appearances of the president of the government. this is referred to in figure 1 as "news". the different ideological tendencies of the television channels in spain mean that their interview programs with experts and television debates do not follow a single argument in support of the government's management. these messages feature contradictory opinions that the media convey to the public as interviews, discussion programs, and talk shows, which increase uncertainty among citizens (figure 3 ). in a public health crisis like the one spain is experiencing, a transparent and empathetic communication style would generate citizen confidence and would be more effective if politicians and experts unanimously tried to stimulate the population to take a positive stance towards the pandemic and the health and economic alert measures imposed by the government. although the generation of trust must be essential in a crisis, the analysis carried out shows the public's distrust of scientific experts and government representatives for a variety of reasons such as access to conflicting sources of information, contradictions in scientific reasoning, changes in decision-making and, above all, political confrontations. trust and credibility, demonstrated through empathy, experience, honesty, and transparency, are essential elements of public health crisis communication [18] . figure 4 analyzes the messages transmitted by the ministry of health in its press releases between march and april. in green, the positive messages were determined, in black the neutral ones and in red the negative ones. the word size indicates the frequency of repetition in the press releases. as can be seen in the word cloud, the negative word "covid" is the most used by the government in its communications. this is followed at a distance by "coronavirus" and "health crisis" with a dark red color that indicates their use in negative messages, but also in neutral tones. "social networks" is a neutral term used mainly to explain the social network campaigns implemented by the government. it is followed by "patients" and "nursing home". however, the most remarkable thing about this word cloud is its words in the green. the communication made by the communication office of the ministry of health has always wanted to give a positive view in all their messages, with "government" as the most used word, followed by "face masks", "ministry of health" or "test". this could indicate a lack of transparency about the situation the country was going through. none of these press releases refer to either the infected or the dead. attempts are made to give a protagonist role, at times, to all the actions carried out by the government. in contrast, figure 5 shows the results of the 106,261 listings made on social media between the same months and shows the feelings and emotions of the population. on this occasion, the word "cases" is the most representative that reflects the number of infections suffered in the country. it is followed by the word "crisis", which represents the public health crisis but also the economic one. the terms "covid" and "coronavirus" are strongly represented, as well as "spain" and "world" which represent the concern of the population in the face of a pandemic of this magnitude. "casualties" is another of the most significant words and is indicative of all those people who have benefited from the terf and who have not yet received the promised aid from the government. the positive messages sent by the government and its experts are counterbalanced by the volume of opinion generated by the media and especially the generalist televisions. some reasons include political parties' criticism of the government's management, contradictions of the experts, the constant increase of infected and dead, spain being among the most affected countries, the state of confinement suffered by society not always in the best conditions, the anxiety of not having financial resources, the population's insecurity in the face of a public health crisis with global effects that are caused by millions of infected people and hundreds of thousands of deaths in the world. all these reasons generate negative feelings and emotions, causing uncertainty and fear among citizens. digital ecosystems reflect this trend in a word cloud with a markedly negative character ( figure 5 ). in contrast, figure 5 shows the results of the 106,261 listings made on social media between the same months and shows the feelings and emotions of the population. on this occasion, the word "cases" is the most representative that reflects the number of infections suffered in the country. it is followed by the word "crisis", which represents the public health crisis but also the economic one. the terms "covid" and "coronavirus" are strongly represented, as well as "spain" and "world" which represent the concern of the population in the face of a pandemic of this magnitude. "casualties" is another of the most significant words and is indicative of all those people who have benefited from the terf and who have not yet received the promised aid from the government. the positive messages sent by the government and its experts are counterbalanced by the volume of opinion generated by the media and especially the generalist televisions. the communications that have the greatest impact on four of the main emotions of the population-fear, sadness, disgust, and anger-are presented. the study has allowed for the some reasons include political parties' criticism of the government's management, contradictions of the experts, the constant increase of infected and dead, spain being among the most affected countries, the state of confinement suffered by society not always in the best conditions, the anxiety of not having financial resources, the population's insecurity in the face of a public health crisis with global effects that are caused by millions of infected people and hundreds of thousands of deaths in the world. all these reasons generate negative feelings and emotions, causing uncertainty and fear among citizens. digital ecosystems reflect this trend in a word cloud with a markedly negative character ( figure 5 ). the communications that have the greatest impact on four of the main emotions of the population-fear, sadness, disgust, and anger-are presented. the study has allowed for the determination of the reaction of the population concerning the covid-19 pandemic and the crisis communication carried out by the government, determining the themes and the feelings of the communications associated with the crisis communication. to this end, the emotion graph corresponding to the period of study is first determined, determining the peaks of emotion that are significant, and those news patterns that generate greater presence and reach in digital ecosystems. secondly, the topics that have most influenced these emotions are analyzed and the patterns that generate them are concluded. figure 6 shows the evolution of the disgust emotion during the study period, where nine peaks can be distinguished where the emotion shows a significant increase. in table 1 , the communications that had the greatest impact on this increase are analyzed in chronological order from 1 march 2020 to 30 april 2020. from these communications, the management of the pandemic is the general theme that most impacts the emotion treated. aspects such as: blaming the pandemic on groups that can be grouped by religion, sex, use of the security forces to censor the population's opinion; lack of care for weak sectors such as the elderly; and the purchase of health material are the conversations that predominate in digital ecosystems. • the religious community is eager for the ministry of health to "point them out" because it leaves them in a "state of defenselessness" and they demand an apology. the evangelicals see it as "very serious" that the ministry of health points to a religious group as a possible focus. 23 march 2020 • a collapse in funeral homes and mortuaries. • spanish health workers are the worst protected. the government is withholding health materials from autonomous communities. the risk of coronavirus is due to gender roles. 14 april 2020 • purchase of masks from opaque companies. the government forces companies to provide workers with protective measures when they cannot buy material. the government spends money on protecting cars when there is a lack of material in hospitals and nursing homes. 20 april 2020 • government members fail to comply with confinement. • government management to protect against future malpractice claims. the political use of pandemic management. use of the guardia civil to minimize the anti-government climate. 23 april 2020 • government control of the media. higher payment for medical equipment by the government. lack of material for workers and they are forced to return to work. the hiring of companies without guarantees to obtain sanitary material. 28 april 2020 • use of the police and confinement to control complaints from the population. the government admits that it lies about the number of tests performed. false count in the number of deaths. finally, in figure 7 , the most relevant topics and their impact value on the emotion of disgust are shown. this shows how the management of masks, censorship in the news, and the transmission of the virus in general and especially in groups of elderly people, predominate in this emotion. figure 8 shows the evolution of the fear emotion during the study period, where five peaks can be distinguished, where the emotion shows a sustained decrease over time. in table 2 , the communications that have had the greatest impact on this temporal progression are analyzed in chronological order from 1 march 2020 to 30 april 2020. of these communications, the rapid growth of the pandemic in spain, the overwhelming social security system, and the economic collapse caused by the covid-19 pandemic are the general themes that have the greatest impact on the emotions addressed. aspects such as border closures, death forecasts, job losses, defective health material, the spanish government being overwhelmed, and deaths in residences are the conversations that predominate in digital ecosystems. finally, figure 9 shows the most relevant issues and their impact value on the emotion fear. this shows how interest in the state of alarm, the transmission of the virus, emergency health material, and deaths of family members predominate in this emotion. figure 10 shows the evolution of the anger emotion during the study period, where eight peaks can be distinguished where the emotion shows sustained growth over time. in table 3 , the communications that had the greatest impact on this temporal progression are analyzed in chronological order from 1 march 2020 to 30 april 2020. from these communications, it can be seen that the loss of employment due to lack of foresight, the delay in activating the health alert, and the opacity in the acquisition of health material by the spanish government during the crisis by covid-19 were the driving themes in this case. aspects such as disinformation for de-escalation, the collapse of the health system, the dubious data on the number of infected and dead people, and the control of the media proposed by members of the spanish government are some of the conversations that predominate in digital ecosystems. finally, figure 11 shows the most relevant topics and their impact value on the anger emotion. this shows how the interest in deaths by a coronavirus, the resources to cure the virus, the diagnosed cases, and the rate of infected, predominate in this emotion. this shows that the lack of prevision predominates in this emotion. figure 11 . the themes related to covid-19 and anger emotion that have impacted most along with its impact value. figure 12 shows the evolution of the sadness emotion during the study period, where eight peaks can be distinguished where the emotion shows sustained growth in time. in table 4 , the communications that had the greatest impact on this temporal progression are analyzed in chronological order from 1 march 2020 to 30 april 2020. of these communications, censorship during covid-19, die of coronavirus, coronavirus patients, infection of coronavirus, and the delay in the incorporation to the labor activity are the general themes that have the greatest impact on the emotion dealt with. aspects such as political interests, entities that the security of the population due to the virus, sale of necessary material by the covid-19 pandemic to foreign countries when it is necessary for spain, healthcare workers exposed to infection by defective health care material are some of the conversations that predominate in digital ecosystems. finally, figure 13 shows the most relevant topics and their impact value on sadness's emotion. this shows how the interest in deaths by covid-19, patients by covid-19, the elderly, and infected workers, predominate in this emotion. as shown in figure 14 , the highest presence of the term covid-19 occurred in the early stages of the pandemic, reaching its highest value on the date when the government of spain announced that it would implement the state of alarm and confinement of the population. from that date onwards, there is a downward trend in the use of this term, until 5 april, when an extension of the state of alarm is announced. the spread of pandemics causes uncertainty and fear among the population. this type of crisis, by not adjusting to specific limits, makes risk communication more critical when designing effective strategies [52, 53] . effective risk communication means that all messages can be presented and shared with the population in a transparent, credible, and easily understood communication process. its main objective is to reduce the knowledge gap between the issuers of information and its recipients to adjust public behavior to proactively address risk [54, 55] . the essential elements for reducing risk and avoiding panic among the population are rapid action by public health organizations and truthful and honest information from governments [56] . even though rodin et al. [57] indicate that in the case of a crisis in public health, stakeholders are structured in international and national public health organizations, national governments, nongovernmental organizations, the media, and citizens, the serious situation experienced in spain has led to new actors taking on a decisive role in communication, modifying the organizational structure originally designed by the government. therefore, the little or no dialogue between the government and the social actors that make up the map of the main publics involved in the covid-19 crisis with different points of view in the face of the pandemic leads to the conclusion that the structure of the stakeholders involved does not determine singular, clear and efficient communication that gives confidence to society. the analysis of the government's communication management shows that the messages emitted, mostly with a positive tone, have been offset by a flow of information from other actors in disagreement with government policies. these are mainly channeled by the media and especially the generalist televisions. in spain, three out of four citizens have used generalist television to keep themselves informed during the pandemic. television is also the medium most used by spaniards to seek out different expert opinions. finally, seven out of ten spaniards say that the diversity of journalists, approaches, and news items on generalist television help them form their own opinions [58] . this information, sometimes contradictory, that reaches the population makes uncertainty and panic be perceived by the citizens through digital ecosystems. there are significant differences between the feelings and emotions of the public about covid-19 analyzed in this study and the tone of the risk communication carried out by the spanish government and the committee of experts represented in figure 4 . risk communication has very close links to the behavioral health issues that affect tens of millions of people. fear and anxiety about a new disease and what could happen can be overwhelming and cause strong emotions in the population. through the monitoring of the emotions and the general sentiment of the people across social media about the covid-19 pandemic reveals that: during this time, the use of the term covid-19 followed a decreasing tendency, motivated by the emotions that the population experienced. if at the beginning, the great concern was the virus, the management carried out by the government, the deaths, the social actions, all caused a change in the terms used in the digital ecosystems, with the virus being a secondary problem about the subjects that influence the emotions. the spread of pandemics causes uncertainty and fear among the population. this type of crisis, by not adjusting to specific limits, makes risk communication more critical when designing effective strategies [52, 53] . effective risk communication means that all messages can be presented and shared with the population in a transparent, credible, and easily understood communication process. its main objective is to reduce the knowledge gap between the issuers of information and its recipients to adjust public behavior to proactively address risk [54, 55] . the essential elements for reducing risk and avoiding panic among the population are rapid action by public health organizations and truthful and honest information from governments [56] . even though rodin et al. [57] indicate that in the case of a crisis in public health, stakeholders are structured in international and national public health organizations, national governments, non-governmental organizations, the media, and citizens, the serious situation experienced in spain has led to new actors taking on a decisive role in communication, modifying the organizational structure originally designed by the government. therefore, the little or no dialogue between the government and the social actors that make up the map of the main publics involved in the covid-19 crisis with different points of view in the face of the pandemic leads to the conclusion that the structure of the stakeholders involved does not determine singular, clear and efficient communication that gives confidence to society. the analysis of the government's communication management shows that the messages emitted, mostly with a positive tone, have been offset by a flow of information from other actors in disagreement with government policies. these are mainly channeled by the media and especially the generalist televisions. in spain, three out of four citizens have used generalist television to keep themselves informed during the pandemic. television is also the medium most used by spaniards to seek out different expert opinions. finally, seven out of ten spaniards say that the diversity of journalists, approaches, and news items on generalist television help them form their own opinions [58] . this information, sometimes contradictory, that reaches the population makes uncertainty and panic be perceived by the citizens through digital ecosystems. there are significant differences between the feelings and emotions of the public about covid-19 analyzed in this study and the tone of the risk communication carried out by the spanish government and the committee of experts represented in figure 4 . risk communication has very close links to the behavioral health issues that affect tens of millions of people. fear and anxiety about a new disease and what could happen can be overwhelming and cause strong emotions in the population. through the monitoring of the emotions and the general sentiment of the people across social media about the covid-19 pandemic reveals that: research shows that the current covid-19 pandemic is creating an added strain on our emotional well-being. topics and themes connected to covid-19 include management, social collaboration, death, safeguarding, and lack of foresight. those are strongly related to health and finances, uncertainty about the length of the quarantine, anger over the loss of control, fear of death, illness, loss of employment, economic instability, loss of loved ones, discontent with the spanish government, transparency, a sense of loneliness and, ultimately, fear of the unknown. research results also demonstrate a lot of mixed feelings. it is observed that the same news, information or media communication generated peaks in different emotions, indicating that they are very mixed between sadness, disgust, anger, and fear. presence analysis reveals that the term covid-19 received the highest presence during the early stages of the pandemic, reaching its highest value on the date when the government of spain announced that it would implement the state of alarm and confinement of the population. from that date onwards, there is a downward trend in the use of the term covid-19. during this time, the use of the term covid-19 has followed a decreasing tendency, motivated by the emotions that the population has experienced. initially, as reflected in the study, only the virus (term covid) was of interest, and later, the consequences and direct impact of the virus on daily life. statement on the second meeting of the international health regulations (2005) emergency committee regarding the outbreak of novel coronavirus (2019-ncov); 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ministry of health of the government of spain masks that the spanish government has distributed to each autonomous community from march 10 to government communication in the digital age: social media's effect on local government public relations cifras de población (cp) a 1 de julio de 2019 detecting spammers on social network through clustering technique detecting spammers on social networks automating visualization, descriptive, and predictive statistics using twitter to better understand the spatiotemporal patterns of public sentiment: a case study in massachusetts, usa ibm watson analytics cloud platform as analytics-as-a-service system for heart failure early detection. futur. internet the online dissemination of nature-health concepts: lessons from sentiment analysis of social media relating to recognizing language and emotional tone from music lyrics using ibm watson tone analyzer the anatomy of a large-scale hypertextual web search engine practical text classification with large pre-trained language models decision making in social media with consistent data. knowl.-based syst estimating the importance of consumer purchasing criteria in digital ecosystems products and services valuation through unsolicited information from social media consistency in positive reciprocal matrices: an improvement in measurement methods natural language processing with python text analytics: the convergence of big data and artificial intelligence methodological study of opinion mining and sentiment analysis techniques automated content analysis and crisis communication research content analysis: an introduction to its methodology populism and independence movements in europe: the catalan-spanish case actualización n • 13. numonía por nuevo conavirus (2019-ncov) en wuhan, provincia de hubei, (china); ministry of health of the government of spain real decreto-ley 10/2020, de 29 de marzo, por el que se regula un permiso retribuido recuperable para las personas trabajadoras por cuenta ajena que no presten servicios esenciales, con el fin de reducir la movilidad de la población en el contexto de la l real decreto-ley 8/2020, de 17 de marzo, de medidas urgentes extraordinarias para hacer frente al impacto económico y social del covid-19 el número de trabajadores afectados por erte se aproxima ya a los dos millones bajo 374 marzo se convierte en el mes de mayor consumo de tv en españa desde que hay registros, según un estudio abril marca un récord histórico mensual de consumo televisivo: 5 horas y 2 minutos diarios por persona appropriate governance responses to infectious disease threats: developing working hypotheses. risk hazards cris climate change and vector-borne diseases: what are the implications for public health research and policy? philos the public and effective risk communication effective risk communication; routledge: london, uk effective risk communication disentangling rhetorical subarenas of public health crisis communication: a study of the 2014-2015 ebola outbreak in the news media and social media in sweden sobre la percepción social de la televisión en abierto the authors declare no conflict of interest. key: cord-343938-0pr18nc9 authors: de la cuesta-gonzález, marta; froud, julie; tischer, daniel title: coalitions and public action in the reshaping of corporate responsibility: the case of the retail banking industry date: 2020-05-25 journal: j bus ethics doi: 10.1007/s10551-020-04529-x sha: doc_id: 343938 cord_uid: 0pr18nc9 this paper addresses the question of whether and how public action via civil society and/or government can meaningfully shape industry-wide corporate responsibility (icr) behaviour. we explore how, in principle, icr can come about and what conditions might be effective in promoting more ethical behaviour. we propose a framework to understand attempts to develop more responsible behaviour at an industry level through processes of negotiation and coalition building. we suggest that any attempt to meaningfully influence icr would require stakeholders to possess both power and legitimacy; moreover, magnitude and urgency of the issue at stake may affect the ability to influence icr. the framework is applied to the retail banking industry, focusing on post-crisis experiences in two countries—spain and the uk—where there has been considerable pressure on the retail banking industry by civil society and/or government to change behaviours, especially to abandon unethical practices. we illustrate in this paper how corporate responsibility at the sector level in retail banking is the product of context-specific processes of negotiation between civil society and public authorities, on behalf of customers and other stakeholders, drawing on legal and other institutions to influence industry behaviour. the scrutiny by governments, non-government organisations and civil society that followed the great financial crisis highlighted how banks can abuse their position as powerful economic intermediaries in pursuit of shareholder value creation. in particular, banks were observed to engage in value extraction through fees or speculative activities disembedded from the real economy (muellerleile 2013) and have collectively resisted calls for change, despite significant and sustained national and international uproar about unethical practices. this is important for two reasons in relation to the wider importance of banking in everyday economic and social life. first, as providers of banking, credit, insurance and other services for small-and medium-sized business, retail banks fulfil important intermediary and enabling functions (froud et al. 2017) . second, access to finance through bank accounts and other financial services is essential for citizens' economic and social participation (schmidt et al. 1999; allen and santomero 1998) . in this sense, retail banking is a foundational infrastructure (froud et al. 2018 ). yet instead of ensuring this basic functionality, banks' actions to defend profitability have had deleterious effects on their customers, including mis-selling of financial products, collapse of small business lending, mortgage foreclosure and retail branch closures (froud et al. 2017; paulet et al. 2015; vives-miró and gutiérrez 2017) . these behaviours are contrary to those we might expect from banks as socially responsible actors; and they are in contrast to the positive impact banks can have on financial inclusion, economic and social development (fernández-olit and de la cuesta-gonzález 2014). in principle, curbs on unethical bank behaviour could result from government action, investor-led initiatives or other pressures from external actors, whereby organisations are compelled or at least encouraged to meet wider stakeholder interests. governments have tended to see this as the role of investors, and many businesses (including banks) have adopted investor-led corporate social responsibility (csr) initiatives to address expectations related to broader impacts on society, the economy and the environment (de bakker et al. 2013; doh and guay 2006; schaltegger and burritt 2010; steurer 2010) . this positivist or instrumental approach to csr recognises stakeholder demands for the primary purpose of sustaining or improving profitability and shareholder value (esteban-sánchez et al. 2017 ) but leaves limited opportunity to meaningfully alter business models or the ethical foundations of business (sternberg 2011) . this approach is also centred on easily quantifiable aspects of responsibility (maniora 2017 ) more than the impact of their intermediary activity on customer welfare and society (fernández-olit and de la cuesta-gonzález 2014). in this sense, corporate responsibility has often been a documentary artefact accounting for the positive impact of the business on society in annual accounts or standalone reports rather than providing meaningful accounts of ethical business behaviour (coupland 2006, p. 3) . such reporting therefore becomes a way of recognising aspects of behaviour that a firm can address-employee diversity or carbon emission reduction programmes, or additions such as sponsoring activities (gao and bansall 2013 )without business ethics effectively incorporated into decisions about the underlying business model (maniora 2017; sternberg 2011) . it is not surprising then that critical observers suggest these instrumental approaches to csr represent corporate 'window dressing', in which social responsibility is treated as an add-on to core operations (frankental 2001; lewis 2016; schaltegger and burritt 2010) . such initiatives do not in themselves embed and normalise responsible behaviour. indeed, the recurrence of socially and economically irresponsible or unethical behaviour by firms individually and collectively raises questions about whether organisation-level actions can provide a meaningful approach to tackle (fundamental) problems characterising an industry (fernández-olit et al. 2019) . drawing on these important themes, this paper considers responsibility initiatives affecting firms across an industry which are the outcome of actions by industry stakeholder coalitions rather than arising through voluntaristic action. such actions are considerably rarer than instrumental, firmlevel csr, despite efforts by civil society to scale up collaborations to target a whole industry (den hond et al. 2014 ). the benefit of assuming an industry perspective lies in what beschorner and hajduk (2017) call 'the downscaling effect': within an industry context, responsibility can be substantiated and thus made clear and manageable for companies and their stakeholders. the industry-level corporate responsibility (icr) framework draws attention to 'interactions between businesses, ngos, political actors and other organisations', (powell and dimaggio 1991; beschorner 2004 ) which may be more evident at an industry rather than an individual firm level. in the specific case of retail banking considered in this paper, 'reform' ambitions emerged before, during and after the crisis, reflecting a significant gap between bank behaviour and expectations of fair and effective financial services held by civil society, private and business customers. misselling of financial products, closure of bank branches (especially in rural areas), failure to lend to small-and mediumsized enterprises (smes), as well as irresponsible lending on property have variously emerged as endemic problems requiring sector-level action (fernández-olit et al. 2019; froud et al. 2017) . the paper addresses the question of whether and how public action (via civil society and/or government) can meaningfully affect industry-wide corporate responsibility behaviour. where problems extend over a sector and challenge the basic function of retail banks from a stakeholder perspective, have actions to improve corporate responsibility been coordinated rather than left to the discretion of individual banks? to explore these issues, we focus on post-crisis experiences in two countries, spain and the uk. these are chosen because, in both cases, there has been considerable pressure from civil society on the retail banking industry to abandon certain activities (mis-selling, repossessions) or counteract others (failure to lend to smes) to curb negative impacts on customers. here, retail banks are economic and political actors (matten et al. 2003; scherer et al. 2006 ) and corporate responsibilities are primarily viewed as reaction to wider changes in societal institutions (dubbink 2004) and to civil society ambition to shift corporate attention and resources towards societal challenges (scherer and palazzo 2011) . socially responsible bank behaviour is therefore not simply an outcome of immediate stakeholder pressures, but a response to democratic forces to curb corporate power towards enacting public needs (driver and thompson 2002; parker 2002) . our analysis engages critically with beschorner et al.'s (2013, p. 26f) conception of icr as embedded in sector-specific collaborative efforts between firms, government and other stakeholders. coalition building and alignment of interests are key success factors. however, the emphasis on icr as collaboration can obfuscate the role of stakeholders in bringing about that change in the absence of industry engagement. therefore we introduce an alternative view of icr as a politically charged negotiation between industry and its stakeholders. we choose retail banking to explore these themes because this industry has been overwhelmingly inactive in responding to problems caused collectively by its members. rather, as explored in this paper, it has been civil society-with public authorities providing necessary though limited support-which has played a key role in recognising problems and engaging retail banks through a process of negotiated responsibility. from a bank perspective, such responsibility is reactive, or even coerced, not developed internally (see, for example, scholte 2013). this analysis acknowledges that industries (and firms as their constituent actors) are primarily concerned with their ability to continue with business-as-usual and may not initiate change, especially when profits will be affected. with this in mind, we show that icr is driven by powerful and legitimate interventions from civil society and government. we focus on these actors not because they are the only possible agents of change, but because they have the capacity to campaign for, or to pressure industry members to adopt more responsible behaviours. the next part of the paper explores the concept of icr and the role of interest alignment and coalition building in achieving a change in ethical behaviours. the spanish and uk retail banking sectors are introduced in the third section, which outlines the extent of corporate responsibility initiatives since 2008. the fourth section then takes two examples to explore the role of civil society in negotiations that eventually led to actions. while notable, the impact of these actions is limited: successful actions have been fragmentary and industry behaviour remains largely reactive, constituting individual redress rather than a more generalised ethical orientation. the implications are considered in the final section. in this section, we outline and develop the concept of industry-level corporate responsibility to explore how stakeholders may be able to negotiate through coalitions and alignments of interests to affect the operation of firms in an industry. the analysis draws on the literature to address two questions: first, how in principle icr might come about, either through industry leadership or coalition building by stakeholders, before exploring resistances to change; and, second, what conditions might allow some actions to be more effective, including the importance of power, legitimacy, magnitude and urgency. an industry-level approach to responsibility represents a relatively new understanding of how firms collectively engage with stakeholder interests on a voluntary basis or under compulsion. beschorner et al.'s (2013, p. 26f .) icr framework draws attention to 'interactions between businesses, ngos, political actors and other organisations', to secure the adoption of corporate responsibility policies as a specific 'organisational field' (powell and dimaggio 1991; beschorner 2004) . for this to be successful, business, civil society and government actors necessarily share assumptions about what corporate responsibility means in a specific industry context. beschorner et al. (2013) argue that, prior to the adoption of icr, key stakeholders (customers, worker organisations, civil society) collaborate and negotiate the type and extent of the policies, though they retain an industry-centric view, with stakeholders taking second stage. more recently, beschorner and hajduk (2017) advocate a cultural perspective to business ethics-cultural business ethics-within which cr initiatives are linked to industry-specific cultural contexts and institutional logics. here they invoke the notion of the organisational field to situate concrete action through network interactions between stakeholders and core businesses to reduce bias towards the company. it is helpful to view icr as an interactive political process that requires negotiation, rather than one that is either top down or bottom up (dunning 2004) , or indeed a combination of both (behrman 2004) . however, the framing by beschorner et al. (2013) and beschorner and hajduk (2017) creates an overly harmonious impression of this process, where, following debates and negotiation, participants can agree on appropriate industry actions. this in turn assumes that agendas are meaningfully represented by stakeholder and industry-led coalitions. a firm's ability to act is constrained by both the shared interests enshrined in trade association membership and the associations' own interests, which can have both positive and negative social outcomes (marques 2017). 1 moreover, industry-led coalitions are likely to have diverse motivations, as indicated by grayson and jane (2013) : they may proactively engage with social inequalities to pre-empt negative impact on industry and limit government oversight; or they may be a prerequisite for market access. such coalitions can also be more instrumental in creating visibility for firms and industry to be seen as 'responsible' through benchmarking or codification. they certainly mobilise resources and provide a strategic space in which industry positions can be consolidated to engage external actors, including government and civil society (ibid 50f.). coalitions may, therefore, be pre-occupied with controlling the narrative to legitimate their collective actions, for example, by setting responsibility agendas that are impactful but limit the effect on industry business models (du and vieira, 2012) . given these different possible motives, industry-led responsibility is likely to imply a limited notion of responsibility that is commensurate with shareholder value priorities and some highly codified, 'ethics-light' additions to the business model (raiborn and payne 1990) . cr actions that are expected to reduce profits for any adopters will disincentivise collective action (sternberg 2011) ; and other actions which may allow some firms to enhance profits may be subject to firm-level gatekeeping, not industry-level action (doane 2005) . under some circumstances industry can organise through self-regulatory institutions, for example, as 'green clubs' to provide collective guidance and control behaviour of members (marques 2017; beschorner et al. 2017) . for example, tischer and remer (2016) illustrate how social banking associations self-regulate conduct and work towards common goals that seek to benefit society and environment. extension of this to the whole of the banking sector, however, is problematic because it requires agreement on what is 'right' and what is 'practical' (raiborn and payne 1990, p. 885) . in other instances, 'industry-led' coalitions at the national and global scale are a response to improved coordination between civil society actors who may focus on industry directly, rather than government indirectly to enact change (grayson and jane 2013; scherer and palazzo 2011) . for example, recognition by civil society that 'target setting' or 'best practice' initiatives by government encourage industry adherence to minimum standards, rather than seeking transformative action, can encourage more direct or disruptive actions to pressure companies and industries to change (de bakker et al. 2013 ). under such circumstances, it is harder for industry-led initiatives to engage constructively with more fundamental, normative notions of ethical behaviour. drawing on these arguments, our framework focuses on how government and civil society can enable and influence icr. figure 1 illustrates key interactions or pathways between civil society, government and industry to enhance icr, as well as sources of resistance. in response to external pressure, industry may individually or collectively engage tactics such as lobbying or reporting; while government has means to enable or to obstruct civil society's ability to promote pressures for change (clark 2011) . ultimately the power of either civil society or government to change industry-wide behaviour is limited (dentchev et al. 2017; carberry et al. 2017) . for example, while civil society has developed persuasive (media campaigns, shareholder resolutions) and disruptive (boycotts, collective legal action) tactics, it lacks the ability to coerce firms directly into adopting icr (carberry et al. 2017 ). governments at different levels often approach icr through generic policy responses which are often fairly ineffective. the eu, for example, is integrating 'sustainability' into a broad financial policy framework in order to mobilise finance for sustainable growth with support from industry and investors (european commission 2018) as well as driving industry and government alliances, to the detriment of civil society which is insufficiently included in these approaches (moon and vogel 2008) . however, industry involvement in new sustainable finance policies could explain, for example, the slow pace of the review even if we share den hond and de bakker's (2007) optimism that civil society activism can influence firm behaviour directly, doing so may be more difficult when such activism targets general, rather than specific, behavioural change of an industry. this is particularly the case where change means not simply ceasing specific practices but developing a more ethical approach to future choices and activities. however, by aligning its interests with government, civil society may be capable of influencing cultural and regulatory conditions of an industry; in other words, it can create a political environment for the diffusion of its objectives (carberry et al. 2017) . the ability of civil society to re-politicise what is increasingly an attempt by government to institutionalise cr (moon and vogel 2008) holds government more accountable in enforcing legal obligations and societal values. in doing so, it creates a set of legitimate pressures on business to act responsibly. but, industry and government can also frustrate civil society ambitions to drive icr: for example, industry associations can resist change while also lobbying government; or industry-government relations may become shaped by revolving-door arrangements or other forms of capture that undermine third-party initiatives, including by displacing the agenda onto more trivial or peripheral issues (tashman and raelin 2013) . this leads to our second question: what conditions might allow some actions-including coalitions or alignments of interest-to be more effective in producing meaningful icr? to identify potential factors that might shape icr we draw on mitchell et al. (1997) , neville et al. (2011) and ali (2017) to highlight a range of features-power, legitimacy, urgency and magnitude-which in some combination might lead to industry-level initiatives. mitchell et al. (1997) develop a conceptual analysis of stakeholder salience based on power, legitimacy and urgency, while others propose different typologies to help explain a greater degree of stakeholder orientation in proactive firms (neville et al. 2011; ali 2017) . in trying to understand how specific industry-level initiatives might come about, the framework also needs to incorporate how stakeholders (civil society and/or government) can create the conditions to promote responsibility without direct or proactive involvement of individual companies. this contrasts with an assumed need for stakeholders to capture the attention of companies or work with them directly, which is prevalent in firm-centred cr debates. in line with the literature on stakeholder salience reviewed by neville et al. (2011) , we suggest that attempts to meaningfully influence icr would require stakeholders to possess both power and legitimacy. unlike myllykangas et al. (2010) , the notion of power defined as having 'power over' [emphasis original] must be relaxed to include 'power to' engage others in the process given the collaborative nature of negotiation. in line with these authors' exploration of legitimacy as socially constructed and the general perception that stakeholder involvement is 'desirable, proper, or appropriate', we consider that power must equally be seen in relation to the action performed and the actors involved. the contextualisation required to make sense of power and legitimacy is provided through accounting for urgency and magnitude. urgency is more widely adopted in discussions of stakeholder salience (see tashman and raelin 2013) defined as the degree to which claims require immediate action, both in terms of time but also recognising criticality of the form within the specific context (myllykangas et al. 2010 ). however, little reference is made to the magnitude of required change. where authors focus on magnitude, they do so in terms of consequences (brown et al. 2016) or 'significance' of change (shropshire and hillman 2007) . however, we argue that magnitude of change can also usefully address the complexity of the task at hand, not just in terms of significance or consequence but also in terms of the relational work that is required as part of the negotiation. getting a single actor to commit to sizeable change is difficult enough; but successfully enacting magnitudinal change across an industry is likely to be more difficult, especially when competitive agendas collide. urgency and magnitude of the proposed action therefore both affect the ability to influence icr, including attempts to develop more responsible behaviour at an industry level through processes of negotiation and coalition building. collaborations between civil society and government are therefore likely to be beneficial where substantive and/or immediate change is required to effect more ethical behaviour at industry level. for example, the moveyourmoney campaign, initially driven by civil society actors from 2009, led to the uk government creation of the current account switching service (cass) in 2013 (seyfang and gilbert-squires 2019; tischer 2013) . in this case, the independent power and legitimacy of civil society and government was enhanced by collaborative efforts: when government joined the civil society campaign, the impact was scaled up from half a million bank customers switching accounts prior to the introduction of cass to 5 million since (tischer 2013; pay. uk 2019) . here, successful collaboration follows individual attempts to seek influence. initial differences are overcome as actors consolidate and extend power and legitimacy, for example, through formal electoral support from society, or less formally through campaigns. this can happen without the explicit support of the industry and even where there is active resistance reflecting concerns for the profitability of members. understanding cr initiatives as a process of negotiation between key actors illustrates the complexity inherent in improving responsibility at industry level and the role of different groups. changes that result from pressure by government or civil society for change, leading to legislative or other actions, may be different to cr actions initiated by the sector. holzer (2008, p. 59f ) unravels some of the complex interactions between those seeking change (external coalitions) and the affected firms. in particular, he notes the propensity of diverse coalitions with dispersed power to assume a passive role during negotiations as control over the process is internalised by the firms' top management. such internalisation may also occur at the level of the industry, to either reject or accept change, facilitated by industry associations. coalitions, however, are brittle: they may be dominated by a set of actors or they may be divided and seek to influence icr independently, which can damage legitimacy. all of these may enable or disable action by management across the industry to resist pressure for icr; and it may therefore limit the power by civil society and government to affect industry behaviour (holzer 2008) . in other words, management (or its representative trade body) may assume the role of political broker, enabling them to strategically manage stakeholder coalition interests or avert external influence (campbell 2007, p. 955) . if, however, icr initiatives are to be understood as resulting from pressure of outside parties-civil society or government-what kind of power is implied, both in making change and in resisting it? some instances of power seem straightforward: government passes a law that requires a specific behavioural change and instructs a regulatory agency to enforce it. this results in a very narrow kind of icr because it reflects compliance rather than voluntary recognition of inherent stakeholder interest. in the absence of voluntary action, desired changes may be sought via incentive systems or by introducing principles or frameworks that encourage better outcomes but do not compel firms to adopt or desist from any particular practices. power here takes a more social form (dowding 1996; lukes 2005) , which reflects the ability of an actor (such as civil society or public authorities) to entice and shape, rather than force, the actions of others (such as retail banks), thus 'furthering their own interests and/ or affecting the interests of others' (lukes 2005, p. 65) . power is also revealed through the extent to which one actor (here, business) can decide how (if at all) to respond to the stakeholder initiative (lukes 1976, p. 129) . in some cases, business may resist all attempts at enrollment by civil society and/or government, especially if there is no (prospect of) legal requirement or a lack of collective public interest. the absence of industry-led cr might reflect some degree of industry power vis a vis other interests-a belief that no significant consequences may follow from inaction-as much as a lack of organisation, even where there may be legitimate concerns. power is, however, often contingent and it may be mediated or created by specific circumstances. business or industry perceptions about when action is necessary will also reflect the context, as civil society or government responses to evolving problems. as such, aspects of power and legitimacy afforded to civil society and government are context and time specific, not permanent or enduring attributes. once irresponsible behaviour is corrected, actors may reorganise resources to focus on alternative issues (roloff 2008) . the framework, therefore, needs to reflect the magnitude of the issue and the urgency with which it must be addressed; these might empower or alternatively undermine the strength of coalitions or the ability of civil society to negotiate. for example, proposed icr actions may affect a set of firms across an industry equally, or disproportionately affect a subset of the actors by virtue of process or product characteristics. the reasons for such considerations become clear if we think about what is at stake. in pushing for new, agenda-setting ethical policies or actions that affect all players within an industry the stakes are relatively high and, therefore, may be met with more (coordinated) resistance from the industry. seeking to influence behaviour across an industry thus may require considerable resource to be spent compared to situations in which one firm is the target of civil society and/or government action. in other cases, urgency (at least as perceived by civil society and/or government) may become a more important driver and traditional forms of negotiation involving consultation and discussion (campbell 2007) may not deliver desired outcomes. thus, the nature of negotiation may be issue-specific, reflecting how power to influence and resist is distributed amongst the various coalition members. 'power' here is to be understood as a fluid expression of changing contexts over time, reflecting the composition of and work undertaken by the coalition. for example, initial ambitious demands can become scaled down to realise more modest change; in this way, magnitude as a driver of significant change may be undermined by an urgent need to act or a willingness to compromise with a more incremental or superficial style of reform. or, magnitude or urgency around a particular issue can allow civil society to mobilise additional financial, political or other resources that augment power and compel change. corporate responsibility reports in the banking industry have served the principal purpose of marketing to interested stakeholders, including socially responsible investors and stock market index managers. from the perspective of the industry, this might be viewed as a cost-effective way to deal with the demands of interest groups and enhance reputation, while avoiding significant and potentially costly changes to business operations and conduct. although most banks have published cr reports as part of their annual accounts or as standalone documents before the crisis (coupland 2006, p. 3), the quality and scope of such reporting differs considerably between banks (novethic 2012, p. 5; scholtens 2009, p. 4) . despite the emergence of the global reporting initiative guidelines (gri 2013, p. 9; roca and searcy 2012), there has been little standardisation of disclosures across the industry, even where specific banking reporting standards or guidelines have been issued. crucially, qualitative reporting is unlikely to become widely established as promoters of esg and sustainable principles tend to prefer readily quantified data-such as greenhouse gas emissions or gender equality-over qualitative data (hiss 2013) . the incorporation of esg criteria in financial product creation further commodifies sustainability as something that is quantifiable (ibid); this is underlined in eu sustainable finance action plan (eu commission 2018). industry stakeholders are also requesting more information on what is measured and how (see freshfields 2019), though it is unclear if this will go beyond reporting to address bank business models in relation to esgs (siew 2015; lyon and maxwell 2011) . even without an overall framework, assessment tools (see, for example, novethic 2012) have been used as a proxy to evaluate retail bank functions, narrowly focusing on easily obtainable parameters such as stakeholder engagement, sponsorship and social engagement, and financial inclusion; and some more industry-specific yet easily quantifiable discussions of responsible lending, responsible marketing and customer relations. the first three can be understood as a response to stakeholder demands and have (albeit minimal) cost implications; the latter three engage more directly with the market in sustaining or increasing customer numbers and lending, and thus are crucial to sustain profitability. pressure to maximise profit is deeply embedded at both cultural and structural levels and has persisted post-crisis despite public disquiet and declining returns (froud et al. 2017) . information asymmetries between bankers and consumers, civil society and government are significant and are an indicator of industry power so that the ability to pressure banks into adopting cr initiatives is restricted and/or requires considerable resources to be spent (ford and philipponnat 2013; scholte 2013) . however, a greater public focus on banking following the crisis made those resources available at both government and civil society level, generating numerous publicly available reports (see, for example, on the uk : nef 2009; cresc 2009; lse 2010) . while much of the high profile censure has been focused on investment banking-for example, widespread market manipulation coordinated by leading international financial conglomerates caused uproar internationallyretail banking has also been characterised by industrywide misconduct, including mis-selling products to consumers or the lack of lending to smes as a result of credit rationing (dowell-jones and kinley 2011, pp. 202-203) . such actions have led to a lack of trust (especially of large banks) among customers (hurley et al. 2014) ; and this is despite the early adoption of cr by the banking industry (soana 2011) . not surprisingly then, the opinion poll data show that the responses to allegations of mis-selling, market manipulations and so on are directed at the retail banking sector as a whole, not simply at individual banks (populus 2017; yougov 2018) . in this post-crisis context, icr initiatives that have arisen can be understood as reflecting both magnitude and urgency. to illustrate the nature and effectiveness of industry-level cr in retail banking, the paper considers two countries, spain and the uk, where significant pressures for change by civil society and/or government can be identified to address aspects of unethical behaviour. these two countries also provide different contexts to explore post-crisis experiences in the same sector. traditionally, spain has a more coordinated market economy with a bank-based financial system, compared with a more liberal market economy in the uk and a market-based financial system. jackson and apostolakou (2010) argue that different systemic environments foster different types of coordination between business and society, thereby producing distinct models or business organisations. however, in the specific case of retail banking there are also common features in terms of how responsibility concerns have tended to be mediated through the interests of private and/or business customers. as a consequence, there could be less potential for conflict between these (customer) stakeholders and industry, compared with other industries where stakeholders may have less obvious or concentrated 'market power'. elsewhere, cr initiatives have covered broader concerns about the environment or human rights, where mobilising customers is only one part of the negotiations. nonetheless, we argue that retail banking is characterised by passivity despite the significant decline in trust noted above: public discontent with retail banking both before and after the crisis has brought little change in the nature or extent of industry-led responsibility. instead, attempts to drive responsible behaviour come either from public authorities or are derived from civil society responses that mobilise consumer or political power. rather than leading ethical change, industry measures can generally be a response to-or compliance with-formal or regulatory initiatives. the lack of proactive industry change may appear surprising given public discontent after high profile mis-selling and eviction scandals in the uk and spain respectively. in the uk, the top 10 financial scandals since 2000 have cost banks £67.4bn collectively (ft 2019), yet market shares of the major players have been relatively unaffected, reflecting the perceived 'hassle' of switching and mimetic business models of banks (panther and farquhar 2004; froud et al. 2017) . to explore this further, we first explore the context in which stakeholder mobilisations took place in spain and the uk. secondly, in the next section, we take two examples and analyse the actions taken by civil society, the extent to which coalitions of interests have been formed and the outcomes of the initiative in terms of embedding icr. the retail banking industries of spain and the uk are both characterised by a lack of diversity and, despite official attempts to change this, there has been an entrenchment of large players with similar business models and a high collective market share. these are also banking systems which have been the subject of widespread concern around treatment of customers, making them interesting cases to explore the nature and extent of icr. this section uses secondary data to outline key trends in the retail banking industries of both countries, the major issues for responsibility and the limited nature of change overall. spain was severely hit by the financial crisis in 2007/08. the doubling of domestic lending by the banking sector from 100% of gdp in 1995 to 215% in 2008 (fernández-olit and de la cuesta-gonzález 2014) illustrates the scale of change in banking and the economy more broadly. much of this newer debt was linked to a property boom: the market for mortgage lending was effectively created during this time, growing from €37.9bn in 1988 to €1065bn in 2008 and equivalent to 61% of total outstanding lending to the private sector (ahe 2012). savings banks (sbs) were the key players, with over half of the market for mortgages, and thus were most affected when the market turned in the postcrisis recession. some private commercial banks and, particularly, sbs required substantial government assistance in the post-crisis era; just as significant was the shrinking of the sb sector, top 10 market share 87% 70% 51% banks participating in m&a and market share in brackets leaving commercial banking interests the dominant force (imf 2012b) and abolishing a regional banking market with government participation in favour of increasing stock market control. only two small sbs survived as many were bailed-out and converted to private banks. as table 1 shows, within a 10-year period, the spanish banking sector moved from a diverse industry featuring more than 60 institutions with different ownership structures and a regional banking market, to an increasingly consolidated and centralised national system dominated by stock market listed banks with only a dozen institutions (ebf 2013, p. 81). the number of credit institutions fell by 43% between 2008 and 2016, and by 2018 the five largest entities accounted for over 70% of the market (in terms of total assets), an increase of more than 50% in ten years and significantly above the average for the euro zone (cruz-garcia et al. 2018). as a consequence, employees and branches have been reduced by nearly one-third between 2008 and 2015 (maudos 2017), though spain still has the second highest bank branch network density in the eu-28. while some reorganisation of the banking network could be deemed necessary, it was initiated in a crisis context and continued in an uncoordinated way because this covers not simply the closure of branches to reduce operating costs, as in most european countries, but also the collapse of the savings bank sector. the process of consolidation and concentration (ft 2013a) was accompanied by a move towards a more homogeneous spanish retail banking sector, with more competition and less collaboration between the remaining larger players as banks have moved out of their traditional regional bases. before the crisis, government action to promote cr in the spanish banking sector focused on legal requirements on good governance, transparency and reporting. while the post-crisis response reflects some acknowledgement of problems, it has been limited and fairly generic. for example, the spanish government followed eu and oecd guidelines on financial education policies to improve financial literacy; and initiatives to increase sme credit through the public finance agency (ico) have also been developed but with little effect (ayuso 2013) . more significantly, the new savings bank law (26/2013), issued to reorient sbs as a locally embedded sub-sector committed to financing smes, had no impact given that most of the spanish sbs had already vanished by 2013 and cannot easily be reinvented. in the absence of government requirements, banks have done little beyond 'soft' voluntary cr in areas like transparency and financial education. thus, while responsibility initiatives have come from government, there has been little apparent or effective coalition building with civil society. nevertheless, as we will see in the next section, laws have emerged to protect customers from aggressive practices in retail banking as a response to civil society pressure and judicial judgements. in contrast, the uk retail banking sector was characterised by a high degree of concentration in a few global financial conglomerates well before the crisis (cruickshank 2000) . despite calls from government and elsewhere to increase competition, concentration has persisted in major retail banking markets (see fig. 2 ), especially in personal current accounts (pcas), mortgages and personal loans (icb 2011, p. 166) . in fact, crisis-related consolidation increased concentration in the uk market: the six biggest retail banks had a market share of more than 90% in 2010, and have lost less than 5% since (fca 2018). sme accounts and lending have historically been even more concentrated: the top five retained 83% of sme current accounts (cma 2016), despite a recent increase in the number of challenger banks, including fintech. if these new banks do gain significant market share from the big players, it is not clear that this will encourage more responsible behaviour. arguably, the attention on cost reduction is likely to continue (including further branch closures) while the large banks seek to imitate the digital technologies and product innovation and seek acquisitions of successful new entrants (knight frank 2018). as in spain, reduced diversity is also a feature of the uk retail banking industry. this started in the 1970s with the opening up of the residential mortgage market (to break-up the 'monopoly' of building societies), continuing with the demutualisation of the largest societies and their subsequent take-over by established publicly listed banks before and after the crisis. in addition to this external threat, building societies have consolidated their activities through a series of mergers, reducing the number of active societies from 481 in 1970 to 44 in 2017 (bsa 2018) and creating one large building society, nationwide (holding more than 60% of sub-sector assets). credit unions which flourished in the us, canada and ireland, have never moved beyond niche status in the uk, despite some modest growth (bank of england 2019). in the uk, civil society has exercised voice by lobbying for and responding to public inquests using two channels. first, civil society organised immediate (g20 protest in 2009) and more sustained (occupy london) forms of protest, as well as public campaigns for change (movey-ourmoney; the robin hood tax, positive money) and alternative economy think tanks such as nef, republica and demos (see, for example, positive money 2012). but dissatisfaction with post-crisis reform was soon absorbed into the wider anti-austerity movement as the long-term socio-economic consequence of the gfc outgrew the 'financial crisis frame' (pianta 2013) , leading to more direct engagement with the policy process. second, although often excluded from policy making at a formal level, civil society groups have submitted responses to regulatory initiatives, for example, in response to the independent commission on banking (positive money 2012; ford and philipponnat 2013) . in europe, civil society has established finance watch in 2011 to 'act as a public interest counter-weight to the financial lobby' (ibid: 188). in terms of post-crisis responsibility in the uk, public bodies (regulatory agencies and government) have been the main source of initiatives, reflecting frustration about the limited changes to culture and behaviour from early and sustained civil society action. the rediscovery of regulation is in marked contrast to the previous explicit commitment to the deregulation of financial services since the mid-1980s (moran 1991 ) and, albeit short-lived, encouragement of business-led cr using a market-based approach (shaefer 2013, p. 243) . while there have been industry-led programmes in financial services (such as around financial literacy), there is little evidence that these have led to significant changes in behaviour and business models (froud et al. 2017) . banking crisis, and the ensuing unprecedented government intervention to support the sector, has led to a marked rebalancing with changes to the regulatory framework and a more active interest in retail banking by government, especially to increase competition. government-led icr initiatives have taken three forms: promotion of new entrant-challenger-banks; encouragement of lending to smes; and the principle of 'treating customers fairly' (considered in the next section of the paper). the first of these rests on the assumption that promoting competition is the mechanism to encourage existing retail banks to treat their customers well; this is a priority that has led to a succession of investigations into the structure of the uk retail banking sector, the most recent of which reported in 2016 (cma 2016). the encouragement of challenger banks-including offering substantial financial support to some new entrants under a capability and innovation fund 2 and simplifying the process of obtaining a banking licence-represents an attempt to reshape the market. unlike in spain, however, there is no explicit preference for different kinds of banks such as savings banks. while a number of new banks have entered the pca and business markets, this has had limited effect on the overall banking structure as many of these are small and present niche offers; indeed, a process of consolidation of new banks is already underway (english 2019) . the second main government objective, to foster lending to smes, has led to initiatives directed at existing banks, such as 'project merlin' launched in 2011. after this project failed to meet targets (independent 2012), a new initiative 'funding for lending' ran from 2012 to 2018 (bank of england 2012) 3 with similar results. despite this, the limited extent of lending by banks to smes remains an official concern, and a new venture, the business bank, was established in 2013 with direct government support (ft 2014). overall, uk government actions to encourage more responsibility across the industry have taken various forms including financial inducements and projects but these have largely not involved effective coalition building. within these broader national contexts, the next section considers two examples which show a greater degree of coalition building reflecting combinations of power, legitimacy, magnitude and urgency and mobilising new and existing organisations. 2 this fund has £425 million held in trust at the bank of england and administered by banking competition remedies ltd to be spent in four rounds or pools to support challenger banks that explicitly target smes. this fund was established after agreement between the uk government and the european commission to implement the £775 million rbs state aid alternative remedies package, resulting from the bailing out of rbs and the subsequent inability to sell williams and glyn bank. see https ://bcr-ltd.com/wp-conte nt/uploa ds/2018/09/ banki ng-compe titio n-remed ies-media -facts heet_final .pdf for more details. following our theoretical framework, we present two emblematic examples to analyse how the magnitude and urgency of industry bad practices provoked coalition building initiatives from civil society and changes at industry level. these were selected because they reflect important and legitimate issues where banks have acted against the interests of their own customers. in both cases, civil society action was central in helping to collectively organise the interests of individual customers and in doing so increase the urgency of the problem and the legitimacy of the action; moreover, civil society action prompts some form of response by government and other public authorities which is necessary to effect change. in each case, we describe the problem, the characteristics of the negotiation process, the actors involved, the reaction of public bodies and industry and the limitations of this process, taking into account the different contexts. the first case, protecting mortgage debtors in spain, is a significant and unprecedented example of mobilisation of power given spain's low level of consumer activism. in this instance, a coalition was built between bank customers with mortgage arrears and other citizens concerned with social justice. the bottom-up coalition drew power and legitimacy from the magnitude of the problem (around half a million households facing or experiencing eviction by their banks) and the urgency that relates to the potential and visible harm that eviction can cause, especially to vulnerable people. pah, as a new, civil society organisation worked effectively and persistently to exert pressure on banks via judicial action and, later, government action. the direct outcome is changes in bank behaviour in relation to these affected households, but this has not extended to any more general embedding of responsibility. there may, however, be more enduring effects through the demonstration of effective civic action, making future stakeholder coalitions more likely. the second case, the response to mis-selling of financial products by banks to uk customers, was made urgent through the action of an established, well-resourced civil society organisation, citizens advice. this organisation used legal process to challenge government inaction in response to massive mis-selling which affected millions of bank customers. while the failure of an insurance policy on a financial product such as a loan is perhaps less serious for the individual customer than a potential eviction, the sheer scale in the second case provided legitimacy. the successful legal action rebalanced power away from the banks in relation to this issue and required government to align itself more explicitly with customer interests. again, this has been a high profile and extended action, yet the extent of responsibility has been limited to specific redress, not behavioural change by retail banks. nor has it shifted government policy in ways that prevent future mis-selling. these cases are developed using secondary data to inform understanding of the nature and scale of the process, the actions taken by civil society, formal responses by government and public authorities and the perspectives of citizens, as set out in the media of different kinds. in each case, the secondary data are used to trace the development of the problem, the critical interventions by civil society and the forms of response by government and other public authorities, including aspects of coalition building, and the extent of short-and long-term change. the major sources for the spanish case are statistical data from cgpj (the spanish national council on judiciary), official court reports, pah reports and media articles. uk data are drawn from regulatory authorities, citizens advice, media and other commentaries. this first example is concerned with the relationship between banks and residential mortgage customers: the effectiveness of coalition building is a consequence of broadening the issue beyond a simple market relation to invoke the wider social justice implications of bank behaviour, which was critical to establishing legitimacy. what is also striking about this example is that civil society was able to co-opt judicial processes to more effectively bring government into alignment. however, while there are demonstrable changes in bank behaviour in some respects, as outlined below, there is no clear evidence of underlying ethical shifts in banking practice led by the industry. lending practices in spain before the crisis increased home ownership. after the crisis, however, rising unemployment contributed to the growing number of mortgage holders unable to meet payments, resulting in mass evictions by the banks: an estimated 500,000 releases or evictions occurred between (pah 2014 . public outcry about the social consequences of eviction and homelessness led to the establishment of a civil society movement, the spanish platform of people affected by mortgages (pah) in 2009, which campaigned for more considerate treatment of distressed debtors. pah is notable as a social movement because it changed the framework surrounding the eviction problem, while also creating nationwide awareness of the resulting injustice. de weerdt and garcía's (2016) analysis of this innovative social movement found that pah empowers people through solidaristic actions to place collective pressure on legislative bodies, governments and banks. newly established collective communication channels enabled these groups to reach agreements with banks to renegotiate or even condone debts, or to extract socially beneficial terms from banks, such as payment in kind or a social rent. these authors conclude that pah has been successful in arguing that the debt problems experienced by spanish households are not the result of individual failure but a consequence of business decision making and practices that put profit ahead of the consumers. the success of the campaign against evictions reflects coalition building around an urgent issue. pah enlisted the eu court of justice, which ruled against the evictions and gave spanish courts new power to stay evictions (ft 2013b). resulting legal and social pressure led to the issuance of the royal decree law 6/2012-a mechanism that allows urgent laws to be passed-to protect mortgage borrowers. this introduced a series of measures, including a voluntary code of good banking practice which included exceptional measures for the resolution of defaults of people in difficult social conditions. a subsequent law (1/2013) and amendments formalised detailed measures to protect mortgage debtors, debt restructuring and social rent, and thereby recognised the social consequences of eviction which had been initially ignored by national government. 4 in an attempt to prevent future bad practice the law also promotes more responsible lending, limiting mortgages to a period of 30 years and a maximum loan-to-value of 80%. however, the law does not universally and retrospectively alter payments as pah had argued for, though it includes a two-year suspension of evictions in cases of 'special vulnerability'. as a result, property can only be repossessed and sold when restructuring is impracticable under specific conditions, according to the code of good banking practice. the pah example illustrates social innovation by organised citizens fighting for social justice. the coalition has incorporated support from 200 collectives and labour unions, more than 100 city councils which have approved motions in favour of the demands of pah and from political groups in 14 regional parliaments across spain (bhandar 2015) . this has produced political action which has shaped governance through creation of new mechanisms for collectively negotiating housing debts with financial institutions, while also influencing new local and regional regulations for access to housing for mortgage victims. by reframing the issue as a collective problem-governments have used an 'individual approach', the pah has focused on collective responses to social problems-pah's campaign contributed to new ways of conceptualising and approaching policy problems (pradel et al. 2013) . the success of pah is underlined by subsequent legal action brought against blackstone, the largest owner of housing in spain with some 40,000 homes. pah has accused blackstone of committing a crime of 'hoarding' empty homes and 'deceptive alteration of the price of things'-buying repossessed homes at a low price and then withdrawing them from the market to sustain high rental values and purchase prices-which are illegal (pah 2018a). this is a particularly sensitive political issue as social housing for rent provides only 1% of spanish homes (compared with around 20% in the united kingdom, france or germany) and there are 3.4 million empty homes. while a remarkable and unusual example of organised citizen action, it is important to ask whether this has enhanced responsibility more generally in spanish retail banking. the effectiveness of pah's social action and heightened awareness of bad practice has encouraged consumer associations and lawyers to engage in a context where traditionally there has been limited consumer mobilisation. however, it is not clear that corporate behaviour has changed more generally. for example, between 2007 and 2018 there were more than 500,000 evictions in spain due to mortgage non-payment and, in recent years, this figure has been increased by rent evictions (pah 2018b). rather than preventing future unethical behaviour, further bad banking practices have emerged. the insertion of floor clauses in mortgage agreements, for example, meant that consumers would not benefit from reductions in euribor rates, but were liable to pay more if this rate went up. this was deemed an 'abusive practice' by the courts and a 2017 royal decree established an extrajudicial channel to settle disputes (boe 2017) and by end of 2019, over €2.2 billion was returned to spanish consumers. 5 these and other practices have undermined public trust in banks, with significant judicial proceedings still awaiting resolution (spanish central bank 2019). overall, this case demonstrates that banks' reaction to civil society pressure may not result in any generalised corporate responsibility but can have issue-specific consequences. business model pressures remain focused on a single-bottom line and civil society initiatives lack the (legislative) muscle to drive meaningful and far-reaching changes in corporate behaviour across an industry. government action was necessary to achieve the outcomes supported by civil society and, later, the judiciary, though there was no immediate response by government to enact structural policy changes to prevent poor behaviour by banks. treating customers fairly (tcf) has been an officially endorsed general principle in the uk since 2006 (shaefer 2013) , applying not only in banking but in other utility sectors like energy. tcf in retail banking was renewed postcrisis after a review of the regulatory framework on financial services and the creation of the new regulator, the financial conduct authority (fca). tcf encapsulates a basic ethical principle to which all organisations regulated by the fca must adhere: a bank 'must pay due regard to the interests of its customers and treat them fairly'. if the principle is embedded in bank behaviour then it should deliver six outcomes which collectively represent 'fair' treatment (fca 2013) . this is not a regulatory framework, nor a set of benchmarks for behaviour; enforcement is via an ombudsman and investigations when things go wrong. however, under a self-interest argument, it might be expected that banks would have an interest in following tcf to ensure that (mis)treatment of customers does not contribute to future scandals, reputational damage and fines, as well as contributing to rebuilding trust in the retail financial services sector. the survival of tcf as a regulatory initiative reflects the continued need for improved transparency and fair treatment, rather than its success in enhancing and enshrining responsibility. the renewal of tcf in 2013 was amidst a series of mis-selling scandals, most notably of payment protection insurance (ppi), an insurance policy sold by banks and other financial institutions linked specifically to debt and credit products. the scale of mis-selling suggests a mass failure by the sector to follow the tcf ethical principle (and a failure of public authorities to take remedial action). moreover, this was not the first instance of mis-selling by uk banks. earlier mass episodes of unacceptable behaviour in relation to selling private pensions and endowment mortgages in the 1980s and 1990s (ferran 2012) had not reformed the incentives systems and culture within banks which allowed serial misselling to thrive. the original failures of mis-selling were compounded by the way that banks dealt with customers who complained. as a result, fines were imposed by the fca on some banks for mis-handling complaints (see, for example, fca 2015). in the specific case of the mis-selling of ppi, the interests of customers were taken forward by citizens advicea network of charities that provide free legal information and advice-which became increasingly aware of the large number of policy holders who had made claims under their policies and been refused pay-outs (citizens advice 2015). as ppi products became more widely sold, it was more likely that they were unsuitable or at least represented very poor value. citizens advice noted in 2005 that there were estimated to be 20 million live ppi policies with an annual premium of £5.3bn, compared with £8bn and £9.5bn, respectively, for property and motor insurance. through their individual charities they observed the massive extent of customer dissatisfaction, though this was disputed by the industry. in particular, it appeared that lower income and vulnerable customers were more likely to have been mis-sold these insurance products (citizens advice 2005). citizens advice collected individual cases to make a 'super complaint' to the regulator, the financial services authority, in 2005. public authorities responded to this civil society action by putting in place a system of fines and compensation for customers who could demonstrate they had been mis-sold ppi. far from recognising their responsibilities, banks via their trade association the british bankers' association (bba) initially mounted a legal challenge to the requirement to pay compensation and indeed continued selling these products for years. in 2011, the bba lost a legal case against new rules intended to prevent mis-selling, which were to be applied retrospectively, hence opening up further claims from customers (guardian 2011) . in the end, the industry had no option but to pay the regulatory fines and customer compensation. uk retail banks created enormous provisions in their financial accounts to meet the compensation costs 6 : by 2019, some £36bn had been paid out by british banks (ft 2019). the issue of corporate responsibility is relevant in two ways: the first is the sale of the financial product by banks, including whether it was suitable for the customer and clearly explained to them; the second is how banks handled the complaints of mis-selling. to some extent, the second issue gained a heightened significance in some of the reporting by public authorities, perhaps because this could be measured and audited more easily than the more fundamental concerns about how banks treat customers. for example, the fca notes in 2014 that firms have improved the way that they handle complaints, though does not comment on whether selling practices are more ethical (fca 2014) . the regulator has since banned certain products and attempted to address selling practices more generally. however, a good test of industry-led responsibility might be whether bank business models have become less reliant on cross-selling (often unsuitable) financial products, thereby embedding the principle of fair treatment of customers into routine practices. while banks have withdrawn some products, as required by the regulator, evidence of further mis-selling has followed the ppi scandal, suggesting that tcf is still not being adopted by banks. for example, in late 2013, lloyds bank was fined £28 m and expected to pay out £100 m in compensation after a new expose about mis-selling a range of financial products by staff (guardian 2013) . it is no surprise that claims management has become an industry in its own right: these companies are looking out for new potential sources of mass claims, including mortgages (again) and packaged current accounts which offer a bundle of services in return for a fee (ft 2019; which? 2018; francis 2019) . in this example, civil society action was central to addressing the massive consequences of mis-selling, by helping to collectively organise the interests of individual customers and in doing so increase both the urgency of the problem and the legitimacy of the action. more broadly, the sustained failure of uk banks to improve their treatment of customers has provided an interesting opportunity for social movements to raise public awareness. for example, move your money claims some success in encouraging switching away from the big banks; though the impact on their business models or behaviour is uncertain. in essence, the initiative represented a market-based approach to irresponsibility, with consumers encouraged to exercise their power by changing their bank. to sum up, this section has analysed two initiatives where actions led by civil society, with responses from government and other public bodies, have had some impact on the banking sector. in both cases, action to address a lack of corporate responsibility is the response to the results of coalitions formed around banks, not a spontaneous act or corporate priority. to the extent that icr has been enhanced, it is reactive not embedded in bank practices. in the spanish example of mortgage holders facing eviction, civil society pressure has worked through public authorities to convert social concern into regulatory requirements which strengthened protection for borrowers. in the uk example of responses to widespread mis-selling, civil society action had the effect of raising the profile and achieving redress for individuals via massive compensation, but without necessarily changing bank behaviour. the implications of these examples are explored in the final section. this concluding section reflects on the initiatives discussed in the paper and their implications for understanding corporate responsibility at an industry level. here we come back to our theoretical framework to highlight several issues arising from the empirical analysis that can be used to frame subsequent research and to inform policy. the paper set out to address the question: whether and how public action (via civil society and/or government) can meaningfully affect industry-wide corporate responsibility behaviour by retail banks. focusing on spain and the uk, we have provided an overview of developments in this sector since the gfc to highlight the very limited extent of industry-led corporate responsibility. two examples which represent exceptional cases of civil society action making problems visible-and to some extent mobilising government and other public authorities-have been analysed to explore the ways in which such action reflects power and legitimacy of actors and the urgency and magnitude of the issues in the building of coalitions around banks. the examples were chosen to highlight civil society responses to responsibility problems across an industry, as well as the importance of some follow up through policy or regulatory change. through these we demonstrate the value of focusing on corporate behaviour at the industry rather than the firm level. the banking industry examples analysed have allowed us to explore the cultural business ethics perspective (beschorner and hajduk 2017) in which the industry is a frame for actors linked to each other by a web of shared beliefs and network-like relations, and with apparently similar understandings of csr (the materiality of issues, the legitimacy of stakeholder demands, and the role of governments). within an industry context, responsibility can be substantiated and thus made clear and manageable for companies and their stakeholders. retail banking is an appropriate case to illustrate the significance of responsibility initiatives at industry level, particularly in relation to the inadequacy of firm-level cr to prevent or respond to problems. the financial crisis and ensuing challenges to business models added urgency and magnitude in ways that could potentially unsettle established behaviours and strengthen legitimacy of civil society organisations. as argued in the paper, retail banks have a longstanding engagement with company-level cr but this has not prepared the industry for dealing with the consequences of irresponsibility or unethical decisions through initiatives or preventative actions. the analysis shows that in these retail banking cases, icr came about through coalition building by stakeholders. it is evident that proactive or industry-led corporate responsibility was limited to more trivial issues (tashman and raelin 2013) and there was little evidence of any incentive for industry collective action (sternberg 2011) to initiate change. instead, banks have been compelled to act following the mobilisation of power through legal processes and (eventually) the enrolling of governments. overall, the analysis in this paper has illustrated how corporate responsibility at the sector level in retail banking is, first, the product of contextspecific processes of negotiation between the sector, civil society and public authorities, on behalf of customers and other stakeholders; and, second, has only limited momentum in enabling behavioural change beyond the initial catalysing events. in both cases, and particularly so in the spanish case, coalitions are created in highly politically charged contexts. set up in response to widespread bad practice and government inactivity, pah was initially unable to claim legitimacy. nonetheless, the scale of the problem addressed and the public interest created soon established pah as a legitimate civil society actor, able to legally challenge both governments and banks. pah effectively created a political environment which allowed the diffusion of its objectives, in line with the argument of carberry et al. (2017) . this pivoted around the idea that evicting mortgage debtors was morally and politically unacceptable. in the uk case, the issues were clearly less politically charged, yet the sheer scale of the issue-the millions of bank customers sold inappropriate insurance products-created a legitimate political force based on evidence of unethical practices. here, our analysis supports myllykangas et al. (2010) , who argue that legitimacy has to be socially constructed, rather than arising from priorities set by government or industry. the post-2008 campaigns against banks are to this extent reflective of broader movements about capitalism, inequality and climate justice, as well as the specific unethical practices. our examples support the argument that attempts to meaningfully influence icr require stakeholders to possess both power and legitimacy (neville et al. 2011) . civil society has limited direct power but can access it through actions and coalitions: in both examples, civil society stakeholders derived power through collective action. the uk example showed how mis-sold customers were brought together by citizens advice, a civil society organisation with legitimacy based on longstanding efforts on behalf of consumers. in the spanish case, action came about through creation of a pressure group with wider membership to campaign initially for mortgage debtors; subsequently, pah has been the basis of wider campaigning on issues relating to rights to housing. such collectivisation is critical because, although retail banking customers are legitimated stakeholders who should be able to exert pressure on business to act responsibly, it is difficult to articulate individual power for many reasons. first, information and resource asymmetries between banking institutions and customers reduce individual's power despite the ethical legitimacy and magnitude of their demands. customer financial illiteracy and mimetic practices of most retail banks also constrain the ability and opportunities of individual customers to negotiate with banks. even when they are aware of their rights, the costs of pursuing them will be an obstacle to individual remediation. however, our examples show how under specific conditions, the magnitude or scale of unethical practices provides opportunities to collectively organise, create visibility for the issue and accumulate pressures for subsequent-albeit limitedaction by government and other public authorities. the ability of civil society to formalise claims of misbehaviour then creates opportunities to effectively engage in negotiations around remediation, despite resource limitations. as we have seen, the magnitude and urgency of customers claims and demands (e.g. see mitchell et al. 1997 ) have allowed civil society to mobilise additional financial, political, legal or other resources that supplement individual power and compel change through the intermediation of regulatory or other changes. these were the main conditions that allowed effective actions through a process of negotiation and coalition building in our examples. thus, civil society action was central to addressing the massive consequences of mis-selling, by helping to collectively organise the interests of individual customers, represent them in legal processes and in doing so increase the urgency of the problem. it should be noted, however, that even though initiatives led by civil society can lead to changes in the way industries are required to act, this does not imply that government priorities or objectives are necessarily aligned with those of civil society stakeholders. where they do exist then, stakeholder coalitions are temporary and contingent. in understanding how stakeholder pressure works, we can draw a distinction between consumer and social pressures. consumer pressures involve those directly affected by irresponsibility such as mis-selling, whereas social pressures reflect a broader constituency: for example, pah is not simply comprised of those who are or might be evicted but represents a more general discontent about bank behaviour on behalf of affected citizens. this would seem to be a stronger and extendable basis for a coalition of interests as it presents problems as a general failure to meet citizen needs, rather than harms done to individual customers. coalition building here responds to ethical issues which relate to housing in this specific instance but could equally cover access to energy, water and sanitation, transport, legal aid or other essential material and social infrastructures. when the unethical behaviour of banks or other industries impacts on citizens' welfare or even their human rights, corporate responsibility becomes a political issue and legislative, executive and judicial powers can be used to guarantee or at least support these rights. in these instances, it is social pressure through established or new civil society organisations rather than individual pressures, which are effective. here, we can draw another interesting comparison. while pah in spain initially lacked legitimacy as a new organisation seeking power to change bank behaviour, citizens advice in the uk had more immediate credibility, as well as legal and other resources to draw on. yet, citizens advice is also limited in scope by its success in advocating for consumer rights, while pah can develop innovative responses to institutional failures through creating new stakeholder coalitions outside its original ambit. while the specific nature of the civil society demand and the context in which problems arise are likely to be important, the negotiating capacity of the actors is a driving force. as a result, pah was able to make evictions an issue that could mobilise legal and political response even while other contemporaneous civil society demands, such as around public health and education, climate change or tax reforms, did not deliver the same level of success. notwithstanding these distinctions, in each case responses by public bodies have been effectively mobilised through the accretion of pressure, with regulatory or policy action triggered by an event (e.g. the super complaint on ppi misselling). effectiveness here is dependent on the ability of civil society to draw on legal or regulatory processes that governments cannot ignore. but, even where reactions to industry-level problems have been effective, they have taken time to initiate and some have attracted resistance. in this sense their development reflects processes of negotiation that take place outside the sector, and indeed in the ppi compensation case, legally challenged by retail banking interests. in the spanish case, the judicialisation of the process and the role played by the courts have transformed individual claims into societal and political claims with regulatory reforms. as for the banks, the industry response can be characterised as reactive. in both cases, banks fought both civil society and regulators to limit their financial responsibilities until the point where they had to comply and, in the uk example, face unprecedented costs. interestingly, these defeats were followed neither by explicit actions to regain customer trust nor attempts to strategically manage stakeholder coalitions to limit external influence (campbell 2007, p. 955) . in this sense, the sustained failure of uk and spanish banks to improve their treatment of customers (borrowers and savers) has provided an interesting opportunity for social movements to raise public awareness. while both examples discussed in the previous section have had a high political and media profile-and have led to extensive redress-there is no indication that they will solve the underlying problems of unethical behaviour. the limited effectiveness of the initiatives can be partly explained by the reactive processes that deliver them and by the scale of the challenges. to some extent this reflects the underlying effective power of the banking industry in relation to both government and civil society; but it is also a consequence of broader socio-economic issues. what then are the policy implications of this analysis? the calls for changes to retail banking in spain and the uk discussed in this paper reflect significant socio-economic issues central to the functioning of a banking system and requiring coherent action across the sector, rather than company-level discretion. our analysis shows that banking does not necessarily or effectively fulfil its intermediary function to support citizens and the (productive and social) economy (fernández-olit and de la cuesta-gonzález 2014). for example, banks over-lent to households in spain to buy houses, while they have under-lent to smes in the uk. retail banks have also failed to design and market products that meet the needs of customers in transparent ways, especially given many customers' lack of financial literacy, asymmetrical information and inertia. it is possible, of course, that episodes such as those we have analysed in this paper could eventually contribute to the development of industry-led corporate responsibility that recognised stakeholder interests and avoided such unethical practices in the future. such action would obviate the need for regulatory responses by public authorities and would avoid extended, high-profile legal processes aimed at seeking redress for specific customers, resulting in substantial financial penalties. from a self-interest argument, our examples might suggest that retail banks could change behaviour to avoid repeated reputational and financial damage. to this extent, policy implications would be limited perhaps to the importance of safeguarding and promoting opportunities for civic action to support accountability. this would imply that the industry assumes stakeholder interest as a goal itself and not as a means to other ends. our analysis would suggest caution, however, in assuming such an outcome because of the persistence of shareholder value as a corporate objective for most banks (froud et al. 2017) . the spanish and uk examples provide different contexts for the enactment of shareholder value: in spain, rapid changes as the sector has moved towards a less diverse retail banking ecosystem provide an unstable backdrop to high-profile stakeholder initiatives; while in the uk, misselling reflects long-running problems in a retail banking sector where shareholder value-driven business models have dominated for 20 years. though the historical context is different, changing bank behaviour in both countries is made difficult by the imperative for financial returns in business environments that are more challenging. this relates not simply to normative notions of ethical behaviour but to questions of practicality and attainability (raiborn and payne 1990, p. 885 ). there has been recent debate more broadly about the importance of long-term corporate objectives and meeting the needs of stakeholders more broadly, as illustrated by the us business roundtable restatement of the purpose of the corporation (business roundtable 2019), but there is little evidence as yet that this presages significant change in business models. in such an unpromising environment for progressive policy, several possibilities can be highlighted. first, different behaviours may be more likely to come through encouraging new kinds of banks (e.g. mutuals) which offer customers a different model; or through controls on banking which more vigorously protect customers from unethical behaviour, rather than relying on compensation after the event. in the case of retail banking, development of a more relational business model in which the needs of customers can be met with appropriate products and services and delivered with better advice and accurate information may help avoid actions that disadvantage customers (fernández-olit and de la cuesta-gonzález 2014). digitalisation processes in the banking industry could help in principle as banks have access to large amounts of data, which allows them to offer personalised products and services to customers to meet their financial needs and not just business objectives (garcía montalvo 2014). but digitalisation processes will not necessarily improve transparency and the quality of financial advice and marketing. some early scandals involving fintech firms suggest that these new actors have picked up 'some bad old habits' displayed by larger incumbents (ft 2016) . second, government cannot abdicate corporate responsibility to (product or capital) markets, but equally, coalitions with civil society are important in directing government and holding it to account. the examples in this paper illustrate a form of negotiated power with government responding to civil society concerns. government also have their own objectives which may direct bank behaviour in particular ways, such as supporting lending to smes to encourage growth, or promoting residential mortgages to expand home ownership, just as they may have reasons why they avoid tougher legislative and regulatory frameworks. these kinds of mediation and capture are likely when the underlying issues like evictions are fundamentally political and government must be seen to respond to public outrage. the challenge for civil society is to align its interests with government, to create 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in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. key: cord-264993-cj75bdm2 authors: rojo marcos, gerardo; cuadros gonzález, juan; arranz caso, alberto title: enfermedades infecciosas importadas en españa date: 2008-10-31 journal: medicina clínica doi: 10.1157/13127586 sha: doc_id: 264993 cord_uid: cj75bdm2 con el crecimiento de los viajes internacionales y la inmigración, en españa ha aumentado el número de pacientes con enfermedades infecciosas importadas, muchas de ellas desde zonas tropicales o subtropicales. paralelamente también se ha multiplicado el número de publicaciones científicas de autores españoles sobre infecciones importadas causadas por parásitos, hongos, micobacterias, bacterias o virus. el riesgo que representan para la salud pública es bajo, aunque para su correcta prevención y su control es importante facilitar el acceso universal a la asistencia sanitaria y a unas condiciones socioeconómicas dignas, así como mantener una formación clínica y epidemiológica actualizada del personal sanitario. estas medidas a escala nacional deben compaginarse con las iniciativas internacionales de control global de estas infecciones. in spain, owing to the rise of international travels and immigration, the number of patients with imported infectious diseases has increased, many of them from tropical or subtropical areas. in parallel, there has been a multiplication in the number of scientific papers with spanish authors about imported infections due to parasites, fungus, mycobacteriae, bacteriae or viruses. the risk for public health is low, althought for their correct prevention and control it is important to ease an universal access to healthcare and fair socioeconomic conditions, along with maintaining an updated clinical and epidemiological training of the health personnel. these nationwide measures must be supplemented with worldwide initiatives of global control of these infections. en los últimos años los profesionales sanitarios hemos visto aumentar el número de pacientes con sospecha clínica o diagnóstico de enfermedades infecciosas que no son propias de nuestro país o que prácticamente habían desaparecido, incluidas las llamadas infecciones tropicales. todas las especialidades médicas y quirúrgicas se ven implicadas, desde los médicos de atención primaria que estudian una eosinofilia en un inmigrante hasta los ginecólogos que controlan a embarazadas con enfermedad de chagas. la mayoría de estas consultas se concentraban en unidades especializadas de grandes centros hospitalarios; sin embargo, actualmente se pueden atender en cualquier hospital o centro de salud de todas las comunidades autónomas. los colectivos de potenciales pacientes con este tipo de infecciones también se han ampliado y diversificado. en enero de 2008 el número de extranjeros empadronados en españa era de 5,2 millones, el 11,3% de la población total, al que habría que añadir un amplio colectivo que no aparece en ningún registro y que se estima en más de 400.000 personas. más de la mitad procede de países de renta baja (prb) de latinoamérica, áfrica y, en menor medida, asia. por otro lado, en 2006 continuó aumentando el número de españoles que viajaron por turismo o negocios a países tropicales o subtropicales hasta superar el millón, lo que ha supuesto una demanda creciente de consultas de consejos al viajero. a esta cifra hay que añadir los extranjeros residentes en españa que visitan a sus familiares y amigos en sus países de origen, un colectivo con un riesgo especial de contraer infecciones, sobre todo los niños, ya que allí viven en las mismas condiciones que la población local y no suelen solicitar consejos al viajero por una baja percepción del riesgo sanitario. por otro lado, en los últimos 5 años se ha adoptado a más de 23.000 niños en el extranjero, la mayoría de prb, a quienes se realizan exámenes de salud al llegar a españa. otros grupos de riesgo son los refugiados, trabajadores estacionales, emigrantes españoles que regresan de vivir y trabajar en países tropicales, expatriados de organizaciones no gubernamentales o militares en misiones internacionales. estas infecciones también pueden transmitirse por transfusiones de hemoderivados, trasplantes, jeringuillas compartidas o por la llegada de alimentos contaminados, animales infectados o insectos vectores, como en la malaria adquirida en la cercanía de aeropuertos por mosquitos anopheles transportados en aviones desde países endémicos (malaria de aeropuerto). la importación de estas enfermedades simplemente refleja la existencia de 3 factores principales: en primer lugar, la gran diferencia de desarrollo económico y sanitario entre los prb y los países más industrializados; en segundo lugar, la diferencia climática, que permite la existencia de vectores eficientes y condiciones ambientales adecuadas para su transmisión, y por último, los grandes movimientos de población, junto a la rapidez y el volumen creciente de los medios de transporte que caracterizan esta época de globalización 1 . las enfermedades tropicales importadas ya fueron motivo de una excelente revisión en esta revista el año 2002 2 , por lo que intentaremos dar una visión actualizada y práctica centrándonos en la experiencia publicada por los profesionales sanitarios españoles. no podemos ser exhaustivos en el repaso de todas las enfermedades, por lo que incidiremos en enfermedades infecciosas importadas que no existen en españa (como la malaria y la histoplasmosis) o son muy raras (p. ej., la lepra y la estrongiloidiasis), infecciones que pueden representar un riesgo actual o potencial para la salud pública (como la tuberculosis multirresistente y las fiebres hemorrágicas) e infecciones cosmopolitas que pueden presentar características especiales al importarse (p. ej., las bacterias enteropatógenas resistentes a quinolonas). para dirigir mejor el proceso diagnóstico resulta básica la formación en enfermedades infecciosas, incluidas las tropicales, el conocimiento de la geografía sanitaria y la actualización permanente sobre los brotes epidémicos o los cambios epidemiológicos que suceden en otras zonas del mundo. en internet hay páginas muy útiles con esta infor-mación (tabla 1). la mayoría de los procesos infecciosos en viajeros e inmigrantes son similares a los que encontramos en nuestro medio, especialmente en las consultas de medicina general de atención primaria o urgencias donde los pacientes no están seleccionados, mientras que las denominadas enfermedades infecciosas tropicales sólo representan un pequeño porcentaje. las enfermedades infecciosas suelen ser las mismas en viajeros e inmigrantes recién llegados, aunque algunas son de más difícil adquisición en viajes de corta estancia o son endémicas sólo de ciertas zonas, como la oncocercosis o la enfermedad de chagas. los inmigrantes pueden presentar cuadros más leves, crónicos o asintomáticos, por lo que en estos pacientes son importantes los estudios de cribado. la probabilidad de presentar determinadas infecciones varía según el origen geográfico de los pacientes 3,4 (tablas 2 y 3), el tiempo de incubación (tabla 4) y el cuadro clínico 5 . otros factores importantes son la edad, los antecedentes médicos, las vacunaciones y la profilaxis, además de las características, las actividades, el recorrido, la época del año y la duración de la estancia en el extranjero. en las consultas especializadas de medicina tropical y del viajero, la mayoría de los pacientes presenta fiebre, diarrea, clínica respiratoria o dermatológica 3 , y un estudio limitado suele ser suficiente para el diagnóstico. hasta en uno de cada 4 pacientes no llega a descubrirse la etiología del cuadro infeccioso, aunque en estos casos el pronóstico suele ser favorable 6 . es importante contar con un servicio de microbiología experimentado y con centros de referencia especializados para realizar técnicas diagnósticas no habituales. respecto a los tratamientos, no hay mucha experiencia en el uso de medicaciones antiparasitarias y pueden presentarse dificultades de suministro por la burocracia y la centralización de los medicamentos extranjeros. es necesario contar con un remanente en las farmacias hospitalarias, como en el caso de la quinina intravenosa para el tratamiento