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The aim of this study was to describe a systematic process of record-linkage, cross-validation, case-ascertainment and capture-recapture analysis to assess the quality of tuberculosis registers and to estimate the completeness of notification of incident tuberculosis cases in The Netherlands in 1998. After record-linkage and cross-validation 1499 tuberculosis patients were identified, of whom 1298 were notified, resulting in an observed under-notification of 13.4%. After adjustment for possible imperfect record-linkage and remaining false-positive hospital cases observed under-notification was 7.3%. Log-linear capture-recapture analysis initially estimated a total number of 2053 (95% CI 1871-2443) tuberculosis cases, resulting in an estimated under-notification of 36.8%. After adjustment for possible imperfect record-linkage and remaining false-positive hospital cases various capture-recapture models estimated under-notification at 13.6%. One of the reasons for the higher than expected estimated under-notification in a country with a well-organized system of tuberculosis control might be that some tuberculosis cases, e.g. extrapulmonary tuberculosis, are managed by clinicians less familiar with notification of infectious diseases. This study demonstrates the possible impact of violation of assumptions underlying capture-recapture analysis, especially the perfect record-linkage, perfect positive predictive value and absent three-way interaction assumptions. [ABSTRACT FROM AUTHOR]

Background and Objectives: The objective was to assess reliability of self-reported sexual histories among sexually transmitted disease clinic attendees who enrolled in a study in 1994.Goal Of This Study: Knowledge about the reliability of sexual data is important to decide whether these measures of sexual behavior can be used in epidemiologic studies of sexually transmitted diseases.Study Design: In 288 attendees, degree of agreement was assessed in responses to an identical set of sexual questions asked independently by a medical doctor and a public health nurse and in responses made by members of the same couple (n = 50) to a public health nurse.Results: In the test-retest comparison, high agreement was found for most questions: kappa-values and exact agreement ranged from 0.73 to 0.96 and 54% to 99%, respectively. Participants interviewed by the medical doctor reported significantly lower numbers of partners and a higher age at first intercourse. Stratified analyses showed variability in agreement across subgroups. Most consistent, women provided more reliable reports than men. In the comparison of couples, substantial agreement was found for the municipality where they met (88% agreement; kappa = 0.72) and contraceptive method (87% agreement; kappa = 0.60), but only moderate agreement was found for frequency of sexual intercourse (26% agreement; kappa = 0.50).Conclusion: The authors conclude that data on sexual behavior can be collected reliably among sexually transmitted disease clinic attendees, although reporting bias does occur. The frequency of sexual intercourse was not sufficiently reliable and should be interpreted as an estimate only. [ABSTRACT FROM AUTHOR]

From a cohort of female sex workers in Nairobi, Kenya, 163 women were observed to seroconvert to human immunodeficiency virus type 1 (HIV-1) and followed to study progression to HIV-1-related disease. The effect of several covariables on disease progression was studied using a Weibull proportional hazards model. The Weibull survival model was fitted to the observed incubation times. Estimates of the median duration to CDC stage IV-A and IV-C disease were 3.5 and 4.4 years, respectively. Condom use before seroconversion was associated with a reduced risk of CDC stage IV-A disease (relative risk = .64, P < .05). The incubation time of HIV-1-related disease is extremely short in this population. [ABSTRACT FROM AUTHOR]

Objective To describe a dynamic compartmental simulation model for Botswana and India, developed to identify the best strategies for preventing spread of HIV/AIDS. Methods The following interventions were considered: a behavioural intervention focused on female sex workers; a conventional programme for the treatment of sexually transmitted infections; a programme for the prevention of mother-to-child transmission; an antiretroviral treatment programme for the entire population, based on a single regimen; and an anti retroviral treatment programme for sex workers only, also based on a single regimen. Findings The interventions directed at sex workers as well as those dealing with sexually transmitted infections showed promise for long-term prevention of human immunodeficiency virus (HIV) infection, although their relative ranking was uncertain. In India, a sex worker intervention would drive the epidemic to extinction. In Botswana none of the interventions alone would achieve this, although the prevalence of HIV would be reduced by almost 50%. Mother-to-child transmission programmes could reduce HIV transmission to infants, but would have no impact on the epidemic itself. In the long run, interventions targeting sexual transmission would be even more effective in reducing the number of HIV-infected children than mother-to-child transmission programmes. Antiretroviral therapy would prevent transmission in the short term, but eventually its effects would wane because of the development of drug resistance. Conclusion Depending on the country and how the antiretroviral therapy was targeted, 25-100% of HIV cases would be drugresistant after 30 years of use. [ABSTRACT FROM AUTHOR]

Background: The London Declaration (2012) was formulated to support and focus the control and elimination of ten neglected tropical diseases (NTDs), with targets for 2020 as formulated by the WHO Roadmap. Five NTDs (lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths and trachoma) are to be controlled by preventive chemotherapy (PCT), and four (Chagas' disease, human African trypanosomiasis, leprosy and visceral leishmaniasis) by innovative and intensified disease management (IDM). Guinea worm, virtually eradicated, is not considered here. We aim to estimate the global health impact of meeting these targets in terms of averted morbidity, mortality, and disability adjusted life years (DALYs)., Methods: The Global Burden of Disease (GBD) 2010 study provides prevalence and burden estimates for all nine NTDs in 1990 and 2010, by country, age and sex, which were taken as the basis for our calculations. Estimates for other years were obtained by interpolating between 1990 (or the start-year of large-scale control efforts) and 2010, and further extrapolating until 2030, such that the 2020 targets were met. The NTD disease manifestations considered in the GBD study were analyzed as either reversible or irreversible. Health impacts were assessed by comparing the results of achieving the targets with the counterfactual, construed as the health burden had the 1990 (or 2010 if higher) situation continued unabated., Principle Findings/conclusions: Our calculations show that meeting the targets will lead to about 600 million averted DALYs in the period 2011-2030, nearly equally distributed between PCT and IDM-NTDs, with the health gain amongst PCT-NTDs mostly (96%) due to averted disability and amongst IDM-NTDs largely (95%) from averted mortality. These health gains include about 150 million averted irreversible disease manifestations (e.g. blindness) and 5 million averted deaths. Control of soil-transmitted helminths accounts for one third of all averted DALYs. We conclude that the projected health impact of the London Declaration justifies the required efforts.

The validity of ecological studies in epidemiology for inferring causal relationships has been widely challenged as observed associations could be biased by the Ecological Fallacy. We reconsider the important design components of ecological studies, and discuss the conditions that may lead to spurious associations. Ecological associations are useful and valid when the ecological exposures can be interpreted as Instrumental Variables. A suitable example may be a time series analysis of environmental pollution (e.g. particulate matter with an aerodynamic diameter of <10 micrometres; PM10) and health outcomes (e.g. hospital admissions for acute myocardial infarction) as environmental pollution levels are a cause of individual exposure levels and not just an aggregate measurement. Ecological exposures may also be employed in situations (perhaps rare) where individual exposures are known but their associations with health outcomes are confounded by unknown or unquantifiable factors. Ecological associations have a notorious reputation in epidemiology and individualistic associations are considered superior to ecological associations because of the "ecological fallacy". We have argued that this is incorrect in situations in which ecological or aggregate exposures can serve as an instrumental variable and associations between individual exposure and outcome are likely to be confounded by unmeasured variables.

Objectives: This study aims to study determinants for the control of diabetes and hypertension in Al Ain Ambulatory Healthcare patients., Method: This is a cross sectional observational study of patients attending ambulatory healthcare centers in Al Ain, United Arab Emirates in 2009. From a yearly audit evaluating the care of patients with diabetes and hypertension, the determinants for improved diabetes and hypertension outcomes were identified from a total of 512 patients and its association with glycemic and blood pressure control were studied., Results: From all variables studied, only the clinic where the patient was treated helped predict both improved blood sugar and blood pressure control. For patients with diabetes, poor control the year before (p<0.001), the number of chronic disease clinic visits (p=0.042) and triglyceride levels (p=0.007) predicted worse control of diabetes. A predictor of poor control of blood pressure (p<0.001) for patients with hypertension was poor control of blood pressure in the year before., Conclusion: In this population, the healthcare system and the team played major roles as determinants in the control of patient's diabetes and blood pressure more than any of the other factors examined.