urgente de la malaria grave. malaria la malaria es la parasitosis importada más relevante en españa por su incidencia, morbilidad y potencial mortalidad 7 . desde su erradicación oficial en 1964, la gran mayoría de los casos son infecciones causadas por plasmodium falciparum adquiridas en áfrica central y occidental 7-11 , aunque también se han descrito casos de transmisión parenteral por plasmaféresis 12 e infecciones asociadas a la inyección de heroína con jeringuillas infectadas 13 y, recientemente, a un trasplante de hígado 14 . por otro lado, se han publicado casos de pacientes con malaria de aeropuerto 15 e infecciones autóctonas de origen incierto 16 , aunque la posibilidad de rein-troducción de la enfermedad es baja debido al estado de desarrollo socioeconómico y sanitario de nuestro país 17 . en el período 1999-2002 hubo 2.044 ingresos por malaria en españa (incidencia de 1,3 casos por 100.000/habitantes/año), de los que el 20,6% correspondió a niños menores de 15 años 8 . sin embargo, en la actualidad esta incidencia podría ser muy superior en las zonas donde se concentran inmigrantes procedentes de países endémicos 10 . en un hospital general de un área de madrid con un alto índice de inmigración, los pacientes con malaria eran generalmente de origen africano y acudieron al servicio de urgencias al regresar de una visita a familiares y amigos en sus países de origen, sobre todo en guinea ecuatorial, nigeria y otros países del áfrica occidental y central. la gran mayoría no había realizado profilaxis y el cuadro clínico más habitual consistió en fiebre y cefalea; el índice de complicaciones graves fue bajo (un 7%, por anemia grave e insuficiencia renal) y no hubo ningún caso mortal 7 . no obstante, en los centros especializados donde se atiende a viajeros no inmunes (turistas, cooperantes u hombres y mujeres de negocios de origen europeo) se han descrito índices más altos de complicaciones y cuadros más graves, como malaria cerebral, edema pulmonar y coagulación intravascular diseminada 10 . el pronóstico de la malaria depende sobre todo de la rapidez con que se establece el diagnóstico y se inicia el tratamiento. en los últimos años se han incorporado nuevas técnicas diagnósticas en la práctica clínica. aunque la gota gruesa continúa siendo el test diagnóstico de referencia, es una prueba subjetiva que requiere microscopistas expertos y no está disponible en todos los centros, sobre todo en los hospitales generales sin unidades especializadas. los tests de diagnóstico rápido, particularmente los basados en la detección de proteína rica en histidina (hrp-ii, antígeno específico de p. falciparum) y aldolasa (una enzima común a las 4 especies), son un complemento idóneo de la gota gruesa y permiten descartar o confirmar el diagnóstico por p. falciparum en 15 min sin necesidad de microscopistas expertos ni equipamiento 18 . su sensibilidad puede ser inferior en la detección de otras especies 19 y no son adecuados para controlar la parasitemia ni el resultado del tratamiento, porque pueden continuar siendo positivos hasta 3-4 semanas después de un tratamiento eficaz 18 . en la práctica clínica, las técnicas de reacción en cadena de la polimerasa (pcr) son útiles para confirmar el diagnóstico microscópico de especie y detectar las parasitemias mixtas y las infecciones en pacientes asintomáticos o con parasitemias muy bajas 20 , aunque su complejidad técnica y su coste limitan su uso, por ahora, al diagnóstico retrospectivo en laboratorios de referencia. la quinina asociada a doxiciclina, clindamicina y sulfadoxina-pirimetamina, o la atovacuona-proguanil son los tratamientos que más se utilizan en europa para la malaria no complicada 21 . los tratamientos combinados con artemisinina que recomienda la organización mundial de la salud como tratamiento de primera elección de la malaria no complicada en áfrica todavía no están comercializados en nuestro país. la tripanosomiasis americana o enfermedad de chagas es una protozoosis endémica en américa del sur y centroamérica, producida por trypanosoma cruzi. la infección se transmite habitualmente por la inoculación transcutánea de secreciones infectadas de las chinches triatominas. después de una breve fase aguda, que puede cursar con fiebre e hinchazón en el punto de inoculación, el parásito invade los tejidos y, tras un período asintomático que se prolonga a veces durante décadas, puede provocar una enfermedad grave, con miocardiopatía dilatada, alteraciones de la conducción cardíaca, megacolon, megaesófago y afectación neurológica 22 . la infección se transmite también por vía oral, al consumir bebidas o alimentos contaminados con heces u orina de las chinches; por vía transplacentaria (infección vertical o congénita), y por la transfusión de hemoderivados 23 o el trasplante de médula ósea u órganos sólidos 24 procedentes de pacientes infectados. recientemente se ha descrito en nuestro país el primer caso documentado en europa de enfermedad de chagas congénita 25 en un neonato de madre boliviana. estos casos subrayan la necesidad del cribado de la enfermedad en embarazadas y donantes de sangre u órganos procedentes de áreas endémicas. a las técnicas de diagnóstico serológico habituales se han sumado recientemente pruebas de pcr anidada y en tiempo real 26, 27 , que permiten detectar el parásito en sangre y ayudan a valorar la eficacia del tratamiento con benznidazol 26 . la esquistosomiasis es una parasitosis endémica en áfrica, asia y américa, que se adquiere por contacto con agua dulce contaminada con cercarias de schistosoma haemato28 . la penetración de la cercaria puede provocar una dermatitis pruriginosa transitoria; a las 3-4 semanas, sobre todo en pacientes no inmunes, se produce una reacción febril con cefalea, artromialgias, hepatoesplenomegalia, diarrea y eosinofilia, conocida como síndrome de katayama 29, 30 . el diagnóstico en los viajeros se sospecha en esta fase por la clínica y el antecedente epidemiológico 31 ; los inmigrantes, en cambio, se infectan normalmente en la infancia y la parasitación suele cursar de forma asintomática, por lo que se detecta en fases avanzadas de la enfermedad, con hematuria, calcificaciones abdominales en la radiografía, uropatía obstructiva e hidronefrosis en la esquistosomiasis urinaria (s. haematobium) 32 , o dolor abdominal con fibrosis hepática periportal y hemorragia por varices esofágicas en los casos de esquistosomiasis intestinal (s. man-soni) 33 . se han descrito brotes de esquistosomiasis en viajeros españoles que se bañaron en la región del país dogón de mali 31 , con una proporción elevada de localizaciones dérmicas y genitales ectópicas 34 , y en burkina faso, con una tasa de infección tras la exposición muy elevada (69%) 29 . s. intercalatum produce una esquistosomiasis intestinal generalmente asintomática 35 y su hábitat se encuentra en focos restringidos de áfrica occidental y central, entre los que se encuentra guinea ecuatorial, donde no se han descrito infecciones por otros esquistosomas. la neurocisticercosis es la infección del sistema nervioso central por la larva del cestodo taenia solium y constituye un problema importante en la región andina de américa del sur, brasil y méxico, así como en el áfrica subsahariana y algunas zonas del sudeste asiático. en españa ha aumentado su incidencia general debido a los casos procedentes de latinoamérica, sobre todo de ecuador, donde casi el 4% de los pacientes ingresados en un hospital con procesos neu-rológicos fueron diagnosticados de neurocisticercosis 36, 37 . la enfermedad se presenta habitualmente en forma de convulsiones tónico-clónicas generalizadas o epilepsia parcial 37 y se diagnostica mediante técnicas de imagen y serología. en la prevención son muy importantes el control veterinario de la carne de cerdo y el tratamiento adecuado de las aguas residuales, así como la detección y el tratamiento de los pacientes infectados por t. solium, especialmente de los manipuladores de alimentos 36 . los geohelmintos son una causa muy importante de retraso del crecimiento y el desarrollo psicomotor en los niños de los prb, donde la organización mundial de la salud recomienda realizar campañas de tratamiento masivo para reducir la carga de la enfermedad en los niños 38 . en un estudio realizado en inmigrantes subsaharianos jóvenes (24 años de media) en situación irregular (< 6 meses en canarias), que se hallaban asintomáticos, se determinó una prevalencia del 23,1% de parasitosis intestinales, de las que un 88% correspondió a geohelmintos (uncinarias, ascaris lumbricoides, trichuris trichiura y strongyloides stercoralis) 39 . las uncinarias en inmigrantes con una residencia inferior a 3 años en españa se han asociado a eosinofilia (52%) y anemia ferropénica (28%) 40 . la eosinofilia es un problema frecuente en este colectivo: en un grupo de 788 inmigrantes africanos recientes se detectó eosinofilia en el 27%; las causas más frecuentes fueron filariasis (29%), esquistosomiasis (17%) y uncinariasis (17%) 41 . de todos los geohelmintos, s. stercoralis es el único con un ciclo autoinfectivo que prolonga la infección indefinidamente y puede causar cuadros graves, a veces mortales, de hiperinfestación en pacientes inmunodeprimidos 42 . no obstante, la parasitación suele ser asintomática y presentarse con eosinofilia o síntomas abdominales leves. aunque en españa hay focos endémicos y se han descrito prevalencias elevadas en trabajadores agrícolas de la comarca de la safor (valencia) 42 micosis crónicas difícil debido a la baja sensibilidad de las técnicas habituales de concentración de larvas en heces 42 . además, el diagnóstico serológico es inespecífico en los pacientes procedentes de zonas endémicas. por este motivo se ha recomendado utilizar la eosinofilia como marcador indirecto de la infección 43 , aplicar técnicas diagnósticas más sensibles de cultivo de larvas 42 o administrar un tratamiento empírico erradicador en pacientes procedentes de zonas endémicas que van a recibir fármacos inmunodepresores. la oncocercosis (onchocerca volvulus) es una filariasis endémica en áfrica occidental y central, frecuentemente importada a nuestro país, sobre todo en inmigrantes procedentes de la isla de bioko, de guinea ecuatorial, donde se determinó una prevalencia del 38% de la población general en 1998, al final de un programa de erradicación con administración masiva de ivermectina 44 . los pacientes pueden presentar prurito, eosinofilia y lesiones cutáneas maculopapulares e hipopigmentarias, y la infección se diagnostica habitualmente en unidades de medicina tropical, donde se realiza la técnica del pellizco cutáneo 4 . la lo iasis (loa loa) es también endémica en áfrica central y suele diagnosticarse por la aparición de edema subcutáneo migratorio (edema de calabar) o por el paso del verme por la conjuntiva ocular. no obstante, la mayoría de los casos de loiasis importados son asintomáticos o se presentan en forma de eosinofilia, a veces con prurito, por lo que algunos autores recomiendan el cribado sistemático con estudio de microfilarias en sangre de los inmigrantes procedentes de las zonas endémicas 45 . una lesión cutánea frecuente en viajeros es la larva cutánea migrans, producida por la penetración a través de la piel de larvas de uncinarias de animales domésticos (ancylostoma braziliense, a. caninum), las cuales se encuentran con frecuencia en tierras arenosas o arcillosas embarradas que están contaminadas con las heces de perros y gatos 46 . suele tratarse de una lesión única eritematosa y serpiginosa, que avanza de forma caprichosa 1-2 mm al día y provoca un prurito intenso. otra parasitosis que cursa como un edema eritematoso migratorio e intermitente o un cordón serpiginoso asociados a prurito intenso es la infestación por larvas de gnathostoma 47 , que se ha observado en pacientes a la vuelta de viajes por méxico y tailandia. uno de estos pacientes presentó afectación neurológica medular 48 . la infección se adquiere habitualmente por la ingestión de larvas infectivas con pescado poco cocinado, fermentado o marinado (ceviche), o carne cruda de reptiles, crustáceos o anfibios, entre otros animales 48 . la infección por entamoeba histolytica puede ser asintomática en los portadores intestinales o causar una diarrea hemorrágica o un absceso hepático caracterizado por fiebre, leucocitosis y dolor en el hipocondrio derecho. el diagnóstico de la infección intestinal se realiza habitualmente por microscopia, aunque para distinguir e. histolytica de la especie no patógena (e. dispar) es necesario realizar técnicas de pcr 49 o de detección de antígenos específicos. el absceso hepático se sospecha por la clínica y la aparición de una lesión ocupante de espacio en la ecografía, tomografía computarizada o resonancia magnética, en un paciente con antecedentes de viaje a zonas endémicas o contacto sexual con personas procedentes de zonas endémicas. en los viajeros se confirma mediante la detección de un único título elevado de anticuerpos frente a antígenos amebianos (por técnicas de enzimoinmunoanálisis, hemaglutinación indirecta o inmunofluorescencia indirecta); en los inmigrantes, sin embargo, es necesario demostrar una seroconversión o realizar pcr en líquido del absceso para confirmar definitivamente el diagnóstico 49 . aunque la mayoría de los casos de absceso hepático amebiano descritos en españa son importados 50,51 , se ha publicado una revisión de 10 pacientes con absceso hepático amebiano que no habían viajado a zonas endémicas, aunque en 2 casos hubo un contacto estrecho previo con otras personas infectadas 52 . los altos flujos de población entre españa y latinoamérica obligan a tener en cuenta la importación de varias micosis sistémicas que son endémicas de américa. la más frecuente es la histoplasmosis (histoplasma capsulatum), que también se encuentra en áfrica (variedad h. duboisii) y más raramente en asia. españa es uno de los países de europa donde se han descrito más infecciones importadas por histoplasma. también hay casos autóctonos en alemania, turquía e italia 53 . la histoplasmosis en viajeros recientes se manifiesta como un cuadro agudo e inespecífico con fiebre y tos, que suele ser autolimitado, aunque en algunos casos el tratamiento antifúngico puede ser beneficioso. el contacto con el hongo en viajeros que vuelven de latinoamérica es bastante frecuente, ya que hasta un 20% presenta una intradermorreacción con histoplasmina positiva, y son factores de riesgo el viaje a centroamérica, dormir al aire libre, una duración del viaje mayor de un mes 54 o visitar cuevas 55 . pueden aparecer brotes epidémicos en viajeros o cooperantes procedentes de la misma zona 56 y transmitirse a través de órganos trasplantados 53 . en inmigrantes o antiguos viajeros a áreas endémicas la histoplasmosis puede cursar como una infección pulmonar crónica, mientras que en inmunodeprimidos -pacientes infectados por el virus de la inmunodeficiencia humana (vih) con recuento de linfocitos cd4 < 150 células/ml o trasplantados-puede manifestarse como una infección diseminada 57 y alta mortalidad a pesar del tratamiento. esta última se debe a la reactivación de una infección latente hasta 50 años después del contacto con el hongo 53 . técnicas como la detección de antígenos, los hemocultivos, preferentemente por el procedimiento de lisiscentrifugación, o la pcr pueden ayudar al diagnóstico 58 . con los tratamientos antirretrovirales de gran actividad es previsible una disminución de casos en los pacientes con infección por el vih. en inmunodeprimidos y en ancianos deberían incluirse medidas preventivas frente a la histoplasmosis en los consejos al viajero 54 . los casos descritos de paracoccidiodomicosis (paracoccidioides brasilienses), antes llamada «blastomicois sudamericana», suelen ser importados por pacientes que han vivido en zonas rurales de venezuela, brasil, colombia, perú, ecuador o argentina, muchos de ellos inmigrantes españoles en latinoamérica que regresaron a su tierra, como galicia 59 o canarias 60 . en la forma crónica del adulto suele presentarse con afectación pulmonar o lesiones granulomatosas destructivas en piel y mucosas, sobre todo bucofaciales. más raramente produce adenopatías o diseminación a otros órganos. no suele tenerse en cuenta el antecedente epidemiológico para el diagnóstico diferencial y se confunde con otros procesos más frecuentes como tuberculosis, sarcoidosis o carcinomas epidermoides 59 . la coccidioidomicosis 61 y la blastomicosis son mucho menos frecuentes y de zonas geográficas más localizadas. también conviene considerar la infección sistémica por penicillium marneffei en pacientes inmunodeprimidos por el vih procedentes del sudeste asiático. se han descrito también casos importados de dermatomicosis como la infección por scytalidium dimidiatum 62 o micetomas 63, 64 . el descenso continuado que se venía produciendo en la incidencia anual de enfermedad tuberculosa en españa desde 1995 se está frenando por la incorporación de nuevos casos en inmigrantes 65 que, en algunas comunidades como madrid, representan hasta el 35% del total 66 . sin embargo, el impacto ha sido menor que en otros países desarrollados porque la incidencia previa era mayor en españa. la enfermedad tuberculosa en inmigrantes tiene un mayor índice de afectación extrapulmonar, aunque la mayoría de los casos son pulmonares, y suele tener su origen en reactivaciones de infecciones latentes, especialmente en los primeros años tras su llegada. las resistencias primarias a fármacos antituberculosos son más frecuentes, ya que muchos pacientes proceden de prb donde ya existen altas tasas de resistencias 67 . el índice de multirresistencia es también mayor, y en españa estos casos proceden principalmente de hispanoamérica y áfrica, sin olvidar a las antiguas repúblicas soviéticas 68 . el antecedente de tratamiento antituberculoso previo es el mayor determinante de multirresistencia y debe aumentar la sospecha 67 . las cepas resistentes, sobre todo las extremadamente resistentes, que incluyen quinolonas, complican los tratamientos, aumentan la toxicidad y dificultan la curación, sobre todo en pacientes con infección por el vih. las pautas de tratamiento en estos pacientes deben comenzar siempre con 4 fármacos hasta conocer los resultados de la sensibilidad 69, 70 . otro problema son las cepas importadas que se han asociado a brotes más importantes y a multirresistencia, como las del genotipo beijing, que ya han demostrado su capacidad de diseminación en gran canaria 71 . es necesario facilitar el acceso de los inmigrantes al sistema sanitario 70 para realizar un diagnóstico temprano y completar un tratamiento correcto; incluso se recomienda un cribado sistemático de tuberculosis a todos los inmigrantes que incluya prueba de la tuberculina, radiografía de tórax y el tratamiento de la infección latente 69 . la infección por mycobacterium africanum representa hasta la mitad de los casos de tuberculosis en algunos países de áfrica occidental y se está importando a nuestro país. pertenece al complejo m. tuberculosis y el cuadro clínico, la epidemiología y el tratamiento son similares a los de la infección por m. tuberculosis. en los últimos 10 años la incidencia declarada de lepra en españa se ha mantenido estable entre 6 y 18 pacientes al año. en 2005 hubo 6 casos autóctonos y 8 importados. su baja incidencia, la dificultad diagnóstica y su apariencia polimorfa conducen con frecuencia a diagnósticos erró-neos. se recomienda descartarla en pacientes, especialmente inmigrantes de prb, que presenten lesiones cutáneas crónicas, anestésicas e hipopigmentadas o eritematosas con afectación del sistema nervioso periférico 72 . en nuestro país hay grupos de investigación en técnicas moleculares para el diagnóstico y seguimiento de la infección por m. leprae 73 . en otro tipo de lesiones cutáneas ulcerosas y crónicas, especialmente en niños africanos de zonas rurales húmedas, hay que pensar en la úlcera de buruli, producida por m. ulcerans. se relaciona con ecosistemas acuáticos, afecta sobre todo a los miembros inferiores y precisa tratamiento quirúrgico y antibiótico durante 6 meses. en viajeros que vuelven con fiebre después de realizar safaris o cacerías en países del sur de áfrica (sudáfrica, botsuana o zimbabue) hay que tener en cuenta la fiebre botonosa africa-na, producida por rickettsia africae. es más leve que la fiebre botonosa mediterránea por r. conorii, frecuente en muchas zonas de españa. el diagnóstico se basa en el antecedente epidemiológico, la picadura de garrapatas y las manifestaciones clínicas de fiebre, escara (con frecuencia múltiple) y exantema, con o sin adenopatías. para su confirmación se precisa el cultivo del microorganismo, la amplificación de su adn y/o la presencia de anticuerpos específicos 74 . en los últimos años ha aumentado la incidencia de infecciones de transmisión sexual (its) en españa 75 . entre otros factores influyen el incremento de las conductas sexuales de riesgo y el aumento de la incidencia de sífilis y gonococia en países del este de europa y del áfrica subsahariana, con una importante emigración. el linfogranuloma venéreo, producido por chlamydia trachomatis, y el chancroide o chancro blando, por haemophilus ducreyi, son its ulcerativas frecuentes en países tropicales, aunque muy raras en zonas templadas. en los últimos años se han confirmado varios brotes en europa 76 y españa: el linfogranuloma venéreo entre varones homosexuales con síndrome anorrectal 77 y el chancroide en colectivos de inmigrantes, especialmente de origen africano 78, 79 . al igual que otras its ulcerativas, el linfogranuloma venéreo y el chancroide facilitan la transmisión del vih y la hepatitis b y c. la infección por bartonella bacilliformis es endémica en los valles interandinos de perú, ecuador y colombia entre los 500 y 3.200 m sobre el nivel del mar. produce un cuadro clínico bifásico con fiebre y anemia hemolítica grave (fiebre de oroya) y, posteriormente, lesiones cutáneas crónicas de carácter benigno (verruga peruana). se transmite de persona a persona por la picadura de mosquitos del género lutzomya, como la leishmaniasis en américa. es muy importante el antecedente de haber visitado o ser oriundo de estas zonas, ya que su diagnóstico precisa de técnicas sólo disponibles en laboratorios de referencia 80 . una bacteria común como staphylococcus aureus puede comportarse de forma más agresiva en la piomiositis tropical, que afecta sobre todo a músculos de las piernas en personas jóvenes y sanas que provienen del trópico 81 . en su patogenia podrían tener un papel importante las enfermedades parasitarias, los déficit nutricionales o los traumatismos repetidos. dado el incremento de viajes de turismo al extranjero para hacer deportes de riesgo y aventura, cuando éstos se realizan en contacto con agua dulce, además de la esquistosomiasis hay que tener presente la importación de leptospirosis. en el año 2000 ya hubo un brote epidémico en el rally eco-challenge, donde se infectaron al menos 80 participantes 82 . en pacientes con riesgo de sufrir rickettsiosis o leptospirosis que necesiten profilaxis antimalárica, la doxiciclina sería una buena opción para cubrir las 3 infecciones. 88 , por lo que se recomienda vigilar los patrones de resistencia para mejorar los tratamientos y evitar su extensión. conviene recordar que las vacunas disponibles sólo protegen parcialmente frente a s. typhi y que en asia también se ha detectado una frecuencia mayor de fiebre entérica por s. paratyphi, una especie no cubierta por las vacunas. aunque excepcional, conviene descartar la infección por vibrio cholerae en pacientes con diarrea que regresan de zonas con brotes de cólera. la mayoría de los virus importados precisan vectores y reservorios que no existen en nuestro medio y tienen un período de incubación relativamente corto. por este motivo se diagnostican más viriasis importadas en viajeros que en inmigrantes y no han supuesto hasta ahora un riesgo importante para la salud pública en españa. sin embargo, esta situación puede cambiar con la posibilidad de importar viriasis de transmisión directa persona a persona y por la llegada de los vectores o animales que sirven de reservorio. hay que destacar que algunas de estas viriasis están presentes en europa (hantavirus, virus productores de encefalitis y fiebre de crimea-congo, entre otros) 89,90 y que el mosquito aedes albopictus, vector de varias arbovirosis, continúa expandiéndose en europa 17 . por otro lado, es muy posible que las condiciones sociosanitarias de nuestro entorno supongan un importante freno para la extensión de estas enfermedades 17 . en nuestro país sólo se han descrito algunas de ellas, principalmente el dengue, y el resto plantea un riesgo potencial de importación que requiere una vigilancia permanente. el diagnóstico de la mayoría de estas infecciones puede realizarse mediante determinación de anticuerpos antiinmunoglobulinas m y g, técnicas de pcr en el suero o en la orina del paciente, análisis de seroneutralización y cultivos celulares en centros de referencia como el laboratorio de enfermedades víricas importadas del centro nacional de microbiología (majadahonda, madrid). desde los años ochenta se ha producido una importantísima expansión del dengue a partir del sudeste asiático hacia el océano pacífico, el caribe y latinoamérica, que ha afectado también a otras partes del mundo [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] . además, las modificaciones medioambientales producidas por el cambio climático están posibilitando la llegada de mosquitos del género aedes (vector de la enfermedad) a países fuera de su entorno habitual 17 , como ee.uu. 92 y algunos países europeos, como francia e italia, y más recientemente españa 94, 95 . esto añade un potencial de expansión de incalculables proporciones. en la última década se han descrito numerosos casos de dengue en españa 96,97 , pero no es posible estimar su incidencia al no ser de declaración obligatoria. es una enfermedad típica de viajeros, fundamentalmente turistas, con una estancia media de unas 3 semanas en países endémicos. en inmigrantes adultos es menos frecuente y en estos casos suele coincidir con viajes de visita a familiares y amigos en sus países de origen. en europa el número de casos registrados en la red de vigilancia tropneteurop desde 1999 a 2007 es de 1.117. en los últimos 5 años se han registrado de 100 a 150 cada año, la mayoría de ellos en turistas que visitaron la india, sudeste asiático, centroamérica, sudamérica, áfrica y australia, por este orden 99, 100 . en 2007 se comunicaron 103 casos, con un ligero aumento porcentual de pacientes procedentes de centroamérica. la presentación fue la habitual, es decir, un cuadro febril con cefalea, mialgias y erupción cutánea que apareció en el 38% de los pacientes. cabe destacar la atención de un mayor número de casos con diarrea. aunque la cifra de ingresos fue mayor que en años anteriores, sólo en 6 casos hubo alguna complicación y únicamente en un paciente se observó un síndrome de shock por dengue hemorrágico. esto podría explicarse por una mayor concienciación y la toma de precauciones por parte de los profesionales sanitarios. la confirmación diagnóstica de la infección por dengue habitualmente se realiza con serología específica, ya que la pcr es positiva sólo en los primeros días. los pacientes con plaquetopenia grave (< 100.000 ϫ 10 9 /l), aumento de la hemoconcentración, hemorragia espontánea o signos de encefalopatía deben ingresar bajo estricta vigilancia. no existe vacuna, por lo que debe advertirse a los viajeros a zonas endémicas para que extremen las medidas antivector. la infección por este virus se describió en 1953 en la frontera entre la antigua tanganica y mozambique. en la india, apareció en calcuta en 1963 y desde entonces se han producido pequeños brotes. sin embargo, en los últimos 2 años el aumento de la incidencia y de la extensión geográfica de la enfermedad ha sido muy notable [101] [102] [103] . los brotes epidémicos más importantes de la historia de esta enfermedad se han descrito en la isla de la reunión, en otras islas del océano índico y, más recientemente, en la india y sri lanka. 121, 122 . en 1966 se declaró extinguida la rabia en españa gracias al éxito de la vacunación animal generalizada 123 . sin embargo, se han sucedido brotes de la enfermedad por la introducción en el país de animales enfermos, como el de málaga de 1977 124 . desde ese año también se están detectando casos anuales de rabia en mamíferos terrestres en ceuta y melilla 124,125 , hasta sumar cerca de un centenar, probablemente por la proximidad del reino de marruecos, en el que esta enfermedad sigue presente. a pesar de que persiste el riesgo de reintroducción de la rabia salvaje a través de los pirineos y de la rabia callejera por el estrecho 125 , algunas comunidades (galicia, cataluña y país vasco) han suspendido la obligatoriedad de la vacuna antirrábica canina. además de la rabia transmitida por mamíferos terrestres, está adquiriendo especial importancia la transmitida por murciélagos hematófagos (principalmente del género desmosus) 125 . en españa se han descrito varios casos, pero todos han sido autóctonos 124, 126 . el síndrome respiratorio agudo grave (sars) está producido por un coronavirus previamente desconocido (coronavirus asociado al sars). los casos acumulados desde el brote inicial rondan los 8.400, con unos 800 muertos 127, 128 . su reservorio animal está relativamente localizado (un tipo de murciélago asiático y las civetas, que parecen desempeñar un papel amplificador), y el hecho de que los síntomas prece-dan a la fase más contagiosa del proceso ha posibilitado que las medidas epidemiológicas, sobre todo la cuarentena, fueran útiles para controlar la extensión de la enfermedad 129 . en españa no se ha comunicado ningún caso. el tratamiento es fundamentalmente de soporte. después de la experiencia del sars, una epizootia sin precedentes de gripe aviar altamente patógena del tipo a, subtipo h5n1, está produciendo en los últimos años casos de enfermedad en humanos (369 hasta el 1 de marzo de 2008) con una alta mortalidad (63%), sobre todo en pacientes jóvenes, y plantea la amenaza de una pandemia de graves consecuencias 130 . si el virus llegara a transmitirse con eficacia entre humanos, habría que tener en cuenta 2 variables que diferenciarían esta pandemia del sars: en primer lugar, el reservorio de aves domésticas y silvestres es inmenso, y las segundas están sujetas a constantes migraciones, por lo que el confinamiento de las aves domésticas y el cierre de los mercados de aves en los focos de aparición de la infección serían insuficientes y deberían extenderse a lo largo de todas las rutas migratorias de las aves, de las que españa es un lugar de paso importante. la segunda diferencia radica en que el período de máxima infectividad en cada individuo precedería al de los síntomas, por lo que la eficacia de la cuarentena sería previsiblemente menor que en el sars. hasta ahora en españa sólo se ha detectado el virus en un ave silvestre (un somormujo), localizada muerta en un humedal de álava (http://www. gripeaviar.es/esp/index.html). en los próximos años es previsible que sigan aumentando en españa el número y la variedad de infecciones importadas, en paralelo con el incremento de la inmigración y de los viajes internacionales. la experiencia recogida en la bibliografía de autores españoles representa un importante cuerpo de conocimiento que puede aprovecharse para mejorar nuestra preparación clínica, microbiológica y epidemiológica, adaptándolo a las características de nuestra población local. el riesgo que para la salud pública suponen las infecciones importadas es pequeño 78, 131 . el más reconocido procede de infecciones cosmopolitas, como la tuberculosis, o rarísimas, como algunas fiebres hemorrágicas. la transmisión fecal-oral en nuestro medio está limitada por las buenas infraestructuras de saneamiento. para las infecciones crónicas transmisibles, como la enfermedad de chagas, se necesitan nuevas medidas de cribado y tratamiento como las que existen para el vih, la sífilis o la hepatitis b y c 22, 132 . otras infecciones tropicales no cuentan con vectores eficientes para propagarse, aunque el cambio climático y la introducción de nuevos insectos como a. albopictus pue-den cambiar este panorama. el reciente brote de fiebre de chikungunya importada en italia ha sido un serio aviso en este sentido, aunque nuestros sistemas sanitarios, hasta ahora, parecen capaces de diagnosticar y controlar su extensión. a escala nacional deben incentivarse las medidas preventivas y potenciar las consultas de consejos al viajero, incluidos los extranjeros residentes que visitan sus países de origen. también debemos defender el acceso universal a la asistencia sanitaria y unas condiciones sociosanitarias dignas para toda la población, a fin de mantener unos indicadores de salud adecuados. sin embargo, el control global de estas infecciones es imposible desde instancias locales o nacionales, por lo que son necesarias iniciativas internacionales como la roll back malaria, la campaña para la erradicación de la polio o los objetivos del milenio de naciones unidas. el éxito de estas campañas disminuirá la morbimortalidad global y aumentará la seguridad sanitaria para todos nosotros, al disminuir la posibilidad de importación de estas enfermedades. un paso más supone la entrada en vigor del nuevo reglamento sanitario internacional en julio de 2007, que pretende mejorar los mecanismos de vigilancia epidemiológica y la coordinación de la respuesta sanitaria internacional frente a nuevos riesgos de brotes epidémicos o pandemias. nuestra responsabilidad como profesionales sanitarios es exigir un mayor esfuerzo de inversión y coordinación internacional para el control de las enfermedades infecciosas, incluidas las clasificadas como olvidadas. queremos agradecer la inestimable colaboración de rosa trueba gómez en la obtención de documentos bibliográficos y expresar nuestra gratitud al dr. josé sanz moreno por la revisión del manuscrito. the basic principles of migration health: population mobility and gaps in disease prevalence las enfermedades tropicales en el mundo occidental geosentinel surveillance network. spectrum of disease and relation to place of exposure among ill returned travelers infectious diseases in immigrants from the perspective of a tropical medicine referral unit illness after international travel etiology and outcome of fever after a stay in the tropics arcos-pereda p. paludismo importado en un hospital general de madrid hospitalización por paludismo en españa durante el período 1999-2002 paludismo importado: una enfermedad emergente clinicoepidemiological study of imported malaria in travelers and immigrants to madrid paludismo importado por inmigrantes en cataluña análisis de 149 casos an outbreak of plasmodium vivax malaria among heroin users in spain malaria infection through multiorgan donation: an update from spain plasmodium ovale malaria acquired in central spain cambio climático en españa y riesgo de enfermedades infecciosas y parasitarias transmitidas por artrópodos y roedores malaria diagnosis by now ict and expert microscopy in comparison with multiplex polymerase chain reaction in febrile returned travellers ineffectiveness of the binax now malaria test for diagnosis of plasmodium ovale malaria usefulness of seminested multiplex pcr in surveillance of imported malaria in spain imported falciparum malaria in europe: sentinel surveillance data from the european network on surveillance of imported infectious diseases grupo de trabajo del taller «enfermedad de chagas importada: ¿un nuevo reto de salud pública?». diagnóstico y tratamiento de la enfermedad de chagas importada chagas disease in a recipient of cord blood transplantation acute chagas disease in a recipient of a bone marrow transplant in spain: case report congenital transmission of trypanosoma cruzi in europe (spain): a case report diagnóstico de laboratorio de la enfermedad de chagas importada development of a real-time pcr assay for trypanosoma cruzi detection in blood samples increasing incidence of imported schistosomiasis in mallorca, spain brote de esquistosomiasis en un grupo de viajeros procedentes de burkina fasso fiebre de katayama en turistas españoles: análisis de 25 casos esquistosomiasis importada por viajeros españoles: estudio clínico epidemiolgico de 80 casos castells reizábal i, álvarez castells a, ricart y de mesones a comparative, clínico-epidemiologic study of schistosoma mansoni infections in travellers and immigrants in spain ocho casos de localización ectópica de la esquistosomiasis en viajeros españoles clinical presentation of schistosoma intercalatum infestation growing frequency of neurocysticercosis in madrid (spain) neurocysticercosis and population movements: analysis of 23 imported cases in spain intervention for the control of soil-transmitted helminthiasis in the community parasitosis intestinales en población inmigrante subsahariana asintomática. gran canaria uncinariasis importada por inmigrantes africanos: estudio de 285 casos helminth-related eosinophilia in african immigrants estrongiloidiasis: epidemiología, manifestaciones clínicas y diagnóstico high prevalence of strongyloides stercoralis among farm workers on the mediterranean coast of spain: analysis of the predictive factors of infection in developed countries reduction in the prevalence and intensity of infection in onchocerca volvulus microfilariae according to ethnicity and community after 8 years of ivermectin treatment on the island of bioko, equatorial guinea cribaje de microfilariasis sanguínea (loa loa) en la población inmigrante de zonas endémicas larva migrans cutánea en viajeros two cases of imported gnathostomiasis in spanish women cutaneous and medullar gnathostomiasis in travelers to mexico and thailand absceso hepático amebiano autóctono: diagnóstico microbiológico por pcr. enferm infecc microbiol clin absceso hepático amebiano: revisión de 13 casos absceso hepático amebiano: observaciones sobre siete pacientes absceso hepático amebiano autóctono: caso clínico y revisión de la literatura médica histoplasmosis in europe: report on an epidemiological survey from the european confederation of medical mycology working group histoplasmosis infection in spanish travelers to latin america imported histoplasmosis in spain infección por histoplasma capsulatum en un grupo de cooperantes en guatemala histoplasmosis diseminada en pacientes con sida. estudio de 2 casos y revisión de la bibliografía española evaluación de una técnica de pcr cuantitativa para el diagnóstico clínico de la histoplasmosis importada paracoccidioidomicosis importada. a propósito de dos casos atypical coccidioidomycosis in an aids patient successfully treated with fluconazole dermatomicosis de importación por scytalidium dimidiatum: a propósito de tres casos mujer de origen filipino con tumoración en un pie tumoración subcutánea en pie tras traumatismo con espina de acacia tuberculosis trends in madrid, 1994-2003: impact of immigration and hiv infection inmigración e incidencia de la tuberculosis en la comunidad de madrid. rev esp salud publica risk factors for multidrug resistant tuberculosis in europe: a systematic review vigilancia molecular de la tuberculosis multirresistente en europa. proyecto mr-tb prevención y control de las tuberculosis importadas situación actual de las resistencias de mycobacterium tuberculosis en la población inmigrante de la comunidad de madrid epidemiological evidence of the spread of a mycobacterium tuberculosis strain of the beijing genotype on gran canaria island lepra simulando otras enfermedades comparison of pcr mediated amplification of dna and the classical methods for detection of mycobacterium leprae in different types of clinical samples in leprosy patients and contacts infección por rickettsia africae. tres casos confirmados por reacción en cadena de la polimerasa vigilancia epidemiológica de las infecciones de transmisión sexual lymphogranuloma venereum proctitis: an emerging sexually transmitted disease in hiv-positive men in the netherlands first case of lgv confirmed in barcelona enfermedades importadas en inmigrantes africanos: estudio de 1.321 pacientes chancro blando y haemophilus ducreyi: ¿una enfermedad y un microorganismo en aumento en españa? la enfermedad de carrión, dos siglos después leptospirosis in «eco-challenge» athletes etiology of traveller's diarrhea in spanish travellers to developing countries trends in antimicrobial resistance in campylobacter spp. causing traveler's diarrhea quinolone resistance among shigella spp. isolated from travellers returning from india mechanism of resistance to several antimicrobial agents in salmonella clinical isolates causing traveler's diarrhea. antimicrob agents chemother susceptibility patterns of enteroaggregative escherichia coli associated with traveller's diarrhoea: emergence of quinolone resistance salmonella enterica serovar typhi: antimicrobial drug resistance in asia and the molecular mechanism of reduced susceptibility to the fluoroquinolones emerging and re-emerging viral infections in europe infecciones por el virus de toscana, el virus del nilo occidental y otros arbovirus de interés en europa dengue in travelers dengue and hemorrhagic fever: a potential threat to public health in the unites states european network on surveillance of imported infectious diseases. severe dengue virus infection in travelers: risk factors and laboratory indicators llegada de aedes albopictus a españa, un nuevo reto para la salud pública first record and establishment of the mosquito aedes albopictus in spain dengue: una enfermedad reemergente. estudio clinicoepidemiológico en 57 viajeros españoles dengue importado en viajeros. xi congreso de la sociedad española de enfermedades infecciosas y microbiología clínica (seimc) diagnóstico y caracterización de las infecciones importadas por dengue en viajeros. xi congreso de la sociedad española de enfermedades infecciosas y microbiología clínica (seimc) diseases of environmental and zoonotic origin team, ecdc. dengue worldwide: an overview of the current situation and the implications for europe chikungunya risk assessment for europe: recommendations for action an outbreak of chikungunya fever in the province of chikungunya fever diagnosed among internacional travellers. united states infección por virus de chikungunya en una viajera española a single mutation in chikungunya virus affects vector specificity and epidemic potential west nile virus: a reemerging global pathogen respuesta ante la alerta de circulación del virus west nile en españa. xi congreso de la sociedad española de enfermedades infecciosas y 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travellers. cdc travel information oms. fiebres hemorrágicas víricas las fiebres hemorrágicas víricas en europa: su control eficaz exige una respuesta coordinada programa de vigilancia y control de las fiebres hemorrágicas virales who. the who expert consultation on rabies estado actual de la rabia animal, con especial referencia a españa ¿cuál es el riesgo real de rabia en españa? rabia transmitida por murciélagos insectívoros en españa severe acute respiratory syndrome (sars) severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection zoonotic viral diseases and the frontier of early diagnosis, control and prevention writing committee of the second world health organization consultation on clinical aspects of human infection with avian influenza a (h5n1) virus. update on avian influenza a (h5n1) virus infection in humans communicable diseases in the immigrant population attended to in a tropical medicine unit: epidemiological aspects and public health issues key: cord-324635-27q3nxte authors: bouza, emilio; brenes, francisco josé; domingo, javier díez; bouza, josé maría eiros; gonzález, josé; gracia, diego; gonzález, ricardo juárez; muñoz, patricia; torregrossa, roberto petidier; casado, josé manuel ribera; cordero, primitivo ramos; rovira, eduardo rodríguez; torralba, maría eva sáez; rexach, josé antonio serra; garcía, javier tovar; bravo, carlos verdejo; palomo, esteban title: the situation of infection in the elderly in spain: a multidisciplinary opinion document date: 2020-09-08 journal: rev esp quimioter doi: 10.37201/req/057.2020 sha: doc_id: 324635 cord_uid: 27q3nxte infection in the elderly is a huge issue whose treatment usually has partial and specific approaches. it is, moreover, one of the areas where intervention can have the most success in improving the quality of life of older patients. in an attempt to give the widest possible focus to this issue, the health sciences foundation has convened experts from different areas to produce this position paper on infection in the elderly, so as to compare the opinions of expert doctors and nurses, pharmacists, journalists, representatives of elderly associations and concluding with the ethical aspects raised by the issue. the format is that of discussion of a series of pre-formulated questions that were discussed by all those present. we begin by discussing the concept of the elderly, the reasons for their predisposition to infection, the most frequent infections and their causes, and the workload and economic burden they place on society. we also considered whether we had the data to estimate the proportion of these infections that could be reduced by specific programmes, including vaccination programmes. in this context, the limited presence of this issue in the media, the position of scientific societies and patient associations on the issue and the ethical aspects raised by all this were discussed. authors for their corrections and amendments. the final document has been reviewed by all the authors. we will now review the questions posed, the arguments made and the conclusion reached for each one. what do we mean when we talk about the elderly? how many are there in spain? how many will there be in the near future? presentation: the who publishes reports on ageing and health, or old age and its consequences, on a regular basis, at least since the 60's. cited here are a few more. we reproduce a paragraph in full [1, 2] "today, for the first time in history, most people can aspire to live beyond the age of 60. in low and middle-income countries, this is largely due to the significant reduction in mortality in the early stages of life, especially during childbirth and infancy, and in mortality from infectious diseases. in high-income countries, the sustained increase in life expectancy today is mainly due to the decline in mortality among older people". the report focuses on a redefinition of healthy ageing based on the notion of functional capacity: the combination of the individual's intrinsic capacity, relevant environmental characteristics and the interactions between the individual and these characteristics. in spain, according to data from the national institute of statistics [3] , 18 .7% of the population is currently over 65. that's about 8.7 million people. if we focus on those over 85, they currently account for 6% of the total population (about 2.8 million). forecasts for 2031 put the number of people over 65 years old at 12 million (26.2% of the population) and those over 85 at 3.9 million (8.5% of the population). thus, between 1960 and 2031, the number of people over 65 will have increased by a factor of 5 (from 2.5 to 12 million), and the percentage will have increased by a factor of 3 (from 8.2 to 26.2 %), while the number of people over 80 will have increased by a factor of 10 (from 370,000 to 3.9 million) and the percentage will have increased by a factor of 6 (from 1.2 to 8.5 per %). once the figures have been established, it is necessary to clarify that, according to the dictionary of the royal spanish academy of language (drael), "old" is "that person of age, commonly one who has turned 70". however, age is a purely theoretical value to distinguish a person as "old" or "elderly". taking the age of 65 as the threshold for the onset of old age dates back to the late 19th century, when less than 10% of those born reached that age. today, more than 90% of people reach the age of 65, so this age limit is shifting towards older ages. nowadays the concept of "old" is more related to "function" than to age. thus, the drael defines health as "that state in which the organic being normally exercises all its functions". therefore, one of the most relevant aspects in considering a person "old" is that they need help to carry out the activities of daily life (bathing, dressing, feeding, moving, etc.). we can find totally independent people in their 80's and others with a high degree of dependency in their 60's. formato es el de la discusión de una serie de preguntas preformuladas que fueron discutidas entre todos los presentes. empezamos discutiendo el concepto de "anciano", las razones de la predisposición a la infección, las infecciones más frecuentes y sus causas, y la carga laboral y económica que suponen para la sociedad. también preguntamos si teníamos datos para estimar la proporción de estas infecciones que podrían ser reducidas por programas específicos, incluyendo programas de vacunación. en este contexto, se discutió la baja presencia de este problema en los medios de comunicación, la posición de las asociaciones científicas y de pacientes sobre el problema y los aspectos éticos que todo esto plantea. the ageing of the population in more developed societies is an incontrovertible fact. in the face of the indisputable success in achieving a longer life for a large proportion of the population, questions arise as to the viability of social protection systems. by 2030, over 25% of the population will be classed as elderly and their quality of life will depend, to a large extent, on avoiding preventable diseases such as infectious diseases. it is a well-known fact that the elderly constitutes a risk group for distinct types of infectious diseases, whose diagnosis and treatment are hindered by several factors. around this fundamental fact, however, we find a lack of answers to simple questions about the size of the problem, its epidemiology, the capacity of the social response to it and the need to plan useful preventive measures to minimise risk and reduce costs. for this reason, the health sciences foundation, which has prevention as one of its main objectives, has organised a discussion and opinion meeting on the infectious diseases situation in the elderly in spain, aiming to answer a series of questions accepted by all the participants. greater difficulty in eliminating secretions. in the digestive tract it is common to find diverticuli in the mucosa that act as microorganism reservoirs. also, losses in secretory function with a tendency to gastric achlorhydria, but, above all, motor function which at oesophageal level, can favour aspiration phenomena. in the urogenital system there are usually alterations arising from pregnancy, childbirth, previous surgeries and local manipulations that make the free flow of urine difficult. in this vein, it is worth adding the frequency of subjecting the elderly to diagnostic or therapeutic examinations that may favour infections. in addition to the deterioration of mechanical barriers, there are losses in non-specific defence mechanisms. these include limitation to increase blood flow and vascular permeability at the infection entry points. the ability to mobilise polymorphonuclear leukocytes rapidly and the agility of phagocyte function is also impaired. chemotactic capacity decreases from the age of 70, as does the capacity for the intracellular destruction of microorganisms. ageing is associated with a chronic, progressive, nonspecific, low-level pro-inflammatory state, for which the english literature has coined the term "inflammageing", which favours an environment conducive to infection and further limits the possibilities of an effective response to it. the deterioration of adaptive immunity ("immunosenescence") associated with the ageing process has been known for years and affects both innate and acquired immunity [4] [5] [6] . immunosenescence includes qualitative losses in t-lymphocyte subpopulations with decreased activity of cd-4 helpers, cytotoxic cd-8s and a limitation in generating t-cell growth factor. ageing determines a tendency to invert the cd4/cd8 t-cell ratio. the number of dendritic cells decreases with age and the response of nk cells to stimulating cytokines is limited. it also increases the activity of cd-8 suppressors. b-lymphocytes are limited in their ability to produce antibodies and to respond to external antigens. furthermore, there is an increase in the production of autoantibodies and circulating immune complexes. a third group of factors that add to the microorganisms and the individual are environmental and social factors, such as hygiene neglect, poverty, isolation and a sedentary lifestyle. the fact of living in nursing homes and the increase in hospitalisations favours an insufficiently quantified environmental exposure [7] . there are multiple factors that explain the higher incidence of infections in the elderly. the clearest are those that have to do with alterations of the defensive barrier mechanisms. immunosenescence is a complex concept involving various alterations in the immunity of the elderly. what are the main clinical syndromes of infection in the elderly? the frequency and even the aetiology of infections af-therefore, the "elderly" is an enormously heterogeneous group in aspects such as the prevalence of chronic diseases (ischaemic heart disease, hypertension, diabetes, copd, etc), the need for consumption of drugs and the existence or nonexistence of physical, mental (dementia, depression) and social (loneliness, isolation, poverty) problems. conclusion: -the definition of elderly is artificial and refers to any person over a certain age (which can be set at 65, 70 or older) who has serious limitations in the exercise of their physical, mental or social functions. -in our society, currently, almost 20% of the population would meet a definition of elderly based exclusively on the criterion of age, but it is estimated that, with this criterion, the percentage in spain will be greater than 25% by the year 2031. the changes that take place throughout the ageing process favour the existence of infections. the simplest explanation is that with age the numerator of the aggression/defence equation increases (greater arrival of microorganisms that are also more virulent) and the denominator decreases (less defence capacity on the part of the organism). we can therefore divide the causes of the elderly person's predisposition to infection into those that depend on the microorganisms and those that depend on the host's defence mechanisms. there is no evidence that the microbiota of the elderly is quantitatively different from that of younger populations, nor necessarily more aggressive. however, it is an incontestable fact that previous infections, antimicrobial treatments, the greater ease of microorganism acquisition and living in proximity to other elderly people, can predispose the elderly to colonization and subsequent infection by multi-resistant microorganisms, with the presence of "superinfections", with a worse response to antimicrobials and increased resistance to them. in terms of host defence mechanisms, there are many factors that make the elderly more labile. mechanical barriers, for example, are the first element of defence, but they deteriorate progressively throughout the ageing process, facilitating the entry of microorganisms. the skin and mucous membranes experience physiological losses and often also those resulting from local or systemic diseases. the most important changes are: thinning, with loss of epithelial and mucosal cells, worse hydration and vascularization, loss of elasticity, decrease in mucous gland secretions of antimicrobial peptides, worse healing, loss of cellular macrophages in the skin (langerhans cells) and immobility with increased local pressure in certain areas. in the respiratory system, there is a decrease in the number of cilia and a slowing down of their activity, a reduction of alveolar macrophages, a decrease of the cough reflex and pend on their situation. in independent elderly people, the most common infections are respiratory conditions caused by viruses or bacteria prevalent in the community, urinary tract infections and intra-abdominal infections. in contrast, in institutionalised elderly people, bladder catheter-related utis, aspiration pneumonias, skin and soft tissue infections, and infections of the gastrointestinal tract predominate. which microorganisms are most common? how does the problem of multi-resistance impact on the elderly? presentation: it is important to remember that infections in the elderly may be caused by a greater variety of microorganisms than in the younger population, so it is essential to obtain samples for culture before administering empirical antimicrobial treatment [8] . thus, for example, while the vast majority of utis in young patients are caused by e. coli, in the elderly their relative importance is less. in the case of pneumonia, there is a higher incidence of gram-negative bacilli (gnb) and as far as meningitis is concerned, they are rarely of viral aetiology, while we must consider gnb and listeria monocytogenes. in a spanish study, including 333 elderly patients (mean age 81.6 years), with utis, the most frequently isolated microorganisms were e. coli, (67%), enterococcus faecalis (15%), klebsiella pneumoniae (10%) and pseudomonas aeruginosa (9%). in up to 8% of cases, more than one microorganism was isolated in the urine. the frequency of bacteraemia was higher with e. coli and lower with e. faecalis and p. aeruginosa and bacteraemia was not associated with a worse prognosis [22] . the frequency of multi-resistance increases with age and comorbidity. in this spanish study, the proportion of extended-spectrum beta-lactamase (esbl) producing e. coli and k. pneumoniae isolates was 20.1% and 36.3%, respectively. in the previously mentioned study of patients attending the emergency department, the elderly accumulated more risk factors for multi-resistance (p < 0.001) and suffered from septic syndrome more frequently (p < 0.001) [16] . there are few studies that analyse the overall aetiology of respiratory infections in older patients, and most work focuses on describing specific populations or groups of pathogens. the aetiological affiliation rate of respiratory infections in the elderly is very low (<30%), and this is due, among other things, to the difficulty many patients have in producing sputum and to the high frequency of empirical treatment [21] . if we analyse the aetiology of cap, the most frequent pathogen is s. pneumoniae (20-80%), followed by h. influenzae (3-39%), respiratory viruses (3-30%), legionella spp.(1-17%) and gnb (3-14%) . it is also necessary to remember the importance of viral pathogens in this population, since the prescription rate of unnecessary antimicrobials is very high in them (46% of the elderly with viral symptoms) [23] . in a study conducted in china, in 6 sentinel hospitals, it was observed that 31.64% of elderly patients with respiratory infection had a viral aetiology (41.8% among extra-hospital infections and 25.7% among fecting the elderly vary depending on the clinical environment (home, nursing home, hospital) and the functional status of the patient. in older, independent and healthy people, respiratory conditions caused by viruses or bacteria prevalent in the community, urinary tract infections (utis), whether catheter-related or not, and intra-abdominal infections (cholecystitis, diverticulitis) are common. in contrast, in institutionalised elderly people, utis related to the bladder catheter, aspiration pneumonia, skin and soft tissue infections and those of the gastro-intestinal tract (git) predominate. in hospitalised elderly people we have to consider nosocomial pneumonia, intravascular catheter associated infections and c. difficile infections as the most prevalent [8] [9] [10] [11] [12] [13] [14] . there is limited data analysing the comparative overall frequency of the different syndromes. in elderly people living in nursing homes, utis (at least 30-40% of healthcare-associated infections), respiratory infections, skin and soft tissue infections and those of the git predominate [15] . in a recent spanish multicentre descriptive study, conducted in 49 emergency departments, 11,399 patients were included, of whom 4,255 (37.3%) were at least 65 years old. compared to younger adults, older patients (mean 78.8 years) had respiratory, urinary and intra-abdominal infections more often, while there was no difference in the frequency of other syndromes [16] . these data are confirmed in chinese studies that analyse elderly patients attending emergency departments and also show a significantly higher incidence of respiratory and urinary infections [17, 18] . in the case of utis, the relative prevalence is influenced by the gender of the patient. thus, for long-term care facility (ltcf) residents and in hospitalised elderly people, uti is the number one cause of infection and is the second most common in older women living in the community [19] . the incidence in men ranges from 0.05/person year (1/20) in men aged 65-74 and reaches 0.08 (1/12) in men over 85. in women, the incidence of uti increases with menopause (0.07 per person/ year: 1/14), increasing to 0.13 per person-year (1/7.5) after age 85 [20] . in indwelling catheter-wearing patients, the incidence of utis is 3.2 cases per 1,000 catheter days, compared to only 0.57 per 1,000 days for all residents (x18). urinary tract bacteraemia was 3-39 times more common in patients with permanent urinary catheterization [20] and uti is also the most frequent cause of community-acquired bacteraemia in the elderly (40-57%). with respect to respiratory infections, the annual incidence of community acquired pneumonia (cap) ranges from 8-18.2 episodes per 1,000 people over 65 years of age and represents 30-40% of hospitalisations in this age group [21] . in japan, 96% of deaths from pneumonia occur in patients over 65 years of age. the risk of cap is 4 times higher in those over 65 compared to those under 45 and 10.8 times higher in those over 85 compared to adults aged 50-64. viral infections are also common in this age range, as we will see later. the most prevalent infections in the elderly de-is estimated at between 4 and 5 episodes per 1,000 days of stay in the residence [33, 34] . the figures rise to 11 for those with some kind of prosthetic material [35] . we have several european halt studies (healthcare-associated infections and antimicrobial use in long term care facilities), with participation from 24 countries, including spain, with a prevalence of infection of 4.7% and 5% at two different times [36] [37] [38] . a french multi-centre study, conducted in 578 nursing homes with 445,000 beds, shows an infection prevalence of 11.23% [39] . the first data on infection in nursing homes in spain come from the epinger study, conducted in community health centres in catalonia, which reported a prevalence of 6.5%, although it should be pointed out that in catalonia the concept of the community health centre would include medium-long term patients, while in the rest of the spanish autonomous communities this concept would be limited to nursing homes [40] . in another study, conducted by san sebastian's fundación matía, an infection prevalence between 6.44% and 4.80% was reported [41] . data derived from the vincat study in catalonia show a prevalence of healthcare-associated infection in long-term care centres of 10.2%, with a great diversity, depending on the type of care unit (subacute 22.3%, palliative 18.7%, convalescent 11.7%, long stay 8.1%) [42] . home is the most recommendable place for the healthy elderly to live, and even for the elderly patient, with healthcare falling to primary care professionals, although sometimes with the collaboration of some hospital resources. the ministry of health, social services and equality has for the first time published the results of the primary care clinical database (bdcap), a tool that allows for a more precise and systematized knowledge of the main health problems in spain dealt with by the doctors on the healthcare frontline. thanks to this register, a detailed picture of the health problems of the spanish population is available from primary care [43] . in this database, infections appear among those over 64 years old with an elevated frequency of 634.1 cases a year per 1,000 people (569.9‰ men and 682.7‰ women). the most frequent correspond to the respiratory system (317 cases/1000 persons/year), followed by urinary tract infections with (84.4 cases/1000 persons/year) and clear female predominance. finally, nosocomial infections are those that occur in hospitalized patients and are present more than 48 hours after admission. they are acquired by transmission from the environment, from other patients or from healthcare personnel. they are considered to be the most preventable cause of serious adverse events in hospitalised patients [44] . in general, these infections are related to invasive diagnostic or therapeutic procedures (urethral catheterization, surgical procedure, vascular catheter, invasive mechanical ventilation), all of which have in common the disruption of the host's own defences by a device or an incision, allowing the invasion of nosocomial infections) [24] . the most common cause was influenza (14% of all patients studied). rsv is also a significant pathogen in this population [25, 26] . the most important cause of git infection in the elderly is clostridioides difficile. c. difficile (c-diff) infection is currently the most prevalent nosocomial infection, affecting in more than 70% of the episodes patients over 65 years of age [27] . moreover, it is in this population that c-diff causes the highest morbidity and mortality, with an increase in c-diff-related mortality from 5.7 to 23.7 deaths per million population per year from 1999 to 2004 [28] in patients with an average age of 84 years having been described in the usa. it is interesting to note the safety of using the same therapeutic options in elderly patients, including faecal microbiota transplantation [29, 30] . the microorganisms causing infection in the elderly are qualitatively the same as in the population of other age groups, although there are quantitative variations. where do they get these infections? what proportion are acquired in nursing homes? at home? in hospital? in addition to the hospital and home environment, the elderly can acquire infections elsewhere, and in particular in other care units. this is the reason why, almost 20 years ago (2002), the term "health care-associated infection" began to be used, which is not only limited to hospitalized patients, but also extends the concept to patients in contact with the health system (home care of patients with high comorbidity and complexity; day care centres; major outpatient surgery units; outpatient dialysis centres; community health centres for chronic or convalescent patients). to a great extent, it is in nursing homes where patients with more comorbidities, polypharmacy consumption, a high degree of dependency and a high prevalence of invasive devices (bladder catheter, nasogastric tube, percutaneous gastrostomy) will be treated. in addition, the environment can facilitate the transmission of microorganisms between residents and healthcare personnel, as well as between residents. for all these reasons and the excessive or inappropriate use of broad-spectrum antibiotics, either empirically or prophylactically, multi-drug-resistant (mdr) infections can be generated. implementation of effective preventive measures in this population is very difficult to organise. in the united states of america, it is estimated that approximately 1.5 million people live in nursing homes and suffer between 1.6 and 3 million episodes of infection annually [31] . the prevalence of infections in these residences is estimated at 10% of the residents [32] and the incidence of new infections infectious diseases are the second cause of such admissions (16.2%), only surpassed by cardiovascular diseases (28.6%). pneumonia and sepsis are the most common infections causing admission in this population [48] . the elderly population also has longer hospital stays (5.5 days for those over ≥65) than those between 45 and 64 (5.0 days) and those between 15 and 45 (3.7 days) [49] . the elderly are treated by virtually every unit in a hospital but it is worth mentioning that those over 65 years of age represent 40% of those admitted to intensive care units [50] . the other group of interest is that of specialised geriatric units, not available in all hospitals, which have been shown to improve the functional status of patients and reduce the number of discharges to long-term care homes [51] . in a study by saliba et al., conducted in israel [52] , out of a total of 81,077 hospital admissions in the elderly between 2001 and 2010, the proportion of admissions due to infectious diseases rose from 16.9% in 2001 to 19.3% in 2010. globally, the most frequent infections causing admission were: those of the lower respiratory tract (lrt) (41.0%), followed by the utis (21.4%), upper respiratory tract (10.2%) and hepatobiliary (9.8%). in spain we do not have precise answers to the questions asked. the proportion of serious infections in the elderly requiring hospitalisation depends on several factors: type of infection, severity of infection and other factors such as the degree of frailty of the elderly, their place of residence and their ability to receive care at home. the environment and the resources available also influence the hospitalisation decision. however, in our environment, most serious infections in the elderly will require hospitalisation for at least a few hours. in spain, serious infections in the elderly can be treated by different professionals depending on the type and severity of the infection, and the environment in which it occurs. a high percentage are treated by "generalists" hospital specialists, or geriatricians. where infectious disease specialists are available they are of course involved in their management, either in beds in their own departments or as consultants. they can also be treated by specialists of the affected organ such as orthopaedic surgeons in the case of infections of prosthetic material, or vascular surgeons in the case of infections of vascular ulcers. and if, in the end, hospital admission is not decided, the patient is cared for by the primary care team. as an example, we have collated the urinary tract infections treated at the hospital general universitario gregorio marañón between 2015 and 2018. when uti is the main diagnosis that motivates admission (about 700 cases a year) about 90% of cases are cared in the medical departments. when it comes to secondary diagnosis (about 2,000 cases per year), the internal medicine and geriatrics departments take care of about 75% of the cases. preventive programmes, such as flu vaccination programmes, reduce the need for hospitalisation for respiratory infections by nearly 30%, both inside and outside spain [53] [54] [55] . microorganisms that are part of the patient's usual microbiota (endogenous microbiota), or selected by the selective antibiotic pressure (secondary endogenous microbiota), or by one found in the hospital environment (exogenous microbiota). to understand the main epidemiological data on hospital infections, the epine study (estudio de prevalencia de las infecciones nosocomiales en españa (study on the prevalence of nosocomial infections in spain)) was developed. this is a multi-centre system for monitoring nosocomial infections, based on the production of an annual prevalence study, which has been conducted since 1990 in a large group of hospitals in spain and was promoted by the spanish society of preventive medicine, public health and hygiene. its methodology guarantees a homogeneous and systematic collection of information, which allows us to understand the prevalence of healthcare-associated infections (hais) at a national level, by autonomous regions and hospitals. since 2012, every 5 years the epine study has been produced jointly with the european study (in 2012 and 2017) under the coordination of the ecdc [45] . based on the latest data published, in november 2017 (313 hospitals and 61,673 patients), a prevalence of nosocomial infection in patients over 65 years of age of 6.07% (infections acquired during the current admission), 7.45% (infection acquired during the current or previous admission) and 8 .76% (the total, including the centre's own or imported) has been reported. it should also be noted that this register shows that in 22% of patients over 65 years of age admitted for an infection, the infection had been acquired in the community (patient's home). the home, nursing homes and community health centres, healthcare centres other than hospitals and the hospital itself are often the places where the elderly acquire infections. the studies reviewed allow us to estimate a prevalence of infection of between 4 and 10% in nursing homes in spain, depending on their complexity, and between 6 and 9% in hospitalised elderly people. in primary care and in the residential environment, there is no homogeneous epidemiological record of this problem. what proportion of severe infections in the elderly require hospitalisation? by whom are they treated? in the united states of america, patients over 65 years of age account for almost 40% of total adult admissions and the cost of these hospitalisations represents nearly 50% of the total cost for hospitalisation, although those over 65 years of age account for less than 20% of the total adult population [46, 47] . those over 65 years of age are admitted to hospital three times more often than those between 45 and 65 years of age, and those aged 85 or over account for 9.2% of all hospital discharges, although they represent only 1.8% of the population as a whole. moreover, in our opinion, in these departments, emergency assessment should not be focused only on the isolated episode for which the patient consults, but the particulars of the elderly person, their functional, mental and social situation should be taken into account. this is a huge workload for the ed. finally, we should bear in mind that the training of ed physicians on these issues is limited [63] as a direct consequence of the self-training of current professionals, which is not always complete, and the lack of a regulated medical specialty in the ed. in spain, between 15 and 25% of emergency department visits occur in the elderly. elderly people come in 14.5% of the time for infections and one third of the infections seen in the emergency departments occur in the elderly. the population over 65 years of age who attend the emergency department often have multiple pathologies and clinical manifestations of infection that may be atypical. in the spanish national health service, emergency activity accounts for a total of 47.2 million consultations per year, of which 26.5 million are attended to in primary care (pc) (outpatient or home), with an average attendance of 0.6 people/ year [64] one-third of emergency consultations in pc are related to infections [65] . in the older patient, infections are more frequent and serious, associated with greater morbidity and mortality [65] [66] [67] . among the elderly, the rate of infection reaches 634.1 cases per thousand people per year. the most frequent correspond to the respiratory system (317 cases per thousand), particularly those of the upper respiratory tract, followed by acute bronchitis and bronchiolitis and pneumonia [65, [67] [68] [69] . in second place are utis, mainly affecting women (114.8 cases per thousand compared to 44.2 per thousand for men) [67]. these are followed by skin and soft tissue infections [69] . most of these cases are dealt with in primary care and only those more serious situations and of uncertain diagnosis are referred. in 75%-80% of cases, cap is diagnosed in pc [65, 70] and streptococcus pneumoniae is the cause of two-thirds of these cases. invasive forms of pneumococcal disease (ipd) are less common, occur in patients with certain risk factors and have high mortality rates [70] . the vast majority of vaccination programmes in spain are carried out in primary care, but the vaccination schedule for older people is neither complete nor promoted as it should be. what is the workload represented by elderly patients in hospital emergency departments? the number of visits to hospital emergency departments (ed) has been increasing progressively for decades. this increase is greater in the elderly, whose population accounts for 15-25% of all visits to the hospital [56] . the incidence and impact of infection in the ed is estimated quite reliably. in spain it is 14.3%, 21% in the usa and around 30-40% in countries such as nicaragua and mexico [57] . the elderly are characterised by a higher probability of atypical presentation of diseases, of suffering from multiple diseases and of consuming many drugs. with regard to emergency care, this implies a more complex clinical evaluation, which translates into a greater request for additional tests and consultations with other specialists, longer stays in the ed (extended periods under observation and in ssus), as well as a greater probability of admission, discharge with undetected or untreated problems and return visits to the ed [58] . all this entails a high risk of adverse episodes [58] and a significant impact on healthcare pressure, resulting in a negative effect on ed saturation [59, 60] . likewise, the prevalence of the frail elderly in the community varies according to the diagnostic criteria. in a study conducted on elderly people admitted to the observation room of an ed in a spanish tertiary hospital, it was verified that only one of them did not have any fragility criteria and on admission almost half of them suffered significant dependence [61] . the detection of the high-risk or fragile patient is fundamental for these departments, for decision-making and in particular for discharge directly from the emergency department. we could highlight that in the recent work of the in-fur-semes group, in a study conducted in 49 spanish eds, 31.7% of infections occurred in patients over 70 years old. of these, 36% were urinary and 51.2% were lower respiratory. in conclusion, when compared with a similar study, conducted twelve years earlier, an increase in the prevalence of infections is observed, with an older patient profile, comorbidity, risk factors for mdr microorganisms and septic syndrome [62] . the latter almost always presents itself as an acute confusional syndrome, which implies a complex differential diagnosis. to what extent do you think that infection in the elderly is preventable? what proportion could be avoided with proper vaccination? in an article published by umscheid et al. [79] , not specifically addressing to the elderly field, it is estimated that 65%-70% of cases of catheter-related bacteraemia or catheter-associated urinary tract infection and 55% of pneumonias from mechanical ventilation or skin and soft tissue infections could be prevented in the hospital environment using the methodology currently available. an infection control programme for older patients includes methods for surveillance and recording of infections, recording and management of multi-resistant microorganisms, outbreak contingency plans, isolation policy and standard precautions, hand hygiene programmes, ongoing education of employees, resident health plans, audits and plans for reporting incidents to health authorities [80] . this set of resources is not available to most of the world's elderly. a group of experts, gathered in a delphi study on infection prevention measures in patients admitted to institutions for the elderly, agreed on 302 recommendations [81] but unfortunately the level of evidence on the effectiveness of each of them is very limited. data on the reduction of different infections by different measures are extremely scattered and limited. some examples are the reduction by 53% of periprosthetic infections with antibiotic prophylaxis [82] , a 60% reduction in episodes of influenza with the physical separation of the young and the elderly, [83] or a 48% reduction in episodes of pneumococcal pneumonia with the 23-valent vaccine [84] . makris et al. [85] conducted a study to test the effect of an infection control programme in 8 institutions for the elderly in the united states of america. they divided the centres into test centres (4) and control centres (4) and studied the incidence of infections in both groups before and after the programme was introduced. in the year prior to the intervention, test sites experienced 743 infections (incidence density rate, 6.33) and control sites 614 infections (incidence density rate, 3.39). in the intervention year, the test centres reported 621 infections, a decrease of 122 infections (incidence density rate, 4.15), while in the control centres, the number of infections increased slightly to 626 (incidence density rate, 3.15). the greatest reduction in infections at the testing centres was in upper respiratory tract infections (p = 0.06). the intervention programme consisted mainly of implementing environmental cleanliness, hand washing programmes and educational talks. therefore, and speculatively, we dare to estimate that a the infection rate in the elderly exceeds 500 episodes per 1,000 sick people per year. primary care handles the vast majority of these episodes and refers only the most serious cases. primary care is responsible for the vaccination programme for elderly people who attend to request it. the vaccination schedule for older people is neither comprehensive nor proactively promoted. what does infection in the elderly entail in terms of days of hospitalisation, financial expenditure and death? to approximate data/figures for variables such as "days of hospitalisation, economic expenditure and death" in a field as broad as "infection in the elderly" is enormously complicated. it must be taken into account that the infectious pathology is very varied and that it can affect people with different locations (community, community health centre or the hospital itself) and conditions. for example, with reference to nursing homes, lim et al. estimate 4 episodes of infection for every 1,000 cumulative days spent in the home in a small group in australia [71] , while much more extensive north american data report 12% of nursing home residents having an infection at the time of the study [32] . this leads to estimates of between 1.64 and 3.83 million episodes of infection per year [31] with annual costs of no less than us$ 1 billion, prior to 2000. in a study conducted in brazil, the cost of an infection in the elderly requiring admission is estimated at 28,714 brazilian reals (€ 6,305). patients are admitted for a median of 24 days compared to a median of 9 days for elderly people admitted for non-infectious causes [72] . of that cost, only 5% is attributable to the purchase of antibiotics. there is a greater volume of data for community-acquired pneumonia (cap) [73] [74] [75] [76] . the cost of cap varies greatly depending on where the treatment takes place. a spanish study [77] found a cost of only € 196 in the case of an outpatient, compared to €1,153 for pneumonia requiring hospitalisation. the costs were higher for subjects ≥65 years. mortality increases significantly in the older patient (25%) with respect to the general population (10%). it is worth noting a publication in spain with a sample of 2,049 subjects, where mortality due to pneumonia is more clearly related to the age group than to the aetiological agent [78] . we have not found precise data calculating overall clearly no one disputes the usefulness of ongoing education in many aspects of life and particularly in the reduction of nosocomial infections. that said, the literature review on the impact of educational programmes on nosocomial infection is irregular, fragmented and often difficult to assess. published studies generally include education as part of intervention programmes in which other measures are included, making it difficult to assess the role of education in isolation. it is also common to talk about the success or failure of an educational programme without detailing what the programme is, what content it has, how it has been implemented and how many people have accessed it. to complicate matters, in the case of the elderly, we have at least three different areas: home, nursing homes and institutions for the elderly and hospitals. in the first, the educational scope is very general and imprecise and is based on the public health and vaccination campaigns that are usually received not only by the elderly population but by the population in general. in the hospital field, we must assume that the literature produced on the impact of educational measures in the different syndromic entities generally includes the elderly population, but does not specifically differentiate it. most of the limited existing information, which we can consider specific to older people, is that generated in nursing homes and institutions that implement these programmes. a study conducted in the usa on 2,514 randomly selected nursing homes [91] asked the homes for information on 34 points related to infection control programmes. most of those responsible for control programmes, when they responded, claimed to have not only that responsibility but others as well (54%) and also to have no specific training in infection prevention (61%). there was great variability in practices carried out in each residence and 36% acknowledged having received an official citation for deficiencies in such control. those residences cited for deficiencies had a statistically lower proportion of staff trained in infection control. this is therefore an area with clear opportunities for improvement. in a systematic review on non-pharmacological infection prevention in long-term care facilities, only 24 papers were selected, the majority of which were randomised studies (67%) and the most common reason was prevention of pneumonia (66%). 54% showed favourable results for the interventions, but the studies had many potential biases [92] [93] [94] [95] [96] [97] [98] [99] . from these studies the 5 main quality markers in infection control in a nursing home were deduced, namely: percentage of long-term patients with pressure ulcers, urinary tract infection, bladder catheter, and vaccinated against influenza and pneumococcal infection. high quality infection control programme in nursing homes could reduce infection rates by up to 50%. but even if we estimate much lower figures, the impact on morbidity, mortality and the economy of such programmes would be enormous and would certainly outweigh their implementation costs. with reference to the second part of the question, the possibility of reducing the problem with vaccines, the data are again scattered and studied for different vaccines individually. in addition, information on the elderly must often be inferred from data on the general population. we refer readers to a recent review on the subject [86] . below is some data on the impact of vaccines of particular interest to the older population. gross et al. [87] in a meta-analysis of 20 cohort studies estimate the effectiveness of influenza vaccination at 56% in preventing respiratory infections, 53% in preventing pneumonia, 50% in preventing hospitalisations and 68% in preventing deaths. in the case of zoster, the vaccine's efficacy is estimated at more than 90% with minimal adverse effects [88] different pneumococcal vaccines have different impacts on the incidence of invasive pneumococcal disease (ipd) infection. a systematic review shows reductions in ipd incidence ranging from 61% as a combined effect of the use of pcv7, pcv10 and pcv13 in those over 65 in canada [89] to a 21% reduction as an effect of the use of pcv7 and pcv13 in israel [90] . with these data it is possible to imagine the added protection that adequate vaccine coverage would provide. an estimated 50,000 americans die each year from vaccine-preventable diseases, and 99% of those who die are adults [86] . increased provision of medical care in large care homes (e.g. those with more than 200-250 beds) could reduce the referral of many elderly residents to hospital emergency services. this provision of medical care would not necessarily be very complex and would cover both simple diagnostic material and the possibility of establishing and carrying out pharmacological therapeutic courses at the centre itself, the prescription of which in most cases still requires medical staff from outside the centre. it would be a way to reduce costs, lessen the burden on the elderly and reduce the overload on hospital emergency departments. it is impossible to give a precise answer to the questions asked, but it seems reasonable to assume that with appropriate prevention programmes, acquired infections in institutionalised elderly people could be reduced by up to 50%. strict adherence to a vaccination programme for the elderly would have an enormous impact on reducing suffering, death and economic waste. what data exist on the effectiveness of educational measures on the incidence of infection in the elderly? ties specifically dedicated to infection. by way of an example, in spain, this occurs among specialists in microbiology and infectious diseases and intensive care specialists. 9.-specifically promote research aimed at preventing infection in elderly patients. 10 .-introduce much more active involvement of patient associations in their management structures. what we say about societies primarily dedicated to the elderly, can be similarly assumed and applied to societies primarily dedicated to infectious diseases and microbiology. the role of the scientific societies dedicated to geriatrics and infectious diseases is to promote alliances in the common field of infection, in aspects of care, teaching and research. they need to look less to the interests of their members and be more proactive in promoting the interests of the patients they serve and incorporate patient associations more into their structures. capacity, understood as the possibility or potential for influence, is qualified by two variables. firstly, for offering free and truthful scientific information at the service of the community. and secondly, for facilitating the adoption of the best possible political decisions with consistency and realism. the rapprochement between professionals in the scientific and political fields must be adjusted to the interest of citizens, who can act as the third pillar in a transparent relationship model and as guarantor of equity befitting a democratic system of government [110] . while scientific experts advise and inform, it is the responsibility of politicians to make decisions and promote efficient measures to the benefit of the population. a complementary characteristic inherent to the scientific task is to exercise a dissemination action of the activity itself, in understandable terms and through accessible and reliable systems [111] . the configuration of platforms within scientific societies and the growing number of independent agencies advising political power represent a reality that aims to bring the contributions of science closer to the systems of governance [112] . in our country, the main function of the congress of deputies is legislative, which entails the approval of laws. the constitution recognises the legislative initiative of the government, the congress of deputies, the senate, the assemblies of the autonomous communities and the people's legislative initiative on the proposal of no less than 500,000 citizens, subject to the provisions of an organic law. these bills are known in spain as law projects when presented by the government and propositions in other cases. they are always submitted to the congress of deputies, except for the propositions of the senate which have to be considered scientific societies are professional associations that bring together generally specific groups (doctors, nurses, technicians, etc.) that essentially seek to defend the professional interests of their members. until now, it has not been common for groups of patients affected by different diseases under the thematic umbrella of each society to participate in them. in spain their impact and political credit is variable. among the most important objectives of most of these societies are such issues as training programmes for professionals, aspects related to the health education of the population in their particular field of competence, research grants, the preparation -sometimes in collaboration with societies of another related specialty -of specific diagnostic and therapeutic protocols, publications and congresses focussed on these topics, and a wide range of other activities, including health policy recommendations to the corresponding administrations that have a direct bearing on the issues discussed here. membership of societies is also not uniform, and often it is the more "senior" components of the profession that are most highly represented in them. their role, in our opinion, is to continue to improve the teaching, care and research produced in the societies' chosen fields in favour of patients, exercising ever greater mediation between the demands of patients and healthcare administration [100] . all societies must go far beyond issuing guidelines and therapeutic recommendations [81, [101] [102] [103] [104] [105] [106] [107] [108] [109] . in our view, scientific societies dealing with diseases of the elderly should promote, in the field of infectious diseases, among others, the following topics: 1.-encourage a proportionate share of its members to subspecialise in infectious diseases. 2.-coordinate and direct multidisciplinary teams specifically dedicated to the infection in the elderly and its prevention. 3.-participate more actively in specific programmes to reduce infections in the elderly, both at the nursing home level and at home and in hospital. 4.-implement vaccination campaigns in the elderly, taking particular advantage of admission to long-stay centres or hospital as opportunities to vaccinate. 5.-to design and disseminate educational projects on infection prevention practices for the elderly in their different environments. 6.-put pressure on health authorities to carry out a large national programme to reduce infection in older people. 7.-to include in the training programme of residents in geriatrics, a rotation in infectious diseases and microbiology as an essential part of the curriculum. 8.-create scientific and professional alliances with socie-to offer a unique system to access scientific information allowing the recovery of different types of documents such as: journals, books, images, theses, and conference proceedings. revista española de geriatría y gerontología (the spanish journal of geriatrics and gerontology) is the publication channel of the society of the same name, a publication founded in 1966 and the doyenne of the specialty in the spanish language [119] . medes is an initiative of the fundación lilly and its database, open and free, contains bibliographical references published since 2001 in a selection of 98 spanish journals covering 50 subjects in medicine, pharmacy and nursing, published in spanish, with 100,000 articles [120] . finally, pubmed is the widely implemented search engine, with free access to the medline database of citations and abstracts of biomedical research articles, offered by the united states national library of medicine and integrating 5,255 worldwide journals since 1966 [121] . the search was conducted with a double strategy: free text and controlled text using "mesh". in the first strategy, a free text search was conducted in the "science direct" and "clinical key" databases with the term 'infection in geriatrics' resulting in 508 and 1,191 findings respectively. the primo search engine (castilla y león online library) returned a total of 190 results for the same term. secondly, and also in free text, with the term 'infection in the elderly', we proceeded to consult revista española de geriatría (the spanish journal of geriatrics), which generated 195 results and medes (medicine in spanish) with 84 results. the second strategy of controlled text was conducted in the pubmed database, returning the following findings: <infection and geriatrics>: 997 results; <infection and aged> (people from 65 to 79 years old): 122.698 results and <infection and aged or aged, 80 and over>: 122.698 results (identical to the previous one). its development over the last decade has been progressive (from figures close to 4,000 in the 2009-2010 biennium, to over 5,000 from 2014 to 2017), excluding the year 2018 from the assessment. we have adopted their classification into thematic areas [122] and the twelve in which 95% of the results were concentrated are: sepsis and bacteraemia, pneumonia, urinary tract infections, central nervous system infections, endocarditis, prosthetic infections, skin infections, gastrointestinal infection, hiv infection, fever of unknown origin, multi-resistance and vaccinations. the scientific output on infections in the elderly, calculated by different databases, has been increasing in the last decade. how do the problems of the elderly impact on the mainstream media? how should the media contribute to the reduction of infection in the elderly? the impact of the problems of the elderly in the media is in the senate, which will later submit them to congress [113] . non-legislative bills, motions and proposals for resolutions are acts of a similar nature that seek the adoption of a non-legislative resolution by congress, by which congress expresses its position on a given subject or issue, or addresses the government urging it to act in a particular direction. the health and social services commission of the congress in the xii legislature offers access on its website to the 226 initiatives processed since its constitution in september 2016 until its dissolution in march 2019, representing an average of 75 per year [114] . of these, those referring to the field of infectious pathology as a whole do not exceed 3%. of particular relevance in the field of infectious pathology have been those relating to the national plan for the elimination of hepatitis c and antibiotic resistance. governance designates the effectiveness, quality and good orientation of state intervention, which provides the state with a good part of its legitimacy in what is sometimes defined as a "new way of governing". above all, it is used in economic, social and institutional operational terms [115] . an inherent aspect of the exercise of policy is the performance of "authority", which is equally composed of legitimacy (right to exercise), personal prestige (moral strength, leadership, honesty, knowledge, efficiency) and power (ability to administer and lead). it is precisely in the "personal prestige" where their synergy with the scientist (also covered by knowledge, honesty and leadership) should be the lever for the improvement of the society they both serve. initiatives on proposals or projects with reference to infection issues represent less than 3% of the total. of particular relevance in recent years have been those relating to the national plan for the elimination of hepatitis c and antibiotic resistance. in order to respond to the scientific output on infection in geriatrics, we will proceed to describe the data sources, the search methodology and the findings, in a way deliberately guided by the recommendations of professionals in our workplace libraries. sciencedirect [116] is a digital platform that has provided subscription access to a large research database, hosting more than 14 million publications from 3,800 academic journals and 35,000 e-books since 1997. clinical key [117], owned by "elsevier clinical solutions", has an intelligent search system, establishing the connection of medical terms with related content. it accesses a collection of resources of clinical guides, algorithms and patient files from fisterra, the database of monographs of medicines marketed in spain, the treaties of the medical surgical encyclopaedia, and books and journals in spanish from the cited publisher. primo is the discovery/search tool used by the castilla y león healthcare online library [118] as a small demonstration of this paradox -the contrast between the rising presence of the elderly in society and their lukewarm representation in the media-, we offer a chart with a comparison of publications on the websites of three generalist newspapers, "el país", "el mundo" and "abc", between the years 2016-2018, with the search for "elderly" and "infection" as key words. a total of 96 news items are recorded that mention the subject studied ( figure 1 ). this is little news, and in most cases linked to events and to the elderly as a risk group. this sample would require further media analysis to ratify this tendency in the treatment of the problems of the elderly and the infections they suffer, but it serves as the tip of the iceberg of relegation, insensitivity and atrophy in news treatment. since the onset of the economic crisis in 2008, the number of dedicated journalists specialising in social and health issues has been substantially reduced in order to divert manpower and resources mainly to political and economic content. if, in this situation, health, science and social issues have been scaled down and cut back in the operation of the media, the elderly, as journalistic content, have been pushed to the very margins of the newsrooms with complete normality; with no agenda, no specialists, no briefings, no planning, no contextualization; to see themselves as mere circumstantial, inconsequential, occasional content, with a light, sometimes frivolous treatment, lacking depth and sensitivity; building a narrative of topics, irrelevance and disconnection from their value and presence in society. this media portrayal of the elderly is in contrast to the ageing of the population, where reliable and accurate statistics limited, deficient, incomplete, unfocused, out of context, stereotyped and with a not particularly constructive, realistic or objective bias. the elderly are invisible in the media and when they appear, the content relating to them is characterised by simplification, victimhood, dramatization and superficiality. the image that the media convey of old age is linked to inactivity, unproductiveness, seniority, illness, dependence and deterioration. old age and its problems, circumstances, needs and contributions, as a social agent and subject, are not among the priorities and themes of general media planning. other groups, sectors, actors or social issues such as immigration, feminism, equality, children, domestic violence, ngos and their services, new technologies and their advantages, effects and risks, harassment in all its forms, health and sanitation, or scientific advances have much more visibility, relevance, monitoring, currency and presence in the media. the problems related to a stage of life that we can place at around 80 years provoke a disinterest and sidelining in the information and journalism that only is unblocked in the face of news related to events, diseases, negative or sensationalist facts or anecdotes, offering a fixed, unmoving and old-fashioned image of a sector of the population that, nevertheless, is increasing due to the increase in life expectancy. in a world where the 21st century grants youth and technology all the plaudits as to what is interesting and important, whether in the press, television, radio, websites or social networks, ageing and old age, as a concept, social and population sector, and newsworthy subject, are moved to a second or third tier on the podium of current affairs and information. citations regarding "infections" in the "elderly" in 3 major general journals of spain formation on the elderly and very elderly has been strengthened, is to promote health and healthcare information in relation to this sector of the population. in this context, the media would be in a position to treat and report, with much higher presence and representation criteria than at present, on the infections of the elderly within the framework of their health and well-being. it is very difficult to reach this third step without the two previous actions, since the handling of a health problem such as infection in the elderly by the media requires a commitment and responsibility in several phases that is part of a comprehensive strategy to provide a journalistic treatment of their problems on a par with their representation and contribution to society. it is necessary to present older people and the elderly removed from the clichés and stereotypes that link them directly and almost solely to the events, the deterioration of their health, family dependence or the hindrance or burden of their role and function in society. it is necessary to offer complete and balanced information in which tasks such as interest in culture, modernity, the future, technology or travel; their capacity to lea in civil society, family, business or education; their initiative in domestic and community tasks; their political or social contributions; or their skills in the practice of sport are inherent. in short, to show their vitality, enthusiasm, enterprise, activity, determination, solidarity or collaboration, beyond their problems or difficulties, which must also be reflected and analysed. it should not be forgotten that though the generation of elderly people now over 75/80 years old may have a more traditional, reserved and passive profile in certain cases -by no means in all-, the new generation of elderly people forecast for 2050, where their number will rise greatly, will experience a huge change with regard to the distorted image of the elderly today. the information that the general media dedicates to the problems of the elderly is minimal, distorted and biased. it is full of clichés and stereotypes that link them directly and almost exclusively to events, the deterioration of their health, family dependency or the hindrance or burden of their role and function in society. information on infections in this population group is even more scarce. presentation: the answer is yes, without a doubt [95, [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] . the reasons are detailed below: studies conducted following scientific evidence criteria in recent years show that pharmaceutical care and the intervention of the pharmacist improve the overall quality of patient care, while the who itself states that point to a doubling of the number of older people by 2050. the data show that in 1960 in spain, there were 6.7 million children under 10 years and 0.4 million people over 80 years, in 2015 the number of children under 10 had fallen to 4.6 million, and over 80 risen to 2.7 million; by 2050 the trend becomes even more acute, with under 10 years predicted at 3.8 million, and over 80, 6.2 million [123, 124] . globally, in the century from 1950 to 2050, total population will triple; the population over 60 will grow by a factor of 10; and the population over 80 by a factor of 28, this last group going from 14 million in 1950 to 386 million in 2050. if information concerning and affecting the elderly continues to be ignored, marginalised and simplified in the media, they will neglect and fail in their mission of gathering information, analysis, data and opinions from a sector of the population with enormous influence on the life and events of a country. without rigorous, truthful, balanced, comprehensive and complete information on the phenomenon of old age, the view and expression of reality will be distorted, fragmented and fractured. to help reduce infection in the elderly, the media must take several steps beforehand and activate new information strategies and actions [125, 126] . review and reformulation of the contents for current events, relevance and interest agendas. the first step is to place general social and health issues on the same level of importance as national or international political, economic or sports information, with the consequent allocation of space, dedication and resources. enhancement of content for the elderly in social and health information. within the social and health content, the news of the old and elderly must be equated in relevance, dedication, selection, monitoring and treatment to other issues related to this journalistic field, with emphasis on the quantity and quality of the information, from the rigour, planning and contextualization to gather studies and data, human stories, opinions, difficulties and needs, social influence, contributions, and challenges in this sector of the population. the aim is to offer a complete, balanced, objective and true vision of their reality, their contributions, their heterogeneity, their variety, their complexity, their evolution and their demands and needs. the problems arising from the increase in age, health, coexistence and economic situation, as well as cultural, sociological, family and psychological aspects, must be approached with an informational style and treatment where ageing is considered from the standpoint of normality in life, with its ups and downs, and not as a hindrance, obstacle or inappropriate or unsustainable expense. the social and cultural role of the elderly, their knowledge and experience, their skills and abilities, should be valued as useful and enriching elements to society. promotion of health and sanitation information in the elderly. the next step for the media, once the general in-ed following scientific evidence criteria in recent years show that pharmaceutical care and the intervention of the pharmacist improve the overall quality of patient care, while the who itself states that pharmacists "contribute decisively to the rational use of medicines". what is the administration doing and what can it do to reduce these problems? from an educational point of view? from the legislative-regulatory point of view? in order to reduce these problems, the state administration must, among other things, launch: 1. prevention strategies and measures to control the transmission of the infection. 2.-vaccination programmes in the elderly. 3.-training and information programmes for health professionals, particularly in the area of rational use of antimicrobials and promotion of the use of appropriate definitions [140, 141] pharmacists "contribute decisively to the rational use of medicines". the decision on how to treat a given infection correctly with the most appropriate antimicrobial requires detailed knowledge of microbiological, clinical and pharmacological issues, but the causes of an optimal result go beyond this and extend to the so-called non-pharmacological basis, among which the behaviours of doctors, patients and pharmacists, as well as the relationships between them, play a fundamental role. the pharmacist is one of the apices of the so-called "human factor triangle" (made up of doctor-patient-pharmacist), a mirror image of the famous "davis triangle" (antimicrobial-microorganism-host). currently, pharmaceutical care aims to obtain the maximum clinical benefit from medicines and to achieve the lowest possible risk in the use of those medicines, which entails the identification, resolution and prevention of medication-related problems (mrp): adverse drug reactions (adr), drug-drug interactions (ddi), deficiencies in physician prescription, errors in the use of medication by the patient and breaking the vicious circle so frequent in the use of antimicrobials formed by self-medication -noncompliance -storage. pharmaceutical care is a process, which includes different stages: active dispensation (supply, delivery, dispatch >>> assistance, help, care), educational advice (health advice in response to a consultation/problem or instruction on the acquisition of a medicine) and pharmacotherapeutic follow-up (documentation and registration of the activity). as far as the hospital pharmacist is concerned, it must be said that they not only participate actively in the rational use of antimicrobials from their role as an active member of the pharmacy commission and the antimicrobial committee, but also get involved on a daily basis in the prudent and correct application of antimicrobial therapy, in order to obtain the most beneficial result from the clinical point of view and the most efficient from the pharmaco-economic point of view. this implies that: the appropriate antimicrobial has been prescribed in accordance with a correct diagnosis and the special characteristics of the elderly patient, it is dispensed under the proper conditions, administered at the indicated doses, at the intervals and for the period intended, it is used with the lowest possible cost, in such a way as to prevent or minimise the development of bacterial resistance and it achieves the desired therapeutic objective. in short, both the community and the hospital pharmacist as first-level health agents play a central role in the field of therapeutic adherence and rational use of antimicrobials, proposing their use in terms of quality of treatment and considering antimicrobials not only by virtue of the active ingredient contained in the corresponding pharmaceutical specialty, but also in terms of useful information ("software"). furthermore, both must take into account that antibiotics and vaccines are the paradigm of societal treatment and the treatment or non-treatment of an individual can affect the community [139] . conclusion: the answer is yes, without a doubt. studies conduct-another precaution is the sanitation of the space in which the elderly person stays so as to make it a healthy environment, including daily cleaning of surfaces, objects and utensils, ventilation, illumination preferably with natural light, and appropriate environmental temperature and humidity [156] . the tendency to unbalanced diets, malnutrition and low fluid intake increases susceptibility to infection. it is essential to promote healthy lifestyles and to provide structured plans for eating, drinking and exercise adapted to individual needs taking preferences and health problems into account [157] [158] [159] [160] [161] [162] . another strategy is the vaccination of the elderly and carers, adjusted for age, particular situation and the approved schedule in each autonomous community [163] . although infectious diseases in the elderly do not always have obvious signs and symptoms, the caregiver detects changes in their baseline situation that may lead to a suspicion of the presence of an infectious process, so education should be provided on how to proceed in the light of this suspicion and what to do when it is confirmed. finally, it is necessary to emphasise the effective management of treatment (dose, administration and side effects) and periodically monitor therapeutic adherence, avoiding self-medication, in order to achieve the optimal effects of non-pharmacological and pharmacological measures, so as to enable prevention, delay deterioration, recover or maintain health [164] . nurses develop interventions for prevention, monitoring and therapeutic adherence control, participating in the care plan for infection in the elderly. the implementation of many of the health promotion and care plans and regulations is the direct responsibility of the nursing profession. how do senior citizens' associations deal with this problem? the issue of health is a priority for the elderly and infection in particular is one of the most frequent causes of morbidity and mortality in the elderly, as has already been mentioned. elderly associations have traditionally focused on chronic rather than acute diseases and therefore have a huge role to play in this area. it is the mission of the elderly associations to encourage and promote the residence of the elderly in a family and social environment that is agreeable to them. it is well known that an older person who lives comfortably at home with family members has less risk of acquiring infections than one who lives alone. in the case of the elderly institutionalised in residences, the elderly associations have the mission to ensure the quality tions for the prevention and control of healthcare associated infections (hais). some examples of the above are programmes such as: "antibiotics: take them seriously" (2017); the "world antibiotic awareness week" (2018); the "european antibiotic awareness day" (2018). a national plan against antimicrobial resistance (pran) run by the spanish agency of medicines and health products (aemps) is essential [142, [143] [144] [145] [146] [147] . the administration has a constitutional mandate to promote health, which is of particular concern to groups as vulnerable as the elderly. among the measures to be implemented, those of an educational nature are especially necessary, both for patients and for their caregivers and healthcare personnel. from a legislative-regulatory point of view, we cannot forget that spain has one of the best health systems in the world. what is the role of nursing in managing and reducing infection in the elderly? how does the training of the caregiver affect this? nurses develop preventive interventions, participate in the monitoring, control, therapeutic adherence and care plan when the infection is established. these competencies are developed inside and outside of healthcare institutions. in the home setting, the focus is on education and providing support for safe practices [148] [149] [150] [151] . professionals, caregivers and elderly people have to distinguish modes of transmission, identify risk factors and susceptible people who may become reservoirs or constitute a vehicle of contagion and understand basic protective and barrier measures. the simplest, most effective and universal procedure is hand hygiene. the world health organization identifies five key times for washing: before and after contact with the person, before performing a clean/septic task, after the risk of exposure to body fluids, and after contact with the patient's environment [152] [153] [154] . when hygiene guidelines are given, it is worth noting other times: before, during and after handling or preparing food, before eating, before giving medication, before and after treating a wound or handling clinical devices, after using the bathroom and after handling used clothing, whether personal, bath or bedding, diapers or waste. after washing, it is important to dry the hands. personal hygiene and topical hydration are other prevention strategies. the skin constitutes a natural protective barrier and is particularly labile in the elderly. its daily care guarantees its integrity and protects it from external assault. this includes body hygiene and protective measures aimed at moisture control and injury prevention. some studies highlight the importance of oral hygiene in relation to respiratory diseases [155] . the great social esteem that existed in ancient cultures for the elder of the group or tribe is well known. he was not only the oldest person but also the biological father, the political leader and, in many cases, the religious authority. and, as anthropologists have pointed out more than once, the "hard disk" of the community, aware of past events of which the younger generations are not, thereby bringing the social group together and giving it its own identity. hence, the elders were not only respected but highly valued and even revered. it is enough to open the books of the bible, for example, to find testimonies of this. its pages over and over again reverential respect for the elder, applying such venerable terms as "patriarch". the bible attributes an extraordinary longevity to the first patriarchs (gen 5; 11,10-26), and even to the later patriarchs, like abraham (gen 17,1.17; 18,12) and moses (dt 31,1; 34,7), and to the prophets, it is difficult to represent them as young people. respect leads the bible authors to attribute centuries-long lives to them. longevity is a sign of their wisdom. the so-called wisdom literature bears good witness to this veneration for the elderly. in the book of ecclesiasticus we read: in your youth you did not gather. how will you find anything in your old age? how appropriate is sound judgment in the grey-haired, the contrast between the ancient civilization of israel and the archaic greek culture, as presented in the homeric poems, is surprising. it is difficult to imagine ulysses, hector or achilles as elders, even though in those poems there are also venerable subjects such as menelaus, agamemnon and priam. the contrast between agamemnon and achilles is particularly significant, for the poet paints the former as an ambitious and selfish man, with an excessive ego who confronts achilles, his best warrior, again and again. heroes, those beings that the greeks considered perfect and semi-divine, are by necessity young and in the fullness of their life force. in greek statuary of these institutions, that they are equipped with the appropriate medical, nursing and social services and that a systematic accreditation of these services is achieved. ideally, these centres should have very significant prevention measures in place and should work closely, on the one hand, with the primary care physicians responsible for the patients, and on the other hand, with the reference hospitals to which the patients have to be transferred at some point. elderly associations must continue to work to improve the care of the elderly in emergency departments, not only from a technical point of view, but also by ensuring the agility of the assessment and dignified conditions for the elderly in these departments. finally, the elderly who are hospitalised are patients who require very rapid mobilization, avoidance of exposure to multi-resistant microorganisms and the fastest possible transfer back to where they came from. elderly associations promote the provision of geriatric beds and services in all hospitals, where structures and organisations are set up specifically to serve the needs of elderly patients with a comprehensive idea of their care. as we have mentioned, prevention is better than cure, and in that sense, the elderly associations can play an important role in emphasizing to the authorities, to the groups of affected people and to healthcare personnel the importance of promoting vaccination campaigns [86] in short, associations for the elderly, whether they are focused on health or not, can play a very positive role that is often overlooked when it comes to improving health. they could work, if possible, promoting and propagating vaccination campaigns. they could also contribute more than they do to other forms of health education, from those oriented towards nutrition or physical activity, to those focused on fighting toxic habits or reporting abuse. all this is of general interest, as well as directly and indirectly affecting the field of infectious pathology. following the recommendations of the expert consensus on frailty in the elderly, active ageing and drug screening in polymedicated patients are important in preventing infections in these patients. elderly associations must play a major role in demanding quality care policies for elderly patients, both in the fields of prevention and treatment. target areas for intervention are the home environment, the outpatient system, nursing homes, hospital emergency departments and hospital care. patient associations can contribute more than they do to other forms of health education, from those oriented towards nutrition or physical activity, to those focusing on combating toxic habits or reporting abuse. what ethical aspects would you highlight in all these problems? modern systems of work organisation have made "efficiency" a major objective of the culture of the second stage of life. there is no doubt that in spain, for example, efficiency has increased three or fourfold in the last half century. and here is the origin of the problem. what do you do when you are no longer "efficient", at least in the way the economy defines efficiency? efficiency is a value that belongs to the category of socalled "instrumental values", "reference values" or "technical values". they are so called as they have no value in themselves, but only in reference to something else or another value. let's think, for example, of a drug. there is no doubt that it has value, at least financially. its most valuable asset is to relieve a symptom or cure a disease. if it wasn't good enough, we'd say "it's not good enough", and we wouldn't pay for it. this means that the value of the drug is in reference to something other than itself, such as well-being, health, life, etc. this happens to all technical instruments. if we were to find a more effective or less expensive drug, there is no doubt that we would choose it, because this is what efficiency is about: the cost/benefit ratio. efficiency is the unit of measurement for instrumental values. the problem is that not everything is instrumental. if they are always in the service of others, it means that these others must stand on their own, otherwise we fall into an infinite regression. these are called "intrinsic values" or "fundamental values". they are the most important in life. they are essential values, values that have worth in their own right, without reference to others. think, for example, of dignity. or many others, such as health, life, beauty, well-being, justice, solidarity, etc. these are all intrinsic values. without them, life is meaningless [165] . furthermore, they have the characteristic of not being measured in monetary units, nor is efficiency a criterion. "health is priceless" it has always been said; "true love is neither bought nor sold"; "only the foolish confuses value and price" said antonio machado. and the list could go on [166] . we can now understand the importance of promoting a culture of old age. during our working life there is no doubt that the fundamental criterion must be efficiency, and therefore economy. but that is, at the same time, the least human part of life. the day is not far off when that part of our existence can be transferred to the robots. and the problem arises: what will we humans do then? will we have anything to do? older people have a fundamental mission in our society, and that is to take charge of promoting intrinsic values and passing them on to younger generations. it's not all about economics. it's not all about efficiency. there are other values, which moreover are the most important, the most human. conclusion: promoting a new culture of the elderly should lead us to avoid not only the discrimination that has occurred throughout western culture, and particularly in recent centuries, but also to give impetus to the promotion of intrinsic values, the most humane, the most important in the lives of individuals and societies. this is the very im-it is impossible to see the decrepitude of the elderly person represented. the poet menander coined a sentence that soon became famous and that plautus translated into latin: quem di diligunt, adulescens moritur, "those loved by the gods die young" (bacchides, 816-817). perfection is in youth, and old age is almost embarrassing. aristotle says that "disease is an acquired old age, old age a natural disease" (gen. an. 784 b . it was important to remember this about the attitude of our culture, the western one, towards the elderly. they've never been held in high esteem. moreover, we can be seen that this esteem has been decreasing over time. this is demonstrated by the words we use to refer to this age group. "viejo" (old) comes from the latin vetus, the opposite of novus, both of which are terms that were designating things, not people. for people, the correct terms were senex and its opposite iuvenis. from senex comes our word "senescence", only used in a very limited sense today. cicero wrote a dialogue de senectute, using the correct term in his language. though, in the various spanish editions that exist, the translation is invariably sobre la vejez. (on old age). old age is not only an improper term, but also a derogatory one. no one sees it that way anymore, because they don't know about this process. but the transition from one term to another is an evident sign of the devaluation that the figure of the elder has undergone in western culture, even though it was originally already much lower than that of other cultures. if we add to this the spectacular increase in life expectancy at birth in the last century, it turns out that this devalued period, which until the beginning of the 20th century was almost anecdotal in the life of western society (it should be remembered that life expectancy at birth in spain had been stable at 25-30 years from the neolithic revolution to the end of the 19th century), has become a period of no lesser and sometimes greater duration than the active life of a person. so much so that human life today can very well be divided into three 30-year periods, the first of which is devoted to vocational training, the second to production, and the third.. it is not very clear to what, among other things, because the training we were given in the first 30 years was aimed at being productive in the second phase, but we were never educated for the "third age". the third and final phase of life, which today has an average duration of 30 years, is a continuous source of problems. it is, at least, in the economic order, as the present pension system seems difficult to maintain, and will be impossible in the near future. but, as important as this is, that's not the biggest problem. the most serious issue is that we have condemned the elderly to being a "passive class", whom inserso (the institute for the elderly and social services) has to ferry from one place to another in order to at least distract them. there is talk of discrimination and abuse of the elderly. in my opinion, the greatest discrimination is this, the fact that the elderly have been deprived of their own role in society; or, 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hospitalizados. higiene de manos the hygienic efficacy of different hand-drying methods: a review of the evidence the authors declare that they have no conflict of interest. this publication has been funded by glaxosmithkline. key: cord-266771-zesp6q0w authors: pablo-martí, federico; alañón-pardo, ángel; sánchez, angel title: complex networks to understand the past: the case of roads in bourbon spain date: 2020-10-06 journal: cliometrica (berl) doi: 10.1007/s11698-020-00218-x sha: doc_id: 266771 cord_uid: zesp6q0w the work aims to study, using gis techniques and network analysis, the development of the road network in spain during the period between the war of succession and the introduction of the railway (1700–1850). our research is based on a detailed cartographic review of maps made during the war of succession, largely improving preexisting studies based on books of itineraries from the sixteenth century onwards. we build a new, complete map of the main roads at the beginning of the eighteenth century along with the matrix of transport costs for all the important towns describing the communications network. our study of this complex network, supplemented by a counterfactual analysis carried out using a simulation model based on agents using different centralized decision-making processes, allows us to establish three main results. first, existing trade flows at the beginning of the eighteenth century had a radial structure, so the bourbon infrastructure plan only consolidated a preexisting situation. second, the development of the network did not suppose important alterations in the comparative centrality of the regions. finally, the design of the paved road network was adequate for the economic needs of the country. these findings are in stark contrast with claims that the radial structure of the bourbon roads was designed ex-novo with political or ideological objectives rather than economic ones. our methodology paves the way to further studies of path-dependent, long-term processes of network design as the key to understanding the true origin of many currently existing situations. few historical processes are so relevant to understand our present as the design and temporal development of transport networks. as these are processes with a strong path dependence (david 1985) , decisions that were made long ago continue to directly and intensely affect society in areas as diverse as economic growth (peters 2003; calderón and servén 2004; faber 2014) , territorial cohesion (badenoch 2010; crescenzi and rodríguez-pose 2012; monzon et al. 2019; naranjo gómez 2016) , urban development (weber 2012; modarres and dierwechter 2015) or electoral processes (nall 2015 (nall , 2018 . consequently, knowledge of the motivations behind the implementation of the new transport infrastructures, of the economic and territorial effects they induced and of the adequacy of their design are therefore important focuses of attention not only for academic analysis but also for social and political debate. in this area, the development of national road networks is one of the issues of greatest interest since they form the basis on which the other transport networks are implemented. the works about the european motorway network (peters 2003; badenoch 2010; crescenzi and rodríguez-pose 2012) , the chinese (faber 2014) or the american one (nall 2015; modarres and dierwechter 2015) are clear examples of this interest. improvements in transport infrastructure have been considered by centuries (ward 1762; smith 1776 ) as essentially positive, as they lead to economic growth and poverty alleviation through reductions in transport costs and the facilitation of market integration (calderón and servén 2004) . however, accessibility problems can sometimes benefit certain economically weaker territories by protecting their producers from competition from other regions with lower costs and greater product variety (peters 2003) . if the development of new transport networks is to improve territorial balance, there must be sectors capable of withstanding increased competition; otherwise, market integration can lead to self-sustaining inequality (martin 1999; asher and paul 2016) . on the other hand, the long time required for the development of road networks can generate permanent differential effects on the development of regions even if the final design is territorially neutral. during the period of network construction, traffic flows are altered, possibly inducing variations in the comparative advantage of cities that can become permanent and subsist after completion (berger and enflo 2017) or even after their disappearance (bleakley and lin 2012; aggarwal 2018) . the case we concern ourselves within this paper, namely the design and first development of the contemporary spanish road network, falls within this area of research, although it is older than the cases mentioned above. interestingly, more than two centuries after charles iii formally established the guidelines that determined its design and its present structure, it continues to be the object of lively social attention, as evidenced by the large number of recent historical (rosés et al. 2010; martínez-galarraga 2010; bel 2011; martinez-galarraga 2012; fernández-de pinedo echevarría and fernández-de pinedo fernández 2013; díez-minguela et al. 2016 ) and non-historical academic works (bel 2010; molinas 2013; holl 2011 holl , 2012 garcia-lópez 2012; martínez-galarraga et al. 2015; garcia-lópez et al. 2015; holl 2016) , as well as by the abundant news or political discussions 1 that take place around it. however, the scope of this paper goes way beyond the specific historic process we study: we are introducing a methodology combining deep and thorough historical research, computer geolocalization techniques, analytical tools of complex network science and agent-based modeling, that can be applied to many other processes. it is becoming increasingly clear that sizable gains can be realized from research that seeks to better understand how local history and context can be leveraged to inform the design of better policy (nunn 2020) . as we will see below, our methodology can be very useful in that context, providing deep insights such as assessing whether a process is pathdependent or not, identifying the effects and disequilibria of processes at multiple levels (national, regional, town), studying counterfactuals to advise policy making, and in sum, providing a faithful picture of the system of interest useful for understanding the past and handling the future. the origin of the current radial structure of the spanish road network and, in general, of its transport network, has been the object of extensive historical debate (tortella 1973; nadal 1975; artola et al. 1978; mateo del peral 1978; gómez mendoza 1982; comín comín et al. 1998; bel 2011) due to its influence on spain's subsequent economic development and its territorial imbalances, but most of the available research addresses the period after 1850. in turn, the possibility that the decisions are taken in the eighteenth and the nineteenth centuries regarding the design of the transport networks have generated a lock-in (arthur 1989 ) that has prevented the subsequent development of more efficient transport networks at present is an issue of great relevance but has not been the subject of many quantitative studies. as far as we know, the studies that have analyzed it from a quantitative perspective have been very limited and focused on the railways (equipo urbano 1972; martí-romero et al. 2020) . the works of carreras montfort and de soto are an important exception, but they mainly refer to the roman period (carreras montfort and de soto 2013; de soto 2019) . their analysis for the roads of the eighteenth century uses the work of escribano (1758) as a main geographical reference, which implies a significant restriction in terms of time reference and potential geographical bias as they acknowledge (carreras monfort and de soto 2010, p. 13) . 1 an indirect evidence of the social interest about this topic can be found by comparing the number of results obtained in google with other similar ones. so, while the searches 'carreteras and "felipe v"' and 'carreteras and "carlos iii"' obtained 174,000 and 1.160,000 results respectively, the searches 'ferrocarriles and "isabel ii"' and 'ferrocarriles and "alfonso xii"' were only 363.000 and 176.000, although these are more recent facts. the interest for non-spanish speakers is also high: 'roads and "charles iii" spain' had 179.000 results while 'roads "albert gallatin"' yields 183.000 hits and '"interstate highway system"' 1.050.000 ones (searched on january 9, 2020). the works that have provided a more direct and quantitative approach to the eighteenth-century road network make a somewhat negative assessment of it (madrazo madrazo 1984b; uriol salcedo 2001; martinez-galarraga 2012) . however, these works concern themselves more with an assessment of its results than with a detailed analysis of its layout comparing it with other alternative designs of the network. in fact, other authors accepted that there were some improvements from the previous situation (herranz-loncán 2005; grafe 2012) . in this context, it has to be borne in mind that path dependence and consequent lock-in are phenomena that occur under particular conditions and are the result of underlying, more fundamental mechanisms (vromen 1995) . therefore, it is necessary to adopt an approach of 'path as process,' in which the development of road networks must be understood as a continuous process of generation and destruction of optimal trajectories for the agents which produce a transformation of the existing socioeconomic structures and regional development trajectories (garud and karnøe 2001; martin and sunley 2006) . this aligns with what bednar et al. (2012) calls 'revised-path dependence,' which is of crucial importance in the interpretation of political and legal issues but also economic decisions. this implies as well that policy choices as the construction of new roads must be evaluated in light of decisions taken during the process, not just the final equilibrium. for our work on the origin and evolution of the radial structure of the spanish road network, these ideas lead us to ask whether the design of the network was unavoidable given the topological characteristics of the territory or whether it resulted from small events as the political decisions. from our point of view, an event generates path dependence when it alters the preexisting dynamics in the system, by exceeding its capacity of resilience. this resilience is usually high, and non-chaotic dynamic systems show a tendency to maintain and recover their dynamics, but if the actions or influences on it exceed certain thresholds they can change their evolution in a lasting way in time. in this framework, the road network can be seen as a system in which the links are continuously weakened and require maintenance to remain functional. improvements to the sections require specific investments to take place. the flows between the nodes derive from their relative position and size, but this is, in turn, affected by the network. there is, therefore, a dynamic of the development of the nodes that can be altered depending on decisions such as the order of execution of the works. this is a complex phenomenon and is multi-scale both in terms of time and space. from a historical viewpoint, the process is affected by the vision of permanence of the human being, and events that last more than one generation are usually considered to be permanent even though they are not permanent. from the spatial point of view, events that do not produce permanent changes in the system when considered as a whole can produce very relevant alterations at the local level. all this makes the consideration of an event as a path-dependent one always complicated and requires a precise definition of the reference framework and the spatial domain under consideration. from the perspective summarized above, in this paper, we use historical data, gis techniques, and network analysis, to critically examine three statements widely discussed in the literature but far from empirically validated. the first statement is that the dynastic change after the war of succession meant the ex novo implementation of a radial design of the road network that replaced a preexisting, less centralized one. the works about the issue consider that the radial structure of the spanish communications network arises around 1720 through the general regulations for the direction and government of the post and post offices of spain (uriol salcedo 1977; madrazo madrazo 1984a, b; ruiz et al. 2015) or, alternatively, and focusing on the roads, with the royal decree issued in 1761 to make straight and solid roads in spain and to facilitate trade between provinces (de gregorio -marqués de esquilache 1761). this radial structure is usually linked to a more centralized vision of spain motivated by the enlightened vision of the new dynasty (uriol salcedo 1985a, b; shaw 2009; carreras monfort and de soto 2010; bel 2011; garcia-lópez et al. 2015; lópez ortiz and melgarejo moreno 2016) . to analyze this statement more precisely, we have divided it into two hypotheses: h1a: 'the newly paved roads of the pre-rail period imply the introduction of a new network design.' h1.b: 'the changes in the road network are linked to the enlightenment vision of the state that came with the bourbon dynasty.' the second statement posits that the new roads generated significant changes in the transport network that led to improving the communications of madrid with the periphery instead of activating the growth of the interior regions (ringrose 1972; anes 1974; carr 1978; madrazo madrazo 1984b) . to verify this statement, quite consolidated in the literature though not entirely (grafe 2012), we will use three hypotheses: h2.a 'the newly paved roads produced important changes on the interregional mobility patterns'; h2.b 'the improvements in accessibility resulting from the newly paved roads were concentrated in a few regions, mainly madrid and the coastal regions, which was a comparative disadvantage for the inland regions,' or, in other words, 'those investments affected the regions differently'; h2.c 'the effects were mainly at the level of cities, not so much of regions.' finally, the third statement we address is whether the network design is compatible with diverse economic efficiency criteria. more precisely, we consider two hypotheses: first, h3.a 'the radial network designed by the bourbon monarchs of the second half of the eighteenth century emerges from a distributed decisionmaking process in which all the populations of the nation are taken into account in a non-discriminatory manner' (martinez-galarraga 2012) . second, h3.b, 'the military, political or administrative criteria outlined by various authors (ringrose, gómez mendoza, madrazo, bel) are compatible with that of maximizing commercial traffic' (ringrose 1972; anes 1974; madrazo madrazo 1984a, b; gómez mendoza 2001; bel 2011) . our research is based on three pillars. first, we carry out an in-depth historic analysis of the time evolution of the land communications in spain, from the midsixteenth century through the eighteenth century. our work presents the most detailed and well-documented study of this process to date, based on an exhaustive search of relevant maps and reports about the structure of the road network. second, we resort to complex network analysis techniques, that are becoming widely used in many disciplines, to quantify the effect of the historical evolution of the road network on the communication structure of the territory. finally, we introduce an agentbased model that allows us to explore different counterfactuals to obtain a network that would result from different decision-making processes. we compare centralized processes with other coordinated, democratic alternatives that considered the distribution of the population in the territory, assessing the relevance of politically motivated decisions on the evolution of the network. in this section, we present an in-depth study of the historic evolution of the spanish land transportation network. we aim to show that the road network in spain that emerged after the war of succession was the same from the beginning of the modern age, since during the sixteenth and seventeenth centuries investments in transport infrastructure were reduced and in most cases limited to road maintenance tasks. although it is pointed out often that the modern road network in spain has its roots in roman roads (uriol salcedo 1985a; bel 2011; garcia-lópez et al. 2015) , this statement is only partially true. to the extent that the orographic conditions, that is, the physical characteristics of the territory such as river and mountains, remained largely unchanged, as advances in construction technologies were not yet too important, 2 and many of the large population centers of the roman era were still relevant at the beginning of the 18th century, both networks show important similarities from their functionality as they give answers to similar problems and, therefore, many of their links connect the same nodes. however, from a technical perspective, they are different, as the roads run along largely mismatched routes. in most cases, eighteenth-century roads only overlap with old carriageways at the entrances to cities, on bridges, and on mountain passes that were still preserved from roman times (cf. "appendix," fig. 21 ). in any event, it is commonly accepted that the network of roads existing at the beginning of the eighteenth century was not structured around particularly important roads or cities, showing high road densities in old castile and low densities in the northwest of the peninsula (galicia and asturias) and the southwest part of the central plateau. it was also a markedly internal network, in which connectivity with coastal towns was practically non-existent, except with catalonia and the north of valencia. in terms of quality, it was quite inadequate, even by the standards of the time (dirección general de obras públicas 1856), making the widespread use of carts in the transport of goods difficult (menéndez pidal 1951; madrazo madrazo 1984a, b; uriol salcedo 2001) . in what follows, we critically consider this view and appraise its accuracy and the data on which it is based. one first point we need to consider is that the spatial relations between townsthe topology-of the underlying road network is a crucial aspect in assessing the suitability of infrastructure investment decisions. however, most studies on changes in the transport network linked to the arrival of the bourbons do not rely on cartographic information, but on books of itineraries and accounts of travelers (madrazo madrazo 1984a; uriol salcedo 2001; bel 2010; carreras monfort and de soto 2010) dating in most cases to two centuries before (villuga 1546; de meneses 1576) or already halfway through the century (escribano 1758) . crucially, maps and itineraries have different purposes, being related to either 'state' or 'process' as explained by (downs and stea 1977) . in the eighteenth century, maps offered much richer and more general information, but were expensive and could sometimes lead to confusion if they were misrepresented. itineraries, on the other hand, were simply lists of the towns located on the roads, i.e., they had much more limited but clearer information. among their main shortcomings was that itineraries cannot be connected, no matter how close they are, if they do not have towns in common; this could make travelers incur big detours. however, their reliability and low reproduction costs meant that they were widely used until the end of the nineteenth century. only in the field of postal communications have maps received some attention (líter mayayo 2005; aranaz del río 2005), although generally from a purely descriptive perspective. it is widely accepted that these itineraries did not reflect the entire network, but only a selection of roads that were relevant to the small public to which they were addressed, given the large proportion of the illiterate population. madrazo madrazo (1984a) , for example, considers that the actual network may have been twice the size of the reported one. further comparison with the information provided in the topographic relations of felipe ii (páez de castro et al. 1578) for toledo and madrid shows that a multitude of roads is missing (alvar ezquerra 1985; madrazo madrazo 1984a) . uriol salcedo (2001) gives further support to the idea that there is a lack of important roads according to other sources, such as chronicles of travelers. in this situation, itineraries remain the most suitable sources for the analysis of the structure of the road network in the sixteenth and seventeenth centuries, as they were generally more accurate than maps. this is not the case, however, for the eighteenth century, 3 in which there were already detailed road maps such as those of de wit (1700), fer et al. (1701), valk (1704 ), visscher (1704 , 1705 , van der aa (1707), senex (1708), mortier and sanson (1708) , allard (1710) , homann and remshard (1710) , mortier (1710) , and moll et al. (1711) . many of these maps, of french, english, and, above all, flemish origin, were compiled for military reasons during the war of succession (1701-1714) and precede by four decades the unfinished work of the jesuits carlos martínez and claudio de la vega, commissioned by the marqués de la ensenada (martínez et al. 1743) , the first national attempt to have a detailed map of the roads of spain. this surprising lack of attention by historians to the cartography of the early eighteenth century is likely to arise from three interrelated motives. on the one hand, it was difficult to access these materials before their digitization and dissemination on the internet. on the other hand, primary sources such as sarmiento (1757) discredited them with claims that in the middle of the century there were still no general maps of spain with the cartographic precision necessary to adequately determine the itineraries by 'air.' this amounts to saying that serious errors made it very difficult to define the general scheme of the road network, because the distances that appeared between the cities were not correct. finally, there was also an inadequate interpretation of secondary sources such as madrazo madrazo (1984a) that confuse the lack of precise general maps with the lack of reliable maps and, in any case, of more detailed and complete maps than the itineraries. despite these issues, road maps of the early eighteenth century, although still imprecise in terms of distances because the location of the cities and towns still showed some degree of error, gather complete information on the road connectivity between them. hence, by applying these connections to current maps in which the locations of the towns and cities is exact, it is possible to reconstruct accurately the old road maps. figure 1 shows the differences between the two visions, i.e., the itinerary vs the map approaches, comparing the network that appears in the itinerary of villuga (1546) with that of the map of valk (1704) . the latter clearly shows that, as in the rest of the maps of the period, the density of the network is quite high and homogeneous in all the territory and that the coastal zones have adequate connectivity with the interior, which contrasts not only with the itineraries of the sixteenth century but also with those of escribano of 1758. importantly, none of the maps analyzed in this work shows a categorization of roads, which suggests that there were no significant differences in quality between the roads included. in general, all of them were quite deficient and scarcely financed, as shown by the report on the state of public works in spain (dirección general de obras públicas 1856, p. 16, translation by the authors): villuga (1546) showing a network with a highly heterogeneous density, i.e., with zones with very many roads and other zones in which they barely exist. notice the important lack of communication with the coast, implying a degree of disconnection between the periphery and the peninsular center. right: map based on valk (1704) , showing a quite homogeneous road density across the iberian peninsula, good communications with the coast, and without noticeable discontinuities across reigns. maps by the authors from the references indicated above the roads that existed in spain before the middle of the eighteenth century were nothing more than simple paths, in which the difficult sections were improved somewhat by building bridges and other works in order to cross the main rivers. these works were executed sometimes by the munificence of the kings, other times with funds provided by the towns or gentlemen who had a direct interest in communications, and in the greatest number of cases resorting to the system of personal service. looking at the degree centrality (defined as the number of connections of a town with others without intermediate steps), we see that the results by madrazo madrazo (1984b) for forty towns in 1720 based on post itineraries (martínez de grimaldo 1720) differ from that obtained through maps (mortier 1710) . thus, in the first case, the average is 1.18, and in the second it is 3.70. concerning the number of cities without documented connections, the result from the itinerary is 52.5% while on the map it is only 5.0%. this means that the view mentioned above, claiming that a large part of the territory was disconnected from the rest and that the network was sparse, is highly questionable, because it is based on itineraries, implying much more subjective and fragmented information. the image that arises from our analysis and, in particular, from the integration of the maps of the time available shows a dense network of low-quality roads that differs little from early nineteenth century maps such as quiroga (1811) (1838), although, naturally, without the newly paved roads built from the second half of the eighteenth century. once philip v was consolidated in power after the war of succession, a profound reform of the communication and transport systems was started according to the ideas of the age of enlightenment. it is important to point out that this reform involves two different processes, 4 although with many points in common, in agreement with the fact that the administrative division was quite confusing throughout the eighteenth century. reforms in the first area focused on improving the postal system and the displacement of elites and had a markedly legal and organizational character. on the other hand, a second, different reform process was aimed at reducing the costs of transport employing important investments in infrastructures. we now discuss these two processes separately. the beginning of the eighteenth century brought about a profound transformation in the management of the spanish postal system, imposed by the communication needs of an empire still of enormous dimensions at a time of great economic precariousness. to this end, in 1706 philip v rescinded the postal monopoly of the vélez de guevara family, which, as descendants of the tassis family, had held it since the sixteenth century. from that moment on, the post was managed by private individuals until 1716, when the position of correo mayor de españa was abolished and the postal service became a centralized public service directly dependent on the crown (rodríguez gonzález 1983) , becoming an important source of income for it. spain thus became one of the pioneering countries in managing the postal service from the state and a model for other european countries. with the postal system fully in the hands of the crown, in 1720 philip v established the bases for its reorganization through the general regulations for the direction and government of the post and post offices of spain. this document, in addition to other measures, includes a list of post roads of eminently radial structure and with a center in madrid that followed to a large extent the main 'unmounted' post roads included in the 17th-century guides, cf. figure 2 ). this hypothesis that the structure of the network of post roads was not an ex novo design, but was based on the preexisting structure, is confirmed by a map made by jaillot on behalf of the marqués de grimaldo (jaillot and martínez de grimaldo 1721) in which 'all the ways and posts of spain are exactly collected and observed, following the memoirs of the major couriers of madrid.' although the date of edition is 1721, the information collected on the senders, and the fact that the information on the postage of the letters corresponds to those in force previously, suggests that it is a map that collects the situation of the network of posts before the promulgation of the 1720 regulation (aranaz del río 2005) and that it was commissioned by the marques de grimaldo to be used as a reference for its reform. with this caveat, we can now compare the jaillot-martínez de grimaldo network changes arising from the 1720 regulations. red, post roads preexisting this regulation that disappeared subsequently. blue, post roads arising after the regulation. gray, post roads preexisting the regulation that remained in use afterward. map by the authors based on martínez de grimaldo (1720) and jaillot and martínez de grimaldo (1721) map with the itineraries resulting from the regulation. the comparison shows no increase in centralism, but, on the contrary, a less radial structure with the incorporation of two important north-south axes, one following the so-called silver way ('ruta de la plata' in spanish, running close and parallel to the border with portugal) and the other following the mediterranean coastline between the french border and alicante. the connection with portugal via ciudad rodrigo and the branch to granada was, however, excluded. for reference, fig. 3 shows two maps of the post roads in the 17th century, obtained from italian couriers, showing a largely similar layout to the one arising from the regulation. to properly understand this discussion, it should be borne in mind that the definition of new post roads does not necessarily mean major changes in the structure of the road network, since it is only remodeling of the routes followed by the couriers to communicate post boxes with each other and thus transmit messages more quickly. this is apparent when we compare the post offices that appear on the map (fer and loon 1701), probably the first post map in spain, with the routes that appear over time. it can be seen that, although the routes undergo great changes, the post offices are, to a large extent, the same (cf. fig. 4 ). this largely virtual design of the post roads facilitates making profound modifications to the routes without major costs, as the location of the staging posts, the only physical element of the network, does not require major modifications. the considerations above do not mean that the definition of the post routes did not have implications for infrastructures. as they were priority routes for the crown, they received greater attention in terms of maintenance; on the other hand, as they were more traveled, they became safer and had better services (new inns), which generated a virtuous cycle that increased their relevance for transport. however, while the remodeling of the post network meant an important improvement in communications and the mobility of the most privileged social (serra 2003) . the information available from codogno (1608), left, and from miselli (1697), right, shows a structure similar to the one to be established by the 1720 regulations, with great axes connecting the center of the peninsula with the big cities in the periphery supplemented with several transversal axes. it can also be seen an east-west axis in the ebro and duero valleys that disappeared after 1720. maps by the authors from the sources indicated above strata, it did not alter to a great extent the capacities of freight transport as tracks remained mostly unpaved. in 1747, ferdinand vi issued a royal decree creating the office of general superintendent of couriers, stations and post offices, in charge of the maintenance of roads and the construction of new ones, placing under the tutelage of the postal service the responsibilities that previously fell on the mayors and quartermasters. as an important novelty, regular financing was established for the development and conservation of the main road network at the expense of the treasury (martín mora 2017). this change in the funding system was because the traditional system, based on local funding and obtained mainly through portazgos (entrance and exit tolls), was insufficient to undertake the intended expansion of the network (bel 2011) . as a result of this interest in improving the road network, the first roads were built in 1749, namely the santander-reinosa road and the guadarrama pass. however, it was not until 1761, with charles iii on the throne, that general legislation on the road network and public works can be considered as thoroughly established (dirección general de obras públicas, 1856). the royal decree issued in 1761 to make straight and solid roads in spain and to facilitate trade between provinces (de gregorio -marqués de esquilache 1761) is a clear example of enlightened action to promote trade and development. it is a brief document of four pages in which it is decided the continuation of the canal of castile and the construction of 'all the roads convenient for the common utility at the expense of the royal treasury, starting with the main ones from the court to the provinces, with a fixed assignment; that concluded these, all the others are implemented, that ensure the easy communication of some provinces with others, and even of some villages with fig. 3 ) shows the effect of the war of succession on communications. the role of madrid as the center of the network is enhanced and connections with the crown of aragón and with portugal decrease, as a consequence of the larger presence there of habsburg supporters. the fact that the borbonic side is more effective in keeping control of the big coastal cities is reflected in the connections with those, that survive the war. the 1704 map, at the height of the war, is similar to the 1701 one, except for the restoration of the connection with andalucía through castilla la nueva and the suppression of the connection to france via valladolid, with two new axes connecting directly to santiago and burgos. this map points to a radial conformation of the network, that appears to be consolidating in the 1721 map, previous to the regulation issued that year and following seven years of peace. in agreement with this, the post network takes a very radial structure, while the transversal axes remain but reduced to the unmounted category. in 1775, the network is the most centralized one, as can be seen from the disappearance of the transversal axes. a less centralized structure is recovered in 1804, with the reappearance of routes like silver way (parallel to the portuguese border), in aragón, and the france-portugal connection through valladolid. in 1821, the process is completed and all routes have become mounted. map by the authors based on de fer and loon (1701), de fer (1704), jaillot and martínez de grimaldo (1721), lópez de vargas y machuca (1760), brion de la tour and desnos (1766), espinalt y garcía (1775 garcía ( , 1804 and de ayala (1821) ▸ others' (translation by the authors). this ambitious infrastructure plan began with the construction of the roads from madrid to andalusia, catalonia, galicia, and valencia and the introduction, for its funding, of a national salt tax to which all people would be subject, 'ecclesiastical or secular, by duty, all contribute to an object that includes the common benefit' (translation by the authors). from 1761, charles iii and his successors carried out an intense infrastructure policy that laid the foundations of the current transport network. in the 1761 royal decree, there is no evidence of a decision on the part of the monarch to build a radial network; instead, the decree develops a desire to favor transport throughout the national territory. indeed, at the time of charles iii's death, twenty-seven years later, the roads built could hardly be considered a radial network (de ita and xareño 1789; madrazo madrazo 1988 ). this does not mean, however, that the construction of all roads was considered to be equally urgent. during the years before the promulgation of the royal decree, there was an active academic and political debate on how to improve the spanish transport network. the prioritization of communications between the capital and the periphery through straight roads as well as the funding of works by the royal treasury appearing in the royal decree of 1761 is largely the result of the influence of road arbiters who made society aware of the urgent need to improve the transport network (madrazo madrazo 1974) . thus, de quintana (1753) proposed the creation of a network of radial roads, starting from the main ports converging in madrid, and another transverse, distributed throughout the kingdom, which would allow a very significant reduction in transport costs. unlike other projects of the time, de quintana's proposal focuses on the means of transport, the ox cart, and the logistics system. he designed a network in which every 3 or 4 leagues oxen would be replaced to achieve greater speed and load capacity, similar to the way horses were replaced on post roads to increase the speed of letters and travelers. two years later, fernández de mesa, with his legal and political treaty of public roads and inns (fernández de mesa 1755), contributed ideas on funding that complemented those already appearing in the royal decree of 1747. he proposed that the construction and maintenance of the roads should be covered by those who benefited from them, mainly municipalities, but also by the lords and the church, something quite controversial at the time. the crown should only contribute to the royal roads 'for being the prince's and enjoy in them the protection, and jurisdiction as well as the usefulness of facilitating the prompt expedition of his orders, posts and military functions' (translation by the authors). along similar lines, miguel sarmiento had a deeply centralist vision, in which the capital had to play a fundamental role in the territorial structuring of the nation (reguera rodríguez 1999). using a purely geometric perspective, he proposed a network of 32 radial roads from madrid to the most remote parts of spain in imitation of the military routes of the romans (sarmiento 1757). the roads should be straight, avoiding the towns, so if any were on their way they should surround them. interestingly, this non-urban design will be used centuries later for the development of the german motorways. to avoid the congestion that would occur in madrid, as the center of the network, he proposed the construction of a circular road to distribute the traffic, in a similar way to the motorways that now surround the cities. one of the reports that probably had the greatest influence on the subsequent development of the road network is the economic project, which introduces various measures aimed at promoting the interests of spain, written by ward in 1760 and published posthumously in 1762 (ward 1762) . among his indications for a better government of the country, he dedicates two chapters to the improvement of transport. however, his attention is very focused on the development of river navigation, dedicating only four of the fifteen pages devoted to this subject to land communications, two of them referring to funding aspects. in general, he considers roads as a subsidiary system to the river (translations by the authors): 'since there can be no navigable rivers or canals everywhere, good roads have to make up for this lack.' it is therefore not surprising that the road needs were limited to 'six major roads, from madrid to la coruña, to badajoz, to cadiz, to alicante and the line of france, as well for bayonne's part as for perpignan's part' as the transversal connectivity was covered by rivers and canals. the choice of these roads was probably based on the importance that these roads had historically had and on the use that was made of them at that time as post roads. these radial ways should be complemented by 'different ways of crossing from one city to another, and making the king the first cost (as befits) is very just, that henceforth the ways be maintained by the villages themselves who will enjoy the benefit of this providence.' like sarmiento, ward emphasizes the importance of the straightness of the roads 'at the cost of any difficulties' because the reduction of the distance compensates with time the higher initial costs. the orientation of the infrastructure plan toward achieving full national connectivity, although generally accepted in the technical and political fields, was not, however, exempt from criticism (reguera rodríguez 1999). jovellanos, in its report on the agrarian law (de jovellanos 1795), considered that it would have been more beneficial to encourage economic activity to improve local connectivity rather than to build major national axes and not to start new projects before those already started have been completed. with the historical review of the development of the spanish road network and its evolution in mind, we now turn to a quantitative study of the most relevant issues related to it. in recent years, profound changes are taking place in the social sciences. the increase in computing power, the availability of more sophisticated software, and the growing accessibility of digitized primary sources mark the beginning of an era of huge methodological changes in the field of economic history. the decreasing costs of mass digitization of maps and other primary sources together with the development of character recognition systems including handwriting thanks to deep learning make it possible to analyze information that until recently was inaccessible or at least untreatable. thanks to these new possibilities, quantitative analysis and economic theory can be combined to advance our understanding of history in new ways (wehrheim 2019) . this is what mitchnener calls 4d economic history, digitally driven data design. the development of 4d has the potential to cover more areas and in greater depth than the exploitation of ipums, the integrated public use microdata series has been done so far (mitchener 2015) . on the other hand, a major contribution to this toolbox has been the geographic information systems (gis) that, by incorporating the time dimension, have become very useful in the field of social sciences (gutmann et al. 2018) . gis consists of an integrated database management system with a mapping tool that allows easy representation of data using maps but also integrates scattered information using location as a nexus and analyzes data spatially. this has allowed historians to handle data with a spatial component in a more powerful and sophisticated way than was common in the past (healey and stamp 2000; ell and gregory 2001) especially in the field of transport (atack 2013; perret et al. 2015) . often, in economics, interdependencies between the different aspects of the phenomena studied are not adequately considered (schweitzer et al. 2009 ), which is a major weakness since the relationships between entities matter whether they are people, objects, ideas, or anything else (brughmans 2013) . rather than focusing on these entities in isolation, the network perspective allows for an explicit examination of these entities to properly understand their behavior (wasserman and katherine 1994; watts 2003; de nooy et al. 2005) . this is particularly common in the area of infrastructures, not just transport, where very often the analysis focuses on differences in regional endowment without taking into account that effects, both positive and negative, may occur far from the location of the entity. space is not just an additional element of the economy: it constitutes, as reggiani and nijkamp (2009) say, an intrinsic feature of any geo-economic system and can give rise to the emergence of complex nonlinear and interactive behaviors and processes in a geographical environment. network analysis allows to overcome these limitations by making these relationships explicit and enabling global analyses of the phenomenon using widely contrasted mathematical tools. to this end, we have made a thorough effort to establish a correct network representing the roads, beginning of course with the proper starting point, namely the situation at the turn of the 18th century. as there is no suitable cartography for this purpose, it was necessary to compile it from the dispersed information available. valk's (1704) map was chosen as the basis for our reconstruction because it has the greatest regional connectivity among those elaborated in the first years of the century. as this map was made taking into account the most important connections between cities, it suffered from a certain lack of national integration through long-distance connections, a problem we solved by resorting to the itineraries of anonymous and pontón (1705) and de b. f. and de grieck (1704). it would have been desirable to integrate all available road information, but it would have resulted in an excessively complex network for simulations; at the same time, we are confident that the so-obtained network is a fairly accurate description of the roads in the early eighteenth century. as we mentioned above, maps from this period showed a distorted view of the road network by incorporating some errors in the location of cities and towns (planimetric problems), but this can be rectified if there are no spatial inconsistencies (topologic problems). this issue can be more easily understood by looking at fig. 5 , which shows the spatial distortions of the valk map by comparing the location on the map of the main cities with what they should have. if the map were correctly drawn, the mesh of distortions would show a homogeneous structure. the errors are planimetric because the mesh, albeit deformed, is not twisted, which would imply the existence of topological problems. the biggest problem, shared by other maps of the time, arises in catalonia, which appears too much to the east. other areas with planimetric errors are eastern andalusia, extremadura, galicia, and asturias. these errors in the knowledge of the reality of the territory could have influenced the design of the network by making politicians think that the distances between the cities were different from the real ones. however, the availability of real travel times in the itineraries could have mitigated these potential biases. to do this, all the villages that appeared on valk's map and on the itineraries of anonymous and pontón (1705) and de b. f. and de grieck (1704) were accurately represented on a modern map and the sections of road that appeared in those sources were represented by straight lines. straight lines were used due to the limitations of available information. the itineraries do not indicate intermediate points between towns, and the routes marked on the map were not reliable due to underlying representation errors. this could lead to the introduction of serious errors in the assessment of the actual distance between towns and consequently of transport costs by not considering the slopes and curves of the roads. to reduce this problem as much as possible, it was assumed that the error between the actual distance and the distance in a straight line was proportional to the roughness of the terrain covered. an approximation of the actual distance was thus obtained by multiplying the straight line distance by a roughness index. unlike what is usual, our index, instead of being based on the general characteristics of the territory (riley et al. 1999) , focuses on the trajectory followed by the road. areas with high roughness may have passes that are easily passable, and that surface-based measurements are unable to incorporate. the construction of the index is simple and intuitive: the number of contour curves crossed by the path divided by the length of the section. in this way, it is possible to overcome the lack of precise information about where the road really passes through. if the road is direct, it has greater slopes and cuts more contour curves, if on the contrary, it makes a detour it is longer but cuts fewer contour curves. figure 6 shows the network finally considered. we want to stress that this is an important result of our research in itself, given our comprehensive historical reconstruction. network of iberian roads at the beginning of the eighteenth century. map by the authors following the method detailed in the text. line thickness is proportional to the roughness index of the corresponding road. this is the network taken as a reference in the remainder of the paper to proceed with our long-term analysis, we need to assess whether or not the so obtained network remains stable. in other words, there should be no major changes in the connectivity of the territory beyond the improvement of the road sections included in the infrastructure plan under analysis. confirming that this hypothesis is correct is difficult given the lack of detailed information on the network and its evolution, since until the final third of the nineteenth century there was no official national route map with the necessary level of detail (depósito de la guerra 1865). however, the fragmented information available seems to indicate that changes in second-order roads were of little importance, maintaining throughout the period a dense network, homogeneous in density, and low quality. further evidence supporting this conclusion comes from the use of road guides as a reference. in this regard, we observe, on the one hand, that the work of escribano (1758) was published continuously, and with hardly any modification, from the third edition of 1767 until, at least, 1823, which indicates that the network did not suffer great alterations in its layout, since the guide did not lose interest for the public. on the other hand, based on this guide, lópez (1809) published four editions in which he completed and corrected the information contained, but without including any new routes, except in the last edition, dated 1828, in which, in the case of catalonia, he incorporated fifty new roads, many of them paved. this confirms the stability of the network and also that the low road density of the peninsular periphery that appears in the guides is not real, but is due to the lack of information and the special interest in the capital's connections, as shown in their titles. 5 interestingly, the comparison of the network presented by escribano and lópez with the anonymous work published in valencia in 1810 with military motifs (anonymous 1810) (annex illustration a2) shows us quite similar information, although not always coincident. there are discontinuities in some paths that disappear when the sources are integrated, which indicates that they are incomplete sources that can lead to errors if considered in isolation. it is important to mention at this point that, in terms of road cartography, there was an important void during the second half of the eighteenth century in which practically only post routes were included in the maps. only at the beginning of the nineteenth century, the needs of military logistics brought up new maps and itineraries. during the war of independence (lópéz de vargas y machuca 1808; nantiat et al. 1810; picquet et al. 1810 ) and the campaign known as 'the 100,000 sons of saint louis' (guilleminot et al. 1823) , foreign armies that operated in spain carried out cartographic works that represented an important improvement to the national maps (puyo et al. 2016) . these military maps have advantages over official ones such as those of de cabanes and gonzález salmón (1829) because they are based on direct inspection of the quality of roads instead of administrative classifications. the network shown by these maps is qualitatively similar to that observed in those made a century earlier during the war of succession: a dense network, fairly homogeneous in its distribution and with a generally low quality of roads, especially in mountainous areas. for this reason, we consider that the network we have inferred from the map of valk (1704) is a good approximation of the road system of the 18th century and the first part of the nineteenth century. before presenting our results, we must discuss a potentially important shortcoming of our work, namely the limitations of the available statistical sources that constrain ourselves to consider domestic inland road traffic only. therefore, we are not including the effects on road transport flows of trade at the borders with france and portugal nor does it cover both cabotage and long-distance maritime traffic. however, we consider that the biases introduced are smaller than what could be expected a priori due to several reasons. to begin with, although incomplete, part of the effect has been included in the analysis to the extent that in the long-term port and border traffic has an impact on the size of cities due to increased commercial activities (lee 1998; galor and mountford 2008) . on the other hand, despite the lack of reliable statistics, it can be accepted that spain's trade with france and portugal and in general with the rest of the countries was rather limited in the eighteenth and early 19th century (bairoch 1974; prados de la escosura 1986 moreira 2006) . as for colonial trade, it was important in terms of value (cuenca-esteban 2008) but not so much so in terms of tonnes transported. if compared to the traffic of national products, the impact on traffic in the network is small (anes 1983; delgado ribas 1986; oliva melgar 2004) . also, the spanish merchant fleet at the beginning of the nineteenth century (lobeto lobo 1989; dubert garcía 2008 ) was of small size compared with the land transport capacity for the period before 1750 offered by madrazo madrazo (1984a) . another relevant aspect of this issue is that the disadvantages of land transport compared to navigation were not as extensive as is usually claimed (carreras monfort and de soto 2010; scheidel 2014) . a natural experiment of the real advantages of ship transport versus land transport in the eighteenth century is given by the canal de amposta. this channel, whose stated objective was to facilitate aragon's trade with america, was begun in 1778 and would have made river ebro navigable up to some 450 km by saving the problems of navigability of the delta. the project was abandoned, however, 5 years later, when it became clear that the high maintenance costs of just 10 km of the canal or the alternative ground portage did not compensate for the potential savings in transport costs (franquet bernis et al. 2017) . about cabotage, several authors highlight its limited relevance as a means of transport compared to land transport (frax 1981; martínez-galarraga 2013) . finally, the few references to ship transport in the itineraries (anonymous and pontón 1705; escribano 1758; lópez 1809; anonymous 1810) and travel books (van der aa and jordan 1700; de laborde 1808) of the eighteenth and nineteenth centuries suggest that it was of little relevance. having made a precise description of the spanish road network at the arrival of the bourbon dynasty and the investments made in the following 150 years in the previous section, we can establish that there were no major alterations to the structure of the network. no new routes were created using large bridges or tunnels, but simply improvements to some of the preexisting roads. in quantitative terms, the interurban road network in the period analyzed was about 150,000 km long, of which only about 6000 km were improved, representing a percentage of approximately 4%. we can now use our approach to answer the previously stated hypothesis about the road structure in spain. we begin by studying the h1a hypothesis relative to whether the radial design of the newly paved roads proposed by ward and materialized in the royal decree of 1761 was an entirely new model or, on the contrary, a simple evolution of the preexisting network. to test this hypothesis, an obvious key requirement is the knowledge of the road structure inherited from the habsburgs. as discussed above, we have quite detailed information about the distribution of roads, thanks to the road maps, but we do not know how the traffic of people and goods was distributed among them because until the second half of the eighteenth century the categories of roads (horseshoe, wheels, etc.) are rarely explained in itineraries or maps. an important exception is the map of spain included in the itinerarium orbis christiani, (matal and hogenberg 1579) , considered the first european atlas of roads (wertheim 1935; lang 1950; schuler et al. 1965) in which the main roads and some of the secondary roads can be seen separately. as it is a road atlas of continental level, it can be assumed that the few roads it incorporates are the most important ones. it has to be stressed that the concept of importance must be understood from transport flows since road quality was very low in the whole spanish network. the matal and hogenberg map (1579) presents a radial structure that differs widely from the decentralized network that appears in the villuga (1546) and de meneses (1568) itineraries mentioned earlier: instead, roads are organized around six main roads that emerge from the center of the peninsula and which coincide, to a large extent, with those that would be proposed almost two centuries later (ward 1762) as the basis for the design of the road network approved by carlos iii in 1761 (de gregorio -marqués de esquilache 1761). this is an important result because it strongly suggests that the structure of the spanish road network did not emerge ex novo with the arrival of the bourbons after the war of succession. the network had already emerged at the end of the sixteenth century, without direct state intervention, as a consequence of the orography and the relative positions of the cities and towns (topological relations), and, as a consequence of this, of the movement of people and goods itself. in this way, the eighteenth-century road arbiters who defended a radial network only formalized a road structure that already existed de facto. to confirm the reliability of the network structure shown by matal and hogenberg (1579), we have compared it with the information available for two different periods (1544-1579) and (1597-1605). 6 to this end we assume, as menéndez pidal (1951) and braudel (1976) did, that the most important roads should tend to appear in a greater number of sources. in this way, the different categories of road sections are established according to the number of times they appear in the sources consulted. as can be seen from fig. 7 , the results of our analysis confirm the map of matal and hogenberg (1579) showing a radial network with center in toledo. the fact that all the available sources taken together grant toledo a central position in the sixteenth-century road network, despite not having a continuous court or an especially large population, seems to be related to some clear locational advantages. these advantages would mainly come from its position in the center of the iberian peninsula, the physical characteristics of the territory, and its relative position concerning the rest of the large cities. it is worth noting that villuga's and meneses' itineraries also imply certain support for this radial view of the network if we consider that the sections that appear repeated on the most occasions are also the most important or frequented (menéndez pidal 1951) (cf. figure 8) . therefore, our study establishes that toledo was the center of the network and, therefore, channeled a large part of the transport flows (braudel 1976) . crucially, the establishment of the capital in madrid in 1561 would only mean a slight modification of the network in red, roads recorded in all three sources; green, roads recorded in two sources, and blue, roads recorded in only one source. map by the authors based on the quoted references the successive decades, especially about the roads of extremadura and valencia that would no longer pass through toledo. in any event, this change has no implication on the h1a hypothesis of our study: according to the evidence presented above and the comparison of the road network established in sect. 3 with the data about the preexisting network, we have to conclude that the radial structure of the spanish road system can be traced back to the middle sixteenth century, and therefore, it cannot be considered an ex novo design. let us know analyze hypothesis h1.b that states that the changes in the road network are linked to the enlightenment vision of the state that came with the bourbon dynasty (madrazo madrazo 1984b; bel 2010) and that can only be sustained if changes in the network occur in subsequent years. figure 9 shows the changes in weighted road density between 1600 and 1766. as can be seen, two-thirds of a century after the establishment of the bourbon dynasty, the network remained virtually unchanged to the situation during the habsburg dynasty so hypothesis h1.b cannot be accepted: changes in the road network are not linked to the accession of the bourbons to the throne. most of the changes in the network must be placed after 1800 of which the enlightenment is not a part. in general, it can be seen that the modifications are not very important and are distributed throughout the territory. the most affected areas can be seen in graph c where the changes are directly represented. the fact that the changes in the network density were basically local suggests that modifications of the road structure of spain impacted many more cities than regions. this is an important issue, also included in our hypotheses, that warrants more discussion in the next section. the next issue that we address in this paper is the claim that the road network was designed by the bourbons to improve the communications of madrid with the periphery instead of activating the growth of the interior regions (ringrose 1972) . for a rigorous consideration of this question, we recall that there were three hypotheses to test. the first (h2.a) relates to the magnitude of the effects generated by the road plan 'the newly paved roads produced important changes on the mobility of the territory.' the second (h2.b) refers to the homogeneity of the regional distribution of its effects 'the positive effects of the construction of the newly paved roads were concentrated in a few regions, mainly madrid and the coastal regions, which was a comparative disadvantage for the inland regions' (ringrose 1972 , herranz-loncán (1766) 2006). finally, the third (h2.c) considers the scope of the effects 'the effects were mainly at the level of cities, not so much of the regions.' regarding the magnitude of investments in roads, undoubtedly, the long reign of charles iii and the first part of the reign of charles iv was important, but not so much from results. indeed, after the successful completion of the roads through guadarrama and from reinosa to santander by ferdinand vi, the period that continues until the end of the 18th century is disappointing, despite the significant resources spent from the salt tax. after half a century of intense activity, it had not been possible to build even half of the main roads, and most of the roads considered completed were impassable. in some cases, this was due to poor maintenance, and in others directly due to the application of inadequate construction techniques (betancourt 1868). such poor results are the consequence of three factors: the bad organization resulting from the lack of unity in management, the shortage at all levels of qualified labor, and the lack of financial resources, not only due to a lack of income fig. 10 evolution of the network of paved roads (1750-1850). gray, the six main roads proposed by ward in 1760, constituting the basis for the radial road structure. red, other roads that can be considered part of the same radial structure. green, transversal roads. dates of completions are approximate. map by the authors based on madrazo madrazo (1984b) but also to inadequate control of expenditure (dirección general de obras públicas 1856, reguera rodríguez 1999). however, in 1799 a general inspectorate, first assumed by the count of guzmán and later by agustín de betancourt, was created, along with a school for the training of the members of the new corps of engineers of roads and canals of the kingdom. the results of these measures were extraordinarily positive, increasing construction activity to an average of more than 300 km per year until the beginning of the war of independence in 1808. this armed conflict caused great destruction of the infrastructures and a serious setback in their development that persisted, with different ups and downs, until the middle of the nineteenth century. in this scenario, one has to look only at the speed with which the network developed to conclude that the relevance of improvements in transport infrastructures was very little in a large part of spain until well into the nineteenth century (cf. figure 10) . for a more quantitative discussion, we consider a network more or less radial as a function of the percentage of transverse connections it contains. in fig. 10 , the built sections corresponding to the six radial axes defined in the royal decree of 1761 7 have been marked in red and the rest in green. it can be seen how, during most of the period analyzed, the kilometers built of transversal roads surpassed those of radial roads (table 1 ). this is confirmed by the radiality index, defined as the quotient between the built kilometers of radial sections and the total, that shows that the period of maximum radiality coincides with the central phase of the network expansion. as the expansion is completed, the radiality decreases. furthermore, these results overestimate the construction of radial roads insofar as the connection with the center was not achieved. looking at, for example, the barcelona-la junquera section as radial is questionable when work has barely begun between madrid and barcelona. the greatest centralizing effect of construction on the network corresponds to the period 1790-1820. until 1790, most new roads were built on the periphery and were not interconnected, with the result that most of the benefits table 1 construction activity and radiality of the new paved road network. source: own elaboration. the data are an approximation of the reference years based on the data provided by madrazo madrazo (1984a) remained in the different regional areas. only after 1820, the closure of the links between the radial roads began to redistribute territorially the improvements in mobility. we thus see that the transversality of the network is not invariable, but rather it depends on time and the frame of reference. the network, seen as a whole, is a fairly homogeneous mesh that cannot be considered radial. however, the situation changes if we consider the importance of connections for people, both from transport flows and the quality of infrastructure. for the flows, a radial structure centered on the middle of the peninsula was observed from the sixteenth century onwards, although there were no notable differences in terms of the quality of the roads. with the bourbon road plan, the paving of the busiest roads was improved. the sequential implementation of the network generates temporary distortions in the relative quality of the roads that alter the flows and, therefore, the commercial advantages of the towns located in it. as we discussed in the introduction, such variations in advantages can be consolidated, remaining after the network is completed and the differences in infrastructure provision disappear. network analysis tools, applied to our rich dataset, make it possible to quantify the effect of these changes on the logistical advantages of the territories using two main indicators: accessibility and betweenness centrality (barthélemy 2011) . we address first the accessibility, defined as the closeness centrality of each city, which is, in turn, the inverse of the sum of transport costs to all other cities of the network through the optimal paths. being an unweighted measure, it has few information requirements but has the disadvantage of considering transport costs for all destinations equally rather than focusing on those with more intense relationships. an accurate assessment of the effect of road improvements on transport costs would require detailed knowledge of the percentage of different uses on each road section. unfortunately, this information does not exist so it must be established based on indirect information. therefore, we have used an approximate value of 25%. we think this value fits a wide variety of situations. horse-drawn couriers can benefit greatly from improved road surfaces while a heavy ox cart on many stretches would not appreciate the difference in speed because the restriction is made by draft animals. a 75% time saving from improving a mountain pass becomes only 7.25% if the road section is 100 km and 2.25% if it is 300 km. the used parameter is a generous value that does not underestimate the effect of investments. in any case, the results are robust against variations of this parameter at least in the range 15-30%. figure 11 shows that there were practically no changes in the accessibility of the network until well into the nineteenth century, which means that there were no major changes in the transport costs of the different regions until the interconnection of the new roads made it possible to take full advantage of their possibilities. the development of the network of newly paved roads did not alter the advantage in transport costs that the center of the peninsula had shown since the sixteenth century. however, as it is often the case, there are two sides to every coin. while we have seen that the design had practically no impact at the level of the territory, it did have quite some impact at the level of cities. in fact, from regional competitiveness, the relative advantage within the region may be more important than the absolute advantage on a national scale. fig. 11 effect of network construction on accessibility. accessibility is on absolute values, the same scale for all maps, and is calculated as described in the text. each point is a town (node) that is part of the road network. the color indicates the total cost in terms of time to go to all the other villages. blue is the lowest accessibility and yellow the highest fig. 12 relative accessibility. the values reported in the maps are relative to the máximum value of the accessibility in each period. values are color coded with dark green corresponding to very low values, green, low, yellow, average, orange, high and red, very high figure 12 shows the relative situation of the different towns and cities in relative terms, i.e., comparing them with the accessibility of the best-communicated nodes at any given time. in this way, it is possible to observe changes in the relative advantages of the territory. before the construction of the newly paved roads, the advantages were basically positional-to be near the center of the territory-, but subsequently, they become dependent on the proximity to the improved network. as we can see, these variations are eminently local and should be attributed to specific cities and towns rather than to regions as a whole. from a more quantitative perspective, variations in accessibility at the regional level can be estimated from weighted averages of the values of the constituent cities. however, the allocation of changes at the regional level could be biased, depending on whether the regions have changes in their territories during the period under consideration (arbia 2001) . between 1700 and 1850, the territorial division of spain underwent important modifications as witnessed by the political maps of the time (sanson and tavernier 1641; sanson 1700; homann 1750; lópez de vargas y machuca 1802; martín de lópez 1834) so it is necessary to choose an invariant region of reference (brown et al. 2005) . this is an important issue as the results of the aggregations will depend on it. the use of the current territorial division in the analysis does not seem appropriate as both local identities and internal borders affecting trade in the eighteenth and first half of the nineteenth century do not exactly correspond to this division (fig. 23) . additionally, the consideration of madrid and its surroundings as a separate region from new castile is a recent fact that does not occur until 1983. in view of this, the map we have selected as a regional reference for this work is that of sanson (1700) as it refers to the beginning of the period analyzed and is the map that martínez de grimaldo (1720) used to establish his post routes. in order to assign the villages included in the analysis to the different regions, the map was rectified to adjust it to the spatial reality of the territory. the data in table 2 show how the general accessibility of the territory in 1850 was significantly higher than in 1700. on a national level, the increase was close to 200%. regional differences range from around 25% to the average and do not show a clear geographical pattern. the table shows that the two castiles, valencia and granada see little change in their relative accessibility concerning the national average. some coastal regions such as catalonia, andalusia, biscay, or guipuzcoa experience notable improvements while others such as asturias, galicia, or murcia worsen. the rest of the inland regions, león, navarra, and la rioja have diverse behavior. the evolution of the variability of regional accessibility, measured by the coefficient of variation, shows a slight increase during the period studied, going from 0.14 to 0.18. these results are highly influenced by what happens in the small regions of the north that appear marked in the table with an asterisk (navarra, guipuzcoa, vizcaya, and la rioja). their small size means that the construction of new roads has a very strong effect on them as they affect a very high percentage of their territory. if we group them into a single region, the coefficient of variation becomes much more stable, going from 0.16 in 1700 to 0.17 in 1850. our analysis leads us to conclude that the verification of hypothesis h2.a regarding whether 'the newly paved roads produced important changes on the mobility of the territory' is ambiguous. the roads significantly improved the accessibility of the whole country. they brought about a very important change in the mobility of the territory but with a fairly homogeneous spatial distribution not generating major alterations in the relative position of the different regions. there were no changes that turned well-communicated areas into bad areas or vice versa. clearly, this must be understood in a relative sense since they all improve. instead, hypothesis h2.b about the positive effects of the construction of the newly paved roads were concentrated in a few regions, mainly madrid and the coastal regions, introducing a comparative disadvantage for the inland regions, can be rejected for several reasons. firstly, madrid did not exist as a region until the end of the 20th century, and therefore, until the institution of the provinces in 1833, it can only be spoken of as a city within the region of new castile. this, like old castile, hardly sees its relative position altered in terms of accessibility. it is true that the city of madrid and some of the surrounding towns experienced a significant improvement in its communications, but other important cities in new castile see as their relative position worsen in economic terms, as we will see later. secondly, and more importantly, the alleged comparative disadvantages faced by the center concerning the peripheral regions are not general-some regions are improving but others that are worsening-and on average they are practically non-existent. to more clearly illustrate this point, fig. 13 summarizes table 2 classifying the regions according to the growth of their accessibility. regions that show significantly below-average variations are represented in blue or pale green, while regions that exceed it are in red or orange, and those that have grown around the national average are colored in yellow. the map shows how the peripheral regions do not improve their overall accessibility with respect to those in the center. although there are regions that improve, there are also regions that get worse. the markedly local origin of the variations in the accessibility of the territory can be noted by comparing the color of the regions with that of the populations that make them up. in many regions, some areas behave very differently from the regional average and are therefore not representative of them. let us now turn to the second indicator introduced above, betweenness centrality, which sheds much light on the impact of the design on cities and shows that the effects of infrastructure investments are not always positive. intermediation or betweenness centrality is the number of optimal routes linking pairs of cities and towns that pass through a given town. this is a predictor of the likely traffic of people and goods passing through a village from other places (barthelemy 2018) . table 4 in the "appendix" as it is not a weighted measure, it does not allow us to determine exactly how much traffic passes through the village, but it does allow us to know how many different origins the travelers have if they follow optimal trajectories in their journeys. these data are important from an economic point of view as it is correlated madrazo (1984a) with the authors' calculations of the centrality. the size of the circles represents the value of their centrality both with the arrival of travelers and with the variety of products traded in the town and, therefore, with the breadth of its market. although every time a road is improved it increases, to a greater or lesser extent, the accessibility of all the nodes of the network, the induced change in terms of betweenness centrality is a zero-sum game that involves improvements for some nodes and worsening for others. changes in traffic flow caused by investments improve the situation of certain nuclei to the extent that they receive more travelers and goods because they are located on a greater number of optimal routes. on the contrary, the nuclei that reduce their betweenness centrality lost economic relevance with the fall in traffic flows. to study this issue, and to have a reference of which were the most important roads at the beginning of the eighteenth century, the information of anonymous and pontón (1705), de b. f. and de grieck (1704), and the map of fer et al. (1701) were integrated similarly as it was done to rebuild the sixteenth-and seventeenth-century networks. as expected, both maps show great similarities. only the best connectivity with portugal in the southwestern area and the consolidation of the north transversal axis santiago-barcelona stand out as differences. the analysis of the changes in betweenness centrality confirms that already in 1700 the structure of potential traffic in the network was radial and with the center in madrid (cf. fig. 14) . the six main axes were complemented by eight others: two of them running north-south, the silver way and the one that follows the mediterranean coast from barcelona to alicante; another two, east-west, the duero axis and the león-zaragoza axis; and four transversal ones, burgos-cáceres, burgos-cuenca-el campillo, zaragoza-teruel-sagunto and albacete-ciudad real. these fourteen axes totaled around 7000 km, of which the six radials accounted for approximately half. the strong correlation between the classification of roads obtained from historical sources for 1700 and the centrality map of intermediation built from an unweighted road network is a strong support for the above hypothesis that in the eighteenth century the differences between roads were not due to differences in quality but to differences in traffic. starting from this situation in 1700, the development of infrastructures in the period 1700-1850 meant greater commercial activity in the cities of the radial axes and, consequently, a decline in those located on the complementary axes, except those of the mediterranean, which maintained their potential traffic practically unchanged, and those of the santiago-barcelona axis, except in the central section león-logroño. the key point here is that these changes happen at the territorial level too, and nodes that were very important within a region also lose power or relevance versus other nodes that are becoming local hubs. table 3 shows the evolution of the concentration of betweenness centrality by regions. infrastructure investments meant that potential traffic was increasingly concentrated in the small number of cities along which the new roads ran. at the national level, the new roads led to an increment of the concentration of betweenness centrality by 20%, from 0.67 to 0.81. the reduction in the coefficients of variation of the gini index indicates a tendency to homogenize the concentration of centrality among the region, suggesting that changes were primarily at the city level rather than at the regional level. indeed, the distinct effect of the development of the road network had on different towns is depicted in fig. 15 . the plots show the change of accessibility and betweenness centrality for some of the main cities in the period 1700-1850. the upper panel shows the evolution of accessibility and betweenness centrality for the main cities as improvements are made to the road network. it is interesting to see how accessibility always improves but betweenness centrality can be suddenly reduced as a result of changes in traffic flows. the central panel in fig. 15 summarizes the previous plot and demonstrates that, in relative terms, the city that benefited the most from the work on the roads in this period was barcelona followed at a certain distance by madrid, granada, and cordoba. instead, for the rest of the cities, betweenness centrality remained basically constant or even reduced, the improvements being restricted to their accessibility. additional information is provided in the lower panel of fig. 15 , where towns connected through radial roads are depicted as green symbols, and otherwise, they are shown in blue (madrid is highlighted in red), with symbol size indicating the distance to madrid. it can be seen from this plot that towns that profited most from the road-building activity in the period are those that are far from the center, and of course those lying along radial roads. the benefit comes mostly from the increase in accessibility, which means their distance to the towns in the network decreases in general, rather than from betweenness centrality, as being in the periphery makes it very difficult for them to be in many shortest paths. again, the case of barcelona is special in this respect, with a large increase in betweenness centrality due fig. 15 improvements to the road network and change in accessibility and betweenness centrality (1700-1850). upper panel, time evolution. circles filled with stripes represent the starting point in 1700, diamonds correspond to the situation after the first investments in 1750, triangles to 1780, squares to 1820, and circles to 1850. colors correspond to different towns as indicated in the plot. middle panel, relative changes in centralities in the period considered. the color code is the same as in the upper panel. lower panel, same as the previous panel but towns are shown in green if they are included in radial roads and in blue otherwise (madrid is shown in red as the center). the shape of symbols indicates broad geographical locations: triangles in the center of the peninsula, roughly castilla, squares in the east (crown of aragón and murcia), diamonds for the south (andalucia and extremadura), and circles for the north (galicia, asturias, país vasco y navarra). the size of the symbol represents the distance to madrid to the improvements along the mediterranean coast as well as in the connection with zaragoza, which made it more advantageous to travel from the east to madrid through barcelona and zaragoza. as noted above, a very important point to make in connection with this analysis is that variations in betweenness centrality are not always positive, as shown by the upper panel of fig. 14 . indeed, they can even be initially of a sign and change when a new development of the network takes place. for instance, teruel saw how the new roads reduced the potential traffic that passed through it until 1820 when the initiation of the zaragoza-sagunto axis allowed it to recover a good part of the lost centrality. the opposite is the case of valladolid. until 1820, its position was slightly improved, but the completion of the radial connections with burgos and benavente meant a drastic reduction in its position advantages. even more dramatic are the cases of toledo and cuenca, clear examples of how infrastructure development can lead cities to logistical irrelevance. toledo had already lost a good part of its position advantages with the opening of the direct road to the south by aranjuez, but the development of the road to andalusia meant a reduction of its centrality as it was built. the closure of the valencia road by the utiel-requena route in 1820 meant a serious deterioration of cuenca`s centrality which had already been worsening since the beginning of the development of the network. the construction in 1850 of a large part of the connection with the barcelona road only meant a reduced recovery of potential traffic, as it only managed to redirect the traffic generated around guadalajara. this is an aspect that is scarcely considered by decision-makers and by the citizenship at large, not only in the eighteenth and nineteenth centuries but today: while road improvement always leads to an increase in accessibility (travel times can only decrease from road improvements), its effect on betweenness centrality and hence on the relevance of a town for many important aspects, e.g., as a trade hub, is highly non-trivial and can be positive or negative. the greater relevance of betweenness centrality versus accessibility when taking advantage of the new roads is highlighted by ghani et al. (2016) for india. although the new roads improve accessibility in a fairly homogeneous way in the territory, most of the benefits are obtained by the towns located on the road. this is further shown in fig. 16 , which shows a general view of how the gradual development of the network altered betweenness centrality of the villages as the different phases took place. these results are consistent with those recently obtained by other authors (berger and enflo 2017) in the sense that transport infrastructure development does not necessarily generate territorial convergence and that transitory shocks generate path dependence in the location of economic activity (bleakley and lin 2012; jedwab and moradi 2016; jedwab et al. 2017) . finally, let us consider hypothesis h2.c, namely that 'effects were mainly at the level of cities, not so much of region.' in light of our analysis of centralities, we have to conclude that hypothesis h2.c is confirmed. although the improvements in terms of accessibility were spread out territorially quite homogeneously, the improvements in the road network significantly modified the trade flows which made the cities and towns along the roads gain importance to the detriment of other cities. this phenomenon is particularly intense at the beginning of the development of the network when the number of improved routes is low because it generates a more intense concentration of traffic. as the concentration increases, the advantages of these cities are reduced from a logistic point of view but can be maintained thanks to the path dependence. temporary advantages can lead to cities developing permanent advantages such as population size, the establishment of fairs, or simply the development of travel habits that keep traffic on the same routes despite the existence of new alternatives. this means that it may be appropriate from an economic policy point of view to alter the optimum sequence in the construction of the network by prioritizing less efficient sections if a territorial rebalancing is to be achieved (pablo-martí and sánchez 2017). figure 17 summarizes the effects of road network improvements on inequalities at the regional level using a β-convergence analysis (barro and sala-i-martin 1992) . in brief, β-convergence is a procedure that allows quantifying the degree of convergence in accessibility. the horizontal axis shows the regional accessibility in 1750 as a deviation from the national average and the ordinate axis shows the average growth of accessibility in the period 1750-1850, also as a deviation from the national average. the low value of the regression slope (0.08) and its scarce explanatory power (r2 = 0.0016) suggest that the construction of the network did not imply important variations in the interregional differences. the potential balancing effect of lower accessibility growth in inland regions (in yellow in the graph) was compensated by very different behaviors among coastal regions. besides, the size of the points indicates the variation in intraregional concentration measured by the gini index of the intermediation centrality. last, but not least, we consider whether the radial network design that was chosen in the second half of the eighteenth century, and especially in the first half of the nineteenth century, was based on economic rationality or whether, on the contrary, it only intended to achieve certain political and administrative objectives. to this end, the empirical network will be compared with the one that would have arisen through decentralized decision-making processes that sought greater efficiency in the transport system. it is not appropriate to speak of a unique criterion of optimality for transport networks, but of many, since the definition of optimality depends both on the objectives set and on the decision-makers. thus, the final assessment will be determined by the decision-making process and, in general, by the system of aggregation of preferences used. it is therefore not possible to determine whether the transport system with its center in madrid, which began in the eighteenth century, is the optimal one: the proper way to frame this question is to ask whether it is among the most reasonable choices for a wide range of assumptions. as the choice of the criteria to optimize and the decision-making system can be very different and influenced by many subjective judgments, we decided to develop a general model that makes it possible to evaluate different options for transport networks using a counterfactual analysis to obtain valid conclusions in the widest possible range of situations. this research aligns with the rapidly growing application of counterfactual analysis using computer simulations in the study of transport networks, even if as of today it is still incipient. such approaches have been the subject of two major criticisms in the past, but are no longer valid to a large extent (casson 2009 ) as we discuss in what follows. it has often been argued that computer simulations cannot be detailed enough for the counterfactual to allow a reliable comparison with reality. however, the current availability of information sources and calculation capacity makes it fully possible to carry out this task. projects such as aimsum (barceló et al. 2005) or mat-sim (horni et al. 2016) show how current simulation systems allow a much better approach to reality than with traditional methods. on the other hand, it has been pointed out that simulation does not allow us to get close enough to reality since it ignores important physical or technological limitations that can seriously alter the analysis. this criticism does not take into account one of the most positive characteristics of this approach and that is that simulation, unlike other methodologies, allows for the incorporation of new restrictions as they become necessary without having to substantially alter the conceptual framework. basically, those two objections are largely superseded by models having enough granularity and versatility that can be run efficiently on the big computing infrastructures available today. this makes computer simulation one of the most appropriate ways to analyze the formation and evolution of transport networks, especially in environments with scarce information such as historical analysis. 8 an alternative approach could be the use of bio-inspired techniques, that in recent years have experienced a notable development. thus, nakagaki et al. (2001) showed the computation capabilities of mud mold-physarum polycephalum to solve problems of determining optimal paths. the results obtained showed a structure comparable to the real one in terms of efficiency, fault tolerance, and transport cost. this methodology has been widely applied for the analysis of transport networks and lately also in the historical analysis (strano et al. 2012; adamatzky 2012; evangelidis et al. 2015) . the evolution of the spanish road network has also been analyzed by mud mold (adamatzky and alonso-sanz 2011) . however, this methodology shows serious problems for its direct application in practical cases that go beyond mere conceptual frameworks given the high sensitivity of the results to variations in the diffusion of chemo-attractors that determine the development of plasmodium. to avoid these limitations, biosimulation is being replaced by computer simulation using cellular automata (tsompanas et al. 2016 ). 9 once we chose to work using computer simulations, the next step is to establish reasonable criteria for the development of the road network and to observe whether the results arising from our approach under each of the criteria differ significantly from those observed in reality. for this purpose, we rely on an optimal transport network generation model developed by pablo-martí and sánchez (2017) , which allows the selection of the sections to be improved from a preexisting network to achieve maximum benefit from a global perspective based on the individual preferences of each of the agents, the optimization criteria, and the voting system. the model starts from the situation of the road at a given time and builds the improved road by choosing one segment at a time according to the different criteria. for the application of interest here, namely the optimality of the improvements of the spanish road network during the eighteenth and nineteenth centuries, we resort as the preexisting network to one built based on information from the map of valk (1704) and the itineraries of anonymous and pontón (1705) and de b. f. and de grieck (1704), as mentioned above, made up of 2343 independent road sections. although the model allows any type of decision-making agent to be established, in this case, the agents are the 1815 towns considered, i.e., the nodes of the network. the weights of the influence of each of the nodes in the selection processes were made based on transport costs and population. 10 for the largest towns, 12.5% of the total, the demographic information provided by correas (1988) was used as a proxy for this variable. for all other cases, class markers were used according to the categorization used by valk (1704) in its map. fig. 18 optimal networks depend on the city they refer to. calculation of the optimal networks for three cities: barcelona, seville and valladolid using the procedure described in the text, based on the dijkstra (1959) algorithm 9 other approaches such as those based on route optimization on cost maps (voigtlaender and voth 2019) or network generation (faber 2014; prignano et al. 2019 ) have the disadvantage of only taking into account local optimization, so they have difficulty in assessing whether intermediate nodes should be incorporated even if they increase the length of the route or consider weightings for the nodes. 10 except in the case of the unweighted model that only transport costs were used. the calculation of the optimal routes is done by applying the dijkstra algorithm (dijkstra 1959) . each node explores the different alternative routes that link it with the other nodes and selects the itineraries that imply a lower transport cost. by way of example, the network that three cities would choose if the decision was made for their benefit alone is presented in fig. 18 . note how tree structures are generated in all cases, distributed radially, and starting from each of the nodes. however, these optimal structures have few sections in common. this is why the construction of a reasonable network that aggregates the preferences of all the nodes is done below through a voting system using different viewpoints. in what follows, and for the sake of simplicity, the total cost of transport is expressed in the model in terms of time, although it would be possible to use other criteria such as monetary ones. about traffic, an estimate is made using gravitational models that take into account both the size of the pair of nodes considered and the squared distance that separates them. based on this information, in every period each node chooses the section that would be most convenient for it to be improved from its accessibility to the rest of the nodes and the section that would produce the largest increase in its traffic. to this end, each node calculates the variation in total transport time and traffic that would result from the improvement of each of the sections in which it has not yet occurred, choosing, in the first case, the one that minimizes it the most and, in the second case, the one that maximizes it the most. thus, agents seek to maximize the benefits derived from the improvement of the network without taking into account the conduct of the rest of the agents, which is why strategic or collusive behavior is not considered in the model. the generation of the improved network is done through the following iterative process. first, each node distributes its vote among all the sections in proportion to the benefit it brings as discussed above. next, the stretch that has obtained the most support is selected and improved. improving a section in the model means that the travel time between the two towns on the section is reduced by 25 percent as done in sect. 4.2. once this has been done, the agents vote again among the rest of the sections, selecting successively the sections to improve until there are no more or the established budget is exhausted. this being a sequential process, the first investments made affect subsequent decisions in a clear example of path dependence. we want to emphasize that this does not necessarily mean that the process is not optimal because a one-time design would hardly be carried out simultaneously so different sections could be disconnected and the advantages of the network could be diminished. even if the result was optimal it would be greatly affected by variations in the budget or changes in the project. whether the planned network was not completed for some reason or, on the contrary, had to be extended, a suboptimal network would be obtained. the sequential approach ensures that the design is optimal for the level of development and investment achieved. to assess the optimality of the network having in mind various economic objectives, three voting systems were established: a. equal voting power. all towns have the same voting power, and their objective is simply to reduce the travel time to the rest of the towns. for this purpose, each town calculates the travel time to each of the other villages for each of the net-work improvement alternatives. once the advantages have been estimated, they distribute their votes among the different alternatives in proportion to the expected benefits. unlike other works (adamatzky and alonso-sanz 2011; equipo urbano 1972; vanoutrive et al. 2018) , this procedure involves an intense effort of calculation as each town must estimate the optimal routes and consequent transport costs or gravitational models for each of the other 1814 towns, for each of the 2343 sections that can be improved, for each of the 300 investments and the three voting systems. this means a total of 1.1 × 10 12 optimal routes, transport cost calculations, and gravitational models. this eminently territorial selection criterion would lead to an optimal network for the transmission of news in a country where there is no telecommunications infrastructure. however, it would be inappropriate if the objective were to promote commercial activity between large population centers, as this criterion does not take into account the importance of traffic between nodes. it would be ideal, for example, to define the post roads. b. population-weighted power. in this case, towns and cities also try to reduce travel time to the rest of the localities. the voting process is similar to the previous case but the voting power of each town is weighted by their population. this criterion has smaller economic applicability than the other two insofar commercial activity is being considered, but only partially because the negative effect of distance between towns is not included. this is more often the case in areas such as cultural dissemination rather than trade and transport. the distribution by place of publication of the books in a library, for example, depends more on the economic and cultural importance of the cities than on their distance. 