Several countries with generalized, high-prevalence HIV epidemics, mostly in sub-Saharan Africa, have experienced rapid declines in transmission. These HIV epidemics, often with rapid onsets, have generally been attributed to a combination of factors related to high-risk sexual behavior. The subsequent declines in these countries began prior to widespread therapy or implementation of any other major biomedical prevention. This change has been construed as evidence of behavior change, often on the basis of mathematical models, but direct evidence for behavior changes that would explain these declines is limited. Here, we look at the structure of current models and argue that the common "fixed risk per sexual contact" assumption favors the conclusion of substantial behavior changes. We argue that this assumption ignores reported non-linearities between exposure and risk. Taking this into account, we propose that some of the decline in HIV transmission may be part of the natural dynamics of the epidemic, and that several factors that have traditionally been ignored by modelers for lack of precise quantitative estimates may well hold the key to understanding epidemiologic trends.

Classic Hodgkin lymphoma (cHL), a germinal-center related B cell neoplasm in almost all cases, is characterized by scarcity of the neoplastic Hodgkin/Reed-Sternberg (H/RS) cells. Epstein-Barr virus (EBV) has been shown to affect cell cycle and regulation of apoptosis. In total, 95 cases of cHL were studied. Five-micrometer sections were prepared and stained with hematoxylin and eosin and immunohistochemical streptavidin-biotin methods for EBV-LMP-1, COX-2, p53, p16, ki-67 and cleaved caspase-3. In-situ hybridization for EBV encoded RNA was used to confirm the detection of EBV in H/RS. There were 49 nodular sclerosis, 32 mixed cellularity, 8 lymphocyte-rich, and 6 lymphocyte-depleted subtypes in this series of cases. EBV, COX-2, p16(INK4A) and p53 were detected in 55% (52/95), 64% (61/95), 62% (59/95), and 65% (62/95) of the cases respectively. EBV was detected in 62% (38/61), 70% (41/59), and 69% (43/62) of COX2, p16 and p53 positive cases respectively. On the other hand, EBV-non-infected cases of cHL are associated with 59% (20/34), 69% (25/36), and 73% (24/33) of COX2, p16 and p53 negative cases respectively. In conclusion, EBV infection is associated with the expression of COX-2, p16(INK4A) and p53. EBV might be the dominant factor in determining the expression of these three proteins.

Background: Legionella is a water and soil bacterium that can infect humans, causing a pneumonia known as Legionnaires' disease. The pneumonia is almost exclusively caused by the species L. pneumophila, of which serogroup 1 is responsible for 90% of patients. Within serogroup 1, large differences in prevalence in clinical isolates have been described. A recent study, using a Dutch Legionella strain collection, identified five virulence associated markers. In our study, we verify whether these five Dutch markers can predict the patient or environmental origin of a French Legionella strain collection. In addition, we identify new potential virulence markers and verify whether these can predict better. A total of 219 French patient isolates and environmental strains were compared using a mixed-genome micro-array. The micro-array data were analysed to identify predictive markers, using a Random Forest algorithm combined with a logistic regression model. The sequences of the identified markers were compared with eleven known Legionella genomes, using BlastN and BlastX; the functionality for each of the predictive markers was checked in the literature., Results: The five Dutch markers insufficiently predicted the patient or environmental origin of the French Legionella strains. Subsequent analyses identified four predictive markers for the French collection that were used for the logistic regression model. This model showed a negative predictive value of 91%. Three of the French markers differed from the Dutch markers, one showed considerable overlap and was found in one of the Legionella genomes (Lorraine strain). This marker encodes for a structural toxin protein RtxA, described for L. pneumophila as a factor involved in virulence and entry in both human cells and amoebae., Conclusions: The combination of a mixed-genome micro-array and statistical analysis using a Random Forest algorithm has identified virulence markers in a consistent way. The Lorraine strain and related Dutch and French Legionella strains contain a marker that encodes a RtxA protein which probably is involved in the increased prevalence in clinical isolates. The current set of predictive markers is insufficient to justify its use as a reliable test in the public health field in France. Our results suggest that genetic differences in Legionella strains exist between geographically distinct entities. It may be necessary to develop region-specific mixed-genome microarrays that are constantly adapted and updated.

Aim: to investigate knowledge, attitude and behaviour toward infection control in two teaching hospitals on the island of Java by means of a questionnaire and to evaluate the use of the questionnaire as a tool., Methods: we investigated knowledge, attitude and behaviour toward infection control in two teaching hospitals on the island of Java by means of a questionnaire to identify problem areas, barriers and facilitators. The target was to include at least 50% of all health care workers (physicians, nurses, assistant nurses and infection control nurses) in each hospital, department and profession. Differences between demographic variables and scores for individual questions and groups of questions were compared using the chi-square statistic and analysis of variance and Spearman's rho was used to test for correlations between knowledge, attitude, self-reported behaviour and perceived obstacles., Results: more than half of the health care workers of the participating departments completed the questionnaire. Of the 1036 respondents (44% nurses, 37% physicians and 19% assistant nurses), 34% were vaccinated against hepatitis B, 77% had experienced needle stick accidents and 93% had been instructed about infection control. The mean of the correct answers to the knowledge questions was 44%; of the answers to the attitude questions 67% were in agreement with the correct attitude; obstacles to compliance with infection control guidelines were perceived in 30% of the questions and the mean self-reported compliance was 63%. Safe handling of sharps, hand hygiene and the use of personal protective equipment were identified as the most important aspects for interventions. Significant positive correlations were found between knowledge, attitude, self-reported behaviour and perceived obstacles., Conclusion: the questionnaire in conjunction with site visits and interviews was a valuable strategy to identify trouble spots in the hospitals and to determine barriers to facilitators of change that should be taken into account when planning interventions. Successful interventions should cover hospital management, the infection control team, as well as the health care workers on the wards.

Objectives: We examined if increased spending and coverage of female sex worker (FSW) interventions were associated with declines in HIV or syphilis risk among young pregnant women (as a proxy for new infections in the general population) in the high-burden southern states of India., Design: Repeated cross-sectional analysis., Setting: We used logistic regression to relate district-level spending, number of sexually transmitted infections (STIs) treated, FSWs reached or condoms distributed to the declines in the annual risk of HIV and syphilis from 2003 to 2008 among prenatal clinic attendees in the four high-HIV burden states of Andhra Pradesh, Karnataka, Maharashtra and Tamil Nadu., Participants: 386 961 pregnant women aged 15-24 years (as a proxy for incident infections in the adult population)., Interventions: We examined National AIDS Control Organisation (NACO) data on 868 FSW intervention projects implemented between 1995 and 2008., Primary and Secondary Outcome Measures: HIV or syphilis infection., Results: HIV and syphilis prevalence declined substantially among young pregnant women. Each additional STI treated (per 1000 people) reduced the annual risk of HIV infection by -1.7% (95% CI -3.3 to -0.1) and reduced the annual risk of syphilis infection by -10.9% (95%CI -15.9 to -5.8). Spending, FSWs reached or condoms distributed did not reduce HIV risk, but each was significantly associated with reduced annual risk of syphilis infection. There were no major differences between the NACO-funded and Avahan-funded districts in the annual risk of either STI., Conclusions: Targeted FSW interventions are associated with reductions in syphilis risk and STI treatment is associated with reduced HIV risk. Both more and less costly FSW interventions have comparable effectiveness.