19 optimal transport networks for the eighteenth century according to the three voting procedures discussed in the text. initial preferences (above) and optimal sequential development (below). the maps at the top show the initial preferences of the populations according to the three criteria. the 300 sections with the highest preference are marked, in order of importance, in red, blue, and finally in black. the final result is quite representative of the initial preference structure but shows a higher level of coordination c. traffic-oriented voting. towns try to maximize the traffic of goods reducing the cost of transport on the most used road sections. it would be the most appropriate system to capture the economic aspects of the network. each town estimates for each road section the effect it would have on its trade with the rest of the towns whether it would be improved by using gravitational models. it is clear, once again, that the structures rationally optimal from an economic point of view are multiple (kolars and malin 1970; rietveld and van nierop 1995) and depend on the objectives set by the intervening decision-makers and the system chosen to reach consensus. figure 19 shows the results obtained using the three criteria indicated above for 300 improved sections, representing 12.8% of the initial network. for a video illustrating the process of network formation, cf. https ://vimeo .com/36275 3400/d23a0 dcabb . the three simulations offer very similar results, indicating that the network obtained is fairly robust with respect to variations in decision criteria. it is therefore an adequate network from the point of view of people's mobility, news transmission and freight traffic. the great similarity of the networks generated by simulation with the network at the beginning of the eighteenth century can be assessed by comparing both networks, as shown in fig. 20 . this also allows us to conclude that both hypothesis h3.a, 'whether the radial network designed by the bourbon monarchs of the second half of the eighteenth century can emerge from a distributed decision-making process in which all the populations of the nation are taken into account in a non-discriminatory manner,' and h3.b, 'it is determined whether the military, political, or administrative criteria outlined by various authors are compatible with maximizing commercial traffic' are correct. these results provide evidence that the radial design followed by the spanish road system during the habsburg dynasty, and which was later used in the eighteenth century to establish the post roads and the bourbon paved roads, was considerably efficient, despite having emerged in an uncoordinated and spontaneously way. the main difference observed between the reality and the simulations is the lack of direct connection with france by irun. this postal route, the mala, does not appear in the simulation because, as discussed above, the model applied only considers national connections. the port and border effects were not included in the weightings of the peripheral populations because reliable information on the magnitude of the effects was not available. this design of the transport network has remained largely valid, as evidenced by its subsequent use in both the deployment of the rail network in the nineteenth century and the road and high-speed train networks of the twentieth century. concerning the questions raised in the introduction about the nature of the dynamic process, we can conclude that the development of the network coincides to a large extent with the country's territorial constraints. that is, it can largely be explained by the initial parameters. insofar as the construction criterion was eminently pragmatic, the road sections were improved, showing 10 greater use in an endogenous and non-intervened manner. however, the development of the network in response to these determining factors was not the only alternative. another network design could have been chosen or followed a different rhythm or sequencing which would have led to different results, especially for the relative importance of cities and transport flows, so it can be considered a genuine path-dependent process. in this paper, we have presented a combined methodology incorporating gis techniques, network science, and agent-based modeling, exemplified through its application to understanding the evolution of the road network in spain in the period 1700-1850. as a first result, our thorough review of the available literature taking advantage of the availability of digitalized maps from the period has led to a description of the roads in that period with unprecedented detail and accuracy, particularly of the situation at the beginning of the eighteenth century (fig. 6 above) . building on that data collection and processing, we have critically assessed several claims that have been widely discussed in the literature without reaching a definitive conclusion. in this section, we summarize our conclusions regarding those claims and close with a brief discussion of other possible applications of our methodology. firstly, it has been claimed by many historians and politicians that the accession of the bourbons to the spanish throne was accompanied by the implementation of a radial design of the road network superseding the less centralist one existing at the beginning of the eighteenth century. instead, our analysis does not support this claim, because as we have seen the successive bourbon kings and officials largely adopted the sixteenth-century design they found in 1700, and we have demonstrated that this design had already a marked radial character. secondly, another commonly held view assumes that the new monarchy introduced changes in the road network that altered the development of the different territories of spain, promoting the capital and forgetting peripheral regions. we find that the bourbon infrastructure policy neither generated significant changes in the transport network nor induced major alterations in territorial balance or privileged the region where the capital was located. during the eighteenth century improvements in the network were sparse and unconnected, so the effects were mainly local. in the first half of the nineteenth century, construction accelerated, almost simultaneously connecting many of the previously unconnected sections. therefore, the potential impulse to the capital due to the implementation of an improved radial structure was accompanied by the construction of relevant transverse connections, resulting in a more or less homogeneous improvement of conditions and commerce along the whole of spain. thirdly, building on a network description of the spanish roads as we have mapped them, and using agent-based simulations with different criteria to choose which parts of the network should be improved and when, we have also shown that the design followed both in the network of post roads and in the newly paved roads was carried out with reasonable economic criteria, both from the transport of mail and the mobility of people and the transport of goods. indeed, a similar structure for the roads arises from the three largely different criteria we have considered as possible counterfactuals, indicating that the actual road network existing by the end of the period considered is compatible with many objective economic optimization criteria. in closing, we want to stress that the increasing availability of historic material in digital form, and particularly of maps amenable to gis analysis, makes our approach widely applicable in the study of socioeconomic historic developments. as we have seen, having an in-depth knowledge of the evolution of the process of interest allows establishing to which degree it is path-dependent, as well as the main effects of the historical sequence of interventions. thus, rigorous, evidence-based approaches involving a detailed review of the new available primary sources, including the cartographical ones, can shed light on the origins of many critical infrastructures that cannot be understood without taking into account their path dependence evolution. a network science analysis based on centralities points to different contexts, in a multilevel structure, where the consequences of the decisions taken can even lead to opposite results, including towns getting better positioned for commerce in a national context while their regions see their options curtailed. of course, other network science tools may be applied to a well-established historical sequence to look for the effects of other types. the use of all those diagnostic tools, combined with agent-based modeling flexible enough to incorporate different decision-making procedures, may prove very useful in dealing with the future development of infrastructures and related systems. our methodology provides a guide to take many arguments out of the political arena and into socioeconomic reality in a manner that can be used to benefit society at large. the 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population and accessibility: an analysis of turkish railroad the augsburg travel guide of 1563 and the erlinger road map of 1524 the socio-economic and demographic characteristics of port cities: a typology for comparative analysis? cartografía y comunicaciones en los documentos de la biblioteca nacional. siglos xvi al xix la marina mercante decimonónica madrid: se hallará este con todas las obras del autor y las de su hijo en madrid plazuela del angel n o 19 qto lópéz de vargas y machuca t (1808) carte des royaumes d'espagne et de portugal óu l'on a marqué les routes de poste, et les limites des diverses provinces et gouvernements : pour servir à l'intelligence des opérations militaires. paris: e. collin, graveur editeur nueva guía de caminos para ir a desde madrid a todas las ciudades y villas más principales de españa y portugal, y también para ir de unas ciudades á otras. primera. madrid: gomez fuentenebro y compañçia ed) paisaje, cultura territorial y vivencia de la geografía. libro homenaje al profesor tres arbitristas camineros de mediados del siglo xviii portazgos y tráfico en la españa de finales del antiguo régimen el sistema de comunicaciones en españa el sistema de comunicaciones en españa reformas sin cambio. el mito de los caminos reales de carlos iii the regional dimension in european public policy pensando en el transporte path dependence and regional economic evolution reglamento general expedido por su magestad en 23 de abril de 1720 exposicion de las operaciones geometricas hechas por orden del rey n.s. phelipe v. en todas las audiencias reales situadas entre los limites de francia y de portugal para acertar a formar una mapa exacta y circonstanciada de toda la españa market integration and regional inequality in spain the determinants of industrial location in spain un estudio de nueva geografía económica e historia económica the long-term patterns of regional income inequality in spain an assessment of its territorial coherence 1579) itinerarium orbis christiani. https ://bilds uche.digit ale-samml ungen .de/ index .html?c=viewe r&bandn ummer =bsb00 01647 5&pimag e=3&v=150&nav=&l=en los orígenes de la política ferroviaria en españa (1844-1877) reportorio de todos los caminos de españa (hasta agora nunca visto) juan villuga 1546 1697) il buratino veridico. o vero inztruzzione generale per chi viaggia the 4d future of economic history: digitally-driven data design infrastructure and the shaping of american urban geography qué hacer con españa. del capitalismos castizo a la refundación de un país a new and exact map of spain & portugal : divided into its kingdoms and principalities &c with ye. principal roads and considerable improvements, the whole rectifyd according to ye. newest observations. i has hsr improved territorial cohesion in spain? an accessibility analysis of the first 25 years: 1990-2015 la importancia del mercado español en el comercio exterior portugués revista de historia contemporánea theatre de la guerre en espagne et en portugal path finding by tube morphogenesis in an amoeboid organism the political consequences of spatial policies: how interstate highways facilitated geographic polarization the road to inequality: how the federal highway program polarized america and undermined cities a new map of spain and portugal : exhibiting the chains of mountains with their passes, the principal and cross road, with other details requisite for the intelligence of military operations impacts on the social cohesion of mainland spain's future motorway and high-speed rail networks the historical roots of economic development el monopolio de indias en el siglo xvii y la economía andaluza: la oportunidad que nunca existió. lección inaugural del curso académico improving transportation networks: effects of population structure and decision making policies roads and cities of 18th century france old myths and new realities of transport infrastructure assessment: implications for eu interventions in central europe una serie anual del comercio exterior español (1821-1913) spain's historical national accounts: expenditure and output modelling terrestrial route networks to understand inter-polity interactions (southern etruria, 950-500 bc) cartographier et décrire la péninsule ibérique: l'héritage militaire français deliciae hispaniae et index viatorius, indicans itinera, ab vrbe toleto, ad omnes in hispani civitates et oppida. ursel: cornelij sutorij mapa de españa dividido en prefecturas y divisiones militares complexity and spatial networks: in search of simplicity. advances in spatial science urban growth and the development of transport networks: the case of the dutch railways in the nineteenth century los "apuntamientos" del padre martin sarmiento sobre la construcción de la red radial de caminos reales en españa a terrain ruggedness index that quantifies topographic heterogeneity los transportes y el estancamiento económico en españa (1750-1850) los viajes «a la ligera» : un medio tradicionalmente rápido de transporte, desbancado por el ferrocarril the upswing of regional income inequality in spain (1860-1930) the post for diuers partes of the world to trauaile from one notable citie unto an other, with a description of the antiquitie of diuers famous cities in europe exploring landscapes through modern roads: historic transport corridors in spain sanson n (1691) les monts pyrenees, ou sont remarqués les passages de france en espagne. chez h. laillot, joignant les grands augustins, aux deux globes sanson n (1700) l'espagne divisée en tous ses royaumes et principautés. jaillot, paris sanson n, tavernier m (1641) carte generale d'espagne et de tous les royaumes der älteste reiseatlas der welt the shape of the roman world: modelling imperial connectivity economic networks: the new challenges a correct map of spain and portugal monopolio naturale" di autori postali nella produzione di guide italiane d'europa, fonti storico-postali fra cinque e ottocento. archivio per la storia postale 14-15:19-80 el siglo de hacer caminos-spanish road reforms during the eighteenth century. a survey and assessment an inquiry into the nature and causes of the the wealth of nations. w, straham and t books ?id=ndlsa aaaca aj&print sec=front cover &hl=es&sourc e=gbs_ge_summa ry_r&cad=0#v=onepa ge&q&f=false vie physarale: roman roads with slime mould paris: chez mme. vve. turgis, rue s. jacques n o 16 et à nouvelle carte politique et itinéraire de l'espagne et du portugal : avec la nouvelle division des cartes en 51 provinces los orígenes del capitalismo en españa. banca, industria y ferrocarriles en el siglo xix apuntes para una historia del transporte en españa. los viajes por la posta en el siglo xviii y en los primeros años del siglo xix apuntes para una historia del transporte en españa. los últimos años de los transportes hipomóviles las calzadas romanas y los caminos del siglo xvi historia de los caminos de españa vol. i hasta el siglo xix 1704) regna hispaniarum atque portugalliae novissima et accuratissima tabula regnorum hispaniae et portugalliae. leiden zeer gedenkwaardige en naaukeurige historische reis-beschrijvinge, door vrankrijk nature's order? questioning causality in the modelling of transport networks el reportorio de todos los caminos de españa: hasta agora nunca visto en el ql allará qlquier viaje q quiera andar muy pvechoso pa todos los caminantes visscher n (1704) regnorum castellae veteris, legionis et gallaeciae principatuum q biscaiae et asturiarum accuratissima descriptio visscher n (1705) regnorum castellae novae andalusiae granadae valentiae et murciae accurata tabula highway to hitler economic evolution: an inquiry into the foundations of the new institutional economics en que se proponen varias providencias, dirigidas à promover los intereses de españa, con los medios y fondos de necesarios para su plantificación. segunda. madrid: joachin ibarra the evolving interstate highway system and the changing geography of the united states economic history goes digital: topic modeling the journal of economic history der erste europäische straßenatlas publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the allocation of effects at the regional level is complicated by the changes in the territorial division that occur during the period. the territorial division of the early eighteenth century was chosen for the calculations. the use of the current territorial division does not seem appropriate as both local identities and internal borders affecting trade do not exactly correspond to this division. the explicit incorporation of toll gates would have been desirable but is not possible because key: cord-007890-bie1veti authors: nan title: ecc-4 abstracts date: 2002-04-16 journal: int j antimicrob agents doi: 10.1016/s0924-8579(02)00033-x sha: doc_id: 7890 cord_uid: bie1veti nan f spain introduction: the prevalence of erythromycin resistance (er-r) in group a streptococci (gas) has increased in spain since early 90s with current rates exceeding 40% in some regions. this study determined the emm -types associated to erythromycin resistance in spain. material and methods: isolates belonged to the sauce* surveillance collection. rapid sequence analysis of specific pcr products was used to deduce emm -types corresponding to the majority of the known gas m serotypes. pcr primers used: gasm1 (5?-tattgcgct-tagaaaattaa-3?) and gasm2 (5?-gcaagttctt-cagcttgttt-3?). sequencing was done with the big dye terminator mix and autosequenator (applied biosystems). dna sequences were subjected to homology searches against the bacterial dna database. results: overall, 670 gas isolates (345 er-r) were analysed. three m-types (m4, st1812 and m12) accounted for 66.4% of the er-r isolates, whereas they just represented a 16.7% of the ery-s. for er-r isolates the strongest association was seen with m4 (or0/12; 95% ci 6.7 á/22.1), and m75 was second after m4 only in the last temporal period of the study (1998 á/1999) . no homogeneous distribution of er-r m-types by centres was seen. conclusions: few m-types (leading by m4) are responsible for the er-r in spain. but for m4, the remaining er-r m types (st1815, m12 and m75) did not show a temporally nor geographically homogeneous distribution. *sauce is an acronym standing for 'sensibilidad a los antimicrobianos utilizados en la comunidad en espana' (susceptibility to the antimicrobials commonly used in the community in spain ) and is the spanish word for the willow tree. significant increase in the prevalence of erythromycin-resistant, clindamycin and miocamycin-susceptible (m-phenotype) streptococcus pyogenes in spain (1998 ( á/2001 purpose: a variety of methods is used for a molecular typing of enterococcus spp. and related gram-positive bacteria. these include dna-based methods such as macrorestriction analysis using pulsedfield gel electrophoresis (pfge), ribotyping, and amplification-based methods such as rapid amplification of polymorphic dna (rapd) and amplified fragment length polymorphism (aflp). we used a homogeneous strain collection of 24 transconjugants resulting from filter-matings with different antibiotic-resistant e. faecium and a recipient isolate from our lab. the influence of transferred antibiotic-resistance determinants on the outcome of different typing methods was investigated. results: fragment patterns resulting from pfge indicated minor differences between the transconjugants and the recipient. in respect to different primers used for rapd, none or only a single fragment shift was detected in the resulting fragment patterns. aflp clusters all transconjugants into a group of major relatedness, but the result was strongly dependent on the mathematical method used for cluster analysis. fragment patterns of digested plasmids showed the possession of different or only widely related plasmids in the transconjugants. conclusions: the results of this study clearly show that under certain situations typing methods commonly used for enterococci and related gram-positive bacteria come to their limits. the sasss network aims to set up a national surveillance study to obtain standardized information on antimicrobial susceptibility to various bacterial pathogens. currently, 25 hospitals are participating in the project from different geographical regions in saudi arabia. during the 1st year (2001), the sasss focused on setting up this network. overall, high frequencies of resistance to antibiotics to different bacterial pathogens in saudi arabia were seen. geographical variations of resistance were noticed, which could be related to different prescribing practices. approximately, 9 and 32% of escherichia coli and k. pneumoniae , respectively, were extended spectrum â-lactamases (ebls) producers. resistance of enterobacteriacae group to carbapenem and pipracillin/tazobactam is low. resistance of pseudomonas aeurginosa to various anti-pseudomonal antibiotics including carbapenem is high and alarming. methicillin resistant staphylococcus aureus (mrsa) comprised 36% of s. aureus isolates. no vancomycin intermediate s. aureus (visa) was detected. high level resistance to gentamicin in enterococcus were seen in 12% of the isolates and only 2% of enterococcus facieum were glycopeptide resistant. resistance of streptococcus pneumoniae to penicillin ranged between 2% to almost 52%. surveillance of antibiotic resistance on a national level is necessarily to give guidance to practicing physicians on the best agents to use. the world-wide problem of betalactam resistance (r) in streptococcus pneumoniae (sp) has been complicated by increasing r to macrolides and some older fluoroquinolones (fq) (ciprofloxacin cip). aim of our study was to evaluate rate of acquisition of resistance to different fq: cip, sparfloxacin (spx) and levofloxacin (lev) of sp strains with different levels of susceptibility to penicillin (p). fifteen strains were serially and daily passaged in subinhibitory concentrations of these four antibiotics by a gradient plate method until acquisition of resistance. clinical strains isolated from children in day-care centers were used. five strains were susceptible (s) to penicillin (p) (one reference strain, four clinical isolates: p micsb/0.064 mg/l): five were intermediate (i) to p (one reference strain: p mic 0.19 mg/l, four clinical strains p mics: 0.5 á/1 mg/l), five were resistant (r) to p (p mics 1.5 mg/l). mean of number of passages (n ) necessary to reach i or r level with each fq as selecting agent are in the following table: spx and lev induced resistance but more slowly than cip. our results show that rate of acquisition of resistance to fq is strongly related to alteration of susceptibility to p, probably by modification of cell wall. these results are concordant with clinical results. clinical relevance of phase variation in pneumococcal opacity: nasopharyngeal (np) colonization in children from day care centers (dcc) soa8.11 carsenti h, mancini g, bensoussan m, dunais b, pradier ch, dellamonica p. archet hospital, infectious disease, nice, france streptococcus pneumoniae (sp) adherence to nasopharyngeal (np) epithelium is a prerequisite for induction of otitis transparent sp (t) have been shown to colonize the np of infant rats better than opaque (o) sp. opaque sp has proven more virulent than the t form during systemic infection in a mouse model. aim of this study was to evaluate phase variation in the nasopharynx of children. sp strains were isolated during a winter epidemiology study of np samples in children from family dcc. mics determinations were performed by e -test for penicillin (p), amoxicilline (amx) and ceftriaxone (cro). serotypes were performed using the quellung reaction. upon oil immersion microscopic examination short chains of six to eight cocci were noted as 0, '/, '/'/, '/'/'/ for absence, 1, 2, !/3 chains by field, respectively. phase variation was detected on catalase trypticase soja plates, amx and cro mics and bactericidal activity was determined for 10 pairs of o and t variants with different serotypes and susceptibility to penicillin. seventy strains of sp were screened for phase variation. nine out of 42 with chain length 0, '/ had o variants while 23 out of 28 strains with chain length '/'/ or '/'/'/ showed o variants. proportion of o variants was predominant when chain length increased. serotype 23f was prevalent. bactericidal activity of o variants showed a four-to eightfold increase of mbc. o variants may be present in np of children while t are predominant form for colonization. these virulent variants with lower level of autolysis showed less susceptibility to killing by antibiotics. they may persist in np and explain the absence of eradication by active molecules. antimicrobial resistance among clinical strains of s. pneumoniae isolated from patients with community-acquired respiratory tract infections (carti) in russia soa8.12 kozlov rs a , bogdanovitch tm a , sivaya ov a , agapova ed b , ahmetova li b , furletova b , gudkova lv b , gugutsidge b , ilyina vn b , marusina b , multich ig b , ortenberg ea b , schetinin ev b , shturmina purpose: to determine the antimicrobial resistance of pneumococci causing carti in different russian cities. methods: a total of 142 non-duplicate strains isolated in 14 russian cities in 2001 were studied. antimicrobials tested included penicillin (pen), amoxicillin (amo), erythromycin (ery), azithromycin (azi), clarithromycin (cla), midecamycin (mid), spiramycin (spi), clindamycin (cli), levofloxacin (lev), vancomycin (van), rifampicin (rif), tetracycline (tet) and co-trimoxazole (sxt). susceptibility testing was performed by broth microdilution with interpretation of the results according to nccls guidelines (2001) a map of bacterial resistance in a hungarian region soa8.16 farkas a a , juhasz a b , orosi p a , miszti c c , balogh m d . a kenezy teaching hospital, hygienie, debrecen, hungary , b kenezy teaching hospital, laboratory, debrecen, hungary , c university of debrecen, microbiology lab, debrecen, hungary , d regional hospital berettyóújfalu, laboratory, debrecen, hungary background: regional trends of microbiological resistance pattern constitute basic data and qualifying criteria for effective infection control. purpose: the aim of our study was to establish an internationally compatible regional database in a hungarian county hajdú -bihar. methods: our model is the national nosocomial infections society publications' format from the u.s. published in 2001. it contains data regarding various icu types, ambulatory patients and hospitalised patients. the same format is used for antibiotic utilisation data and device related infections' rates as well. we collected cleaned data of years 2000 á/2001 from all the microbiological laboratories of our county. results: ciprofloxacin p e. coli 6.8 4.5 9.6 75 á/above 90 susceptibilities not significantly different from u.s. data were as follows: mr cns, streptococcus pneumoniae /penicillin and 3rd generation cephalosporin, pseudomonas aeruginosa /piperacillin and enterobacter spp. and escherichia coli /ceftriaxon. conclusions: this database proved to be a very useful tool for choosing primary wards of active surveillance including places for infectious disease physician's visit (icu, rehabilitation unit). additional analysis is needed at an individual institution's level for other heavily used (or useable) antibiotics and bacteria as well (aminoglycosides, beta-lactam á/beta lactamase inhibitor combinations, 2nd generation cephalosporins, corynebacteria . to compare epidemiological, clinical, and immunological features of add before and after haart introduction, between the 436 patients (p) diagnosed in 1985 á/1995, and the 103 p detected since 1997, in a case-control study. though the mean number of newly diagnosed aids p had a sharp drop in the haart era, from 65 p/year in 1991 á/ 1995 to 22 p/year since 1997 (p b/0.001), the distribution of add and underlying immunodeficiency showed limited changes. when excluding a greater frequency of tuberculosis (tb) (p b/0.001) and wasting syndrome (p b/0.04), all other add did not show a different frequency before and after 1997. a tendency towards a higher mean cd4 count at aids disease was noticed: 78 vs 61 cells/ml (p b/0.003), with a significant difference for candida esophagitis , toxoplasmosis, kaposi sarcoma and tb (p b/0.002 á/b/0.03). the limited variation of clinical and immunological presentation are attributable to the poor impact of haart before aids recognition: 88.4% of p detected since 1997 did not receive haart or had insufficient compliance to antiretrovirals, so that 58.2% of p were aids presenters. during the haart era, an increase of mean age and sexual transmission was found (p b/0.001). notwithstanding the effects of haart on the natural history of hiv disease, the consequences on add distribution and related immunodeficiency were negligible, since most p could not benefit from haart before aids onset. a high clinical suspicion for add should be maintained when facing p with missed or undertreated hiv disease. radata */communication internet platform management of resistance analysis guided haart switch for implementation in clinical practice of hiv-infected individuals soa9.3 paech v, lorenzen t, stoehr a, plettenberg a. ifi, interdisciplinary infectiology and immunology, hamburg, germany purpose: hiv-resistance analyses are indicated to prepare switch of haart in hiv-infected individuals with failure to ongoing haart regimen. specialists at several responsible sites often feel lack of complementary informations if interpretation of resistance analyses is done independent from each other. clinical benefits from resistance analysis assays are sigfnificantly higher for those physicians, who can access external advice from hiv-experts for possible treatment options. the database concept 'radata' (www.radata.de) was developed in germany to generate expert advice for implementation in haart switch. results: fifteen hiv-treatment centres, seven laboratories and 15 high ranked authorities in hiv-medicine contribute to radata database since it is started in january 2002 in germany. hiv-infected subjects are eligible to participate at the project after presentation of failure to haart (viral load !/1000 c/ml). expert advice is generated after all data are evaluated and based on recommendations of 2 á/4 external hiv-experts. observation after therapy switch is scheduled for a period of 12 months. conclusions: radata is a novel database concept with features for evaluation of data and availability of complementary information to participating sites. the project is designed to provide its proficiency to patients and centres from germany and foreign countries. further information will be provided after the number enclosed subjects have enlarged. in vitro effects of hiv infection on abc transporter expression and antiretroviral drug efficacy soa9.4 therefore, we evaluate in primary cultures of human monocytederived macrophages (mdm) and lymphocytes, effects: (1) of retroviral infection and haart on the expression and activity of p-gp and mrp; and (2) of specific inhibitors of these host proteins on antiretroviral activities of nrti, non-nrti and ip. results: on the one hand, we evidenced a transitory increase of p-gp mrna expression in lymphocytes and mdm in response to in vitro hiv infection. this was correlated to an increased p-gp cell surface expression and activity, and an increased tnf-alpha production and mrna. in contrast, no significant modulation of mrp was observed. on the other hand, psc833 and probenecid potentiated in vitro the anti-hiv activity of azt and indinavir. these effects were accentuated when psc833 and probenecid were combined. conclusion: these results showed that: (1) hiv infection by increasing abc transporter expression could favorise the efflux of antiretroviral drugs and decrease their pharmacological effects; and (2) specific inhibitors of these transporters could reverse these deleterious effects. effects of interferon alpha plus ribavirine therapy on frequencies of hcv, hiv and cmv specific cd4-t-cell responses in peripheral blood of hiv/hcv coinfected patients after 6 months of treatment soa9.5 methods: two groups of patients with chronic hcv infection were studied: 26 hiv coinfected progressors with antiretroviral therapy and 13 hiv-negative controls. twelve hcv/hiv and 9 hcv patients have already reached 6 months of ifn-alpha'/ribavirine therapy. virusspecific cd4-t-cells in peripheral blood were analyzed by ifngamma-elispot-assays using hiv-p24, one cmv and three hcv (core, ns3, ns4) antigens. results: (1) at baseline, hcv-specific cd4-th1-cells frequencies were significantly lower than hiv-and cmv-specific ones; (2) frequencies of cd4-th1-cells against hcv as well as against cmv were similar in the two groups; (3) in hcv'//hiv'/, hcv specific cd4-t-cell frequencies did not change between baseline and 6th month of anti-hcv treatment, decreased in three and increased in only one case. hiv-and cmv-specific frequencies were decreased in seven patients. similar results were observed in hiv-negative group. conclusion: (1) hcv-specific immune responses might be more prone to tissue compartmentalization than hiv-specific ones; (2) immune defects induced by hiv infection might not be responsible for the low level of hcv-specific responses observed in hiv-progressors; (3) ifn-alpha'/ribavirine therapy influence on hcv-and hivspecific cd4-t-cell frequencies after 6 months of treatment will be discussed. frequencies of hiv-1-p24 specific th1 cells (elispot) are correlated with plasma hiv-1 viral load in a cohort of lt-np and slow progressors soa9.6 martinez v a , alatrakchi n a , costagliola d b , bonduelle o a , agut h c , autran b a , alt study group a . a hopital pitié-salpêtrière, laboratoire d'immunologie cellulaire, paris, france , b faculté de medecine saint-antoine, inserm sc4, paris, france , c hopital pitié-salpêtrière, laboratoire de virologie, paris, france background: hiv-1-specific t helper-1 cell responses have been associated with long-term-non-progression (lt-np) in hiv infection but the correlation between frequencies of hiv-1-p24-specific th1 cells and viral load has not yet been studied. we prospectively quantified these frequencies by using an ifn-gamma elispot assay in a cohort of lt-np. methods: a cohort of 62 lt-np and slow progressors (infection !/ 8 years and cd4 counts !/600/mm 3 ) was analysable. hiv-1-p24specific t cells were analyzed using: proliferation, ifn-gamma eli-spot assays and ifn-gamma production in cell supernatants. results: wide ranges were observed in the frequencies of hiv-1-p24-specific cd4 th1 cells as assessed by elispot (0-3770 sfc/106 pbmc) with a median of 70 sfc/106 pbmc. these frequencies were negatively correlated with viral load (r0/(/0.304, p 0/0.026) but not with cd4 counts and associated with a low level of t cell activation assessed by cd71 on cd4 cells (r0/(/0.266, p 0/0.035). similar results were obtained with t cell proliferation and ifn-gamma production. conclusion: interestingly, the numbers of hiv-1-p24-specific th1 cells correlate with plasma viral load, independently of cd4 counts indicating that: (1) the defect in hiv-1-specific cd4 th1 cells does not reflect the global cd4 depletion; and (2) these responses are strongly correlated to the control of virus replication. impact of drug á/drug interactions on therapeutical management of active tuberculosis in hiv infected patients soa9.7 martinez v a , truffot c b , caumes e c , katlama c c , jarlier v b , bricaire f c , jouan m d . a department of infectious and tropical diseases, pitié salpêtrière hospital, institut pasteur, unité de génétique mycobactérienne, paris, france , b department of bacteriology, pitié salpêtrière hospital, paris, france , c department of infectious and tropical diseases, pitié salpêtrière hospital, paris, france , d institut pasteur, unité de génétique mycobactérienne, paris, france since 1996 and the use of haart, management of hiv patients with active tuberculosis raised the question of drug á/drug interactions and therapeutical management of both infections. retrospective cohort study: follow-up of 43 hiv patients with active tuberculosis diagnosed between 1996 and 2000. studied data included evolution of tuberculosis and hiv, cd4 cell counts, plasma hiv viral loads, antituberculosis and antiretroviral regimens. ninety-four percent of patients were treated by quadruple combination antituberculosis drug with rifabutin for five patients. fourteen patients were treated by double antiretroviral therapy of nucleoside reverse transcriptase inhibitors (nrtis) and 29 by triple or more drugs (nrtis and/or nonnucleoside reverse transcriptase inhibitors nnrtis and/or protease inhibitors pis). the median follow-up was 24 months. there was no difference on cd4 cell counts and viral loads in the two groups and between the patients treated by nnrtis and pis at the diagnosis of tuberculosis, at the time of antituberculosis drug discontinuation and concerning cure rates of tuberculosis. on the other hand, the plasma hiv viral load was significantly better controlled in patients with nnrtis than with pis (p b/0.005). in hiv patients with active tuberculosis receiving haart, antiretroviral combination including nnrtis allows a better control of viral replication than regimen including pis without impact of the use of rifampin or rifabutin. adherence is essential to the effectiveness of antiretroviral therapy. a pharmacy visit would improve the patient advisement. a survey was carried out over a period of 3 months in the u.m.i.t. a self-report was distributed to 150 patients. ninety were evaluated. for 66%, information's given by the clinician were sufficient and for 76% the treatment advice cards were useful. however, 72% of them would like to attend a pharmacy visit. the topics they would prefer to be tackled were drug interactions (51%), side effects (49%) and effect of forgetting (44%). the treatment was well accepted and tolerated for, respectively 91 and 65% of the patients. the viral load and the cd4 count were well known by, respectively 52 and 46%. however, inaccurate pattern of treatment was frequent ( !/50%) and bad adherence was observed: treatment forgotten occasionally (60%), regularly (30%) or inadequate attitude when the treatment was forgotten (76%). number of pills, dose frequency, length of the treatment would be risk factors of nonadherence. for the majority of patients, a pharmacy visit is necessary and beneficial. the first result shows a better understanding of the treatment, an improvement of the adherence and an enhancement of plasma concentration of antiretroviral drugs. in vivo activity of glycopeptides against s. aureus infection in a rabbit endocarditis model: is mic predictive for in vivo efficacy? soa10.3 asseray n, caillon j, lemabecque v, jacqueline c, batard e, potel g, bugnon d. laboratoire antibiologie, faculte de medecine, nantes, france we have studied the in vivo efficacy of vancomycin (v) and teicoplanin (t) against five staphylococcus aureus (sa) strains: two methicillin-susceptible (mssa 1 and 2), two methicillin-resistant (mrsa 3 and 4) and one glycopeptide-intermediate (gisa 5) strain, in a rabbit endocarditis model. mics of v and t (v/t) were 0.5/0.25, 1/0.5, 1/1, 0.5/0.5, and 4/8, for mssa 1, mssa 2, mrsa 3, mrsa 4, and gisa 5, respectively. the animals were randomly infected with one of these strains, then treated for 2 days by v or t. a continuous infusion of v, simulating a 30 mg/kg/24 h human dose was used. t was infused as a continuous infusion allowing simulating a 6 mg/kg human dose, following an initial bolus. these regimens achieved clinically relevant serum steady-state concentrations of glycopeptides ( !/20 mg/ l). results were as follows: expressed in log cfu/g of vegetations (mean9/sd, followed in parenthesis by the number of rabbits used). purpose: to determine the prevalence of the decreased glycopeptides susceptibility among 187 clinical isolates of staphylococcus aureus collected from patients hospitalized in strasbourg university hospital between 15/01/2000 and 01/03/2000. the susceptibility to glycopeptides of 38 s. aureus isolates collected from hospital environment during approximately the same period was also investigated. methods: the susceptibility to glycopeptides was studied among the mrsa isolates, using: á/ detection of the decreased susceptibility to glycopeptides using agar plates containing 6 mg/l teicoplanin, á/ detection of hetero-visa strains using agar plates containing 4 mg/ l vancomycin, á/ determination of the mics of vancomycin and teicoplanin using the agar dilution and the e -test strips methods. results: thirty-nine percent of s. aureus clinical isolates (74 out of 187 strains) are mrsa. no visa or hetero-visa strain was detected. six percent mrsa isolates are teicoplanin intermediate s. aureus strains. in the environment, 13% s. aureus isolates are methicillinresistant (five out of 38). the five strains are all susceptible to glycopeptides. conclusion: the results regarding vancomycin are reassuring. however, the high rate of mrsa and the presence of teicoplanin intermediate s. aureus isolates prove that prevention and control measures need to be improved. comparative investigation of polymerase chain reaction and a conventional methods for detection of methicilin resistant staphylococcus amont clinical isolates soa10.5 kantardjiev tv a , vacheva-dobrevski rs b , panajotov sv a , bachvarova am a , velinov ti a , levterova vs a . a national center of infectious and parasitic diseases, microbiology, sofia, bulgaria , b military medical academy, clinical microbiology, sofia, bulgaria purpose: identification on methicillin resistant staphylococci has a great clinical implication and significant impact of antibiotic therapy. the aim of this study is to compare the disc-diffusion test (ddt), oxacillin agar screen test (oast) and pcr for detection of mec a gene. fifty selective clinical isolates (41 staphylococcus aureus and nine s. epidermidis ) determined as methicillin resistant by ddt were enrolled in the study. ddt was performed with oxacillin disk (1 mkg/ml) on mueller-hinton agar (mha) without nacl (nccls, 2000) . oast was performed on mha with 4% nacl, oxacillin 6 mkg/ ml, t 35 8c. these strains was genotypically characterized for the mec a gene presence by pcr method using the mec a 1-5?-aaa atc cat ggt aaa ggt tgg c-3? and the mec a 2 á/5?-agt tct gca gta ccg gat ttg c-3? primers (gibco, brl) . results: in the group of 50 mrs isolates, detected by pcr, positive results were as follow: 23 s. aureus and six s. epidermidis . for six s. aureus isolates ddt and oast were positive; pcr-negative. for two s. aureus and two s. epidermidis isolates pcr was positive; phenotypic methods-negative. conclusions: accurate and rapid detection of mrs is a constant challenge for laboratories. the pcr assay (first time in our country) appears to be more reliable than routine susceptibility testing for the rapid diagnosis of mrsa infections at hospitals, particularly due to the heterogeneous resistance of many strains. 7.39/1.7 (6) 9.79/0.9 (5) 8.79/0.9 (5) 8.49/1.3 (8) 8.29/1.1 (4) v 3 . 0 9/1.3* (7) 8.39/1.5 (5) 3.09/0.9* (4) 6.69/1.6 (6) 6.79/1.9 (6) t 3 . 0 9/0.6* (4) 7.59/0.4 (4) 4.59/1.6* (6) 8.29/0.6 (4) 5.79/1.9 (6) distribution and antibiotic susceptibilities of bacteria isolated from suspected urinary tract infections of inpatients in hungary soa13.2 rozgonyi f, csukás z, kamotsay k, szabó d, ostorházi e, berek z, maródi c. institute of medical microbiology, semmelweis university, budapest, hungary between l january 1997 and 31 december 2000, a total of 12, 143 urine samples were cultured 40% as native urine (nu) and 60% as uricult-plus (up) (orion diagnostica, finland) . cultivations were negative in 39% of nu and 42% of up specimens, while contamination was revealed in 20% of nu and 30% of up. in the clinical bacteriologically evaluable positive 1726 nu and 1656 up cultures, the distribution of the gram-negatives was very similar with the predominance of escherichia coli (43 and 41%) followed by enterobacter spp. the distribution of gram-positives differed significantly according to the types of specimens. nu resulted in 13% group-d and 6% group-b streptococcus while up did 22 and 1.5%, respectively. third generation cephalosporins and fluoroquinolons were equally very effective against e. coli strains, while ampicillin inhibited growth of 42% only. carbapenems, cefepime and the fluoroquinolons were the most active against enterobacter strains. interestingly, trimethoprim'/ sulfarmetoxazole combination could inhibit more than 75% of enterobacteriaceae strains. piperacillin'/tazobactam (89%), imipenem (83%), and ciprofloxacin (82%) could be the drog of choice against pseudomonas aeruginosa . enterococcus strains were highly sensitive to glycopeptides (100%), nitrofurantoin (99%), imipenem (95%) and amoxicillin'/clavulanic acid (94%). antimicrobial susceptibility levels of escherichia coli isolates cultured from urine at a tertiary care teaching hospital. temporal trend and comparison between community-acquired and nosocomial urinary tract infection soa13.3 nanetti a, manfredi r, valentini r, calza l, chiodo f. uni versity of bologna, infectious diseases, bologna, italy in order to assess the local temporal trend of antibiotic sensitivity of the most common urinary tract bacterial pathogen, all urine-cultured escherichia coli isolates were reviewed as to susceptibility profile, and specimen source (community-versus hospital-acquired infection). when evaluating sensitivity levels of 2070 community-acquired pathogens (1999 á/2001), a significant resistance rise was limited to cotrimoxazole (p b/0.01) and nalidixic acid (p b/0.02), while a tendency towards increased resistance regarded norfloxacin (p 0/ 0.05) (fig. 1) . when 1570 community-acquired e. coli isolates were compared with 2687 nosocomial strains (tested in the years 2000 á/ 2001), a greater susceptibility of community-acquired e. coli isolates was limited to cotrimoxazole versus all other compounds in the year 2000 (p b/0.03), while it was extended to amoxicillin, cephalotin, nitrofurantoin and piperacillin in the year 2001 (p b/0.0001) (fig. 2) . on the whole, e. coli showed an elevated sensitivity rate ( !/90% of tested strains) to nitrofurantoin, gentamicin, amikacin, and 2nd-and 3rd-generation cephalosporins, while only amoxicillin and piperacillin had a mean resistance rate !/30%, regardless of the community or nosocomial origin. a permanent surveillance of sensitivity levels of the most common pathogens responsible for infectious diseases enables to identify local antimicrobial activity and its temporal variations, and plays a key role in starting empiric therapy, pending bacterial identification and in vitro assays. conclusion: in uti, the antimicrobial agents such as 1st cg combined with aminoglycosides are recommended as initial treatment as well as the 3rd cephalosporin generation at monotherapy. in addition, the fluoroquinolones and aminoglycosides are effective in uti. prevalence of resistance mutations to antirretrovirals and relation to virological failure s3.4 garcia f a , suarez s a , alvarez m a , martinez nm a , valera b b , pasquau j b , hernandez quero j a , maroto mc a . a hospital san cecilio, microbiology, granada, spain , b hospital virgen nieves, microbiology, granada, spain purpose: to investigate the prevalence of resistance mutations in the reverse transcriptase (rt) and protease (p) genes of hiv and to relate it with the type of virological failure (vf), we have studied 88 patients (11% naïve or pregnant women, 31% were first vf, 23% were second vf, 35% more than two vf. resistance mutations were investigated using trugene hiv-1 genotyping kit (visible genetics). results: global prevalence of resistance mutations for rt inhibitors (rti) has been !/20% for m41l, d67n, k103n, m184v, l210w, t215yf, and for l10i, m36i, l63p, a71vt, l90m for p inhibitors (pi). the prevalence of resistance mutations for the naïve patients studied was very low (a98g, v118i for rti and l10i, m36i, m46i */all n0/1 */and l63p n0/4 for pi). for patients on first vf only k103n, m184v, t215yf (rti) were !/20%, as well as l10i, d30n, l63p (pi); when patients on second vf were studied, then m41l, e44d, k103n, m184v, g190a, l210w, t215yf, k219qe (rti) and m36i, l63p, a71t (pi) were !/20% prevalence; finally, when patients with more than two vf were studied, the following resistance mutations were !/20%: m41l, d67n, k70r, k103n, v118i, y181c, m184v, g190a, l210w, t215yf (rti), and l10i, m36i, m46il, l63p, a71t, l90m (pi). conclusions: the prevalence of primary resistance in the population studied is very low; the prevalence of mutations in the reverse transcriptase and protease genes increase in parallel to the type of virological failure. genotypic resistance in hiv-1 rna from patient plasma compared with rapid virus isolation and phenotypic resistance in patient pbmcs s3.5 stuermer m, groeschel b, cinatl j, doerr hw. institute for medical virology, university clinic frankfurt, frankfurt, germany objective: to compare hiv-1 virus isolation in the presence of antiretroviral drugs with plasma hiv-1 genotyping. materials and methods: hiv-1 genotyping was performed using the viroseqtm vers. 2 from applied biosystems. interpretation of genotype was done according to international standards. cd4-cells were purified from patient plasma and cultivated in microtiter plates coated with anti-cd3 and anti-cd28 antibodies in the presence of different concentrations of antiretroviral drugs. virus production was measured using a p24 antigen assay. phenotypic activity was expressed as 50% reduction of p24 concentrations. results: seventeen samples were analyzed. for 11 samples results were obtained from both methods, two samples could not be analysed by phenotyping and four samples not by genotyping. only 3/11 samples showed total and 2/11 samples partial concordance, 6/11 samples showed discordance between the two assays. in discordant samples the genotype gave a definite interpretation. conclusion: hiv-1 virus isolation and phenotyping from pbmcs may overcome the problem of currently used resistance assays, which analyse only the reverse transcriptase and the protease gene of hiv-1. possible mutations in other regions may influence viral fitness and therefore contribute to the growth of the virus population present. the lack of concordance between the two assays is related to the different blood compartments used. the clinical value of resistance tests using pbmcs is under investigation. interleukin-6 co-operates with a new type i ifn, ifn-tau to inhibit early steps of hiv-i biological cycle s3.6 rogez c a , clayette p a , martin m a , dereuddre-bosquet n a , martal j b , dormont d c . a cea, drm, fontenay-aux-roses, france , b inra, physiologie animale, jouy-en-josas, france , c cea, crssa, ephe, drm, fontenay-aux-roses, france background: type i interferons (ifn) exhibit efficient antiviral activities notably against hiv, but severe side effects restrict their clinical uses. ifn-tau is an ovine or bovine non-cytotoxic type i ifn which displays higher inhibitory effects towards hiv replication than ifn-alpha, particularly in human monocyte-derived macrophages (mdm). the antiretroviral activity of ifn-tau seems to involve antiviral and immunomodulatory mechanisms: il-6 synthesis is increased in dose-dependent manner in mdm treated with ifn-tau and a specific inhibition of il-6 biological activity decreases its antiretroviral efficiency. results: after a 1-h infection, a significant decrease of intracellular hiv rna amount was found in mdm treated with ifn-tau. in parallel, no additive inhibition was observed with ifn-tau during the elongation of proviral dna. these results suggest either an inhibition of hiv nucleocapsid uptake or an immediate hiv rna degradation, and the expression of 2?,5?-oas, mxa protein and pkr was then measured. ifn-tau induced the expression of these three host cell factors. the role of il-6 on these different steps was evaluated and we showed that il-6 co-operates with ifn-tau during the very early step of hiv biological cycle. conclusion: altogether, these results evidence that ifn-tau uses the same antiretroviral pathway as others type i ifn in mdm, and that il-6 takes part to its inhibition of early steps of hiv biological cycle. actinomycin-d as a modulator of resistances due to cell-wall active agents like bacitracin (bc) and lysozyme (lz) s4.7 chakrabarty an a , dastidar sg b . a calcutta university, medical microbiology, calcutta, india , b jadavpur university, pharmaceutical technology, calcutta, india it was observed that development of lzr in the lzr mutants took placed at three different levels and was accompanied with unselected, distinctive and elevated levels of bcr. similarly, bcr in bcr-mutants were also detected at three different levels. although the levels of bcr (100/200 mg/ml) in the bcr mutants could be raised only by persistent efforts, an increase in the levels of lzr (as cross-resistance) in the same mutants could be easily achieved. a correlation of actinomycin-d resistance with lzr and bcr of the mutant bacteria and the effects of lipase treatment on the same showed a 4 á/20-fold rise in actinomycin-d resistance of the lzr and bcr mutants of gram-positive bacteria compared with their correspondence wild-types. these findings suggest that lzr and bcr are controlled by several genes accounting for reduced cell-wall and cell-membrane permeability and indirectly, by phenotypic alteration of the lipid content of the cell-wall. thus, the alteration of cell-walls and membranes and a phenotypic extra lipid layer can work in conjunction with the efflux pump mechanisms finally determining the levels of drug-resistance. experimental development of drug resistance to non-antibiotics: a role of alteration of membrane fluidity and efflux systems s4.8 dastidar sg a , mazumdar k a , asok kumar k a , chakrabarty an b . a jadavpur university, pharmaceutical technology, calcutta, india , b department of medical microbiology, calcutta university, calcutta, india drug resistance among clinical strains was studied by selecting mutants resistant to promazine (pr) and methdilazine (md). the results showed that successive step-up mutants of pr and md developed cross-resistance to several unrelated drugs, which in subsequent steps had broader resistance spectra with higher levels of resistance. experiments on the membrane fluidity or permeability of bacterial cells using diphenyl hexatrine (dph), a fluorescent probe on md-mutants showed that three was marked reduction in the membrane fluidity and permeability. when several analogues of the basic phenothiazine structure, e.g. 2-chlor-methyl-n -methyl-pyrrolidine (cmp), methyl-1-methyl-2-pyrrolidone-4-carboxylate (mmpc), 3 hydroxymethyl-n -methyl-pyrrolidine (hmp) and md with final substitution were tested for antibacterial function on different strains, highest activity was observed with respect to md. with anaerobic bacteria the resistance(s) dependent on efflux pumps showed higher levels of resistance even to md. we have found the non-antibiotic agents triflupromazine, trimeprazine and diclofenac sodium have high degree of activity against vibrios, staphylococci and pseudomonads. the explanation of such a phenomenon in terms of possible efflux pumps will be discussed. csf, plasma and urine pcr in lyme neuroborreliosis s7.3 pícha d a , moravcová l a , lásiková š a , marešová v a , ž ïárský e b . a charles university, 2nd medical school, 1st clinic for infectious diseases, prague, czech republic , b department of cellular and molecular biology, charles university, 3rd medical school, 1st clinic for infectious diseases, prague, czech republic the main reason for high diagnostic value of pcr in neuroborreliosis (nb) is the direct way of spirochete detection. two sets of primers in nested pcr were used: one for plasmide gene encoding ospc protein and second for chromosomal gene 16s rdna. so far 25 patients with clinically manifested involvement in nb were enrolled into the prospective designed study (being continued). the main including criterion was positive prove of intrathecal specific antibody secretion (in 22 patients) and pcr positivity in csf (in 3). all patients were repeatedly examined by neurologist and samples of csf, plasma and urine were taken: (1) before treatment; (2) after treatment; (3) after 3 months. before treatment were 12 patients pcr positive in csf, six in plasma, and 10 in urine. five were parallel positive in csf and plasma and four in all three body fluids. urine after treatment was positive in seven (28%) cases and completely negative after 3 months. the pcr has had relative high sensitivity (44 %), but does not rich the sensitivity of antibody index (88%). supported by grant mzcr 6244; 111300003. consumption of imipenem correlates with b-lactam resistance in pseudomonas aeruginosa s12.5 lepper pm a , hö gel j b , trautmann m a , grusa e c . a department of medical microbiology and hygiene, university of ulm, ulm, germany , b department of biostatistics, university of ulm, ulm, germany , c hospital memmingen, central pharmacy, memmingen, germany purpose: in the present study we investigated the monthly consume of three anti-pseudomonas-active antibiotics, namely imipenem, piperacillin/tazobactam (pt) and ceftazidime during a period of 3 years (1997 á/2000) . the use of these antibiotics was correlated to the rate of resistance in pseudomonas aeruginosa . results: inspection of the time series for use of imipenem, ceftazidime, and pt, and the corresponding time series for resistance (each available from july 1997 to july 2000) indicates a remarkable coincidence between use of imipenem and resistance against the three antibiotics mentioned. pearsons's coefficient of correlation for the use of imipenem and the resistance against imipenem was 0.62 (p b/0.001), between imipenem use and pt resistance was 0.57 (p b/0.005), and between imipenem use and ceftazidim resistance 0.56 (p b/0.005). we found positive regression coefficients quantifying an association with imipenem use in the same month (p b/0.01) and with the use during the preceding month (p b/0.05). the same was true when checking dependence of ceftadizime resistance (p b/0.05) and pt resistance (p b/0.01) on imipenem use observed during the same month. neither the use of ceftadizime nor of pt could be identified as factors creating resistance to one of the three antibiotics under consideration within a reasonable period of time. conclusion: there might be a strong pressure towards resistance created by carbapenems. this could limit the use of carbapenems for initial empiric therapy. treat hard and fast: short course antibiotic treatment and its relation with patient compliance and effectiveness s12.6 perez-gorricho bpg a , ripoll m b , pechere jc c . a niño jesus hospital, infectious diseases, madrid, spain , b insalud, outpatient consult, madrid, spain , c university of geneve, microbiology, geneve, switzerland 'treat hard and fast ': short course antibiotic treatment and its relation with patient compliance and effectiveness. finding the important implications for the way in which physicians manage patients with mild á/moderate respiratory tract infections, and the relation of this management with the perception of antibiotic effectiveness, and the compliance with the antibiotic regimen has been the main purpose of the research. in a pan-european market research study of more than 3000 patients, designed to determine behaviour to the antibiotic management of mild-moderate respiratory tract infections, patient expectations of antibiotic therapy were identified, particularly those aspects that relate to efficacy and compliance. the study identifies three key drivers of patients perceived antibiotic efficacy: length of antibiotic course, time to onset of symptom relief and time to complete resolution of symptoms. the results demonstrate that once daily treatment for short periods is perceived by patients to be significantly more effective than longer antibiotic courses and thus better meets patient expectations of therapy. in this study, a macrolide, azithromycin, was selected as the drug therapy of shortest course, being the antibiotic with the shortest dosage schedule for common outpatient infections. the perception of efficacy with short course therapy also correlates with overall satisfaction with management by the physician and with patient compliance with antibiotic therapy. purpose of the study: group b streptococci (gbs) remain a major cause of neonatal infections. consensus guidelines have recommended an intrapartum antibioprophylaxis by amoxicillin, which has reduced the incidence of early-onset neonatal gbs infections. however, an increased incidence of beta-lactam-resistant gram-negative neonatal sepsis has been reported. the aim of our study was to analyse the consequences of this antibioprophylaxis on the intestinal microbial colonization of newborns. a study of the fecal flora was carried out on 50 stools samples from 3 days-old newborns divided into groups: group a intrapartum treated mothers (n 0/25); and group b untreated mothers (n0/25). both groups were matched with regards to known factors affecting intestinal microbial colonization: gestational age, type of delivery and feeding. results: colonization by enterobacteria and enterococci was not significantly different and occurrence of amoxicillin-resistant enterobacteria was similar (11/13 and 13/16 in groups a and b, respectively). however, the colonization by clostridia was modified: the number of newborns colonized was significantly less important in group a than in group b (group a: 3/25 and group b: 10/25 p b/0.05). conclusion: in our study, intrapartum antibioprophylaxis did not affect intestinal colonization by aerobes but reduced significantly colonization by clostridia, potentially anaerobic pathogens. impact of an antibiotic policy restricting the use of b-lactams and macrolides on the incidence of clostridium difficile associated diarrhoea in general medical, renal and elderly patients s12.8 boswell tc a , pacey s b , broomfield s c , westmoreland d c , yates c c . a nottingham city hospital, microbiology, nottingham, uk , b nottingham city hospital, pharmacy, nottingham, uk , c nottingham city hospital, infection control, nottingham, uk the purpose of the study: to investigate the short-term impact of a new antibiotic policy for the treatment of urinary and respiratory infections on the incidence of clostridium difficile associated diarrhoea (cdad) in hospitalised medical, elderly care and renal patients. the results obtained: a policy restricting the use of b-lactams (except parenteral penicillin), and promoting alternative antibiotics including levofloxacin for pneumonia, and doxycycline for non-pneumonic respiratory infections, was launched in july 2000. as a result there was a significant and sustained reduction in use of aminopenicillins, cefuroxime and macrolides, with a corresponding increase in doxycycline and levofloxacin. the incidence of cdad was determined during the 1st 12 months of the new policy and compared to the last 12 months of the old policy. the incidence of cdad fell from 10.02 to 4.91 per 1000 patients, and from 1.2 to 0.59 per 1000 in-patient days (p b/0.00001). in contrast, there was no change in the incidence of cdad in other specialties (surgery, oncology etc.) that had not introduced the new policy. there was no change in the incidence of nosocomial bacteraemia with quinolone-resistant coliforms or mrsa, despite the increased use of levofloxacin. conclusions: hospital-wide reduction of b-lactam and macrolide use in medical patients can result in a significant and immediate reduction in cdad. longer follow-up will determine if this effect is sustained. use of imipenem/cilastatin i.v. (tienam i.v.) for the treatment of low respiratory tract infections in intensive care units s12.10 izzo l a , orsetti r b , boschetto a a , binda b a , della casa u a , caramanico l a , la mazza a a . a department of surgery, universitá degli studi di roma 'la sapienza','p. valdoni', rome, italy , b s. camillo-forlanini, intensive care unit, rome, italy ventilator associated pneumonia (vap) is considered the most frequent infection in the intensive care unit (icu), occurring in 9 á/24% of patients intubated for longer than 48 h besides nosocomial pneumonia is a common complication in the critically ill surgical or trauma patient. inadequate treatment can lead to the complications of acute respiratory distress syndrome (ards), empyema, and lung abscess. the most important aetiological agents both in vap and in pneumonia which arise as complication in surgical or trauma patients are bacteria, whit a marked predominance of staphylococcus aureus and pseudomonas aeruginosa . the authors present their experience (30 cases) on the employment of imipenem/cilastatin i.v. (tienam i. v.) as initial empirical monotherapy at the dose of 500 mg)/3/day or 1 g)/3/ day for the treatment of the serious lower respiratory tract infection in an icu. tienam is a well tolerated broad spectrum antibacterial agent that is effective against the majority of gram-positive and gram negative aerobic and anaerobic bacteria including most pseudomonas species. except one patient deceased for causes related to his very poor general conditions and three cases in which has been necessary the addition of an aminoglycoside, in all the other patients the imipenem/ cilastatin (tienam) monotherapy has shown satisfactory clinical and bacteriological responses. clinical auditing of the impact of recommendations on antibiotic treatment s12.11 kinoo j a , david-ouaknine f a , hacquard b a , echard y a , decazes jm b . a centre hospitalier lagny marne la vallée, lagny sur marne, france , b hospital saint louis, paris, france the aim of this study was to assess the impact of curative antibiotic recommendations on suitable prescriptions at lagny-marne la vallée hospital (general hospital, 714 beds). two prospective exhaustive audits were made (all complete hospitalizations, excluding psychiatry, february á/may 1997 and 2000) of the detailed curative antibiotic prescriptions, before and after distribution of internal recommendations. the same methodology, designed by a multidisciplinary team, was used for both periods. the same antibiotics were available at the pharmacy. the prescriptions were assessed by an infectious diseases specialist and a pharmacist using pre-established criteria: literature recommendations (1997 audit), internal recommendations (2000 audit). six hundred and fifty-six prescriptions for 498 patients were collected and analysed in 1997, 738 for 497 patients in 2000. exhaustivity of the recovered prescriptions was over 95%. patient characteristics, infection sites and microbiological findings were similar for both groups. suitable prescriptions were significantly increased (47 á/59%, p b/0.001). unsuitable prescriptions (economic reasons, too short or too long course, incorrect administration, or underdosage) were significantly reduced. prescriptions for incorrect indications were unchanged and necessary combined treatment not being prescribed, increased. local recommendations improved prescriptions, but efforts have to be done in order to go on the improvement of the practice behaviour. cost-effectiveness analysis of antibiotic therapy in hospitalized patients with copd exacerbations (ae-copd) s12.12 beghi g, aiolfi s, maghini l, patruno v, aiolfi e. s marta hospital, pulmonary rehabilitation unit, a.o., rivolta d'adda, italy antibiotic costs represent a high burden of total drug costs for hospital administrations. a scientific approach considering also the economic aspects of each therapeutic decision may gain optimal treatment objectives at pondered costs. in our study we retrospectively evaluated the clinical effectiveness and costs of antibiotic therapy in patients with ae-copd. from 1997 to 2001 , 1058 our retrospective study results support previous pharmaco-economic considerations according which in choosing an antibiotic regimen for ae-copd we must take into consideration the expected clinical and microbiological results without forgetting to consider the economic burden of our decisions. significant increase in fungaemia due to non-albicans candida species s20.4 shah pm. klinikum der j.w. goethe universitaet, schwerpunkt infektiologie, frankfurt am main, germany until 1996, predominant candida species in blood cultures was candida albicans . it accounted for 72.8% of all candida species cultured from blood. since then we have observed a gradual increase in number of non-albicans candida species. from 1999, onwards nonalbicans candida species out-number c. albicans . this observation is especially important as non-albicans candida species are generally non-susceptible to azole derivatives and empirical use of azoles in suspected candidaemia should not be recommended. amphotericin b is uniformally active against almost all candida species. echinocandin may be an alternative. see figure below. a search for newer antifungal chemotherapeutics s20.5 chakrabarty an a , dastidar sg b , saha b b , basu l b . a calcutta university, medical microbiology, calcutta, india , b jadavpur university, pharmaceutical technology, calcutta, india fungal infections due to the mucor-rhizopus (m-z) group present formidable problems due to lack of appropriate and effective drugs against them, as seen in increasing number of clinical situations; death due to mycoromycosis is nearly inevitable. we analysed the biological 'weak-spots' of the mucor-rhizopus group and attempted to devise suitable drugs using their weak-spots. we have noted that like many free-living fungi, the m-z fungi are facultatively chemoautotrophic (can grow on simple sources of carbon and nitrogen and a solution of mineral salts), like the human pathogenic chemoautotrophic nocardioform bacteria. we devised a minimal medium based on that of davis and mingioli, supplemented with simple chemical compounds as sole sources of carbon and nitrogen. the key chemical here was diphenylamine with trypan blue (dpa á/tb) and other similar sources of c and n. we found that while media free of these chemicals (controls) allowed good growth of different strains of m-z fungi, a mixture of dpa á/tb completely prevented their growth over a wide concentration range. experiments with immunocompromised mice showed that these drugs at the concentrations used are well tolerated; mice experimentally infected with several clinical isolates of m-z fungi and receiving these chemicals showed that these fungi could not grow in vivo. in vitro activity of newer fluoroquinolones against multi-drug resistant salmonella typhimurium s33.4 nolones resistance is being also reported. we have studied the in vitro activity of b-lactams and fluoroquinolones against multi-drug resistant s. typhimurium from human sources. material and methods: fifty multi-drug resistant s. typhimurium were tested against cefazolin, cefuroxime, cefotaxime, cefepime, ofloxacin, levofloxacin, and moxifloxacin, by the agar dilution method according nccls guidelines. results and conclusions: all the strains were resistant to four or more of the following antibiotics: ampicillin, tetracyclines, chloramphenicol, streptomycin, sulphonamides and nalidixic acid. a high proportion of strains were intermediate or resistant to amoxicillin/clavulanate. we found no resistance to cephalosporins. nevertheless, 26% were intermediate to first and/or second gen. cephalosporins. cefotaxime and cefepime were the most active cephalosporins (mic50: 0.1 mg/l). though increasing fluoroquinolones resistance has been described among this kind of strains, no resistance to fluoroquinolones was found here. levofloxacin was the most active fluoroquinolone (mic90: 0.06 mg/l), followed by ofloxacin (mic90: 0.1 mg/l) and moxifloxacin (mic90: 0.2 mg/l). high rates of resistance to antibiotics by salmonellae from diarrhoeic children in zliten-libya s33.5 ghenghesh ks a , ben ali m b , abuhelfaia a b , dufani ma a . a faculty of medicine, al-fateh university, medical microbiology, tripoli, libyan arab jamahiriya , b faculty of arts and sciences, el-ghomes university, biology, el-ghomes, libyan arab jamahiriya salmonellae are major bacterial cause of diarrhoea in libya particularly in children. included in the present study 23 salmonella species isolated from 169 children with diarrhoea in zliten city-libya. the children aged between a few days to 10 years. the organisms were tested for their susceptibility to antibacterial agents using the disc diffusion method. of the isolates examined, 23 (100%) were resistant to ampicillin, 22 (95.7%) to amoxicillin á/clavulanic acid combination, 20 (87%) to cefoxitin, 22 (95.7%) to chloramphenicol, 21 (91.3%) to doxycycline, 18 (78.3%) to gentamicin, 1 (4.3%) to nalidixic acid, 1 (4.3%) to trimethoprim á/sulphamethoxazole and none (0.0%) were resistant to norfloxacin. a strong relationship was observed between the availability of antibiotics in the pharmacies of the city and resistance of the isolated salmonellae to these drugs. the misuse of the antibiotics by the community may be an important factor (among others) in the emergence of these high rates of resistance by the salmonellae examined. effect of ceftriaxone along with probiotics administration on intestinal ecosystem and betalactamase activity s34.6 bertazzoni minelli e a , benini a a , zoppi g b . a department of medicine and public health-pharmacology section, university of verona, verona, italy , b department of paediatrics, university of verona, verona, italy oral bacteriotherapy during antibiotic treatment is a much debated topic. aim: to study whether different probiotics can prevent imbalance of the intestinal ecosystem (dysbiosis) in children during therapy with ceftriaxone (cx). methods: fifty-one children (mean age 5.1 years) with febrile respiratory tract infections were treated with cx 50 mg/kg/day iv, alone (therapy 1) and along with the following preparations: saccharomyces boulardii (2); enterococcus spp. (3); lactulose (4); l. casei gg (5); l. rhamnosus , l. bifidus and l. acidophilus (6); b. bifidum and l. acidophilus (7); and a mixture of various lactobacilli and bifidobacteria at high concentrations (8). faecal samples, collected before and after treatment, were analysed for microflora composition, cx concentration, and beta-lactamase (bl) activity. results: cx causes intestinal dysbiosis. no c. difficile was found. faecal bl increased after therapy in all treated groups. cx alone increased bl activity in 60% (3/5) of children (no activity before treatment); a higher incidence (75 á/80%) was found in groups 2 and 5. after therapies 3, 4, 6, 7, and 8, bl activity was found in 1 or 2 more children. cx was detected in 36% of faecal samples. conclusions: the probiotics administration seems to protect against dysbiosis caused by cx and to contain the increase in faecal bl activity. the effects differ according to the probiotic administered and are peculiar to certain bacterial species. these preliminary data need further studies. comparative study of initial and acquired drug resistance in pulmonary tuberculosis in iran s37.4 mansoori d, arami s, mirabolhasani z. nritld, infectious disease, tehran, islamic republic of iran purpose: resistant to anti-tuberculosis agents particularly multiple drug resistant (mdr) is a major obstacle in treatment tuberculosis in the world. between september 1996 and march 2000 for 273 smear and culture positive pulmonary tuberculosis patients (old 0/86, new0/ 187) pretreatment susceptibility tests of isolated bacilli to inh, rif, emb and stm were performed by standard proportional method and the results were attributed to three groups: (i) newly diagnosed without any history of treatment; (ii) patients with history of treatment for one course; (iii) patients with history of treatment for two or more courses supposed to be mdr cases. the results were collected for each drug individually and different combinations of two, three and four medications. results: resistance to one, two, three and four drugs was significantly increased in group iii comparing to groups ii and i, also in group ii compared to group i. we observed a high rate of primary resistance to inh and stm in groups i and ii and a high rate of mdr (inh and rif resistance) in groups ii and iii. conclusion: the duration of bacilli exposure to antituberculosis agents in the past is a major factor in developing resistance. in contrast to who's guideline, due to high rate of primary resistance especially to stm in our area, we do not recommend addition of stm for treatment of patients whose initial four-drug regimens have been failed (group ii). donors, to understand host interactions with this bacteria, to develop new methods of diagnosis and define new vaccine candidates. nineteen tb patients and seven healthy donors were enrolled in french hospitals. cellular immune responses were evaluated by lymphoproliferation and ex-vivo quantification of specific th1 cells by elispot-ifn-gamma assays. four recombinant proteins of m. tuberculosis were tested: esat-6, 85b, erp and tb b1.3 and compared with tuberculin. we confirmed that 85b (but not esat-6 in our study) gives higher responses in tb patients compared to donors according to the results in proliferation assay (p 0/0.04). in addition, frequencies of th1 cd4 specific cells for esat-6 and tuberculin were statistical different between the two groups (p0/0.04 and 0.028, respectively). 41.1% for 85b and 70.5% for esat-6 of the patients tested were responders in elispot-assay versus 57.9% for both in proliferation assay. for the new antigens erp and tb b1.3, no difference was observed between the two groups. in conclusion, 85b and esat-6 are recognised by a large number of our patients. they seem to be promising antigens for the development of new methods of diagnosis or for the development of new vaccines. erp and tb b1.3 are not preferentially recognised by tb patients. other exported antigens will be tested. the incidence of tuberculosis (tb) is increasing worldwide. in recent some years, geographical differences in the incidence of tb in former yugoslavia have been observed. an important rise in tb cases was registered in the bordering region of bosnia. it is likely that poorer living conditions, influenced by war and emotional stress, may promote such rising incidence of tb. renal tuberculosis was diagnosed in 25 patients (female 21, male 4) from district brcko in bosnia, during the period of 2 years, 2000 á/2001. at the same time none patient had active pulmonary tb lesions, fibrous lesions were noticed in 18 patients, but we did not diagnose any signs of previous pulmonary tb in seven patients. seven patients developed relapse of renal tb after 1 á/5 years of previous treatment. guided by clinical parameters, precisely done renal echosonography enabled early suspicion and searching for renal tb, by radiological and other methods. bacteriological diagnosis was performed by detection mycobacterium tuberculosis on loewenstein á/jensen medium in 18 patients. pcr as simple, fast and highly sensitive method enabled diagnosis in incipient stadium of disease, so antituberculous therapy could be instituted some months earlier. prompt diagnosis of renal tuberculosis (using pcr, besides standard methods) is necessary, otherwise delayed diagnosis may be dangerous. a study on resistance to first generation anti-tuberculosis drugs in mycobacterium kansasii s37.7 mirsaeidi sm, farnia p, mohammadi f, mansoori sd, jabbari r, taghizadeh r, masjedi mr, velayati aa. national research inistitute of tuberculosis and lung diseases, infectious diseases and immunology (nritld ), tehran, islamic republic of iran purpose: this research has been performed to determine antibiotic resistance of atypical mycobacteria especially mycobacterium kansasi . results: twenty-three pigmented colonies which indicated atypical agents from nritld's mycobacterium culturebank were selected, they then underwent type identification and antibiogram for inh, rif, etb, stm. nine samples were m. kansasi and 14 were other non-mtb, 4 was m. gordonei , 2 m. xenopi , 3 mac, 1 m. bovis , 2 m. tererra , 1 m. asiatioum , 1 m. marinum and 1. mean age in m. kansasi cases was 34'/ 8.1 year and in non-kansasi cases 52'/ 15.6 year and in whole society ntm was 44.9'/16.4. frequency of resistance in kansasi group were 4 to inh (44%), 4 to rif (44%) 4 to etb (44%), 5 to stm (55%) and prevalence of mdr was 4 (44%) and in non-kansasi group frequency of resistance were 13 (92%) to inh, to rif 9 (64%), to etm 9 (64%) and to stm was 10 (71%), to mdr was 9 (64%). conclusion: a significant difference was seen between the age groups of patients who are affected with m. kansasi and non-kansasi (p b/ 0.01), also in frequency of resistance to first generation anti-tb drugs. m. kansasi is detected as the most common atypical mycobacterium agent in pulmonary infections and attention to antibiogram is recommended before treatment. buruli ulcer caused by mycobacterium ulcerans , is the third most common mycobacterial after tuberculosis and leprosy in west africa. nowadays, the only effective treatment is surgery. it consists in a large excision of the lesions, often followed by a skin transplant. in this study, the effectiveness of rifampin, amikacin and their combination were estimated in the treatment of mice, which were infected experimentally by m. ulcerans . after 15 weeks of treatment with rifampin, amikacin or their combination, no more viable bacilli were found in infected tissues. the animals were kept for 3 other months. among the mice treated with rifampin alone, two mice out of 30 relapsed. the minimal inhibitory concentration of these isolated strains went from 0.5 to 8 mg/ml. the dna sequence, obtained from a 93-pb of the rpob gene from these strains, showed a missense mutations, which affect a ser-415 replaced by a phenylalanine. this modification on the gene leads to an important inefficacy of treatment when rifampin was used alone. this study showed that rifampin and amikacin have a bactericidal action on m. ulcerans and that a combination of these antibiotics is necessary to avoid the selection of resistant mutants. histopathologic and electron microscopy studies of a severe isolated hiv enteropathy detected in an aids presenter. favorable response to haart introduction or1.1 manfredi r, calza l, chiodo f. university of bologna, infectious diseases, bologna, italy advanced hiv infection was detected in a heterosexual female with a 1-year history of chronic diarrhoea and severe wasting, as expressed by a body weight of 39 kg, a cd4'/ count of 64 cells/ml, and a plasma viraemia of 2.5 million copies/ml. a malabsorption syndrome was confirmed by d-xylose test, but repeated pathogen search tested negative at stool examination and light microscopy, scanning electron microscopy (em), and transmission em study of enteric mucosa. em assays detected an ultrastructural modification of duodenal mucosa never reported to date: an extensive thinning of enterocytic microvilli, disappearance of glycocalix, and large vacuolization of the enterocyte cytoplasm. two weeks after starting an indinavir-based haart, diarrhoea disappeared and our patient significantly gained body weight: 6 kg after 4 months,15 kg after 8, and 18 kg after 1 year, paralleling a cd4'/ increase to 299 cells/ml, and undetectable hiv viraemia. the subsequent 3-year follow-up confirmed absence of gut disturbances, a stable body weight, a cd4'/ count of 350 á/480 cells/ml, and hiv viraemia persistently b/50 copies/ml. repeated endoscopy and related histopathologic and em assays documented a notable improvement of mucosal damage, with complete cure reached after 2 years of haart. a direct intestinal localization of hiv may be responsible for severe diarrhoea, malabsorption, and wasting, though the morphological features of hiv enteropathy are still unclear. haart acts favourably also against isolated hiv-related enteropathy. kaposi's sarcoma in a non-hiv immunocompetent adult: relapsing due to the development of a squamus cell carcinoma or1.2 sioula e a , magira ee a , georgopoulou c a , rontogiani d b , gounaris t a . a evagelismos, internal medicine and infectious diseases, athens, greece , b evagelismos, pathology, athens, greece a 26-year-old heterosexual hiv negative girl was diagnosed with cutaneous kaposi's sarcoma. the disease was started 2 years earlier with the appearance of lesions on the left feet and on the right knee. absolute number of cd4 and cd8 were 1200 and 486 cells/dl, respectively with a decreased lymphocyte proliferation. human herpesvirus type 8 had been detected in biopsy specimens and she placed on recombinant interferon alpha-2b. follow up few months later the lesions decreased in size. two years after the onset of the disease the patient readmitted because of a mass on the left paratracheal region along with mediastinitis. her body temperature was increased. the patient underwent thoracic ct scan, which demonstrated mediastinal well defined soft tissue infiltration associated with mediastinitis and a well-defined mass in the left paratracheal region. the mass biopsy revealed squamous cell carcinoma. several violaceus lesions were observed on the arms, hands and face. severe bilateral lymphedema of the legs with a reddish papules nodules and tumors from 0.5 to 7 cm in diameter on the soles, toes and calves were present. this case illustrates the significant relapsing of the cutaneous kaposi's sarcoma soon after the appearance of and the carcinoma and the mediastinitis. a 58-year-old male patient with insulin-dependent diabetes underwent cardiac surgery for aortocoronary bypass 2 years ago. two weeks after surgery he developed mediastinitis and sternal osteomyelitis caused by methicillin-resistant staphylococcus aureus (mrsa). twice, revisions and plastic surgery for sternal osteomyelitis were performed. the patient received initially treatment with vancomycin. then the patient received intravenous outpatient treatment with teicoplanin for 6 weeks followed by by treatment with fusidic acid and then trimethoprim/sulfametrol. the fistula was closed. four months later he presented again with substernal pain and purulent discharge. the culture revealed the growth of staphylococci which were first mistaken for coagulase-negative staphylococci. after closer investigation these staphylococci were identified as small variant mrsa. computer tomography (ct) revealed multiple mediastinal abscesses. the patient was treated with intravenous linezolid 600 mg bid for 10 days and then switched to oral linezolid 600 mg bid. the oral therapy was pursued for 16 weeks under close surveillance. the patient improved substantially, the purulent discharge disappeared. the mediastinal abscesses were not detected any longer by ct at the end of treatment. the treatment with linezolid was well tolerated. platelets decreased initially but rose to normal values without treatment modification. nosocomial pneumonia due to stenotrophomonas maltophilia in a profound granulocytopenic patient hospitalized for community-acquired staphylococcus aureus severe sepsis or1.5 radulescu a a , sasca n b , lupse m c , tatulescu d c . a university of medicine and pharmac, epidemiology, cluj-napoca, romania , b the teaching hospital of infectious diseases, laboratory, cluj-napoca, romania , c university of medicine and pharmacy, infectious diseases, cluj-napoca, romania objective: to present the diverse opportunistic infections in immunocompromised patients and treatment difficulties. findings: a 35-year-old women was admitted to the teaching hospital of infectious diseases cluj with a 2-day history of fever, myalgia, lumbar pain, hemorrhage syndrome. severe sepsis was diagnosed and the conditions that evolved in it were paronychia in a patient with chronic leukemia having prolonged and profound granulocytopenia due to aggressive treatment with ifn. the condition at admission was critical due to trombocytopenia ( b/2000 platelets/ml) and hemorrhage syndrome. the evolution was favorable under antimicrobial treatment (imipenem), blood and platelet transfusion, intravenous immunoglobulins, granulocyte colony-stimulating factor, antifungal prophylaxis and supportive care. blood and pus cultures revealed mssa. in the 6th day of hospitalization she developed bronchopneumonia and respiratory failure. the sputum culture was positive for stenotrophomonas maltophilia susceptible to ceftazidime, fluoroquinolones. treatment was unsatisfactory until introducing ticarcilline á/clavulanate and ciprofloxacine. she had uneventful recovery despite remaining granulocyto-trombocytopenic. conclusions: treatment of infections with emerging agents in immunocompromised patients is difficult, guidance by results of susceptibility testing being misleading with a poor correlation between the tests and treatment outcome. early disseminated listeriosis in a liver transplant recipient (ltr): a rare case due to an in vitro multiresistant strain or1.6 manfredi r, de ruvo n, vivarelli m, bellusci r, montalti r, la barba g, abtueli aden a, cucchetti a, attard l, calza l, cavallari a. university of bologna, infectious diseases, bologna, italy a ltr receiving cyclosporin, azathioprine and steroids, developed an extraordinary episode of sepsis and pleural effusion due to a multiresistant listeria monocytogenes (lm) isolate. a lm strain serov. 4 showing the same, extensive resistance pattern (all penicillins and 1stand 2nd-generation cephalosporins), was isolated from multiple blood cultures and pleural fluid 2 weeks after surgery, while stool exam was negative. our p spent her life in countryside and bred some animals, but denied consumption of uncontrolled food. iv cotrimoxazole administration achieved a complete clinical and microbiological cure in 10 days. underlying immunodeficiency may prompt unusual/severe lm infection, but because of its usual community-acquired origin, lm disease remains infrequent in hospitalized p. only seven anecdotal reports of lm infection were described in ltr, 1986 á/2000, all but 1 occurring months á/years after surgery. an early respiratory and systemic infection caused by a community-acquired lm strain which proved resistant to first-choice antibiotics, but had a favorable response to cotrimoxazole (used only once in a ltr with lm sepsis), characterized our episode. an epidemiological survey retrieved the possible source of this usually community-acquired infection. lm should be regarded as an emerging opportunistic pathogen in ltr, and specific risk factors should be seeked. when immunodeficiency is of concern, the unpredictable sensitivity of lm should prompt in vitro assays to adjust antimicrobial therapy problems for discussion hbv á/hcv and liver carcinogenesis: where does the viral influence end? or2.2 pappas ga. university hospital, internal medicine, ioannina, greece hepatocellular carcinoma (hcc) is a major clinical problem worldwide, usually evolving over a long-standing liver pathology, in the latter stages in the form of cirrhosis. hbv and hcv chronic infection is a common etiology of cirrhosis, and hence, hcc. a number of studies have attempted to clarify the role of these viruses into the progression towards hcc. does their end in the stage of cirrhosis? is progression towards hcc independent of the etiology of cirrhosis (since alcoholic cirrhosis also proceeds to hcc)? do the trials with interferon alfa for patients with hbv or hcv cirrhosis exhibit a favorable result due to the antiviral properties of interferon, or is interferon exhibiting anti-oncogenic potential?, and is hcc cytokine and hormone sensitive (view ongoing trials with somatostatine analogues versus hcc)? (hence, if we treat alcoholic cirrhosis patients with interferon could we have a favorable response?). which patients with hbv or hcv cirrhosis are eligible for interferon treatment?: interferon treatment is a potential hazard for those with thrombocytopenia. how ethical is it to conduct a randomised trial where one leg of cirrhotic patients is left without antiviral therapy? and on the basis of which classification system should the two legs of such a trial be separated? moreover, do viral proteins with oncogenic potential exist (the controversy over the recently discovered hbv protein is still, unresolved)? a major topic awaiting for a major debate. to assess the role of hiv-associated campylobacteriosis (c) according to haart availability, 17 patients with positive culture were identified since 1991. compared with the â/1000 hiv-infected p followed in the last decade, no epidemiological differences were shown, save a greater sexual exposure to hiv (p b/0.005). the introduction of haart caused a drop of frequency of c (from 1.8 to 0.9 episodes per 1000 p-year; p b/0.0001), and modified clinical features, with disappearance of dissemination and mortality, reported in 7 and 2 patients before 1996 (p b/0.03). hiv-related immunodeficiency and disease stage were significantly related to c features before and after haart availability: p b/0.0001 for cd4 and neutrophil count, p b/0.007 for aids diagnosis. most cases (15) were community-acquired, but alimentary or environmental risk factors were never found. ten patients received cotrimoxazole prophylaxis (nine before 1996; p b/ 0.03), while no relationship occurred with steroid or antibiotic use, caused 14 cases out of 17. a 100% sensitivity was found to quinolones, followed by cephalosporins (82.3%), gentamicin (76.5%), macrolides (64.7%), and cotrimoxazole (47.1%). a 8 á/18-day antimicrobial therapy cured 16 p , but relapses caused by similar strains occurred in 6 patients within 2 á/8 weeks, all in the pre-haart era (p b/0.05). c still occurs in the haart era, probably due to its varied mode of transmission. the frequency of c is greater in hiv-infected patients, but less frequent visceralization, recurrences, and mortality characterized the haart era. objective: to determine the incidence and risk factors for nosocomial viral respiratory infections (nrvi) and involvement of human coronaviruses (hcov) in a neonatal and pediatric intensive care unit. methods: prospective observational study. nasal samples were obtained by cytological brush at admission and weekly thereafter for all hospitalized infants. nasal samples were taken monthly from staff. virological studies were performed, using immunofluorescence for respiratory syncitial virus (rsv), influenza viruses, paramyxoviruses, and adenoviruses; both immunofluorescence and rt-pcr were used for hcov detection. results: during 1998, 42 hcov related nrvi were detected in 152 nn and six in 92 children. three hcov-related outbreaks were observed (february, august and december), associated with a high prevalence of infection in staff. during august outbreak, 18 hcovinfected nrvi were detected over 23 hospitalized infants. seventy-five of hospitalized preterm nn with gestational age under 32 weeks and 52.4% of staff members were infected. risk factors for nrvi in nn were birth weight, gestational age, ventilation, oxygenation and hospitalization length. ninety-two percent of infected preterm nn were symptomatic, mainly with bradycardia and respiratory worsening. conclusions: these data provide additional evidence for a significant role of hcov in nrvi occurring in hospitalized preterm nn. strain typing and screening of 8 dna targets to assess echinococcus sp transmission in new and old geographic endemic foci or2.5 bart jm a , piarroux r a , dia l b , benchikh-elfegoun mc c , vuitton da a , bardonnet k a . a serf, parasitology, besancon, france , b national centre of veterinary study, parasitology, nouakchott, mauritania , c university of mentouri, parasitology, constantine, algeria purpose: cystic echinococcosis is due to echinococcus granulosus. parasite cycles depending on the main intermediate host species involved in different foci have been described promoting mixed infection in the same definitive host. strain typing is a tool to identify the main intermediate host involved via the dogs in the human infection route and to focus the control measures. many dna targets have been used to compare samples and to access the parasite cycle in different countries. but no study has compared the value of each of these targets. eight targets have been tested in mauritania where echinococcosis is an emergent disease, and in algeria where strain typing has never been done. thirty-five cyst samples from human, ovine, camel and bovine have been tested with six nuclear and two mitochondrial targets. results: the two mitochondrial targets and four out the six nuclear targets have allowed to discriminate the different foci. two strains have been found infectious to human : the 'sheep' strain in algeria and the 'camel' strain in mauritania. conclusion: although overlapping geographically sometimes, this raises the question of the respective genetic evolution of the different strains and of their involving in human infection. alveolar echinococcosis in france: an update or2.6 bardonnet k, bresson-hadni s, bartholomot b, gérard a, watelet j, beytout j, saurin jc, piarroux r, vuitton da, who centre collaborating for prevention and treatment of human echinococcosis, university of franche-comté, besançon, france introduction: the highest prevalence rate for alveolar echinococcosis (ae) in europe has been found in france. in 1997, a french observatory of human ae was done in order to get data that could be used to evaluate presentation, evolution and management of ae. material-methods: french cases were collected for the period 1982 á/ 2002. registration of every case was performed with the subject's agreement. a questionnaire was filled in by referring to the patients' medical files or to practitioners or to patients themselves. completeness of the collection of cases was ensured by multiplying the sources of information. results: two hundred and sixty nine french patients were registered. sex ratio averaged 1. mean age at diagnostic was 54.8 years. 12.5% of diagnosis was performed in 'echinococcosis free' french areas. symptoms, but not always specific liver symptoms, were present at diagnosis in 76.4% of cases. the liver was the main location of lesions in 93.6% of cases. a wide spectrum of management of the patients was observed, accounting for regional differences. conclusion: this french observatory of human ea will facilitate a better management of the disease at the national level. it shows new epidemiological trends, and especially an extension of the endemic area. can coins and paper currency transmit bacillus anthracis ? or2.7 ghenghesh ks. faculty of medicine, al-fateh university, medical microbiology, tripoli, libyan arab jamahiriya anthrax is an often fatal bacterial infection caused by bacillus anthracis . recent events that began in september 2001 in us has gained the organism worldwide attention and heightened awareness of and concern about anthrax. many cases of anthrax with a number of deaths have been reported as a result of contact with envelopes, sent through postal mail, containing b. anthracis endospores. a number of studies have shown that currency is colonized with bacterial organisms, that include enteropathogens (e.g. shigella sp.), other enteric flora (e.g. escherichia coli ) and potential pathogens (e.g. staphylcoccus sp. , pseudomonas sp. and bacillus sp.). furthermore, methicillin-resistant s. aureus (mrsa) isolates that produced enterotoxin (seb) and toxic shock syndrome toxin-1 also been reported. all of these studies do agree on that currency may be considered as a method of spreading potentially pathogenic and pathogenic bacteria in the community. therefore, currency could also be a vehicle for spreading other highly pathogenic organisms that include b. anthracis . in addition, the introduction of the 'euro' could also allow such bacteria greater freedom to travel across the euro zone. the threat of using currency, particularly paper notes, in spreading lethal organisms should be investigated and proper measures to prevent the use of such a method by terrorists should be implemented. salvage of temporary femoral catheters for haemodialysis using antibiotics in ambulatory patients or2.8 gerasimovska v, oncevski a, dejanov p. department of nephrology, clinical centre, skopje, the former yugoslav republic, macedonia the stay of femoral catheters (fc) for haemodialysis is typically short-term for several days. we used fc as a temporary vascular access (va) for a longer period of time in outpatients going on regular ambulatory haemodialysis, who had a problem with their permanent access. we analysed 43 patients who were discharged from hosptal with fc. duration time of fc was between 13 and 183 days (average 44.2 days) with cummulative total of 1989 days. the incidence of bacteriaemia was 2.51 episodes/1000 catheter days. in six patients we had signs of infection, so according to our protocol we took blood cultures from peripheral vein, and from catheter (at same time) and started with antibiotic therapy (ab) systemically and locally (ab was 'locked' in catheter) with different duration of time. dominant microorganism was staphylococcus coagulasa negative, and much less staphylococcus aureus , and enterococcus.ab that were frequently used were: cefotaxim, vancomycin and ciprofloxacin. at one of six patients we removed catheter at once without trying to save the catheter. catheter tip was sent for microbiological analysis too. criteria for catheter-related bacteriemia (crb) was found in only one patient, and for possible crb in five patients after we removed the catheters. in the absence of clinical signs of infection, ab treatment was not provided for positive tip culture alone or for positive blood culture of the catheter with negative blood culture from peripheral vein. advances in meningitis education or2.9 holt de a , tait mi b , cavanna al b , worgan-brown s a , hart b a . a the meningitis trust, stroud, uk , b the computer-aided learning unit, school of health science, university of wales, swansea, uk background: meningitis remains an important cause of death worldwide despite improvements in diagnosis, treatment and prevention. clinical and lay awareness of the disease relies on education, however educational delivery has changed and the introduction of material suitable for computer and internet application is now necessary. we have developed educational material on cdrom and on the internet applicable both at tertiary university and secondary school level. application: a computer-aided learning program on cdrom, covering all aspects of meningitis has been produced. it is suitable for undergraduate teaching of healthcare professionals from student nurse and doctors to pharmacists. in order to reach school children in a form acceptable to both pupils and teachers, we have developed a curriculum-linked website. these applications are simple to use and can be incorporated into existing courses of study, so that issues raised can be discussed with tutors and group peers. comment: the introduction of new methods of teaching and learning mean that compatible educational material must be produced. we believe that these applications, focusing on meningitis, are the first of their kind and that they offer tutors the opportunity to progress their teaching of the disease both in methodology and content. brivudin compared to famciclovir for improved therapy of herpes zoster: effects on acute disease and postherpetic neuralgia or3. potentially treatment-related adverse events occurred in 11.8% of the brivudin recipients and in 10.1% of the famciclovir recipients (p 0/ 0.26). conclusions: in zoster patients ]/50 years, brivudin 1)/125 mg and famciclovir 3)/250 mg showed equivalent effects on prevalence and duration of phn. brivudin is as effective as famciclovir in stopping viral replication in acute herpes zoster. brivudin offers the advantage of a once daily dosage regimen while being as well tolerated as famciclovir. activity of complexes of pt(ii) and pd(ii) with pyridine-2-carbaldehyde thiosemicarbazone (hfotsc) (acta virol., 2001, 45, 87) with selectivity index (si) 1.5 times higher than that of acyclovir (acv). in order to evaluate virus specific response and structure á/activity relationships we continue our investigations with three pt(ii) and three pd(ii) complexes. the activity was evaluated against sensitive to acv hsv 2 (strain bja) and resistant strains r-100 (hsv 1) and pu (hsv 2) and compared to that obtained against strain victoria (hsv 1) infection. si was indicative for activity. the virus specific response was demonstrated by the fact that viruses sensitive to acv were also sensitive to pt(hfotsc) 2 ]cl 2 , while acv resistant viruses were sensitive to [ptcl(fotsc) ]. the structure á/activity relationship was proved by the fact that the less active against hsv infection was [pd(fotsc)]. influenza diagnosis, treatment, and the impact of new antivirals on current treatment behaviours during influenza outbreaks or3.3 schaetz l a , sessa a b , a hoffman-la roche f. basel, switzerland , b italian college of general practitioners, italy introduction: annual influenza epidemics severely affect individuals, families, health care systems and society. the availability of new and specific antivirals provides an opportunity for better management of influenza. methods: during the 1999/2000 and 2000/2001 influenza seasons, physicians ( â/100/country) and public ( â/1000/country) in the usa and europe were interviewed to determine perceptions of influenza and behaviours for its treatment. results: patients recognise influenza illness as severe and identify it by symptoms of fever, muscle aches/pains and cough. physicians use these symptoms to diagnose influenza clinically (93% fever, 78% muscle aches/pains, 47% cough); their main treatment objective being to reduce complications. antibiotics for influenza treatment are broadly recommended/prescribed by about 30% of european physicians, whereas currently available antivirals are only recommended by 10%. the recommendation of antivirals by us physicians increased from 47% (season 99/00) to 62% (00/01) and markedly decreased antibiotic use (from 25 to 11%). experience from the two influenza seasons shows that influenza antivirals are only used while the virus is circulating and that the volume of use is proportional to the size of the outbreaks. conclusions: experiences in the usa show that with prompt outbreak information antivirals can be used appropriately in times of influenza activity. influenza treatment with oseltamivir: costs and benefits for the individual as well as for society or3.4 objective: to evaluate the effects of treatment of influenza with antivirals (oseltamivir) on health outcomes and costs to patients and society. methods: based on clinical trial data and data from the literature a simulation model has been developed. the underlying clinical pathway covers morbidity and mortality due to influenza and its specified complications. health outcome data and costs were attached to events in the model. the model compares various scenarios, which are defined by treatment schemes within defined populations and other parameters. application of the model is shown using uk unit cost data simulating an otherwise healthy adult population comparing oseltamivir with usual care. results: early treatment results in reduced morbidity, which translates into faster recovery and return to normal activities (1.93 days). lower morbidity and mortality make this a cost-effective intervention from a societal perspective. the analysis covers more than 10 different scenarios and the incremental cost effectiveness ratios will be discussed. conclusion: antiviral treatment appears to be effective in terms of health outcome and cost for otherwise healthy adults from the perspectives of both the individual patient and society. however, this effect is very sensitive to time when treatment is started and the accuracy of the diagnosis of influenza. oseltamivir is well tolerated by all patient groups or3.5 thakar b a , dutkowski r b , froelich e c , gilbride j a , ward p a . a roche global development, welwyn, uk , b f hoffman-la roche, nutley, usa , c f hoffman-la roche, basel, switzerland introduction: oral oseltamivir, the ethyl ester pro-drug of a potent inhibitor of influenza virus neuraminidase, is licensed for the treatment and prophylaxis of influenza in the usa. patients and methods: safety data [adverse events, laboratory safety evaluations] derived from clinical trials involving !/12 000 subjects (including â/1000 children and â/1200 high-risk adults) and 400 healthy volunteers in a large study investigating ecg parameters. spontaneous event reports from medwatch or yellow-card reports following use by â/2 000 000 individuals worldwide. an observational case-control study of !/10 000 subjects with influenza-like illness treated with oseltamivir. results: oseltamivir was well tolerated in clinical trials; drug-related side-effects were limited to transient gi effects occurring in 5/1:10 exposed individuals. these resolved spontaneously and caused drop out in b/1% of treated subjects. no effects on ecg parameters were noted at doses ]/sixfold above the licensed regimen. oseltamivir had no adverse effects on pulmonary function. no additional effects were identified among high-risk adults or children, or following prolonged dosing for prophylaxis. occasional reports of liver dysfunction have been documented post-marketing but causal association has not been established. conclusions: oral oseltamivir is an effective and safe antiviral suitable for influenza management in all patient groups. the decision to stop the vaccination against smallpox and the loss of specific immunity of a high proportion of the population made apocalyptic the perspective of a natural or provoked re-emergence of smallpox. therefore, it is important to improve the current capacities to prevent or to treat the orthopoxvirus infections. uracil dna glycosylase (udg) is one viral enzyme indispensable to the replication of poxviruses. udg of the copenhagen strain of vaccinia virus (vv) was characterized with the aim of defining specific inhibitors susceptible to be used as a new class of active antiviral substances on the viruses of the orthopoxvirus genus. the activity of this enzyme was analysed in real time, in an original method, on a pcr quantitative instrument by digestion of amplified dna revealed by fluorescent intercaled molecules. this technique was used to screen and select several active antiviral substances on udg. moreover, the antiviral activity was estimated by the cytopathic effect of the vv on infected vero cells. the cytotoxicity was determined by inhibition of trypan blue exclusion. the specificity of action of each tested compound was estimated by the selective index (50% cytotoxic dose/50% effective dose). two antiviral compounds were selected for their inhibitory effect on udg activity and on vv replication in vero cell culture : ('/)-5-iodo-2?-deoxyuridine and 4-chlorouracil. these compounds are candidates for the chemotherapy of poxvirus infections. objective: to study the efficacy and tolerance of russian antiviral drugs produced from dna in a limited resources context. results: the drug derinat was produced from salmons' milt. mm of dna was 270 á/500 kda, hyperchrome effect !/37%, protein content b/0.5%. the conjugation of the dna with fe3'/ resulted in a new drug named ferrovir which influences dna and rna synthesis during early stages of hiv-1 replication by blocking the virus's action on cells' metabolism and reduces cytomegalovirus titre in fibroblast cells for 1.5 á/2.0 ig tcid50. a protective effect of ferrovir against fatal herpes encephalitis mice was found. the drugs are not toxic. ic50!/ 4000 mg/ml. ec90 of ferrovir against hiv-1 was 800 mg/ml. in limited clinical trials patients received 75 mg of drugs twice daily (7 á/14 days). administration was well tolerated and no side effects were observed. derinat in 88.1% cases of herpesvirus infection (42 patients) improved the healing and shortened duration of illness. hiv-infected patients (34) treated with ferrovir showed sustained, elevated cd4'/ counts and a significant reduction in hiv-1 viral load (median 1.8 ig). the apparent remission was found in patients with concomitant hiv and herpes virus infection. conclusions: antivirals show good antiviral potency against rnaand dna-viruses; are well tolerated by patients and are useful in case of mixed infections; low price makes them accessible to populations with low financial resources. ortho total hcv core antigen assay can aid early prediction of response in patients treated with interferon/ribavirin or3.8 lunel f a , veillon p b , payan c b . a ahu angers, laboratoire de bacterio-virologie, angers, france , b chu angers, laboratoire de bacterio-virologie, angers, france aim: evaluate the predictive value of total hcv core antigen assay and viral kinetics in patients with chronic hcv. methods: one hundred and twenty two patients infected by genotype 1, 4, 5 or pretreatment viral load (bdna 2.0, chiron) !/3 meq/ml, with no previous treatment, received 6 mu interferon (ifn) during 12 months (m). ribavirin was given with ifn after 3 months therapy, for 9 months in patients with detectable rna. viral load was expressed as log (ui/ml) and hcv ag as log (pg/ml)/10 000). results: pretreatment ag values were correlated with viral load (r 2 0/0.779). we observed a rapid decrease of ag (5.2 log pg/ml) and viral load (5.1 log ui/ml) after m1 in sustained responders (sr). in patients who relapsed (rr) after ifn alone, the fall was less important (2.6 log pg/ml, 3.6 log ui/ml) during m1. in sr and rr to combination therapy, the decrease of ag and viral load at m1 was, respectively, (ag: 1.2 and 1.4 log pg/ml; rna: 2.4 and 1.5 log ui/ml). we did not observed significant variation of ag and viral load in nonresponders. the negative predictive value of hcv rna and ag after m1 of treatment were 100%, and positive predictive values were 81 and 82%. after 1 month of ifn alone, the hcv ag decrease was highly predictive of sr, correlated with rna negativation and early reduction of hcv rna ( !/2 log). conclusion: early measurements of total hcv core antigen are useful to predict long-term response to treatment. lamivudine in the treatment of acute hepatitis b or3.9 vincenti a, meini m, luchi s, de gennaro m, ricciardi l, moneta s, scasso a. infectious diseases department, infectious diseases, lucca, italy acute hepatitis b is a self-limiting infection, but in some cases its course may be particularly severe. we report a case of a 77-years-old woman affected by acute hepatitis b treated with lamivudine. on admission in the hospital the alanino-aminotransferase was1060 u/l, the aspartate-aminotransferase 1017 u/l, bilirubin 10,2 mg/dl, hbsag, hbcigm and hbeag were positive, hbv dna was 300.000 copies/ml. during the following days, the levels of ast and alt gradually rose; on the 14th day prothrombine time was 39%, bilirubin 30 mg/dl and the patient developed signs of encephalopathy. four plasmapheresis were practiced without benefit, so the patient was treated with lamivudine, 100 mg/day. after 24 days of therapy, lamivudine was discontinued because of the appearance of diffuse maculopapular rash. at this time the results of liver function tests were normal; after four months hbsag and hbv dna were no longer detectable. in our patient lamivudine prevented an acute hepatic failure. our experience suggests a promising role of lamivudine in the treatment of acute hepatitis b, but how long such therapy have to be practiced and in which patients? prospective, controlled, clinical studies using lamivudine in patients with acute-hepatitis b are necessary. the cost-effectiveness of amantadine versus symptomatic care in the treatment of influenza or3.10 morris s a , carman wf b , barber j c . a city university, london, uk , b west of scotland specialist virology centre, glasgow, uk , c alliance pharmaceuticals, chippenham, uk aim: to assess the cost-effectiveness of amantadine versus best symptomatic care in the treatment of influenza in the uk. methods: we constructed an economic model populated with parameters from the published literature. the model structure is the same as that used in the economic evaluation of zanamivir published by the national institute for clinical excellence in the uk. we conducted a cost-utility analysis (incremental cost per qaly gained) of amantadine versus best symptomatic care. the analyses are conducted for all adults (average-risk group) and the at-risk population (high-risk group), based on the prevalence of influenza over an average season and when the virus is circulating. the perspective is that of the nhs. results: in the average-risk group the incremental cost per qaly gained of amantadine relative to best symptomatic care is uk£30,488 during an average influenza season and uk£12,538 when the virus is circulating. for high-risk individuals the figures are uk£35,278 and uk£14,526, respectively. the results are sensitive to the hospitalisation rate. conclusions : if the threshold for cost-effectiveness is £20,000 per qaly gained amantadine represents value for money in the treatment of influenza in a variety of scenarios, including the baseline for both average-risk and high-risk groups when the virus is circulating. background: surveillance studies all over the world have revealed an extraordinary increase in the prevalence of penicillin resistant streptococcus pneumoniae . the newer quinolones are believed to have broad activity against s. pneumoniae . methods: a total of 87 penicillin resistant clinical strains isolated from patients at hacettepe children's hospital, ankara, turkey between 1999 and 2001 were tested for their in vitro susceptibility to various antibiotics that are commonly used in the treatment of respiratory tract infections. the minimum inhibitory concentrations (mics) of the penicillin, amoxicillin/clavulanic acid, doxycycline, azithromycin, clarithromycin, ceftriaxone, ciprofloxacin, levofloxacin, moxifloxacin and gemifloxacin were determined using the nccls recommended procedure for e -test. results: the range of mics, mic50 and mic90 values for all agents tested against the strains are shown in the table. gemifloxacin and moxifloxacin had the highest in-vitro activity among the quinolones tested. all strains tested were susceptible to b/0.2 mg/ml gemifloxacin, b/1 mg/ml moxifloxacin and 2 mg/ml levofloxacin. conclusions: there is some degree of resistance to all the drugs except the newer quinolones which were active against all isolates studied. purpose: stenotrophomonas maltophilia prevalence is growing, mainly in some hospital areas. s. maltophilia is frequently multidrug resistant. fluoroquinolone (fq) resistance varies from one to another study, but in whole resistance is moderate to high. gyra and parc qrdr partial codes have been recently described. we have studied correlations between fq-resistance and mutations in these sequences in s. maltophilia clinical strains. material and methods: gyra and parc qrdr regions from six fqresistant and two fq-susceptible s. maltophilia clinical strains were amplified and sequenced. mics of ciprofloxacin (cfx), gatifloxacin (gfx) and clinafloxacin (cnfx) were determined by the agar dilution method, according guidelines defined by nccls for p. aeruginosa . results and conclusions: mics ranges of cfx, gfx and cnfx for resistant strains were 8 á/32, 1 á/32 and 0.5 á/8 mg/l. susceptible strains had mics of cfx, gfx and cnfx of 1, 0.2 and 0.06 á/0.1 mg/l, respectively. most susceptible and resistant strains had no significant mutations in the fragments sequenced. only one resistant strain (mic of cfx 16 mg/l) and one susceptible strain (mic of cfx1 mg/l) had a significant gyra mutation, the same in both strains (ile112 á/val). thus, fq resistance in s. maltophilia shall derive from changes in other areas in the topoisomerases or probably from other mechanisms of resistance, such as efflux pumps. purpose: corynebacterium urealyticum is the cause of encrusted cystitis and other inespecific utis and systemic infections. it is frequently multi-drug resistant, with a high rate of resistance to fluoroquinolones (fq). the mechanisms of resistance to fqs have not been described in c. urealyticum . we describe the c. urealyticum parc gene qrdr region and its relationship with quinolone resistance. materials and methods: the activity of ciprofloxacin (cfx), levofloxacin (lfx), gatifloxacin (gfx), clinafloxacin (cnfx) and moxifloxacin (mfx) against 30 c. urealyticum clinical strains was determined following nccls guidelines for enterococci. we amplified and sequenced their parc qrdr by standard methods. results and conclusions: five strains (16.6%) were cfx-susceptible (mic 0.1 á/0.5 mg/l), 5 had mics 1 á/2 mg/l and 20 (66.7%) were highlevel cfx-resistant (mic 32 á/128 mg/l). cnfx was 64-fold more active than cfx. mfx and gfx had mics90 of 4 and 8 mg/l. all the strains, including the type strain, showed a c to t change at the 2614 position referred to wild type s. aureus parc gene, leading to a ser-80-phe change, described as the main parc change in fq-resistant s. aureus . this finding suggest that this mutant sequence, as compared with parc sequences from other grampositives, might be the wild-type for this species, and might explain in part its high resistance rate, and its apparent lightness to develop high-level resistance. purpose: during routine surveillance, we identified 32 ciprofloxacinresistant (mic!/8 mg/l) pneumococcal isolates and compared clinical details and resistance patterns. results: they were isolated from sputa (29) and blood cultures (3) from adults, most with heart or lung disease. hospital admissions were common; half had been inpatients in the previous 3 months. nineteen patients received quinolones in the preceding 3 months, in part reflecting the local policy (introduced in 1997) of penicillin and ofloxacin for first line treatment of pneumonia. thirteen patients had radiological signs of pneumonia and 10 were pyrexial with raised inflammatory markers. agar dilution mics for quinolones, including norfloxacin with and without reserpine, penicillin and erythromycin were performed. an increase in norfloxacin mics was noted over the period 1997 (16 á/64 mg/l) to 2001 (256 mg/l). fluoroquinolone efflux was suggested in three isolates. resistance to moxifloxacin (mic 8 á/16 mg/l) was noted from 1998 onwards. all isolates were serotype 9v and resistant to penicillin (mic!/0.5 mg/l). thirty-one were resistant to erythromycin (mic!/1 mg/l). conclusion: the 1997 policy of using quinolones may have contributed to the development of quinolone resistance and this cluster of isolates. the increasing levels of quinolone resistance observed raise concerns about the future use of newer quinolones for the treatment of respiratory infections. s. maltophilia has emerged in the last years as an important nosocomial pathogen, inherently resistant to most of the antimicrobial agents. new quinolones has been proposed as a treatment of choice because their enhanced activity, but several parameters (t a , atmosphere, method) can affect the results of mics. methods: we have performed mics using two different methods (agar dilution and microdilution) and different conditions: 35 and 30 8c of temperature; atmosphere of o 2 and co 2 , and incubation times of 18, 24 and 48 h. a total of 78 strains were assayed with nine quinolones following standard nccls. comparisons were made between results with 18 á/24 and 24 á/48 h using the x 2 -test (a 0/0.05). results: no differences were found between 18 á/24 and 24 á/48 h results with agar dilution, except with 3 atbs in the case of mics at 30 8c co 2 . on the contrary, almost all the atbs showed significant differences in the results with 24 and 48 h using microdilution method, at any condition of ta or atmosphere. comparison of mics (p values, significance level 0/95%) with incubation times of 24 and 48 h at different procedure conditions. the incubation time is a parameter that seems to affect significantly the results of mics of quinolones when microdilution method is used, whereas only few differences can be encountered with the agar dilution method. results: breakpoints were used as proposed by nccls 1999. during the study period the pneumococci resistance was noted as follows: 65% to pc, 39% to em and 73% to sxt. the rank order of activity of the five fqs against multi-drug resistant pneumococci was: cip (mic 90:2 mg/l), ofx (mic 90:2 mg/l), lvx (mic 90:1 mg/l), grx (mic 90:0.25 mg/l), tvx (mic 90:0.25 mg/l). conclusions: in romania, fluoroquinolones represent alternative treatment to beta-lactams and macrolides for first-line empirical treatment for respiratory tract infections caused by pneumococci but, continued vigilance for emerging resistance to fqs is further indicated. introduction and material/methods: susceptibility testing (semiautomated broth microdilution method, sensititre, trek diagnostics, usa, following nccls recommendations) was performed with six different quinolones to 817 streptococcus pneumoniae isolates with a ciprofloxacin-cip */mic ]/2 mg/l collected in two consecutive sauce$ surveillances in spain (1996 á/97/1998 á/99). nccls resistance (r) breakpoints were used ( ]/8 for ofloxacin-ofl and levofloxacin-lev; ]/2 for sparfloxacin-spa; ]/4 for gatifloxacin-gat */and moxifloxacin-mox), but for gemifloxacin-gem */where ]/1 was used. results were as follows. conclusions: for cip-r isolates gem and mox were the most active agents. gem was the only agent not influenced by cip mic increase regarding prevalence of r , with 0% resistance for strains with cip mic ]/8 mg/l. $sauce is an acronym standing for 'sensibilidad a los antimicrobianos utilizados en la comunidad en españ a' (susceptibility to the antimicrobials commonly used in the community in spain) and is the spanish word for the willow tree. in vitro activity of gatifloxacin and seven other antibiotics against respiratory and urinary tract pathogens from the community. first results of the basic */study ps110 grimm h, on behalf of a european multicenter study group, institute for med. microbiology, 88250 weingarten, germany a total of 24 centers in austria, belgium, france, germany, italy, portugal, spain and switzerland are involved in the basic study (bacterial annual susceptibility information collection). the mics of gatifloxacin (gati), ciprofloxacin (cipro), clarithromycin (clari), benzylpenicillin g (pen), amoxicillin (amox), amoxicillin/clavulanic acid (augm), cefuroxime (cur) and cefixime (cix) were determined using the microdilution method. each center is requested to investigate 30 strains each of the following species: s. pneumoniae (spn), s. pyogenes (spy), s. aureus (sau), e. faecalis (efa), m. catarrhalis (mca), h. influenzae (hin), e. coli (eco), k. pneumoniae (kpn), p. mirabilis (pmi) and p. aeruginosa (pae). so far approximately 1400 strains are enrolled. some important mic90%/percentage resistance were as follows: from the oral antibiotics tested gatifloxacin has the highest activity and broadest spectrum against all relevant respiratory and urinary tract pathogens. gatifloxacin is a promising alternative for therapy of respiratory tract bacterial infections. in vitro activity of gatifloxacin against bordetella pertussis in comparison with erythromycin, ciprofloxacin and levofloxacin ps111 bourgeois n, pangon b, ghnassia jc, doucet-populaire f, de versailles ch. microbiologie, le chesnay, france purpose of the study: bordetella pertussis infections are far more common in adults and adolescents than is generally estimated. however, they are often not recognised. infected or colonised adults can act as a reservoir of infection, passing it to children. fluoroquinolones are currently recommended for the treatment of respiratory tract infection in adult patients, which is usually empirical. gatifloxacin is a novel 8-methoxyquinolone, with a potent activity against both gram-negative and -positive bacteria. the in vitro activity of gatifloxacin was compared with those of erythromycin, the drug of choice for both treatment and prophylaxis of pertussis, ciprofloxacin and levofloxacin, against 52 clinical isolates strains of b. pertussis including 12 erythromycin resistant strains. results: we used the agar dilution method on mueller á/hinton medium supplemented with 10% horse blood to determine the mic of each antibiotic. gatifloxacin (mic90, 0.125mg/l) was as active as ciprofloxacin and levofloxacin (mic90, 0.06mg/l) against both sensitive erythromycin (mic90, 0.015 mg/l) and resistant erythromycin (mic90, !/512 mg/l) strains. conclusion: gatifloxacin may be an effective drug in the treatment or prophylaxis of adults with suspected or confirmed pertussis. ex vivo serum activity (killing rates) after gemifloxacin 320 mg versus trovafloxacin 200 mg single doses against ciprofloxacin-susceptible andresistant streptococcus pneumoniae ps112 calvo a a , giménez mj b , alou l a , gó mez-lus ml a , aguilar l b , prieto j a . a microbiology department, universidad complutense, madrid, spain , b glaxosmithkline, medical department, tres cantos, madrid, spain serum bactericidal activity was measured ex vivo after single dose administration of gemifloxacin (gem) 320 mg and trovafloxacin (tro) 200 mg to 12 healthy volunteers in a randomized, cross-over phase i trial. blood samples were collected 1 h (cmax) after dosing and serum killing rates were determined against a serotype 3 penicillin (pen) á/ciprofloxacin (cip) susceptible strain (s3) (mics of 0.03, 1, 0.015 and 0.06 mg/l for pen, cip, gem and tro) and a serotype 9 pen á/cip resistant strain (s9) (mics of 2, 4, 0.03 and 0.25 mg/l for pen, cip, gem and tro). tubes with 1.6 ml of serum sample and 0.4 ml broth (50% todd á/hewitt'/50% hbss) were incubated over 3 h at 35 8c. final inocula was 10 7 cfu/ml. mean colony counts for samples and controls (k ) are shown in the figure: gem exhibited higher colony counting decrease of the initial inocula, versus tro, for both strains. after 3 h incubation, the initial inocula decrease obtained with tro and the cip susceptible strain was similar to that obtained with gem and the resistant strain, showing a lower influence of cip mic increase in the ex vivo bactericidal activity of gem versus tro. urine bactericidal activity after administration of gemifloxacin and trovafloxacin single doses in a phase i study ps113 garcía-calvo g a , parra a a , giménez mj b , ponte c a , aguilar l b , soriano f a . a fundación jiménez díaz, medical microbiology, madrid, spain , b glaxosmithkline, medical, madrid, spain urine bactericidal activity after o.d. administration of gemifloxacin (gem) 320 mg and trovafloxacin (tro) 200 mg, was assessed in six adult males in a cross-over phase i trial. urine killing rates (ukr) against escherichia coli atcc 25922 (mic mg/l of 0.008 and 0.015 for gem and tro) and s. saprophyticus atcc 1970 (mic mg/l 0.015 and 0.06 for gem and tro) were performed with samples collected at 0, 2 á/4, 16 á/24 and 60 á/72 h. a 1.6 ml of iso-sensitest broth and 0.4 ml of bacterial logarithmic growth were added to 2 ml sample, giving a final inoculum of 107 cfu/ml. colony counting was performed after 1, 2, 3 and 4 h incubation. percentages of initial inocula reduction (iir) were calculated. mean urine concentrations measured by bioassay were (mg/l): 28.4, 14.7 and 0.5 for gem, and 3.6, 3.0 and 0.1 for tro. against e. coli , an iir of 99.9% was obtained after 2 h incubation with all samples except with tro at 60 á/72 h. against s. saprophyticus an iir of 90% was obtained after 3 h incubation with all samples except with tro at 60 á/72 h, where bacterial regrowth was found. the maintenance over 72 h of gem urine antibacterial activity suggests its efficacy in the treatment of uncomplicated cystitis. influence of the decreased susceptibility to ciprofloxacin on gemifloxacin versus levofloxacin efficacy in experimental pneumococcal pneumonia in guinea pigs ps114 garcia-olmos m a , parra a a , gimenez mj b , garcia-calvo g a , ponte c a , aguilar l b , soriano f a . a fundacion jimenez diaz, medical microbiology, madrid, spain , b glaxosmithkline, medical, madrid, spain the efficacy of ciprofloxacin (cip), levofloxacin (lev) and gemifloxacin (gem) in the treatment of pneumococcal pneumonia was assessed in a guinea pig model using three strains (s) with mics (mg/l) of 2, 2 and 0.03 (s1), 32, 4 and 0.25 (s2) and 64, 32 and 1 (s3) for cip, lev and gem, respectively. intraperitoneal treatments started 1 h after s. pneumoniae intratracheal inoculation, and continued t.i.d up to four doses. ten animals were included in each group. doses (mg/kg) used were 20, 16 and 6 for cip, lev and gem, respectively, in order to mimic auc0-24 h and cmax obtained in humans after standard doses. animals that survived 48 h after inoculation were sacrificed and colony counts were performed in lungs ( the purpose of the study levofloxacin (lfx) is a fluoroquinolone whose activity against both gram-negative bacilli and gram-positive cocci enables its use in monotherapy for the treatment of nosocomial pneumonia. our aim was to study the pharmacokinetic á/pharmacodynamic appropriateness of lfx 500mg iv bid in the treatment of six inpatients with ventilator-associated pneumonia (vap) (459/25 years; 4m á/2f; 749/9 kg). blood and urine samples were collected in steadystate conditions at appropriate intervals. lfx concentrations were analysed by hplc. the aetiological agent was identified in all the cases and its in vitro sensitivity to lfx was always assessed. the results obtained mean values (9/sd) of the major pharmacokinetic parameters were: cmax, 8.789/2.05 mg/ml; vdss, 1.259/0.36 l/kg; t1/2b, 4.699/0.87 h; cl, 3.659/1.01 ml/min/kg; auc0-t, 32.479/12.80 mg/ml h. cumulative urinary excretion was 82.899/10.23%, confirming that lfx clearance is mainly renal. clinical cure and microbiological eradication were obtained in all the patients after a 7 á/13 day therapy. a suprainfection due to acinetobacter anitratus insensitive to lfx occured in 1 case. the major pharmacodynamic parameters of fluoroquinolone efficacy were significantly higher than the proposed threshold (cmax/mic !/10; auc/mic !/125) in all the cases. the conclusion reached the findings suggest that lfx 500 mg bid iv may be considered effective in the treatment of vap caused by sensitive bacteria. comparative pharmacokinetics of levofloxacin in patients with lower respiratory tract infections (lrti) being treated with sequential therapy ps116 pea f a , brollo l a , lugatti e b , di qual e a , dolcet f b , talmassons g b , furlanut m a . a institute of clinical pharmacology and toxicology, dpmsc, university of udine, udine, italy , b division of pneumology, sm misericordia hospital, udine, italy the purpose of the study levofloxacin (lfx) is a fluoroquinolone whose activity against both gram-negative bacilli and gram-positive cocci enables its use in monotherapy for the treatment of lrti. our aim was to study the pharmacokinetic á/pharmacodynamic appropriateness of a standard switch lfx iv/os regimen (500 mg iv od for 5 á/7 days followed by 500 mg os od for 4 á/10 days) in the treatment of seven inpatients with lrti (709/17 years; 6m á/1f; 769/15 kg). blood samples were collected in steady-state conditions at appropriate intervals. lfx plasma concentrations were analysed by hplc. the aetiological agent was identified in 2/7 cases and its in vitro sensitivity to lfx was assessed. the results obtained absolute oral bioavailability was 1.079/0.19, with a cmax of 10.899/3.39 vs 8.369/3.90 mg/ml after iv and oral administration, respectively. no significant difference in the main pharmacokinetic parameters was observed between the two routes. the major pharmacodynamic parameters of fluoroquinolone efficacy were significantly higher than the proposed threshold (cmax/mic !/10; auc/mic !/125) in the two assessable cases. all the patients were clinically cured after a 9 á/15 day therapy. the conclusion reached the ad interim findings show that lfx 500 mg od may guarantee per os an exposure similar to that achievable after iv administration, suggesting that sequential therapy may be considered effective in the treatment of lrti. levofloxacine in the exacerbations of copd due to pseudomonas ae ps117 micheletto c, tognella s, pomari c, dal negro r, ospedale orlandi, div.pneumologia, bussolengo, italy development of antibiotic resistance in bacteria is a problem of great concern. gram-negative bacteria, including multidrug-resistant (mdr) pseudomonas aeruginosa (ps), are responsible for a significant proportion of episodes of copd exacerbations, particularly in elderly (1). aim was to check the susceptibility to common antimicrobial treatments against ps strains isolated from bronchial secretions in patients with severe exacerbations of copd. methods: microbial investigations were conducted on 290 specimens: spontaneous purulent sputum (88.4%), and tracheobronchial aspirates (11.6%, collected with a protected specimen brush). results: fifty-seven ps pathogen strains (106 cfu) were identified (19.6%) and tested over a 6-month period: ps. aeruginosa 91.2%; ps. putida 3.5%; ps. fluorescens 3.5%, and burkholderia cepacia 1.8%. the assessed susceptibility to most common antibiotics was: levofloxacine (90%), ciprofloxacine (84%), ipenem cil. (88%), ceftazidime (84%); amikacin (84%), and piperacillin'/tazobactam (74%). a much lower susceptibility was found for ticarcillin á/clavulanic acid (58%), gentamicin (48%), and netilmicin (40%). (1) at present, levofloxacine proves the most effective antimicrobic option for treating copd exacerbations due to ps infection; (2) a much more efficient policy of antibiotic prescribing should be promoted in order to prevent the selection of resistant strains in these cases. these results confirm the excellent 'in vitro' activity of levofloxacin against nosocomial gram-negative pathogens, including the esbl producing strains (90% of escherichia coli , e. cloacae and k. pneumoniae were inhibited at 0.5 mg/l). levofloxacin was more rapid than ciprofloxacin to determine a bactericidal effect particularly against s. maltophilia . moreover, considering the favourable pk/pd profile, levofloxacin can represent a valid therapeutic option for the treatment of severe gram-negative nosocomial infections. moretti f, quiros-roldan e, casari s, chiodera a, viale p, carosi g. university of brescia, institute of infectious and tropical diseases, brescia, italy a 34-year-old man, ivdu, hiv positive was attended in aur hospital for fever and toracic pain. a x-chest radiography revealed a round lesion of 5 cm near the lingula with central hyper-diaphan area. lymphocytes cd4'/ count was 21 cells/mm 3 and viral load 91.900 cp/ ml. hospital stay rhodococcus equi was found in cultures of peripheral blood, faecal and sputum specimens. antibiotic treatment with oral rifampin (600 mg/qd) and with intravenous imipenem (500 mg tid) was started. due to the persisting fever, immodificated radiography and negativity for p. carinii , mycobacteria and bacteria in bal coltures, imipenem was substituted by parenteral vancomycin (400 mg bid). after 10 days, because of persisting fever and increase of the diameter of the lung lesion (6 cm) vancomycin was sustituted by oral levofloxacyn (500 mg bid), continuing rifampin. after a 4 days course of levofloxacyn therapy the fever remitted. the patient was discharged with levofloxacyn (500 mg bid) and rifampin and, after 2 months of follow-up, a radiological control pointed-out a remarkable resolution in the lung lesion. we may suppose that levofloxacyn can be effective for the treatment of r. equi infection, even if more studies (particularly controlled studies) are necessary. liberti a a , izzo b a , loiacono l b , calabria g a , patarino t a , izzo e a . a ii department, naples, d. cotugno hospital, italy , b iii department, naples, d. cotugno hospital, italy the increasing prevalence of salmonella typhi strains with reduced susceptibility of chloramphenicol had prompted the search for other antibiotics with the same efficacy.quinolones are a class of antibiotic with an activity in vitro and in vivo against enteropathogenes. we inwestigated the use of levoxacin in two regimens of treatment of typhoid and paratyphoid infection. patients and methods: thirty-two adult patients were incluted in this study from september 1999 to april 2001; 26 patients had positive culture for s. typhi and six had positive cultures for s. paratyphi . all isolated were fully susceptible to levoxacin. we compared treatment with levoxacin for 7 days, 500 mgr b.i.d. (group 1, 16 patients), with treatment for 10 days, 500 mgr b.i.d. (group 2, 16 patients). clinical cure was defined as defervescenze of fever by day 3 of treatment, with an absence of complications and no clinical relapse during the followup. results and conclusion: the clinical cure rate was 87% (14 patients) for group 1 and 94% (15 patients) for group 2; the difference in these rates was not statistically significant. the blood cultures of all patients were sterile by day 2 of treatment and remained so until the 6th month of follow-up, no subjects had clinical or microbiological relapse and all stool cultures remained negative, also. the two regimens of treatment was good tollerated and no adverse event was registered; it was concluded that levoxacin treatment for 10 days in enteric fever is not necessary the mulidrug-resistence of s. typhi led to the use of quinolones as the first-line drug in the treatment of enteric fever. pefloxacin in the treatment of patient with acute infectious diarrhoea ps121 troselj-vukiae tvb a , strahinja v b , poljak i a , stojanoviae d c , nikoliae n d . a department of infectious disease, university hospital center, rijeka, croatia , b glaxosmithkline, marketing, rijeka, croatia , c dept. rijeka, institute of public health, rijeka, croatia , d dept. rijeka, maritime academy, rijeka, croatia the purpose of the study was to investigate clinical and bacteriological efficiency in 5 and 7 days pefloxacin treatment and to compare it with symptomatic therapy. the results obtained in 47 patients treated with pefloxacin the therapy was clinically effective already in the third day while in the control group this happend in the 7th day. bacteriological eradication was noted in 18 patients (95%) of the first and 25 patients (93%) of second group in the 5th days of the treatment. they all had negative cultures 1 and 4 weeks after pefloxacin protocols were completed. only 22 patients (63%) in control group had negative stool cultures in the 7th day of the treatment and all of them 4 weeks after it ended. there was no statistically significant difference in clinical (p 0/0.232) and bacteriological (p 0/0.972) efficiency between 5 and 7 days pefloxacin treatment protocols. both protocols significantly differed in clinical (p b/0.001) and bacteriological (p0/0.017) eradication from the control group. the conclusion reached is that the efficiency of pefloxacin (quinolones) in the treatment of acute infectiuos diarrhoea and justifies their use in the more severe forms of the disease. dalhoff a a , ullmann u b , schubert s b . a bayer ag, wuppertal, germany , b university of kiel, institute of med. microbiology, kiel, germany background: the antibacterial activity of moxifloxacin (mxf) was compared to levofloxacin (lev), amoxicillin (amx), clarithromycin (cla) and erythromycin (ery) in an in vitro model. method: pharmacokinetics in bronchial mucosa (bm) and serum (s) following single oral doses of 400 mg mxf or cla and 500 mg lev, amx or ery were simulated using a one compartment model. bacteria tested staphylococcus aureus (nos. 133, 25895), streptococcus pneumoniae (nos. 4241, 672). aliquots were taken (0 á/8 h) and plated on to brain heart infusion agar for enumeration. results: s. pneumoniae 4241 was eliminated by all agents studied. significant differences were apparent with s. pneumoniae 672 and the s. aureus strains: objective: to compare the safety and efficacy of once-daily moxifloxacin with once-daily ceftriaxone in the treatment of cap in hiv-infected patients (pts). methods and results: in a retrospective survey, oral moxifloxacin (400 mg daily)/12 á/15 days) was compared to standard regimen of i.v. ceftriaxone (2 g daily)/10 á/12 days) for treatment of cap in hiv'/ pts. adults pts with clinical signs and symptoms of cap and consistent chest x-ray findings were included. pts had a median age of 39 years (range 29 á/529 and 70% were male). demographic characteristics were similar in both treatment groups; 15 pts received mxifloxacin and 25 pts ceftriaxone. clinical success rates were 94% for moxifloxacin and 96% for ceftriaxone. at a post-study evaluation approximately 8 weeks later, 2 moxifloxacin-treated pts and 3 ceftriaxone-treated pts had relapsed. the adverse events reported were comparable for both treatment groups. there were four-related adverse events (3 gi, 1 headache) for moxifloxacin-treated and 7 (4gi, 3 skin) for ceftriaxonetreated pts. conclusion: the results of this study show that moxifloxacin as oral therapy is as effective and well tolerated as i.v. ceftriaxone in the treatment of hiv'/ pts with cap. therapy with moxifloxacin was not associated with any significant clinical or laboratory abnormalities. these data suggest that once-daily oral administration of moxifloxacin is potentially convenient and cost-effective alternative therapy for cap in pts with hiv infection. moxifloxacin in the treatment of acute maxillary sinusitis after first-line therapy failure or acute sinusitis with high risk of complications ps124 gehanno p a , berche p b , perrin a b , arvis p c . a ent department, bichat claude bernard hospital, paris, france , b microbiology department, necker enfants malades hospital, paris, france , c bayer pharma, medical affairs department, paris, france the efficacy and safety of moxifloxacin (mxf) 400 mg once daily for 7 days was evaluated in the treatment of acute maxillary sinusitis after first-line therapy failure, or acute sinusitis with high risk of complications. in this prospective, multicenter study, a total of 216 patients with acute bacterial sinusitis confirmed by sinus x-ray were valid for efficacy analysis: one hundred and seventy five patients (81.0%) had an acute maxillary sinusitis which failed to respond to a previous antibiotic therapy given for a mean duration of 7.2 days, and 41 (19.0%) had an acute sinusitis with high risk of complications (frontal: 24, pan-sinusitis: 15 and sphenoid: 2). ninety two patients (42.6%) were microbiologically valid. clinical cure and continued clinical cure rates at 7 á/10 and 28 á/35 days post-therapy were 92.6 and 99.0%, respectively. clinical cure rates at 7 á/10 days post-therapy were 94.9 and 82.9% in sinusitis after first-line therapy failure and in sinusitis with high risk of complications, respectively. bacteriological eradication rate during therapy (day 3 á/4) was 95.7%. at 7 á/10 days post-therapy. bacteriological success rates were 97.1% in patients who failed to respond to a previous antibiotic and 95.4% of patients who had sinusitis with high risk of complications. 12.2% of patients experienced drug-related adverse events, abdominal pain (2.4%), nausea (2.4%) being the most frequently reported events. mxf was rapidly effective and a well-tolerated treatment for this kind of infection. neisseria gonorrhoeae with decreased susceptibility to penicillin and ciprofloxacin: novel mutation patterns in the gyr a and par c genes of ciprofloxacin resistant isolates and plasmid profile of penicillin resistant isolates of n. gonorrhoeae in india (delhi) ps125 chaudhry u, saluja d. dr. b. r. ambedkar center for biomedical research, university of delhi, delhi, india commercial sex workers (csws) serve as the most important reservoir of gonorrhoea. periodic monitoring of the antimicrobial susceptibility profile of neisseria gonorrhoeae in a high-risk population provides essential clues regarding the rapidly changing pattern of antimicrobial susceptibilities. in india, such a surveillance of the in vitro antimicrobial susceptibility of n. gonorrhoeae was established in 1997. significant increasing trend of penicillin and ciprofloxacin resistance with high mic of 2 á/16 and 1 á/32 mg/ml, respectively were found over the years (1997 á/2001) . the molecular basis of ciprofloxacin resistance, i.e. mutations in the gyr a and the par c genes of 170 isolates, were analyzed. four isolates (with an mic of 32 mg/ml for ciprofloxacin) harbored triple mutations (ser-91 to phe, asp-95 to asn and val-120 to leu) in the gyr a gene. the third mutation of val-120 to leu, lies downstream of the quinolone resistance determining region of the gyr a and has not been described before in gonococcus. in addition, these isolates had a phe-100 to tyr substitution in the par c, a hitherto unknown mutation. the alterations in the par c gene were seen in these isolates only in the presence of changes in the gyr a gene and comprised amino acid changes at codons 91, 100, 104, 109, and 131. the presence of b-lactamase plasmid among the penicillinresistant isolates was determined by their plasmid profiles and further confirmation was carried out by a pcr based protocol. our findings suggest that emergence of penicillin and ciprofloxacin resistance in n. gonorrhoeae isolates from a major std center in india, indicates the need for the increased awareness and prudent use of antimicrobials. in vitro activity of newer antibiotics against methicillin-resistant staphylococcus aureus ps126 gutierrez zufiaurre mn, sanchez hernandez j, munoz-bellido jl, garcia-rodriguez ja. hospital universitario de salamanca, microbiología, salamanca, spain purpose: mrsa are frequently co-resistant to a number of structurally unrelated antibiotics. more than 70% mrsa are resistant to gentamycin, ciprofloxacin, macrolides and clindamycin. newer antibiotics active against multi-drug resistant grampositives have been developed. we have tested the in vitro activity of newer antibiotics against genetically-characterized, high level ciprofloxacin resistant mrsa. material and methods: thirty-six ciprofloxacin-resistant, gyra/grla mutant mrsa clinical strains were tested against levofloxacin (lfx), ciprofloxacin (cfx), moxifloxacin (mfx), gatifloxacin (gfx), erythromycin (er), telithromycin (tl), linezolid (lin), synercid (syn) and vancomycin (va). mics were determined by the agar dilution method, according nccls guidelines. results and conclusions: all the strains were resistant to cfx, 55,5% were lfx-susceptible and 63.9% were gfx-susceptible. nevertheless, mics of lfx and gfx for all susceptible strains was in the highest extreme of the susceptibility range. mfx was the most active quinolone. almost all the strains were high-level er-resistant with constitutive mlsb phenotype. tl did not improve significantly its behaviour, although it was 10-fold as active as er against the only er-susceptible strain. va, lin and syn had excellent activity against all the strains. they showed a very homogeneous behaviour against all the strains that were included in a range of 1 á/4 mg/l of lin and va and 0.5 á/1 mg/l. sanchez hernandez j, gutierrez zufiaurre mn, munoz-bellido jl, garcia-rodriguez ja. hospital universitario de salamanca, microbiología, salamanca, spain purpose: corynebacterium urealyticum is the etiologic agent of encrusted cystitis and inespecific utis, and can be also involved in systemic infections. c. urealyticum is frequently multi-drug resistant, so only glycopeptide antibiotics and tetracyclines have high susceptibility rates, while fluoroquinolones resistance rates vary significantly. we have tested the in vitro activity of linezolid, telithromycin, synercid and newer fluoroquinolones against multi-drug resistant c. urealyticum clinical strains. material and methods: sixty-four c. urealyticum clinical strains were tested against levofloxacin (lfx), ciprofloxacin (cfx), moxifloxacin (mfx), erythromycin (er), telithromycin (tl), linezolid (lin), synercid (syn) and vancomycin (va). mics were determined by the agar dilution method according guidelines defined by the nccls for enterococci. results and conclusions: results confirm the high resistance rate to older fluoroquinolones and macrolides, with !/50% cfx resistance and 100% er-resistance. lfx was more active (mic90 32 mg/ml). mfx was the most active fluoroquinolones (mic90 4 mg/ml). tl improve its behaviour in respect to er (range 0.5 á/1 mg/ml). va, lin and syn had excellent antimicrobial activity. no resistant strains were found. mic90 were 1, 0.5 and 1 mg/ml, respectively. mics were similar for all the strains independently of their resistance to other antibiotics plasma concentrations, urinary excretion and bactericidal activity of linezolid (600 mg) versus ciprofloxacin (500 mg) in healthy volunteers after a single oral dose ps128 wagenlehner fme a , wydra s a , onda h a , kinzig-schippers m b , sö rgel f b , naber kg a . a hospital st. elisabeth, urologic clinic, straubing, germany , b institute for biomedical and pharmaceutical research, (ibmp), nürnberg-heroldsberg, germany purpose of the study: in a randomized cross-over study 12 volunteers received a single oral dose of 600 mg linezolid versus 500 mg ciprofloxacin to assess plasma concentrations (up to 24 h), urinary excretion (by hplc), and urinary bactericidal titers (ubt) up to 120 h. the mean maximum plasma concentration of linezolid was 12.1 mg/ ml and of ciprofloxacin 2.4 mg/ml. the cumulative renal excretion (mean) of parent drug was 40%/41% for linezolid/ciprofloxacin. ubts were determined for a reference strain and five gram-positive clinical uropathogens with the following mics (mg/ml) for linezolid/ciprofloxacin: s. aureus atcc 27278 (4/0.25), s. aureus (mssa) (2/32), s. aureus (mrsa) (2/128), s. saprophyticus (msse) (2/0.5), e. faecalis (2/1), e. faecium (2/2). results: median ubts measured within the first 6 h for linezolid were 1:96 for enterococcal strains and 1:128 to 1:256 for the four staphylococal strains. median ubts for ciprofloxacin were 1:64 for the two enterococcal strains, 1:384 to 1:512 for the two ciprofloxacin susceptible, 1:1.5 for the two resistant staphylococcal strains. areas under the ubt á/time-curve showed statistically significant differences only for the two ciprofloxacin resistant staphylococcal strains in favour of linezolid. conclusion: linezolid exhibited the same bactericidal activity against ciprofloxacin resistant as susceptible strains. linezolid should be tested for treatment of complicated uti due to gram-positive uropathogens in a clinical trial. whitehouse t a , cepeda ja a , tobin purpose: we performed pharmacokinetics within a double-blind, randomised trial comparing linezolid and teicoplanin in intensive care patients with known or suspected gram-positive infection. they received either 600 mg linezolid intravenously 12-hourly, or 400 mg teicoplanin 12-hourly for the first three doses and once daily thereafter (or every 3rd day if renally impaired). blood samples were collected to create serum pharmacokinetic profiles. linezolid was quantitated by hplc and teicoplanin by fluorescence polarization immunoassay. results: twenty two patients were studied in the linezolid group (m á/f 13:9, mean age 54 years [range 19 á/90 years]). median treatment duration was 8.5 days (range 4 á/18). eighteen patients were treated with teicoplanin (m á/f 13:5, mean age 57 years [range 17 á/86]) for median 9 days (range 4 á/17). steady state peak concentrations (mean9/ sd) for linezolid and teicoplanin were 12.89/5.0 and 10.59/4.7 mg/l, respectively. trough concentrations at day 4 were 4.79/4.3 mg/l for linezolid and 7.99/2.5 mg/l for teicoplanin. recommended breakpoints of staphylococcus aureus are 4 mg/l for linezolid and 8 mg/l for teicoplanin. accumulation occurred in one 90-year-old linezolidtreated patient with impaired renal function. conclusion: current recommended dosing regimens for linezolid and teicoplanin are generally appropriate in the critically ill, though a more detailed analysis is required. stamos g, lebessi e, ioannidou s, paleologou n, kallergi k, foustoukou m, 'p. and a. kyriakou ' children's hospital, microbiology, athens, greece the purpose of the study was to investigate the susceptibility of methicillin resistant staphylococcus aureus (mrsa) isolates from a 500-bed paediatric hospital to quinupristin/dalfopristin (q/d, streptogramin combination) and linezolid (lzd, oxazolidinone). material: we performed a retrospective analysis of 85 mrsa strains, isolated from patients hospitalized in miscellaneous medical departments [neonatal unit (35) , surgical wards (15), orthopaedic wards (9), oncology unit (7), other wards (8) and outpatient clinic (11)], during a 3-year period (1998 á/2000) . the sources of isolation were pus (23), throat (22), nasal (8), bronchial (5), skin (6), stool (6) ear (4) and other (11) specimens. all isolates were sensitive to glycopeptides, while 22.4% were resistant to gentamicin and 7.1% to erythromycin. methods: the sensitivity testing was performed by a disk diffusion method (bbl sensitivity disks, becton dickinson), according to nccls guidelines. the breakpoint zone diameters for lzd and q/ d were ]/21 and ]/19 mm for susceptibility and 5/17 and 5/15 mm for resistance, respectively. results: all isolates were proved to be susceptible to both antibiotics. the mean inhibition zones were 29.1 mm for lzd and 26 mm for q/d. conclusions: lzd and q/d are very promising antimicrobial agents, showing excellent activity against mrsa clinical isolates. the prudent therapeutic use is strongly recommended to avoid the emergence of resistance. in vitro activity of streptogramins and oxazolidinones against streptococcus pneumoniae clinical isolates ps131 stamos g, lebessi e, paleologou n, psatha m, sanida p, zaphiropoulou a, foustoukou m, 'p. and a. kyriakou ' children's hospital, microbiology, athens, greece the purpose of this study was to evaluate the in vitro activity of linezolid (lzd), a member of oxazolidinones and the streptogramin combination quinupristin/dalfopristin (q/d) against clinical isolates of streptococcus pneumoniae from a tertiary care paediatric hospital. material: a total of 53 pneumococcal isolates exhibiting reduced susceptibility to common antibiotics were included in the study. the strains were isolated from middle ear fluid (34), eye (4), nasal (5) blood (6) and other (4) cultures during the last 4 years. the percentages of the isolates that were resistant to penicillin, erythromycin, cotrimoxazole and clindamycin were 67.9, 67.9, 67.9 and 26.4%, respectively. methods: the susceptibility testing was performed by a standard disk diffusion method (bbl sensitivity disks, becton dickinson). in case of marginal results or intermediate sensitivity to quinupristin/ dalfopristin, the mic was determined using the e -test method (ab biodisk). results: all isolates were found to be sensitive to lzd. q/d was very active as well, except for two isolates that exhibited intermediate susceptibility, showing cross-resistance to macrolides and clindamycin, as well. conclusions: the new antimicrobial agents show excellent activity against resistant to common antimicrobials pneumococcal isolates, but the clinical use is not suggested, unless no other therapeutic solutions are available. linezolid is a new oxazolidinone with excellent activity against gram-positive organisms including glycopeptide-resistant strains of staphylococci and enterococci. in icu linezolid has been used for the treatment of severe gram-positive infections in a control trial. the susceptibility pattern of all gram-positive isolates from icu patients has been studied. methods: a total of 2427 specimens from icu patients were processed, 767 were from patients enrolled in the antibiotic trial. all methicillin-resistant staphylococcus aureus (mrsa), coagulase-negative staphylococci (cons), enterococcus sp and methicillin-sensitive staphylococcus aureus (mssa) were tested. the break point for linezolid was 4 mg/l and for teicoplanin 8 mg/l. isolates were tested for susceptibility by e -test. results: linezolid (1063 isolates) mic 50/90 (mg/l) were as follows: mrsa (n 0/541) 0.6/2, cons (n0/143) 0.9/1.4, enterococcus sp (n0/39) 0.7/0.8, mssa (n0/340) 0.8/1. teicoplanin (782 isolates) mic 50/90(mg/l) mrsa (n0/415) 1.9/3.5, cons (n 0/100) 4/7.4, enterococcus sp (n0/24) 0.9/1.4, mssa (n0/243) 2.2/2.6. all grampositive isolates were inhibited by concentrations of linezolid below the breakpoint including eight strains of staphylococci resistant to teicoplanin. conclusions: linezolid was highly active against grampositive isolates. resistance to teicoplanin was similar to other reported series. there was no emergence of resistance to linezolid. mrsa colonization is often a limiting factor for discharge from icu. clearance of mrsa is seldom achieved with conventional glycopeptide treatment. the oxazolidinone, linezolid, has excellent soft tissue and respiratory tract penetration and might be expected to eradicate carriage in some patients. we recently performed a doubleblind randomized trial in 204 icu patients with known/suspected gram positive infection. 100 received intravenous linezolid, 600 mg b.d., and 104 patients received teicoplanin 400 mg o.d. mrsa clearance was assessed at end of treatment (eot), at 7-and 21days follow-up. results: in the linezolid and teicoplanin groups, 45 and 43 were known to be colonized with mrsa at study entry, respectively, while 39 and 40 were not. detection of clearance of mrsa colonization at eot was 51% for linezolid vs 19% for teicoplanin group (x b p b/ 0.005), at 7 days it was 35% vs 14% (x b p b/0.1), and at 21 days 19% vs 33% (ns). conclusion: short-term mrsa clearance can be achieved in significantly more patients treated with linezolid however this was not maintained at 21 days, either because of incomplete initial eradication or recolonization. further analysis will follow when molecular typing of the isolates is completed. penetration of linezolid into bone, fat and muscle during hip arthroplasty ps134 lovering am, bannister gc, zhang j, macgowan ap, southmead hospital, bcare, bristol, uk there are limited data describing the concentrations and penetration of linezolid (lzd) into tissues, such as bone, that can be used to guide therapy for non-vascular infections. here we report the concentrations and penetration of lzd for bone, fat and muscle in comparison with cefamandole (cmd). twelve patients received 600 mg lzd as a 20 min infusion and 1000 mg cmd as a bolus injection immediately before hip arthroplasty. bone, fat, muscle and blood samples were collected at timed intervals after the infusion and assayed by a validated hplc method. for bone, peak levels of both agents occurred 10 min after administration with mean levels of lzd 9.1 mg/kg versus cmd 17.5 mg/kg, decreasing to lzd 5.7 mg/kg versus cmd 9.7 mg/kg at 30 min. correction for blood concentrations gave penetration of lzd 51% versus cmd 25% at 10 min and lzd 46% versus cmd 23% at 30 min. for fat and muscle, peak levels occurred 20 min after infusion. mean levels were lzd 5.2 mg/kg versus cmd 10.9 mg/kg (fat) and lzd 13.4 mg/kg versus cmd 10.9 mg/kg (muscle). correction for blood concentrations gave penetration of lzd 37% versus cmd 19% (fat) and lzd 95% versus cmd 31% (muscle). we conclude that linezolid exhibits rapid penetration into bone and associated soft tissues achieving levels in excess of the mic for sensitive organisms; with a similar distribution and penetration profile to agents currently used for treatment of infections in these tissues. bacqué e a , barrière jc a , berthaud n b , desmazeau p b , dutruc-rosset g b , dutka-malen s b , ronan b b . a aventis pharma, chemistry, paris, france , b aventis pharma, disease group, paris, france xrp2868 is a new oral streptogramin composed of 2 semi-synthetic synergistic components in a 30/70 (w/w) association: rpr202868 (5d-(1-morpholino)methyl-5d,5g-dehydro pristinamycin i e ) from pi a and rpr132552 [(16r )-16-deoxy-16-fluoro pristinamycin ii b ] from pii b by original synthetic routes. the association has antibacterial activity against staphylococci including methicillin */mls b -resistant strains (mic90 range: 0.12 */1 mg/ml), streptococci (mic90: 0.25 mg/ml), pneumococci including multidrug resistant strains (mic90: 0.50 mg/ ml), enterococci including vancomycin-resistant strains (mic90: 4 mg/ ml), m. catarrhalis and neisseria spp. (mic90: 0.12 mg/ml), h. influenzae (mic90: 1 mg/ml), legionella spp. (mic90: 0.06 mg/ml) and anaerobes (mic range: 0.06 á/4 mg/ml). xrp2868 is generally bactericidal at the concentration of 2 á/4)/the mic against s. aureus , s. pneumoniae , h. influenzae and demonstrates consequent pae (2.1 á/ !/5.7 h at 2 á/4)/mic, following an exposure of 0.25 á/2 h). mutants of s. aureus to xrp2868 were isolated at low frequencies (3.6)/ 10 (9 á/9.7)/10 (10 ) at 2)/ and 4)/mic while no mutant could be isolated at 8)/mic. these results suggest that xrp2868 (30/70 w/w) is a promising compound for the treatment of community-acquired infections. ex vivo evaluation of rpr202868/rpr132552 (xrp2868), a new oral streptogramin ps136 berthaud n, diallo n. aventis pharma sa, infectious disease group, paris, france the intra cellular activity of xrp2868, was assessed in j774 murine macrophages containing ingested staphylococcus aureus (three strains) or l. pneumophila (one strain). at the concentration of 8 )/ the mic, growth of s. aureus was strongly inhibited after a 3-h period of incubation (d log 10 cfu/ml vs t 0 controls range: (/2.16 á/(/1.24, according to the strain tested). at the concentration of 8)/ the mic, growth of intracellular l. pneumophila was inhibited after a 48 á/ 72-h period of incubation (d log 10 cfu/ml vs t controls about (/1.30 and (/1.48 at 48 and 72 h, respectively). rpr202868 and rpr132552 alone had also inhibiting effect on bacterial growth (d log 10 cfu/ml vs t 0 controls after 72 h of incubation about (/1.54 and (/0.87, respectively). the bactericidal activity of xrp2868 was also assessed against slowly growing s. aureus , under experimental conditions mimicking those observed in patients with an infected indwelling device (first step of infection: adherence to inert support; declared infection: biofilm model). under the experimental conditions, xrp2868 demonstrated a rapid and potent bactericidal effect against s. aureus adherent to an inert support or included in biofilm. this effect was observed at each of the three concentrations tested (5, 10, 50 and 8, 100 and 200)/ mic, respectively). in vivo evaluation of xrp2868 (rpr202868/rpr132552), a new oral streptogramin ps137 berthaud n, huet y, aventis pharma sa, infectious disease group, paris, france the oral efficacy of xrp2868, was assessed in staphylococcus and pneumococcal murine infections. mice were challenged ip ( )/10, and )/100 times ld 50 ). abscesses were established by intramuscular injection of about 10 7 bacteria into the right thigh of mice. pneumonia was established by intranasal injection of about 10 7 bacteria. mice were treated twice a day for 1 (staphylococcus aureus septicaemia and abscesses), 2 (s. pneunomoniae septicaemia) or 3 days (s. pneumoniae pneumonia). six to 15 days post infection, for septicaemia and abscesses the results were expressed as ed 50 , whereas for pneumonia they were expressed as the dose yielding an average survival time (ast) significantly longer than that of the untreated infected controls. xrp2868 was efficacious in the treatment of experimental infections in mice caused by mls b -sensitive and -constitutively resistant s. aureus (ed 50 range: 20 á/44 and 24 á/60 mg/kg/administration in septicaemia and abscess models, respectively). it was also efficacious in the treatment of infections caused by s. pneumoniae whatever the serotype and the resistance profile of the strains tested (ed 50 range: 28 á/55 mg/ kg/administration in septicaemia, ast: 50 mg/kg/administration). these results suggest that xrp2868 might be effective for the treatment of staphylococcal and pneumococcal community-acquired infections. xrp2868 (rpr202868/rpr132552), a new oral streptogramin: bactericidal activity and pharmacokinetics in a model of streptococcus pneumoniae mouse pneumonia ps138 berthaud n, huet y, diallo n. aventis pharma sa, infectious disease group, paris, france the bactericidal activity against streptococcus pneumoniae of xrp2868, a new oral streptogramin composed of two semi-synthetic synergistic components in a 30/70 (w/w) association (rpr202868, pristinamycin i derivative and rpr132552, pristinamycin ii derivative), was assessed in lungs of mice with pneumonia. mice were inoculated intranasally with about 10 7 cfu of strain 6254-01 (mls bresistant). eighteen hours later (t 0 ), animals received xrp2868 (120 mg/kg p.o). the administration was repeated 6, 24, 30, 48 and 54 h afterwards. to study the influence of varying the ratio of pi to pii component administered on activity and pk parameters, ratios of rpr202868 to rpr132552 ranging from 0/100 to 100/0 were also administered under the same conditions. after an oral unitary administration at 120 mg/kg, xrp2868, as well as ratios of rpr202868 to rpr132552 ranging from 50/50 to 90/10, demonstrated strong and quick bactericidal activity in lungs. lung levels of rpr202868 and rpr132552 were generally equal or two times higher than blood levels. resulting rpr202868/rpr132552 ratios in blood and lung, although not in accordance with the initial ratio administered, were synergistic for 3 á/4 h in blood and for 1 á/3 h in lungs explaining the activity observed. conclusion: based on in vitro data, telithromycin is a good candidate for the treatment of rti. in vitro evaluation of abt-773, telithromycin and azithromycin against streptococcus pneumoniae , moraxella catarrhalis , haemophilis influenzae and methicillin-resistant staphylococcus aureus ps140 steele-moore l, berg d, barnes i, couch k, klein j, holloway w. christiana care, infectious disease, wilmington, us macrolide resistant streptococcus pneumoniae (sp) is a worldwide concern predominantly because these isolates tend to be multiply drug resistant. new agents with increased activity against these pathogens are clinically important. the ketolide class of antimicrobial agents demonstrate excellent in vitro activity against sp, even those that are macrolide resistant. the in vitro activities of the ketolides abt-773 (a) and telithromycin (t) were compared to azithromycin (az) against clinical isolates of sp, moraxella catarrhalis (m.cat), haemophilis influenzae (h.flu) and mrsa. organisms tested: 51 strains of sp (including 14 az resistant), 25 h.flu, 25 mrsa and 10 m.cat. microdilution mic tests were performed following nccls recommendations using freshly prepared plates containing haemophilis test medium for h.flu, cation adjusted mueller-hinton broth (camhb) with laked horse blood for sp and camhb for m.cat and mrsa. the new ketolides, a and t had superior activity against sp including the az resistant strains (mic90s: a0/0.12 mcg/ml, t 0/0.25, az0/4). all compounds had excellent activity against m.cat while none demonstrated activity against mrsa. h.flu activity was comparable among a, t and az. these new ketolides are not currently approved by the fda; however t has been approved in europe. ló pez h, vidal gi, salomó n jm, scaglione m, zitto tr. centro de infectología, infectious diseases, buenos aires, argentina objective: we evaluated the impact of the initial treatment failure rate, hospitalisation and costs in outpatient treatment of adult cap in argentina comparing amoxicillin, clarithromycin and telithromycin. method: a probabilistic model was implemented in outpatient treatment of cap. we estimated an initial treatment with amoxicillin, clarithromycin or telithromycin. we assumed expected clinical cure at 90.1, 88.5 and 94.6%, respectively. for those patients with failure treatment we evaluated a second-line of antibiotics (amoxicillin followed by clarithromycin and clarithromycin followed by new fluorquinolone) or hospitalisation. patients with telithromycin and failure treatment must be hospitalised without a second line of outpatient treatment. costs of cap included drug's costs by 10 days, medical visits, chest radiographies, analysis and hospitalisation. results: we estimated treatments in 100 patients and first-line drug failure in 10, 11 and 5 patients with amoxicillin, clarithromycin and telithromycin, respectively. costs in outpatient treatment were: hospitalisation $12,224 and $13,489.4; second-line drug $1039 and $1045; second-line hospitalised $1320.4 and $1232 with amoxicillin and clarithromycin, respectively and hospitalisation with telithromycin $6137. conclusions: telithromycin showed lower clinical failure, hospitalisation and costs in cap. some studies suggest shortening cap telithromycin treatment to 7 days helping adherence to treatment and decreasing costs even more. the new macrolides */a good alternative of tetracycline in the treatment of mediterranean spotted fever ps142 popivanova nip a , petrov aip a , boykinova obb a , kazakova zkk a , baltadjiev agb b . a medical university, infectious disease, plovdiv, bulgaria , b department of anatomy, medical university, plovdiv, bulgaria mediterranean spotted fever (msf) caused by rickettsia conorii appears an endemic disease for some regions in bulgaria. frequently the disease has a severe course with multiple organ lesions. the early and adequate treatment is of extreme importance for the outcome of the disease. searching an alternative antibiotic treatment of this disease we considered macrolides for their good cell and tissue penetration and dose-dependent bacteriostatic and bactericide effect. we treated 27 msf patients with doxycycline 2)/100 mg/day, 25 patients with clarithromycin 2)/250 mg/day, as well as 25 patients with midecamycin 2)/400 mg/day and midecamycin acetate 30 mg/kg/day. as a surrogate marker for treatment evaluation the effect on the febrile syndrome was used. our findings showed that by the 5th day of treatment the fever normalized in 89.47, 88.24 and 76.47% of the patients treated with doxycycline, clarithromycin and midecamycin, respectively. for the same period the patient fever decreased below 38 8c in 100, 100 and 94.12%, respectively. the intoxication symptoms were influenced within the same period equally in all treated patients. conclusions: we suggest that the new macrolides appear a good alternative of tetracycline on patients with msf. erythromycin resistance of gram /'// cocci in bulgaria. benefits of the new macrolides in the treatment of respiratory infections ps143 popivanova ni a , yovtchev ip b , dobreva md c , argirova ta c . a medical university, infectious disease, plovdiv, bulgaria , b medical university, ear-nose-throat disease, plovdiv, bulgaria , c medical university, microbiology, plovdiv, bulgaria in the recent 2 years we tested erythromycin sensitivity of 474 species of gram /'// cocci isolated from throat and nose secretions, ear and eye effusions, sputa, cerebrospinal fluid and blood cultures, vaginal and urethral secretions, urine and fecal samples from patients with inflammatory diseases of the listed organs and systems. staphylococcus aureus , staphylococcus coagulase /(//, streptococcus â-haemolyticus , enterococcus were isolated. of these microorganisms s. aureus was the most abundant. our resistograms revealed sensitivity of the gram /'// cocci in 76.97 and 68.60% for 2000 and 2001, respectively, and resistance of 23.03 and 31.40%, respectively. in the tests with midecamycin and midecamycin acetat the same microorganisms showed sensitivity of 85.38% and resistance of 14.62%. the clinical findings showed excellent effect of the new macrolides including clarithromycin and azalides */azithromycin. we conclude the resistance of gram /'// cocci and especially of s. aureus to erythromycin increases very quickly and has reached dramatical extent. by now, the new 14, 15, and 16-membered ring macrolides and azalides show high antibacterial activity and good clinical effect. pappas ga, liberopoulos e, tsiara s, elisaf m, tsianos e. university hospital, internal medicine, ioannina, greece quinupristin/dalfopristin (q/d) is a novel injectable streptogramin antibiotic which initiation in therapeutics was hailed as an important step towards treatment of vancomycin-resistant enterococcus faecium (vref) species. initial reports concluded in an excellent response of vref to q/d. reports of q/d-resistant strains of e. faecium have emerged, both in usa and europe. we report two cases of e. faecium bacteremia in which the responsible isolate was not sensitive to q/d. the first patient was a woman with acute leukemia and septicemia. e. faecium was cultured from blood samples: the species was resistant to almost all antibiotics, exhibiting sensitivity only to tetracycline (!), while its sensitivity to q/d was indermediate. the second patient was a man with endocarditis, in whom blood cultures isolated e. faecium sensitive to a number of antibiotics, including ciprofloxacin and vancomycin; still the sensitivity to q/d was indermediate. q/d has not been officially introduced to the antibiotic arsenal of greek medicine. moreover, the drug has never been used in our hospital, not even experimentally. other e. faecium species isolated in our hospital have been sensitive to q/d. how much hope can be put on a drug that seems to be partly useless before its initiation? increasing reports of v/ q-resistant strains of e. faecium from all over europe raises fears that the v/d story might well end before it begins. varadinova t a , diakov t a , karagiozova d a , genova p a , pardon p b , baudry c b , quideau s b . a sofia university, virology, sofia, bulgaria , b et institut du pin, centre de recherche en chimie moleculaire, universite bordeaux 1, bordeaux, france vegetable tannins posses a wide range of biological activities. the aim of the present study was to evaluate the cytotoxicity of five purified vegetable tannins against mdbk cells. the maximal nontoxic concentrations (mnc) and the concentrations required to inhibit cell growth by 50% (cc 50 ) were evaluated after 24, 48 and 72 h periods of action. mnc values after 48 h indicated that compounds stimulated cell surveillance when applied in concentrations lower than 0.01 mm. cc 50 values indicated: (i) a decrease in cytotoxicity after 48 h as cc 50 were up to 70 times lower than those observed after the 24 h period, and (ii) a re-increase in cytotoxicity when the period of action was prolonged up to 72 h as cc 50 were 2500 times lower than those observed after the 48 h period. these data thus appear to reveal the capability of the investigated natural polyphenolic products to stimulate cell surveillance in a time-dependent manner. antibacterial effect survey of enoxolone on periodontopathogenic and capnophilic bacteria isolated from specimens of patients with periodontitis ps146 salari mh a , kadkhoda z b , sohrabi n a . a tehran university of medical sciences, pathobiology, tehran, islamic republic of iran , b tehran university of medical sciences, dentistry, tehran, islamic republic of iran objectives: most of the microorganisms associated with periodontitis are capnophilic and anaerobic bacteria. purpose of this study was to detection of antibacterial effect of enoxolone on periodontopathogenic and capnophilic bacteria. methods: in this study 136 periodontopathogenic and capnophilic bacteria were isolated from 400 specimens of patients with periodontitis by culture method. an anti-bacterial activity of enoxolone against these microorganisms was investigated by minimum inhibitory concentration (mic) and minimum bactericidal concentration (mbc) methods. results: based on our findings the mic, mbc and lethal does 50 (ld50) of enoxolone for actinobacillus actinomycetemcomitans , eikenella corrodens and capnocytophaga were '8, 16, 64', '16, 16, 32', and '8, 16, 32' mg/ml, respectively. conclusion: our results show enoxolone has antibacterial effect on a. actinomycetemcomitans , e. corrodens and capnocytophaga spp. sakalova stn. medical university, microbiology, grodno, belarus we have synthesized diamides of dicarboxylic acids, with components such as 5-nitrothiazole benzolsulphamides and triazol. all the above compounds exhibited bacteriostatic activity towards some microorganisms. for further studies of bacteriostatic activity of amides and diamides of dicarboxylic acids, as well as for determination of 'structure á/activity' relationship, we have synthesized a range of monoamides. antibacterial activity of the synthesized compounds was studied in vitro by agar dilution methods. for this purpose, approximately 50 various gram-positive and -negative microorganisms including clinical strains of staphylococcus aureus , bacillus subtilis , serratia marcescens , escherichia coli , proteus morganii , micrococcus lisodeicticus , staphylococcus epidermidis , shigella sonnei , salmonella typhimurium , yersinia enterocolitica . minimum inhibitory concentration was expressed in mg/ml. nitazole was used as a comparison substance. analysis that new derivatives of 5-nitrotiasole have high antibacterial activity relative towards certain microorganisms included strains obtained from infection department's patients. results will be shown. microbial susceptibility to the essential oil of ziziphora clinopodiodes lam. ps148 purpose of the study: antimicrobial activities of essential oils vary from oil to oil and from one micro organism to another. the antimicrobial and chemical properties of essential oil from ziziphora clinopodiodes lam. has not been studied and hence the present study was planned to evaluate those properties against a series of micro organisms viz, escherichia coli , staphylococcus aureus , pseudomonas aeroginosa , klebsiella pneumonia , bacillus subtilis , bacillus licheniformis , streptococcus faecalis , candida albicans and saccharomyces cerevisiae . results: z. clinopodiodes lam. essential oil was found to have remarkable antimicrobial property against all the microorganisms but p. aeroginosa . the oil exhibited its best antimicrobial activity within a maximum of 45 min. seventeen components were identified by gas chromatography and mass spectrometry (gc and gc/ms) analysis of the oil, out of which pulegone (24.5%), neomenthol (12.8%), cyclohexene,5-methyl-3-(1-methenyl)trans (12.2%), 2,4-cycloheptadien-1-one,3,6,6-trimethyl (9.2%), piperitone (4.2%), and limonene'/ 1,8-cineole (4.1%) constitute major parts of the oil. conclusion: monoterpenes seem to have antimicrobial role. it seems necessary to explore antimicrobial properties of new harmless antimicrobial agents from natural sources as substitutes for common chemical drugs. methanol extract of carpobrotus edulis enhances killing of methicillin resistant staphylococcus aureus phagocytosed by thp-1 human monocyte derived macrophages and promotes the release of modulators of cellular immunity ps149 although alkaloids from the family mesembryanthemaceae have anti-cancer activity, species of this family have received little attention. because these alkaloids also exhibit properties normally associated with compounds that have activity at the level of the plasma membrane, we have studied a crude methanol extract of carpabrotus edulis , a common plant found along the portuguese coast, for properties normally associated with plasma membrane active compounds. the results of this preliminary study show that the extract is non-toxic at concentrations that prime thp-1 human monocytederived macrophages to kill ingested methicillin resistant staphylococcus aureus and promote the release of lymphokines associated with cellular immune functions. the extract also induces the proliferation of thp-1 cells within 1 day of exposure and 2 days earlier than that induced by phytohemagglutinin. similar results were obtained with monocyte-derived macrophages isolated from human peripheral blood. the active component or components of the plant extract may be exploited as intracellular active anti-bacterials as well as modulators of cellular immunity. enhancing of erythromycin production by saccharopolyspora erythraea nur001 with common and uncommon oils ps150 hamedi j a , malekzadeh f a,b saghafi-nia ae b . a department of biology, faculty of science, university of tehran, tehran, islamic republic of iran , b shafe-e-sari co., antibiotic production co., teheran, iran enhancing effect of various oils on the erythromycin production by saccharopolyspora erythraea nur001 were evaluated in a complex medium consisting soybean flour and dextrin as the main substrates. the biomass, erythromycin, dextrin and oil concentrations, and ph value were measured on a daily basis. also, the kinds and frequencies of fatty acids of the oils used were determined. saturated fatty acids in the shark oil were higher than that of vegetable oils used. erythromycin concentration in the melon (cucumis melo var. inderus cultivar mashhad ) seed oil containing medium was 4.56 times higher than that of the control medium (without oil) and 1.18 times higher than that of rapeseed oil containing medium. erythromycin concentration in the other oil containing media, including rapeseed, soybean, shark (carcharhinus dussumieri ), and safflower oils was 3.88, 3.03, 2.59, 2.44 time higher than that of control medium, respectively. the melon seed oil had the least enhancing effect on the biomass production, and thus decreasing the cost of the biomass separation. can varicella be eliminated by universal childhood vaccination ? */ epidemiological and economic data from germany ps151 wutzler p a , banz k b , neiss a c , goertz a d , bisanz h d . a institute for antiviral chemotherapy, university of jena, jena, germany , b outcomes international, basle, switzerland , c institute of medical statistics and epidemiology, technical university, munich, germany , d glaxosmithkline, pharma, munich, germany purpose: universal varicella vaccination in childhood is expected to reduce substantially the number of uncomplicated cases of chickenpox and to decrease the number of complicated cases requiring hospitalization. to generate fundamental data for decisions of the health authorities epidemiological and health-economic data were collected in two large studies. using an age-structured decision analytic model the benefits, costs and cost-effectiveness of a varicella immunization program over a period of 30 years were assessed. results: it could be shown, that the vast majority of varicella cases occur in children aged less than 8 years. in 16.3% of the cases a severe course was assessed. overall incidence of complications was estimated to be 5.7%. a routine varicella vaccination program targeting healthy children could prevent 82.6% of varicella cases and over 4700 major complications per year provided the coverage rate would be 85%. under these conditions the elimination of varicella is predicted to be achievable within 15 á/20 years. a combined measles, mumps, rubella and varicella vaccine is expected to provide the required coverage. conclusions: routine childhood varicella vaccination appears to be a highly efficient strategy to significantly reduce the sizeable burden of varicella and leads to significant savings from both societal and payer's perspective. bulgakova va, balabolkin ii, sentsova tb. scientific center of child health, russian academy of medical sciences, scientific research institute of pediatrics, moscow, russian federation objective: to estimate efficacy of vaccine influvac at children with allergic diseases. methods: twenty children aged 3 á/18 years with allergic diseases received vaccine influvac (solvay pharma). for the control group of children, with allergic pathology did not receive this vaccine because of an intolerance of chicken protein (10 children). results: all vaccinated children for the observable season of 6 months did not get influenza. general and aboriginal reactions to a vaccine did not occur. in control group for the observable season two children were ill with influenza and four children with acute respiratory virus infection (60%). among vaccinated children there was an increase in titre to a protective level (1:40 and above) to all to three strains of influenza 30 days after injection. vaccine influvac can be recommended for an immunisation against influenza of children with an allergic pathology because of efficacy and absence of side effects. ló pez h, zitto tr, vidal gi, cánepa mc, salomó n jm, scaglione m. centro de infectología, infectious diseases, buenos aires, argentina objectives: our study examines the possible economic impact of the influenza on health working adults in argentina, and the intervention cost saving with immunization. methods: this is a theoretical study based on a mathematical model. population data was published in 2001s national statistics. the global incidence of influenza infection was estimated at 5%. we have estimated the direct cost on influenza infection (outpatient visits, drugs and hospitalization) and indirect cost (work absenteeism and productivity loss) and projected net saving for the 20 á/64 year-old vaccinated group. the vaccine effectiveness was estimated at 70 and 90%. the price of vaccine was $8 each. results conclusion: influenza vaccination is effective in diminishing cases of flu and reducing working-day loss. its a safe and cost-effective vaccine. ló pez h, zitto tr, cánepa mc. centro de infectología, infectious diseases, buenos aires, argentina flu infection is a major cause of illness and one of the most common cause of work absenteeism, increasing institution costs, healthcare provider visits, use of drugs, and decreasing work productivity. vaccine against flu has an effectiveness between 70 and 90%, in health adults. objective: evaluate the impact of flu-like respiratory tract infections in a health institution staff during 1 year, comparing vaccinated with not-vaccinated groups. methods: we evaluated all causes of absenteeism along 1 year (2001), based on the written note made by the professional who has evaluated ill people, selecting flu-like respiratory infection causes. we evaluated age, working days loss related to illness, and cost on vaccinated and not-vaccinated groups. results: one hundred and sixty eight of the total staff (479 people) were vaccinated, 21 of them had flu-like infection, resulting in 40 working days lost. for not-vaccinated group, 33 people had flu and 56 lost days. lost cost for vaccinated group was of $1267, and for notvaccinated group, $1874. conclusion: we observed a decrease in working days loss and money waste related to flu-like infections on the vaccinated group. because of safety and effectiveness of vaccine against flu, the implementation of vaccination will be cost-effective for all institution staff. we studied functioning of the interferon system in 108 children with atopic bronchial asthma (ba) at the age of 2 á/14 years. the control group included 10 healthy children. we investigated the interferon status (method of grigoryan s.) and serum concentrations of ifngamma (ifng) (elisa). there was a decrease in the ifn-producing ability of leukocytes to the synthesis of ifna at 50% and ifng at 84% of children with ba. serum level of ifn of children with ba during all period of illness is compared to the children without predisposition to atopy (94.99/10.3 and 192.39/7.8 pg/ml accordingly) was significantly decreased. production of ifna increased after using viferon (recombinant a2b ifn and antioxidants). decreased ability of gammainterferonogenesis in the most children was not affected by the action of immunomodulators. there was shown interferon system's dysfunction in the development of atopy and increasing predisposition to respiratory infections and to persistent of atypical infections in children with ba. harxhi a, pilaca a, pano k. university hospital center of tirana, infectious diseases, tirana, albania congo-crimean haemorrhagic fever is viral disease with a high rate of mortality that is caused by a nairovirus, bunyaviride species. this is a zoonotic disease, which affects sporadically humans and is geographically distributed even in eastern europe and balkan. during the months of may and june 2001, in northeast of albania were reported eight cases of haemorrhagic fever. serologic tests performed in the laboratory of reference in thesaloniki, greece confirmed the diagnosis of congo-crimean haemorrhagic fever. in the mean time, who reported the outbreak in southwest kosovo of 69 cases suspected for haemorrhagic fever from which 18 were confirmed laboratory as congo-crimean haemorrhagic fever. we are describing here the clinical history of one of eight cases with cchf in albania. from the epidemiological point of view this case was considered peculiar, as it was the only one hospitaly acquired, and due to the gravity of the haemorrhagic syndrome was admitted at the intensive care unit at infectious diseases service, university hospital center of tirana. results: in the study were included 150 patients ]/18 years of age with documented hbsag-carrier ]/6 months (average age */39.4 years, male */58%, female */42%). hbv dna in serum was tested by qualitative and quantitative pcr (commercial test-system ampli-sens hbv). hbeag, hbeab, hbsag were detected by elisa (hoffmann la roche). hbv dna by qualitative pcr was detected in 41% patients, by qualitative pcr was detected in 13% patients in the concentration ]/10 5 copies/ml, in 4.3% ]/10 6 copies/ml, in 4.3% ]/10 7 copies/ml, in 2.1% ]/10 8 copies/ml ( fig. 1 ). hbv dna level distribution among the hbsag carriers. elevated (1.5 the upper limit of normal) alt level was determined in 3.8% of the hbv dna negative and 25.4% of the hbv dna positive patients. hbeag was detected in 10.2% of the hbv dna positive patients and had not been determined in the hbv dna negative patient. eleven percent of patient had the combination of the biochemical, serological and virology criteria, which are typical for active chronic hepatitis b (hbsag-carrier !/6 months, hbv dna ]/ 10 )/5 copies/ml, elevated alt). conclusion: in smolensk 41% of the hbsag-carriers have viral replication confirmed by qualitative pcr. eleven percent of them have active chronic hepatitis b. kandemir o a , polat a b , kaya a a . a medicine of faculty, mersin university, clinical microbiology and infectious disease, mersin, turkey , b medicine of faculty, mersin university, pathology, mersin, turkey the exact potential of nitric oxide in the pathogenesis of chronic viral hepatitis is not known. the elevated nitric oxide production is assumed to be responsible for the pathological changes in many inflammatory conditions, mainly via peroxynitrite, a potential oxidant that is produced by the reduction of superoxyde anion with nitric oxide. the intensity and the distribution of the immunohistochemical staining of intrahepatic inducible nitric oxide synthase were studied in the biopsy specimens obtained from 63 patients with viral hepatitis and 13 patients with elevated transaminase levels from other etiology. hepatic inducible nitric oxide synthase staining was significantly more intense in the viral hepatitis group (p 0/0.000). inducible nitric oxide synthase staining levels correlated well with the severity of the viral hepatitis using the knodell's liver histological activity index (r0/0.393, p 0/0.002). among the viral hepatitis group, the pathological distribution of the inducible nitric oxide synthase staining favored the periportal regions whereas less staining was observed in the bile duct and parenchyma regions. as nitric oxide mediated nitration of hepatocellular proteins is found to be elevated in the inflamed hepatic tissues and it well correlated with the severity of the disease, we suggest that inducible nitric oxide synthase can possibly have a critical role in the pathogenesis of chronic viral hepatitis. there were 36 patients under observation who were divided into two groups, the first of 18 patients (eight chronic virus hepatitis; three chronic virus hepatitis'/steatosis; four steatohepatitis; three chronic cryptogenic hepatitis; there were 14 men and four women aged from 35 to 74. the second group consisted of 18 patients, eight with chronic virus hepatitis; four with steatohepatitis; six with chronic cryptogenic hepatitis. there were 15 men and three women aged from 40 to 80. diagnosis was confirmed with the help of clinical data, biochemical tests, serological markers, psr-diagnostics and ultrasound examination and computer tomography of the abdomen. in the first group of patients the treatment with ursofalk was administered at the dosage of 10 mg/kg of body mass from 1 month to 3 years with improvement in general condition of the patients: heaviness, pain under the right rib, nausea and skin itch have disappeared. in all the cases, improvement in the biochemical blood analysis took place during treatment. the average index of alt activity was before */105.88 u/l, after */62.06 u/l and ast */156.44 and 95.05 u/l; alp */196.39 and 171.87 u/l; ggt */163.2 and 82.86 u/l; chol */5.38 and 4.8 mmol/l; tg */2.15 and 1.75 mmol/l. in the second group of patients the treatment was carried out with various hepatoprotectors during the courses from 1 to 6 months. before the average index of alt activity was 181.3 u/l, after */165.5 u/l; ast */126.9 and 129.0 u/l; alp */229.8 and 213.5 u/l; ggt */204.2 and 238.0 u/l; chol */5.85 and 5.67 mmol/l; tg */1.72 and 1.8 mmol/l. treatment of patients suffering from hepatitis of viral and other aetiologies with ursofalk produces a positive effect on both clinical symptomatic and biochemical indices. remission was more stable during a long period of taking the preparation. the hepatoprotective effect of ursofalk during the 3 years was sustained for the whole of the period of the treatment. after stopping, an acute attack of cytolytic syndrome was observed. with other hepatoprotectors we did not get any improvement in clinical scene of the disease or in biochemical indices. shavlov nm, kletsky sk. minsk, belarus hsv-1 and -11 have possibility to damage different organs and systems. sometimes they cause damage of the liver, which resemble viral hepatitis. the etiology of such hepatitis may be confirmed only by results of liver biopsy. we have diagnosed 12 cases of herpetic hepatitis: eight children and four adults. clinical course was different. in five cases the acute beginning took place: high temperature, the jaundice at the 2 á/3 day (the level of bilirubin was 200 á/350 mkmol, especially direct), cholestasis, the pain in upper right part of abdomen. the ascites was found in three patients with acute hepatitis during 1st week from the beginning of disease. in seven cases the beginning was gradual. the temperature was subfebrile, prolonged; malaise and moderate pain in upper part of abdomen were constant complaint. the jaundice was moderate; bilirubin increased until 120 mkmol. the level of alt was moderately increased (5 á/7 times). the blood analysis showed moderate leukocytosis with neutrophilia, and increased sre. the serological markers of hepatitis a, b, c, d were negative in all cases. hsv-1 and -2 were found in the blood. the diagnosis was defined by the results of hystochemical investigations, when the viruses were found in liver bioptat, and confirmed with the results of specific treatment. specific damage of liver cells was found: protein dystrophy and specific inclusions in cell nucleus. in all cases the treatment with acyclovir were given. the results we have observed during 1st week: the temperature became normal, the jaundice decreased and bilirubin was normal during 5 á/10 days. in one case the recidive took place 2 weeks later after treatment. the second course of acyclovir with intron a gave good results. nesic z a , delic d b , prostran m a , vuckovic s a , stojanovic r a . a department of pharmacology, school of medicine, university of belgrade, belgrade, yugoslavia , b clinical center of serbia, institute for infection and tropical disease, belgrade, yugoslavia the large number of unsolved cases of acute and chronic hepatitis has most probably the viral etiology. in mid 1990s, two independent groups of authors reported a new human hepatotropic virus, with flavivirus like genomes, hepatitis g virus (hgv). the aim of this pilot study was to determine the prevalence of hepatitis g viral infection among patients at high risk of exposure to blood and blood products, as well as to evaluate if the risk of hgv infection was higher among them than in the general population. immunoenzyme test on microtitration plate for detection antibodies against hgv e2 antigen in plasma or sera (r&d systems, minneapolis, usa) was used for evidencing anti-hgv igg antibodies in sera. anti-hgv antibodies were detected in the control group (blood donors) in 8.3% (2/24) patients. prevalence of anti-hgv antibodies among i.v. drug users was evidenced in 42.8% (9//21), in hemophiliacs 41.2% (7/17), in patients acquiring multiple blood transfusion 42.8% (3/7), in hemodialyzed patients 33.3% (4/12) and in patients with transplanted organs 57.14% (4/7). our results suggest that patients exposed to blood or blood products have a higher risk of hgv infection than general population. evaluation of ortho total hcv core antigen assay in assessment and follow-up of patients treated for chronic hcv ps162 lunel f, veillon p, payan c. chu angers, laboratoire de bactério-virologie, angers, france an assay to quantitate 'total' hvc core antigen (hcv ag) in serum or plasma, may reflect viral load, has been developed by ortho-clinical diagnostics. methods: we evaluated hcv ag with two quantitative assays for hcv rna: bdna 3.0 (bayer) and monitor 2.0 (roche). we studied 191 samples from untreated patients and 237 from 144 patients with chronic hcv treated with ifn or ifn/ribavirin. results: correlation of ag and quantitative assays was high (r0/ 0.85 for bdna 3.0 and 0.83 for monitor 2.0). no difference between the levels of rna and ag among hcv genotypes (r0/0.82 á/0.96) was found. ag values, before treatment, were significantly lower in sustained responders (sr) than in other groups (5.4 log versus 6 log, p b/0.001). in patients treated with ifn or combination therapy, we found very good correlation between decrease and negativation of ag and viral load: 2 log iu/ml decline after m1 of interferon was significantly correlated with the negativation of hcv ag and sr. thirty-eight/41 of sr had a rna load decrease !/2 log iu/ml and 39/ 41 had a negativation of hcv ag after m1. conclusion: total hcv core ag appears to be a new tool for monitoring patients with hcv infection. hepatitis c virus rna and hcv core antigen kinetics predict the efficiency of interferon-alfa and ribavirin therapy in naive patients infected by hcv genotype 2 or 3 ps163 fifty-five patients infected by genotype 2 or 3 were treated with a primary dose of 3 (if hepatitis c virus (hcv) rna b/3 meq/ml) or 6 million units of interferon alfa-2b (ifn) thrice weekly for 12 months. ribavirin was added at month 3 (m), until m12 if hcv rna was found positive after m2 of ifn. the viral kinetic was assessed during the follow up by serial measurements of hcv rna (bdna 3.0 and monitor 2.0) and using a new assay from ortho-clinical diagnostics which is able to quantify total hcv core antigen. sustained virologic response was observed in 65% of the patients (36/55). after 1 month of ifn treatment, sustained responders had a fall of hcv rna and hcv core antigen higher than non-responders (4.339/1.84 log ui/ml versus 0.159/0.31 log ui/ml, p b/0.001, for hcv rna) and (1.689/ 0.89 log (pg/ml)/10 000) versus 0.179/0.18 log (pg/ml)/10 000) p b/ 0.001, for hcv core antigen). after 1 month of ifn, the positive and negative predictive values of sustained response were, respectively, 100 and 17.4% for hcv rna negativation and 97.5 and 37.5% for hcv antigenemia negativation. these results suggest that both kinetics of viral load and antigenemia are highly predictive of sustained response. theodorou m, petinelli i, pontikaki d, mela c, blana a, papanastasiou a, toliopoulos a, stavrakaki m, sagkana e. microbiology department, western attika general hospital, greece, egaleo, greece greece has accepted a big number of economic immigrants lately. we investigate the prevalence of hepatitis b/c as well as the epidemiological features that might influence the public health. 1.235 economic immigrants from: albania 630, eastern europe 411 and from asiatic-african countries 194, visited our hospital to be checked in order to get a health certificate to obtain the green card. they where tested for hepatitis b/c. the serological markers were determined by immunoenzymatic method. all hbsag('/) and anti-hcv were further tested for hbv dna and hcv rna by competitive rt pcr. hcv rna('/) were genotyped by strip hybridization immunoassay. in 630 albanians 17.5% were hbsag('/), 14.6% hbv dna('/), 1.1% anti-hcv('/) and 0.8% hcv rna('/). in 411 east europeans 5.1% were hbsag('/), 4.4% hbv dna('/), 2.43% anti-hcv('/) and 1.9% hcv rna. in 194 asians-africans, 2.6% were hbsag('/) and 2% hbv dna('/). in 101 pakistanis, 26.7% were anti-hcv('/) and 22.0% hcv rna('/). of the rest of asians-africans, 11.82% were anti-hcv('/) and 9.3% hcv rna('/). albanians: higher prevalence of hbv infection (14.6%). greek blood donors: 1% pakistanis: hcv infection is 22% (predominance of 3a type), general greek population: 2%. public health services in greece and europe must take appropriate measures. el zawawy la a , mohamed on b , ali sm a , eissa me a , allam sr a . a faculty of medicine, parasitology, alexandria, egypt , b high institute of public health, microbiology, alexandria, egypt the purpose of the study was to investigate the influence of schistosomal suppression on the antibody response to hepatitis-b vaccine (hbv) and to study if the vaccine has any protective effect on experimental () infection. the results obtained revealed that infection reduced the serum antibody level against hbv. parasitological and histopathological findings showed significant protection against infection. the conclusion reached was; in order to reduce the incidence of virus-b infection especially in schistosomiasis endemic areas, public health officials should evaluate a policy for regulation of hbv booster vaccination to enhance the population immunity against hepatitis-b infection. cooper e, fisher t, shingadia d. newham general hospital, family clinic, london, uk sustained anti-retroviral combination chemotherapy requires excellent adherence to the regimen so as to suppress viral replication sufficiently to delay the emergence of resistance. if chemotherapy were taken to scale, e.g. in africa, erratic adherence might soon lead to multi-resistant circulating virus. we reviewed our experience in a well established london family clinic with a team including community nurses. we reviewed the records of the 23 african immigrant children, aged 2 á/14, treated with anti-retrovirals exclusively at our centre throughout 2001. whereas 14 had undetectable hiv rna within the year, only four had undetectable rna throughout the year. four failed therapy through proven resistance mutations, but nine were considered through circumstantial evidence to have rising viral loads primarily because of poor adherence. three were known to have stopped taking drugs for extended periods. the three boys over 11 years were unreliable in adherence, but the one girl in this age-group was fully adherent. our preliminary assessment is that for the children in our families, despite a team approach and home visits, nonadherence to haart may be twice as common as selection of a dominant viral mutant as a primary cause of failure to sustain viral suppression. quiros-roldan e, moretti f, castelli f, el-hamad i, carosi g. the prevalence of hiv related lipodystrophy-syndrome depending on the definition and severity of lipodystrophy ranges from 5 to 80%. we have retrospectively reviewed the medical records of 58 african patients followed. the characteristics are shown in the 3.4% of africans had triglycerides !/200 mg/ml and 1.7% had cholesterol !/250 mg/ml, none had both metabolic alterations. glycemia !/120 mg/ml was observed in 8.6% patients. it is interesting highlight that in any the africans morphological changes were noted and all of them showed weight stable. although the low prevalence of metabolic alterations may be attributed to the different ethnic alimentary behavior if self-body perception by african is not as accurate as by caucasian on the estimation of the body changes have to be investigated. alabaz d a , alhan e a , yaman a b , evliyaoglu n a , kocabas e a , aksaray n a . a division of pediatric infectious diseases, cukurova university, adana, turkey , b department of microbiology, cukurova university, adana, turkey hepatitis a virus (hav) infection is usually asymptomatic in children. however, it may occasionally cause a severe disease with high morbidity and mortality, and loss of school or business days. in a previous study, we have shown that every one of two to three school children from upper social classes living in adana carries high risk of hav infection. it is well known that maternally transmitted anti-hav antibodies interfere with hav vaccination. in an effort to determine the optimal age for hav vaccination, 122 babies (52% girls and 48.5% boys) born in our hospital were prospectively followed up at least 24 months for the presence of maternal antibodies to hepatitis a (anti-hav igg). anti-hav igg titers were measured from the blood specimens obtained at birth from the mothers and from the offsprings at months, 0, 3, 6, 9, 12, 15, 18, 21 and 24. the prevalence of positive anti-hav at birth (95%) was similar to those of hav seroprevalance studies carried out in adults in our area. the disappearance of antibodies occurred between the 1st and 21st month of life. the prevalence of anti-hav igg among children aged 0, 9, 12, 15, 18 and 21 months were 95, 60, 32, 9, 4 and 0%, respectively. in light of these findings, we suggest that hepatitis a vaccination be given after 21 months of age. earlier vaccination may be ineffective due to interference with maternally transmitted anti-hav antibodies. ghaderi b, alaghebandan r, rastegar lari a. department of microbiology, iran university, tehran, islamic republic of iran diarrhoea is a major public health problem in developing countries. amoebiasis is one of the most common causes of diarrhoea in iran as an endemic area for amoebiasis. little, however, is known about the extent of the condition in our society. the aim of this study is to determine socio-demographic and clinical characteristics of patients with intestinal amoebiasis. during july and august 2001, we collected 90 patients with diarrhoea among 5000 patients who visited at a referral hospital in shahriar area (in countryside of tehran), iran. thirty out of 90 patients (33%) had intestinal amoebiasis and were followed up prospectively until the resolution of the illness. nineteen of 30 (63.3%) patients were male and the remaining of 36.7% was female. the patients were aged 1 á/76 with mean of 28.4 years. most of the patients (70%) were below 30 years of age and the peak of occurrence was between the age of 17 and 26 years. watery diarrhoea with abdominal cramps was the main clinical feature. seventy percent of patients were resident in urban area and the remaining (30%) in rural area. average family income was low and all patients were in low socioeconomic level. water supplying system for all patients was pipeline water. low socioeconomic level associated with poor personal hygiene was the most important factor for highly prevalence of this problem in our society. also it seems that food plays important role in transmission of protozoa then water. the new strategy for allele identification of the genes coding for pertactin and pertussis toxin subunit s1 in bordetella pertussis ps170 bordetella pertussis strains demonstrate a significant polymorphism in toxin s1 subunit and pertactin, which are major protective antigens of the organism. monitoring the changes in prevalence of particular alleles of genes coding for these proteins in local b. pertussis populations is an essential issue in cases of the observed decrease of vaccination effectiveness. we have developed a new method for allele identification of these genes, which eliminates the necessity of dna sequencing. the approach is based on the identification of the number of repeats or the presence of specific nucleotides in the polymorphic regions or residues, respectively, of the genes and utilises products of their full or partial pcr amplification. the nucleotide heterogeneity in each polymorphic site is analysed either by the differential digestion of the amplicons or by the arms (amplification-refractory mutation system) methodology. numbers of repeats in particular regions of the genes are revealed by the size analysis of the adequate pcr products or their restriction fragments. in all cases the presence, size or pattern of dna molecules obtained is visualised by the agarose gel electrophoresis. the preliminary analysis of the recent and archival b. pertussis strains identified in poland was performed using the described approach. the presented strategy provides a much easier, faster and more cost-effective than dna sequencing mean to study the polymorphism of the major b. pertussis antigens. vaccination coverage and history of vaccine preventable infectious diseases among students in second year of medicine and pharmacy of tours university ps171 borderon jc a , hamed a b , ragot s b . a centre hospitalier universitaire, tours, france , b médecine préventive universitaire, tours, france the purpose of this study was to determine the level of infectious risk in students who will be exposed to patients. information was obtained by a questionnaire for each student, and by checking medical records for immunization coverage and vaccine preventable infectious diseases. answers could be specified for 138 students, of whom 97 females (f) and 41 males (m). the number of non-immunized students was against diphtheria: two, tetanus: three, pertussis: four, poliomyelitis: two, hepatitis b: six, and hepatitis a: 127, respectively. among the 52 students non-vaccinated against measles, 14 (nine f and five m) had no history of that disease. among 56 (31 f and 25 m) non-vaccinated against rubella, 17 (10 f and seven m) had no history of that disease, uncertain in seven others (six f and one m). the date of vaccination was often late regarding recommendations. fifteen students had no history of varicella. one student had not received bcg vaccination. fifty-eight students had received two, and 14 three bcg vaccines. post-bcg tuberculin skin testing was missing after 28 first bcg, 14 second and 3 third bcg. the date of the first tuberculin test was often one or several years after bcg vaccination. adverse effects of vaccination were rarely reported: two cases of fever (dt polio, measles); three cases of local reaction (dt polio, dtp polio). one case of contraindication for influenza vaccine: egg allergy. the survey shows failure in immunization coverage actually recommended in health care students. objectives: to present the morbidity of rabies and evaluate the efficiency of our prophylaxis scheme in lasi county. material and method: we made a retrospective study of the rabies cases in the patients admitted in our unit in a 13th-year period. we have analysed all the clinical, epidemiological and biological aspects. results: in a 30-year period, 22 cases of rabies were admitted in the clinical infectious diseases hospital lasi. the highest incidence was for 1986 á/1990 */eight cases (36%); the highest yearly cases were three cases in 1974 and 1986. most of the patients were male (59%), came from suburban areas (21 patients). eight cases occurred in may á/june, wild animals were involved in half the cases (fox, wolf). for 18 patients, no prophylaxis was performed and an incomplete course in four cases. the period of time to the appearance of the first symptom was 18 á/120 days. the prophylaxis scheme led to a good protection. conclusions: in lasi county, rabies is a problem with a prevalence of 0.73%/year. trends in the use of antimicrobials in riyadh in 2000 were analyzed. data was obtained from a survey of 652 randomly selected families of school children aged 6 á/8 years in a 3-month period in 2000. one hundred and ninety-nine (33.8%) students were on antibiotics in the month preceding the study; 108 (56%) received antibiotics for the diagnosis of pharyngitis; 177 (90%) students antibiotics were prescribed by a physician; and in 161 (83%) the duration of antibiotics was less than 1 week. this study shows a major problem in antibiotics prescription in our community and also the need to establish effective antibiotics policy in general practice to limit the potential emergence of drug resistance bacteria in the community. mir s a , cura a a , erdogan h a , guler s a , sengul gn a , koyu a a , ozinel ma b . a department of pediatrics, ege university medical faculty, izmir, turkey , b department of microbiology, ege university medical faculty, izmir, turkey antibiotic susceptibility spectrum of childhood urinary tract infection agents are geographical variation. the current antibiotic regimens and the selection of antibiotics for prophylaxis should be re-evaluated periodically. the objective of our study was to determine the local resistance rates to antibiotics and to give a direction for the selection of antibiotics in uti treatment. we evaluated 4124 urinary culture assays retrospectively, sent from pediatrics and pediatric surgery inpatient and outpatient clinics of our hospital during the last 6 months, and investigated the isolated pathogens and the resistance rates to antibiotics. in addition, the data obtained were compared with of 5 years ago. with respect to the resistance rates to antibiotics of uti pathogens, the resistance rates of e. coli for carbapenems, aminoglycosides and third generation cephalosporins were 1, 10 and 10%, respectively as before, but the rates for ampicillin increased from 67 to 75% and for tmp-smx it increased from 49 to 61%. we concluded that the resistance profiles to antibiotics should be reviewed every 5 years at least and thus the selection of proper antibiotics would lessen the morbidity as well as the medical expenses. chanturidze tk, tsiklauri r. ministry of labor, health and social affairs, public health, tbilisi, georgia purpose: since 1991 infectious diseases (id) are increasing in georgia. this study is aimed to reveal economic barriers of effective id control by assessing financial contribution to id from public and private sources, household's total spending on health and their capacity to pay. sources: 1) national household expenditure and revenue survey. 2) who fair financial contribution methodology. 3) meta-analysis. results: 51.8% of population leaves under the poverty level; 70% out of total household expenditure (average 270 gel; us$ 130) 30% is spent on food */non-subsistence income covers expenditures on goods and services including health; 15% of population refuses health services because of inability to pay; public spending on health comprises 33% of total health expenditures; public spending on id control is below 1 gel per capita; almost all private spending goes to id treatment and equals to 28.6 gel per patient. conclusions: insufficient public spending on id control transfers the burden to the population with extremely low capacity to cover health expenses. refusal to utilize health services, and incomplete treatment and increases the threat of id spread and drug resistance. government should increase the allocations to id from public sources for effective id control in georgia. antimicrobial consumption trends in children's university hospital ps177 ratchina s a , averchenkova l b , jarkova l a . local surveillance of antimicrobial (am) consumption is essential to promote the rational use of this group of drugs. the purpose of this study was to analyze the trends of am use in the children university hospital in 1998 and 2000. data on am usage were obtained from the hospital drugstore requests in the 250-beds multi-ward children university hospital. consumption was expressed as the number of ddd per 100 bed-days (b á/d). the total am consumption figures were similar in 1998 and 2000 (7.7 and 8.2 ddds/100 b á/d, respectively) with notable differences in am prescribing patterns. penicillin consumption increased from 1.8 to 3.8 ddds/100 b á/d mostly due to amoxicillin. the overall aminoglycoside usage remained comparable (0.95 vs. 0.82 ddds/100 b á/d) though amikacin has considerably replaced gentamicin. there was a sevenfold increase of ciprofloxacin (0.03 vs. 0.2 ddds/100 b á/d) along with the evident decrease of tetracycline and co-trimoxazole consumption found (1.5 vs. 0.9 ddds/ 100 b á/d and 0.8 vs. 0.1 ddds/100 b á/d, respectively). the tendency to prescribe more effective in respect of the local resistance data and/or more safe am was detected in 2000 comparing with 1998 that can be explained by the introduction of the local guidelines for infectious diseases management in 1999. clarithromycin in the treatment of chronic prostatitis caused by chlamydia trachomatis */a pilot study ps178 the aim of this pilot study was to determine the efficacy and tolerability of clarithromycin in the treatment of chronic prostatitis caused by chlamydia trachomatis (ct). fifty-two patients older than 18 years of age with diagnosed chronic chlamydial prostatitis were enrolled. the presence of ct in expressed prostatic secretion or urine specimen voided immediately after prostatic massage was confirmed by isolation on mccoy cells and lugol staining. the majority of patients suffered from suprapubic pain and pain in the groin. twelve patients had no clinical symptoms. according to rectal palpation, prostate gland was normal in 35 patients, tender and soft in 12 and firm in five patients. clarithromycin was administered orally 500 mg twice daily for 14 days. simultaneously the patients' partners received 500 mg orally twice daily for 7 days. clinical efficacy and tolerability of administered clarithromycin were evaluated 1 á/7 days and 4 á/6 weeks after the end of treatment. bactericidal efficacy of administered drug was evaluated 4 á/6 weeks after the end of treatment. the eradication of ct was achieved in 30 out of 40 patients, while 28 patients were clinically cured. two patients had nausea and elevated serum transaminases. in asymptomatic patients, the eradication of ct was achieved in 10 of 12 patients who reported no side effects. this pilot study has shown an excellent efficacy and tolerability of clarithromycin in the treatment of patients with chronic chlamydial prostatitis. women with diagnosis of urinary tract infections (uti) often demonstrate vaginal colonisation with alpha-haemolytic escherichia coli strains. in the present study we decided to evaluate a distribution of virulence genes encoding for cytotoxic necrotizing factor type 1 (cnf1), p-fimbriae, s/f1c-fimbriae aerobactin (aer), and afa genes in alpha-haemolytic e. coli strains isolated from gynaecological material in our region and to compare the detected sequences in clinical isolates of other diagnostic groups. of 127 alpha-haemolytic e. coli strains, 41 were isolated from urine, 44 from gynaecological specimen, and 42 were faecal strains. e. coli strains were tested for the production of haemolytic phenotype on blood agar plates. the amplification of virulence factors was performed by pcr according to previously described protocols (le bouguenec et al., 1992; blanco et al., 1996; and yamamoto et al., 1995) . we found that all gynaecological alphahaemolytic strains were positive for cnf1, (p b/0.001 compared to 78% of urine strains, and p b/0.0001 compared to 61% of faecal strains). similarly, sfa/foc specific dna sequences were found in 100% of gynaecological isolates (p0/0.01 compared to 85% of urine strains and p 0/0.005 compared to 83% of faecal strains). from this point of view, the female genital tract seems to be a potential reservoir of these uropathogenic e. coli strains. azithromycin in the treatment of pelvic inflammatory disease caused by chlamydia trachomatis ps180 administered in 35 hospitalized patients with chlamydial pid. the diagnosis was made prior to hospitalization. microbiological analysis of urine, blood and swab specimens collected from endocervix, vagina and urethra confirmed c. trachomatis to be the single suspected causative pathogen of pid. the presence of c. trachomatis in swab specimens from endocervix was examined by dnk/rnk hybridization. azithromycin was administered 5 á/7 days after samples for microbiological analysis were collected in dose of 1)/500 mg iv for 5 days. clinical efficacy and tolerability of therapy were assessed 1 á/7 days after the end of therapy and clinical and microbiological analysis 3 á/4 weeks after completion of therapy. the eradication of c. trachomatis and normalization of gynecological findings were achieved in 33 and disappearance of subjective symptoms in 30 patients. no side effects and deviations from normal values in hematologic and biochemical blood parameters were recorded. this study showed high bactericidal efficacy, rapid clinical effect and good tolerability of once-daily administration of 500 mg azithromycin for 5 days in the treatment of patients with pid caused by c. trachomatis . altindis m a , cevrioglu s b , aktepe oc a , cetinkaya a . a kocatepe university school of medicine, microbiology, afyon, turkey , b kocatepe university school of medicine, obstetrics and gynecology, afyon, turkey diagnosis of the causative organism of the vaginitis is usually based on clinical criteria. a standardized, laboratory based and rapid diagnostic test for the identification of these organisms is desirable. to determine the laboratory method that best predicted the causative organism, we calculated the sensitivity, specificity and predictive value of positive and negative test for clinical criteria, an oligonucleotide probe test (affirm vpiii-bd usa) and compared them with the combination of positive vaginal culture and gram-stained vaginal smear. we evaluated 40 consecutive women aged 21 á/48 years, attending for vaginal discharge. vaginal swab specimens were used for culture of gardnerella vaginalis , trichomonas vaginalis and candida sp, preparation of a vaginal smear for gram-stain interpretation and wet mount evaluation and affirm test. affirm detected g. vaginalis in 10 (25%), candida sp in three (7.5%) women and no trichomoniasis case found by any methods. the sensitivity and negative predictive values of affirm test and clinical signs were same (100%) in identifying of bacterial vaginosis. however, affirm test was more specific (94 vs 72%) and also has higher positive predictive value (80 vs 53%) than clinical signs. we did not evaluate the results for patients with candidiasis because of less number. according to these results affirm-microbial identification tests are objective and specific for the rapid diagnosis of the bacterial vaginosis. comparison of efficacy of single dose of tinidazole with standard dose of metronidazole in giardia lamblia infection (preliminary report) ps182 fallah m a , moshtaghi aa b . a university of medical sciences, parasitology, hamadan, islamic republic of iran , b university of medical sciences, pediatrics, hamadan, islamic republic of iran objectives: giardia lamblia is the most common intestinal protozoa in developing countries. treatment of the infection with metronidazole, the drug of choice, requires a long course of therapy and produced some side effects. the object of this study is to determine efficacy and side effects of tinidazole in g. lamblia infection. this is a preliminary report of an ongoing trial. methods: a randomized controlled clinical trial was carried out and 47 subjects with g. lamblia infection were treated with tinidazole or metronidazole. tinidazole 50 mg/kg single dose and metronidazole 25 mg/kg three times a day for 7 days were given orally to 24 and 23 children, respectively. parasitological cure was documented when there were consecutive negative stool examinations at 1 á/2 weeks after therapy. results: twenty-one of 23 individuals treated with tinidazole and 20 of 24 children treated with metronidazole had parasitological cure. cure rates between two groups were not significant statistically. no major side effects were observed except one case in metronidazole group who had mild headache and abdominal pain for 2 days. conclusions: we concluded, tinidazole at the dose has efficacy equal of metronidazole in the treatment of g. lamblia infection. because of single dose prescription, short course of therapy and good compliance of patients, this preparation is preferred to metronidazole in giardial infection. ebeid fa, seif el-din sh. theodor bilharz research institute, pharmacology, cairo, egypt b-carotein was given in different doses starting from 2.5 to 10 mg/kg body weight (b.w.) for different groups of albino mice 4 days before infection with s. mansoni . infection of animals was done by body immersion using 80 egyptian strain of s. mansoni cercariae/mouse. forty-nine days after infection the animals were sacrificed and hepatic and mesenteric worms were extracted and determined. ova count in liver and intestinal tissue and the total number of worms/animals were also determined in experimental groups comparing with infected control animals. the results indicated marked decrease in number of worms and ova count in both liver and intestine comparing with control ones. this reduction increased significantly with increasing dose. it was concluded that b-carotein could be used as a prophylactic agent against s. mansoni infection. barisic z, babic-erceg a, borzic e, zoranic v, carev m, kaliterna v. department of microbiology, public health institute, split, croatia the aim of this study is to determine frequency of pseudomonas aeruginosa urinary tract infection (uti) in outpatient's population in south croatia and to suggest optimal antimicrobial treatment for these patients. during 3 months long observation period, from total number of 13 158 examined urine specimens, significant bacteriuria was found in 2341 specimens. p. aeruginosa was the sixth most common isolate, it was isolated from 94 specimens (4.02%). these 94 specimens were taken from 57 different patients. susceptibility testing was performed by disk diffusion method, and the following results were obtained: resistance to cefibuten occurred in 94.74% patients, to norfoxacin in 49.12%, to ciprofloxacin in 47.37%, to gentamicin in 42.11%, to netilmicin in 35.09%, to amikacin in 24.56%, to ceftazidime in 3.51% and to imipenem in 1.75% patients. p. aeruginosa strains showed better susceptibility to tested parenteral antibiotics than to antibiotics for oral use which complicated treatment in outpatients. the best susceptibility was shown to imipenem, but this drug is inappropriate for use in outpatients setting, so the best choice for treatment p. aeruginosa uti in our outpatients is treatment with ceftazidime, and the second choices are aminoglycoside drugs amikacin and netilmicin. silan l a , breza j b , krcmery v jr. c . a department of internal medicine, derer s university hospital, bratislava, slovakia , b department of urology, comenius university school, bratislava, slovakia , c department of pharmacology, st. elisabeth cancer institute, bratislava, slovakia we studied the clinical efficacy of oral treatment with ciprofloxacin/ cpf/ alone and combined with clarithromycin in patients with complicated urinary tract infection/cuti/ with or without an indwelling catherer. patients were randomly allocated to 600 mg cpf/cpf group/ or to 600 mg cpf plus 600 mg cam/combination group/ for 14 days. evaluation was done on day 14 according to the criteria advocated by the japanese urinary tract infection committee. in patients with a urinary catherer, the combination achieved a higher complete bacterial elimination rate /50%/ and clinical efficacy rate / 84%/ than cpf alone /30 and 61.5%, respectively/. while no significant difference was found in the bacterial elimination rate between the two groups, the clinical effect of the combination /40%/ was superior to that of cpf alone /23%/ in patients with an indwelling catherer. the better clinical efficacy of the combination may partly be attributed to the antibiofilm effect of cam in the clinical setting. the results also indicated that difficulties still remain in the treatment of cuti in patients with an indwelling catherer. in conclusion, clinical study suggested that cam might have an inhibitory action on biofilm formation in the clinical setting. combination of cam with other appropriate antimicrobial agents may have a favorable effect on the treatment of cuti. vesicoureteral reflux and urinary tract infections */the management of primary vesico-eureteral reflux in children ps186 the children studied presented with primary vesicoureteral reflux at derer s universitz hospital in bratislava between 1974 and 1994. seven hundred and sixty patients, 179 boys and 581 girls, suffering from primary vesicoureteral reflux in age from 6 months to 18 years were tested and systematically analyzed outcomes data for seven treatment alternatives. key outcomes identified were probability of reflux resolution, likelihood of developing pyelonephritis and scarring, and possibility of complications of medical and surgical treatment. available outcomes data on the various treatment alternatives were summarized and the relative probabilities of possible outcomes were compared for each alternative. conclusions: increased of urinary tract infection, vesicoureteral reflux nephropathy includes early diagnosis, appropriate evaluation, effective atb therapy, and surgery indicated. the main determinants of renal damage are bstruction, age, sex, predisposition on renal scarring, reflux grade and laterality, therapeutic delay, individual susceptibility, bacterial virulence and immunogenetic status. 