Background: We assessed the severity of the 2009 influenza pandemic by comparing pandemic mortality to seasonal influenza mortality. However, reported pandemic deaths were laboratory-confirmed - and thus an underestimation - whereas seasonal influenza mortality is often more inclusively estimated. For a valid comparison, our study used the same statistical methodology and data types to estimate pandemic and seasonal influenza mortality., Methods and Findings: We used data on all-cause mortality (1999-2010, 100% coverage, 16.5 million Dutch population) and influenza-like-illness (ILI) incidence (0.8% coverage). Data was aggregated by week and age category. Using generalized estimating equation regression models, we attributed mortality to influenza by associating mortality with ILI-incidence, while adjusting for annual shifts in association. We also adjusted for respiratory syncytial virus, hot/cold weather, other seasonal factors and autocorrelation. For the 2009 pandemic season, we estimated 612 (range 266-958) influenza-attributed deaths; for seasonal influenza 1,956 (range 0-3,990). 15,845 years-of-life-lost were estimated for the pandemic; for an average seasonal epidemic 17,908. For 0-4 yrs of age the number of influenza-attributed deaths during the pandemic were higher than in any seasonal epidemic; 77 deaths (range 61-93) compared to 16 deaths (range 0-45). The ≥75 yrs of age showed a far below average number of deaths. Using pneumonia/influenza and respiratory/cardiovascular instead of all-cause deaths consistently resulted in relatively low total pandemic mortality, combined with high impact in the youngest age category., Conclusion: The pandemic had an overall moderate impact on mortality compared to 10 preceding seasonal epidemics, with higher mortality in young children and low mortality in the elderly. This resulted in a total number of pandemic deaths far below the average for seasonal influenza, and a total number of years-of-life-lost somewhat below average. Comparing pandemic and seasonal influenza mortality as in our study will help assessing the worldwide impact of the 2009 pandemic.

HIV-1 is grouped phylogenetically into clades, which may impact rates of HIV-1 disease progression. Clade D infection in particular has been shown to be more pathogenic. Here we confirm in a Nairobi-based prospective female sex worker cohort (1985-2004) that Clade D (n = 54) is associated with a more rapid CD4 decline than clade A1 (n = 150, 20.6% vs 13.4% decline per year, 1.53-fold increase, p = 0.015). This was independent of "protective" HLA and country of origin (p = 0.053), which in turn were also independent predictors of the rate of CD4 decline (p = 0.026 and 0.005, respectively). These data confirm that clade D is more pathogenic than clade A1. The precise reason for this difference is currently unclear, and requires further study. This is first study to demonstrate difference in HIV-1 disease progression between clades while controlling for protective HLA alleles.

Background: Approximately 2.4 million people are living with HIV in India. This large disease burden, and potential for epidemic spread in some areas, demands a full understanding of transmission in that country. We wished to quantify the effects of key sexual risk factors for HIV infection for each gender and among high- and low-HIV risk populations in India., Methodology: We conducted a systematic review of sexual risk factors for HIV infection from 35 published studies. Risk factors analyzed were: male circumcision/religion, Herpes Simplex Virus 2, syphilis, gonorrhoea, genital ulcer, multiple sexual partners and commercial sex. Studies were included if they met predetermined criteria. Data were extracted and checked by two researchers and random-effects meta analysis of effects was conducted. Heterogeneity in effect estimates was examined by I(2) statistic. Publication bias was tested by Begg's test and funnel plots. Meta regression was used to assess effect modification by various study attributes., Results: All risk factors were significantly associated with HIV status. The factor most strongly associated with HIV for both sexes was HSV-2 infection (OR(men): 5.87; 95%CI: 2.46-14.03; OR(women): 6.44; 95%CI: 3.22-12.86). The effect of multiple sexual partners was similar among men (OR = 2.46; 95%CI: 1.91-3.17,) and women (OR = 2.02; 95%CI: 1.43-2.87) and when further stratified by HIV-risk group. The association between HSV-2 and HIV prevalence was consistently stronger than other STIs or self-reported genital ulcer. If the strong associations between HSV-2 and HIV were interpreted causally, these results implied that approximately half of the HIV infections observed in our study population were attributable to HSV-2 infection., Conclusions: The risk factors examined in our analysis should remain targets of HIV prevention programs. Our results confirm that sexual risk factors for HIV infection continue to be an important part of Indian HIV epidemic 26 years after it began.

Background: Legionella, the causative agent for Legionnaires' disease, is ubiquitous in both natural and man-made aquatic environments. The distribution of Legionella genotypes within clinical strains is significantly different from that found in environmental strains. Developing novel genotypic methods that offer the ability to distinguish clinical from environmental strains could help to focus on more relevant (virulent) Legionella species in control efforts. Mixed-genome microarray data can be used to perform a comparative-genome analysis of strain collections, and advanced statistical approaches, such as the Random Forest algorithm are available to process these data., Methods: Microarray analysis was performed on a collection of 222 Legionella pneumophila strains, which included patient-derived strains from notified cases in The Netherlands in the period 2002-2006 and the environmental strains that were collected during the source investigation for those patients within the Dutch National Legionella Outbreak Detection Programme. The Random Forest algorithm combined with a logistic regression model was used to select predictive markers and to construct a predictive model that could discriminate between strains from different origin: clinical or environmental., Results: Four genetic markers were selected that correctly predicted 96% of the clinical strains and 66% of the environmental strains collected within the Dutch National Legionella Outbreak Detection Programme., Conclusions: The Random Forest algorithm is well suited for the development of prediction models that use mixed-genome microarray data to discriminate between Legionella strains from different origin. The identification of these predictive genetic markers could offer the possibility to identify virulence factors within the Legionella genome, which in the future may be implemented in the daily practice of controlling Legionella in the public health environment.

Background: The prognosis, specifically the case fatality and duration, of untreated tuberculosis is important as many patients are not correctly diagnosed and therefore receive inadequate or no treatment. Furthermore, duration and case fatality of tuberculosis are key parameters in interpreting epidemiological data., Methodology and Principal Findings: To estimate the duration and case fatality of untreated pulmonary tuberculosis in HIV negative patients we reviewed studies from the pre-chemotherapy era. Untreated smear-positive tuberculosis among HIV negative individuals has a 10-year case fatality variously reported between 53% and 86%, with a weighted mean of 70%. Ten-year case fatality of culture-positive smear-negative tuberculosis was nowhere reported directly but can be indirectly estimated to be approximately 20%. The duration of tuberculosis from onset to cure or death is approximately 3 years and appears to be similar for smear-positive and smear-negative tuberculosis., Conclusions: Current models of untreated tuberculosis that assume a total duration of 2 years until self-cure or death underestimate the duration of disease by about one year, but their case fatality estimates of 70% for smear-positive and 20% for culture-positive smear-negative tuberculosis appear to be satisfactory.

In the last decade, syndromic surveillance has increasingly been used worldwide for detecting increases or outbreaks of infectious diseases that might be missed by surveillance based on laboratory diagnoses and notifications by clinicians alone. There is, however, an ongoing debate about the feasibility of syndromic surveillance and its potential added value. Here we present our perspective on syndromic surveillance, based on the results of a retrospective analysis of syndromic data from six Dutch healthcare registries, covering 1999–2009 or part of this period. These registries had been designed for other purposes, but were evaluated for their potential use in signalling infectious disease dynamics and outbreaks. Our results show that syndromic surveillance clearly has added value in revealing the blind spots of traditional surveillance, in particular by detecting unusual, local outbreaks independently of diagnoses of specific pathogens, and by monitoring disease burden and virulence shifts of common pathogens. Therefore we recommend the use of syndromic surveillance for these applications.