3) the one and only absolute indication for surgical management is failure of medical therapy to prevent chronic recurrent pyelonephritis, renal injury or other reflux complications and eliminations of the reflux condition will minimize their likelihood. genetically conditioned immunopathogenic mechanisms are involved in the pathogenesis of the chronic recurrent pyelonephritis in patient suffering from vur. for most children we recommended continuous antibiotic prophylaxis as initial treatment-medical therapy is based on the principle that reflux often resolves with time, and antibiotics maintain urine sterility and prevent infections while the patients awaits spontaneous resolution. 6) vur predispose an individual to renal infection, the immunological and inflammatory reaction caused by a pyelonephritic infection may result in renal injury or scarring. silan l a , breza j b . a department of internal medicine, derer s university hospital, bratislava, slovakia , b department of urology, comenius university school of medicine, bratislava, slovakia elderly patients with uti are believed less likely to be cured by antimicrobial therapy than younger patients. the reasons for this poorer outcome have not yet been clarified. we have investigated the efficacy of antimicrobial therapy in elderly patients with complicated uti. five hundred patients, 260 men and 240 women, who had complicated uti/268 symptomatic and 240 symptomatic and were 21 á/80 years of age, were treated with one of three different drugs, one was a never quinolone and two were oral cephems. multivariate logistic regression analysis of treatment outcome revealed that the clinical response was significantly related to general underlying diseases and diseases of the urinary tract, but not to age, symptomatic or asymptomatic uti, or infection site such as the kidney or bladder. we concluded that the clinical effectiveness of an antimicrobial agent was not directly related to age, and that urological examination for underlying disease and control of them is quite important for effective treatment and control of complicated utis, especially in elderly patients. the study on the frequency and antimicrobial resistance of escherichia (e ) coli in urine isolates of patients admitted to maribor teaching hospital in 1998 and 2000 ps188 rebersek gorisek j a , baklan z a , unuk s a , novak d b . a department for infectious diseases, teaching hospital maribor, maribor, slovenia , b department for microbiology, regional institute of public health maribor, maribor, slovenia purpose: the aim of the study was to determine the frequency and antimicrobial resistance of escherichia coli isolated from urine samples of patients admitted to maribor teaching hospital in 1998 and 2000. the frequency and the antimicrobial resistance were compared between years 1998 and 2000. methods: in the prospective study going on between 1998 and 2000, all urine isolates from patients at maribor teaching hospital were collected and analysed. urine cultures were done using the modified sanford method. the susceptibility testing was performed by disk diffusion method according to nccls. results: in the year 1998, 2563 urine isolates and in the year 2000, 2325 urine isolates were analysed. e. coli represented 39.1% of urine isolates in 1998 and 39.4% of urine isolates in 2000. e. coli resistance rates (%) to amoxycillin was 39.5 in the year 1998 and 38.4 in the year 2000; to amoxycillin/clavulate was 15.4 and 10.5; to cefalotin was 7.8 and 5.7; to cefaclor 2.8 and 2.18; to trimethoprim sulfamethoxazole was 15.0 and 18.4; to ciprofloxacin was 4.9 and 6.9; to gentamicin was 2.3 and 2.2. conclusion: compared to 1998, the frequency of e. coli isolated from urine samples is similar to that in the year 2000. the resistance to amoxycillin, cefaclor and gentamicin is stable. the resistance to trimethoprim sulfamethoxazole and ciprofloxacin is increased and the resistance to amoxycillin/clavulate and cefalotin is decreased. prevalence of the resistance to metronidazole, furazolidone and nitrofurantoin in helicobacter pylori clinical strains ps189 de la obra sanz p a , roman jl a , lomas e a , villar h b , lopez-brea m a . a hospital de la princesa, microbiology, madrid, spain , b hospital de san agustin, microbiology, aviles, spain the objective of this study was to determine the prevalence of metronidazole, furazolidone and nitrofurantoin resistance in helicobacter pylori clinical isolates. methods: a total of 286 strains of h. pylori were included in this study. all these were tested against metronidazole, and 164 against furazolidone and nitrofurantoin by an agar dilution method. resistance was defined as: metronidazole, mic !/8 mg/l; and mic !/4 mg/l for furazolidone and nitrofurantoin. results: sixty-eight strains were resistant to metronidazole (23.8%). the mic50 and mic90 values were 1 and 32 mg/l, respectively. three of 164 strains (1.8%) were furazolidone resistant (mic 0/4 mg/l), two of these strains were metronidazole resistant (mic0/16 mg/l) and they had mic of 2 mg/l for nitrofurantoin. the mic50 and the mic90 were 0.125 and 0.5 mg/l, respectively for furazolidone. only one of the 164 strains (0.6%) was nitrofurantoin resistant (mic 4 mg/l), this strain was metronidazole resistant (mic 128 mg/l) and had a mic0/1 mg/l for furazolidone. the mic50 and the mic90 were 0.5 and 1 mg/l, respectively for nitrofurantoin. conclusion: the low frequency of furazolidone and nitrofurantoin resistance, compared to metronidazole suggests that the furazolidone and the nitrofurantoin may be good alternatives to metronidazole for treatment of h. pylori infections. antimicrobial resistance of campylobacter isolated from human origins ps190 zhukhovitsky vg, drabkina iv. department of bacteriology, botkin hospital, moscow, russian federation the purpose of the study was to determine the antimicrobial resistance of 50 thermophilic enteropathogenic campylobacter spp. (tec) isolated from human under acute diarrhoea in 2001 in moscow. among 50 tec strains 45 c. jejuni and five c. coli were identified. the antibiotic tested by disk diffusion test on mueller-hinton agar with sheep blood were ampicillin (a), amoxycillin/clavulanate (ac), imipenem (i), meropenem (m), erythromycin (e), clarithromycin (cl), tetracycline (t), doxycycline (d), gentamicin (g), azithromycin (az), chloramphenicol (ch), lincomycin (l), ciprofloxacin (c), nalidixic acid (na). the resistant rate of the tec isolates was highest for na (42%) followed by a (38%), t (36%), d (20%), n (20%) and cl (16%). a moderate resistance rate was obtained for a (8%), ch (6%), az (6%), ac (2%). none of the isolates demonstrated resistance to i, m and g and four of 50 isolates (8%) were sensitive for all the antibiotics tested. mic90 to na was estimated as 64 mg/l. among 21 na resistant tec strains 20 (40%) were identified as c. jejuni and one (2%) as c. coli . among c. jejuni and c. coli na resistant rate was 44 and 20%, respectively. one na resistant c. coli and nine na resistant c. jejuni were resistant to ciprofloxacin. ring c, atanassova v. department of food hygiene and microbiology, school of veterinary medicine, hannover, germany aim of the study: poultry meat is known to be often contaminated with salmonella and other foodborne pathogens and thus has to be considered as a possible source for human infections. the aim of the study was to monitor the resistance of salmonella isolates from poultry meat of different european countries to various antibiotics. material and methods: from september 2001 to december 2001 a total of 422 samples of frozen poultry meat from france, germany, italy, spain, the netherlands and portugal were examined for the prevalence of salmonella using classical cultural detection as well as rflp-pcr. all isolates were tested for their sensitivity towards ampicilline, kanamycine, ciprofloxacine, tetracycline, trimethoprim, sulfamethoxazole, nalidixic acid and erythromycine using standard procedures. results: from 18.01% of all examined samples salmonella spp. were isolated. of these isolates 32.9% were characterized as salmonella , 42.1% as s. hadar and 17.1% as s. typhimurium . nearly 100% of all isolates were resistant to erythromycin. resistance towards four or more isolates was observed in several cases. discussion: the consumption of poultry meat, if insufficiently prepared, has still to be considered as a major source for human infection with salmonella spp. the question arises whether the resistance of the isolates to various antibiotics is of clinical importance in the treatment of the patients. objective: to provide insight into the epidemiologic situation of salmonellosis for the nis area (the largest area in serbia, with inhabitants */648,000). methods: the material was processed at the institute for public health (epidemiology and microbiology divisions). isolation of microorganisms was performed on apparatus for rapid identification (vitek-biomerieux) and by applying elisa tests and classical microbiological methods. results: in the period 1992 á/2000, 2857 salmonella laboratory confirmed cases were reported. the greatest number of diseased in the 0 á/4 years group. the most frequent isolated salmonellae were: s. enteritidis (83.7%) and s. typhimurium (11.2%), s. hadar , s. agona , s. virchow , s. infantis , s. derby , s. enteritidis showed the greatest sensitivity to antibiotics with the infrequent resistance to ampicillin and trimethoprim-sulfamethoxazole. s. typhimurium showed the greater resistance to the wide spectrum of antibiotics and some isolates were resistant to all antibiotics tested. the less common types of salmonella were sensitive to all antibiotics except trimethoprimsulfamethoxazole and ampicillin. conclusion: specific resistance to some antibiotics was related to serotypes. typhoid fever */retrospective study of 52 cases in lebanon ps193 tohme a, abboud j, ghayad e. hôtel-dieu hospital, internal medicine, beirut, lebanon objectives: to present epidemiological and clinical features of typhoid fever in lebanon. methods: fifty-two patients were seen at hotel-dieu hospital of beirut between 1995 and 1999. diagnostic criteria were positive blood culture for s. typhi or paratyphi and/or a somatic o agglutinin titer ]/ 1/160 as determined by the widal test with symptoms suggestive of typhoid fever. we also present an epidemiological study of 3864 cases registered by the ministry of health during the same period. results: among the 3864 cases, 40% of the patients' ages were between 15 and 40 years and 33% were less than 14 years. the overall male to female ratio was 0.98 and 24% of cases were seen on january, february and 11% on august. among the 52 patients, young adults were the most affected. average duration of symptoms before the diagnosis was 109/8 days. the main presenting symptoms were: fever (96%), diarrhoea (37%), abdominal pain (31%) and headache (29%). complications were noted in 33% of cases and digestive complications were the most prevalent. leucopenia was not a helpful diagnostic marker. s. typhi was the most frequent (84%) serotype identified. resistance to ampicilline was 13%, to cotrimoxazole and chloramphenicol 10% for each. the mortality rate was 2%. conclusion: typhoid fever is still an endemic disease in our country and the occurrence of resistant strains of s. typhi will favor ceftriaxone or fluoroquinolones in the treatment. maaloul i a , hammami b a , zambaa f a , elleuch r a , hammami a b , -ben jemaa m a . a chu hedi chaker, service des maladies infectieuses, sfax, tunisia , b chu habib bourguiba, laboratoire de microbiologie, sfax, tunisia although its not very frequent, the psoas abscess is not an exceptional entity. in order to specify its clinical, biological, radiological and evolutionary features, a retrospective study has been led in our service, on a period of 14 years (january 1988 á/december 2001). on the whole, 25 cases have been listed. they were 16 men and 9 women. the age average was 40 years (extreme 14 á/74 years). the study did not find any underlying diseases, except diabetes mellitus for three patients. the clinical symptoms were dominated by fever with abdomino-lumbar aches (20 cases), and psoitis (eight cases). biology showed an inflammatory syndrome in all cases and a hyperleucocytosis in 17 cases. the diagnosis of psoas abscess, evoked on clinical data, has been confirmed by the imagery data: ultra-songraphy (16 cases), ct scanning (six cases), magnetic resonance imaging (three cases). the tubercular etiology has been confirmed in six cases, among which two were associated to escherichia coli (one case) and to brucella melitensis (one case). the other etiologic agents were dominated by staphylococcus aureus (eight cases), b. melitensis (two cases), e. coli (one case), bacteroides fragilis (one case), streptococcus anginosus (one case), fusobacterium nucleaticum (one case) and candida glabrata (one case). all patients received an anti-infectious treatment adapted to the micro organism in question. a drainage of the abscess has been realized for 15 patients (percutaneous: nine cases, surgical: six cases). the evolution was favourable for 23 patients. however, two patients had a relapse after stopping the treatment. conclusion: the diagnosis of the psoas abscess, difficult on the clinical data, is based on the imagery techniques (us, ct, rmi). the percutaneous drainage guided by the imagery is recommended (in an etiological and therapeutic aim). associated to an adapted antibiotherapy, it allows to defer a surgical drainage. zezoski mbz, nikolova o, gavriloski pmg. medical center, infectious diseases, prilep, the former yugoslav republic, macedonia purpose: to make a list of the most frequent abdominal changes in patients with human brucellosis. materials and methods: there were 769 new patients with human brucellosis, between 01 1991 and 12 2001. diagnosis was made using standard clinical, biochemical and serological investigations (bab, wright, coomb's, rvk, 2-mercaptoethanol, elisa igm and igg), and specially ultrasound examination of the abdomen and retro peritoneum. results: weight loss is the most frequent change, presented in 665 (86.5%) patients. follow atypical abdominal pain in 89 (5.3%), vomiting in 59 (7.7%), diarrhea in 44 (5.3%), enlarged liver in 594 (77.2%), enlarged spleen in 573 (74.5%) and hepatic lesion with increased ast and alt in 174 (22.6%). conclusion: although frequent, abdominal changes seldom could be missed in patients with human brucellosis. we recommend routine ultrasound examination with standard biochemical test for liver function, due to avoid unnecessary complications. osteoarticular complications are common in brucellosis. the most common site of involvement is the sacroiliac joint. the osteoarticular complications such as, sacroiliitis and spondylitis are diagnosed with radiologically. in the present study, we aimed to determine the severity (grade) of sacroiliitis by using some laboratory parameters such as esr, crp and tube agg test. seventy-two (34 male, 38 female) patients with brucellosis were included in the study. osteoarticular involvement was present in 44 patients. the most common osteoarticular finding was sacroiliitis in the patients (86%). twenty (20) healthy subjects were formed the control group. there was statistically significant difference between patients and controls regarding esr, crp, and tube agg test (p 0/0.000, 0.0017, 0.000, respectively). in addition, sacroiliitis has an effect on esr and crp. there was a positive correlation between the grade of sacroiliitis and the value of crp (p0/0.006, r 0/0.414). in conclusion, it has been suggested that, crp may be used as an auxiliary or a secondary parameter in grading sacroiliac joint involvement in brucellosis. magira ee a , papandreoy s a , gounaris t a , spirelis ma a , tasopoulos g a , anagnostopoulou m b , paniara o b , gounari p a , sioulal e a . a evagelismos, internal medicine, athens, greece , b evagelismos, microa 65-year-old greek farmer was admitted to the hospital because of painful scrotal swelling, hepatosplenomegaly, lumbar pain and lowgrade fever accompanied by profuse sweating. his life style included occupational animal exposure ingestion of raw milk and dairy products. the laboratory data were within the normal ranges. focal hypoechoic right testicular lesions, swelling of the concurrent epididimis along with an increase in the vascularity of the right testis were seen on an echo examination. these findings were consisting in unilateral epididimo-orchitis. a ct scan of the lumbar spine area showed a decrease of the signal intensity localized in the anterior aspect of l5 vertebral body at the diskovertebral junction involving the subchondrial parts of the l5 and s1 vertebrae standard tube agglutination test was positive for antibodies to brucella melitensis (titer !/1/1280). cultures of blood specimens were positive for b. melitensis . the patient had been given to a combination of antibiotics with doxycycline, streptomycin and rifampin. a remarkable improvement of his clinical condition was showed 2 weeks later. this case illustrates the following point: in areas in which brucellosis is endemic when scrotal abnormalities are seen the possibility of genitourinary tract complications of brucella should be considered. pappas ga a , akritidis nk b , mastora m b , tsianos e a . a university hospital, internal medicine, ioannina, greece , b 'g. hatzikosta ' hospital, internal medicine, ioannina, greece aims and scope: to determine the incidence and forms of complications associated with brucella infection. patients and methods: we studied the 100 most recent patients, in all larger series approaching 1000, diagnosed as suffering from brucellosis, and assessed the presence of signs and symptoms of arthritis and spondylitis, or other forms of bone involvement. the diagnosis of brucellosis was based on serology or isolation of brucella species from blood cultures or cultures from other media. results: osteoarticular complications were noted in 23 patients, 13 presenting with arthritis, and 10 presenting with spondylitis. eight patients presented with genitourinary complications, either orcheoepididymitis (four patients), or hematuria resolving with treatment (four patients). meningitis was present in two patients. gastrointestinal complications (vomit and diarrhea) were present in three patients, while one patient presented with ascites. respiratory tract complications, in the form of pneumonia (four patients) or bronchitis (three patients) were noted in seven patients, while one patient with pneumonia exhibited pleural fluid. skin rashes, of macular type, were present in three patients. no patient presented with complications from the heart. hematologic complications were frequent, in the form of severe (one patient) or moderate (two patients) pancytopenia, isolated thrombocytopenia (three patients), or lymphocytosis (eight patients). akritidis nk a , pappas ga b , mastora m a . a 'g. hatzikosta ' hospital, internal medicine, ioannina, greece , b university hospital, internal medicine, ioannina, greece aims and scope: to determine the incidence and modes of bone and joint involvement in the course of brucellosis. patients and methods: we studied the 100 most recent patients, in all larger series approaching 1000, diagnosed with brucellosis, and assessed the presence of arthritis and spondylitis. the diagnosis of brucellosis was based on serology or isolation of brucella species from blood cultures. results: twenty-three patients exhibited a form of osteoarticular involvement. arthritis was present in 13 patients, most often involving the knees, but also the hips, elbows, even smaller joints as intephalangeal joints of the hand. synovial fluid, when aspirated, was often characterised by an intense mononuclear infiltrate. spondylitis was present in 10 patients, most often involving the lumbar spine, but also the thoracic spine. the characteristic erosion on the upper anterior crest of the vertebral body was visible in plain x-rays in three patients, while mri and bone scan were helpful in other cases. discussion: osteoarticular involvement in the course of brucellosis is the most common focal presentation of the disease. acute brucellosis is often accompanied by bone and joint ache, especially of the lumbar spine, still frank involvement in the form of arthritis and spondylitis is not rare. arthritis usually presents in the acute form of the disease, while spondylitis tends to be characteristic of a chronic form of the disease, often necessitating prolonged use of antibiotics. bosilkovski m, krteva l, caparoska s, grozdanovski k, sajn b. clinic for infectious diseases and febrile conditions, medical faculty, skopje, the former yugoslav republic, macedonia one hundred and twenty-six patients with brucellosis were studied prospectively. seventy-eight (61%) of them had osteoarticular involvement. peripheral arthritis in 46 (59%) patients was the most frequent, followed by spondilitis in 27 (35%), sacroiliitis in 15 (19%), rarely bursitis, tendinitis and osteomyelitis. the overall male to female ratio was 2:1. their average age was 39 (sd 20) years. direct contact with animals was the reason for acquisition of the illness in 59% of patients, in 29% alimentary or aerogenous route was incriminated, and in 12% the route of aqisition was unknown. the average duration of the symptoms from the onset to establishing the diagnosis was 68 (sd 78) days. the main presenting symptoms were joint pain (100%), sweating (77%), fatigue (58%) and fever (57%). hepatomegaly was present in 58%. in 49% of patients, involvement of some other system was evident. comparison with patients, who did not have osteoarticular illness, showed that patients with osteoarticular involvement had significantly more often joint pain, fatigue, weight loss and more prolonged duration of symptoms before the diagnosis was established. doxycycline and chloroquine as combination therapy for chronic q fever endocarditis ps201 calza l, attard l, manfredi r, chiodo f. division of infectious diseases, university of bologna, s. orsola hospital, bologna, italy introduction: endocarditis is the main clinical manifestation of chronic q fever, occurring in about 60 á/70% of all reported cases, and it is diagnosed almost exclusively in patients with either cardiovascular abnormalities or an immunocompromised condition. case report: a 62-year-old caucasian male patient with biological prosthetic aortic valve was first hospitalized because of an interstitial pneumonia. six months later, our patient was re-admitted owing to intermittent fever, chills and weight loss. echocardiographic study showed a small vegetation of 12 mm in diameter on left cusp of aortic valve. serology for coxiella burnetii revealed a complement-fixing igg antibody titer to phase i antigen of more than 1:2048, consistent with chronic q fever endocarditis. antimicrobial therapy with i.v. doxycycline and oral chloroquine was started, leading to a clinical and echocardiographical recovery. therapy was continued by oral doxycycline and chloroquine, and the patient remained asymptomatic during a 2-year follow up. conclusion: the optimal treatment of q fever endocarditis has not been well established: the most effective antimicrobials are fluoroquinolones and rifampin, but chloramphenicol, doxycycline and trimethoprim are also useful. the role of chloroquine in combination with doxycycline seems to be promising, because chloroquine may increase the lysosomal ph, enhancing the doxycycline bactericidal activity. akritidis nk a , pappas ga b , mastora m a , liappis e a , tsianos e b . a 'g. hatzikosta ' hospital, internal medicine, ioannina, greece , b university hospital, internal medicine, ioannina, greece aims and scopes: to review the incidence and the forms of lower respiratory tract infection in patients suffering from q fever, and their clinical and radiological characteristics. patients and methods: twenty-seven patients diagnosed as suffering from q fever, were assessed for the presence of lower respiratory tract infection. the diagnosis was confirmed serologically. results: thirteen patients expressed lower respiratory tract pathology, as confirmed by clinical examination and chest x-ray. in 11 of these patients the main cause of admission was respiratory tract symptoms, ranging from dry cough to hemoptysis. chest x-ray was pathological in 13 patients: 10 patients had lobar pneumonia, two of them multiple nodular opacities, and one of them bronchopneumonia. hepatitis was a common finding. all patients were treated with tetracycline. discussion: although coxiella burnetii infection is acquired via the respiratory tract, it is paradoxical that symptoms attributed to the lung are not invariably positive. q fever pneumonia is an atypical pneumonia that usually follows a benign course. diangostic suspicion is usually raised by the epidemiologic pattern and the accompanying mild hepatitis. pleural effusion is not a common finding. the usual radiologic appearance of q fever pneumonia is that of a lobar or segmental pneumonia. one important aspect of q fever pneumonia is its common presentation in the form of multiple nodular opacities often necessitating the exclusion of malignancy. (16), culture (4), and serology'/culture (2). there were 0 á/4 cases per year, mainly in october (73%). a history of exposition to hare was present in 24/25 (96%) and to marmot in 1/25 (4%). skinning (18/25 72%), animal contact (5/25 20%), bite (1/25) and wound during bait preparation with frozen meat for hunting (1/25) were noted. the initial clinical presentation was ulceroglandular (77%), glandular (19%) and pneumonic (4%). the involved nodes distribution was axillary (12/24), cubital/axillary (10/24) and cubital (2/24). median incubation period was 3 days (range 1 á/6); time to consultation 3 days (range 0 á/7), and time for effective treatment 7 days (range 0 á/23). an initial diagnosis of tularemia was made presumptively in 42%. effective antibiotic regimen used was aminoglycosides in 73% (19/26), and tetracyclines in 27% (7/26). note that intravenous netilmicin was used in 6 cases. complication rate was 35% (9/26) with one death (4%), and was associated with delay in effective treatment ( !/8 days of illness) (p b/0.05). conclusion: in our area tularemia occured mainly in male population, during autumn, with a short incubation period and history of hare contact. delay before appropriate treatment increased the complication rate. bompolaki i, doukakis s, triantafillidou d, polimili g, kastanakis m, nikiforakis k, vittorakis e, kastanakis s. first medical department, 'saint george ' general hospital, chania, greece a severe frontal and/or retroorbital headache represents the most common neurologic manifestation of murine typhus. other neurologic manifestations as confusion, stupor, nuchal rigidity and in severe cases delirium, extreme agitation or coma appear less commonly. eightyfour patients with compatible clinical status of murine typhus and high serological titers of antibodies against rickettsia typhi, were studied from our team. seventy-four patients (88%) presented headache and nine patients (11%) presented confusion. one patient (1.1%) presented nuchal rigidity in combination with severe headache and confusion giving us the suspicion of meningitis. in this case a lumbar puncture was performed emergently and the cerebrospinal fluid (csf) was examined. the findings of csf were proteins: 9 mg/dl, wbc: 16/ml and glucose: 73 mg/dl and its culture was negative. all patients were treated with a specific anti-rickettsial treatment. the outcome of murine typhus was favorable for all 84 patients (100%). no one patient presented neurologic sequelae. conjunctivitis usually accompany rickettsial diseases such as rocky mountain spotted fever, epidemic typhus and murine typhus. eightythree patients with compatible clinical status of murine typhus and high serological titers of antibodies against rickettsia typhi , were studied from our team, during a period of time between january 1993 and the first semester of 1998. the clinical examination of these patients revealed the presence of conjunctivitis in 21/83 patients (25.6%). in the same time these patients referred retroocular pain and mild photophobia. this study showed that in murine typhus the injection of conjunctivae is rather common. almost a quarter of the patients presented conjunctivitis despite the fact, that this ocular manifestation is less severe than in other typhus and spotted fevers. eighty-three patients with compatible clinical status of murine typhus and high serological titers of antibodies against rickettsia typhi , were studied from our team, during a period of time between january 1993 and the first semester of 1998. three blood samples were obtained from each patient for the study of their hematological abnormalities. the first sample was obtained on admission, the second sample 2 weeks after the first, the third sample, 1 month after the second. on admission 26/83 patients (31%) presented anemia, 6/83 patients (7%) presented leukopenia and 42/83 patients (51%) presented thrombocytopenia. the mean value of hematocrit, white blood cells and platelets was 12.4 g/dl, 6.1)/10 3 and 147)/10 3 /ml, respectively. two weeks later anemia was presented in 45/83 patients (54%), 3/83 patients (4%) presented leukopenia, 3/83 patients (4%) presented leucocytosis and 15/83 patients (18%) presented thrombocytopenia. the mean value of hematocrit, white blood cells and platelets was 11.3 g/dl, 7.0)/10 3 and 248)/10 3 /ml, respectively. one month later 11/42 patients (26%) had anemia and 2/42 patients (5%) presented thrombocytopenia. the mean value of hematocrit, white blood cells and platelets was 12.4 g/dl, 6.4)/10 3 and 242)/10 3 /ml, respectively. our study showed that early thrombocytopenia and anemia are frequent in murine typhus and that white blood cells count is usually normal. renal function in murine typhus: a study of 83 cases ps207 doukakis s, polimili g, triantafillidou d, kastanakis m, vittorakis e, palla k, kastanakis s. first medical department, 'saint george ' general hospital, chania, greece the clinical course of murine typhus is usually uncomplicated and the mortality rate is low ( b/1%). advanced age and prolonged interval before administration of a specific anti-rickettsial treatment are correlated with severity of the disease. renal function in murine typhus is usually unaltered except in elderly patients with prolonged hypotension. eighty-three patients with compatible clinical status of murine typhus and high serological titres of antibodies against rickettsia typhi, were studied from our team, during a period of time between january 1993 and the first semester of 1998. three blood samples were obtained from each patient for the study of their renal function. the first sample was obtained on admission, the second sample approximately 2 weeks after the first, the third sample, taken from the half of the patients, was obtained one month after the second. on admission 4/83 patients (5.0%) presented acute renal failure. the outcome of murine typhus was favourable for all 83 patients (100%). the four patients who presented acute renal failure reversed after the administration of anti-rickettsial treatment and careful administration of fluids. in murine typhus the induction of hypovolaemia insufficiently corrected by normal homeostatic mechanisms may lead to prerenal azotaemia. in these cases the immediate onset of an antirickettsial treatment and the correction of hypovolaemia are essential for the rapid clinical improvement of the patient. experimental ocular toxoplasmosis: clinical, histopathological, immunological and therapeutic studies ps208 el zawawy lae a , hammoda na a , allam sr a , ali sm a , galal as b . a faculty of medicine, parasitology, alexandria, egypt , b faculty of medicine, ophthalmology, alexandria, egypt the purpose of the study was to investigate clinical, histopathological, immunological and therapeutic features of an experimental model of ocular toxoplasmosis in sensitized and non sensitized rabbits and to assess the influence of treatment by interleukin2 (il-2) on ocular lesions. the results obtained was that 'toxoplasma' retnochoroiditis developed in both groups of rabbits with more pronounced effect in non sensitized animals. administration of il-2 improved ocular lesions in both groups with more evident effect in sensitized rabbits. immunological findings were consistent with clinical and histopathological observations. the conclusion reached was that; ocular lesions were manifested in non sensitized rabbits more than in sensitized ones. il-2 revealed a significant impact on improving the host defense against toxoplasm infection in eye. immunotherapy with il-2 would open the way for a new range of treatment based on immunomodulation. express-diagnostic of streptococcus antigen for the adequate antibiotic therapy in patients with pharyngitis ps209 pertseva to, konopkina li, kireeva tv. dsma, internal medicine , dniepropetrovsk, ukraine the purpose of the study: evaluation of effectivness of streptococcus express-diagnostic for the adequate antibiotic therapy in patients with pharyngitis. results: we deal with clinical and microbiological comparison in 53 patients with pharyngitis. using of streptococcus antigen express diagnostic in swabs from the backside of pharynx allowed to get positive results in the seven cases (13.2%). following cultural study has confirmed these results. positive test was more probable in patients with pronounced fever (more than 38 8c), headache, weakness and in cases associated with chronic tonsillitis. isolated streptococcus pyogenes was susceptible to ampicillin, claritromicin, erytromicin, azytromicin, , clindamicin, ceftriaxon, levafloxacin, oxacillin, cefuroxim, roxytromicin. conclusion: using of the express diagnostic of streptococcus antigen allows to restrict groundless prescription of antibiotic therapy in patients with other types pharyngitis (i.e. viral, candidal etc.). alabaz d a , turgut m a , kocabas e a , tumgor g a , yaman a b , alhan e a . a division of pediatric infectious diseases, cukurova university, adana, turkey , b department of microbiology, cukurova university, adana, turkey chickenpox is a common viral infection that usually follows a benign, self limited course in healthy children. the most common complication in children with varicella is superimposed cutaneous infections with pyogenic bacteria (streptococcus pyogenes and staphylococcus aureus ). varicella gangrenosum, a necrotising soft tissue infection complicating the vesicular eruption of chickenpox, is rare. here we present three cases with necrotising soft tissue infections following chicken pox. these children were admitted because of common crusted lesions and necrotising soft tissue infection over the neck, the back, and the inguinal area. they all had the contact history and ensuing vesiculopapular rush. these infections were caused by group a streptococci in two cases, and s. aureus in one case. after instituting of appropriate antibiotic therapy, each patient underwent a surgical exploration with fasciotomies and debridement. widespread use of varicella vaccine may decrease invasive infections in children, adolescents, and adults, thus decreasing the burden the disease with its complications impose up on the family and the society . cefprozil is a second generation cephalosporin. the aim of this open, multicentre, non-comparative study was to investigate the efficacy and safety of cefprozil in the treatment of streptococcal tonsillopharyngitis. fifty-eight patients were clinically assessed for signs and symptoms of streptococcal infection. laboratory confirma-tion was sought using three tests; culture, rapid strepto test and estimation of antistreptolysin (aso). one or more tests were done in 47 of the 58 patients. treatment was for 5 days, 25 mg/kg per day in children, 500 mg per day in adolescents. patients were again clinically assessed on the 5th á/6th day. the results showed clinical success in 56 patients (96.5%) and in 46 of the 47 who had laboratory tests (97.8%). two patients had treatment withdrawn because of nausea and abdominal pain (3.5%). of the 47 patients with laboratory tests at least one test was ositive. the most helpful was the strepto test giving the quickest positive result in 92% of those tested (38/41). culture was positive in 58% of those tested (24/41). the aso test was of limited value. in conclusion, cefprozil showed high clinical efficacy and safety in the treatment of streptococcal tonsillopharyngitis. tsiara s, militadou g, milionis c, elisaf m. internal medicine department, university of ioannina, ioannina, greece streptococcus group b agalactiae (gbs) is a rare pathogen for healthy male adults. we present an old man in whom (gbs) was isolated in blood cultures. case report: a 79-year-old man was admitted to the hospital in order to investigate osteolytic lesions in the lumbar spine. two weeks before, he experienced severe low back pain radiating to the right leg and fever arising to 39.50 8c with chills and rigors. a gbs was isolated from blood cultures and treatment with penicillin was initiated. a spine ct scan revealed osteolysis in the t12 and s1 vertebrae and the patient transferred to us. he was a previously healthy man. he received only antihypertensive therapy. on admission he was afebrile with arthralgias and myalgias. on clinical examination there was tenderness on the right pleurospondylic angle radiating to the right leg. laboratory data on admission: hb: 11.2 g/dl, wbc: 7.4)/10 9 /l, esr: 77 mm/h. biochemical values, serum protein electrophoresis, rectal examination and a prostatic specific antigen (psa) were normal. a bone marrow aspiration and biopsy were negative. a transoesophageal ultrasound revealed vegetation on the right cusp of the aortic valve, with low grade regurgitation. an mri of the lumbar spine revealed infectious myositis with concomitant osteomyelitis involving the l4, l5 vertebrae without any evidence of osteolytic lesions. a thorough investigation did not revealed any underlying immunosuppressive disease. treatment with vancomycin and gentamycin iv was initiated and the patient discharged from the hospital in excellent health after 6 weeks. discussion: gbs infections usually occur in neonates and pregnant, or in adults with underlying disease as diabetes mellitus or immunosuppression. the most common site of infection is soft tissue. we present this case because gbs infections are rare in the elderly in the absence of underlying disease. common sites of involvement are soft tissues, while bone, joints, and heart valves account to 1 á/2% of the involved organs. although our patient had more than one site of involvement he responded well to medical treatment without surgical debriment or heart valve replacement. objective: to evaluate the safety and efficacy of rhugm-csf in combination with broad-spectrum antibiotics for the treatment of ccnf. methods and results: a retrospective review of all patients (pts) with ccnf treated with antibiotics'/rhugm-csf at our hospital from january 1997 to december 2001 was performed. five patients were identified with the diagnosis of ccnf. ages ranged from 33 to 71 years; there were three women and two men. dental infection was the most common source of ccnf in 90%. one patient had acute tonsillitis leading to ccnf. all cases studied experienced infection of the neck with spread into the submandibular, submental, sublingual, retropharyngeal, and parapharyngeal spaces. all infections were polymicrobial. diabetes mellitus was a co-morbidity in one case. all pts were treated with dual antibiotic coverage (vancomycin'/meropenem), rhugm-csf (10 mcg/kg/daily given s.c.) and aggressive wound care. rhugm-csf was given for 7 á/10 days. in spite of the severity of the infection all pts recovered and do not experienced local or systemic complications. discussion: ccnf is a severe bacterial infection of the cervical fascia resulting in extensive fascial necrosis with widespread undermining of the surrounding tissues. prompt antibiotic therapy combined with rhugm-csf resulted in a 100% overall survival in our experience. to our knowledge, this is the first report describing the successful treatment of ccnf with use of broad-spectrum antibiotics combined with rhugm-csf. the following case adds to the clinical manifestations and course of meningococcal disease. a previously healthy 3-year-old girl presented acutely with high fever purpuric rash including conjuctival haemorrhages and hypotension. the child had also neck stiffness. a presumptive diagnosis of meningococcal septicaemia was made and treatment with penicilline, chloramphenicole, fluids and inotropes was initiated. laboratory investigations showed wbc: 4300/ml, hb: 12.2 g/dl, hct: 39.5%, esr: 1 mm in the first hour, pt: 26 s, aptt: 90 s. neisseria meningitidis group b was isolated from the blood cultures. csf obtained after antibiotics were started did not grow n. meningitidis . the patient had an adverse outcome. she died after 12 h of hospitalization. this patient developed a fulminating meningococcal septicaemia. shock is a clinical diagnosis arising from the failure of compensatory mechanisms that maintain perfusion of vital organs at the expense of non vital. septic shock results from loss of circulating plasma volume due to increased vascular permeability and maldistribution of intravascular volume. in young children there is a prevalence of serogroup b meningococcal disease which can be explained by the immaturity of the immune system and by the fact the group b capsule synthesis is known to inhibit alternative complement pathway activation. this case emphasizes the need for further protection against n. meningitidis group b. . results: forty-eight patients were included in this study. the etiological agents were: viral (n 0/26, 54.2%, mean ('x ) age0/28 years), streptococcus pneumoniae (n 0/8, 16.6%,'x age0/53), neisseria meningitidis (n0/7, 14.6%, 'x age0/28), s. viridans (n0/6, 12%, 'x age0/34), p. multocida (n0/1, age 75). the peak incidence of bacterial meningitis was in winter (pneumococcal 73%, meningococcal 86%, s. viridans 83%) .the cerebrospinal fluid (csf) findings in viral meningitis were 'x white cells 0/340/mm 3 , 'x pmn0/27%, 'x glucose csf/ serum 0.55, 'x protein 39 mg/dl and in bacterial meningitis were 'x white cells0/5800/mm 3 , 'x pmn0/80%, 'x glucose csf/ serum0/ 0.2, 'x protein0/350 mg/dl, gram stain was positive in 55%, culture was positive in 45%. all pneumococcal and meningococcal strains were susceptible to penicillin. the case fatality rates for pneumococcal and meningococcal meningitis were 25 and 14.3%, respectively. conclusions: the cases of bacterial meningitis were according to typical epidemiological features of age and season. the case fatality rate of pneumococcal meningitis appear to be high regardless of susceptibility to penicillin. none had received pneumococcal vaccine prior to becoming ill. diagnosis and therapy of meningococcal meningitis */trend and particularities of a 'romanian model' ps216 lintmaer i, moroti r, popescu a, popescu c. institute of infectious diseases matei bals , unit 5 , bucharest, romania background: newer diagnosis methods and antimicrobials are expected to change the management of menigococcal meningitis (mm) and to improve its prognosis. objectives: to determine the changes in the diagnosis methods and therapy of mm patients in a infectious diseases hospital. to compare mm management in bucharest with literature data. methods: retrospective rewiew of mm in adult patients hospitalized over a 6-year period. our results were compared with other studies made in the 90s, taken from medline. results: there were 97 episodes of mm during the study period (52 episodes in 1995 á/1997 and 45 episodes in 1998 á/2000) . we noticed a defined diagnosis increase and increased blood culture specificity. the antimicrobial monotherapy was maintained but penicilin was replaced by ceftriaxone. hhc was replaced by dexamethasone in pathogenic therapy. we noticed a shorter length of treatment and a reduced lethality. the most important differences between our results and other studies are: monotherapy regimens are less frequent and therapy lengths are longer; however, prognosis is similar. conclusions: the mm management has been modified in the last 3 á/ 4 years: prognosis is improved, but the changes do not bring clear cost/ effective benefits. tiouiri th, kilani b, amari l, zouiten f, kanoun kf, ghbontini a, ben chaabene t. rabta hospital, infectious diseases, tunis, tunisia objectives: in order to study epidemiological, clinical and therapeutical characteristics of the infective endocarditis (ie). methods: we reviewed all the cases of ie fulfilling the duke criteria. data were collected during a 19-year period (1980 á/1998) in the unit of infectious diseases. results: one hundred and eight cases were identified. the mean age was 37.5 years. sex ratio was 0.8. eighty-five ie (78.6%) occured in patients with native valve, and 23 ie (21.4%) with prosthetic valve. fever was the most common sign, 12% had a congestive heart failure, 26.9% had cutaneous signs. the most common primary focus of ie was orthodontic. blood cultures were positive in 63% of cases. in one case, serological test identified rickettsia conori . streptococci and staphylococci were isolated in 27.8 and 25.9%, respectively. echocardiography detected abnormalities in 63.4% of cases. rheumatic heart disease was the most predisposing condition. empirical therapy was based on combination of b lactam with aminoglycoside. recovery was obtained for 60 patients. cardiac surgery was performed in 26 cases. overall mortality rate was 19.4%. conclusion: ie affects young persons. prevention needs eradication of acute rheumatic arthritis. a major outbreak of legionnaires' disease in spain: diagnostics aspects ps218 guerrero c a , toldos cm a , yagü e g b , ramírez c a , rodríguez t a , -segovia m a . a hospital morales meseguer, servicio de microbiología, murcia, spain , b departamento de microbiología, facultad de medicina, universidad de murcia, murcia, spain objective: to evaluate the value of different methods (serological tests, culture of respiratory secretions, blood cultures and urinary antigen testing) for the diagnosis of legionella pneumophila pneumonia during an outbreak in spain. results: we have studied 542 patients from a recent outbreak of legionellosis in murcia (spain). the diagnosis was achieved in 305 patients. urinary antigens were positive in 187 patients. in the 355 patients with urinary antigen negative the serological response was demonstrated by indirect immunofluorescence (ifa) in 118 patients. all blood cultures processed were negative. sputum samples were obtained from 154 patients, of these l. pneumophila was isolated only in six patients. in all of them direct immunofluorescence test (dfa) was positive. conclusions: although the serological diagnosis was the most sensitive method the urinary antigen testing was of great value in the rapid diagnosis of the legionella's outbreak in murcia. the isolation of l. pneumophila by culture showed a poor sensitivity probably because of the low severity of the illness. purpose: to evaluate chloramphenicol for an initial empiric antibiotic treatment of purulent meningitis in adults. study group: one hundred and twenty patients hospitalized for the diagnosis purulent meningitis in the department in years 1997 á/2000, 67 males and 53 females, age range 15 á/81 years, mean age 52.6 years. children up to 15 years were not included. method: a retrospective analysis of the study group focused on antibiotic treatment both initial and changes during treatment. results: chloramphenicol was used as an initial antibiotic in 59 (49%), 3rd generation cephalosporin in 30 (25%), penicillin in 21 (17%), ampicillin in five (4%) and other antibiotic in five (4%), respectively. during treatment chloramphenicol was switched for 3rd gen cephalosporin in seven of 23 patients with streptococcus pneumoniae meningitis and in five of 28 patients with meningitis of unknown etiology. the reason for the change was non-improving csf formula in three, persisting csf culture positivity in two and persisting coma in seven patients. conclusion: because of repeated necessity to switch chloramphenicol for 3rd gen cephalosporin during treatment of purulent meningitis of pneumococcal and unknown etiology the initial treatment strategy was changed in 2001. third gen cephalosporin is now used as a first choice antibiotic, what is in consent with international recommendation of treatment. to evaluate and compare groups treated initially with chloramphenicol and with 3rd gen cephalosporin will need several more years. low prevalence of multi-drug resistant mycobacterium tuberculosis in jerez de la frontera-cadiz (spain) ps220 alados jc, aller ai, de miguel c, de francisco jl, calbo l. hospital del sas-jerez , microbiologia, jerez de la frontera, cadiz, spain introduction and aim: previous reports indicate that multi-drug resistance mycobacterium tuberculosis (mtb) is an worldwide problem. the aim of this study was to review the resistance of mtb to the first-line antimycobacterial agents in our area. material and methods: over a period of 4 years (1998 á/2001), 151 strains of mtb isolated from non-treated patients with tuberculosis (38 strain in 1998, 48 in 1999, 37 in 2000 and 28 in 2001) were studied. these isolates were tested for in vitro drugs susceptibility to isoniacid-i, rifampicin-r, streptomycin-s and ethambutol-e using the bact/ alert method (organon teknica) as described by the manufacturer. results: our results showed that 10.6% (16/151) strains were resistant to one or more drugs. single drug resistances were detected on nine strains to i (6.3%), one to r (0.66%), two to s (1.3%), one to e (0.66%). three mtb strains were resistant to more than one drug but only one was multi-drug resistant (i'/r).the incidence of i-resistant strains over the period fell from 13% in 1998 to 3.6% in 2001. conclusions: (1) multi-drug resistance is not an important problem in our area. (2) isoniacid resistance was declined to an admissible level. to investigate the anti-tuberculosis drug resistance pattern of pulmonary tuberculosis isolates in southern taiwan, an area with higher tuberculosis incidence and mortality than other regions of the island, we performed a hospital-based surveillance at a southern taiwan medical center from 1996 to 2000. the combined drug resistance rates to at least one of five first-line agents was 84.8%, and to both isoniazid and rifampin (multi-drug resistance, mdr) was 11.4%, indicating high resistance rates compared with those reported in the who/iuatld global project and in northern taiwan. the resistance rates to two second-line drugs, cycloserine, and kanamycin, were 75.7 and 23.7%, respectively. a significant decreasing trend in resistance rates to all drugs except streptomycin was observed during the 5-year period. though combined drug resistance rate may not be the most accurate tool as it includes previously treated cases which inflates the resistance rate, the observation of trends in the susceptibility of pulmonary tuberculosis in accompany with the increasing percentages of tuberculosis patients receiving complete treatment course and the decreasing percentages of cases lost of follow-up in kaohsiung after the institution of new governmental regulations for case management in 1997 suggest the usefulness of intervention programs. lipid profile in patients with multidrug resistant pulmonary tuberculosis ps223 extrapulmonary tuberculosis may sometimes present with confusing clinical manifestations. a 77-year-old female patient was admitted with a history of recurrent supra-sternal abscess for 1 year. mri confirmed the presence of sternal osteomyelitis and an anterior mediastinal mass. the diagnosis of tuberculosis was proved by histologic examination and acid-fast stain. the patient was treated with first-line agents, which isoniazid, rifampin, pyrazinamide, and ethambutol. tobacco smoking as a factor of the decrease of chemotherapy effectiveness and of the development of the drug resistance in patients with pulmonary tuberculosis ps225 shprykov as a , zhadnov vz a , shprykova on b . a medical academy, department of tuberculosis and lung diseases, nyzhny novgorod, russian federation , b medical clinic for infectious #2, laboratory of bacteriology, nyzhny novgorod, russian federation studies of the effect of smoking on the results of chemotherapy of 798 patients with tuberculosis of lungs. intensive tobacco smoking slowed down clearance of positive sputum and of lung tissue destruction (in smokers 92.1% and 70.1 vs. 98.0% and 90.6% in nonsmokers, p b/0.01). drug-resistant mtb strains have been found to be isolated more often in smokers */43.4 vs. 19.4% in non-smokers, p b/ 0.01. resistance to streptomycin and isoniazid prevailed, reaching in heavy smokers 50.0 and 30.5%, respectively. resistance to rifampicin increased 1.5 times. the concentration of rifampicin in the blood serum of heavy smokers decreased in 1.8 times. clinical data are in complete correlation with the findings of our experiments: 67% of experimental cultures developed resistance to streptomycin, isoniazid and less to rifampicin in the study of drug sensitivity under the effect of tobacco smoke condensate. thus, our findings show the development of drug resistance in mtb under the effect of components of tobacco smoke and also showed less effectiveness in therapy. kilani kb, ammari la, tiouiri ht , ben chaabène tbc. rabta hospital, infectious diseases, tunis, tunisia guerrero c a actinomycosis is a chronic disease characterized by abcess formation, tissue fibrosis and draining sinuses. it is caused by anaerobic bacteria belonging to the genus actinomyces. thoracic actinomycosis may involve the lungs, pleura, mediastinum or chest wall. the authors present a case of pulmonary actinomycosis complicating a cervicofacial site. a 32-year-old man with a history of cervicofacial actinomycosis treated by penicillin g 2 years ago was admitted because of right-sided chest pain for 2 months before presentation, cough and fever. physical examination shows a painless indurated mass in the neck with multiple fistula of the sternum. chest radiograph and ct scan revealed a mass in the upper lobe of the right lung with an infiltrate of the upper lobe of the left one. magnetic resonance imaging confirms the previous lesions, with extending process to the sternum and right collar bone. bronchoscopy was performed while patient was on antimicrobial therapy. culture of bronchoalveolar lavage fluid was negative. transbronchial biopsy was not conclusive. fungal serologies were negative for aspergillosis, histoplasmosis, blastomycosis. bacterial examination of purulent drainage from sternal wound shows inclusion bodies identified as actinomyces. he was treated then with penicillin iv for 2 months, than switched to doxycycline. after 8 months of treatment, he is asymptomatic with radiological improvement. kanellopoulou m a , skarmoutsou n a , iglezos i b , mylona e a , martsoukou m a , apostolopoulou f b , papafrangas e a . a laboratory of clinical microbiology, sismanoglio general district hospital of attica, athens, greece , b 2nd department of pneumology, sismanoglio general district hospital of attica, athens, greece introduction: achromobacter xylosoxidans is a rare human pathogen. it is an important cause of bacteremia in patients with cardiac diseases, malignancies and immunosuppression. it has been recently recognized as an emerging microorganism in cystic fibrosis (cf), whose its pathogenic role is unknown. aim: to investigate the sensitivity to eleven different antibiotics of 27 a. xylosoxidans strains isolated from adults with cf, during 2001. methods: the susceptibility was tested by kirby bauer and microdilution methods (wider i, fransisco soria melguizo, s.a.), according to nccls recomendations. results: the resistance to antibiotics was as follows : gentamicin, tobramycin, aztreonam 100%, amikacin 96%, ceftazidime 85%, ticarcillin 66%, carbapenems, cotrimoxazole 59%, colistin 51% and piperacillin 22%. conclusions: (1) a. xylosoxidans isolated from cf patients appeared resistant to the most usually tested antibacterial agents. (2) colistin which is used as aerolized antibiotic for cf patients seems to be effective in the half of the isolated strains. (3) piperacillin was the most active antibiotic against a. xylosoxidans . morris ka, perry jd, jain s, gould fk. microbiology department, freeman hospital, newcastle upon tyne, uk alafosfalin, l-alanyl-l-1-aminoethylphosphonic acid, is an antibacterial peptide mimetic which inhibits peptidoglycan biosynthesis. we report the in-vitro activity of this compound in combination with ceftazidime, cefsulodin, fosfomycin, piperacillin/tazobactam, aztreonam, ciprofloxacin and timentin. drug combinations were evaluated against 20 burkholderia cepacia strains, and 20 pseudomonas aeruginosa strains isolated from patients with cystic fibrosis. for this purpose a chequerboard technique was adopted using doubling dilutions of each antibiotic incorporated into a highly defined agar medium free of antagonists. the minimum inhibitory concentrations (mics) and fractional inhibitory concentrations (fics) of all the antibiotic combinations were determined which revealed the antibiotic interaction occurring. alafosfalin in combination with ceftazidime, meropenem, piperacillin/tazobactam and timentin demonstrated the highest percentages of synergy in both b. cepacia and p. aeruginosa . synergy was shown to occur in 15, 15, 10 and 10% of b. cepacia strains respectively, and in 10, 5, 5 and 5% of p. aeruginosa strains. these four combinations were re-tested with all 40 isolates and the results were shown to be reproducible. alafosfalin shows potential as a treatment for cystic fibrosis patients colonised with p. aeruginosa and/or b. cepacia , when applied in combination with these agents. community-acquired pneumonia */does its aetiology matter? ps229 lintmaer i, popescu a, popescu c. institute of infectious diseases matei bals, unit 5, bucharest, romania the aetiology of a pneumonia is not one of the criteria used to determine pneumonia's severity. however, it is accepted that identified based á/based therapy is less expensive (and possibly more effective). objectives: our study aims were to: (1) to evaluate the role of aetiology identification in pneumonia; (2) to evaluate the first-line therapy in pneumonia. methods: we conducted a retrospective study in an infectious diseases hospital on 1126 patients with pneumonia. we excluded all the cases with nosocomial pneumonia. primary end-point was the 28day clinical failure (deaths, icu admission), secondary end-points were the average time of fever and length of stay and the antimicrobial regimen changes. results: causative agent identification rate was 24.6%. the evolution was different for patients with identified aetiology compared with other patients in terms of: 28-day failures, length-of-stay and changes of the antimicrobial regimen. the 61 patients with inadequate first-line therapy had a more severe course of illness with a greater rate of 28day clinical failure, longer fever and length-of-stay. conclusions: pneumonia's treatment was better for the patients with identified causative agent. that is why we should include aetiology among the pneumonia severity criteria, especially at an 'after 3-day therapy' re-evaluation. results: pneumomococcal aom was detected in 94 children (41.0%) and s.pn. was the only pathogen in 80.9%. the resistance rates of the organism to antibiotics were as follows: penicillin 48.9% (micb/1 mg/ml; intermediately resistant 31.9%, mic 1.5 mg/ml 8.5%, and mic!/2 mg/ml; highly resistant 8.5%), erythromycin 55.3%, clindamycin 11.7%, cotrimoxazole 41.5% and chloramphenicol 6.4%. all isolates were uniformly susceptible to rifambicin and vancomycin. the large majority of pneumococcal isolates (80.8%) had the mphenotype and the remaining strains (19.2%) the constitutive mls phenotype. a various of serogroups were detected; the serogroup 19 was the most predominant one (50.0%), followed by serogroups 14 (14.9%), 23 (10.6%) and 6 (6.4%). the non-typable s.pn. strains compromised the 8.5% of the strains. conclusions: high prevalence of resistance to penicillin, macrolides and cotrimoxazole in pneumococcal aom of childhood was recognized. a strategy for preventing aom caused by drug-resistant pneumococci is mandatory to start. material and methods: a total number of 82 strains were examined. the sensitivity test was performed by kirby bauer, microdilution method (pasco, difco) according to nccls guidelines and by e -test. results: a percentage of 5.5 % of s. pneumoniae strains revealed high level resistance to penicillin (mic]/2 mg/ml), while the 28% showed intermediate resistance (mic 0.12 á/1 mg/ml). the resistance to erythromycin and cotrimoxazole was 8.3 % (mic ]/1 mg/ml) and 5.5 % (mic]/4/76 mg/ml), respectively. all strains were sensitive to cefotaxime (mic 0.05 mg/ml), vancomycin (mic5/0.5 mg/ml), meropenem (mic 5/0.25 mg/ml) and levofloxacin (mic5/2 mg/ml). conclusions: (1) the prevalence of high resistance s. pneumoniae to penicillin seems to be low in examined strains (5.5%). (2) intermediate resistance to penicillin of s. pneumoniae isolates was high as expected (28%). (3) most of the strains were sensitive to erythromycin (91.7%) and cotrimozaxole (94.5%). (4) s. pneumoniae isolates were completely (100%) sensitive to levofloxacin, vancomycin and meropenem. beghi g, aiolfi s, maghini l, patruno v, aiolfi e. s marta hospital, pulmonary rehabilitation unit, a.o., rivolta d'adda, italy aim: of this study was a retrospective (1997 á/2001) evaluation of the more effective and practical antibiotic treatment in 1058 ae-copd patients (pts) admitted to our unit. methods: before introducing any antimocrobial drug, sputum specimens were collected for microbiological purposes, while blood analysis, to monitor adverse systemic effects, were performed at the beginning and the end of treatment. antibiotic treatment ranged from 8 to 15 days according to four regimens: regimen a (832 pts)0/oral therapy only: 30.9% with amc 1 g b.i.d.; 24.4% with cip 500 mg b.i.d.; 17.4% with dox 100 mg u.i.d.; 10.2% with lev 750 mg u.i.d.; 8.5% with cla 500 mg b.i.d.; 7.8% miscellaneous. regimen b (94 pts)0/sequential therapy (e.v. for 3 days0/oral): 56.4% with amc 1 g b.i.d.; 37.2% with cla 500 mg b.i.d. regimen c (68 pts)0/e.v. therapy only: same drugs. regimen d (64 pts)0/an association of two antibiotics. results: of 1058 evaluated pts, only 199 (19.6%) required a second regimen of treatment because of failure of the previous one: 19.7% of regimen a; 12.7% of regimen b; 23.5% of regimen c, and 14% of regimen d. mild adverse effects were detected only in four pts. our results confirm that oral antibiotic treatment is practical, safe, and effective, and can be considered as the first line regimen also in hospitalized patients with ae-copd. becher g a , gillissen a a , rothe m b . a st. george medical center, robert-koch-hospital, leipzig, germany , b filt, lung and chest diagnostics ltd., berlin, germany patients with severe form of chronic obstructive pulmonary disease (copd) are prone by frequent exacerbations. bacterial infections are judged to cause at least half of exacerbations. haemophilus influenzae and streptococcus pneumoniae are the most frequent isolates, gramnegative bacilli account for the severe cases, aggravating the inflammatory process in the airways eventually leading to respiratory insufficiency. the aim of this ongoing placebo controlled, parallel group, mono center study trial is to evaluate beneficial effect of cefixim to reduce bacterial load and pulmonary inflammation in patients (n0/ 30) with acute bacterial exacerbation of severe copd. thus, 30 patients received in randomized fashion either cefixim (400 mg/day) or placebo (5 days). on days 1, 2, 5 and 8 breath condensate is collected using 'ecoscreen' (jaeger germany) for ltb4-, il-8-, nitrite-and ph-analysis. in parallel sputum gathered for detection of bacterial strains, and for ltb4-, and il-8 quantification purposes. these data are compared to clinical outcome parameters such as lung function tests, radiographic findings, serum inflammatory markers and length of hospital stay. the preliminary data obtained confirm successful antibiotic therapy with oral cefixim in bacterial related acute exacerbations of copd is a useful approach to reduce bacterial load, and concomitantly lower inflammatory indices of the central and peripheral airways leading to clinical improvement of the patients. soriano garcia f a , fenoll a b , fernandez-roblas r a , coronel p c , gimeno m c , rodenas e c , garcia m a , granizo jj d . a fundacion jimenez diaz, microbiology, madrid, spain , b instituto de salud carlos iii, centro nacional microbiologia, majadahonda, spain , c tedec meiji farma, scientific, alcala de henares, spain , d fundacion jimenez diaz, epidemiology, madrid, spain purpose: to describe the susceptibility of streptococcus pneumoniae against cefditoren and 10 other antimicrobials by serotype a multicenter study in south europe was carried out. a total of 877 strains were collected between september 2000 and march 2001 from adult patients (more than 16 y.o.) with respiratory tract infection (respiratory tract samples and blood cultures). all the isolates were sent to a central laboratory (fundació n jiménez díaz, madrid, spain) where susceptibility test was performed by broth microdilution (sensititre) following nccls recommendations. serotype was determined by quellung reaction and dot assay in carlos iii institute in 806 strains. results: a total of 25 strains (3.1%) were not typable. the most prevalent serotypes were 23 (15.4%), 6 (11.4%), 19 (10.8%), 3 (9.6%), 14 (8.9%) and 9 (8.1%). two hundred and sixty-four strains were grouped in 27 different serotypes. the proportion of susceptible strains by serotype to penicillin, erythromycin and levofloxacin were: serotype 3 (90.9, 93.5, 100%); 6 (50.0, 34.8, 96.7%); 9 (36.9, 86.2, 93.8%); 14 (38.9, 48.6, 94.4%); 19 (60.9, 44.8, 97.7%); 23 (58.9, 49.2, 99.2%). the mic 90 to cefditoren was 5/0.03 (serotype 3); 0.5 (serotype 6, 9 and 19) and 1 mg/l (serotype 14 and 23). conclusions: the most prevalent serotype was 23. the susceptibility was higher in serotype 3 than in serotypes 14 and 23. community acquired pneumonia */a study among closed military community of young people ps235 martynova av, turkutyukov vb, vostrikova aa, andryukov bg. vladivostok state medical university, epidemiology, vladivostok, russian federation purpose: the etiology of pneumonia is still partly unknown. we should like to clear up an etiological role of respiratory pathogens in community-acquired pneumonia among youth. and we had chosen for it a model of a closed community both investigation of etiology of disease and for further investigation of mechanisms of transmission drug-resistant mechanisms. methods: we studied 300 adults in age of 17 á/25 from closed military collectives who presented to two public hospitals (one urban and one rural) with acute radiologically confirmed pneumonia during winter 2000 á/2001. we did blood and lung-aspirate cultures, mycobacterial cultures, serotype-specific pneumococcal antigen detection, and serology for viral and atypical agents. results: streptococcus pneumoniae is recognized as an important cause of community-acquired pneumonia, it probably accounts for 65% of cases of community-acquired pneumonia among youth. chlamydia pneumoniae and mycoplasma pneumoniae responsible for approximately 20% of cases. haemophilus influenzae caused 7.5% sever cases of disease, 3% of all cases were due to moraxella catharralis . conclusion: pneumococcial infection accounted for 65% of the cases diagnosed. s. pneumoniae was the most common bacterial infective agent, with a low incidence of both m. pneumoniae and s. pneumoniae . other causative pathogens occurred only within groups of individuals with deficiency of immunological status. berezin en a , cardenuto md a , nobuko e b , guerra ml c , brandileone mc d . a santa casa, pediatrics, s. paulo, brazil , b santa casa, microbiology, s. paulo, brazil , c adolfo lutz, microbiology, s. paulo, brazil , d adolfo lutz, bacteriology, s. paulo, brazil to determine antimicrobial susceptibility of sp isolated from the upper respiratory tract, we collected np swab specimens from 80 children, between 3 months and 5 years old. those children attended the outpatient clinic in s. paulo city, with diagnosis of bacterial infection requiring antibiotic therapy between march 15, 2000 to may 20, 2001. penicillin susceptibility of isolates was determined by screening with oxacillin 1 mcg disk and performing the minimal inhibitory concentration by the e -test. we performed also susceptibility test for amoxicillin and cefaclor. results: sp was recovered from np of 42 children (52.5%). the carriage of sp was more prevalent in children attending day care centers, children with young siblings at home, and children with tobacco users at home. the prevalence of penicillin non-susceptible strains was 40.4% all of them with intermediate resistance. all the strains were susceptible to amoxicillin and 19.2% were resistant to cefaclor. serotypes 14.6b, 19f, 9n, 4, 6a and 5 were the most common. these findings suggest that nasopharyngeal isolates of streptococcus pneumoniae from children with upper respiratory infections can be used to conduct surveillance for antimicrobial resistance in a defined geographic area. we were able to conclude also that penicillin intermediate resistent strains can be susceptible to amoxicillin. hinojosa rm a , saenz a a , collazo m a , echaniz g b . a universidad autonoma de nuevo leon, infectologia, monterrey, mexico , b instituto nacional de salud publica, epidemiologia, cuernavaca, mexico the emergence of penicillin-and multidrug-resistant pneumococcal strains has become a global concern, necessitating the identification of the epidemiological spread of such strains. material: ninety streptococcus pneumoniae clinical isolates were collected from march 1997 through march 1999. typing was done by the capsular reaction with pooled, type, or group antisera. susceptibility testing to 11 antimicrobials was done by the e -test and the disk diffusion method. results: only 46 (51%) s. pneumoniae strains were classified by serotyping; the most frequent types were 6a/b, 23f, 9v, 19f and 4. the oxacillin screening test detected 37.2% penicillin-resistant s. pneumoniae strains isolated from children and 44.6% from adults. the susceptibility percentage of s. pneumoniae to ceftriaxone was 93% in both children and adults. s. pneumoniae isolates from children exhibit a susceptibility of 88% to azithromycin, while in adults 91% of the isolates were susceptible. for the rest of the antimicrobial agents, the susceptibility ranged from 69 to 89%. s. pneumoniae had a lower susceptibility to ceftazidime and ciprofloxacin. conclusions: ceftriaxone and azithromycin had a good in-vitro activity against s. pneumoniae strains. but the percentage of penicillinresistant s. pneumoniae detected in this study is alarming, therefore we conclude that a continuous surveillance system is necessary in mexico. vertkine al, prokhorovitch ea, alexanyan la. a retrospective analyses of 221 cases of ambulant pneumonia with fatal outcome was made. among the patients who died from ambulant pneumonia the prevailing age was over 60 (63.8%) and the prevailing sex was male (68.8%). 95.9% had pneumonia accompanied with some pathology: chronic lung disease (43.9%), alcoholism (26.2%), diabetes mellitus (10.4%). 62.5% of the patients had a big volume of lungs lesion */55.7% of the patients suffered from bilobular pneumonia and 6.8% */from trilobate pneumonia. in 57.0% of the cases pneumonia was complicated with abscess formation and/or exudative pleurisy. we studied the antibiotics therapy used for the patients treatment. the change of antibiotics was made only in 53 cases (24.0%) whereas in the other cases no change of preparations was made though the signs of the therapy non-effectiveness were obvious. thus, the rational antibiotics therapy with the timely change of non-effective antibacterial drug is significantly important. while choosing the antibiotics, the patient's age, the accompanying diseases, the volume of the lungs lesion and complications which define pneumonia seriousness are to be taken into consideration. perronne c a , rouveix b b , guillemot d c , zuck p d , reitz c e , tsatsaris a e . a hôpital raymond poincaré, service de maladies infectieuses, garches, france , b hôpital cochin, paris, france , c institut pasteur, paris, france , d hôpital de metz, metz, france , e laboratoires abbott, rungis, france objectives: to describe the management of lower respiratory tract infections (lrti) in healthy adults, by general practitioners (gp). methods: a questionnaire was sent to a representative national sample of 4092 gps. this questionnaire assessed their perception and management of lrti, the indication for antibiotics (ab) in a case of lrti in a healthy adult with no focal signs and no signs of severity, knowledge of the micro-organisms responsible for acute bronchitis and knowledge of the afssaps (french agency for the safety of health products) recommendations. results: three thousand seven hundred and thirty-eight gps, who reported seeing an average of 131 patients per week, including 10.39/ 9.6 patients with lrti, returned the questionnaire. the main results are presented in the following for the majority of gps, the main objective of the visit is to determine the indication for antibiotics. according to gps, alp and whooping cough are rare, while atypical pneumonia is frequent. gps also declare that the diagnosis of alp is often easy right from the first visit, in contrast with that of atypical pneumonia. complementary investigations are not often requested. gps consider that they often delay prescription of antibiotics (41%) and declare that they tend to prescribe a macrolide as first-line treatment. finally, gps have a poor knowledge concerning the micro-organisms responsible for acute bronchitis and the majority of gps declare to be familiar with afssaps recommendations. perronne c a , rouveix b b , guillemot d c , zuck p d , reitz c e , tsatsaris a e . a hôpital raymond poincaré, service de maladies infectieuses, garches, france , b hôpital cochin, paris, france , c institut pasteur, paris, france , d hôpital de metz, metz, france , e laboratoires abbott, rungis, france objectives: to study the management of one case of lower respiratory tract infection (lrti) in adults by general practitioners (gps). methods: prospective study conducted on a representative national sample of 4092 gps. each gp had to include the first healthy adult patient seen during the 3-week data collection period, either on a home visit or in the office for recent cough and acute fever !/37.8 8c. clinical data, the diagnostic perception and the therapeutic approach to the patient were collected by means of a standardised questionnaire, distributed by abbott laboratories. results: three thousand seven hundred and thirty-eight general practitioners included 3738 patients. conclusions: during lrti in adults, gps observe few focal signs, confirming the marked predominance of bronchitis compared to pneumonia. in view of the frequency of the signs, the diagnosis of pneumonia appears to be overestimated. one-third of clinical situations were diagnosed as 'bacterial superinfection of acute bronchitis', despite it is not a recognised diagnostic entity. antibiotic prescription was immediate in 87% of cases and delayed in 10% of cases. this last point shows that clinical practice differs from the gp's perception of their described prescribing practice shown in a simultaneous survey (56% of gps declared that they prescribed antibiotics immediately, while 41% delayed this prescription). results: thirty-three patients (20 men, mean age 49 b 19 years, mean apache ii score 15.3 &bdqup;b 7.3) during the years 1998 á/ 2001 were prospectively studied. thirteen patients (39%) had no identifiable risk factor for severe cap. an etiologic factor was revealed in 15 patients (45%). in 14 of them this was achieved with noninvasive methods. psb cultures were taken from eight patients and were positive in only 1. the offending organisms included: streptococcus pneumoniae in six cases, gnb as the sole pathogen in six cases, haemophilus influenzae (with s. pneumoniae or klebsialla pneumoniae ) in two cases, s. aureus in two and legionella pneumophila in one patient. initial antibiotic regimen a combination of marcodile '/3rd gen cephalosporin9/aminoglycoside was successful in 12 patients who all survived and had to be changed empirically or according to culture results in 17 patients who had a mortality of 65%. the overall mortality rate was 42%. the identification of the causative factor did not seem to have any impact on survival. conclusion: severe cap in our icu was most often caused by s. pneumoniae and gbn. the high mortality of this entity seems to be influenced by the immediate use of the appropriate antibiotic combination and not by the identification of the causative organism. this underscores the need for knowledge of topical microbiology which helps in designing an effective empirical initial antibiotic regimen. mily mn a , golubev sa b , lugovoy vy a , voronov gg b . a vitebsk emergency hospital, pharmacotherapy unit, vitebsk, belarus , b basic and clinical pharmacology department, vitebsk state medical university, vitebsk, belarus purpose: the study aims were to assess the spectrum and predictors of the antibiotic use during pneumonia management in a regional emergency hospital in belarus. patients, treatment and physicians characteristics of 195 cases (2000 á/2001) were collected and possible associations were examined with using defined daily doses methodology (ddd) and american thoracic society (ats) guidelines. results: the mean treatment duration was 13.99/7.4 days, the total antibiotic ddd/100 bed-days was 130.4. the ddd/100 bed-days of the most used antibiotics were: penicillins 54.0; aminoglycosides 29.5; macrolides 21.9; cephalosporins 9.8; tetracyclines 8.2. in manova certain ats categories were associated with ddd/day, but not with frequency of definite antibiotic use. ddd/day was higher in case of multilobar infiltrates ( conclusion: our study indicated the low rate of macrolides and cephalosporins using, and the high one of aminoglycosides. antibiotic prescriptions were associated with disease severity and physician personality rather then with empirical choice rules recommended. acute exacerbation of copd: most frequent infecting agents and their suspectability to the different types of penicillins. analysis of medical documentation ps243 pertseva to, bogatska ke, gashynova ky. dsma, internal medicine , dniepropetrovsk, ukraine number of copd cases has been increased in ukraine. treatment of acute exacerbation (ae) of copd is not always successful because of inadequate antibiotic therapy. the aim of study was to reveal most frequent infecting agents and their susceptibility to the different types of penicillins in patients with ae of copd. medical documentation of 48 patients with ae of copd (type i) was studied. data of sputum analysis and susceptibility of isolated agents to penicillin, ampicillin, oxacillin and amoxicillin/clavulone acid were evaluated. there were patients with haemophilus influencae/parainfluencae (43.8%), klebsiella pneumoniae (25%), staphylococcus aureus (12.5%), pseudomonas fluorescens , pseudomonas putida , serratia marcescens , serratia liquefaciens (6.8% each), streptococcus agalactiae , acinetobacter baumanii (4.1% each) in samples of sputum. in 31.3% cases there was mixt infection. 6.8% had no any bacterial agents. only 10% of agents were susceptible to penicillin, 35% */to ampicillin, 15% */to oxacillin. however, 70% of microorganisms were susceptible to amoxicillin combined with clavulone acid. this study has shown that most frequent infecting agents caused ae of copd were gram-negative microorganisms and s. aureus . according to antibiogram the prescription of amoxicillin/clavulone acid is most expedient in this case. pertseva to, bogatska ke, konopkina li, kireeva tv, gashynova ky. dsma, internal medicine department, dniepropetrovsk, ukraine we examined 32 patients (22 men, mean age 52.39/4.7 years) with acute exacerbation of cob (type i). the most frequently isolated agents were haemophilus influenzae and parainfluenzae */eight patients, gram-negative rods in 8, staphylococcus aureus in two and mixed in six and one patient had no bacterial agents isolated in their sputum. high susceptibility to azithromycin was found in all cases of gram-positive agents and in h. influenzae and parainfluenzae . other gram-negative agents were resistant to this drug in vitro. however, treatment with 500 mg/day during 3 days was clinically effective in 93.7% of cases. only 25.0% of patients had a further acute exacerbation of cob. there were peculiarities of the infecting agents causing acute exacerbation of cob in this study: klebsiella pneumoniae and s. aureus were found more frequently than in other studies. high efficacy of surnamed in the treatment of acute exacerbation of cob was established in 68.7%. 25.0% had partial positive clinical effect after this therapy. there were no patients with adverse events. efficacy and tolerance of amoxicillin 30 mg/kg bid versus amoxicillin 15 mg/kg tid in the treatment of acute otitis media (aom) in children 5/2 years ps245 borek m a , guggenbichler jp b . a biochemie gmbh, international medical department, kundl, austria , b department of pediatrics, university of erlangen, erlangen, germany five hundred and sixteen patients (mean age 49/2.6 years) with clinical and otoscopic diagnosis of aom were included in a randomized, double blind, multicentre study, and were treated 10 days either with amox 30 mg/kg bid or amox 15 mg/kg tid. assessments were made during therapy (day 3 á/5), after end of therapy (eot, day 12 á/14) and follow up (fu, day 38 á/46). the primary efficacy endpoint was the clinical response at eot defined as success (cure/improvement) or failure. both regimens were well tolerated; one or more drug-related adverse events (aes) were reported in 17.2% (11/64) of bid patients and in 21.7% (13/60) of tid patients. the most frequently reported drugrelated aes in each group were gastrointestinal symptoms (bid 11.5% vs. tid 13.5%), which were mainly of mild or moderate severity. both regimens were clinically equivalent. the higher cure rates in the bid group suggest a possible higher benefit from bid therapy in children 5/ 2 years. children attending family day-care (fdc) should be less exposed to upper respiratory tract infections than those in group day-care (gdc) and therefore to antibiotic treatment; fewer should thus carry resistant bacteria. to test this hypothesis, np carriage of sp and hi with reduced susceptibility to penicillin (pdsp and hi bl'/, respectively) was investigated among children in fdc (maximum three children) and in gdc (25 á/100 children) in the alpes maritimes (france) between november 1999 and march 2000. a two stage cluster sample of children attending gdc or fdc was selected. np samples were cultured for sp and hi. penicillin susceptibility was tested by disk diffusion and e -test, and b-lactamase production by api-nh † tests (biomerieux, lyon). two hundred and thirty-five children in fdc and 298 in gdc aged 6 á/36 months were sampled. age and sex distribution were similar in both groups. sp was isolated in 80 children in fdc (34%), and in 163 (54.7%) children in gdc (p b/10 á/6 ). proportions of pdsp were 52.5 and 55.8%, respectively (p0/0.6). hi was present in 37.6% of children in gdc vs. 23.8% in fdc (p b/ 0.001). proportions of hi bl'/ were 40.2% vs. 46.4%, respectively (p0/0.4). antibiotic exposure during the previous 3 months concerned 46.2% of children in gdc vs. 48.7% in fdc (p 0/0.6). there was no correlation between antibiotic use and carriage of pdsp or hi b'/ strains. sp and hi carriage rates are significantly lower among children in fdc than in gdc. advising alternative types of daycare for children attending gdc should reduce exposure and thus limit the spread of resistant bacteria. however, the proportion of pdsp and hi bl'/ is similar in both groups and comparable patterns of antibiotic use are observed. continued efforts must concentrate on parental education and enforcement of recommendations for management of pediatric upper respiratory tract infections. during a period between january 1999 and august 2001, 43 invasive haemophilus influenzae (hi) isolates had been collected at the children's hospital of tunis. we used haemophilus test medium to test antibiotic susceptibility. the mic of beta-lactams was measured by e -test. beta-lactamase production was determined by using the cefinase test and biotyping by apinh. presence of capsular antigen was determined by using hi typing anti sera. hi strains were isolated from meningitidis (35), bacteremia (5) and arthritis (3). all strains were serotype b and 62.2% of them belonged to biotypes i and ii. amoxicillin resistance with beta-lactamase producing mechanism occured in 34.8%. mic90 of beta-lactamase producing strains was 32 vs 0.5 mg/l in non-producing one. there is no betalactamasenegative amoxicillin resistant among these invasive isolates. antibiotic resistance concerned chloramphenicol: 9.3%, trimethoprim-sulfamethoxazole: 11.6%, tetracycline: 4.6% and kanamycin: 11.6%. invasive hi infections in tunisian children's were always associated with type b strains. introduction of a hib vaccine programme in tunisia is recommended. the aim of this study was to analyse the clinical picture and treatment of neurological manifestations of neuroborreliosis in children. the study included 22 children (2 á/16 years) with neuroborreliosis diagnosed on the basis of the clinical and serologic criteria. symptoms of facial palsy occurred in six children symptoms of iii á/vi cranial nerves palsy in three children, meningitis in four and paresthesias in three. symptoms of v or viii nerve palsy, mental disturbances, radiculoneuritis or cerebellitis were found in singular cases. all children received ceftriaxone intravenously 3 á/4 weeks. total recovery was obtained in 18 children following the first course of therapy. recovery following the second course of therapy (amoxicillin) occurred in one child with mental disorders and one with vi nerve palsy. improvement was achieved after the second course in the patient with radiculitis, however, muscular atrophy persisted. irreversible, unilateral deafness was found in a child with viii nerve palsy in spite of three courses of therapy applied. infection with borrelia burgdorferi in children causes a wide spectrum of neurological manifestations. facial palsy was the most common sign in our study. applying ceftriaxone in the treatment of neuroborreliosis is characterised by a good effectiveness. double infection by c. pneumoniae and m. pneumoniae as a cause of cystic changes in the lungs ps249 streharova a, moravcikova d. department of infectious diseases, university of trnava, trnava, slovakia chlamydia pneumoniae and mycoplasma pneumoniae are human respiratory pathogens manifested in early childhood. immunological disbalance could trigger autoaggressive diseases. the authors describe the case of a15-year-old girl with development of multiorgan failure and septic state, which followed multiple cystic changes in the lungs. the girl did not have a diagnosis of cystic fibrosis. the authors consider that cystic changes are a consequence of double infection by c. and m. pneumoniae. dzarlieva m, momeva l, temelkovska g, balevska p, pejkovska m. medical centre, neonatology, bitola, the former yugoslav republic, macedonia unicef skopje has supported a nationwide safe motherhood needs assessment in representative samples of hospitals. eighteen of 28 maternity wards and facilities renovated and certified as 'babyfriendly'. all mature newborns with successful adaptation to extra uterine life and satisfactory vital parameters are 24 h during the day with their mothers at rooming-in system. aim: with rooming-in system we reached decreasing of incidence of neonatal infections. material and methods: history records of newborns from our department. for the period of 9 months, 907 neonates have been borne. with suspection of infection there */49 babies (5.4%). newborns borne through meconium stained liquid */40 (4.4%). results: microbiological findings: from blood culture */staphylococcus coagulaza negative from swabs */staphylococcus aureus , escherichia coli , staphylococcus epidermidis. conclusion: in 1999, from all babies who had risk factors for infection in 56 newborns (5%) we had positive findings and in year 2000 (before rooming-in sistem), in 44 (3.9%). after that period (with rooming-in) 15 newborns (1.5%). with rooming-in system we reached decreasing in incidence of neonatal infections by breaking the chain of infection */only mothers take care of their babies with help of the staff. newborns are in their micro environment, the same they will have at their home. with this practice we have also reduction of nosocomial infections. a study on antibiotic susceptibility and resistance factor transmissibility among antibiotic resistant salmonellae isolated from children affected to diarrhea ps251 sharifzadeh a. azad university of shahrekord, microbiology, shahrekord, islamic republic of iran in spite of happened drug resistance, antibacterial therapy still is the best route of treatment of salmonellosis in man and animals. in order to detection of dominants serotypes of salmonellae in children and detection of antibiotic susceptibility and r-factor transmissibility among those isolated salmonellae. this study was conducted on 400 diarrheic stool samples were collected from children affected by diarrhea in ayatollah kashany hospital of shahrekord, during spring of 1999 to autumn of 2000. after isolation and identification of salmonellae, seven serotypes were detected. one of those was s. typhi and another six serotypes were s. paratyphi b . in order to detection of antibiotic different antibiotic disks were used in disk diffusion method. best results were taken from ceftizoxim, cephtriaxon, cephazolin and chloramphenichol. the r-factor were transferred from isolated salmonellae to escherichia coli k12 in all of cases of resistance to penicillin and ampicillin. pharyngeal colonization by streptococcus pneumoniae and group a bhs were evaluated in 652 randomly selected school children aged 6 á/ 8 years in riyadh, saudi arabia. fifty-six children (8.6%) had positive culture for either organisms of the 56 isolates from school children, 17 (30%) were s. pneumoniae , of them 14 (82%) were penicillin-sensitive, three (18%) were penicillin-resistant, and two (11.7%) were resistant to two antimicrobials. forty isolates of bhs (71%) were group a bhs. all isolates were penicillin and erythromycin sensitive. the carrier rate among school children for penicillin-resistance s. pneumoniae and resistance to two antimicrobials were (4.6%) and (3%), respectively. the carrier rate of group a bhs was (6.1%). riyadh has a low rate of antibiotic-resistant s. pneumoniae and a similar rate of group a bhs carriers among school children as that seen in temperate areas. boukadida j a , boukadida n b , hannechi n a , said h b , erraii s a , elmhabrech h a . a chu f. hached, laboratoire de microbiologie, sousse, tunisia , b c s base, sousse, tunisia the acute pharyngitis is a very frequent pathology in which group a streptococcus is the most incriminated bacteria. however, other non a b-haemolytic streptococcus (sbna) could be responsible. the aim of this work is to determine the part of each non a b hemolytic streptococci (sbna) in acute pharyngitis and the related antibiotics susceptibility pattern. the study was realized in sousse-tunisia (north africa) during 5 months from may 2001. the origin materials of isolates are throat swab (transystem venturi, copan, bovezzo). the mean age of patients is 23 years with extremes 3 á/72 years. the samples are cultured on blood agar plates in a delay of 3 h maximum. identification was done to samples that have over than 20 b-hemolytic colonies, groupage with pastorex strep. sanofi pasteur france, susceptibility pattern according to nccls norms, mic is determined by e -test. the control strain is s. pneumoniae atcc 49619. twentyone clinical isolates of sbna are distinguished from 80 clinical isolates of b-hemolytic streptococci recovered from 143 patients with acute pharyngitis without symptoms of viruses' infections (tearing, corysa, sneeze). all b-hemolytic streptococcus represents 55.94% of all collected samples. sbna were 26.25% of the isolates. sbna were 11 strains group g streptococci, seven strains group c streptococci and three strains group f streptococci. susceptibility pattern of each sbna to antimicrobial agents is as follow: group g streptococci: peni g 0/100%, amoxicillin 0/100%, pristinamycin 100%, clindamycin and erythromycin0/45.46%, tetracyclin 0/9.1%, telithromycin 63.63% and levofloxacin0/45.45%. group c streptococci: peni g0/ 100%, amoxicillin 0/100%, pristinamycin 100%, clindamycin0/ 57.15%, erythromycin0/42.86%, tetracyclin0/71.42%, tel-ithromycin0/85.72%, levofloxacin0/100%. group f streptococci-peni g0/100%, amoxicillin0/100%, clindamycin0/66.66%, erythro0/33.34%, tetracyclin 0/66.66%, telithromycin 0/100%, levofloxacin0/66.66%. all sbna have mic to penicillin g under 0.1 mg/l. according to available data, penicillin g and amoxicillin still the reference treatment of acute bacterial pharyngitis in spite of the new antibiotics introduction. berezin en a , quevedo sg b , nicolla l b , viegas d c , eizenberg b d , pedrosa f b , santos ag a . a santa casa, pediatrics, s. paulo, brazil , b elly lilly, scientific, s. paulo, brazil , c fac. abc, pediatrics, santo andre, brazil , d university hospital, pediatrics, s. paulo, brazil a multicenter, open label, prospective, randomized trial in which patients 2 á/16 years of age with proven gabhs pharyngitis were randomized to receive either 10-day course of the broad spectrum oral cephalosporin, cefaclor or a 10-day course of amoxicillin. patients were included if they have signs and symptoms of streptococcal tonsillopharyngitis and a rapid streptococcal rapid test positive . patients were evaluated at days 3 á/5, 13 á/16 and 24 á/35 posttherapy. pharyngeal cultures were conducted at baseline and at follow-up visit (13 á/16 days). we considered for bacteriologic eradication analysis only patients with positive culture to gabhs. there were 148 patients with a rapid streptococcal rapid test. clinical success were achieved in around 95% of the patients. for evaluate eradication of the initial pathogen we considered 42 patients of the amoxil arm and 40 patients of the cefaclor arm. thirty-four of 42 patients of the amoxil arm (80.9%) and 36 of 40 (90%) patients of the cefaclor arm were considered bacteriological cured at the second culture performed at day 13 á/16. ten days of a penicillin or amoxicillin therapy may not be the best therapeutic choice for all pediatric patients. in developing countries where rheumatic fever is still an important problem to evaluate the bacterial eradication achieved with the different antibiotics may be important. prophylactic affect of saccharomyces boulardii for antibiotic-associated diarrhea in a paediatric age group ps256 erdeve o, tiras u, camurdan mo, tanyer g, dallar y. ankara education and research hospital, pediatrics, ankara, turkey the process resulting in antibiotic associated diarrhea is the alteration of enteric flora due to bacteria. saccharomyces boulardii is a yeast, isolated from cover of a kind of hazelnut and its usage became widespread recently. there is no enough study about s. boulardii activity at pediatric ages. we aimed to define s. boulardii activity on azithromycin and sulbactam-ampiciline, and associated diarrhea at pediatric age group. the 18.9% of cases only with antibiotic usage developed diarrhea, whereas rate was 5.7% for probiotic using group (p b/0.05). all of the clostridium difficile toxin a defined cases were from sulbactam-ampiciline using group. the rate of diarrhea for sulbactam-ampiciline using group was 25.6%, while it was 5.9% for group used s. boulardii as probiotic beside sulbactam-ampiciline (p b/ 0.05). it was observed that probiotic usage decreases diarrhea rate four times (p b/0. 05). when age groups considered, the rate of sulbactamampiciline associated diarrhea increased at 1 á/5 ages and s. boulardii effect on preventing diarrhea was significant at 1 á/12 ages (p b/0.05). antibiotic associated diarrhea is a common clinical problem at pediatric age group. s. boulardii is a hope giving probiotic especially for sulbactam-ampiciline associated diarrhea. grey e a bilikova e a , hafed bm a , kovacicova g a , chovancova d b , huttova m b , krcmery v a . a school of health, trnava university, trnava, slovakia , b postgraduate academy of medicine, neonatal clinic, bratislava, slovakia the purpose of the study: the aim of the study was to find out, whether artificial abortion of a mother has impact on neonatal infection of her future baby. the results obtained: therefore, we compared 39 neonates with infection, who were born to mothers with past history of abortion (1 á/7 artificial abortions within 10 years), with the babies of mothers, who have not experienced abortion before. control group consisted of 207 neonates hospitalized at the same clinic, at the same time period. according to the analysis of risk factors for neonatal infections, it was found, that prematurity (28 á/32 weeks of gestation) (30.77 vs. 14.01%, p 0.019) and low birth weight-1500 á/2500 g (58.97 vs. 39.13%, p 0.03) were significantly more frequently observed in babies of mothers with past history of abortion. drug abuse (heroin) (12.82 vs. 1.45%, p 0.003) and nicotine use (15.38 vs. 2.42%, p 0.0027), were more significantly related to neonatal infections in babies of mothers with past history of abortion. etiological analysis showed that only candida albicans (5.13 vs. 0%, p 0.024) was significantly related to neonatal infections in mothers with past history of abortion. the conclusion reached: in conclusion, artificial abortion has not only direct impact to the health of the mother, but also on her next pregnancy. bacteraemia and patient mortality in a peadiatric intensive care unit ps258 armenian sh, singh j, arrieta ac. children's hospital of orange county, infectious disease, orange, usa purpose: this study will identify the factors that significantly contribute to mortality in patients with bloodstream infections (bsi) at a pediatric intensive care unit (picu). results: medical records of 63 patients who were admitted to the picu and had a documented bsi were reviewed. there were 74 separate episodes of bsi's, with nine patients having multiple bsi's during their hospital stay. a casecontrol model was used. cases were bsi's with eventual mortality (n0/27; 36.5%) and controls were those who survived bsi (n0/47; 63.5%). patients who died were older (5.7 vs. 2.4 years; pb/ 0.01), more likely to have a nosocomial bsi (42.9 vs. 16.7%; pb/ 0.05), longer hospitalization prior to bsi (30.5 vs. 9.8 days; pb/ 0.05), and have a polymicrobial bsi (66.7 vs. 30.6%; pb/ 0.05). infection related mortality (irm)-defined as death within 7 days of bsi */was significantly higher in those receiving inadequate antibiotic treatment at the time of diagnosis of bsi (54.5 vs. 12.7%; p b/ 0.01), as well as in those with gram negative bacteremia and/or fungemia (35 vs. 13%; p b/ 0.05). logistic regression was used to adjust for potential confounding variables. conclusions: we found that being older, multiple organisms, and a longer hospitalization prior to the bsi were significantly associated with overall patient mortality. irm was significantly higher for those with inadequate initial antibiotic coverage and in those with gram negative bacteremia and/or fungemia. somer a a , gü r d a , diri s a , yalcýn i a , salman n a , ongen b b , gü rler n b . a department of pediatric infectious diseases, istanbul university istanbul medical faculty, istanbul, turkey , b department of microbiology and clinical microbiology, istanbul university istanbul medical faculty, istanbul, turkey teicoplanin is a glycopeptide antibiotic active against a broad range of gram-positive pathogens including methicillin-resistant staphylococci and offers the advantages of once daily administration, choice of administration route, lack of requirement for routine therapeutic drug monitoring and lower propensity to cause nephrotoxiticy and anaphylactoid-like reactions. in this study the efficacy and safety of teicoplanin were evaluated retrospectively in children with serious bacterial infection. sixty-three children (18 girls, 45 boys) aged between 1 month and 15 years were treated with teicoplanin (three loading dosages of 10 mg/kg at 12 h intervals, followed by a maintenance dosage of 10 mg/kg/day). the infections treated were pleural empyema (n0/25), joint and bone infections (n 0/22), septicemia (n0/9), skin and soft tissue infections (n0/4), and lung abscess (n0/3). the pathogens isolated were staphylococcus aureus (n 0/30, 16 of which were methicillin resistant), coagulase-negative staphylococci (n0/4), s. pneumoniae (n0/4), and group a hemolytic streptococci (n 0/2). the duration of therapy ranged from 14 to 81 days (median 28 days). clinical success (cure plus improvement) was achieved in 96.8% of cases. no side effects attributable to teicoplanin therapy were encountered. teicoplanin appears to be an effective and well-tolerated treatment for serious gram-positive infections in children. the risk of infection is present in all children with acute leukemia. two hundred and sixty episodes of febrile neutropenia were analyzed in 149 children (aged 1.5 á/16 years) with aml */43 cases and all */ 106 cases over 10 years during cytostatic therapy (protocols: mbfm */ 87 aml and mbfm */90 all). a degree of fn occurred in 90% of cases in aml, in 53% */in all. the sites of infection were: blood'/ central venous catheter (32%) and respiratory tract (49%). pathogens isolated from blood were: gram-positive */cns */70%, streptococcus spp. */18.7%, gram-negative */enterobacteria */41%, pseudomonas aeruginosa */23%, candida spp. */23.5%, aspergillus spp. */5.9%, other */5.9%. for the treatment of fn we used empirical antibiotics regimens. clinical response was noticed: in 1st line of therapy */ cephalosporins 3 á/4 generation used */45%, carbapenems used */60% as 2nd á/3rd lines */vancomycin */70%, amphotericin b */80%. thirtytwo percent of children with aml and 5.2% children with all died because of sepsis. conclusion: carbapenems are more active in the 1st line of antibiotics therapy both for patients with aml and all. vancomycin is useful in the 2nd line for patients with all. amphotericin b and vancomycin are useful in combination in the 2nd line for patients with aml. pavlenishvili ivp. medical academy, pediatrics, tbilisi, georgia our drug of choice in cases of complicated neonatal sepsis i. pavlenishvili, g, iobashvili tbilisi, medical academy georgian society of pediatrics chemotherapy (gspc) with collaborations of drug and therapeutic committee (dtc) of childers hospital 'republic' finished the observation study about nosocomial infections of neonatal icu in above mentioned hospital. study begins from november 2000. during this period we observe 45 cases of neonatal sepsis, most of them were due gram-negative bacteria. thirty-four cases of neonatal sepsis were cause different stains of escherichia coli , proteus spp. and acinetobacter . we notice that during last 2 years the role of acinetobacter in etiology of neonatal sepsis and nosocomial complications of neonatal sepsis in our hospital is gradually increased. as our observation reveals most optimal in the case of complicated neonatal sepsis was (according criteria of dts) use of ceftasidime. almost in all cases we used ceftasidime with success. we have only one case of mortality. since the macrolide resistance (mr) in streptococcus pyogenes has been increasing in europe, we studied the incidence and genetic basis of mr in s. pyogenes in russia. s. pyogenes isolated at baseline and during follow-up visits from children with acute pharyngitis receiving penicillin or midecamycin (16-membered macrolide) were studied. mr was evaluated by agar dilution (nccls), resistance mechanisms */by pcr. a total of 149 s. pyogenes were obtained at the baseline, 21 (14%) of which were erythromycin-resistant: 19 strains (90%) were erm (a)-positive, one */mef (a)-positive, and one was negative for all primers used. all erm (a)-strains were inducibly resistant to clindamycin and represented seven pfge profiles with one profile found in 11/ 19 strains. in three midecamycin treated patients mr was selected during the therapy (one strain had erm (a), one */mef (a), one */ unknown resistance determinant). mef (a)-strain obtained during follow-up visit had different pfge pattern with mef (a) strain isolated at baseline, while both the baseline and follow-up strains with unknown mechanism of resistance had unique pfge pattern. these data showed moderate incidence of erythromycin-resistant s. pyogenes in smolensk. ribosomal methylation (erm (a)) was the most common mechanism and though the polyclonal nature of mr was established, most erm (a)-strains belonged to only a few clones. bacillus cereus infections in traumatology-orthopaedy department: retrospective study and re-evaluation of healthcare practices ps263 bacillus cereus was cultured for 30 patients from traumatology department who had developed postoperative wound infections between august 1997 and march 2000. all patients presented inferior members open fractures, frequently contaminated with telluric material and requiring external fixators. genomic study of clinical isolates by pulsed field gel electrophoresis and random analysis polymorphic dna, allowed us to eliminate an outbreak. furthermore, the reduced delay in which patients developed the infection (6 days'//-2) led us to re-evaluate the procotols used in our institution. indeed, all patients had received amoxycillin '/ clavulanate iv 2g for antibioprophylaxis during anesthetical induction then relayed per os for 48 hours. because of the production of a potent beta-lactamase by the bacteria, this association could not be efficient. furthermore, accordingly to the afnor en 1040 norm, we have tested clinical isolates' sensitivity to the principal antiseptics used for antisepsis and disinfection (iodophors, chloride derivated and biguanidines) and observed a major resistance of all strains tested. even if these postoperative wound infections are considered as nosocomial because of the delay in appearance, we actually think that bacillus cereus were initially present in telluric material. this fact led us to propose a systematic screening for bacillus at admission for this type of wound and to administrate quinolones such as ciprofloxacin for prophylaxis. internal thiols and reactive oxygen species in the candidacidal activity exerted by a n-terminal peptide of human lactoferrin ps 264 the purpose of the study: the emergence of candida albicans strains resistant to current antifungals points to the need for new antifungal agents, e. g. antimicrobial peptides. the results obtained : we report that hlf(1-11), a synthetic nterminal peptide of human lactoferrin, displays excellent killing effect against fluconazole-resistant c. albicans and that sub-optimal concentrations of this peptide combined with fluconazole act synergistically. previous investigations revealed that hlf(1-11) required an energized mitochondrion, atp release by candida , and ligation of atp receptors for its killing effect. we now report that reactive oxygen species (ros) are involved in the killing effect of hlf(1-11). since internal thiols protect cells from oxidative damage, our observation that hlf(1-11) caused a 20% reduction of internal thiols in candida is of interest. as expected, n-acetyl-l-cysteine (nac), which is a precursor of glutathione and a ros scavenger, inhibited the killing effect of hlf(1-11). diamide, which oxidizes internal thiols, was candidacidal and hlf(1-11) and diamide acted synergistically in killing c. albicans and ros production. moreover, the hlf(1-11)-induced activation of mitochondria was inhibited by nac, indicating that internal thiols/ros affect mitochondrial activity. the conclusion reached : the candidacidal activity of hlf(1-11) involves ros production and reduction of internal thiols. objective : an audit was conducted to explore the observation of increasing resistance to ciprofloxacin in enterobacteriacea isolated from specimens from such patients in the hematology unit. results : enterobacteriacea isolates in specimens from such patients processed over the years 1997 to 2001 were examined. number of specimens per year was */109, 152, 132, 160 and 170 respectively and the annual percent ciprofloxacin resistant enterobacteriacea from these was 2%, 9%, 12%, 14% and 21%. conclusion : conclusion drawn from the audit was that rapid rise in ciprofloxacin resistance may possibly be attributed to the use of this fluoroquinolone as a single agent in dose of 250/500 mg [cut off patient weight 40 kg] twice a day in neutropenic patients till neutrophils exceed 500/c.mm. subsequent to the audit, prophylaxis protocol was modified to use of oral colistin 3-mega units/twice a day in combination with ciprofloxacin 250/500 mg twice a day. a prospective audit is proposed to test the benefits of this combination. rhinocerebral zygomycosis: diagnostic dilemma for emergency physician: can the associated morbidity and mortality in this rare but deadly disease be reduced? ps 266 samavedam s, guleri as. western infirmary, clinical microbiology, glasgow, united kingdom rhinocerebral zygomycosis [rcz] is a rare, invasive, rapidly progressive opportunistic infection caused by ubiquitous fungi of the order mucorales. it usually occurs in diabetics or immunocompromised patients. the emergency physician will typically see patients with rcz in its earliest stages masquerading as a variety of other less serious diseases. the key markers like necrotic patch on hard palate, nasal septum or turbinate, marked facial pain, and cellulites with marked eye and neurological signs may present late in disease. we report a case of rcz caused by rhizopus arrhizus [oryzae] in an 84 year old woman with poorly controlled diabetes. she presented with a right-sided facial droop of short origin and being generally unwell. ct scan was non-conclusive and delayed presentation of key markers of rcz permitted disease to rapidly progress. despite an intensive antifungal therapy with ambisome and insulin sliding scale, patient rapidly succumbed within 4 days. fine needle aspiration cytology is less invasive, easier and equally effective alternative to pre op biopsy. the key to successful reduction in morbidity and mortality associated with this rapidly fatal disease is -increasing awareness of the disease, an early diagnosis, correction of underlying metabolic derangement, prompt intensive antifungal therapy with amphotericin b and radical surgical debridement of the necrotic tissue. an 'optimal dosage' of ambisome requires discussion. clinical audit in the haematology ward of a tertiary care hospital: study of degree of correlation between bacteraemia and oro-pharyngeal screens in immunocompromised patients over five years and role of antibiotic prophylaxis ps 267 guleri as, butcher i. western infirmary, clinical microbiology, glasgow, united kingdom introduction : a clinical audit was carried out over 5-years [1997] [1998] [1999] [2000] [2001] in the immunocompromised patients including neutropenic patients and bone marrow [autograft] transplant recipients in hematology ward of gartnaval general hospital, glasgow, a tertiary care center. objective : it was aimed to establish the degree of correlation between bacterial isolates in oro-pharyngeal screen during bacteraemia episodes and role of antibiotic prophylaxis. methods purpose : to assess whether antiretroviral therapy (art) intensification, gm-csf use and remune initiation before stopping art lead to viremia containment, and long periods off art. methods : ten adults with chronic hiv disease, hiv-1 rna levels (vl) b/1.7 log copies/ml and median cd4'/ -t cell count of 385/ml were enrolled. after art intensification with ddi (6 months) '/ hydroxyurea [hu](5 mo.) '/ gm-csf (3 mo.) and a remune dose, art was stopped but remune continued. art was resumed if rebound vl did not decrease to b/4.7 log in 3 months or if cd4'/ counts decreased to b/200. results : vl rebounded in all patients after stopping art, and 7 developed an acute retroviral syndrome (ars). cd4'/-t cells decreased, and cd8'/38'/ increased (5-fold). after a median stoppage of 16 weeks, art was resumed in 9 patients and vl decreased to b/ 1.7 log, cd4'/ counts were regained, il-2 and il-15 levels rose. at the 2nd interruption, 9/9 patients had a rebound, and 3/9 had a 2nd ars, but peak vl and loss of cd4'/ were lower (p 0/0.003). after 21.3 weeks off art, 8 patients resumed therapy. the breadth and magnitude of hiv-specific activity increased and thymus size grew. the patients were off art for a median of 49.5 out of 80 weeks. two of them are off art for 80 and 44 weeks respectively ( vlb/4 log). conclusions : this approach led to a high ars incidence, long periods off art, increases in hiv-specific responses, il-2 and il-15 levels, and thymus size. urinary tract infection in hospitalized population is a significant problem. this is a study of catherized patients urinary infection in corfu hospital. in 2000 á/2001, 3500 urine cultures were sent to our bacteriology laboratory. 650 of them were collected from the catheters. clinical data of age and type of disease were analysed. the samples were cultured on mc conkey agar-urotube and vitek cards. the organisms identified with vitek automatic system. the sensitivity was tested with vitek and kirby-bauer method. results: no growth of organisms in 46.5%. positive cultures 35%. 62.2% of the bacteria were gram((/) rods (45.6% e. coli , pseudomonas spp. 0%), 16% were gram('/) cocci (enterococcus spp.) and 22% was candida spp. the resistance of e. coli was: 37% to ampicillin , 17% to co-trimoxazol and 2% to quinolons. e. faecalis was resistant 10% to vancomycin . conclusions : (1) the possible interference of acetaminophen in the amoxicillin/ clavulanic acid (a/c) or erythromycin (ery) efficacy in the treatment of acute otitis media (aom), and its possible role in the evolution to otitis media with effusion (ome), were determined in a gerbil model. a 23f streptococcus pneumoniae strain exhibiting a mic of a/c and ery of 1/0.5 and 0.12 mg/l, respectively, was used. both antibiotics were tested at 2.5 and 10 mg/kg. acetaminophen at 50 mg/kg was administered 30 min before each antibiotic dose. antibiotic concentrations in serum and middle ear exudate were determined. both antibiotics significantly reduced the number of culture-positive ears and colony counts, with serum concentrations over the mic of the microorganism for ]/15% of the dosing interval. antibiotic concentrations in middle ear exudate were almost identical in animals receiving and not receiving acetaminophen. clinical and microbiological efficacy was correlated with antibiotic concentrations in middle ear exudate ]/1.7 times the mic of the microorganism, for both antibiotics. both antibiotics demonstrated efficacy in the treatment of pneumococcal aom, with the same rate of ome. acetaminophen, concomitantly administered, did not interfere the efficacy of the two antibiotics tested and did not prevent the evolution of aom to ome. parra a a , ponte c a , cenjor c b , garcía-olmos m a , giménez mj c , aguilar l c , soriano f a . a fundación jiménez díaz, medical microbiology, madrid, spain , b fundación jiménez díaz, otorrinolaryngology, madrid, spain , c glaxosmithkline, medical department, madrid, spain a gerbil model of otitis media with effusion (ome) induced by haemophilus influenzae (amoxicillin/clavulanate-a/c-and erythromycin-ery-mics of 1/0.5 and 4 mg/l, respectively) was used to evaluate the efficacy of a/c (10/2 and 15/3 mg/kg) and ery (20 and 50 mg/kg). antibiotics were administered subcutaneously 2 h post-middle ear inoculation, and continued t.i.d for 24 h, with or without acetaminophen (ap), at 50 mg/kg, administered 30 min before each antibiotic dose. antibiotic concentrations in serum and middle ear (me) were measured by bioassay. me samples for colony counting were collected on day 2. a/c reduced (p 5/0.05) positive me samples and colony counts versus untreated controls or ery: me positive cultures of 90% for controls, 0% for a/c 15, 7% for a/c 10, 17% for a/c 10'/ap, 90% for ery 20, 57% for ery 50 and 87% for ery 50'/ap. this was due to a/c (but not ery) concentrations in me exceeding 1.8 times the mic despite the higher percentage of antibiotic penetration of ery versus a/c (43 versus 8/14%). animals receiving ap showed less polymorphonuclear cells and more bacteria in me than those receiving only antibiotics, suggesting that the anti-inflamatory drug diminish the phagocytes and therefore, the efficiency in bacterial clearance. amoxycillin treatment for acute otitis media caused by penicillinresistant streptococcus pneumoniae . a pharmacodynamic analysis pm103 parra a a , ponte c a , cenjor c b , garcía-calvo g a , giménez mj c , aguilar l c , soriano methods: a serotype 23f streptococcus pneumoniae strain exhibiting a mic of amoxycillin of 1 mg/l was used in an experimental model performed in gerbils (meriones unguiculatus ) following previously described procedures. amoxycillin was tested at the following doses: 0.2, 0.4, 0.8, 1.25, 2.5 and 5 mg/kg. amoxycillin concentrations in serum and middle ear exudate were determined after drug administration. results: doses of ]/2.5 mg/kg significantly reduced the number of culture-positive ears, colony counts and otorrhoea (p 5/0.05) as compared with untreated controls or animals treated with doses lower than 1.25 mg/kg. doses of ]/2.5 mg/kg achieved antibiotic concentrations in the middle ear 1.4 á/2.4 times higher than the mic of the infecting strain and serum concentrations over the mic for 14 á/19% of the dosing interval. conclusions: amoxycillin at doses achieving serum concentrations similar to those obtained in children after standard doses, obtained therapeutic and microbiological efficacy regardless the susceptibility of the infecting strain. better correlation was found between antibiotic efficacy and antibiotic concentrations in middle ear exudate than between efficacy and serum concentrations, which were suboptimal from the pharmacodynamic perspective. increasing prevalence of amoxycillin á/clavulanate-resistance among e. coli strains in a hungarian university hospital pm104 veréb i, vígh a, urbán e, hajdú e, nagy e. department of clinical microbiology, university of szeged, szeged, hungary background: amoxicillin á/clavulanate resistance (acr) is an emerging problem in escherichia coli as reported from different parts of europe. the aims of the present study were to evaluate statistically the prevalence of acr among e. coli isolates and to investigate the genetic background of the resistance. methods: all e. coli strains isolated between 2000 1 1 and 2001 9 1 were screened for acr by kirby á/bauer disc diffusion method. the resistance to other beta-lactam á/beta-lactamase inhibitor combinations and to different beta-lactam antibiotics were also tested. selected strains underwent determination of beta-lactamase activity. confirmatory tests for suspected extended spectrum beta-lactamase were performed. pcr testing for tem and shv genes were carried out on plasmids isolated from selected strains. results: in 2000 out of 1109 e. coli strains 102 (9.2%) were found to be resistant to amoxicillin clavulanate (amc). most of the resistant strains (95%) were obtained from the genitourinary tract and no acr isolate was found in blood cultures. in 2001 out of 2167 isolates 239 (11%) proved to be acr and 2.5% were isolated from blood cultures and 66.9% from the genitourinary tract. thirty-five selected strains were further analysed. thirty-two were also resistant to (sam) and six were further resistant to tzp. quantitative beta-lactamase determination showed increased activity in strains which were partially susceptible to amc. the presence of esbl could be proved only in three acr isolates. this open parallel-group study compared the efficacy and tolerability of cef with cfix 400 mg once daily in the treatment of community acquired uncomplicated uti. seventy-eight female patients were randomized to receive either oral cef or cfix for 5 or 10 days. the efficacy of treatment was evaluated by clinical response (by symptoms of uti dysuria frequency urgency suprapubian pain and by clinical signs) by bacteriologic response and health status measures at baseline and posttherapy. results: the clinical cure (complete resolution of symptoms and signs) rate for patients receiving cef was 95.12% of the 41 evaluable patients and 89.18% of the 37 patients receiving cfix. bacteriologic response (based on the results of urine cultures obtained posttherapy) the pathogen was eradicated in 82.3% for cef 73.3% for cfix. no drug related side effects have been reported in cef and side effects were experienced by 5.40% of the patients receiving cfix. improvement in health status comparing visual scale scores baseline and poststudy to have detected a higher change in average score from 17 to 94 in cef, from 20 to 82 in cfix. wilcoxon improvement value was significant on the 3rd day of therapy in case of cef and on the 5th day of therapy in cfix group. in conclusion, the results of this study indicate that cef course is more effective than cfix in producing a favourable clinical outcome and achieving higher bacteriologic eradication rate, furthermore cef was better tolerated. cefepime is a fourth generation cephalosporine that has a broader spectrum of antibacterial activity than the third generation cepfalosporines and is more active in vitro against gram-positive aerobic bacteria. the purpose of this study was to measure cefepime concentrations in plasma, bile fluid and gall bladder tissue in patients undergoing cholecystectomy. thirty patients 12 male, 18 female, mean age: 48 years had data acceptable for analysis and were included in this study. all patients received iv 2 g of cefepime. several hours after administration and at different time intervals, during surgery, samples were obtained from plasma, bile fluid and gall bladder tissue concomitantly. antibiotic levels were measured by an agar diffusion method. the mean delta time was 2849/255 min. the values for plasma, bile fluid and gall bladder tissue, were 33.69/28.5, 6.69/4.3 and 16.19/12.9 mg/ml, respectively. the plasma/bile fluid ratio was 2.69/ 2.4. there was a significant correlation between plasma and gall bladder tissue concentration (r0/0.771, p0/ b/0.0001). a correlation between bile fluid and plasma cefepime concentration was not observed. the minimum inhibitory concentration (mic) data from previous in vitro studies indicate that the cefepime concentration observed in plasma bile and tissue samples of this study would be adequate against typical biliary tract pathogens. furthermore, these cefepime concentrations correlated well with the favorable clinical outcome reported in previous clinical studies in biliary tract infections. there was also good correlation between delta time and plasma and tissue concentrations and if the dose were given closer to the time of surgery, cefepime concentration would be higher reducing the possibility of an infection. objectives: the use of antibiotics may lead to decreased colonization resistance and increased formation of resistant bacteria. present concept was developed to overcome these untoward effects. methods: b-lactamase of bacillus licheniformis was overproduced in bacillus subtilis . this targeted recombinant b-lactamase enzyme (trbl) was released in the small bowel from a controlled-release formulation. beagles (n0/6) were treated bid with either 20 mg/kg ampicillin (i.v.)'/placebo (p.o.), 20 mg/kg ampicillin (i.v.)'/trbl (p.o.) or only placebo (i.v.'/p.o.). stool was collected at days 4 and 10. samples were cultured for total and main groups of aerobic and anaerobic bacteria and yeast. temperature gradient gel electrophoresis (tgge) was used to separate the ribosomal rna genes. results: ampicillin'/placebo group had clearly decreased counts of both aerobic and anaerobic bacteria during the treatment, whereas those receiving trbl had only minor overall changes and some occasional changes by single species. intravenous ampicillin decreased the fecal similarity percentage to 60%. the similarity percentage during treatment with ampicillin'/trbl did not differ from that of placebo (86 vs. 81%). conclusions: according to our results the trbl can maintain the large intestinal microflora almost unchanged. these results indicate that trbl is a promising novel approach for overcoming the ecological adverse effects on gut flora caused by b-lactam antibiotic agents. adamis since broad-spectrum â-lactams combined with amikacin are often applied for nosocomial infections, their pharmacokinetic interactions might be interesting. one gram of aztreonam and 0.5 g of amikacin were administered intravenously single and in combination in six healthy volunteers. blood samples were collected at regular time intervals and concentrations of antimicrobials were determined by a microbiological assay applying a strain developing resistance to single agent after serial passages. mean concentrations of amikacin in serum when administered alone and in combination with aztreonam were 26.2 and 20.3, 11.8 and 12.3, 8.4 and 12.2, 6 .3 and 9.7, 1.8 and 4.3 and 0 and 1.3 mg/ml immediately after and 0.5, 1, 2, 4 and 8 h after infusion of antimicrobials. respective concentrations of aztreonam were 63.5 and 25.3, 27.5 and 21.6, 24.2 and 10.5, 19.5 and 13.6, 5.8 and 4.4 and 1.8 and 4 .0 mg/ml. aucs for amikacin when administered alone and in combination with aztreonam were 35.59/10.9 and 50.59/7.8 mg h/l, respectively. respective auc for aztreonam were 99.79/35.2 and 76.49/31.5 mg h/l. it is concluded that the co-administration of aztreonam and amikacin results in earlier clearance of aztreonam and in higher levels of amikacin compared to the administration of each single antimicrobial. molecular modelling of b-lactams reveals the structural basis for their inhibition of penicillin-binding proteins, susceptibility to b-lactamases and oral bioavailability pm110 grail bm, gupta s, payne jw. school of biological sciences, university of wales, bangor, uk b-lactam antibiotics are peptide mimetics that act as suicide substrates for transpeptidase enzymes that cross link bacterial cellwall peptides. for the first time, the structural and electronic features needed for their recognition by transpeptidase have been fully described, using innovative molecular modelling techniques to compare the conformational forms adopted by cell-wall peptides and blactams. comparison of features in the backbone and c-terminal regions of conformers of active b-lactam antibiotics and model cellwall peptides, has allowed definition of the molecular recognition template required for substrate recognition by transpeptidase. these shared structural features allow both to act as substrates and to acylate the active-site serine. however, a significant difference in a critical backbone torsion between the two substrates, provides an explanation for the inability of the enzyme á/antibiotic complex to undergo the deacylation step that causes inhibition of transpeptidase. on the other hand, b-lactamases appear to have evolved molecular mechanisms that facilitate the deacylation reaction through compensating for the altered structural orientations in b-lactams caused by the different backbone torsion. finally, analysis of the conformer repertoires of blactams for structural features required for substrate uptake by peptide transporters, provides insights into how their structures can be tailored for optimal oral absorption. antimicrobial susceptibility of proteus mirabilis clinical isolates producing extended spectrum beta-lactamases (esbls) pm111 objectives: the aim of the present study was to determine in vitro susceptibility to antimicrobials of proteus mirabilis isolated from urinary tract infections. methods: we studied the susceptibility profile of esbl positive p. mirabilis strains in three adopted children from india with age range from 20 months to 2 years. esbl was identified using the synergic effect of clavulanate with betalactams (ceftazidime and cefotaxime the in vivo efficacy of amoxicillin (amx) sub-therapeutic doses (3.12 mg/kg, t.i.d for 48 h, achieving serum levels over the mic of only 3% of the dosing interval) and concomitant specific serotherapy (single intraperitoneal dose of 1/4 diluted hyperimmune serum (hs) obtained from mice immunized with the heat-inactivated strain) was assessed in a pneumococcal sepsis balb/c mouse model. mice (five mice/ treatment group) were intraperitoneally infected with 1.5 )/10 8 cfu/ ml of a serotype 6b penicillin-resistant strain (mic of 2 and 4 mg/l for penicillin and amx, respectively). treatments started 1 h after bacterial inoculation. study groups were: control (k; receiving nonimmune serum (nhs)), amx'/nhs, hs, and amx'/hs. survival rates (%) over time were: purpose of the study: the study was performed to determine the consumption of imipenem and resistance of gram-negative pathogens (pseudomonas aeruginosa , acinetobacter sp., klebsiella sp., escherichia coli , proteus mirabilis , serratia marcescens , enterobacter sp. ) to imipenem. gram-negative pathogens were isolated at the sestre milosrdnice university hospital from zagreb, croatia, in 1999 and 2000. the imipenem sensitivity testing was performed by disk diffusion and e -test methods. the consumption of imipenem was expressed in ddd/100 hospital days in the same periods. results obtained: imipenem resistance of acinetobacter sp. decreased significantly in the year 2000 (p0/0.0052), especially in the first 6 months (p 0/0.021) when the lowest consumption of imipenem was recorded. imipenem resistance of other gram-negative pathogens did not decrease significantly. conclusion reached: comsumption of imipenem might lead to changes in resistance to imipenem among acinetobacter strains. vacheva-dobrevski rs, savov ez. military medical academy, clinical microbiology, sofia, bulgaria purpose: acinetobacter baumanii is becoming increasingly frequent nosocomial pathogen at our hospital, and beta-lactam resistant strains are on the increase, especially among icu isolates. to study the susceptibility of a. baumanii clinical isolates to beta-lactams and to determine the esbl-producing strains during 2001, year. a total 438 gram-negative nonfermenters (gnnf) isolates was investigated by semiautomated mini api system (bio merieux, france). eighty-four a. baumanii non-repeated isolates was studied for esbl-producing by double-disk synergy test (ddt) and atb-blse test (bio merieux, france). mics for beta-lactams were determined by e -test (ab biodisk, sweden). results: a. baumanii (n0/84) showed a multidrug resistance. the isolates were resistant to cefotaxime (79%), cefoxitin (96%), ceftazidime (49%), amoxicillin/clavulanate (76%), piperacillin (72%), aztreonam (84%), imipenem (12%). the 32 (38%) of investigated a. baumanii expressed esbl activity and originated more frequently from icu (78%). esbls producing strains were isolated from endotracheal aspirate (52%), surgery wounds (29%), blood culture (5.7%). conclusions: in general resistance levels were higher in clinical isolates a. baumanii to beta-lactams. the ddt seems to be a practical method for esbl-screening; atb-blse method is more sensitive. our study display to be the first report of esbl-producing a. baumanii strains from our country. carbapenems seems to be the most active agents against a. baumanii . salmonella infantis , strain 111, was isolated from a newborn baby at wassila bourguiba maternity in tunis. it exhibited high resistance to penicillins, extended-spectrum cephalosporines (cefotaxime, ceftriaxone, ceftazidime, cefpirome) and aztreonam but remained susceptible to cefoxitine and imipenem. involvement and characterization of enzymatic mechanism in b-lactam resistance were investigated in strain 111. isoelectricfocusing revealed that this strain produced a b-lactamase of pi 6. this enzyme had a broad-substrate profile, hydrolyzing amoxicillin, ampicillin, ticarcillin, cephaloridine, cefuroxime, cefotaxime, ceftriaxone, cefpirome and ceftazidime. the highest specific activity was observed with ampicillin. cefotaxime was hydrolyzed the most efficiently of the extended-spectum cephalosporines. the pi 6 extended-spectrum b-lactamase (esbl) was inhibited by clavulanic acid and sulbactam. no inhibition of the esbl was observed with 1 mm edta. thus, no metal ion is involved in hydrolysis for this b-lactamase. resistance due to the production of the pi 6 esbl was transferred with dna plasmid into escherichia coli . on the basis of substrate and inhibition profiles and isoelectric point, the pi 6 esbl was not previously described in s. infantis in tunisia. the presence of such a resistance on a plasmid raises concer for rapid dissemination among bacteria and loss of effectiveness of blactams. poizot-martin i a , enel p b , benhaïm s c , vion-dury f c , dinh t c , drogoul mp c , gastaut ja c . a assistance publique hôpitaux de marseille, cisih sud, pr ja gastaut, marseille, france , b assistance publique hôpitaux de marseille, cellule santé publique dmi2, marseille, france , c assistance publique hôpitaux de marseille, cisih sud, marseille, france objective: to assess liver biopsy (lb) practices in a cohort of 255 co-infected hcv and hiv patients followed up in an hiv specialized medical unit. method: transversal study with questionnaire among patients in pre-therapeutic's evaluation with pcr'/ and without lb at 6 months. results: among the 255 patients, 28 (11%) are lost of follow up, 159 (62.3%) have had lb, 68 (26.2%) have no lb. the characteristics of these 68 patients are: median age 0/38.59/6 years; sex ratio 0/2.14, cdc-stage a0/33.3% b 0/47.0% c 0/19.7%, undetectable viral load0/33.3%, median cd40/3269/204, anti-retroviral therapy0/ 95.5%, hcv-genotype 10/46.7%; 3a0/31.7%; 40/21.7%. causes of non-made lb are: (1) refusal from patients because of biopsy's fear0/ 35.3%; (2) contraindications because of hiv infection0/33.8% (clinical events0/16.2% which contraindicate anti-hcv treatment, grade iii thrombocytopenia0/8.8% which contraindicate biopsy, non-adherence to previous hiv follow up0/8.8%); (3) other0/30.9% (alcoholism0/13.2%, psychiatric/depressive disorders0/11.8%, decompensated cirrhosis0/5.9%). drug use or methadone/buprenorphine treatment are not considered as contraindication. conclusion: one-third of patients are afraid of lb. alcoholism and psychiatric/depressive disorders are the principal contraindications to anti-hcv treatment. it seems important to improve information of patients about lb and to focus on alcohol and psychiatric/depressive disorders management in such population. kashiwagi kk a , furusyo nf a , nakashima hn a , kashiwagi sk b , hayashi jh a . a department of environmental medicine and infectious disease, kyushu university, fukuoka, japan , b national kyushu medical center, fukuoka, japan the purpose of the study: the aim of this prospective study was to explore the effect of htlv-i co-infection on the development of hcc among patients with chronic hcv viremia. a total of 764 consecutive patients with chronic hcv viremia were studied and followed-up over a mean period of 5.1 years: 172 (22.5%) were infected with htlv-i infection and 592 (77.5%) were not. the results obtained the annual hcc development rate was 3.4% in patients co-infected with hcv and htlv-i and 1.4% in patients infected with hcv alone. hcc was significantly higher in 33 (19.2%) of the 172 patients co-infected patients than in 39 (6.6%) of the 592 patients infected with hcv alone (p b/ 0.001, logrank test). in patients under the age of 55 years, hcc development was significantly higher in seven (17.1%) of 19 patients co-infected with hcv and htlv-i than in eight (2.9%) of 220 patients with hcv alone (pb/ 0.05, logrank test), whereas there was no significant difference in hcc development between patients over age 55 with or without htlv-i infection (26 (2.0%) of 131 and 31 (9.9%) of 312, respectively). the conclusion reached htlv-i infection accelerates the development of hcc in chronic hcv patients, especially among patients under the age of 55 years. to analyze hbv genotype-related clinical differences among patients with chronic hbv infection, all 158 patients were serially tested for serum alanine aminotransferase (alt) and hepatitis b e antigen (hbeag) and followed up for a mean 10.8 (6.4) year period. genotypes b and c were found in 58 (36.7%) and 100 (63.3%) of the patients, respectively. hbeag positivity and alt abnormality rates at the start of the observation period were significantly higher in genotype c patients (66.0 and 84.0%) than in genotype b patients (34.5 and 22.4%). the annual rate of spontaneous hbeag disappearance in genotype b patients was much higher than in genotype c patients (8.38 versus 2.34%, respectively). patients with genotype c who were continuously hbeag negative from entry had significantly higher alt abnormality (58.8%) than those with genotype b (19.2%). interestingly, patients with genotype c who became hbeag negative by interferon treatment had high alt abnormality (58.8%). all patients with alt abnormality were serum hbv dna positive. these findings indicate that hbv genotype c patients are more severe liver deterioration because of the delay of hbeag disappearance and continued hbv replication after hbeag disappearance. nossik nn a , nebolsin ve b , zheltukhina ga c , yevstigneeva rp c . a the d.i. ivanovsky institute of virology, viral reproduction, moscow, russian federation , b pparminterprisis co., chemistry, mocow, russian federation , c moscow state academy of fine chemical technology, piptide chemistry, moscow, russian federation objective: to study the effects of 'gamma'-l-glutamylhistamine (glu-ha) derivates on non-specific immunity ('alfa'-ifn, 'gamma'-ifn and nk cell activity) and antiviral activity on the experimental influenza and herpes virus infections in mice. the glu-ya and its derivate glu-ii were synthesized by peptide chemistry techniques. the glu-ha and glu-ii was administered i.p. 0.05 and 0.5 mg/kg before and after influenza virus (type a/aichi) and showed a protective effect even at the high infective dose (100ld50) */the rate of protection0/ 42 á/51/60% in the positive/control group. they were not very effective in the protection of herpes simplex virus encephalitis in mice. the model of the physico-emotional stress in mice was used to investigate the ifn system and nk cell activity. the production of ifns and nk cell activity of splenocytes decreased in 2 h after the stress and back to normal level in 7 á/10 days. it was shown that glu-ha and glu-ii can protect or substantially prevent the decrease in nk cell activity and ifns synthesis in post-stress period (so normally did not induce the ifns' synthesis). conclusions: the glu-ha and glu-ii showed antiviral effect against influenza virus infection in mice. the immunomodulating activity and ability to normalize the ifn synthesis and nk cell activity depressed the post-stress period and probably play an essential role in the antiviral activity. no dose adjustment of an anti-influenza prodrug oseltamivir is required in patients with hepatic impairment pm120 oo c a , snell pr b , liu b a , martin d b , simkins t b , small i b , ward p b . a hoffmann-la roche inc., global development, nutley, usa , b roche products ltd., global development, welwyn garden city, uk background: oseltamivir (ose; ro 64-0796, tamiflu † ) is an oral ethyl ester prodrug of its active metabolite oseltamivir carboxylate (oc: ro 64-0802), a potent and selective neuraminidase inhibitor of the influenza virus. the purpose of the study is to evaluate the need for ose dosage adjustment in hepatic impaired patients (hi). method: healthy volunteers (hv) versus hi (child-pugh score 7 á/ 9) [matched on the basis of age (9/10 years), gender and weight (9/ 20%)] were compared. each subject received 75 mg ose. results: based on c max (ng/ml) and auc inf (ng h/ml) analysed using nominal times, ls mean ratios and 90% ci between hi and hv were similar. ose* values in hi were marginally elevated but not sufficiently to require dose adjustment. the aim of this study is to investigate the influence of molecular structure of macrocyclic pyridinophanes and their analogs on antiinfluenza and antiherpetic activity of these compounds. we used 4d-qsar approaches on the basis of simple representation of molecular structure. such representation for biologically active substances allows the description of the spatial structure of compounds with the complete stereochemical information. it determines spatial structures either promoting or interfering of the concrete biological activity. it is easy to realize the molecular design of compounds with the given level of activity with the help of the combinations of simplexes. statistic characteristics for qsar of partial least-squares models are satisfactory (r0/0.92 á/0.97; cvr0/0.76 á/0.86). the molecular fragments that increase the antiviral activity were defined and will be demonstrated. this information was used for design and directed synthesis of several novel antiviral agents with predicted high anti-influenza or antiherpetic activities. predicted activities were confirmed experimentally. 4d-qsar approaches are useful for development of antiviral compounds. this work was partially supported by intas foundation (grant intas 97-31528). lozitsky vp. ukrainian mechnikov research anti-plague institute, chemotherapy, odessa, ukraine the purpose of this study was to research the anti-influenza activity of proteolytic inhibitor e-aca. it prevents the enhancement of proteolysis during the interaction of virions with cell membranes and decreases penetration of virions into cells. e-aca brings down proteolytic cleavage of ha-precursor to ha-1 and ha-polypeptides and reduces the infectious virus harvest. it shows the prophylactic and therapeutic action during the experimental influenza reducing the enhancement of alkaline proteases activity in lungs after infection. e-aca promotes the intensification of specific antibodies production and cell immunity, prevents vessels' permeability and hemorrhagic phenomena, decreases the destruction of bronchi's epithelium. it reduces the duration of intoxication, catarrhal instances and hyperthermia in sick children. e-aca improves the indexes of immunity, non-specific resistance and decreases the rate of bacterial complications. application of e-aca for treatment influenza and other arvi in children is recommended in ukraine on the base of results of our researches. the higher effects demonstrated as a result of combine usage of e-aca with specific ig, or deitiforin, or unithyol, or ribavirin. in our opinion, the study of effectiveness of e-aca combine application with inhibitors of influenza na is the perspective direction of anti-influenza researches development. we should we treat immediately all varicella patients with acyclovir if the patient is older than 20 years pm123 during past 2 years in institute for infectious and tropical diseases in belgrade, 89 immunocompetent varicella patients were treated and cured. among them 32 were older than 20 years (35.95%). x-rays were performed in all patients. diagnosis of pneumonia was made in 32 patients (35.95%), but in 26 (81.25%) patients older than 20 years. varicella is a benign, self-limited disease, if it strikes early, i.e. preschool, school children and teenagers. at that time there is no need for specific therapy. but in neonates, immunocompetent adults and in all immunocompromised patients it can be difficult and life-threatening disease. in immunocompetent adult population pneumonia is a very serious, sometimes fatal complication. knowing the pathophysiology of primary varicella á/zoster infection, specific therapy with acyclovir should be started immediately after making the diagnosis in patients older than 20 years, without waiting for x-ray proof of pneumonia. brivudin compared to acyclovir for the treatment of herpes zoster: effects on acute disease and posttherapeutic pain pm124 objective: comparison of efficacy and safety of brivudin 1)/125 mg and acyclovir 5)/800 mg, both for 7 days, in the treatment of herpes zoster. methods: randomised, double-blind study on 1227 immunocompetent patients ]/18 years (brivudin: n 0/613, acyclovir: n 0/614). a subgroup of patients ]/50 years (brivudin: n0/309, acyclovir: n0/299) was examined for the occurrence of posttherapeutic pain in a poststudy survey. posttherapeutic pain was defined as any zoster-associated pain, regardless of intensity, after the end of acute zoster. results: brivudin was superior to acyclovir in reducing time to last occurrence of new vesicles (rr(itt): 1.13 [1.01 á/1.27], p 0/0.01). the advantage of brivudin was more pronounced in patients ]/50 years (rr(itt): 1.16, [1.01 á/1.34], p0/0.02). incidence of posttherapeutic pain was significantly lower with brivudin (32.7%) than with acyclovir (43.5%, p0/0.006). duration of pain was comparable in both treatment groups (rr: 1.11, [0.93 á/1.32], p 0/0.27). potentially treatment-related adverse events occurred in 7.7% of the brivudin recipients and in 10% of the acyclovir recipients. conclusions: brivudin 125 mg once daily for 7 days is superior to standard acyclovir in stopping viral replication in acute herpes zoster. in patients ]/50 years, brivudin is more effective than acyclovir in reducing the risk of developing posttherapeutic pain. brivudin is as well tolerated as acyclovir. varadinova t a , genova p a , garcia-raso a b , terron a b , fiol j b , badenas f b . a laboratory of virology, sofia university, sofia, bulgaria , b chemistry, universitat de les balears, palma de mallorca, spain we have published that cu(ii) complexes of acyclovir (acv) are active against hsv infection (mbd, 1996) . here we present data on the activity of acv complexes of ni(ii), cd(ii), co(ii) and ag(i) against resistant to acv hsv 1 strain r-100 in comparison with the effect against acv sensitive strain victoria. selectivity indexes (si) compared to that of acv were indicative for activity. the following data were obtained: (i) 1 was 10 times less selective inhibitor of strain r-100 than of strain victoria; (ii) under the action of [cd(acv)cl 2 ], [ni(acv) 2 (h 2 o) 4 ]cl 2 ×/2acv and [ni(acv)(no 3 )] 3 ×/5h 2 o was up to 90% higher than that in the control; (ii) 2 was 28 times less selective inhibitor than acv; (iv) si of 3 was two times higher for strain r-100 and five times lower for strain victoria then that of acv. these data show that the selectivity of acv against resistant hsv 1 strains can increase when acv is bond to a proper metal ion. methods: an antiviral activity against herpes simplex virus of the type i (hsv-i/leningrad/248/88) and variant hsv-1 (vvt/4/00r) resistant to acyclovir was determined using commonly accepted method. viruses were grown on a continuous culture. maximal toxic dose was determined by the administration of compounds orally (300 mg/kg) or intraabdominally (100 mg/kg) to white mice that had mass 18 á/20 g. condition of the animals was controlled during 72 h. mice pneumonia model was used for the testing activity in vivo. results: derivatives tested have activity against hsv-1 and hsv-1 resistant to acyclovir. maximum protection of the cells up to 80% was reached at concentration of compounds 100 á/10 mg/kg. tested compounds have low toxicity and animals did not die after intraabdominal and after per oral administration of the substances. using these compounds led to essential relief of diseases in animals. the number and square of virus specific areas of inflammation in lung was decreased to compare with control untreated group. tested compounds protected animals similar to acyclovir that was used as control. conclusion: derivatives of carboalkoxysulfanilic acids are active against hsv in vitro and in vivo and act on the acyclovir resistant variant viruses. markiewicz r a , szepietowski jc b . a jelfa s.a., medical department, jelenia gora, poland , b department of dermatology, university of medicine, wroclaw, poland background: denotivir is a 5-benzoamino-4?-chloro-3-methyl-4isothiazolecarboxanilide anti-inflammatory agent with antiviral and immunomodulatory activities. it possesses also mild antibacterial and antifungal action. the purpose of the study: the aim of this presentation is to give an overview of recent studies demonstrating denotivir efficacy in herpetic infections. the results obtained: in vitro studies revealed that denotivir in the doses below its cytotoxicity (about 25 um) significantly inhibited (by 90 á/99%). herpes simplex virus (hsv)-1 and hsv-2 replication in fibroblast and kidney cell cultures. moreover, it was showed that denotivir in the dose of 37 mg/ml markedly inactivated hsv-2 after 30 min incubation in 37 8c. in giunea pigs research, 2% denotivir in 90% dmso appeared to be superior to 90% dmso alone and untreated groups in the therapy of animal skin infected by hsv-2. there was no huge difference in eythema and oedema scorings between studied groups, however in the group treated with denotivir, in contrast to others, no vesicles developed. several clinical studies showed usefulness of denotivir in controlling herpetic infections in dermatology, ophthalmology and otolaryngology. in the majority of studies within few hours after the drug application itch and pain relief was noted and within 1 á/2 days the vesicular lesions were dried up. the conclusion reached: in conclusion, denotivir is an effective antiherpetic agent. this study was conducted on 12 cows affected with teat papillomatosis. in the first step, each cow was located on one of three groups. the first group contained four cows from 1 to 4 years that were treated with fig tree (ficus carica) latex. the second group contained four cows from 1.5 to 4 years that were treated with a 10% solution of salicylic acid, and the third group contained four cows as control. in group one and two following treatment with fig tree latex and salicylic acid, superficial necrosis begun from day 5 and all of the warts disappeared by day 30. in the control group, after day 20, there were no changes in number of lesions, but some of them were larger than first observation. on day 25, one of the marked warts disappeared and on day 35 another wart was disappeared but six were present until day 45. comparison of effects of salicylic acid and fig latex showed similar effects in treatment of udder papillomatosis in cow. laboratory markers of skeletal muscle toxicity in hiv-infected patients: a cross-sectional case-control survey of frequency, potential correlation with antiretroviral therapy, clinical significance, and outcome pm130 manfredi r, motta r, patrono d, calza l, chiodo f, boni p. to assess skeletal muscle toxicity among â/1000 hiv-infected outpatients (p), the 129 p who had ]/1 altered cpk assay ( !/195 u/l) between may and november 2001, were compared with 387 p randomly selected among those who had ]/2 laboratory exams in this 6-month interval, in a 1:3 case-control study. among the 129 p with altered cpk levels only six were females, and 110 received antiretrovirals. the overall frequency of altered cpk among all p who underwent ]/2 laboratory workouts in 6 months was 14.4%. cpk alteration was transient in 98 p, with values ranging from 196 to 3463 (mean 256.29/62.3) u/l, but was recognized ]/2 times in 2 á/6 months in 31 p (24%), 24 of them showing concomitant high aldolase levels (3.1 á/10.8 u/l). a myopathy or a rhabdomyolisis were recognized in four p only; a myositis was confirmed in one p by histopathology. in a multivariate logistic regression analysis, when excluding the unexpected prevalence of the male gender (p b/0.0001), no significant difference emerged between p and controls as to age, risk for hiv infection, iv drug use, duration of hiv infection, prior anti-hiv therapy and its length, selected drug combinations, administered nucleoside analogues,hiv disease stage, mean cd4'/ count and hiv viremia, signs and duration of lipodystrophy, increased glucose, triglyceride and cholesterol levels, and other therapies. muscle abnormalities, though frequently asymptomatic, are underestimated hiv disease complications, and the role of metabolic (i.e. mitochondrial) alterations, deserves investigation. poor efficacy of non-nucleoside reverse transcriptase inhibitor (nnrti)based salvage haart in hiv-infected patients heavily pre-treated with all other classes of antiretroviral compounds pm131 manfredi r, calza l, chiodo f. infectious diseases, university of bologna, bologna, italy poorly comparable literature series show conflicting results of nnrti-based rescue haart: 20 á/70% rate of virologic success. to assess the response to a 4 á/5-drug rescue haart including a nnrti, 72 patients (p) treated with nucleoside analogues (na) and protease inhibitors (pi) for !/18 and !/15 months, respectively but naïve to nnrti, with a viremia !/10 000 copies/ml, were prospectively followed during 1 á/2 years, provided that they ensured a !/90% adherence. efavirenz was used in 41 p, nevirapine in 29, and delavirdine in two. most p (88.9%) had an early laboratory improvement, but mean peak viral load decrease was 0.4 log, and a significant reduction vs baseline (p b/0.02) lasted 3 months only. a mean 17% increase of zenith cd4 count was obtained (p b/0.001), but only 18.1% of p remained !/200 cells/ml 1 year after switch to nnrti. in a multivariate analysis, the concurrent introduction of novel pi(s) (32 p) and/or different na(s) (19 p) acted favorably until the 9th month of follow-up (p b/0.04), while genotypic mutations conferring nnrti cross-resistance, usually associated with a broad resistance profile, predicted failure in all p (p b/0.001), and the response did not vary according to duration and type of prior therapy, and selected nnrti. a deep salvage nnrtibased haart has a poor and transient virologic outcome also in nnrti-naïve p, while a more evident and sustained immunologic response is expected. p who can introduce novel pi/na and have no mutations impairing nnrti activity are entitled to a better outcome. fatal lactic acidosis without elevation of liver-enzymes during the treatment with stavudine, didanosine and efavirenz: a case report pm132 winzer r, langmann p, väth t, zilly m, klinker h. medizinische poliklinik der universität würzburg, schwerpunkt hepatologie/infektiologie, ürzburg, germany nucleoside reverse transcriptase inhibitors (nrtis) cause various side effects, many of which are thought to be due to their effects on mitochondria. a 36-year-old hiv positive (hiv rna: 6000 copies/ml, cd4 cell count: 359/ml), obese (body-mass-index: 40.9), therapy-naïve female patient, who after 7 months of well tolerated and effective antiretroviral therapy (stavudine, didanosine, efavirenz), had slight gastrointestinal discomfort and suddenly developed a lactic acidosis (arterial-ph 7.03 [7.36 á/7.44 she died 4 days later despite intensive care (continuous venovenous haemodiafiltration, sodium-bicarbonate infusion, high doses of vitamins, respiration). the pathologic examination showed an enlarged liver (2370 g) with yellowish appearance and pasty consistency, which microscopically appeared as a massive macro-and microvesicular fatty degeneration, and only slight signs of terminal pancreatitis. this reported case gives evidence that a massive lactate acidosis may develop without previously disarranged laboratory parameters for liver or pancreatic function. a fatal outcome may evolve without further accompanying-illnesses. efficacy and tolerability of atorvastatin in the treatment of hypercholesterolemia in hiv-infected patients receiving haart pm133 calza l, manfredi r, chiodo f. division of infectious diseases, university of bologna, bologna, italy introduction: significant increases in plasma triglyceride and cholesterol levels have been reported in patients treated with haart, and prolonged metabolic imbalances could significantly act on the longterm prognosis and outcome of hiv-infected persons. patients and methods: fourteen hiv-infected patients on pi-based haart since at least 12 months and presenting hypercholesterolemia ( !/290 mg/dl) of at least 6-month duration and unresponsive to a hypolipidemic diet and physical exercise, have been treated with a single daily dose of atorvastatin (20 mg) for 18 months. results: one patient was ecluded from evaluation due to early dropout. ongoing antiretroviral treatment included ritonavir in four cases, indinavir in four, nelfinavir in three, and saquinavir hard-gel in two. at the close of 18-month follow-up of atorvastatin therapy, a decrease of total cholesterol level of 21.9% versus respective baseline value was observed; eight out of 13 patients reached normal values for cholesterol. mild gastroenteric symptoms were found in only one of the 13 treated patients, while no skeletal muscle and liver toxicity has been observed. discussion: in our study, pharmacological treatment with atorvastatin proved certainly effective in the management of diet-resistant hypercholesterolemia, and was associated with a favourable tolerability and adherence profile. the effect of combination antiretroviral therapy regimens on hiv-1 proviral dna level in peripheral blood mononuclear cells (pbmcs) was examined in 12 hiv-1-positive patients, using endpoint dilution pcr and serially cloning and sequencing of the gag region of hiv-1. the major clone was defined as the most numerous of 10 analyzed clones, and observation periods ranged from 8 to 32 months (mean, 19.89/10.2 months). in five patients (one with primary-stage hiv-1 infection) receiving three antiretroviral drugs, hiv-1 rna levels reduced to undetectable (i.e. b/100 copies/ml). hiv-1 proviral dna levels and the number of major clones reduced in four of these patients. hiv-1 rna levels reduced, but remained detectable, in five other patients. in the two remaining patients (both receiving two rather than three antiretroviral drugs) hiv-1 rna levels increased. these results suggested that the population of the major clones may be affected when hiv-1 rna levels reduce following combination regimens of antiretroviral therapy. saquinavir hard gel (shg) as a part of a spontaneous 12 á/18-month deintensification anti-hiv regimen following successful highly active antiretroviral therapy (haart) pm135 manfredi r, calza l, chiodo f. infectious diseases, university of bologna, bologna, italy the induction-maintenance concept was poorly studied in hiv'/ patients (p), and shg was never assessed after prolonged response to potent protease inhibitors (pi)-based haart. shg-naïve p who refused indinavir, ritonavir, or nelfinavir-based haart after achieving long-term viral suppression, and resorted to shg'/2 nucleoside analogues (na), were followed prospectively. in 60.7% of the 61 p assessed for 12 á/18 months, ]/1 na was changed. prior haart was interrupted after 8.49/2.9 months, due to adverse events (46 p), or p's request (15 p), while a viremia b/50 copies/ml was present since 4.79/ 1.5 months. a viremia of 50 á/1000 hiv-rna copies/ml was maintained in 49 p (80.3%), while a higher viral load occurred in 12 p after 5.99/0.6 months, and was related to a pre-haart viremia !/100 000/ ml, a more frequent !/100% recovery of cd4 count, mutations of codons 48 á/90, and failure to change na (p b/0.05 á/0.001). a cd4 drop !/20%/150 cells/ml was found after 7.19/0.5 months in only eight p, who also had virologic failure: immunologic deterioration was earlier and deeper when na were not changed (p b/0.05). all the 37 p who introduced shg'/novel na after a successful !/6-month induction with a potent pi-based haart had a stable 12 á/18-month outcome. a suboptimal haart including the less effective but better tolerated shg may be effective for !/1 year, especially when novel na are introduced, and specific mutations are absent. despite a lower potency, drugs with a good safety and compliance profile may be recovered for simplified regimens. objective: to evaluate efficacy of antiretroviral therapy (art) with two or three drugs in the nervous 'reservoir'. patients: thirteen acute neurological and art naive aids patients underwent a paired and simultaneous sample from plasma and cerebrospinal fluid (csf) for a quantitative detection of hiv-1 rna (amplicor roche) before art. all patients underwent a ct and/or mr of the brain to perform a diagnosis. all of them had an hiv related neurological acute inflammatory disease. after diagnosis all patients received art: 7/13 received two nrti and 6/13 received haart including two nrti and one protease inhibitor. all patients underwent a paired and simultaneous follow-up from plasma and csf during the 2nd month of treatment. results: in all patients baseline levels of hiv-rna were higher (p b/ 0.05) in the plasma (log 10 5.37'/0.93) than in the csf (log 10 4.33'/1.379). the 7/13 patients who received dual therapy had undetectable levels (cut-off 200 copies/ml) of viral rna at the follow-up in csf, but not in plasma: three of these seven patients had a detectable plasma hiv-1 rna. all 6/13 patients with haart had undetectable hiv-1 rna both in plasma and in csf at the follow up. conclusions: dual nrti therapy is rapidly effective in csf (because of an high penetration of drugs through a more permeable blood á/brain barrier and lower hiv rna baseline levels) but not in plasma. haart is rapidly and equally effective both in csf and plasma. there are no reports of fulminant and fatal hepatic failure after the start of highly active antiretroviral therapy (haart) in an hiv subject without chronic viral hepatitis. case report: a 30-year-old naive aids woman with clinical symptoms due by a pcp was observed. baseline alt was increased (0.5 m.n.v.) because of a mild hepatosteatosis and a silent cholelithiasis. serology for hbv, hdv and hcv was negative; igg anti-hav, anti-ebv, anti-cmv and anti-hsv were present. hiv-1 rna was 5.7 log 10, cd4'/ count was 26/ml. during the pcp treatment with cotrimoxazole alt values increased ( !/5 m.n.v.); nevertheless, she completed the treatment. liver enzymes returned to the pre-treatment values over several days. then she started haart with stavudine, lamivudine and efavirenz. after 10 days the patient showed an efavirenz-related skin rush that resolved within 5 days, without treatment discontinuation. fourteen days after the start of haart jaundice appeared. laboratory revealed severe alt increase ( !/8 m.n.v.) and hyperbilirubinemia (17 mg/dl) and she died because of an acute liver failure syndrome within few days. an haart efavirenzbased regimen can result highly hepatotoxic when given in presence of a hepatosteatosis, of a recent hepatotoxicity caused by a nonantiretroviral treatment and of a previous idiosyncratic reaction to efavirenz. our experience with bulgarian herbal extracts for improving the general condition of hiv-positive patients pm138 methods: we used a combination of 19 bulgarian herbal extracts and treated six patients, divided in two groups: three with symptomatic and three with asymptomatic hiv-infection. the all three patients with asymptomatic hiv-infection were treated only with herbal extracts, another three patients with symptomatic hiv-infection were treated with combination of herbal extracts and anti-retroviral therapy. the general status of patients has been evaluated by both subjective and objective surveillance. the immunologic monitoring has been performed by absolute count of cd4'/ lymphocytes. results: all patients have shown an obvious improvement in their general condition: high spirit and working capacity, good appetite and sleep, a restoration of body weight. the number of cd4'/ lymphocytes has been lightly increased or constant. conclusion: the combination of bulgarian herbal extracts has shown significant positive effect on the general condition and improve the quality of life. antifungal activity of in vitro and in vivo combinations of voriconazole with 5-fluorocytosine and amphotericin b against candida and cryptococcus spp pm139 hitchcock ca, andrews rj, lewis bgh, pye gw, oliver gp, troke pf. pfizer global research and development, department of discovery biology, sandwich, uk purpose: the present study was designed to determine whether the activity of voriconazole (vor), a novel triazole, was reduced against candidal and cryptococcal infections by the addition of standard antifungal agents, amphotericin b (amb) and 5-fluorocytosine (5-fc). vor was tested in combination with standard antifungal agents both in vitro, using a checkerboard mic determination test, and in vivo in immune normal guinea pig models of fungal infections. the results indicate that the efficacy of vor against candida albicans and c. neoformans was not antagonised by amb or 5-fc in vitro. furthermore, in guinea pig models of systemic candidiasis and intracranial cryptococcosis, no antagonism was observed between the lower doses of vor and either amb or 5-fc on the basis of reductions in tissue fungal loads. at the highest doses of vor, both amb and 5-fc showed some antagonism, but the combinations were still effective in significantly reducing fungal tissue loads compared with vehicle-treated control animals. conclusion: these results suggest that vor may be used in combination with standard antifungal agents, and future studies to elucidate the clinical potential of vor combination therapies in the management of candida and cryptococcus infections are warranted. itraconazole in the treatment of pityriasis versicolor pm140 tiodorovic j, jovanovic d, binic i, nikolic lj. faculty of medicine, clinic of dermatovenerology, nis, serbia, yugoslavia a comparison of two short-term dose schedules with itraconazole was carried out in 50 patients with pityriasis versicolor. the patients were divided in two groups. each group consisted of 25 patients who completed the therapy and controls. the clinical diagnosis was confirmed mycologically, by direct microscopic examination. the first group received 400 mg of itraconazole daily for 3 days. the second group received 200 mg daily for 5 days. the patients were controlled clinically and mycologically 15 and 30 days after the initiation of treatment. erythema, scaling and pruritus was evaluated clinically. clinically and mycologically cured patients accepted as cured. the cure rate were 76% in the first group and 72% in the second group at day 30. the effects of these two groups are similar. none of the patients reported side-effects. fungal urinary infections: emerging species, antifungal susceptibility trends and antibody response pm141 badawi he a , kamel ai b , fam ns a , el-sayed me a , elian sae c . a theodor bilharz medical research institute (tbmri ), microbiology, giza, egypt , b theodor bilharz medical research institute (tbmri ), urosurgery, giza, egypt , c faculty of medicine, medical microbiology and immunology, cairo university, cairo, egypt objectives: to assess the role of candida species in 120 patients with urinary tract infections (utis) with or without schistosomiasis and/or cancer bladder, to compare chromogenic; chromagar (cma), biggy agar; morphologic (corn meal, rice agar-tween 80) media and biochemical candifast test for identification of candida species. susceptibility to antifungal agents using e -test and candifast and the performance of elisa test for detection of anticandida antibodies (igm and igg) in serum were evaluated. results: c. albicans was the most frequent (43.4%) species responsible for fungal utis. however, non-albicans species, c. glabrata (23.3%), c. tropicalis (20%) and c. krusei (13.3%) were also isolated. rice agar-tween 80 was found to be cheap, available and sufficient to make a final identification (100%). cma could not identify c. glabrata . biggy agar could not adequately differentiate candida species. candifast biochemical identification showed low sensitivity of 83.3%. e -test on sabouraud dextrose agar (sda) is simple method for mics determination and could detect s-dd strains in case of azoles. conclusion: the emergence of non-albicans species such as c. glabrata , c. tropicalis and c. krusei have contributed to complicated utis. this necessitates accurate isolation and identification of candida to the species level. morphology on rice agar-tween 80 and antifungal susceptibility using e -test on sda is a simle rapid scheme for routine identification of clinically important yeasts. purpose: classification of allergic fungal rhinosinusitis (afr) is based on the immunologic relationship of the host to the fungus. afr must be differentiated from other fungal rhinosinusitis infections, which include acute invasive, chronic invasive, fungal balls and saprophytic colonization. although many cases of fungal rhinosinusitis is caused by species of aspergillis , dermatiaceous moulds have become an emerging pathogen in immunocompetent individuals. results: our case study involved a 36 year male suffering from facial pain, headache, postnasal drip and loss of smell. he was hiv negative and a nonsmoker. the following laboratory tests were performed: ige-2331.40 (0.00 á/25.00) iu/ml iga-2.16 (0.70 á/4.00) g/l igm-0.61 (0.40 á/ 2.30) g/l allergen specific ige for alternaria */20.00 (0.00 á/0.5) ku/l fbc-normal except eosinophils slightly raised 0.60 (0.00 á/0.50))/10 9 / l. ct scans indicated fungus proliferation, bone erosion and extension of disease into adjacent anatomic area. sinus tissue following debridement was sent for microscopy and culture. hyphae was microscopically observed and cultures yielded two dermatiaceous fungi, bipolaris spp and alternaria spp . conclusion: it is important to differentiate these two species from curvularia , helminthosporum , drechelria and exserohilum . knowledge of these dermatiaceous fungi is important in directing appropriate antifungal therapy and selecting the correct antigens for postsurgical immunotherapy after initial debridement and irrigation. antifungal activity of in vitro and in vivo combinations of voriconazole with 5-fluorocytosine and amphotericin b against aspergillus fumigatus pm143 hitchcock ca, andrews rj, lewis bgh, pye gw, oliver gp, troke pf. pfizer global research and development, department of discovery biology, sandwich, uk purpose: a key requisite for a new antifungal drug is to demonstrate that it is devoid of significant antagonism in combination with other agents. combinations of the new triazole, voriconazole (vor), and standard antifungal agents (5-fluorocytosine or amphotericin b; 5-fc or amb) were tested against aspergillus fumigatus in vitro and in guinea pig models of infections to confirm that antifungal activity was not antagonised by using combination therapies. vor was studied in combination with amb or 5-fc in vitro, using a checkerboard mic determination test, and in vivo, using immune normal and immunocompromised guinea pig models of systemic aspergillosis. results: the results indicate that the potency of vor was not antagonised by amb or 5-fc in vivo; indeed, at lower concentrations of vor, significant improvements in reducing fungal burden in both in vivo models were achieved by the addition of amb. in vitro, no antagonism was found between vor and amb, although 5-fc had a significant antagonistic effect on vor activity. conclusion: these results from in vitro and in vivo models of aspergillosis suggest that vor may be used in combination with standard antifungal agents and, therefore, justify further examinations of vor combination therapies in a clinical setting. in vitro activity of caspofungin compared to that of amphotericin b, fluconazole, and itraconazole against candida species pm144 arikan s, sancak b, hascelik g. department of microbiology and clinical microbiology, hacettepe university medical school, ankara, turkey purpose: to evaluate the in vitro activity of caspofungin against various candida spp. and particularly against isolates with decreased amphotericin b, fluconazole, and itraconazole susceptibilities. methods: susceptibility tests were done by nccls m27a microdilution guidelines for 239 clinical candida strains. the mics (mg/ml) were read at 24 and 48 h. results: caspofungin mics at 24 h are shown in the table. mics at 48 h were similar to 24 h readings. expectedly, no evidence of crossresistance was detected between caspofungin and other drugs tested. caspofungin was similarly active against fluconazole-or itraconazolesusceptible and resistant isolates. conclusions: (1) caspofungin is active in vitro against all candida spp. tested. (2) caspofungin mics are slightly higher for c. parapsilosis compared to other species. (3) its activity against fluconazole-and itraconazole-resistant isolates is noteworthy. (4) validation of these data require clinical investigations. oropharyngeal microbiological samples of 80 bmt patients were evaluated. weekly cultures (days (/7, 0 and '/7) revealed presence of fungi in 27 patients (33.7%): in four (5%) patients before bmt only, in 12 (15%) after bmt only, and in 11 (13.8%) both before and after bmt. in one patient candida norvegensis was isolated from the throat, buccal and palatal surfaces. three c. albicans , two c. krusei , and three c. norvegensis from four patients were chosen to comper their antifungal sensitivities and extracellular virulence factors. using fungitest method we determined the sensitivities of these isolates to flucytosine, amphotericin b, miconazole, ketoconazole and fluconazole. the fluconazole sensitivities were also determined by the e -test. on the basis of the fungitest data the three c. norvegensis isolates were sensitive to flucytosine, amphotericin b, and also to ketoconazole. in case of fluconazole and miconazole they proved to be susceptible dependent upon dose. the mic fluconazole values determined by the e -test for the three c. norvegensis isolates were 96, ]/256 and ]/256 mg/ml, respectively. the oropharyngeal isolates of c. norvegensis produced high amounts of extracellular aspartic protease and phospholipase similarly to c. albicans strains. these enzymes may contribute to the pathogenesis of this new emerging candida species. in vitro activities of antifungal and antiseptic agents against rhodotorula sp pm148 preney l, théraud m, guiguen c, gangneux jp. laboratory parasitologie-mycologie, chu de rennes, france purpose of the study: rhodotorula species are common saprophyte yeasts widespread in nature. since the last 10 years, they have been implicated in several severe infections, especially in immunocompromised patients, and various antifungal therapies were used. however, only limited data are available on the susceptibility of rhodotorula sp. to antifungal and antiseptic agents. material and methods: in this work, we evaluated the in vitro activities of eight antifungal agents against 30 strains of rhodotorula (21 strains of r. rubra and nine strains of r. glutinis using atb fungus system (biomerieux) and etest strips (ab-biodisk). beside, the effect of eight antiseptic agents was assessed on a suspension of r. rubra . the quantification of yeasts after exposure to antiseptic agents was performed by subculturings using a microtitration method in 96well plates. results and discussion: all strains tested were susceptible to amphotericin b, 5fc, and nystatin. twenty-nine out of 30 strains were susceptible to ketoconazole, 21 out of 30 were intermediate to econazole. all strains were resistant to fluconazole (cmi!/64 mg/ml) and itraconazole (cmi!/1 mg/ml), and 29 out of 30 were resistant to miconazole, suggesting that antifungal therapy must be adapted when rhodotorula yeasts are implicated in invasive infection. beside, 5 min exposure to sodium hypochlorite 128, chlorhexidine 0.5% or ecodiol (isopropyl alcohol'/alkylamin) showed fungicidal activities. susceptibility testing of aspergillus fumigatus and emerging aspergillus pathogens by a modification of the nccls m38-p method pm149 logotheti m a , kapsanaki-gotsi e b , velegraki a a , zagoura d b . a department of microbiology, mycology reference laboratory, medical school, university of athens, athens, greece , b biology department, section ecology and systematics, university of athens, athens, greece aspergillosis in high risk groups of patients is still associated with high mortality rate (30 á/90%). aspergillus fumigatus is the primary pathogen, while other opportunistic aspergillus species are emerging. amphotericin b (ab), itraconazole (it), voriconazole (vo) and terbinafine (te) minimum inhibitory concentrations (mic) were determined by modifying the nccls m38-p microdilution method. stock drug solutions were prepared in rpmi 1640, dimethyl sulfoxide (dmso), and polyethylene glycol (peg 400). inocula, of the a. fumigatus group (7), a. flavus group (6) (2) and the m38-p quality control strains were prepared according to, and by modifying, the nccls guidelines. plates were incubated at 30 and 35 8c and read at 24 and 48 h. peg 400 effectively dissolved it and vo, while either dmso or peg dissolved te. low 30 and 35 8c á/48 h ab, it, vo and te mics (0.062 á/0.5 mg/l) were recorded. a. terreus (1) and a. parasiticus (2) were resistant to ab. certain clinical isolates demonstrate clinical and in vitro resistance. standardization of susceptibility testing would offer reliable assistance in selecting and monitoring antifungal therapy. otag f, aslan, g, ozturk c. microbiology department, faculty of medicine, mersin university, mersin, turkey rates of opportunistic fungal infections have risen markedly. because some of these species have potential resistance to antifungal agents, rapid presumptive species level identification is crucial in allowing for directed antifungal therapy. in this study, 55 isolated yeasts from the clinical specimens were identified by atb id 32 c (biomerieux, france). the number of identified yeasts were, respectively; 33 (60%) candida albicans , six (10%) c. glabrata , five (9.1%) c. tropicalis , three (5.4%) c. parapsilosis , two (3.6%) c. krusei , two (3.6%) c. kefyr , one (1.8%) c. guillermondii , one (1.8%) c. dubliniensis . twenty-one of 55 strains were investigated for antifungal sensitivities by atb fungus kit (biomerieux, france). the results are as follows: 100% sensitivity was detected to myconasol, 94% to flusitozin, nystatin and econasol, 95% to amphtericin b and ketokonazol. it is important to achieve empirik treatment of the opportunistic candida infections and the following of resistance to antifungals. shakhmatov da, strelchenco, ov. novosibirsk state medical academy, dermatovenerology, novosibirsk, russian federation at the present stage in russia with a background of a high case rate of syphilis, it becomes necessary to exclude biological false positive serological tests. because the serodiagnosis of syphilis has significant limitations, the direct detection of t. pallidum in suspect blood may serve as an alternate diagnostic strategy. polymerase chain reaction (pcr) has been the most widely used amplification method. the study of 56 patients receiving examination related and treatment for syphilis in std clinic and persons directed from other hospitals where routine serologic examination revealed doubtful results. pcr reaction was carried out with nested primer pairs based on the dna sequence of the 47 á/1 and 47 á/2 kda gene of t. pallidum . pcr was utilized with whole blood. a complex of serological tests: fta-abs and tit was used as the &rdqup; gold standard''. as a result the sensitivity of pcr was 91.2% and specificity was 90.9%. selective comparison of pcr results with vdrl, the fta-abs and treponemal immobilisation test (tit) has shown concurrence 96.8%. in conclusion, the preliminary results of pcr in whole blood in syphilis detection revealed its high sensitivity and specificity; possibility to obtain rapid results in unclear cases. chlamydia pneumoniae (cp) is an atypical pathogen whit intracellular location, whose eradication is very difficult. in the past years it has been objects of many studies that lead to the demonstration of a relationship between its presence and the development of widespread multifactorial pathologies such as atherosclerosis and asthma. the lack of its eradication can become an important clinical and social problem. the study objective is the comprehension of pathogen á/host interaction mechanism, to characterize therapeutics protocols that cold lead to complete eradication of cp from organism. the research had been principally made on the studying the molecular mechanisms that are at the root of pathogen permanence inside host cell. using proliferation and apoptosis tests we underlined a different behaviour of infected cells towards control cells. in presence of p1 (20 mg/ml), i.e. a peptide that can inhibit the proliferation and induce apoptosis in vitro inhibiting nf-kb, uninfected cells proliferation decreased of 35% in comparison whit the controls, while the one of infected decreased only of about 15%. moreover, using various apoptosis-inducers, the infected cells showing apoptosis were about 10% while the uninfected were about 40%. the caspace iii activity increased significantly in uninfected cells. in conclusion, cp could delay its elimination from the host inhibiting the apoptosis via nf-kb activation. hryniewiecki t a , gzyl a b , rawczynska-englert i a , a department of acquired valvular heart disease, national institute of cardiology, warsaw, poland , b department of sera and vaccines, national institute of hygiene, warsaw, poland infective endocarditis (ie) frequently causes problems in diagnosis, especially where blood cultures are negative and with fungal etiology (also as a fungal superinfection in bacterial ie). the purpose of the study: the purpose of the study was to evaluate the usefulness of broad-range fungal pcr in diagnosis of fungal superinfection of bacterial ie. twenty-five blood samples were taken for analysis from patients with infective endocarditis. ie was diagnosed according to duke criteria including positive blood cultures. suspicion of fungal superinfection was established on serological investigation in five patients, confirmed by blood culture in two patients. control group consisted of 15 patients without infection. dna was isolated using the commercially available s.n.a.p. kit. amplification products were analyzed by gel electrophoresis stained with ethidium bromide. the results obtained: fungal dna was found in two patients with fungal superinfection of bacterial ie confirmed by culture. in the remaining patients with ie and controls no fungal dna was found. the conclusion reached: broad-range fungal pcr is a fast and inexpensive tool for the detection of fungal dna, but it is more prone to contamination than species-specific pcr. the method may be valuable in the identification of fungal superinfection of bacterial ie or diagnosis of fungal ie. rivanera d, lilli d, lozzi ma, piunno m, mancini c. microbiology, science and public health, rome, italy aim: the aim of this study was to evaluate the eia method for detection of antibody to ttv virus (ttv) and to investigate the anti-tt virus prevalence in patients with hepatitis b (hbv) virus, hepatitis c (hcv) virus, in group of 'high risk'subjects to hepatitis and in healthy subjects. the elisa methods (nuclear laser vienna lab) using ttv s and ns antigens: orf1 (770 aa) and orf2 (202 aa) was applied to detect anti-ttv; the serological screening was performed from 250 samples to italian subjects. results: the positive rates of anti-ttv antibodies were 11.29% in 62 patients with hepatitis b á/c and 14.06% in 119 'high risk' hepatitis patients. the anti-ttv was also found in 7.56% in 69 healthy people. conclusions: the anti-ttv were detected in all groups studied, however, its positive rate was similar in patients with hepatitis b á/c and in 'high risk' hepatitis respect to heathly people. our results shown that tt virus is frequent in italy both in patients infected by others transmitted viruses and in general population. the positivity found in healthy adults included in our studies suggests that the virus might be transmitted non-parenterally. the study of pattern of antibody to ttv may be an infectious marker of ttv similar to that of anti-hcv. a stress test on a miniaturized identification system designed for neisseria and haemophilus pm155 rich m a , bannatyne rm a , memish za b . a king fahad national guard hospital, division of microbiology, riyadh, saudi arabia , b king fahad national guard hospital, infection prevention and control, riyadh, saudi arabia we report an incident that occurred in our laboratory when the bbl crystal identification system for neisseria and haemophilus was used to identify a haemophilus-like-organism. the numerical profile generated was not in the system database. conventional biochemical tests subsequently revealed an identification of brucella melitensis , a common isolate in our area. as a result of this revelation we subjected this system to a mini 'stress-test' with a collection of 20 isolates of b. melitensis . two numerical profiles were obtained, 1740616606 and 1740616607, neither of which are listed in the system database. brucella species have been misidentified as moraxella species, moraxella phenylpyruvica , and as haemophilus influenzae biotype iv in various identification systems. two cases of laboratory-acquired brucellosis have been attributed to misidentification. to its credit the bbl crystal identification system for neisseria and haemophilus neither generates a profile number with a misidentified organism nor assigns a confidence level. instead it properly directs the user to resort to conventional methods to secure an identification. if further studies on additional brucella isolates and strains from different geographical sources confirm the unique biochemical profiles identified here, it may be worthwhile to incorporate these into the database where they would be of considerable assistance in areas where brucellosis is widespread. cloning and characterization of aflmp1 in aspergillus flavus pm156 chong tk, woo pcy, leung asp, yuen ky. the university of hong kong, microbiology, hong kong, hong kong purpose of the study: to clone and characterize an antigenic protein for serodiagnosis of infection caused by aspergillus flavus which is the commonest aspergillus species causing aspergilloma (ao) and invasive aspergillosis (ia) in asia. result obtained: we cloned the aflmp1 gene, which encodes the first antigenic cell wall protein in a. flavus . aflmp1 codes for a protein, aflmp1p, of 273 amino acid residues, with sequence features that are present in mp1p and afmp1p, the antigenic cell wall mannoprotein in penicillium marneffei and aspergillus fumigatus that we described previously. it contains a serine-and threonine-rich region for o glycosylation, a signal peptide, and a putative glycosylphosphatidylinositol attachment signal sequence. specific anti-aflmp1p antibody was generated with recombinant aflmp1p protein purified from escherichia coli to allow further characterization of aflmp1p. indirect immunofluorescent staining indicated that aflmp1p is present in the cell walls of the hyphae and conidia of a. flavus . furthermore, it was observed that patients with ao and ia due to a. flavus develop a specific antibody response against aflmp1p. conclusion reached: this suggested that the recombinant protein and its antibody may be useful for serodiagnosis in patients with ao or ia, and the protein may represent a good cell surface target for host humoral immunitiy. grape purpose: to investigate the basis for increasing resistance to trimethoprim and sulphamethoxazole. methods: pcr screening for integrons of 105 clinical urinary tract isolates was performed. isolates were tested for resistance to 12 antibiotics. integrons in 14 isolates were sequenced. results: integrons of class 1 were found in 43 isolates and class 2 integrons were found in 10. eight isolates in the study were resistant to five antibiotics or more and not shown to carry any integron. nineteen of 69 isolates resistant to trimethoprim did not carry integrons. only one of these isolates was shown to carry sul1 and is thus probably also carrying an integron. none of the 19 isolates were shown to carry dfr8 , one of five trimethoprim resistance genes known to exist outside integrons. three isolates were resistant to sulphonamides but were not shown to carry neither sul1 nor sul2 . only dfr and aad gene cassettes were found in the sequenced integrons. conclusions: resistance to trimethoprim in 19 of 69 trimethoprim resistant isolates is mediated by genes not detectable, as in the case with three sulphonamide resistant isolates. sequenced integrons that contain dfr genes do not carry any gene cassettes mediating resistance to modern antibiotics. unusual diagnosis tool for an unusual presentation of alveolar echinococcosis: report of two cases of local progression after an animal bite pm158 bardonnet k, bart jm, loiseau j, gérard a, estavoyer jm, heyd b, badet jm, dubiez a, piarroux r, bresson-hadni s. who collaborating centre for prevention and treatment of human echinococcosis, university of franche-comté, besançon, france introduction: the classical human contamination route for alveolar echinococcosis (ae) is ingestion of eggs. two exceptional human cases are reported with extensive local evolution of ae after a bite. case no. 1: between 1954 and 1972, a patient underwent surgery seven times for a muscle growing tumour which developed after a bite. the diagnosis of muscle ae was assessed on histopathological examination. in 1980, serological tests were in accordance with echinococcus sp infection. case no. 2: in 1985, a man presented 'cat-scratch fever' with a right supraclavicular tumefaction following a cat bite. between 1986 and 2000, five recurrences occurred. different surgical explorations indicated multiple abscesses of the cervical muscles. in 2000, serological tests were in favour of echinococcus sp infection and the pathologist described a parasitic wall suggesting hydatidosis, but specific pcr from histological samples prompted the diagnosis of ae. conclusion: in these exceptional observations, the liver which is the most usual location of ae was lesion-free. the chronic inflammatory ae lesions have developed in the local lymphatic chain area of the bite site. to perform diagnosis in these very unusual forms of ae, it is necessary to add unusual tests such as specific pcr to classical tests. antibiotic resistance in foodborne salmonella is an emerging public health concern. integrons are now recognized as the main genetic vehicles of antibiotic resistance in gram-negative bacteria, including in salmonella . the purpose of the present study was to investigate the presence of class i integrons in resistant isolates of several serotypes of salmonella isolated from poultry products and to determine their association with multidrug-resistance phenotypes. a total of 20 isolates of salmonella belonging to seven different serotypes were tested. the most frequent multiresistant phenotype, found alone or together with other resistances, was to streptomycin and tetracycline. all but seven were resistant to three or more antimicrobial agents, including quinolones and amoxicillin. pcr analysis with the 5?cs and 3?cs primers detected the presence of class i integrons of 1.5 kb in one isolate, with the multiresistant phenotype: amoxicillin, chloramphenicol, streptomycin, trimethoprim-sulphametoxazol and tetracycline. our findings suggest that the uncontrolled use of the antimicrobial agents in food animals may have contributed to the development of the pattern of resistance observed in salmonella isolates. also the presence of integrons in low prevalent human salmonella serotypes but associated with food animals underscores the public health problem of antibiotic resistance acquisition and spread. prevalence and antimicrobial resistance of campylobacter jejuni and c. coli isolated from broilers and pigs in france pm161 avrain l a , humbert f b , sanders p c , kempf i a . a afssa, umb, ploufragan, france , b afssa, hqpap, ploufragan, france , c afssa, lermvd, fougères, france in 1999, 620 caeca from standard, export or free-range broilers and in 2000, 600 fecal samples from pigs, were collected in french slaughterhouses. prevalence of campylobacter jejuni and c. coli strains was 56.6% in standard, 51.3% in export and 80% in free-range broilers. in standard and export productions, the most often isolated species was c. jejuni , whereas c. coli was predominant in free-range production. 53.8% samples collected from pigs contained c. coli . the sensitivity of strains to ampicillin, nalidixic acid, enrofloxacin (broilers) or ciprofloxacin (pigs), tetracycline, erythromycin and gentamicin was tested by an agar dilution method. in broilers, the percentages of resistant strains were, respectively 22, 25, 17, 57, 0.3 and 0% for c. jejuni and 29, 43, 40, 70, 31 and 0% for c. coli . in pigs the percentages of resistant c. coli were, respectively 12, 21, 12, 83, 65 and 0%. in broiler production, significant differences between distributions of species or percentages of resistant strains were observed according to type of production or administrated antimicrobials. the enzyme dhps (dihydropteroate synthase) participates in the folate synthesis pathway, and is well recognized as the target for sulphonamides. the enzyme preceding dhps in this pathway, pppk (dihydropterin pyrophosphokinase), is another interesting candidate drug target. the metabolic role of pppk is to provide one of the substrates for dhps. earlier studies have suggested that pppk and dhps enzymes need to have physical contact with each other for full enzyme activity. studies of potential interactions between the enzymes have been initiated. so far, indication of a weak interaction has been detected in gelfiltration experiments and the two-hybrid system. to confirm these results, we are currently developing a method to study substrate channeling, as interfering with such interactions could lead to impaired growth and thus be used as inhibitory drugs. we have also cloned and sequenced the operons coding for the enzymes in the folate biosynthesis from different clinical isolates of streptococcus pyogenes . comparisons revealed some isolates with a mosaic structure in the operon, suggesting that horizontal transfer of genetic material has occurred. multi-resistance gene cluster on a plasmid in a clinical isolate of e. faecium pm163 werner g, hildebrandt b, klare i, witte w. department of nosocomial infections, robert koch institute, wernigerode branch, germany purpose: strain uw786 was isolated from an urine sample of a patient with a permanent catheter. the purpose of our study was to identify and localize the resistance determinants in this isolate. results: isolate uw786 was resistant to the following antibiotics: penicillin, ampicillin, gentamicin (high-level), streptomycin (highlevel), erythromycin, clindamycin, vancomycin, teicoplanin, ciprofloxacin, moxifloxacin, nourseothricin, rifampicin, and fusidic acid (lowlevel, mic0/4 mg/l); but showed susceptibilities to oxytetracycline, phosphomycin, chloramphenicol, trimethoprim/sulfamethoxazol, linezolid, and quinupristin/dalfopristin. hybridization, pcr and sequencing experiments localized a cluster consisting of several resistance genes in a composite element on a plasmid. the cluster included genes and transposons tn1546 (vana) á/tn917 (ermb) á/tn1505 (aade á/ sat4 á/apha-3). the plasmid itself was not transferable in filter-matings into a fusidic acid high-level resistant enterococcus faecium recipient while selecting either for erythromycin or vancomycin resistances. however, after transposing a tn916-related determinant into uw786, determinants became mobilizable with the help of the conjugative transposon. transconjugants were, besides others, high-level resistant to fusidic acid, but susceptible to penicillin and ampicillin. pfge of transconjugants demonstrated a pattern almost identical to the recipient but clearly different from the donor. conclusion: resistance genes in e. faecium could be arranged in a cluster and are mobile via mobilizable/transferable plasmids. lilli d, rivanera d, barbacini ig, lozzi ma, mancini c. department of science and public health, university la sapienza, microbiology, rome, italy aim: hepatitis g virus (hgv), a new rna virus that is parenterally trasmitted has frequentley been found in patients with chronic hepatitis c infection but its role in chronic liver desease is unknown. the aim of this study was to determine the prevalence of hgv infection in patients infected with hcv. ninety-eight patients infected with hcv were evaluated for the presence of hgv rna. the hcv genotypes distribution was 30 genotype 1b, 10 genotype 1a, 54 genotype 3a and four genotype 4c/4d. hcv rna and hgv rna were detected by rt-nested pcr. results: infection with hepatitis g virus was detected in 21 (21.4%) patients and 77 (78.6%) were hgv rna negative. none of our patients with genotypes 1a and 4c/4d results hgv rna positive. prevalence of hgv infection was 10% in patients infected with hcv genotype 1b and 33.3% with genotype 3a. conclusions: infection with hgv occurred frequently (21.4%) in this sample of patients with chronic hepatitis c. we observed a height prevalence of hcv/hgv coinfection in patients infected with hcv genotype 3a. this association with hcv genotype 3a was indipendent of the source of infection, infact some of our patients have not history of intravenous drug use. characterization of extended-spectrum beta-lactamase (esbl)mediated resistance in salmonella spp. from durban, south africa pm165 moodley p a , essack s b , gajee k a , sturm w a . a department of medical microbiology, nelson r. mandela school of medicine, school of infection, university of natal, durban, south africa , b school of pharmacy and pharmacology, university of durban westville, durban, south africa background: gastroenteritis is a common condition among the paediatric population presenting to king edward viii hospital in durban, south africa. from july 2001, we noticed that the susceptibility of the salmonella spp. isolated from stool samples among these children were resistant to multiple antibiotics. aim: to characterize the phenotype of the resistance mechanisms involved. methods: minimum inhibitory concentrations (mics) of ampicillin, azithromycin, ciprofloxacin, cefepime, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefoxitin, chloramphenicol, cotrimoxazole and gentamicin were determined by means of the agar dilution method. isolates were subjected to the e -test for extended-spectrum betalactamase (esbl) production. isoelectric focusing was performed as a preliminary step in enzyme characterization. results and conclusion: thirty isolates of multiresistant salmonella spp. were obtained. antibiogram typing revealed six different resistance phenotypes. all isolates depicted ceftazidime/ceftazidime á/clavulanate ratio of !/8 and were considered putative esbl-producers. isolates expressed 1 á/3 beta-lactamases each with pi values ranging between 5 and 8.2 indicative of tem-, shv-and/or ctx-m-related esbls. nine isolates expressed two beta-lactamases each and two isolates expressed three beta-lactamases each. there was evidence of the simultaneous expression of both tem-and shv-derived esbls as well as the simultaneous expression of multiple tem-or shv-derived esbls in single isolates, a phenomenon reported in esbl-positive klebsiella pneumoniae isolated at the same hospital. neutrophils exhibit reduced chemiluminescence response to serum opsonized klebsiella pneumoniae producing extended spectrum b-lactamases (esbl) pm166 objective: to investigate the ability of esbl and non-esblproducing klebsiella pneumoniae isolates treated with human serum to induce a chemiluminescence response in neutrophils. methods: oxidative burst induced by the interaction of esbl (n0/ 81) and non-esbl-producing (n0/152) klebsiella pneumoniae isolates with neutrophils from healthy individuals was monitored by measuring the chemiluminescence response (cl). pooled sera from healthy individuals served as source of complement for pretreatment of the bacteria. cl responses triggered by serum treated zymosan served as positive control. the serum opsonized klebsiella strains were arbitrarily graded as high (h) and low (l) inducers of cl when the cl response induced by the bacteria was cl b/60 and !/60%, respectively, of that induced by opsonized zymosan. results: out of 152 non-esbl-producing klebsiella isolates, 61.8% induced high cl response in neutrophils whereas only 42% of 81 esbl-producing klebsiella isolates did so (pb/ 0.02). conclusions: strains harboring the esbl plasmid were more virulent than non-esbl-producing strains by virtue of their higher tendency to escape serum-dependent recognition by neutrophils. osiris */an automated system for susceptibility testing in agar diffusion technique pm167 chegrani f, kolbert m, shah pm. universitätsklinik frankfurt, zentrum der inneren medizin med iii schwerpunkt infektiologie, frankfurt am main, germany objective: osiris measured zone sizes were compared to manually measured inhibition zones using round 90 (rp) and 120 mm mueller hinton square agarplates (sqp). variations of 9/3 mm in zone size measurements were defined as tolerable. 'very major errors' (vme) were defined as classification of a resistant organism as sensitive by osiris. thirty thousand two hundred and ninety-eight single measurements testing 42 antibiotics on 352 staphylococci and 113 enterobacteriaceae were done according to the din 58940 recommendations. results: vancomycin, rifampicin, gentamicin gave the best results on rp with a concordance of 96, 88 and 86%. vancomycin, rifampicin, teicoplanin performed best with 97, 94, 93% on sqp testing staphylococci . worst results on rp gave cefuroxim (43.8%) and fosfomycin (55.1%), on sqp fosfomycin (36.4%), ofloxacin (88.1%). for enterobacteriaceae amikacin (100%), gentamicin (100%), ciprofloxacin (100%) performed best on rp; worst nalidixinacid (32.5%), piperacillin (82.5%). concordance on sqp amikacin (100%), cefotaxim (100%), gentamicin (100%), nitrofurantoin (72.5%), cotrimoxazol (90%). very major errors were seen in b/1% of all test performed. interpretation: osiris is a rapid and reliable system for susceptibility testing with round and square agarplates and has an excellent expert system. altindis m a , aktepe oc a , kocagoz t b . a kocatepe university school of medicine, microbiology, afyon, turkey , b diomed inc. tr, istanbul, turkey dio-bacit, in a two section plate, that contains 5% sheep blood agar on one side and sheep blood agar with bacitracin (2 mg/ml) was compared for its efficiency in identification of group a beta hemolytic streptococcus (gabs) with other two different growth plates, one containing 5% sheep blood agar with bacitracin (b) and the other containing b-sxt. we used latex-agglutination for this comparision. throat specimens obtained from 490 cases were inoculated to dio-bacit plates, first to one side with 5% sheep blood agar and to the other side with b. after an overnight inoculation at 37 8c, colonies with beta hemolysis an 5% sheep blood agar but no growth with b, were inoculated to 5% sheep blood agar again and antibiogram identification discs containing 0.04 u b and 1.25 and 23.75 mg sxt (oxoid, uk) were placed onto the plate and incubated overnight at 37 8c. after that, colonies with beta hemolysis were defined as b-sensitive while colonies resistant to sxt were defined to be gabs. all colonies are serologically classified by latex-agglutination (oxoid, uk). seventy-one (14.5%) inoculations revealed growth of gabs at dio-bacit plates. after inoculating these colonies to 5% sheep blood agar, 72 of them were found to be sensitive to b, while 67 were found to be sensitive to b but resistant to sxt and 58 of them were defined as gabs by latex test. when compared with latex-agglutination test, we found dio-bacit method's sensitivity and spesificity to be 92 and 96.9%, respectively. method: agar diffusion technique as recommended by din 58940 was used to determine izs (read using aura and manually) for 178 staphylococci and 22 enterobacteriaceae . variations in automated measured zone sizes of 9/3 mm to the manual readings were considered to be within acceptable range. results: six thousand and fifty-two zone sizes were determined for staphylococci and 748 for enterobacteriaceae . mha displayed tendency to smaller zone sizes in automated readings than isa, as well in staphylococci and enterobacteriaceae . on the other side automated readings presented on isa more precise results than mha. overall less major discrepancies ( b/3 mm) were found on isa. izs were generally smaller on mha. the tables below show differences in manually and automated measured zone sizes on different media and species. we discovered seven more cases of resistance in the case of metronidazole. we did not have such experience with clarithromycin. conclusion: our results show that e -test is comparable to ad for clarithromycin, but for metronidazole our findings confirm nccls recommendantion. classical ad is time consuming for every day use in the laboratory. the use of screening agar plate with 8 mg/ml of metronidazole to detect possible resistance could be the solution. rokosz a a , sawicka-grzelak a a , meszaros j b , luczak m a . a department of medical microbiology, the university medical school, warsaw, poland , b department of bacteriology, state institute of hygiene, warsaw, poland purpose: to identify esbl-positive strains and to compare two methods applied for the detection of extended-spectrum beta-lactamases (esbls). methods: two hundred and sixty strains of gram-negative rods were cultured from clinical specimens from hospitalized patients. identification of strains was performed in the automatic atb system (biomerieux, france). these strains were identified as esbl-positive on the basis of the double-disc synergy test (ddst according to jarlier et al., 1988) results. all strains were also determined using a novel method of esbl detection (dd, diagnostic disc) according to appleton (1999) . two discs were applied in this test: cpd (cefpodoxime) and cd 01 (cefpodoxime/clavulanic acid) (oxoid, england). results: consistent results of two methods (ddst and dd) were obtained in the case of 166 from among 260 of examined strains (60.4%). consistent results concerned 161 out of 222 strains of enteric rods (72.5%) and only five from among 38 other strains (mostly nonfermenting rods). conclusions: the novel method of esbl-producers detection (dd) is more objective and easier for interpretation than the double-disc synergy test (ddst). diagnostic disc test should be used as the basic one or to confirm the results of ddst in difficult cases. assessment of e -test for determining penicillin resistance in pneumococci pm172 sener b, yeniþehirli g, ercis s, hasçelik g. department of clinical microbiology, hacettepe university medical faculty, ankara, turkey there is a greater need for susceptibility testing methods that distinguish between susceptible and resistant pneumococci. an alternative method could be the e -test, which is compared with the reference agar dilution method in this study. penicillin susceptibility of a total of 149 pneumococci was determined by e -test and agar dilution methods. streptococcus pneumoniae atcc 49619 and enterococcus faecalis atcc 29212 were used as controls. the results were given in the effect of anoxic conditions on the minimum inhibitory concentration of metronidazole in helicobacter pylori pm173 de la obra sanz p, lomas e, roman jl, alarcon t, lopez-brea m. the objective of this study was to determine the effect of incubation under anoxic conditions on the metronidazole resistance of helicobacter pylori . methods: a total of 35 clinical isolates were used in this study. mics were determined by an agar dilution method using mueller-hinton agar plus 7% lysed horse blood. three plates series contained twofold dilutions of metronidazole from 256 to 0.008 mg/l were prepared. the first one was incubated under microaerophilic conditions (oxoid) for 3 days; second and third series were incubated anaerobically (anaerobic system, oxoid) for 8 and 18 h, respectively, and were then transferred to the microaerophilic enviroment up to complete 3 days of incubation. results: with microaerophilic incubation, 12 of 35 strains were resistant (mic50 and mic90 were 1 and 32, respectively). with 8 h anaerobic preincubation, four of 35 strains were resistant (mic50 and mic90 were 0.5 and 4, respectively). with 18 h anaerobic preincubation, 1 of 35 strains was resistant (mic50 and mic90 were 0.25 and 1, respectively). conclusions: anaerobic preincubations causes an increase in sensitivity to metronidazole, the extent of which was dependent on the length of the anaerobic period. methods: the susceptibility to antibiotics was performed by microdilution method according to nccls guidelines. the production of b-lactamase was tested by nitrocefin sticks (oxoid). results: the mics50/mics90 (mg/ml) appeared, respectively: ampicillin 1/4, amoxicillin/clavulanic 0.06/0.12, cefaclor 1/1, ceftriazone 0.06/0.5, erythromycin 0.12/0.25, azithromycin 5/0.03/0.06, clarithromycin 0.12/0.12, ciprofloxacin 0.03/0.06, imipenem 5/0.015/0.06, tetracycline 5/0.25/5/0.25, trimethoprim/sulfamethoxazole 0.25/0.25. b-lactamase was detected in 98.5% of the strains. conclusions: (1) m. catarrhalis isolates were uniformly susceptible to all tested antimicrobials except ampicillin. (2) the production of blactamase was responsible for ampicillin resistance (98.5%). (3) m. catarrhalis strains had almost the same behavior 'in vitro' to the tested microlides (erythromycin, azithromycin, clarythromycin). rokosz a, sawicka-grzelak a, luczak m. department of medical microbiology, the university medical school, warsaw, poland purpose: to isolate, identify and determine the drug-susceptibility of fungal strains cultured from fecal samples routinely submitted for detection of clostridium difficile and its toxins in cases of antibioticassociated diarrhea (aad). methods: one hundred fecal samples from hospitalized patients were examined (may á/october 2001). c. difficile toxins a/b were detected directly in stools with c. difficile tox a/b ii test (techlab † , usa). fecal specimens were inoculated on ccca and candida id (biomerieux, france) media. c. difficile and fungi were identified with standard microbiological procedures. susceptibility of fungal strains to anti-fungal agents was determined (atb fungus, biomerieux, france). results: c. difficile toxins were detected in 38 and c. difficile strains were isolated from 23 of examined specimens. sixty-two fungal strains of 8 genera were cultured from 50 stool samples (24 c. albicans isolates). massive fungal growths were observed on primary plates in all cases. fifty-five fungal strains were susceptible to nystatin, 53-to 5fluorocytosine, 52-to amphotericin b, 45-to ketoconazole, 43-to miconazole and 39-to econazole. conclusions: in some cases of antibiotic-associated diarrhea fungal strains are responsible for symptoms of this disease. certain persons having aad should be treated with anti-fungal agents. results: a total of 291 isolates (33.2%) were penicillin nonsusceptible (intermediate and resistant) and 308 (35.1%) were erythromycin non-susceptible. non-susceptibility to both antibiotics was found in 183 (20.9%). conclusions: if penicillin administration eliminates all penicillin susceptible strains, the prevalence of penicillin non-susceptible strains will increase as well as the erythromycin non-susceptible ones. this means that the proportion of erythromycin non-susceptible strains should increase from 35.1 to 62.9%. at the same time, if erythromycin eliminate all susceptible strains to this antibiotic, the prevalence of penicillin non-susceptible strains would increase from the initial 33.2 to 59.4%. these data can explain the co-selection results observed in different surveillance studies. antimicrobial susceptibility and capsular types/groups of streptococcus pneumoniae isolates causing pneumococcal diseases in bulgaria pm178 setchanova l a , gergova r a , ioneva m b , sredkova v c . a department of microbiology, medical university, sofia, bulgaria , b department of microbiology, ii city hospital-sofia, sofia, bulgaria , c department of microbiology, faculty of medicine, pleven, bulgaria a prospective study of pneumococcal infections was performed in cooperation with five clinical microbiology laboratories in bulgaria. mics values to 12 antimicrobials and serotype/serogroup distribution were determined for 242 strains of streptococcus pneumoniae . pneumococci were isolated from patients with systemic or respiratory infections. the incidence of penicillin g-intermediate and penicillin gresistant isolate was 27.3 and 10.3%, respectively. the rates of resistance to other antimicrobials were: cefotaxime/ceftriaxone */ 6.2%; erythromycin */21.5%; clindamycin */7.8%; tetracycline */ 24%; chloramphenicol */26.4%; trimethoprim/sulfamothoxazole */ 38%; ciprofloxacin */10.7%; rifampin */3.7%. the s. pneumoniae isolates belonged to 19 capsular types/groups. the most common serotypes/serogroups in bulgaria are 1, 3, 5, 6, 9, 14, 19 we aimed to determine the pneumococcal antibiotic resistance rates and the serotypes of those resistant isolates in our hospital. the mic values of 212 isolates (year 1996 á/2001) were determined by agar dilution method. serotyping was performed by using 12 pooled antisera of the pneumo-test. the results were as follows (n 0/212). objectives: to asses the antimicrobial susceptibility of clinical isolates of pseudomonas aeruginosa obtained from 1997 to 2000 and to monitor trends in antimicrobial resistance. methods: mics were determined by microdilution testing according to nccls. the antibiotics tested were: ceftazidime (caz), aztreonam (atm), imipenem (imp), gentamicin (cn), tobramycin (tb), amikacin (ak) and ciprofloxacin (cip). results: a total of 1293 isolates were included. urine was the most common site of isolation for outpatients isolates (61.2%) while for hospitalized patients respiratory samples were the most frequent (40.2%). susceptibility to antibiotics was: 90% caz, 87.5% atm, 93% imp, 76.8% cn, 95.5% tb, 96.7% ak and 81.9% cip. comparison of susceptibility data through 1997 á/2000 showed that the increase in the resistance rate was significative for caz (4.6 vs 12.9%), atm (9.9 vs 18%), cn (18 vs 26%), tb (1.85 vs 6.9%), ak (1.6 vs 5.7%) and cip (15.17 vs 21%). significant differences were found under the following circumstances: isolates from intensive care units and from inpatients were significatively more resistant to caz, atm and imp. isolates from respiratory samples were more resistant to caz and atm and isolates from urine samples were more resistant to cip. conclusions: although the antimicrobial susceptibility level has been decreasing p. aeruginosa isolates still show good susceptibility percentages for all antibiotics tested. antimicrobial susceptibility testing of clinical isolates of bordetella pertussis : report on 27 isolates from rouen, france pm181 lemee l a , nouvellon m a , caron f b , lemeland jf a . a chu rouen, bacteriologie, rouen, france , b chu rouen, maladies infectieuses et tropicales, rouen, france reports of an increased clinical incidence of pertussis and the development of resistance by bordetella pertussis to erythromycin prompted the collection and antimicrobial susceptibility testing of recent clinical isolates from patients, who were hospitalized in rouen between 1991 and 1999. mics of nine antimicrobial agents (erythromycin, josamycin, spiramycin, roxithromycin, ketolide hmr 3647, cotrimoxazole, ciprofloxacin, rifampicin and amoxicillin) were measured by agar dilution method on mueller-hinton agar containing 5% horse blood. mbcs of erythromycin and rifampicin were also determined against four isolates of b. pertussis . all isolates were fully susceptible to the nine antimicrobial agents tested. mics 90 (mcg/ml) were 0.03 for erythromycin, ketolide hmr 3647 and ciprofloxacin, 0.06 for josamycin, 0.25 for spiramycin, roxithromycin and rifampicin, 0.5/2.5 for cotrimoxazole, and 1 for amoxicillin. mbcs (mcg/ml) were 0.125 á/0.5 for eyrthromycin and 0.5 á/1 for rifampicin. in conclusion, our isolates of b. pertussis remain extremely susceptible to all antimicrobial agents tested, especially macrolides. no resistance was detected. finally, if erythromycin remains the molecule of choice, other macrolides (c14 and c16) also confirm their good in-vitro activity. in addition, the good in-vitro potency of rifampicin, together with its great diffusion within the respiratory tract, suggests that rifampicin has potential clinical efficacy in pertussis too. the emergence of streptococcus pneumoniae (sp) with diminished susceptibility to penicillin g (psdp) suggests the use of other antibiotics such as newer fluoroquinolones (fq). the resistance phenotypes of 252 consecutive pneumococcal strains isolated from patients of four hospitals (observatoire régional des pneumocoques du nord-pas de calais) were studied: 39 strains were susceptible to penicillin g and 213 were psdp. reference strains provided from the centre national de réfeacute;rence des pneumocoques were added to the study. the activity of pefloxacin, ciprofloxacin, norfloxacin, sparfloxacin, levofloxacin and moxifloxacin was studied. reserpine was used to detect the efflux phenotype. methods used were performed according to the recommendations of the comité de l'antibiogramme de la société française de microbiologie. for each strain, the resistance phenotype to fq was deduced by comparison of mics or diameters obtained with those obtained with the reference strains of known phenotypes. fq resistance phenotypes were not correlated to blactam agent susceptibilities. wild type phenotype was observed among 76.9 and 77.5% of the susceptible and psdp strains, respectively. a 'wild efflux' mechanism, deduced by addition of reserpine to norfloxacin, represented the predominant phenotype. it was detected among sp susceptible to penicillin g (23.1%) as well as among psdp (17.4%). the aim of this study was to determine macrolide resistance phenotypes of sp isolated in three french departments (alpes maritimes, doubs, nord) from nasopharyngeal aspirates of children aged 3 months to 3 years attending a dcc. a random sample of children attending randomly selected dccs was obtained during three periods (spring, autumn and winter 1999) in each department (10 494 children attending dccs and 2565 children sampled). analysis of macrolide susceptibility of sp strains was performed using the ca-sfm method. out of 1262 strains, 64.7% had decreased susceptibility to penicillin (spdp) and 77.5% were resistant to erythromycin. the triple disk diffusion method (erythromycin (e), clindamycin (cl) and spiramycin) was used to determine resistance phenotypes. macrolide resistance is a well known phenomenon in france and is confirmed by our study. these results show that the constitutive phenotype is predominant as in other parts of europe and the frequency of efflux mechanism is lower than that observed in the usa and canada. developing antibiotic resistance surveillance of helicobacter pylori in england and wales pm184 elviss nc, owen rj. central public health laboratory, laboratory of enteric pathogens, london, uk purpose: helicobacter pylori antibiotic resistance is a key contributing factor in â/10% of infected patients failing drug treatment. our aim was to survey rates of primary in-vitro resistance at different locations, and links to disease severity. antral gastric biopsies/cultures were received from phls in chelmsford, mid-essex (1115 isolates 1995 á/2001); london (103 isolates 1999 á/2000); and bangor, north wales (165 isolates1999 á/2001). susceptibilities to metronidazole (mtz), clarithromycin (cla), tetracycline (tet) and amoxicillin (amx) were tested by disc diffusion and also by e -test for cla and mtz. results: overall resistance rates (1383 isolates) were 38% for mtz and 8% for cla. all were susceptible to amx and tet. dual resistance rate was 5%. breakdown by location showed some marked differences. mtz resistance was highest in london (63%) compared to 37% in chelmsford and 20% in bangor. by contrast cla rates were 11% for london, and about 5% for bangor and chelmsford. in london, the majority of mtz resistant isolates were from non-uk borne individuals (75% non-uk vs 25% uk). comparison of duodenal ulcer-associated isolates with those from non-ulcer patients indicated similar rates of mtz resistance (28%). conclusion: resistance rates may vary significantly between locations depending on the local population with non-uk birth being a key risk factor for primary resistance with a mtz resistant strain. local resistance rates should be taken into account in test and treat strategies. potrykus j, benetkiewicz m, wegrzyn g. department of molecular biology, university of gdansk, gdansk, poland purpose of the study : because of their ability to extrude a wide range of compounds, multidrug efflux pumps have recently become an important issue in combating bacterial infections. acrab-tolc is the major efflux system of escherichia coli . we investigated the effect of acra on plasmid-borne and intrinsic chloramphenicol, tetracycline and ampicillin resistance. results and conclusions: recently, we reported a chloramphenicol sensitivity of e. coli mutant expressing cat , the chloramphenicol resistance gene. the strain was shown to bear a nonsense mutation in the acra gene. our studies indicate that this mutation is, at least in part, responsible for the observed chloramphenicol sensitivity phenotype. the mutation seems also to influence the strain's susceptibility to ampicillin and teta (c )-mediated (plasmid-borne) tetracycline resistance. although the teta(c) protein retained its biological function, there was a considerable growth impairment of the mutant strain when cultured in tetracycline containing medium. deletion of the acrab locus prevented any growth in the presence of tetracycline. upon the addition of ampicillin, the mutant underwent lysis more rapidly than the control strain. such was also observed in acrab deletion derivatives of other e. coli strains. we are trying to elucidate the role of the acra gene product in the phenomena described above. existence of efflux pumps in wild type isolates of drug-resistance bacteria pm186 raja ray rr. medical microbiology and parasitology, calcutta university, kolkata, india efflux pumps possessed by the bacterial cells of different kinds of bacteria had presented as a newer mode of drug resistance in many organisms. the capacity of bacterial cells to cause outward flow of noxious agents was known, however, for a considerable time with respect to tetracycline. recently, interest in the efflux pump system has brought to light some previously ill-understood mechanisms of drug resistance, involving noxious agents, toxins or poisons. we have found high level of resistance in pseudomonads towards cetrimide and other germicides for which no definite chromosomal/plasmid-mediated genes/mechanisms could be identified. likewise, occurrence of nonantibiotic sensitive vibrios, staphylococci and pseudomonads in the background of their high level of resistance to most of the common antibiotics suggest a mechanism of interference with the efflux pump, which accounts for such sensitivity in such cases. involvement of multiple resistance of marine isolates of v. parahaemolyticus to numerous clinically used antibiotics to which they have never been exposed also suggests a possible role of efflux pumps in determining such resistance */that these can simultaneously develop against multiple marine toxins/poisons and other noxious agents. interaction between oxacillin and glycopeptides in a teicoplanin-resistant mutant of staphylococcus epidermidis with reduced susceptibility to vancomycin pm187 greco aa, ben hassen a. laboratory service of national bone-marrow transplant center, tunis, tunisia we selected a laboratory-generated mutant of staphylococcus epidermidis capable of growing in the presence of 256 mg/l of teicoplanin (353b tm256), from a methicillin-resistant (mic!