Large Q-fever outbreaks were reported in The Netherlands from May 2007 to 2009, with dairy-goat farms as the putative source. Since Q-fever outbreaks at such farms were first reported in 2005, we explored whether there was evidence of human outbreaks before May 2007. Space-time scan statistics were used to look for clusters of lower-respiratory infections (LRIs), hepatitis, and/or endocarditis in hospitalizations, 2005-2007. We assessed whether these were plausibly caused by Q fever, using patients' age, discharge diagnoses, indications for other causes, and overlap with reported Q fever in goats/humans. For seven detected LRI clusters and one hepatitis cluster, we considered Q fever a plausible cause. One of these clusters reflected the recognized May 2007 outbreak. Real-time syndromic surveillance would have detected four of the other clusters in 2007, one in 2006 and two in 2005, which might have resulted in detection of Q-fever outbreaks up to 2 years earlier.

Objectives: We explored whether excesses in influenza severity can be detected by combining respiratory syndromic hospital and mortality data with data on influenza-like illness (ILI) cases obtained from general practitioners., Methods: To identify excesses in the severity of influenza infections in the population of the Netherlands between 1999 and 2005, we looked for increases in influenza-associated hospitalizations and mortality that were disproportionate to the number of ILI cases reported by general practitioners. We used generalized estimating equation regression models to associate syndromic hospital and mortality data with ILI surveillance data obtained from general practitioners. Virus isolation and antigenic characterization data were used to interpret the results., Results: Disproportionate increases in hospitalizations and mortality (relative to ILI cases reported by general practitioners) were identified in 2003/04 during the A/Fujian/411/02(H3N2) drift variant epidemic., Conclusions: Combined surveillance of respiratory hospitalizations and mortality and ILI data obtained from general practitioners can capture increases in severe influenza-associated illness that are disproportionate to influenza incidence rates. Therefore, this novel approach should complement traditional seasonal and pandemic influenza surveillance in efforts to detect increases in influenza case fatality rates and percentages of patients hospitalized.

Background: Antiretroviral therapy (ART) for HIV infection reconstitutes the immune system and improves survival. However, the rate and extent of CD4+ T cell recovery varies widely. We assessed the impact of several factors on immune reconstitution in a large Kenyan cohort., Methodology/principal Findings: HIV-infected female sex workers from a longitudinal cohort, with at least 1 year of pre-ART and 6 months of post-ART follow-up (n = 79), were enrolled in the current study. The median pre-ART follow-up was 4,040 days. CD4 counts were measured biannually and viral loads where available. The median CD4 count at ART initiation was 180 cells/ul, which increased to 339 cells/ul at the most recent study visit. The rate of CD4+ T cell increase on ART was 7.91 cells/month (mean = 13, range -25.92 to 169.4). LTNP status prior to ART initiation did not associate with the rate of CD4 recovery on ART. In univariate analyses, associations were observed for CD4 recovery rate and duration of pre-ART immunosuppression (r = -0.326, p = 0.004) and CD4 nadir (r = 0.284, p = 0.012). In multivariate analysis including age, CD4 nadir, duration of HIV infection, duration of pre-ART immunosuppression, and baseline viral load, only CD4 nadir (p = 0.007) and not duration of immunosuppression (p = 0.87) remained significantly associated with the rate of CD4 recovery., Conclusions/significance: These data suggest that prior duration of immune suppression does not predict subsequent recovery once ART is initiated and confirm the previous observation that the degree of CD4 depletion prior to ART initiation is the most important determinant of subsequent immune reconstitution.

Objective: Vaccine-induced CD8(+) T-cell responses in primates have been associated with a reduced simian immunodeficiency virus plasma viral load and enhanced T-cell responses, but cellular vaccines have shown limited success in human trials. We previously described HIV-specific T-cell responses in two groups of highly exposed, persistently seronegative Kenyan female sex workers, and a subset of these participants have subsequently acquired HIV. We examined the impact of pre-existing CD8(+) T-cell responses on post-acquisition outcomes., Design and Methods: HIV-specific CD8(+) T-cell responses had been examined in highly exposed, persistently seronegative participants from the Pumwani and Kibera cohorts, using a combination of virus-specific lysis, proliferation, interferon-gamma production, or all. Plasma viral load set point and HIV-specific T-cell proliferation and cytokine production were now examined post hoc by blinded investigators in the subset of participants who acquired HIV., Results: Pre-acquisition cellular immune assays and post-infection viral load were available for 46 participants, and HIV-specific CD8(+) T-cell responses had been detected in 25 of 46 (54%) participants. Pre-acquisition CD8(+) T-cell responses were associated with a lower post-acquisition HIV viral load set point in both cohorts (pooled analysis, 3.1 vs. 4.1 log(10) RNA copies/ml; P=0.0002) and with enhanced post-acquisition HIV-specific CD8(+) T-cell proliferation (3.8 vs. 1.0%, P=0.03), but with a trend to reduced post-acquisition CD8(+) T-cell interferon-gamma responses., Conclusion: HIV-specific CD8(+) T-cell responses prior to HIV acquisition were associated with a lower HIV viral load and an altered functional profile of post-acquisition CD8(+) T-cell responses.

Background: Although syndromic surveillance is increasingly used to detect unusual illness, there is a debate whether it is useful for detecting local outbreaks. We evaluated whether syndromic surveillance detects local outbreaks of lower-respiratory infections (LRIs) without swamping true signals by false alarms., Methods and Findings: Using retrospective hospitalization data, we simulated prospective surveillance for LRI-elevations. Between 1999-2006, a total of 290762 LRIs were included by date of hospitalization and patients place of residence (>80% coverage, 16 million population). Two large outbreaks of Legionnaires disease in the Netherlands were used as positive controls to test whether these outbreaks could have been detected as local LRI elevations. We used a space-time permutation scan statistic to detect LRI clusters. We evaluated how many LRI-clusters were detected in 1999-2006 and assessed likely causes for the cluster-signals by looking for significantly higher proportions of specific hospital discharge diagnoses (e.g. Legionnaires disease) and overlap with regional influenza elevations. We also evaluated whether the number of space-time signals can be reduced by restricting the scan statistic in space or time. In 1999-2006 the scan-statistic detected 35 local LRI clusters, representing on average 5 clusters per year. The known Legionnaires' disease outbreaks in 1999 and 2006 were detected as LRI-clusters, since cluster-signals were generated with an increased proportion of Legionnaires disease patients (p:<0.0001). 21 other clusters coincided with local influenza and/or respiratory syncytial virus activity, and 1 cluster appeared to be a data artifact. For 11 clusters no likely cause was defined, some possibly representing as yet undetected LRI-outbreaks. With restrictions on time and spatial windows the scan statistic still detected the Legionnaires' disease outbreaks, without loss of timeliness and with less signals generated in time (up to 42% decline)., Conclusions: To our knowledge this is the first study that systematically evaluates the performance of space-time syndromic surveillance with nationwide high coverage data over a longer period. The results show that syndromic surveillance can detect local LRI-outbreaks in a timely manner, independent of laboratory-based outbreak detection. Furthermore, since comparatively few new clusters per year were observed that would prompt investigation, syndromic hospital-surveillance could be a valuable tool for detection of local LRI-outbreaks.

Background: The cost effective provision of quality care for chronic diseases is a major challenge for health care systems. We describe a project to improve the care of patients with the highly prevalent disorders of diabetes and hypertension, conducted in one of the major cities of the United Arab Emirates., Settings and Methods: The project, using the principles of quality assurance cycles, was conducted in 4 stages.The assessment stage consisted of a community survey and an audit of the health care system, with particular emphasis on chronic disease care. The information gleaned from this stage provided feedback to the staff of participating health centers. In the second stage, deficiencies in health care were identified and interventions were developed for improvements, including topics for continuing professional development.In the third stage, these strategies were piloted in a single health centre for one year and the outcomes evaluated. In the still ongoing fourth stage, the project was rolled out to all the health centers in the area, with continuing evaluation. The intervention consisted of changes to establish a structured care model based on the predicted needs of this group of patients utilizing dedicated chronic disease clinics inside the existing primary health care system. These clinics incorporated decision-making tools, including evidence-based guidelines, patient education and ongoing professional education., Results: The intervention was successfully implemented in all the health centers. The health care quality indicators that showed the greatest improvement were the documentation of patient history (e.g. smoking status and physical activity); improvement in recording physical signs (e.g. body mass index (BMI)); and an improvement in the requesting of appropriate investigations, such as HbA1c and microalbuminurea. There was also improvement in those parameters reflecting outcomes of care, which included HbA1c, blood pressure and lipid profiles. Indicators related to lifestyle changes, such as smoking cessation and BMI, failed to improve., Conclusion: Chronic disease care is a joint commitment by health care providers and patients. This combined approach proved successful in most areas of the project, but the area of patient self management requires further improvement.

Correlation between cycles in human stature and those in economic variables is well established. A recent review of international trends in this area provided information from most parts of the world but none on Arabs in the Middle East or more specifically the gulf region. The United Arab Emirates experienced a transformation in economic and social life followed the discovery of oil in the late 1960s and the wealth that it generated. No data is available on human growth at this period of time because its population never had health services prior to the 1970s. A study on conventional cardiovascular risk factors in 2004-2005 included 817 randomly selected national adults (> or =18 years) from both genders. The relationship between height and age in this study showed both men and women have increased in height with time demonstrating the secular change in height most likely a result of changing socioeconomic factors.

Background: Over the last 30 years the citizens of the United Arab Emirates have experienced major changes in life-style secondary to increased affluence. Currently, 1 in 5 adults have diabetes mellitus, but the associations (clustering) among risk factors, as well as the relevance of the concept of the metabolic syndrome, in this population is unknown., Aim: To investigate the prevalence and associations among cardiovascular risk factors in this population, and explore to what extent associations can be explained by the metabolic syndrome according to ATP-III criteria., Method: A community based survey, of conventional risk factors for cardiovascular disease was conducted among 817 national residents of Al Ain city, UAE. These factors were fasting blood sugar, blood pressure, lipid profile, BMI, waist circumference, smoking, or CHD family history. Odds ratios between risks factors, both unadjusted and adjusted for age and sex as well as adjusted for age, sex, and metabolic syndrome were calculated., Results: Various risk factors were positively associated in this population; associations that are mostly unexplained by confounding by age and sex. For example, hypertension and diabetes were still strongly related (OR 2.5; 95% CI 1.7-3.7) after adjustment. An increased waist circumference showed similar relationship with hypertension (OR 2.3; 95% CI 1.5-3.5). Diabetes was related to an increased BMI (OR 1.5; 96% CI 1.0-2.3). Smoking was also associated with diabetes (OR 1.9, 95% CI 1.0-3.3).Further adjustment for metabolic syndrome reduced some associations but several remained., Conclusion: In this population risk-factors cluster, but associations do not appear to be explained by the presence/absence of the ATP-III metabolic syndrome. Associations provide valuable information in planning interventions for screening and management.

Objectives: To examine the impact of an intensive HIV preventive intervention (IPI) among female sex workers (FSW) on community HIV transmission, as represented by HIV prevalence among young antenatal clinic (ANC) attenders in Karnataka state, south India., Methods: The IPI was initiated in 18 of the 27 districts in Karnataka in 2003, and was generally at scale by mid-2005, covering over 80% of the urban FSW population. We examined trends over time in HIV prevalence from annual HIV surveillance conducted among ANC attenders in Karnataka under the age of 25 years from 2003 to 2007, comparing the IPI with the other districts., Results: Overall, HIV prevalence among ANC attenders under 25 years of age declined from 1.40% to 0.77%. In a multivariate model, the decline in HIV prevalence in the IPI districts compared to the other districts was statistically significant (P = 0.01), with an adjusted annual odds ratio of 0.88 (95% CI 0.79-0.97). The decline in standardized HIV prevalence in the IPI districts over the period was 56%, compared to 5% in the non-IPI districts., Conclusions: Although this analysis is limited by lack of precise comparative data on intervention coverage and intensity, it supports the notion that scaled-up, intensive, targeted HIV preventive interventions among high-risk groups can have a measurable and relatively rapid impact on HIV transmission in the general population, particularly young sexually active populations as represented by ANC attenders. Such focused intervention programmes should be rapidly taken to scale in all HIV epidemics, and especially in concentrated epidemics such as in India.

Objectives: To estimate the antibiotic use of individuals visiting public healthcare facilities in Indonesia and to identify determinants of use against a background of high resistance rates., Methods: Patients on admission to hospital (group A), visiting a primary health center (group B), and healthy relatives (group C) were included in the study. A questionnaire on demographic, socioeconomic, and healthcare-related items including health complaints and consumption of antibiotics was used. Logistic regression was performed to determine the co-variables of antibiotic use., Results: Of 2996 individuals interviewed, 486 (16%) had taken an antibiotic. Compared to group C (7% consumption), groups B and A exhibited a three-fold and four-fold higher use of antibiotics, respectively. Respiratory (80%) and gastrointestinal (13%) symptoms were most frequent. Aminopenicillins and tetracyclines accounted for 80% of the prescribed antibiotics. Similar antibiotics were self-medicated (17% of users). Age less than 18 years and health insurance were independent determinants of antibiotic use. Urban provenance, being adult, male, and having no health insurance were independent determinants of self-medication., Conclusions: In addition to health complaints, other factors determined antibiotic consumption. In view of the likely viral origin of respiratory complaints and the resistance of intestinal pathogens, most antibiotic use was probably unnecessary or ineffective. Future interventions should be directed towards healthcare providers.

Objective: In the United Arab Emirates (UAE) cardiovascular mortality is a leading cause of death. Yet, there is a dearth of data on its risk factors., Methods: A cross-sectional community based study on established cardiovascular risk factors carried out between February 2004 - February 2005 in Al-Ain City, UAE. Subjects were interviewed, blood pressure, weight, height, fasting blood sugar, and lipid profile measured. Framingham risk scores were used for risk assessment., Results: Eight hundred seventeen subjects (403 males and 414 females) completed the survey, of these 28.4% had a Framingham risk assessment score of more than 20%, 23.3% had diabetes mellitus, 20.8% hypertension, 37.3% obesity, 22.7% metabolic syndrome, and 19.6% of male smoked. Coronary heart disease was reported in 2.4%. Lipid profiles were abnormal in 64% of the males, and in 53.9% of the females, mostly due to low high-density lipoproteins or high triglycerides levels., Conclusion: The overall cardiovascular risk assessment of the population screened calls for targeted interventions.

This article estimates the magnitude and quality of antibiotic prescribing in Indonesian hospitals and aims to identify demographic, socio-economic, disease-related and healthcare-related determinants of use. An audit on antibiotic use of patients hospitalized for 5 days or more was conducted in two teaching hospitals (A and B) in Java. Data were collected by review of records on the day of discharge. The method was validated through concurrent data collection in Hospital A. Multivariate logistic regression analysis was performed to determine variables to explain antibiotic prescribing. Prescriptions were assessed by three reviewers using standardized criteria. A high proportion (84%) of 999 patients (499 in Hospital A and 500 in Hospital B) received an antibiotic. Prescriptions could be categorized as therapeutic (53%) or prophylactic (15%), but for 32% the indication was unclear. Aminopenicillins accounted for 54%, and cephalosporins (mostly third generation) for 17%. The average level of antibiotic use amounted to 39 DDD/100 patient-days. Validation revealed that 30% of the volume could be underestimated due to incompleteness of the records. Predictors of antibiotic use were diagnosis of infection, stay in surgical or paediatric departments, low-cost nursing care, and urban residence. Only 21% of prescriptions were considered to be definitely appropriate; 15% were inappropriate regarding choice, dosage or duration, and 42% of prescriptions, many for surgical prophylaxis and fever without diagnosis of infection, were deemed to be unnecessary. Agreement among assessors was low (kappa coefficients 0.13-0.14). Despite methodological limitations, recommendations could be made to address the need for improving diagnosis, treatment and drug delivery processes in this setting.