/256 mg/l), teicoplanin-sensitive (mic 4 mg/l) and vancomycin-sensitive (mic 2 mg/l) clinical isolate of s. epidermidis (353b so). in a previous work, we studied the different phenotypic characteristics acquired by the teicoplanin-resistant mutant 353b tm256 (20th interdisciplinary meeting on anti-infectious chemotherapy, december 2000, poster sessions, 82/p1). in this work, we examined the interaction between oxacillin and glycopeptides against this teicoplanin-resistant mutant of s. epidermidis with reduced susceptibility to vancomycin. to study the combined antibiotic activity of oxacillin and glycopeptides, we used different methods: a modified disk diffusion test, the e -test, time-kill assays and population analysis profiles. the synergistic activity of glycopeptides in combination with oxacillin against the teicoplaninresistant mutant 353b tm256 was demonstrated with a bactericidal effect. no synergy was seen against the parental strain 353b so. moreover, the synergy between glycopeptides and oxacillin occurred with suppression of the subpopulation with the highest level of glycopeptides resistance. we concluded that combination of glycopeptides and oxacillin may be a possible alternative in the treatment of infections caused by methicillin-resistant, teicoplanin-resistant s. epidermidis . compositional changes in microcosm biofilms induced by application of minocycline: a preliminary study pm188 the aim of the study was to observe the effect of application of minocycline upon microcosm dental plaques. the plaques were cultivated in a constant departmenth film fermentor (cdff), which produces biofilms under conditions mimicking those present in vivo. the composition of the biofilms was determined by viable counting on selective and non-selective media. the proportion of antibiotic resistant genera within the biofilm was determined by viable counts utilising media containing minocycline (16 mg/ml). before commencing antibiotic pulsing, the biofilms had a total viable anaerobic count of 1.26)/10 10 cfu per biofilm, with negligible (6 cfu/biofilm) minocycline-resistant bacteria. however, 24 h after introduction of the antibiotic, the total count had been reduced to 1.02)/10 9 cfu/biofilm whilst the number of minocycline-resistant bacteria had risen to 1.23)/10 6 cfu/biofilm. at the final sampling time point (192 h) the total viable anaerobic count was 5.82)/10 8 cfu/biofilm whilst the number of minocycline-resistant bacteria was 1.12)/10 7 cfu/biofilm. hence, there is a very low basal level of inherent resistance to minocycline within microcosm dental plaques, but this increases considerably once the biofilms are exposed to minocycline. mechanism of resistance to aminoglycosides (amg) e. coli isolated from children with community-acquired urinary tract infections (cau-tis) pm189 methods: during the 2000 á/01 years nine centers took part in the study. the mics of antimicrobials were determined by the agar dilution method as described in the nccls guidelines. results: a total of 710 consecutive urine isolates from 692 children aged 1 month to 18 years with cauti were collected. the most frequently isolated species from children with cauti was e. coli (52.3%), followed by klebsiella spp. (8.0%) and proteus spp. (7.6%). results of the in vitro susceptibility testing of e. coli to amg are shown in table below. resistance of the strains was conditioned on production of amg-modifying enzymes. there has been found following phenotypes among resistance strains: gentamicin á/ tobramycin á/netilmicin (77.8% */aac(3)-v and 13.9% */aac(3)-iv enzymes) and gentamicin á/tobramycin (8.3%, due to ant(2ƒ) enzyme). conclusion: amikacin is most active amg against e. coli . resistance to gentamicin and netilmicin was mainly determined by production of aac(3)-v enzyme. effect of b-lactamase inhibitors (b-l-i) on the evolution of resistance (r) to b-lactams (b-l) in gram the b-lactams antimicrobials still are the most frequently used. among the bacteria responsible of high resistance to b-lactams are gramnegative rods; its most frequent mechanism is the production of b-lactamase. the use of b-l-i has reversed partially this mechanism of resistance. we expect changes in the frequencies of r using b-lƒci after more than 10 years. since 1988, the venezuelan group of bacterial resistance, with 29 health institution in the country; analyse and publish data on bacterial resistance of isolates from patients with bacterial infection coming from hospitals. it was used diffusion disk, according nccls. the software program whonet (world health organization net) was used. we follow the trends of r of gram-negative rods to b-l alone and with b-l-i during the decade 1988 á/1998. statistical analyses were made by evaluating the differences among percentages of resistance between the two series (p 5/0.05). results and discussion: the difference in r between b-l and b-l/b-l-i are: (1) piperacillin, piperacillin/tazobactam: between 10 and 30% of r for most isolated, except for escherichia coli (45%) and serratia spp. (60%); (2) ampicilin, ampicilin/sulbactam: between 10 and 30%; (3) cefoperazone, cefoperazone/sulbactam: between 5 and 25%. how is expected gramnegative rods resistance to b-lactams with a b-l-i is lower than the b-lactam alone; furthermore the difference between both series, grows higher with time. these results are relevant and they were not expected, since b-l-i have been shown to be b-lactamase inductors. trends in the resistance (r) to b-lactams and others antimicrobials in p. aeruginosa in venezuelan medical centres. nosocomial (nos) and communitarian resistance pm191 in order to approach the infection produced by resistant bacteria, it is convenient to consider the hospital and the community as two separate ecosystems. the hospital ecosystem has special relevance in the infection and r of gramnegative aerobic bacilli. today, they are the main responsible of nos infection, with special reference to pseudomonas aeruginosa . infection by resistant bacteria is a world wide problem, specially related to nos. since 1988, the venezuelan group of bacterial resistance, with 29 health institution in the country; identify, analyse and publish data on bacterial r to antimicrobials: b-lactams, quinolones and aminoglicosides of isolates from patients with bacterial infection coming from hospitals and the community. it was used diffusion disk, according nccls. the software program whonet (world health organiza-tion net) was used. statistical significance (p 5/0.05) was determined by application of the x 2 technique. we show significant differences in the r of p. aeruginosa nos and communitarian (highest differences: piperacilina 40/7%, tobra 40/4%). we also established significant differences between the r arising in public hospitals and private hospitals (highest differences: ceftazidime 50/5%, amika 25/ 5%). we show the tendency in decreasing of frequency of r since 1998; this is more evident in private hospitals (b-lactam and aminoglicosides). new antimicrobials and new mechanism of action, and in the future the new technology will solve today's problem. however, the most important tools we have today are prevention and antimicrobials, and we must make them suitable. susceptibility to antibiotics of enterobacter cloacae and citrobacter freundii from drinking water pm192 quintera sm, sousa jc, peixe l. department of microbiology, faculty of pharmacy, university of oporto, oporto, portugal the increased use of antimicrobials in farming, together with the practice of raw sewage discharge into receiving waters, has resulted in a significant increase in the number of antibiotic resistant bacteria present in aquatic environment. our objective was to determine the antimicrobial susceptibility, with focus on b-lactam resistance, among enterobacteriaceae strains isolated from raw drinking water samples. several isolates (n0/107) of enterobacter cloacae and citrobacter freundii obtained from drinking waters were screened for antibiotic susceptibility patterns, using the agar diffusion technique, according to nccls's procedures. only 55% of e. cloacae strains, as well as 37% of c. freundii strains show resistance to amoxicillin and amoxicillin/ clavulanic acid. a reduced incidence of resistance to several others antibiotics was also observed. the obtained results suggest that strains isolated from raw drinking water have greater susceptibility to antimicrobial agents than pathogenic strains from hospital or outpatients infections. the 'natural' antimicrobial resistance phenotypes, usually described for c. freundii and e. cloacae , only seem to apply to strains isolated from human infections. notwithstanding the high susceptibility of the tested isolates to b-lactams, the role of environmental bacteria as a reservoir of resistance genes justify its periodical monitoring as a valid index for resistance spreading. a snapshot of the soil. using bacterial communities for tracing the evolution of metal-resistance pm193 quintera sm a , sousa jc a , peixe l a , monteiro nm b . a department of microbiology, faculty of pharmacy, university of oporto, oporto, portugal , b department of zoology and anthropology, faculty of sciences, university of oporto, oporto, portugal it is well known that pathogenic bacteria, specially those resistant to antimicrobial agents and heavy metals poses public health risks of great concern, and its detection, namely in soils is generally related to pollution. in this study, the heavy metal resistance patterns of the microflora isolated from polluted (dump area) and unpolluted soil environments were examined. the plate growth covering percentage in the soil samples was determined using mueller-hinton plates supplemented with different heavy metal (al3'/, cd2'/, cu2'/, pb2'/, hg2'/ and zn2'/) concentrations. parallelly, using icp-aes, it was possible to ascertain the real heavy metal concentration for each soil sample. we found that the percentage of plate growth covering from the used samples was closely linked to the level of chemical pollution measured for each location. moreover, using anova, we found significant differences between locations. the dump site showed the highest tolerance to all the tested metals (newman á/keuls test). this pattern of results was consistent when using the data from the icp-aes. furthermore, it was possible to observe that pseudomonas spp., with a relatively high mic for the studied metals, might become a relevant model for both public health issues and eco-toxicological studies. biochemical characteristics of environmental isolates of listeria monocytogenes pm194 moshtaghi h a , garg sr b , mandokhot uv b . a shahrekord university, food hygiene, shahrekord, islamic republic of iran , b haryana agricultural university, food hygiene, hisar, india purpose: the investigations were carried out to study the biochemical reactions of listeria monocytogenes isolated from different sources in the environment. results: a total of 12 isolates of l. monocytogenes were obtained from 230 samples of agricultural soil, faecal matter of animals and sewage. all the isolates were gram-positive, small rods, catalase positive, oxidase negative, motile with tumbling motility in hanging drop at 22 á/25 8c, aerobic, facultative anaerobic, fermentative and produced acid from glucose. all the isolates of l. monocytogenes were beta haemolytic and positive for camp reaction with staphylococcus aureus . all the isolates were negative for phenyl alanine deaminase, ornithine decarboxylase, lysine decarboxylase, malonate utilization and beta galactosidase tests. these were also negative for acid production from arabinose, d-xylose, mannitol, soluble starch and sucrose but acid was produced in rhamnose, salicin, and trehalose. hydrogen sulfide production was recorded in tripticase soy broth with lead acetate paper strips but negative with triple sugar iron agar. all the isolates were found to hydrolyse aesculin. out of 12 isolates of l. monocytogenes only two produced acid from lactose. in serotyping all the isolates were serotype 4b. conclusion: we can conclude that l. monocytogenes serotype 4b at least in fermentation of lactose shows different reactions. methods: the samples were pre-enriched in bhi broth with and without vancomycin (6 mg/l) and then plated onto m-enterococcus agar with and without antibiotics: vancomycin (6 mg/l), gentamicin (125 mg/l), kanamycin (500 mg/l), and streptomycin (1000 mg/l). representative colonies of each morphology were isolated and identified as enterococcus sp as previous described. pcr was used to identify e. faecium and e. faecalis and to characterise vancomycin resistant genotype. api20strep was also used in the identification. susceptibility testing to 11 antibiotics was performed by an agar dilution method (nccls). results: three hundred and fifty-three enterococci were isolated from 92 of a total of 99 faecal samples (93%, n 0/92/99). the majority of enterococci were identified as e. faecium , e. faecalis and enterococcus sp. resistance to almost all antibiotics studied was observed: vancomycin */3.0%; teicoplanin */3.0; ampicillin */21.2%; tetracyclin */81.8; erythromycin */86.9%; ciprofloxacin */78.8%; chloramphenicol */54.5%; gentamicin */17.2%; streptomycin */ 78.8%; kanamycin */77.7%; linezolid */0%. the vancomycin resistant enterococci presented a vana genotype. conclusion: resistance to several common antibiotics used in therapy was observed among enterococci isolated from healthy human from community. many of these isolates presented multi-resistance. of concern is the presence of vana genotype among these populations that may constitute a reservoir of vancomycin resistant genes. antimicrobial resistance in tetracycline-resistant oral bacteria pm196 mercury release from dental amalgam may select for mercuryresistant oral bacteria. mercury resistance is often associated with multiple antibiotic resistances. the aims of this study were to determine whether tetracycline-resistant oral bacteria from children with and without amalgam fillings were also resistant to: (a) mercury; and (b) multiple antibiotics. tetracycline-resistant organisms were isolated on iso-sensitest/blood agar containing tetracycline (8 mg/ml). the mic of hgcl 2 and several antibiotics were determined using agar dilution (bsac). one hundred and three organisms were isolated from patients without amalgam. ninety-one were streptococcus species, seven neisseria species, three veillonella dispar and two rothia species. fifty-seven percent exhibited resistance to at least one antibiotic, 12% were mercury-resistant, 42% were penicillin-resistant, 11% were ampicillin-resistant and 23% erythromycin-resistant. fiftytwo organisms were isolated from patients with amalgam. forty-five were streptococcus species, five neisseria species, one v. dispar and one staphylococcus aureus . sixty-three percent exhibited resistance to at least one antibiotic, 23% were mercury-resistant, 38% penicillinresistant, 11% were ampicillin-resistant and 31% showed erythromycin-resistance. statistically, the results showed that in tetracyclineresistant organisms, the presence of dental amalgam did not affect the level of resistance to mercury or to the antibiotics tested. conway-wallace hl a , mullany p a , bedi r b , wilson m a . a eastman dental institute, university college london, microbiology, london, uk , b eastman dental institute, university college london, transcultural oral health, london, uk the purpose of this study: to determine the prevalence of antibioticresistant oral bacteria in children who had not received antibiotics during the 3 months prior to sampling. plaque samples were obtained from 16 children aged 4 á/6 years and plated onto media containing: penicillin, ampicillin, tetracycline, erythromycin and vancomycin. resistant isolates were enumerated, sub-cultured and frozen for subsequent identification. the process was repeated 6 and 12 months later. the results obtained: bacteria resistant to each of the antibiotics were present in all of the children at each sampling time (except in the case of ampicillin and penicillin at 0 months). the proportion of antibiotic-resistant bacteria in the oral microflora ranged from ]/13.7 (erythromycin) to 5/0.5% (ampicillin). the proportions of bacteria resistant to a particular antibiotic remained reasonably constant over the 12-month sampling period. in only two cases (penicillin and ampicillin) was there a statistically significant change in the proportions of resistant bacteria at different time periods. the conclusion reached: the results of the study have revealed that bacteria resistant to a wide range of antibiotics may be isolated from children who have not been administered these agents during the 3 months prior to sampling. furthermore, in many cases the proportion of bacteria resistant to a particular antibiotic remains constant over a 12-month period. antimicrobial use in the intensive care unit: results of a pharmacoepidemiological study in italy pm198 periti p. e.i.f.t. srl, firenze, italy a retrospective survey of antimicrobial chemotherapy use in 560 intensive care units in italy was carried out in 1999 using a computerized questionnaire under the auspices of the journal of chemotherapy. of the icus contacted, 43.4% replied, being mainly general or post-surgical and pediatric units having a mean of 10 beds, nine doctors and 20 nurses. the antimicrobial agents used in these wards were almost always polychemotherapy with prevalent use of beta-lactams, aminoglycosides and glycopeptides or as empirical treatment during the first 72 h after hospital admission. the continual use of medium-high dose combinational antimicrobial chemotherapy was justified by microbiological testing, which revealed that more than one-third of bacterial pathogens were resistant. approximately, 60% of gram-positive bacteria were methicillin-resistant, whereas about 13% of gram-negative strains were resistant to at least one of the tested antibiotics. forty percent of the responding icus furnished microbiological testing data, of which three quarters indicated the incidence of chemoresistance of the isolated strains. fungal infections were less frequent than bacterial, the most commonly isolated agent being candida spp. in conclusion, the sample of icus examined showed adequate and reasonable use of antimicrobial agents, with heavy reliance on medium-high dose combination therapy due to the elevated incidence of resistant isolates found. plasma concentrations (p), urinary excretion (u) and bactericidal activity of gatifloxacin (gat) 400 mg versus ciprofloxacin (cip) 500 mg in 12 healthy volunteers after a single oral dose pm199 boy d a , kinzig-schippers m b , sö rgel f b , well naber kg a . a hospital st. elisabeth, urologic clinic, straubing, germany , b institute for biomedical and pharmaceutical research, ibmp, nürnberg-heroldsberg, germany twelve volunteers received a single oral dose of 400 mg gat versus 500 mg cip to assess p up to 36 h, u (by hplc), and urinary bactericidal titers (ubt) in eight intervals up to 120 h. the mean pmax of gat/cip was 3.35/2.12 mg. the ucum (mean) for gat/cip was 81.0/43.2%. the ubts, i.e. the highest twofold dilution of urine still bactericidal, were determined for nine uropathogens and one reference strain */mics (mg/ml) (microdilution) for gat/cip: escherichia coli atcc 25922 (0.008/0.008); e. coli (0.06/0.06); klebsiella pneumoniae (0.03/0.016); proteus mirabilis (0.25/0.06); pseudomonas aeruginosa (1/ 0.125); s. saprophyticus (0.125/0.25); two strains of s. aureus (0.06/ 0.125); two strains of e. faecalis (0.5/1 and 8/32). the median ubts measured within the first 6 h for gatifloxacin were between 1:16 and 1:1024 for the five gram-negative strains (incl. p. aeruginosa ) and between 1:8 and 1:1024 for the five gram-positive strains. the median ubts for ciprofloxacin were between 1:64 and 1:1024 for the gramnegative strains (incl. p. aeruginosa ) and between 1:1.5 and 1:768 for the five gram-positive strains. for the ubts up to 12 h, gat was significantly superior to ciprofloxacin in all gram-positive strains, not different in the two e. coli strains, and inferior in the klebsiella , proteus and pseudomonas strains. for the ubts at 12 á/24 h, gat was generally superior to cip, but showed no difference in the proteus and pseudomonas strains. gat showed overall comparable urinary bactericidal activity as cip. this is in agreement with a clinical study performed previously. malaria is one of the most prevalent endemic infectious disease affecting humans. in bichat hospital 111 cases of malaria acute illness were reported during 2001. among them, 96 patients were hospitalised and intravenously treated by quinine. this retrospective study consisted of comparing the therapeutic drug monitoring (tdm) of quinine distinguishing, respectively 36 and 60 patients cured in infectious medical department (imd) and intensive care unit (icu) where a standardised quinine regimen was established (62 and 47% malaria attacks, respectively). in icu, the treatment consisted of an infused loading dose 16 mg/kg/4 h of quinine diluted in 5% glucose followed by 24 mg/kg/day. plasma quinine maximal concentrations were assessed after selective liquid á/liquid extraction and spectrofluorometry detection. statistical analysis was performed using t -test. results showed that patients had comparable weight (71.49/19.7 and 70.89/17.9 kg) but quinine doses and plasma concentrations were significantly different in icu and imd, respectively (20.29/6.5 versus 22.79/3.7 mg/kg/day, pb/ 0.001 and 11.49/3.3 versus 10.39/3.2 mg/l, p b/ 0.01). in icu and imd, respectively: 57 and 49% were in the therapeutic range (10 á/15 mg/l) with 29 and 43% below the requested therapeutic concentration (10 mg/l) and 13 and 8% above the limit of toxicity (15 mg/l) conveying the importance of tdm in intravenous quinine treatment to avoid infra-therapeutic or toxic concentrations. simultaneous central nervous system distribution using microdialysis and pharmacokinetic á/pharmacodynamic modelling of the electroencephalogram effect of norfloxacin in rats pm201 chenel m, marchand s, dupuis a, bouquet s, couet w. university of pharmacy, pharmacology, poitiers, france purpose: to investigate the epileptogenic activity of norfloxacin by a pharmacokinetic á/pharmacodynamic (pk á/pd) modelling approach and to assess the contribution of distributional processes across the blood á/brain barrier (bbb) to the delayed effect. methods: rats (n0/10) received an iv bolus dose of norfloxacin (150 mg/kg). convulsant effect was quantified by electroencephalogram (eeg) recording during 9 h post-dose. arterial blood samples were collected for drug assays in plasma. unbound norfloxacin concentrations were monitored in brain extracellular fluid (ecf) using microdialysis with in vivo calibration of the probes by retrodialysis with ciprofloxacin. results: the eeg effect reached its maximum between 70 and 190 min post-dose. a pk/pd effect compartment model was successfully fitted to these data. the relationship between effect and concentration at the effect site was best described by a spline function. norfloxacin concentrations in brain ecf were relatively low compared to plasma levels (ecf/plasma areas under curve (auc) ratio equal to 9.79/ 2.8%), but central distribution was rapid. therefore, the effect versus brain ecf concentrations curves still exhibited a marked hysterisis. conclusion: the delay observed between plasma concentrations and norfloxacin convulsant effect cannot be explained by a slow distribution of norfloxacin across the bbb. pagoulatou a a , kanellakopoulou k b , vafiadou m a , kostakopoulos th c , kastriotis i b , giamarellou h c . a department of anesthesia, sismanoglio general hospital, greece , b 4th department of internal medicine, athens medical school, athens, greece , c department of urology, athens medical school, athens, greece csf kinetics of van and fu were studied in 57 patients who underwent short urological surgery under spinal anesthesia. patients were excluded if they were already receiving an antibiotic or were suffering from renal and hepatic dysfunction. van was administered at 1 g over 1 h infusion. serum and csf samples were collected post-dose and the mean serum levels were as follows: 30 min á/1 h: 21.1 mg/ml (five patients), 1 á/2 h: 10.1 mg/ml (five patients), 2 á/4 h: 8.5 mg/ml (six patients), 4 á/6 h: 6.7 mg/ml (six patients) and 6 á/8 h: 5.15 mg/ml (seven patients). fu was administered at 500 mg dose over 1 h infusion. serum and csf samples were taken post-dose and the mean serum concentrations were found as follows: 0 á/30 min: 43.08 mg/ml (six patients), 30 min á/1 h: 41.7 mg/ml (six patients), 1 á/2 h: 33.8 mg/ml (five patients), 2 á/4 h: 27.8 mg/ml (six patients), 4 á/6 h: 25.6 mg/ml (five patients). in csf, both van and fu were undetectable. it is concluded that in the absence of meningeal inflammation van and fu do not penetrate (with the applied microbiological assay) the csf barrier. comparison of the pharmacology of intravenous and orally given moxifloxacin in an in-vitro model pm203 wiegand i, pfeil e, wiedemann b. university of bonn, pharmaceutical microbiology, bonn, germany purpose: the intravenous form (iv) of 400 mg moxifloxacin (mox), one of the newer fluoroquinolones, has been recently approved by the fda. during the iv treatment higher peak serum concentrations are achieved in comparison to the oral administration (po) of the same dose. the antibacterial activity of fluoroquinolones is concentration dependent. we therefore simulated human pharmacokinetics of single po and iv dosages of 400 mg mox in an in-vitro model using six different gram-negative and -positive pathogens to elucidate the different effect of these two dosing schedules. results: the comparison of the pharmacological parameter auc/ mic shows an increase ( table 1 ) that could predict an enhanced antibacterial effect. however, the analysis of the killing curves with the following parameters, ka.max (maximal killing activity) and aac (area above the killing curve between 0 and 24 h), reveals no major difference between the po and iv dosage. conclusion: the serum concentration after oral administration is already sufficiently high to show the optimal bactericidal effect of mox that can only be slightly increased by higher peak concentrations and higher auc/mic ratios. thus the concentration dependence is not linear but ends already at concentrations achievable by oral dosing and documents that auc/mic calculations cannot easily be translated into dosing schedules. background : bacteria growing in vivo multiply much more slowly than in vitro. whether the bactericidal activity of quinolones may be affected by an increase in generation time (g) was studied in batch cultures. methods: by limiting the nutrient supply, generation times were lengthened from approximately 0.45 to 1.5 h up to 3.9 h. alternatively, the quinolones were added to the bacterial cultures during the lag-, exponential-and stationary phase. recent clinical isolates of escherichia coli were exposed to multiples of the mics of ciprofloxacin or norfloxacin. the 'killing rates' were calculated in analogy to the growth rate. results: the bactericidal activity of the quinolones tested against e. coli was minimally influenced by the reduced generation time. ciprofloxacin concentrations of ]/2)/mic eliminated the test strains within 5/2 h from the test system if added during the lag or exponential growth phase; four times higher concentrations were needed to reduce cfus by 99% within 2 h, if added during the stationary phase. norfloxacin was significantly less active. conclusion: in contrast to norfloxacin, the bactericidal activity of ciprofloxacin is minimally affected by the generation time or growth phase of the bacteria. wiegand i, pfeil e, wiedemann b. university of bonn, pharmaceutical microbiology, bonn, germany purpose: moxifloxacin (mox) is one of the newer fluoroquinolones, now available for parenteral application. the pharmacology of an intravenous once-daily dose (od) of 400 mg mox was determined with five gram-negative and -positive pathogens (streptococcus pyogenes , streptococcus pneumoniae , moraxella catarrhalis , escherichia coli , and klebsiella pneumoniae ). a twice-daily dose (bid) of 400 mg mox was simulated with the gram-positive species in order to increase the bactericidal effect. results: to determine the efficacy, killing curves were analyzed, and following parameters were calculated: ka.max: maximal killing activity [log cfu]; ka. conclusion: an intravenous once-daily dose of mox is active against all tested pathogens. the gram-negative species are rapidly killed (ka.1 h similar to ka.max). there is no pronounced initial effect on the two gram-positive species but a general slow reduction in the viable cell count (ka.max is reached after 24 h). the efficacy of mox (measured as aac and ka.max) on s. pyogenes and s. pneumoniae is to some extent increased after the second dose. however, the analysis of the killing curves reveals no major difference between od and bid. even the od nearly gives the maximal bacterical activity of mox against gram-positive pathogens. objectives: to evaluate the dose proportionality of amoxicillin and to compare the respective pk/pd parameters of two dosage regimens. methods: the dose proportionality of amoxicillin was evaluated using linear regression of mean auc 0-inf and c max data of 13 different bioequivalence studies (n0/477 volunteers) performed with formulations containing various amounts of amoxicillin alone or in the combination with clavulanic acid. the volunteers received a single oral dose in the range of 250 á/1000 mg. amoxicillin plasma concentrations were determined by hplc/uv or lc/ms/ms methods. time above mic (tmic) expressed in% of dosing interval was calculated with three target mic values (0.5, 1.0 and 2.0 mg/l) for 500 mg 8hourly and 1 g 12-hourly dosage regimens. results: the absorption of amoxicillin (auc 0-inf ) showed a linear dependence with a correlation coefficient of 0.975. the correlation coefficient of the linear regression for the cmax dependence on the actual dose was 0.909. the respective tmic for both dosage regimens were very similar, with largely overlapping confidence intervals, supporting a pd breakpoint of 2 mg/l for the 1 g 12-hourly regimen (tmic ]/2 mg/l: 42.8%, 95% ci 38.6, 46.9%). conclusion: this analysis shows the dose proportionality of amoxicillin over the dosage range of 250 á/1000 mg and supports the pharmacodynamic rationale for a 1 g bid dosage regimen. piperacillin/tazobactam concentration profile after high dose administration pattern in nosocomial pneumonias due to mecanical ventilation pm207 pedeboscq s a , gruson d b , bassoua v a , hilbert g b , pometan jp a . a st. andré hospital, pharmacy, bordeaux, france , b pellegrin hospital, reanimation, bordeaux, france the piperacillin (p)/tazobactam (t) antibacterial spectrum covers the largest part of bacteria responsible for pneumonias due to mechanical ventilation. but, due to important bacterial inoculum and pharmacokinetic parameter modifications in intensive care patients, high doses of beta-lactamines seem to be necessary to obtain antibiotic concentrations above suspected bacteria's mic (minimal inhibitory concentration) . this led us to compare, in patients with pneumonia due to mechanical ventilation, two intermittent administration patterns: 4 g three times a day (usual pattern) versus 4 g four times a day (high dose pattern). this study is carried out in collaboration with intensive care unit, bacteriological department and pharmacy where antibiotic concentrations are determined. twenty-three takings of blood are executed within a 48 h period, in addition to two bronchial secretion samples. concerning p seric concentrations, the high dose pattern seems to be more adapted because of relatively high residual concentrations ( !/20 mg/ml). three hours after each injection, t seric concentrations are lower than the 4 mg/ml activity threshold. first and second day residual bronchial concentrations of p seem to be sufficient although t concentrations are below activity threshold. these results are to be correlated with the mic determined by the bacteriological department, and only this correlation will make us able to conclude the better efficacy of the high dose pattern in intensive care patients. anti-inflammatory drugs interference in absorption and tissue penetration of amoxycillin pm208 del fiol fs a , menon sz b , caramez th b , celotto tf b , lopes ras b . a university of sorocaba, pharmacology, sorocaba, brazil , b school of pharmacy, university of sorocaba, sorocaba, brazil antibiotics and anti-inflammatories are frequently associated in clinical practice. there is some concern about the quantity of antibiotic that reaches the infection sites, which may be reduced in the presence of an anti-inflammatory drug. the purpose of the present study was to analyse how steroids (dexamethasone (dexa)) and aines (celecoxib (cele)) influence on the penetration of amoxicillin to inflamed tissues. thirty female rats (rattus norvegicus ) were used with surgically implanted pvc sponges on their backs to form granulomatous tissue. one week later the animals were divided into three groups. one group received only amox (40 mg/kg), another received amox (40 mg/kg) plus cele (6.0 mg/kg) and the last received amox (40 mg/kg) plus dexa (0.3 mg/kg). one hour later the animals were sacrificed and the concentration of amoxicillin in the serum and tissue investigated. there was no difference among the groups in the quantity absorbed (amox0/18.879/2.05 mg/ml; amox'/cele0/18.209/1.89 mg/ml and amox'/dexa0/18.139/2.28 mg/ml). there was a reduction in the tissue concentration of amoxicillin (p b/ 0.01 tukey-kramer) for the group that received the drug with dexamethasone. for the other groups, there was no difference in the tissue concentration of amoxicillin. the results indicated that in inflamed tissue, a significant reduction of antibiotic penetration was induced by sinultaneous dexamethasone therapy. prediction of the optimal amoxicillin dose regimen based on coupling of pharmacokinetic data and bactericidal activity pm209 background: given its short half-life, amoxicillin (amx) should be administered at least three times a day to patients with acute exacerbations of chronic bronchitis, in order to achieve serum concentrations well above the mic of the responsible pathogen. however, several authors have recommended twice-daily administration of a higher dose for a shorter period. we assessed the relationship between amx sputum concentrations and antibacterial activity following two treatment schedules in healthy volunteers. subjects and methods: twelve healthy volunteers were randomized to receive amx for 4 days at a dose of either 1 g bd or 500 mg bd. serum and sputum were collected every day, 3 h after the morning administration, and again 2 days after the last dose. amx concentrations were determined by hplc with fluorometric detection. sputum killing activity was determined against haemophilus influenzae , streptococcus pneumoniae and moraxella catarrhalis . results: mean serum concentrations measured 3 h after the morning administration were 1.5 (500 mg bd) and 1.95 mg/l (1 g bd), and were above the mics of the three microrganisms. in contrast, sputum concentrations were always below 0.5 mg/l. in terms of sputum killing activity, 1 g bd was more effective than 500 mg bd against s. pneumoniae and m. catarrhalis , whereas no sputum samples were active on h. influenzae . conclusion: the optimal amoxicillin treatment schedule cannot be established on the basis of serum pharmacokinetics only. galmiche h, louchahi k, tod m, drugeon h, giroud jp, rouveix b. service de pharmacologie clinique, hopital cochin, paris, crepit 93, hopital avicenne, bobigny, service de microbiologie, hopital laennec, nantes, france background: cysteine-based mucolytics are commonly used in combination with antibiotics to treat patients with acute exacerbations of chronic bronchitis (aecb). they are also used to allow in vitro mic determination in sputum specimens. we conducted an in vitro and ex-vivo compatibility study designed to detect a possible interaction between mucolytics and antibiotics. methods: serial samples of bronchial secretions were collected from aecb patients and from healthy volunteers who received 1 g of amoxicillin twice a day for 4 days. two mucolytics were used to fluidify sputum specimens: 2,3-dihydroxy-1,4-dithiolbutan (digest-eur † ) and acetylcysteine (10% solution). amoxicillin was assayed using a chromatographic system with fluorometric detection. each sample was also tested in a microbiological assay. results: amoxicillin could not be detected in the presence of the mucolytic agents. conclusions: this mucolytic á/amoxicillin interaction may be explained by amoxicillin fixation to fluidified mucoproteins, and should be taken into account when assessing antibiotic efficacy in vivo. del fiol fs a , ferro c b , albuquerques et b . a university of sorocaba, pharmacology, sorocaba, brazil , b uniso, school of pharmacology, sorocaba, brazil physicians frequently recommend that macrolides should be administered with milk to decrease the discomfort they cause. thus the objective of this study was to verify the interference of milk in the absorption and distribution of erythromycin (eryt); clarithromycin (clar); roxithromycin (roxi) and azithromycin (azit). forty female rats (rattus norvegicus ) were used with surgically implanted pvc sponges on their backs for granulomatous tissue formation. one week later the animals were divided into groups that received the drugs eryt, clar, roxi and azit with and without milk (3.5 ml/kg [ca'/'/]0/1.1 mg/ml). the animals were sacrificed and the serum and tissue concentration of the drugs was investigated. there was no reduction (pb/ 0.05 tukey-kramer) in the serum and tissue concentration in the presence of milk for azit and clar. there was a 27% reduction for roxi in the serum concentration in the presence of milk (11.84 9/1.35 and 8.639/1.34 mg/ml), but no alteration in the tissue concentration. there was a 33% reduction for eryt (p b/ 0.05), in the serum concentration in the presence of milk (10.209/ 1.06 and 6.839/0.88 mg/ml) and a 40% reduction in the tissue concentration. the milk decreased the effectiveness of treatments with erythromycin and roxithromycin and the bioavailabilities of this macrolides were affected by co-administration with milk. del fiol fs a , souza gp b , duzzi mr b . a university of sorocaba, pharmacology, sorocaba, brazil , b uniso, school of pharmacology, sorocaba, brazil the degree to which tetracyclines are absorbed differs greatly. this absorption is impaired by the concurrent ingestion of divalent and trivalent cations. thus the objective of this study was to investigate the interference of milk in the absorption and distribution of tetracycline (tetr), oxytetracycline (oxyt), minocycline (mino) and doxycycline (doxy). forty female rats (rattus norvegicus ) were used with surgically implanted pvc sponges on their back for granulomatous tissue formation. one week later the animals were divided into groups that received the drugs: tetr; oxyt; mino; and doxy with and without milk (3.5 ml/kg [ca'/'/]0/1.1 mg/ml). the animals were sacrificed and the drug concentrations in the serum and tissue were determined. there was no reduction (pb/ 0.05 tukey-kramer) in the serum and tissue concentrations in the presence of milk for mino. there was a 25% reduction (p b/ 0.05) for doxy in the serum concentration in the presence of milk (11.249/0.61 and 8.409/0.41 mg/ml) and 32% in the tissue concentration. for oxyt, there was a reduction of 34% (pb/ 0.05) in the serum concentration in the presence of milk (14.579/1.51 and 9.549/1.51 mg/ml) and 16% in the tissue concentration. the tetr results show a 35.4% reduction (p b/ 0.05) in the serum concentration in the presence of milk (13.469/3.39 and 8.699/3.03 mg/ml) and 40% in the tissue concentration. milk decreased tetracycline bioavailability and effectiveness. isotopic studies with oxine labelled platelet. platelet kinetics in thrombocytopenic malaria patients pm213 introduction : thrombocytopenia is a common feature in human malaria (1). excessive splenic platelet pooling has been suggested to play a role in uncomplicated cases of malaria, but a moderately shortened platelet life span during the period with decreasing parasitaemia seems the most plausible cause of the frequently observed thrombocytopenia (2, 3). consumption coagulopathy, eventually manifested as disseminated intravascular coagulation, has been described in malaria (4). in uncomplicated malaria, however disseminated intravascular coagulation is rarely found (3). results: in malaria patients the sequestration was not different to normal. platelet half-life was reduced in patients with p. falciparum malaria to 10 á/17 h (normal â/8 days). in one patient with p. vivax malaria platelet half live was 59.5 h. conclusion: no significant differences in the sequestration of platelets when compared to healthy individuals could be detected by 111 in-labelled platelet scintigraphy. especially, no enhanced splenic sequestration, as previously expected, was the cause of the thrombocytopenia. therefore, other mechanisms than sequestration are responsible for the dramatically reduced life span of the platelets during acute malaria. zaharanka ag, rozhdestvensky da. vitebsk state medical university, vitebsk, belarus aim: the studying of chromatingeterogenic test (ct) results in sperm of subjects taking doxycycline (d) and some macrolides (erythromycine (e), jozamycine (j), and azytromycine (a)) in moderate therapeutic doses. methods: forty healthy volunteers (20 á/23 years) were studied. daily dose of d was 0.2; e was administered in dose 0.25 four times per day 10 days; j */0.5 before meals twice daily 10 days; a */0.25 before meals once daily 5 days. ct for evaluation of dna condition in human spermatozoids was performed before treatment (twice), on the 5th and 10th days of treatment, as well as after 1 and 2 months after treatment course completing. results: ct data analysis revealed that the mean amount of defective spermato-zoids before treatment was 18.5'/3.5%. by the 5th day of d treatment the index of de-natured dna was 63.4'/6.5% (pb/ 0.001), by the 10th day */80.4'/7.2% (pb/ 0.001). one and 2 months after the d treatment course the amount of generative cells with denatured dna was 54.5'/4.6 and 42.5'/3.8%, respectively (p b/ 0.001 in both case). under e treatment the amount of defective spermatozoids changed as 38.2'/4.2 (5th day), 42.4'/2.7 (10th day), 35.6'/2.5 (after 1 month), and 30.5'/4.2% (after 2 months) (pb/ 0.05 in any case). under a using the ct results at the same control points were 39.5'/4.7, 46.5'/3.2, 40.2'/3.5, 25.6'/3.2% (pb/ 0.05 in any case); and under j treatment */18.2'/2.5, 20.3'/2.5, 17.2'/3.2, 15.2'/ 4.2%, respectively (p !/0.05 in any case). conclusions: the data obtained permit to conclude that d demonstrates the high level of toxicity to male generative cells. this effect preserves during 2 months after the course of d treatment. objective: to study the effect of aggressive isolation and decontamination measures to control an outbreak of multi-resistant acinetobacter baumanii (mr-ab) in an icu. the outbreak: the index case was transferred from a mediterranean hospital, directly into an open-plan 10-bedded icu, with severe injuries to his head and thorax. he died shortly after admission. sputum, bronchoalveolar lavage fluid, blood cultures and a chest drain swab grew mr-ab, resistant to ampicillin, co-amoxiclav, aztreonam, amikacin, ceftazidime, cefotaxime, cefuroxime, ciprofloxacin, gentamicin, meropenem, piptazobactam, tobramycin and sensitive only to colistin. within 10 days, mr-ab was isolated from two further icu patients. all isolates demonstrated identical antimicrobial susceptibility profiles. the icu was closed to admissions and thoroughly cleaned. all patients were isolated and their contacts screened. the icu was reopened, however, mr-ab was isolated from a fourth patient. this patient was isolated, the icu closed, for a second time, thoroughly cleaned, and all contacts isolated until discharge. all subsequent patients screened were negative for mr-ab conclusion: this illustrates the importance of aggressive isolation measures and thorough supervised cleaning in control of an outbreak, and the need to screen patients for resistant bacteria before admission to the intensive care unit in a general hospital. extended spectrum beta-lactamase-positive bacteria isolated in neonatal intensive care unit pm216 sandorcinova z a , siegfried l a , kmetova m a , viragova s b . a institute of medical microbiology, faculty of medicine, university of p.j. safarik, kosice, slovakia , b hospital, kosice-saca, neonatal intensive care unit, kosice, slovakia extended-spectrum beta-lactamases hydrolyse all penicilins, cephalosporins, including third-generation cephalosporins and aztreonam. esbl are predominantly produced by klebsiella spp. but may be presented in other enterobacteriaceae, too. the aim of present study was to investigate the occurrence of esbl-producing bacteria isolated from patients hospitalized at the neonatal intensive care units (icu). fifty escherichia coli and 35 klebsiella spp. were isolated from rectum of patients hospitalized at the neonatal icu. the mics of antimicrobial agents were determined by the standard agar plate dilution method according to the nccls guidelines. for screening of esbl production we investigated strains showing reduced susceptibility (mic equal and/or more than 2 ml/l) to at least one of third generation cephalosporins. esbl production was detected by double disk synergy test (ddst), e -test for esbl, and pcr employing specific primers for the presence of blashv and blatem genes. by using ddst and e -test, among e. coli isolates, an expression of esbl was detected in the three by the former method, while among klebsiella spp. isolates, a production of esbl was found in the two by the latter method. in esbl-positive e. coli strains the presence of blatem genes fragments was detected while in esbl-positive klebsiella spp. genes encoding for shv-type beta-lactamases were found. isolation of staphylococci from wound swabs and their susceptibility to antibiotics pm217 markov mij, shopovski e, despotovski v, angelevski a, nikolovski b. military hospital, microbiology, skopje, the former yugoslav republic, macedonia purpose: to determine percent of staphylococci from wound swabs and to establish their susceptibility to antibiotics. material and method: the wound swabs have been evaluated with standards microbiological techniques. bacteria have been identified with strips from the 'atb expression' system. the susceptibility testing has been performed with strips with dilution technique, read by the same system. results: during the last 5 years (01 01 1997 á/25 02 2002), a total of 1978 wound swabs have been evaluated in the military hospital in skopje. positive bacterial finding have been determined in 1345 (68%) swabs with 1575 isolated bacterial species, from which 587 (37.3) were staphylococci: staphylococcus aureus 460 (29.2%) isolations (173 methycillin resistant s. aureus ); s. epidermidis 79 (5.0%); s. haemolyticus 21 (1.3%); s. hominis 11 (0.7%); s. chromogenes and s. lugdunensis nine (0.6%); s. intermedius , s. lentus , s. sciuri and s. warneri all with seven (0.4%) isolations. the susceptibility of s. aureus was to: penicillin 2%, ampicillin 15%, amoksicillin/clavulonic acid 67%, ceftazidime 66%, gentamicin 29%, tetracycline's 28%, erythromycin 61%, lincomycin 44%, ciprofloksacin 95%, cotrimoxazole 82%, vancomycin 100%, fusidic acid 96%, cefixime 57%, and azitromicin 78%. conclusion: in our study most frequently isolated bacteria from the wound swabs were staphylococci, especially s. aureus . susceptibility, except for the penicillin (2%), was high to other antibiotics. the study went on from january 1999 to december 2000. at maribor teaching hospital, 2288 staphylococcus aureus isolates were collected. in 1999, 114 (10%) and in 2000, 73 (6.4%) were mrsa. mrsa were recovered from routine clinical material and from surveillance swabs (nose, throat, skin). for isolation, conventional culture media were used and for surveillance swabs mrsa-screening plate (manitol salt agar with 6% oxacillin) and trypticase soy broth with 6.5% nacl were added. s. aureus was identified by catalase, dna-se and tube-coagulase test. antibiotic susceptibility was determined by the disk-diffusion method according to ncci guidelines. all 187 mrsa isolates were tested for sensitivity to the following antimicrobials: gentamicin, netilmicin, ciprofloxacin, erythromycin, chloramphenicol, tetracycline, cotrimoxazol, vancomycin and clindamycin. it was found that all mrsa isolates were sensitive to vancomycin and partially or totally resistant to the rest. there were no important differences between the years 1999 and 2000. our mrsa isolates were completely (100%) susceptible to vancomycin, but resistant to the other antimicrobials in use to some extent. although the monitoring of mrsa susceptibility to antimicrobials once a year did not show any important change in antimicrobial resistance, the periodical monitoring of mrsa susceptibility to antimicrobials and revaluation of current treatment regimens of mrsa infections is necessary. staphylococcus aureus strains with reduced susceptibility to vancomycin among clinical isolates in university hospital in warsaw pm219 the visa and especially h-visa are very difficult to be found in the routine laboratory. in our investigations we examined 1011 of s. aureus strains isolated and stored in our laboratory for several last years (1997 á/2001) . most strains were isolated in 2000, and some in 2001. for all staphylococcal strains mrsa as well as mssa the mics of vancomycin were performed by the standard dilution method. among strains isolated in the last year three strains were recognized as visa (mic values were 8 mg/l). the frequency of visa was 0.3%. in the aim of founding the h-visa strains the population analysis was used. for this analysis all strains growing on the concentration 4 mg/l of vancomycin from the inoculum 10 6 were chosen. it was 54 strains, but only 32 of them were recognized as h-visa. the frequency of h-visa among investigated strains was about 3%. most but not all of the h-visa and all visa strains were methicillin resistant. in vitro activity of vancomycin, teicoplanin and oxacillin against staphylococci isolated from patients of surgical intensive care unit pm220 kucukates e, karayel n, kansiz e. institute of cardiology, university of istanbul, istanbul, turkey objectives: oxacillin-resistant staphylococci have emerged as a major infection control problem in our hospital. the aim of this study was to evaluate the in vitro activity of vancomycin, teicoplanin and oxacillin against staphylococci. material and methods: this study was performed between january 2000 and december 2001, at university of istanbul, institute of cardiology. the antimicrobial susceptibilities of 179 staphylococci isolates for vancomycin, teicoplanin and oxacillin have been investigated by e -test according to nccls guidelines. results: fifty-five (30.73%) of 179 clinical isolates were staphylococcus aureus . one hundred and twenty-four (69.27%) of 179 clinical isolates were coagulase negative staphylococci (cns). none of 179 staphylococci isolates were resistant to vancomycin. but three of cns isolates were intermediate and six of cns isolates were resistant to teicoplanin. twenty-eight (50.9%) of 55 s. aureus were resistant to oxacillin. ninety (72.60%) of 124 cns isolates were also resistant to methicillin. conclusions: nosocomial staphylococcal infections, especially in intensive care units increase day by day. staphylococcal infections are a major problem in many hospitals. according to our experiences the rate of oxacillin resistant staphylococci isolates in our hospital has also increased. methicillin-resistant staphylococcus aureus (mrsa) is a clinically significant pathogen because mrsa is resistant to many kinds of antibiotics and causes nosocomial infections around the world. the antiseptics are used for prevention of infections by mrsa. antisepticresistant mrsa strains have been isolated from clinical specimens. antiseptic resistance genes confer resistance to many kinds of drugs structurally and the resistance mechanism is the energy-dependent drug efflux system. in addition, the fluoroquinolone (fq)-resistance gene, nora , confers also resistance to many kinds of antiseptics. we studied the relation of the susceptibility to antiseptics and fqs of mrsa strains isolated in japan. a total of 420 strains of mrsa were isolated from 14 hospitals in japan from 1998 to 1999. acriflavin (af), acrinol, benzethonium chloride, benzalkonium chloride and chlorhexidine digluconate were used as the antiseptics. norfloxacin and sparfloxacin were also used in this experiment. the mic was determined by agar double-dilution method as recommended by the nccls. about 65% of mrsa showed resistance to af (mic: !/64 ug/ml). no strain was resistant to a specific antiseptic. fq-susceptible strains were susceptible to all antiseptics. this study showed that antiseptic-resistant mrsa are widely spread at hospitals in japan. the drug of choice in treatment of serious infections caused by mrsa was still vancomycin, however sometimes failures were observed, especially in monotherapy. some conflicting are present in literature about an effect of combined action of vancomycin and betalactams. in the present work, the common effect of vancomycin and methicillin against chosen staphylococcus aureus strains was examined. the investigated strains were characterized as visa, h-visa and clones obtained from h-visa in population analysis. two methods were performed: e -tests with methicillin and vancomycin placed on the media supplemented with the second antibiotic and the chessboard micro-analysis with increasing concentrations of both antibiotics. the fic indexes were calculated for different combinations of concentrations. on the basis of the fic indexes it was shown that the simultaneous action of vancomycin and methicillin was synergistic in all examined strains visa and h-visa, but only in appropriate concentrations. in different combinations the observed effect was addition or indifference. antagonism was never observed. the synergistic effect was not observed in the case of standard s. aureus strain sensitive to methicillin. supplementation of media with 4% of nacl substantially decreased the observed effect. incidence of antibiotic resistance in staphylococcus aureus strains in hungary with special reference to mrsa pm224 ghidán á , maró di c, csukás z, kamotsay k, szabó d, ostorházi e, rozgonyi f. institute of medical microbiology, semmelweis university, budapest, hungary between january 1997 and december 2000, a total of 3109 staphylococcus aureus strains isolated from patients admitted to the clinics of the semmelweis university were examined for antibiotic sensitivity with the disc diffusion test. resistance to individual antimicrobials were as follows: penicillin 84%, oxacillin 25%, erythromycin 31%, ciprofloxacin 15%, amikacin 12%, netilmicin 8%, tobramycin 10%, gentamicin 20%, clindamycin 22%, mupirocin 4%, tetracyclines 34%, chloramphenicol 9%, teicoplanin 2% and vancomycin 0%. all mrsa were b-lactamase producer. they showed coresistance to erythromycin (53%), ciproflxacin (36%), amikacin (29%), netilmicin (23%) and mupirocin (10%). multiple resistant mrsa strains to mupirocin'/tetracyclines'/chloramphenicol amounted to 0.9%. triple resistance to oxacillin'/ciprofloxacin'/netilmicin was 14%. the detection of meca gene by pcr in randomly chosen mrsa qualified with 1 mg oxacillin disc resulted in only 15% meca positivity indicating that the traditional disc diffusion test overestimates the frequency of mrsa strains particularly in such an environment where the usage of penicillins and cephalosporins is so liberal as in hungary. consequently, the selective pressure for blactam-resistance and b-lactamase induction exists everywhere. this conclusion is coherent with the relatively low frequency of multiple resistant mrsa strains and urge the need of a routinely available genetic method to apply for mrsa detection. objectives: the main objectives of this study were to monitor antibiotic resistance, identify new/emerging resistance mechanisms at an early stage, prevent their dissemination, early detection and prevent the outbreaks. methods: our laboratory used antibiotic disc sensitivity testing methodology (nccls 1993) . zone sizes were measured objectively using a biomic automated radius zone reader. results: throughout 2 years (january 1999 till december 2000) we have surveyed 3190 organisms collected from outpatient departments (1145, 35.8%), radio-oncology department (992, 31.1%), medical department (765, 23.9%), obg department (217, 6.8%), surgical-oncology non icu department (207, 6.5%), icu department (175, 5.5%). from 1543 (100%) strains of enterobacteriaceae 68 (4.4%) were resistant to 4th generation fluoroquinolone and 44 (2.9%) strains were esbl positive. from 416 (100%) strains of staphylococcus aureus were only five (1.2%) strains resistant to methicilin (mrsa). we collected 370 (100%) strains of enterococci, whereabout only two (0.5%) were resistant to glycopeptides (vre). from 235 (100%) strains of pesudomonas aeruginosa , 97 (41.2%) were resistant to aminoglycosides. conclusions: national restrictive antibiotic policy hand in hand with local hospital antibiotic policy and regular rotation of antibiotics used in prevention and treatment on all departments is leading in our case in positive situation in antibiotic resistance in comparing with other slovakian and european centers. antimicrobial resistance of nosocomial strains of staphylococcus aureus pm226 dekhnich av, stratchounski ls, edelstain ia, narezkina ad. institute of antimicrobial chemotherapy, smolensk, russian federation purpose: to determine the antimicrobial resistance of staphylococcus aureus causing nosocomial infections in smolensk regional hospital. results: a total of 140 s. aureus strains isolated during 2000 á/2001 were studied. antimicrobials tested included oxacillin (oxa), erythromycin (ery), clindamycin (cli), gentamicin (gen), vancomycin (van), linezolid (lnz), tetracycline (tet), chloramphenicol (chl), rifampicin (rif), fusidic acid (fus), trimethoprim/sulfamethoxazole (ts), ciprofloxacin (cip), mupirocin (mup), quinupristin/dalfopristin (qd). susceptibility testing and its interpretation were performed by agar dilution according to nccls guidelines where applicable. results are presented in the conclusions: the most active antimicrobials were vancomycin, linezolid, quinupristin/dalfopristin, fusidic acid, mupirocin, followed by co-trimoxazole, rifampicin. beta-lactams, macrolides, lincosamydes, tetracyclines and chloramphenicol should not be used for the treatment of nosocomial s. aureus infections. we investigated all staphylococcal infections within 2 years among 246 neonates hospitalized for infection in the neonatal icu in a tertiary neonatal referral center. univariate analysis, to assess risk factors for neonates infected with staphylococcus aureus (121) vs. without s. aureus (125) was performed. from the total number of 246 cases, in 121 cases s. aureus was isolated from various samples; in 16 cases from blood cultures, in 36 cases from urine, in 18 cases from eye swabs and in 29 cases from gastric content (no significant differences in comparison with control group). colonization with s. aureus , was a predictor of infection: nasal swabs, throat swabs, ear swabs, skin swabs and umbilical swabs were significantly more commonly observed in neonates infected with s. aureus , than with other infections. etiological analysis showed that co-pathogens escherichia coli and viridans streptococci were significantly more frequently associated with neonatal infection caused by s. aureus , in comparison to other organisms. according to localization of infection site, conjunctivitis and thrush stomatitis was the commonest s. aureus neonatal infections. outcome was similar to other infections and without any significant differences between both groups. mortality was similar to other infections, probably because: initial therapy in our centre contains an antistaphylococcaly active agent (cefuroxime or cefotaxime plus aminoglycosides). morozova ot, semina na. laboratory of hospital infections, central research institute of epidemiology, moscow, russian federation purpose is to study the role of enterococcus spp. in the aetiology of nosocomial infections among the patients of the childrens clinical hospital and susceptibility of these strains to antibiotics. methods: the strains of enterococci were isolated from 66 patients with hospital infections in 2000 á/2001. results: the aetiological structure of enterococcus -infections showed the predominance of skin and soft tissue infections (39.4%), urinary tract infections (33.3%), bloodstream infection (10.6%), pneumoniae (4.5%), infection of central nervous system, gastrointestinal tract, eye, surgical wound infections were of rare incidence (3 á/ 1.5%). various nosological forms of infections were caused more often by e. faecalis than e. faecium (72.7, 27.3%). the antibiotic resistance to ampicillin and other beta-lactams occured in 100% of e. faecium isolates, but all strains of e. faecalis were susceptible to these drugs. high-level gentamicin resistance demonstrated e. faecalis isolates */ 29.0%, e. faecium */100%; and high-level streptomycin resistance showed e. faecalis */67.7%, e. faecium */88.8%. all the e. faecalis were active against fluoroquinolones, but e. faecium were resistant in 22.0%. there were no vancomycin resistant enterococci. conclusion: e. faecalis predominated in the aetiological structure of nosocomial infections due to enterococcus spp. antibiotic resistance patterns for two species of enterococci were different, all the strans were susceptible to vancomycin. evaluation of antimicrobial resistance of enterococcus spp. experience of 6 years (1996 á/2001) pm229 lopez-barba j, jesus de la calle i, solino-ocañ a i, rodríguez-iglesias m, perez-ramos s. microbiology laboratory, puerto real university hospital, cádiz, spain objective: determination of quantitative changes in antimicrobial resistance of enterococcus isolated from clinically significant not urinary samples of patients remitted to the laboratory of microbiology during a 6 years period (1996 á/2001) . material: the period of the study was comprised between 1996 and 2001. the samples has been processed for the isolation of enterococcus following conventional methods. were isolated 3424 enterococci strains. the identification and susceptibility to antibiotics have been performed in automated system microscan(c) dade-behring(c) through panels combo cgp. the data were processed by the statistical system statgraphics plus 4.1. results: of the 3424 enterococcus , have been identified 3298 e. faecalis and 126 e. faecium . the resistance is shown in table 1 . conclusions: the resistance to va and tei of e. faecalis remains through last 4 years (2 á/3%). the high resistance to erythromycin and tetracilin ( !/70%) and the resistance (30 á/31%) to quinolones, antibiotics all of them used in community-acquired infections justify the susceptibility testing to the clinical strains isolated of this group of microorganism. in e. faecium the antimicrobial resistances was high and increasingly to imipenem, meropenem, erythromycin and quinolones. characteristics of strains e. faecium colonizing the neutropenic patients pm230 abbassi ms, achour w, gréco a, ben hassen a. laboratory of bone marrow transplant center, tunis, tunisia digestive colonization by enterococcus faecium in the neutropenic patients under gut decontamination is important. seventeen multiresistant strains of e. faecium isolated from stools of seven neutropenic patients were the target of an epidemiological analysis through the determination of the mics of amoxicillin, gentamicin, vancomycin, the transferability gentamicin resistance to the recipient strain e. faecalis jh2-2 by filter-mating assay, analysis of plasmid profiles of e. faecium -strain and of transconjugants and the amplification by pcr of the gene aac(6?)-aph(2??) coding for the bifunctional enzyme by using primer m13771 who gives a fragment of 174 kb. among the seventeen strains, eleven had the same antibiotype a1, 12 had a gentamicin mic!/4096 mg/l. the mic90 of the amoxicillin was of 128 mg/l. all the strains were sensitive to vancomycin. ten strains harbored a plasmid of 70 kb transfered at a frequency of 6.10 á/5, also found in gentamicin-resistant transconjugants. however, strains belong to nine distinguished plasmids profiles. all high-level gentamicin resistant-strains had a positive pcr amplification of the aac (6?)-aph (2ƒ) gene. the features of the studied strains establish their endogen origin, specific for every patient, sharing only high-level resistance to gentamicin. gut decontamination treatment with gentamicin enhance either the spread and the preservation of easy-transferable plasmid carrying genetic transposable element. frequency and antibiotic resistance of bacteria isolated from patients suffering infectious complications following the implantation of prosthetic devices pm231 kristó f k, rozgonyi f. institute of medical microbiology, semmelweis university, budapest, hungary for patients with indwelling joint prosthesis, early recognition and prompt therapy for infection in any location may be critical to reduce the risk of seeding the joint implant heamatogenously. a year period (2001) a total of 2440 swabs of aspiration from patients with infectious complications following the implantation of prosthetic devices were cultured. cultivation and identification of the strains were performed by conventional methods and by vitek system (biomȇrieux) and susceptibility testing by disc diffusion. potentional pathogens were recovered in 324 cases (13.27%). gram positive cocci, in particular staphylococcus spp. proved to be the most commonly isolated bacteria. coagulase-negative staphylococcus (cns) was isolated more frequently (48%), followed by s. aureus (28%), enterococcus faecalis and e. faecium (11%), gram-negatives (3%), anaerob isolates (7.5%). resistance to individual antimicrobials of s. aureus and cns were as follows: methicillin 8 and 47%, clindamycin 4.5 and 21.7%, fluoroquinolones 0 and 18%. mupirocin resistant strains of s. aureus were not found, while 7.7% were among the cns strains. our results could be essential for the rational selection of treatment at our orthopedic wards. results: in the analysed period the percentage of isolated enterococcus sp. strains among all non-repetitive clinical isolates in 1999, 2000 and 2001 was 3.9, 3.1 and 51%, respectively. cultured strains were identified as e. faecalis, e. faecium, e. gallinarum and e. avium . the most prevalent was e. faecium strains, isolated with a frequency of 75, 62 and 75%, respectively. vancomycin-resistant strains were all identified as e. faecium and in 2001 they comprised 17% of all isolates of this species. conclusions: (1) the frequency of isolation of enterococcus sp. in blood cultures of haematological patients remained relatively stable in 1999 á/2001. (2) the predominant enterococcal species isolated from these patients was e. faecium . (3) in 2001 we recorded for the first time an emergence of vancomycin-resistant e. faecium , which comprised 17% of all isolates of this species. kalai s, ben hassen a, achour w, greco a. laboratory of microbiology, national bone marrow transplantation center, tunis, tunisia from april 1998 to june 2000, 47 non-repeated strains of pseudomonas aeruginosa were isolated from 42 immunocompromised patients. thirty-six percent of strains were isolated from abscess, 27% from blood culture and 11% from urine. susceptibility to antibiotic was studied by the routine disk diffusion method (ca-sfm). mics were determined using agar dilution to 11 antibiotics (5b-lactams, four aminosides and two fluoroquinolones). serotyping of the different trains was performed using antisera to the international antigenic typing systems serotypes. the study showed 80% of resistance to c cochin port royal hospital, service de gynecologie-obstetrique site st vincent-de-paul, paris, france , d cochin port royal hospital, cclin, paris, france aims: to determinate risk markers of an outbreak of postpartum endometritis due to group a streptococcus . design: a case-control study using data collected with a structured form. setting: the cases of postpartum endometritis were diagnosed in the department of obstetric of the paris hospital network during 5 days (december 1999 á/january 2000). the group of controls consisted of women delivered in the same department during the same period. participants: cases (n0/3) and controls (n0/59). findings: cases had smoked more often during pregnancy (67 vs. 16%; p 0/0.089) and received more often immunosuppressive treatment than controls (33 vs. 0%; p 0/0.060). instrumental delivery has been needed more often for cases than controls (67 vs. 13%; p 0/0.062). cases had been hospitalized after delivery in a ward z of the department more often than controls (100 vs. 23%; p 0/0.017). they had been examined after delivery more often by a midwife x (100 vs. 18%; p0/0.009) and a nurse y has provided care to cases and not to controls (33 vs. 0%; p 0/0.051). conclusion: smoking, receiving immunosuppressive treatment during pregnancy, and instrumental delivery were significantly associated with postpartum endometritis (pb/ 10%). a midwife and a nurse might be involved in the transmission of the infection. petoukhova i a , sokolova e a , dmitrieva n a , nummaev b b . a laboratory microbiology, cancer research center of russia, moscow, russian federation , b department of oncogynecology, cancer research centre, moscow, russian federation the aim of the study was to assess efficacy of perioperative ap. total 241 pts were included. two hundred and one pts with cervical cancer (cc) undergone extensive hysterectomy, 22 pts with cancer of vulva (cv)-extensive vulvoectomy, 18 pts with ovarian cancer (oc) á/ extensive/combined operations. fifty-one pts (group 1) received ap with amoxicillin/clavulanate (am/cl) 1.8 g iv 30 min prior to operation, then 1.2 g iv thrice per day for 3 á/5 days. fifty pts (group 2) received cefotaxime (ctx) 2 g iv 30 min prior to operation, then 1 g four times per day for 3 á/5 days'/metronidazole (mtz) 500 mg two times per day for the same period. one hundred and forty pts were retrospective control (they received ii á/iii generation cephalosporins or linkosamides only after operation). the rate of swi in pts with cc, cv and oc was 13.5, 73, 29%, respectively; dwi */16.2, 0 and 21%, respectively; uti */72, 80, 42.8%, respectively. the ap with am/cl was more effective compared to ctx'/mtz (swi */6 vs 18%, respectively, pb/ 0.05, dwi */9.8 vs 14%, respectively, p b/ 0.05). the rate of postoperative uti was equivalent in two groups (62 vs 74%, p 0/n.s.). thus, ap with am/cl is preferrable option in extensive operations in og pts. fifty-eight patients were randomized into two groups. group 1, a treatment consisting of 31 patients and group 2, consisting of 27 patients as a control. the patients were at the age of 679/1.2 and had had different surgical interventions with general anaesthesia from 1 to 3 h and accompanying copd (89%). artificial pulmonary ventilation was used in 45 cases. in the early post-surgery period the patients of group 1 were administered inhalation therapy, including ipratopium of bromide in the combination with fenoterol (atrovent, berodual) and ambrocsol (lazolvan) through a nebulizer. the inhalation therapy was not administered to the patients of group 2. under the influence of the inhalation therapy pulmonary ventilation and respiratory metabolism was restored faster in all the resuscitation patients (in group 1 */by the end of the first 24 h, in group 2 */on the 3rd á/4th day). the percent rate of pef1 was 76.7'/4.1 and 56.4'/4.5, respectively. artificial pulmonary ventilation ended in 9.2 and 7.3 h, respectively. the time of the patients' stay in the resuscitation department was 3.2 days in group 1 and 4.6 days in group 2. by the end of the 1st week pneumonia developed in one patient from group 1 and in eight patients in group 2. aerosol therapy application accelerates medication delivery to the respiratory tracts, increases the local activity and effects good prophylaxis for surgical hospital pneumonia. variation in ethiology of early and late onset ventilator associated pneumonia pm250 nikolopoulos j, daganou m, michailidou m, karabela e, kavada k, retsou s, antoniadou a, rasidakis a. department of respiratory abstracts s100 failure and icu, sotiria general and chest disease hospital, athens, greece purpose: to compare the distribution of causative microorganisms, their susceptibility to antibiotics and outcome of 'early' and 'late' vap in a greek icu. methods and results: retrospective study of mechanical ventilated (mv) patients (pts) with early and late vaps during a 6-month period. diagnosis of vap was made by clinical, radiographic criteria and quantitative cultures of bronchial secretions. vap was diagnosed in 17 pts (26%) out of 67 consecutive admissions in icu. all pts before the development of vap received antibiotics. three episodes of vap (17.6%) were developed before the 7th day of mv (early vap) and were caused: (1) by multi-resistant acinetobacter; and (2) by antibiotic-susceptible pseudomonas aeroginosa . in this group one pt died from septic shock related to vap and two pts survived. fourteen pts (82.4%) developed vap after the 7th day of mv (late vap). five cases were caused by multi-resistant p. aeroginosa , two cases by mrsa, two cases by multi-resistant acinetobacter, two cases by susceptible to antibiotics klebsiella pneumoniae , and three were polymicrobial and caused by multi-resistant microorganisms (mrsa and gnb). four pts died (28.6%) from septic shock related to vap, five pts (36%) died because of another cause and five pts (36%) survived. conclusions: early and late onset episodes of vap were caused by 'potentially drug-resistant bacteria'. p. aeroginosa as a cause of early vap was susceptible. mortality attributed to early and late vap was similar. antibiotic prophylaxis in oncological and major reconstructive orthopaedic surgery pm251 de biase p, ciampalini l, astone a, capanna r. azienda ospedaliera careggi, oncological and reconstructive centre, aoc, florence, italy during last year patients scheduled for oncological surgery or major reconstructive procedures were randomised to either vancomycin or teicoplanin prophylaxis. prophylaxis was performed with either vancomycin 1 g i.v. twice daily or teicoplanin once daily 400 i.v. two hundred patients were included. four patients did not agree the study protocol and were excluded. we treated 98 patients with teicoplanin and 98 patients with vancomycin. out of the 196 patients 117 were operated for oncological disease, while the remaining 79 underwent major orthopaedic procedures. we experienced 10 cases of red man syndrome, and five cases of moderate hypotension. five patients had postoperative complications: two deep venous thrombosis, one pulmonary embolism, two postoperative haematoma. in five patients we observed a wound dehiscence; two of these patients showed clinical sign of ssi and microbiological examinations were positive for mrsa. one patient recovered from infection with medical therapy, while the other patient showed a local tumour recurrence and was amputated at the thigh. at last surgery infection was still present clinical and at microbiological examination. in conclusion we had an infection rate of 1.02% which is comparable to the infection rate of a 'clean' surgery in patients with normal risk of infection. teicoplanin showed lower toxicity, has a longer half-life and has a simpler way of infusion and it is our current choice in high risk surgery. injuries with contaminated sharp articles in health care workers in general hospital celje, slovenia pm252 lesnicar g, sibanc b. department of infectious diseases, medical center celje, celje, slovenia in a prospective study carried out from january 1997 till june 2001, we registered 133 subcutaneous injuries with sharp objects, mostly in nurses and cleaning service workers. in 19% of cases the incident occurred outside the hospital, in persons who were not medical workers. in 69 cases the injury causing object was a needle that had been used in known patients, 14 of which were hepatitis b positive. fifty-five (48.2%) of the injured health workers had been previously vaccinated against hepatitis b; the protective antibodies to hepatitis b in the blood were found in 35/114 (30.7%) health workers only, while the tests for antibodies to hepatitis c and hiv were negative in all cases. following the incident, the majority of the injured persons, i.e. 102, were vaccinated against hepatitis b, while 46 persons (34.6%) also received passive prophylaxis with human immunoglobulin against hepatitis b. none of the injured persons have developed the disease or showed evidence of sero-conversion. in the year 2000 the general as well as specific preventive measures practised in our hospital became more rigorous. thus, approximately 80% of our health workers at risk have already been vaccinated against hepatitis b. to improve measures preventing dissemination of multidrug-resistant bacteria (mrb), a cross-sectional survey (2000) was conducted to analyse healthcare workers' (hcws) isolation precaution knowledge for mrb infection at 21 investigation and outpatient departments excluding four declaring not to be involved in care to mrb patients (emergency, obstetrics, nuclear medicine, and bacteriology). two hundred and eight hcws answered (67% of the paramedical staff, 28% of the physicians). thirty-three percent of them reported they do not know frequently or always the patient mrb status. they (82%) wish mrb status to be mentioned on the test form or on the advice request letter. mrb patient visit or test was appropriately timed in 62% answers. gowns (61%) or masks (58%) use were not systematically reported. other hcws (74%) reported better isolation precaution knowledge than physicians (58%) and nurses (81%) than investigation assistants (58%). physicians declared lower compliance with use of gowns, gloves or draw-sheets than other hcws. they had also lower education in isolation precautions and were less interested in education programs. this study suggests the necessity to improve mbr infection information. physicians and investigation assistants seem to be insufficiently aware of hospital infection control. therefore, education strategies targeted at physicians and investigation assistants working at outpatient and investigation departments should be developed. outbreak of clostridium difficile -associated diarrhoea in infectious disease department: risk factors and hygiene measures assessment pm254 henoun loukili n, martin m, remy v, hansmann y, christmann d. hôpitaux universitaires de strasbourg, maladies infectieuses et tropicales, strasbourg, france (shock)'/4* (bedridden status)'/4* (age !/65 years)'/3* (previous antibiotic treatment) and points (women)0/6* (shock)'/4* (bedridden status)'/4* (age !/65 years)'/3* (immunosuppression). the vast majority of patients (89 and 87% of males and females, respectively) could be classified in the subgroups with lower scores (six points or less) which had a very limited risk of death (0 á/2.5 and 0 á/2.3% for men and women, respectively), whereas for patients in the highest score subgroup (11 points or more), the risk was 100% for men and 91% for women. conclusion: risk stratification of patients with ap is possible from simple clinical variables available on admission. procalcitonin (pct) and c-reactive protein (crp) for differentiation of systemic inflammatory response syndrome (sirs), sepsis and severe sepsis pm259 lupse m a , ursu l b , slavcovici a a , carstina d a . a clinical department, teaching hospital of infectious diseases, cluj-napoca, romania , b laboratory department, teaching hospital of infectious diseases, cluj-napoca, romania objectives: to evaluate the value of pct in the differentiation of patients with sirs, sepsis, severe sepsis and bacteremia in comparison to crp. design: prospective study including patients who meet criteria for sirs, sepsis or severe sepsis (consensus conference of the accp/ sccm) admitted over 18-month period. patients and method: a total of 67 patients were included: eight with sirs, 35 with sepsis and 24 with severe sepsis. sixteen from 59 patients had bacteremia. pct and crp were evaluated in the first 24 h after admission: pct by brahms pct-q test and crp by turbidimetric assay. the sensitivity, specificity, predictive value of different cutoff points for crp and pct were determined. results: with a cut off point of 0.5 ng/ml for pct and 0.6 mg/dl for crp sensitivity and specificity for sepsis were 73%, respectively 75% (ppv 95.6, npv 27.3) and 96%, respectively 17% (ppv 87.2, npv 75). a cutoff point of 2 ng/ml for pct accurately predict severe sepsis (sensitivity 80%, specificity 100%, ppv 100). a pct level of at least 10 ng/ml was a good predictor for bacteremia (sensitivity 86%, specificity 90%, ppv 73.7 and npv 95). conclusion: pct is a good discriminating marker to characterize the level of inflammation caused by infection and can predict bacteremia . giamarellou h a , aoun a b , klastersky j b , anagnostopoulos n c , galani l c , grecka p c , panaretou e c , papageorgiou e c , repoussis p c , syrseloudis pct has been considered as a useful diagnostic marker in neutropenic patients with bacteremia and/or severe sepsis (giamarellos-bourboulis ej et al. clin infect dis 2001; 32:1718) . in an attempt to define its value in the diagnosis of localized infections in neutropenic hosts, daily determinations of pct and of c-reactive protein (crp) were performed before and after the onset of fever in 50 subjects 27 male and 22 female aged 48.69/18.7 years with various haematologic malignancies (aml 26, nhl 17, mds 5, all 2) developing neutropenia ( b/500 pmns/mm 3 ) after chemotherapy. thirty-three patients were presented with fever of unknown origin (fuo) and 17 with localized bacterial infections (lbi; pneumonia 7, acute pyelonephritis 4, soft tissue infections 3, acute pharyngitis 3). pct was determined by an immunoluminometric assay and crp by nephelometry. it is concluded that febrile neutropenia followed by a localized bacterial infections is accompanied by significantly higher levels of pct than in case of fuo (47.99/3.64 vs 0.519/0.16 ng/ml). similar differences are not observed with crp, which lacks the appropriate specificity. our study included 35 patients who were categorized as having proven (9), probable (11), or possible (5) systemic fungosis according to eortc criteria; 10 showed no sign of infection, and were used as controls. blood samples were received on the 1st, 3rd, and 5th day from the onset of signs of a fungal infection, and then twice a week. pct levels were determined by an immunochemioluminent assay, and candida and aspergillus antigen levels by elisa. in only five patients pct indicated early signs of infection, albeit at barely detectable limits. six patients, however, showed significantly increasing titres preceding time of death. positive antigens titres were observed only in 10 patients who had proven or probable systemic fungosis. only half of the control group had negative antigen titres; a high rate of false negatives was also observed. both pct and antigens titres increased in parallel in 4/6 patients with unfavorable outcome. pct and antigens titres cannot reliably indicate early diagnosis of systemic fungal infections although may be used as a prognostic tool of severity. lactulose, a factor that decreases endotoxaemia, in obstructive jaundice? pm262 koutelidakis im a , papaziogas v a , makris i a , giamarellos-bourboulis ej b , giamarellou h b , papaziogas t a . a thessaloniki med school, 2nd surgical clinic, thessaloniki, greece , b 4th department internal medicine, athens medical school, athens, greece bacterial translocation is a process implicated in the pathogenesis of spontaneous peritonitis. in order to evaluate the impact of lactulose administration on systemic endotoxaemia, obstructive jaundice was induced in 11 rabbits by common bile duct ligation. animals were divided into two groups, group a of five rabbits not receiving lactulose and group b of six rabbits, which received 1.5 ml/kg of lactulose orally by an oral catheter. blood was collected daily, before and after operation for a total duration of four days. samples were applied for culture and for determination of endotoxins (lps) by the lal qcl-1000 assay. concentrations of lps (mean9/sd) of group a were 1.159/0.74, 2.249/0.74, 1.609/0.81 and 2.349/0.70 eu/ml on the 1st, 2nd, 3rd and 4th day, respectively. respective concentrations of lps (mean9/sd) of group b were 0.849/0.28, 0.659/0.12, 0.819/0.20 and 0.609/0.42. all blood cultures were sterile in both groups. differences activity of linezolid against nosocomial strains of staphylococcus aureus in russia: results of multicentre study pm221 were included in the study. antimicrobial susceptibility testing was performed by agar dilution method in accordance with the nccls recommendations. all tested strains including 295 mrsa strains (33.6% of all strains) were found to be susceptible to linezolid with the mic ranged from 0.5 to 4 mg/l. both mic 50 and mic 90 were 2 mg/l. conclusions: linezolid had excellent in vitro activity that was not affected by resistance to other classes of antimicrobials susceptibility to antiseptics of mrsa isolated in japan during 1998 á 60% to piperacillin, 55% to ceftazidime, 71% to cefepime, 13% to imipenem, 51% to amikacin and 55% to ciprofloxacin. fiftythree percent of p. aeruginosa strains were multiresistant (25 strains) and were isolated in 12 patients. wild phenotype to b-lactams was observed in 30% of strains. the most frequent b-lactams resistance phenotypes were: cephalosporinase over production (34%) and penicillinase (11%). imipenem, ceftazidime and piperacillin-tazobactam were the most active b-lactams (mic 50 of 4.16 and 32 mg/l, respectively) these results showed high rates of antibiotic resistance and predominance of o11 serotype in multiresistant strains compared to the o12 serotype in europe. infectious complications sustained by stenotrophomonas (xanthomonas ) maltophilia in hiv at present, very limited informations are available about s. maltophilia infections in the setting of hiv disease. patients and methods: a retrospective survey of clinical and microbiological records of 1374 hiv-infected patients referring to out tertiary care centre between 1991 and 2000 was performed, in order to identify all episodes of s. maltophilia infections, and analyze its epidemiological, clinical, and microbiological variables. results: sixty-one episodes of s. maltophilia infection were observed in 59 patients: sepsis/bacteraemia in 48 cases (78.7%), lower airways infection in five, urinary tract infection in four, pharyngitis in two, lymphadenitis and liver abscess in one case each. forty-seven out of 61 episodes of s. maltophilia infections (77%) occurred as nosocomial disease, generally in association with advanced immunodeficiency, neutropenia, instrumentation, and prior antimicrobial therapy. bacterial isolates showed an elevated resistance profile against many betalactam compounds, aztreonam, imipenem, and aminoglycosides. conclusion: s. maltophilia represents an emerging opportunistic pathogen in hiv-infected patients extended spectrum beta-lactamases producing germs in intensive care units pm235 university of medicine and pharmacy 'victor babes ', microbiology, timisoara, romania injury and complications lasted 22 months, demanded for 11 surgical procedures and total cost was 1 comparison of different methods for detection of extended spectrum beta lactamases (esbls) and their genetic relatedness among enterobacteriaceae clinical isolates in a research medical institute pm242 methods: one hundred out of 178 isolates that were screened positive for esbls were tested with double disk synergy test (ddst), three dimensional test (tdt), e -test-esbl and vitek-esbl test. pulsed field gel electrophoresis (pfge) analysis was applied to 13 esbls; five klebsiella pneumoniae and eight escherichia coli . results: revealed the prevalence of esbls in 25.8% of clinical isolates. the sensitivities of the ddst, tdt, e -test and vitek were 100, 73, 86.9 and 47.8%, respectively. in the ddst, aztreonam was the most sensitive indicator (93.4%). pfge demonstrated that 80% of k. pneumoniae were derived from a single clone whereas 62.5% of e. coli isolates were derived from two different clones. non-clonal origin was demonstrated in 20% of k. pneumoniae and 37.5% of e. coli . conclusion: there is an increased prevalence of esbls. the ddst is the most sensitive, practical and cost effective diagnostic method reliable for routine use in our laboratory. both clonal spread and plasmid dissemination contributed to the concurrent nosocomial outbreaks caused by esbl-producing k severe nosocomial infections due to stenotrophomonas maltophilia pm243 the teaching hospital of infectious diseases total 241 og pts after extensive hysterectomy (201 pts), extensive vulvoectomy (22 pts) and extensive/combined operations for ovarian cancer (18 pts) were analysed. ic developed in 74 pts. one hundred and sixtyseven pts had no ic. twenty-eight of 50 rf analysed were independent rf of ic. most important included: age !/50 years (p0/0.0002), grade 2 á/3 obesity (p 0/0.0002), diabetes mellitus (p 0/ 0.0002), diagnosis of cervical cancer (p 0/0.0001), history of pre-cancer of vulva postpartum endometritis due to group a streptococcus : a case-control study pm247 unite operationnelle d 'hygiene all isolates were sensitive to vancomycin. among gram-negative bacteria klebsiella spp. was isolated in 21.6% of cases, acinetobacter baumanii in 13.5%, enterobacter spp. in 8.1%, providencia spp. in 2.7%. of the klebsiella spp. isolates 25% were resistant to amikacin, 85% to cephalosporins, 87% to piperacillin/ tazobactam. all were sensitive to imipenem. of the a. baumanii isolates 100% were resistant to amikacin, aztreonam, cefoperazone, cefotaxime, ceftriaxone, piperacillin; 60% to ampicillin-sulbactam, 80% to ceftazidime, and 40% sensitivity to imipenem antimicrobial activity of selected pharmacopoeial antiseptics analysed according to european standards pm270 european committee for standardisation approved several european standards (en), describing test methods establishing, whether an antiseptic has or does not have a bactericidal or fungicidal activity under the laboratory conditions defined by en. the aim of the study was to investigate, if some chemical compounds in concentrations recommended by polish pharmacopoeia for skin disinfection, comply european standards requirements. methods: basic bactericidal (en 1040) and fungicidal (en 1275) activity were investigated as well as bactericidal activity of products for hygienic and surgical handrub and hand wash used in human medicine (pren 12054). all methods and used neutralizers were validated. standard strains: staphylococcus aureus , pseudomonas aeruginosa , escherichia coli , e. hirae , candida albicans and a. niger were used, when en standards were evaluated. results: ethanol, izopropanol and n -propanol caused viable microbial count reduction required by ens in pharmacopoeial concentrations the purpose of the study: we collected 226 bacteriological samples from adult and neonate patients who were admitted in intensive care units (icu) . the aim was to observe the colonization status with microbes that may have a nosocomial potential and to establish circulating phenotypes in icus. the results obtained from a total of 226 samples 61 strains of gram negative bacteria (enterobacteriaceae family) were isolated. fourteen strains showed extended spectrum beta-lactamases (esbl) phenotype (eight strains of klebsiella pneumoniae , three of escherichia coli , two of klebsiella ornithynolitica , one of klebsiella oxytoca ). we used both disc diffusion test (extended antibiotic susceptibility test and synergy test to visualize 'champagne stopper' pattern) and mini api † system.the conclusion reached: we put in evidence a massive colonization with germs that may have a nosocomial potential especially microbes that produce esbl (22.9% from all enterobacteriaceae isolated) which implies a rational policy in prescribing antibiotics in hospitals from western part of romania.carbapenem activity against nosocomial gram-negative rods pm236sawicka-grzelak a a , rokosz a a , meszaros j b , luczak m a . a department of medical microbiology, university medical school, warsaw, poland , b department of general and transplantation surgery, university medical school, warsaw, poland purpose: to determine a susceptibility of nosocomial gramnegative rods to carbapenems.methods: two hundred strains of gram-negative rods were cultured from clinical specimens from hospitalized patients (july á/november 2001). identification of strains was performed in the automatic atb system (biomerieux, france). susceptibility of strains to carbapenems: imipenem and meropenem was determined with disc diffusion method according to nccls recommendations. esbl-producing strains were detected with double-disc synergy test (ddst according to jarlier et al., 1988) or a novel method of esbl detection (dd, diagnostic disc) according to appleton (1999) . two discs were applied in this test: with cefpodoxime (cpd) and with cefpodoxime/clavulanic acid (cd 01) (oxoid, england) .results: one hundred and ten strains of enteric rods and 90 strains of non-fermenting rods were cultured. twenty eight (14%) esblpositive strains were detected. carbapenems were active against 96% of enteric rods. the percentage of non-fermenting rods susceptible to imipenem was 70 and to meropenem */60.conclusions: carbapenems: imipenem and meropenem demonstrated high activity against clinical strains of enteric rods. however, the antibiotics were less active against nosocomial strains of nonfermenting rods.inhaled antibiotics against multiresistant bacteria in bronchial secretions of icu patients: a preliminary report pm237horianopoulou m a , kanellopoulou m b , paraskevopoulos i a , valakis k a , kyriakidis a a , lambropoulos s a . a intensive care unit, sismanoglio general hospital, athens, greece , b department of microbiology, sismanoglio general hospital, athens, greece purpose: the aim of this study was to assess the effectiveness of aerosolized ampicillin/sulbactam, ceftazidime and colistin, in icu patients with multiresistant acinetobacter baumannii or pseudomonas aeruginosa colonization of the respiratory tract.methods: fifty-three intubated, mechanically ventilated patients participated in the study. multiresistant a. baumannii , sensitive only to ampicillin/sulbactam, or p. aeruginosa , sensitive to ceftazidime or colistin, were isolated from the bronchial secretions (10 5 á/10 8 cfu/ ml). all 53 patients were subsequently treated with intravenous ampicillin/sulbactam, ceftazidime or colistin, whereas 27 of them were also given the same antibiotic in aerosolized form.results: a decrease in the number of colonies by 10 3 á/10 6 cfu/ml was observed, following 2 á/4 days of combined treatment with both intravenous and inhaled antibiotic. none of the 27 patients developed vap. in the 26 patients who only received the antibiotic intravenously, the decrease ranged from zero to 10 4 cfu/ml, after 7 days of treatment. two of 26 patients developed vap.conclusions: our results suggest that the administration of aerosolized antibiotics represents an effective means of preventing ventilator-associated pneumonia caused by a. baumanni and p. aeruginosa . introduction: pseudomonas aeruginosa is an important nosocomial pathogen. resistance to certain beta-lactam antimicrobial agents among p. aeruginosa is increasing. despite the development of new antibiotics multiresistant strains of p. aeruginosa represent an important therapeutic problem. the aim of this study was to investigate the activity of imipenem, amikacin, piperacillin, ciprofloxacin, ceftazidime, against clinical isolates of p. aeruginosa . methods: a total of 54 isolates by tracheal aspiration from hospitalized patients, admitted to intensive care units were identified as p. aeruginosa using an algorithm that included: gram stain, pigment, oxidaze ('/0,) and gram negative identifications microscan walkaway-96 (dade behring) were used according to the manufactures instructions. minium inhibitory concentrations were determined using walkaway, interpretation based on ncclsm 100-s9, january '99.results: the respiratory tract was the single site of isolation for this study. the best activity was showed by imipenem 25%, followed by amikacin 22%, piperacillin, pip/tazobactam, ciprofloxacin had the same sensitivity 11%.conclusion: a high level resistance to antibiotics was observed to p. aeruginosa isolated from tracheal aspiration. carbapenems seem to be the most active against p. aeruginosa in this study. materials and methods: clinical samples were collected from patients admitted to this hospital. only one isolate per patient was included. antimicrobial susceptibility testing was performed as recommended by the nccls. all bacterial isolates were tested by dd and ad to provide a comparison of both test results. very major error was considered when the strains were resistant (r) by ad and susceptible (s) by dd and major error when s by ad and r by dd. categories of s and r were stablised using the breakpoints suggested by mensura (2000) . colistin r strains was typed by rep-pcr.results: among the 35 strains included in this study 30 (85.7%) were s to colistin and five (14.2%) were colstin r by ad, of this five colistin r strains four (11.4%) were s to colistin by dd and one was r by both methods. all r isolates were similar by rep-pcr.conclusions: most of the ad colistin resistant strains were s when tested by dd indicating that this method is not useful to determine the resistance to colistin. rep-pcr patterns show that the spread of a colistin r clone seems to be involved. methods: gnb were isolated from per-operative biopsies (pob) and/ or from articular punction (ap). patients (pts) received cfp, 2 g bid'/ ofl, 200 mg tid or cip, 400 mg bid intravenously for 28 days, followed by a prolonged oral fq monotherapy. cure was defined as: resolution of all clinical signs of infection, normalization of the biological inflammatory profile at the end of treatment (eot) and absence of infection at the same site during the post-treatment followup period (ptfu).results: all of the 20 studied patients [mean age 0/48 years] had hospital acquired bji. seventeen/20 had an infected orthopedic device (prosthetic joints0/6, other orthopedic prosthetic devices0/11). culture of 17 pob and 5 ap yielded to pseudomonas sp. (11), enterobacter cloacae (6), others (4). vancomycin was added for six pts co-infected by gnb-mrsa. nineteen/20 pts underwent a surgical intervention (debridement0/11, removal-replacement0/7, amputation0/1). after ptfu period of 17 months (range 3 á/29), the overall success rate was 12/17 (88.2%) without serious adverse events.conclusion: cfp á/fq combination was safe and efficient in the treatment of hypercase gnb, bji.treatment of posttraumatic mrsa osteomyelitis of the femur with longterm cotrimoxazole */a case report pm241 the authors report a case of posttraumatic osteomyelitis of the femur caused by methicillin-resistant staphylococcus aureus (mrsa), following the shot injury. relapses of the infection occured in 3 months interval and were treated by revision, debridement, lavage and vancomycin. because of laboratory signs of renal insufficiency vancomycin became contraindicated for treatment of the third relapse of infection and the different approach was employed: classic open treatment of bone infection sec. orr was combined with a long-term administration of high-dose cotrimoxazole. the patient was given cotrimoxazole 9600 mg daily divided in four doses (120 mg/kg/24 h) for 2 months, then for gastrointestinal complaints with lowered dose of 5760 g daily for next 6 months. the wound completely healed. during 18 months after the final surgery there was no relaps of infection, but the atrophic pseudoarthrosis of the femur resulted. the patient can walk with a rigid orthesis and two crutches. the whole treatment of the objective: to present a variety of severe nosocomial infections due to stenotrophomonas maltophilia in patients hospitalized in tertiary medical units from cluj.results: during the last year nine strains of s. maltophilia obtained from patients with severe infections and hospitalized in different wards were isolated. all but one were considered nosocomial infections: four cases of pneumonia, one urinary tract infection, three cases of surgical wound infections and one case of endocarditis under surgical treatment. the cases of pneumonia were either primary occurring in a granulocytopenic patient with leukemia or secondary in patients that underwent surgical treatment. in the case of endocarditis the ethiology was established after surgery from the damaged valve in a negative hemoculture patient with a poor outcome under medical treatment. in all cases of surgical wound infection bacteremia occurred diagnosed on clinical basis in the presence of severe sepsis or hematogenous dissemination in the lung. the urinary tract infection occurred in a patient after urinary surgery and having a catheter in place. the immediate evolution was favorable in all cases but treatment was difficult due to the highly resistant strains and to underling diseases.conclusions: s. maltophilia should be considered in nosocomial severe infections and prophylaxis by interrupting environmental transmission has to be promoted. sawicka-grzelak a, rokosz a, luczak m. department of medical microbiology, university medical school, warsaw, poland purpose: to identify and determine the drug-susceptibility of esblpositive strains isolated from urine samples.methods: seven hundred and twelve strains of gram-negative rods were cultured from 4000 urine samples from hospitalized patients during 5 months (july á/november 2001). identification and susceptibility were performed in the automatic atb system (biomerieux, france) using id 32 e, id 32 gn and atb ur 5 strips. esbl-activity was detected with double-disc synergy test (ddst according to jarlier et al., 1988) or using a novel method of esbl detection (dd, diagnostic disc) according to appleton (1999) . two discs were applied in this test: with cefpodoxime (cpd) and with cefpodoxime/clavulanic acid (cd 01) (oxoid, england).results: five hundred and ninety-five strains (83.6%) belonging to enterobacteriaceae family, 115 strains (16.1%) of non-fermenting rods and two strains (0.3%) of other gram-negative rods were isolated. eighty-two esbl-producing strains (11.5% of all strains) were detected. fifty-nine esbl-positive strains were susceptible to nitrofurantoin, 58-to norfloxacin and ciprofloxacin and 54-to fosfomycin.conclusions: esbl-positive strains were detected most frequently among enteric rods (80 strains). nitrofurantoin and quinolones were the most active in vitro antibacterial agents against examined esblpositive uropathogens. results: the mechanisms of resistance were evaluated phenotypically using 12 different aminoglycosides. a total of 257 aminoglycoside resistant gram-negative strains were studied. one hundred fifty-eight strains were collected in 1995 á/1996, 52 in 1998 and 47 in 2000. the resistant profiles were determined: enterobacteriaceae */152; pseudomonas aeruginosa */62; acinetobacter spp. */43. the most frequently phenotypes were gt (gentamicin, tobramycin) */48% and gtnet (gentamicin, tobramycin, netilmicin) */35%. the gt phenotype due to production ant(2ƒ)-i enzyme, the gtnet á/aac(3)-v (87 strains), aac(3)-iv */one strain and aac(2ƒ)-i */one strain. the resistance to amikacin in 7% strains was due to production aac(6?)-i (3%) and aph(3?)-vi (4%). the most of examined strains were simultaneously resistant to kanamycin and neomycin caused by production of aph(3?)-i (69%). only seven strains were resistant to all aminoglycosides due to impermeability of outer membrane. no substantial differences were observed between years.conclusions: the main mechanism of aminoglycoside resistance is fermentative modification. the high rate to gentamicin and tobramycin was due to production of ant(2ƒ)-i and aac(3)-v. amikacin and isepamicin were the most active aminoglycosides against gramnegative nosocomial isolates.the incidence of clostridium difficile associated diarrhoea (cdad) increased in our department from january to june 2001.objective: to confirm the out break of cdad, to identify the risk factors and assess the effectiveness of the measures implemented for controlling this outbreak.methods: cdc definitions were used to identify the cases. the scope of the outbreak was defined. cdad incidences during the outbreak period and during the same period in 2000 were compared. risk factors (reduced mobility, antibiotic treatments . . .) were studied for patients whom length of hospital stay (lhs) was more than 6 days. contact precautions and environmental cleaning with clona implemented were assessed.results: seventeen episodes of cdad were identified. sex ratio: 1.41, mean age0/58.5, mean lhs0/36 days, mean delay for cdad occurring0/21 days. one hundred and fifty-two patients involved in the study of risk factors. relative risk (r.r.) evaluated were: blactams (r.r.0/7.62, ic95%: 1.03 á/56.56), reduced mobility (r.r.0/ 7.61, ic95%: 1.76 á/32.85). incidence of cdad was less than two cases per 1000 days of hospitalisation after june 2001.conclusion: we confirmed the outbreak of cdad in our department b-lactams and reduced mobility were identified as risk factors for cdad. measures implemented to control the outbreak were effectiveness.positive heart transport fluid cultures associated with severe infections in heart transplant recipients pm255 at the mount sinai hospital in new york city 256 heart transplants were performed between 1986 and june 2000. cultures were routinely performed on all heart transplant transport fluids. culture data was available for 204 of these patients. in total 24/204 (11.8%) were positive for bacteria, fungi or both. the organisms isolated included coagulase negative staphylococci (13), pseudomonas aeruginosa (2), staphylococcus aureus (1), acinetobacter baumanii (1), serratia mercescens (1), enterobacter cloacae (1), escherichia coli (1), proteus mirabilus (1), enterococcus faecalis (1), viridans streptococci (1), and fungi (aspergillus fumigatus (1), penicillium species (1), and rhodotorula rubra (1). two heart transplant recipients had two organisms isolated from the transport fluid. isolation of resistant gram-negative bacilli in the transport fluid was associated with significant infection in 3/5 patients (60%) with the same organism. the observed infections were pneumonia secondary to e. cloacae , sternal wound infection secondary to p. aeruginosa , and bacteremia secondary to p. aeruginosa . it appears prudent to provide prophylaxis against resistant gram negative bacilli to prevent infections. zacharof ak, flevaris c, petrogianopoulos c, karachalios g, vroulis j, chartzoulakis g, drakogiorgos g, loizidou a, svoukas g. 2nd department of internal medicine, hellenic red cross hospital, athens, greece objective: we studied the trends of nosocomial bloodstream infection and calculated the population-attributable risk for death among hospitalized patients. methods: we perform a 15-year retrospective study for all patients (n 0/79 160), admitted to our department between 1986 and 2000.results: between 1986 and 2000, a total of 1577 patients developed 1763 episodes of nosocomial bloodstream infection. the crude infection rates increased linearly from 7.2 to 25.4 per 1000 discharges (1.11 á/1.93 episodes per 1000 patient-days) during the 15-year study period. increases in the infection rates were due to gram-positive cocci, yeasts and essentially explained by infections caused by coagulasenegative staphylococci, staphylococcus aureus , enterococci, and candida species, respectively. although the crude mortality in patients with nosocomial bloodstream infections decreased from 45% in 1986 to 28% in 2000, the in-hospital population-attributable mortality among infected patients increased from 5.5 deaths per 1000 discharges in 1986 to 8.2 per 1000 discharges in 2000. the etiologic fraction or the proportion of deaths in patients with bloodstream infection to all deaths occurring in the hospital increased from 15.4% in 1986 to 26.4% in 2000.conclusions: the incidence and the population-attributable risk for death among patients experiencing nosocomial bloodstream infections increased progressively during the last 15 years in our department.ventilator-associated pneumonia before and after intensive care unit temporary closure pm257 results: we compared the incidence, causative organisms and mortality of vap in two different time periods. period 1 june to december 1999. period 2 june to december 2000. between those two periods the icu remained closed for 4 months because of reconstruction works.period 1: sixty-seven consecutive patients (pts) were studied with bronchial secretions cultures at least 2 days after mechanical ventilation (mv) initiation. the vap was diagnosed by clinical, radiological and microbiological criteria in 17 pts (26%). causative organisms included: pseudomonas aeruginosa 8, acinetobacter 5, staphylococcus aureus 4, klebsiella pneum. 3, enterobacter 1. in three cases vap was proved polymicrobial. fourteen (14) episodes of vap (82%) were developed after 7 days mv (late vap) and were attributed to multiresistant microorganisms. mortality of vap was 29%.period 2: among 66 consecutive pts, vap was diagnosed in 21 (32%). causative organisms included: acinetobacter 10, p. aeruginosa 8, s. aureus 4, k. pneumoniae 3, escherichia coli 1. five (5) cases were polymicrobial and 14 cases were 'late vap' (67%). causative microorganisms had similar patterns of sensitivity to antibiotics (compared to period one). mortality of vap was 38%.conclusion: temporary icu closure had no significant influence on the incidence, distribution of causative organisms, their sensitivities to antibiotics and mortality of the vap. efstathiou sp a , pefanis av a , tsioulos di a , tsiakou ag a , zacharos id a , kanavaki s b , mountokalakis td a . a third university department of medicine, sotiria general hospital, athens, greece , b microbiology laboratory, sotiria general hospital, athens, greecepurpose: the aim of this study was to derive a scoring system for the prediction of outcome in adult patients with acute pyelonephritis (ap) severe enough to need hospitalization. therefore, the charts of 225 patients (102 men, median age 67 years) were reviewed.results: logistic regression analysis identified in both sexes four independent correlates of in-hospital mortality, the coefficients of which divided by 0.5 and rounded to the nearest interval, resulted in the following integer-based scoring system: points (men)0/6* between concentrations of lps of the two groups were statistically significant on the 2nd and the 4th day (p b/ 0.05). it is concluded that the administration of lactulose may decrease systemic endotoxaemia in the field of obstructive jaundice.nosocomial infections: a prevalence study in the island of crete pm263 doukakis s a , tzimis l b , perogambrakis g a , kalloniatou m a , christodoulakis n a , evaggelopoulos a a , koutsoumba d a , kastanakis s a . a first medical department, 'saint george ' general hospital, chania, greece , b pharmacy department, 'saint george ' general hospital, chania, greeceprevalence surveillance is a rapid and inexpensive mode to estimate the problem of hospital-acquired infections (hais). to study the problem of nosocomial infections in our hospital, a prevalence study was made from our team in 1999. the study included 265 patients (the total number of hospitalized patients at the time of the study). from these patients 129 were males (49.0%) and 136 females (51.0%). one hundred and ninety-one patients (72.0%) belonged in the groups of age between 50 and 89 years. fifty-seven patients had a urine catheter (22.3%). one hundred and fifty-five/265 patients (58%) received antibiotics and from these 99 patients received one antibiotic and the remaining 56 patients two or more. a nosocomial infection was found in 13 patients and consequently the prevalence of hais was 5.0%. among these, urinary tract infections were six (46.1%), lower respiratory tract infections were three (23.0%), surgical site infections were three (23.0%), and bloodstream infections was one (7.7%). the incidence of multiresistant bacteria was primarily enterococcus spp and secondary, pseudomonas aeruginosa , enterobacter spp, klebsiella pneumoniae , escherirchia coli , staphylococcus aureus , enterobacter cloacae . unfortunately prophylactic chemotherapy of long duration was found despite the suggestions of the infection control committee. regarding age the highest incidence of hais occurred in the third age group. bagirova ns, dmitrieva n. laboratory of microbiology, cancer research center of russia, moscow, russian federation objectives: to determine the pathogens and susceptibility to antimicrobials.methods: blood samples were collected from 430 adult pts (1997 á/ 2001). the bacteraemic episodes were classified according to the definitions of the cdc. laboratory detection of bacteraemia and fungaemia was performed according to cumitech 1b (blood cultures iii, 1997). susceptibility testing was performed by disk diffusion method (nccls).results: the total number of blood samples */1371, 249-positive (18.2% episodes of significant bacteraemias). bsi was confirmed microbiologically in 137 of 430 febrile pts (31.9%). the most frequent pathogens were gram('/) cocci (62.7%) (p b/ 0.0001), gram((/) bacilli */22.7%, fungi */11.4%. coagulase-negative staphylococci (cns) represented 38.9%, staphylococcus aureus 12.4%, streptococcus spp. 4.9%, enterococcus spp. 5.9%, enterobacteriaceae 15.1%, pseudomonas aeruginosa 3.2%, other non-fermenting */5.9%, yeast 8.1%, mould 3.2%, anaerobes 2.7%. one hundred percent cns were resistant to penicillin, 68.4% to oxacillin, 36.6% to clindamycin, 39.5% to cefazolin, 80.3% to ceftazidime, 48.7% to ciprofloxacin, 51.3% to gentamicin, and no isolate was resistant to vancomycin. the predominant pathogens in all types of hm were gram('/) cocci (mainly cns). all gram('/) microorganisms were sensitive to vancomycin. katashinsky o a , opriatova t b , tchuev p c . a state clinical hospital, anaesteziology, odessa, ukraine , b state clinical hospital, bacteriology, odessa, ukraine , c medical university, anaesteziology, odessa, ukrainethis investigation was carried out in odessa state clinical hospital during 2000 á/2001. of the patients with post-operation complications, 60% of 518 gram-negative cultures were sensitive to ceftazidime and 72% to amikacin. sixty-nine percent of 143 gram-positive cultures were resistant to penicillin g, but they were sensitive to vancomycin and nitrofurantoin in 100 and 92% of cases, respectively. sixty percent of 366 isolates of pseudomonas aeruginosa were sensitive to ceftazidime and 71% to amikacin. rates of resistance to carbenicillin and gentamicin were 60 and 66%, respectively. one hundred and fortythree isolates of escherichia coli were studied and 65% of them were resistant to ampicillin 67% to cephalothin and 70% to tetracycline. of the isolates tested against ciprofloxacin, all were sensitive. one hundred and eight isolates of staphylococcus aureus were studied and they were resistant only to penicillin g (69%). staphylococcus aureus was sensitive to erythromycin (65%), tetracycline (65%), oxacillin (83%) and vancomycin (100%). all 34 isolates enterococcus faecalis were sensitive to nitrofurantoin and 70% to ciprofloxacin. the majority of s. aureus and e. faecalis isolates were susceptible to most other antibiotics, but the majority of e. coli isolates were resistant to the studied antibiotics expect ciprofloxacin.campylobacter foetus bacteraemia in an immunocompromised patient: a case report pm266monno r a , ierardi e b , rendina m b , ceci g a , luzzi i c , de vito d a , rizzo g a , francavilla a b . a department of internal medicine and public health, university of bari, bari, italy , b department of emergency and organ transplantation, university of bari, bari, italy , c istituto superiore di sanità, rome, italy a 33-year-old woman was admitted for recurrent fever. the patient underwent a liver transplantation and splenectomy in 1985. she had followed immunosuppressive therapy until 1995 when tacrolimus was added for chronic rejection. in 1999 non-hodgkin lymphoma was diagnosed and chemotherapy was started. six months later because of the presence of two metastatic encephalic foci affecting the optic chiasm, a new chemotherapy course was started with the regression of lesions. in january 2000 she was treated with steroid recycle and cyclosporine á/azathioprine á/prednisone reintroduction. fever occurred after 2 months and cytomegalovirus (cmv) infection was diagnosed. treatment with ganciclovir was started with clinical remission. in november 2000 cmv infection recurred and blood cultures were positive for a bacterium that was identified as campylobacter fetus . the patient was successfully treated with intravenous ciprofloxacin. bacteremia frequently occurs in cancer patients. bacteremia due to c. fetus are rare, occurring mainly in immunocompromised patients. c. fetus expresses a proteinaceous surface layer that confers serum resistance. in our patients steroid and immunosuppression may have contributed to the development of lymphoma. all of these factors and chemotherapy have contributed to cmv infection and all have made the patient susceptible to bacteremia with this infrequently found bacterium. the clinical microbiologist should be aware of this infection in immunocompromised host. minenko sv, dmitrieva nv, sokolova en, ptushkin vv. bone marrow transplantation department, n.n. blokhin cancer research center, moscow, russian federation c'/a is the standard regimen as empirical therapy for febrile neutropenia (fn). activity of c against g'/ bacteria and g(/ bacteria, producing chromosomally-mediated b-lactamases (e.g. ampc) is suboptimal. cep is active against a broad range of g'/ and g(/, including ampc producing bacteria. the purpose of the study was to compare the efficacy of two regimens in the treatment of fn.methods: patients with fn received either cep (2 g/8 h) or c (2 g/8 h) plus amikacin (15 mg/kg/day) or netilmicin (5 mg/kg/day). data were collected prospectively.results: a total of 35 pts with 41 episodes (35/41) of fn were included. fifteen/19 in cep group and 20/22 in c'/a group. the median duration of neutropenia grade 4, distribution of age, sex and underlying disease were comparable in both arms. mdi was in 37 and 24%, cdi in 21 and 18% fuo in 57 and 63% in fep and c'/a groups correspondingly. response to the initial empirical regimen according to ihs criteria was in 58% of cep and 27.3% of c'/a groups (p 0/ 0.05). modification of therapy with a change of cep or c to carbapenem took place in 31 and 40% of cep and c'/a groups (p0/0.5). no patient in either treatment group died due to the presenting infection. tolerability of cep was good and no laboratory abnormalities took place. transient elevation of serum creatinin level was observed in two patients c'/a group.conclusions: cep monotherapy is as effective as c'/a combination in the treatment of patients with fever and granulocytopenia purpose of the study: retrospectively, we analysed 60 patients with intraabdominal infection for aetiology, risk factors, and outcome from 11 hospitals in slovak republic within 1 year (march 00 á/march 01). results: in this group significantly more frequent were older patients ( !/65 years) with cancer (65 vs. 16%, p b/ 0.0007). acinetobacter spp. (50 vs. 7%, p b/ 0.0001) and enterobacteriaceae (83 vs. 39%, pb/ 0.04) were predictive for monoinfection. pre-treated patients with other antibiotics had inferior prognosis and more risk factors: permanent urinary catheter (95 vs. 67%, pb/ 0.05), ventilation or intubation (91 vs. 17%, pb/ 0.0001) and polymicrobial infection (86 vs. 33%, pb/ 0.0002). the risk factors with poor prognosis were enterobacteriaceae (30 vs. 14%, pb/ 0.04), diabetes mellitus as underlying disease (18 vs. 54%, p b/ 0.2) and uraemia (4 vs. 40%, p b/ 0.002). surprisingly, negative prognostic factor was also non-effective previous antibiotic therapy. failed patients died significantly more frequently patients due to underlying disease. cefoperazone/sulbactam was shown to be useful, effective and well tolerated also in one group of patients with 75% efficacy of treatment, and it belongs to a group of antibiotics suitable for treatment of nosocomial infections. 