Syndromic surveillance is increasingly used to signal unusual illness events. To validate data-source selection, we retrospectively investigated the extent to which 6 respiratory syndromes (based on different medical registries) reflected respiratory pathogen activity. These syndromes showed higher levels in winter, which corresponded with higher laboratory counts of Streptococcus pneumoniae, respiratory syncytial virus, and influenza virus. Multiple linear regression models indicated that most syndrome variations (up to 86%) can be explained by counts of respiratory pathogens. Absenteeism and pharmacy syndromes might reflect nonrespiratory conditions as well. We also observed systematic syndrome elevations in the fall, which were unexplained by pathogen counts but likely reflected rhinovirus activity. Earliest syndrome elevations were observed in absenteeism data, followed by hospital data (+1 week), pharmacy/general practitioner consultations (+2 weeks), and deaths/laboratory submissions (test requests) (+3 weeks). We conclude that these syndromes can be used for respiratory syndromic surveillance, since they reflect patterns in respiratory pathogen activity.

Objective: A group of commercial sex workers in the Pumwani Sex Worker Cohort, established in 1985 in Nairobi, Kenya, remain HIV-1 uninfected despite heavy exposure to HIV-1 through active sex work. Previous studies showed that this resistance is associated with a strong CD4+ T-cell response, which suggested that human leukocyte antigen class II antigens are important in resistance/susceptibility to HIV-1 infection. DRB1 is the most polymorphic locus among class II genes and forms haplotypes with DRB3, DRB4 and DRB5. The aim of this study is to investigate the role of DRB alleles/haplotypes on resistance/susceptibility to HIV-1 infection., Design: In total, 1090 women enrolled in the Pumwani cohort were genotyped for DRB1, DRB3, DRB4 and DRB5 using a high-resolution sequence-based method. Allele/haplotype frequencies were compared between HIV-positive women and women who have remained HIV negative for more than 3 years despite frequent exposure., Methods: Human leukocyte antigen DRB genes were amplified, sequenced and genotyped using a two-step sequence-based method. Allele/haplotype frequencies were determined using PyPop32-0.6.0. Statistical analysis was conducted using SPSS 11.0 for Windows., Results: Three DRB1 alleles were associated with resistance: DRB1*010101 (P = 0.016; odd ratio (OR): 2.55; 95% confidence interval (CI): 1.16-5.61), DRB1*010201 (P = 0.019; OR: 1.86; 95% CI: 1.10-3.15), and DRB1*1102 (P = 0.025; OR: 1.72; 95% CI: 1.07-2.78). DRB1*030201 (P = 0.038; OR: 0.48; 95% CI: 0.23-0.98), DRB1*070101 (P = 0.035; OR: 0.54; 95% CI: 0.30-0.97), DRB1*1503 (P = 0.0004; OR: 0.34; 95% CI: 0.19-0.64), and DRB5*010101 (P = 0.001; OR: 0.37; 95% CI: 0.20-0.67) were associated with susceptibility. The haplotype DRB1*1102-DRB3*020201 was associated with HIV-1 resistance (P = 0.041; OR: 1.68; 95% CI: 1.02-2.78), whereas the haplotypes DRB1*070101-DRB4*01010101 (P = 0.041; OR: 0.52; 95% CI: 0.28-0.98) and DRB1*1503-DRB5*01010101 (P = 0.0002; OR: 0.30; 95% CI: 0.15-0.58) were associated with susceptibility. These associations with resistance/susceptibility to HIV-1 were independent of previously reported alleles HLA-DRB1*01 and HLA-A*2301., Conclusion: Our findings indicate that human leukocyte antigen DRB-specific CD4+ T-cell responses are an important factor in resistance/susceptibility to HIV-1 infection.

Background: Pre-exposure prophylaxis (PrEP) is a promising new HIV prevention method, especially for women. An urgent demand for implementation of PrEP is expected at the moment efficacy has been demonstrated in clinical trials. We explored the long-term impact of PrEP on HIV transmission in different HIV epidemics., Methodology/principal Findings: We used a mathematical model that distinguishes the general population, sex workers and their clients. PrEP scenarios varying in effectiveness, coverage and target group were modeled in the epidemiological settings of Botswana, Nyanza Province in Kenya, and Southern India. We also studied the effect of condom addition or condom substitution during PrEP use. Main outcome was number of HIV infections averted over ten years of PrEP use. PrEP strategies with high effectiveness and high coverage can have a substantial impact in African settings. In Southern India, by contrast, the number of averted HIV infections in different PrEP scenarios would be much lower. The impact of PrEP may be strongly diminished or even reversed by behavioral disinhibition, especially in scenarios with low coverage and low effectiveness. However, additional condom use during low coverage and low effective PrEP doubled the amount of averted HIV infections., Conclusions/significance: The public health impact of PrEP can be substantial. However, this impact may be diminished, or even reversed, by changes in risk behavior. Implementation of PrEP strategies should therefore come on top of current condom campaigns, not as a substitution.

Objectives: To determine the association of DQ antigens with resistance and susceptibility to HIV-1., Design: Despite repeated exposure to HIV-1, a subset of women in the Pumwani Sex Worker cohort established in Nairobi, Kenya in 1985 have remained HIV-1 negative for at least 3 years and are classified as resistant. Differential susceptibility to HIV-1 infection is associated with HIV-1 specific CD4 and CD8 T cell responses. As human leukocyte antigen-DQ antigens present viral peptides to CD4 cells, we genotyped human leukocyte antigen -DQ alleles for 978 women enrolled in the cohort and performed cross-sectional and longitudinal analyses to identify associations of human leukocyte antigen -DQ with resistance/susceptibility to HIV-1., Methods: DQA1 and DQB1 were genotyped using taxonomy-based sequence analysis. SPSS 13.0 was used to determine associations of DQ alleles/haplotypes with HIV-1 resistance, susceptibility, and seroconversion rates., Results: Several DQB1 alleles and DQ haplotypes were associated with resistance to HIV-1 infection. These included DQB1*050301 (P = 0.055, Odds Ratio = 12.77, 95% Confidence Interval = 1.44-112), DQB1*0603 and DQB1*0609 (P = 0.037, Odds Ratio = 3.25, 95% Confidence Interval = 1.12-9.47), and DQA1*010201-DQB1*0603 (P = 0.044, Odds Ratio = 17.33, 95% Confidence Interval = 1.79-168). Conversely, DQB1*0602 (P = 0.048, Odds Ratio = 0.68, 95% Confidence Interval = 0.44-1.05) and DQA1*010201-DQB1*0602 (P = 0.039, Odds Ratio = 0.64, 95% Confidence Interval = 0.41-1.03) were overrepresented in the HIV-1 infected population. DQA1*0504-DQB1*0201, DQA1*010201-DQB1*0201, DQA1*0402-DQB1*0402 and DQA1*0402-DQB1*030101 genotypes were only found in HIV-1 positive subjects (Odds Ratio = 0.30-0.31, 95% Confidence Interval = 0.03-3.70), and these women seroconverted rapidly. The associations of these DQ alleles and haplotypes with resistance and susceptibility to HIV-1 were independent of the previously reported human leukocyte antigen-DRB*01, human leukocyte antigen A2/6802, and human leukocyte antigen-A*2301., Conclusion: The associations of DQ alleles and haplotypes with resistance and susceptibility to HIV-1 emphasize the importance of human leukocyte antigen-DQ and CD4 in anti-HIV-1 immunity.

Human immunodeficiency virus type 1 (HIV-1) is able to evade the host cytotoxic T-lymphocyte (CTL) response through a variety of escape avenues. Epitopes that are presented to CTLs are first processed in the presenting cell in several steps, including proteasomal cleavage, transport to the endoplasmic reticulum, binding by the HLA molecule, and finally presentation to the T-cell receptor. An understanding of the potential of the virus to escape CTL responses can aid in designing an effective vaccine. To investigate such a potential, we analyzed HIV-1 gag from 468 HIV-1-positive Kenyan women by using several bioinformatic approaches that allowed the identification of positively selected amino acids in the HIV-1 gag region and study of the effects that these mutations could have on the various stages of antigen processing. Correlations between positively selected residues and mean CD4 counts also allowed study of the effect of mutation on HIV disease progression. A number of mutations that could create or destroy proteasomal cleavage sites or reduce binding affinity of the transport antigen processing protein, effectively hindering epitope presentation, were identified. Many mutations correlated with the presence of specific HLA alleles and with lower or higher CD4 counts. For instance, the mutation V190I in subtype A1-infected individuals is associated with HLA-B*5802 (P = 4.73 x 10(-4)), a rapid-progression allele according to other studies, and also to a decreased mean CD4 count (P = 0.019). Thus, V190I is a possible HLA escape mutant. This method classifies many positively selected mutations across the entire gag region according to their potential for immune escape and their effect on disease progression.

Objectives: Female sex workers (FSWs) form a core group at high risk of both sexual HIV acquisition and secondary transmission. The magnitude of these risks may vary by sexual risk taking, partner HIV prevalence, host immune factors and genital co-infections. We examined temporal trends in HIV prevalence and per-act incidence, adjusted for behavioral and other variables, in FSWs from Nairobi, Kenya., Methods: An open cohort of FSWs followed since 1985. Behavioral and clinical data were collected six monthly from 1985 to 2005, and sexually transmitted infection (STI) diagnostics and HIV serology performed. A Cox proportional hazards model with time-dependent covariables was used to estimate infection risk as a function of calendar time., Results: HIV prevalence in new FSW enrollees peaked at 81% in 1986, and was consistently below 50% after 1997. Initially uninfected FSWs remained at high risk of acquiring HIV throughout the study period, but the rate of HIV acquisition during unprotected sex with a casual client declined by over four-fold. This reduction correlated closely with decreases in gonorrhea prevalence, and predated reductions in the Kenyan HIV population prevalence by over a decade., Conclusions: The per-act rate of HIV acquisition in high-risk Nairobi FSWs fell dramatically between 1985 and 2005. This decline may represent the impact of improved STI prevention/therapy, immunogenetic shifts in at-risk women, or changes in the proportion of HIV exposures occurring with clients who had acute HIV infection. Declining HIV incidence in high-risk cohorts may predict and/or be causally related to future reductions in population prevalence.

Background: Prevalent herpes simplex virus type 2 (HSV-2) infection increases human immunodeficiency virus acquisition. We hypothesized that HSV-2 infection might also predispose individuals to acquire other common sexually transmitted infections (STIs)., Methods: We studied the association between prevalent HSV-2 infection and STI incidence in a prospective, randomized trial of periodic STI therapy among Kenyan female sex workers. Participants were screened monthly for infection with Neisseria gonorrhoeae and Chlamydia trachomatis, and at least every 6 months for bacterial vaginosis (BV) and infection with Treponema pallidum, Trichomonas vaginalis, and/or HSV-2., Results: Increased prevalence of HSV-2 infection and increased prevalence of BV were each associated with the other; the direction of causality could not be determined. After stratifying for sexual risk-taking, BV status, and antibiotic use, prevalent HSV-2 infection remained associated with an increased incidence of infection with N. gonorrhoeae (incidence rate ratio [IRR], 4.3 [95% confidence interval {CI}, 1.5-12.2]), T. vaginalis (IRR, 2.3 [95% CI, 1.3-4.2]), and syphilis (IRR, 4.7 [95% CI, 1.1-19.9]). BV was associated with increased rates of infection with C. trachomatis (IRR, 2.1 [95% CI, 1.1-3.8]) and T. vaginalis (IRR, 8.0 [95% CI, 3.2-19.8]). CONCLUSION; Increased prevalences of HSV-2 infection and BV were associated with each other and also associated with enhanced susceptibility to an overlapping spectrum of other STIs. Demonstration of causality will require clinical trials that suppress HSV-2 infection, BV, or both.

This study documents the determinants and plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) among hypertensive and normotensive subjects in a multi-ethnic population in the United Arab Emirates (UAE). We obtained demographic, anthropometric and clinical data, together with fasting NT-proBNP and biochemical indices from 128 hypertensive patients and 138 normotensive subjects matched for age, gender and ethnicity. Plasma NT-proBNP levels were significantly (P<0.001), and several-fold higher among hypertensives (median 5.92, inter quartile range (IQR): 1.79-18.48 pmol/l) than normotensives (median 1.78, IQR: 0.59-4.32 pmol/l) in the total study population, and the same was true for the ethnic groups separately. Similarly, plasma levels of glucose, blood urea nitrogen (BUN) and creatinine, but not insulin, were significantly (P<0.05) higher among hypertensives than normotensives. For all subjects combined, log NT-proBNP correlated positively and significantly with age (P<0.01), log glucose (P<0.05), systolic blood pressure (SBP, P<0.001), log BUN (P<0.001) and log creatinine (P<0.001). Multivariate regression analysis showed that NT-proBNP levels were independently and positively correlated with SBP, age, gender, log BUN, Emirati and South East Asian ethnic groups and inversely associated with current exercise. In conclusion, we found circulating levels of NT-proBNP to be significantly increased in hypertensive versus normotensive subjects in the UAE and independently related to SBP, age, gender, indices of renal function and possibly exercise. Our results further suggest a possible modulating effect of ethnicity on NT-proBNP levels.

Background: Recent clinical trials in Africa, in combination with several observational epidemiological studies, have provided evidence that male circumcision can reduce HIV female-to-male transmission risk by 60% or more. However, the public health impact of large-scale male circumcision programs for HIV prevention is unclear., Methods: Two mathematical models were examined to explore this issue: a random mixing model and a compartmental model that distinguishes risk groups associated with sex work. In the compartmental model, two scenarios were developed, one calculating HIV transmission and prevalence in a context similar to the country of Botswana, and one similar to Nyanza Province, in western Kenya., Results: In both models, male circumcision programs resulted in large and sustained declines in HIV prevalence over time among both men and women. Men benefited somewhat more than women, but prevalence among women was also reduced substantially. With 80% male circumcision uptake, the reductions in prevalence ranged from 45% to 67% in the two "countries", and with 50% uptake, from 25% to 41%. It would take over a decade for the intervention to reach its full effect., Conclusion: Large-scale uptake of male circumcision services in African countries with high HIV prevalence, and where male circumcision is not now routinely practised, could lead to substantial reductions in HIV transmission and prevalence over time among both men and women.

Objective: To compare the rate of surgical site infection (SSI) before and after an intervention period in which an optimized policy for antibiotic prophylaxis was implemented. To demonstrate that a more prudent, restrictive policy would not have a detrimental effect on patient outcomes., Design: Before-after trial with prospective SSI surveillance in the Dutch nosocomial surveillance network (Preventie Ziekenhuisinfecties door Surveillance [PREZIES]), using the criteria of the Centers for Disease Control, including postdischarge surveillance for up to 1 year., Methods: During a preintervention period and a postintervention period (both 6-13 months), 12 Dutch hospitals collected data on antimicrobial prophylaxis and SSI rates. The study was limited to commonly performed surgical procedures in 4 specialties: vascular, intestinal, gynecological and orthopedic surgery. Selected risk factors for analysis were sex, age, American Society of Anesthesiologists classification, wound contamination class, duration of surgery, length of hospital stay before surgery, and urgency of surgery (elective or acute)., Results: A total of 3,621 procedures were included in the study, of which 1,668 were performed before the intervention and 1,953 after. The overall SSI rate decreased from 5.4% to 4.5% (P=.22). Among the procedures included in the study, the largest proportion (55%) were total hip arthroplasty, and the smallest proportion (2%) were replacement of the head of the femur. SSI rates varied from 0% for vaginal hysterectomy to 21.1% for femoropopliteal or femorotibial bypass surgery. Crude and adjusted odds ratios showed that there were no significant changes in procedure-specific SSI rates after the intervention (P>.1)., Conclusions: An optimized and restrictive antibiotic prophylaxis policy had no detrimental effect on the outcome of clean and clean contaminated surgery, as measured by SSI rate.

Objective: To estimate the proportion of antiretroviral therapy (ART) eligible adults (15-49 years) with tuberculosis potentially identifiable through tuberculosis services using a CD4 count below 350 cells/mm3 as cut-off value for ART initiation., Methods: Using TB notification rate data, HIV seroprevalence data, and estimates of the size of the adult population (15-49 years) in 18 sub-Saharan African countries with an HIV seroprevalence of > 5%, calculations of the number of ART eligible adults with tuberculosis presenting to tuberculosis services were made. Assumptions were made on the tuberculosis notification rates in the age-group 15-49 years, the HIV-infected population with a CD4 count below 350 cells/mm3 and the relative risk of developing tuberculosis, and average duration from HIV infection to death. The probability of having a CD4+ count below 350 cells/mm3 given a diagnosis of tuberculosis was estimated using Bayes' theorem, and estimates of the number of patients with a CD4 count below 350 cells/mm3 identifiable through tuberculosis were made. The number needed to screen to identify one ART eligible patient through tuberculosis services was estimated for each country., Results: ART eligible adults with tuberculosis potentially identifiable through tuberculosis services in the 18 countries ranged from 2% to 18% of the total HIV-infected adult population with a CD4+ count below 350 cells/mm3 and would average 10% of all such HIV patients. The number needed to screen to identify ART eligible patients through tuberculosis services ranged from 1.4 to 4.2, against 8.6 to 65.4 if adults aged 15-49 are randomly screened for low CD4 counts., Conclusion: Tuberculosis services are an important entry point for identifying ART eligible patients. Given that dually infected patients identified through tuberculosis services contributed to 10% of the HIV-infected adult population with a CD4 cell count below 350 cells/mm3 in the 18 sub-Saharan African countries, major efforts are required beyond the tuberculosis services in detecting patients that should benefit from ART. However, the low number needed to screen gives opportunity to use tuberculosis services in AIDS control and ART scaling-up programmes.

Background: Factors determining human sexual behaviour are not completely understood, but are important in the context of sexually transmitted disease epidemiology and prevention. Being obese is commonly associated with a reduced physical attractiveness but the associations between body mass index, sexual behaviour and the risk of acquiring sexually transmitted infections has never been studied., Methods: The National Health and Nutrition Examination Survey (NHANES) files of 1999-2000 were used. Linear regression was used to relate the reported number of sex partners in the last year and lifetime to Body Mass Index (BMI). Logistic regression was used to relate Herpes Simplex Virus type II (HSV-2) antibodies to BMI and other variables., Results: Data on 979 men and 1250 women were available for analysis. Obese (mean number of partners for men:1.12, women: 0.93) and overweight (mean for men: 1.38, women: 1.03) individuals reported fewer partners than individuals of normal BMI (mean for men: 2.00, women: 1.15) in the last year (p < .0.01 & p < 0.05 for men, p < 0.05 & n.s. for women). The same relationship held for lifetime partners in men (mean 11.94, 18.80, and 22.08 for obese, overweight and normal BMI respectively (p < 0.05 & n.s. for obese and overweight vs normal respectively), but not in women (mean 7.96, 4.77, and 5.24 respectively). HSV-2 antibodies were significantly correlated with the number of lifetime partners in both men and women, with the odds of being HSV-2 positive increasing by 0.6% (p < 0.01) and 2.7% (p < 0.01) for men and women respectively. HSV-2 antibodies increased with age, even after adjustment for lifetime partners (p < 0.01). Being obese (HSV-2 prevalence 15.9 and 34.9% for men and women respectively) or overweight (HSV-2 prevalence 16.7 and 29.3 for men and women respectively) was not associated with HSV-2 antibodies (HSV-2 prevalence for normal BMI: 15.6 and 23.2% respectively), independent of whether the association was adjusted for life time sexual partners or not. There was evidence of substantial misreporting of sexual behaviour., Conclusion: Obese and overweight individuals, especially men, self report fewer sex partners than individuals of normal weight, but surprisingly this is not reflected in their risk of HSV-2 infection. HSV-2 antibodies provide information not contained in self-reported number of partners and may better estimate sexual risk than self-reported behaviour.

In interphase, chromosomes occupy defined nuclear volumes known as chromosome territories. To probe the biological consequences of the described nonrandom spatial positioning of chromosome territories in human lymphocytes, we performed an extensive FISH-based analysis of ionizing radiation-induced interchanges involving chromosomes 1, 4, 18 and 19. Since the probability of exchange formation depends strongly on the spatial distance between the damage sites in the genome, a preferential formation of exchanges between proximally positioned chromosomes is expected. Here we show that the spectrum of interchanges deviates significantly from one expected based on random chromosome positioning. Moreover, the observed exchange interactions between specific chromosome pairs as well as the interactions between homologous chromosomes are consistent with the proposed gene density-related radial distribution of chromosome territories. The differences between expected and observed exchange frequencies are more pronounced after exposure to densely ionizing neutrons than after exposure to sparsely ionizing X rays. These experiments demonstrate that the spatial positioning of interphase chromosomes affects the spectrum of chromosome rearrangements.

Background: Hypertension, notably untreated or uncontrolled, is a major risk factor for cardiovascular diseases (CVD) morbidity and mortality. In countries in transition, little is known about the epidemiology of hypertension, and its biochemical correlates. This study was carried out in Al Ain, United Arab Emirates, to characterize self-reported (SR) normotensives and hypertensives in terms of actual hypertension status, demographic variables, CVD risk factors, treatment, and sequalae., Methods: A sample, stratified by SR hypertensive status, of 349 SR hypertensives (Mean age +/- SD; 50.8 +/- 9.2 yrs; Male: 226) and 640 SR normotensives (42.9 +/- 9.3 yrs, Male: 444) among nationals and expatriates was used. Hypertensives and normotensive subjects were recruited from various outpatient clinics and government organizations in Al-Ain city, United Arab Emirates (UAE) respectively. Anthropometric and demographic variables were measured by conventional methods., Results: Both under-diagnosis of hypertension (33%) and under-treatment (76%) were common. Characteristics of undiagnosed hypertensives were intermediate between normotensives and SR hypertensives. Under-diagnosis of hypertension was more common among foreigners than among nationals. Risk factors for CVD were more prevalent among SR hypertensives. Obesity, lack of exercise and smoking were found as major risk factors for CVD among hypertensives in this population., Conclusion: Hypertension, even severe, is commonly under-diagnosed and under-treated in the UAE. Preventive strategies, better diagnosis and proper treatment compliance should be emphasized to reduce incidence of CVD in this population.

Studies on a dose-response relation often report separate relative risks for several risk classes compared with a referent class. When performing a meta-analysis of such studies, one has to convert these relative risks into an overall relative risk for a continuous effect. Apart from taking the dependence between separate relative risks into account, this implies assigning an exposure level to each risk factor class and allowing for the nonlinearity of the dose-response relation. The authors describe a relatively simple method solving these problems. As an illustration, they applied this method in a meta-analysis of the association between body mass index and diabetes type 2, restricted to results of follow-up studies (n=31). Results were compared with a more ad hoc method of assigning exposure levels and with a method in which the nonlinearity of the dose-response method was not taken into account. Differences with the ad hoc method were larger in studies with fewer categories. Not incorporating the nonlinearity of the dose response leads to an overestimation of the pooled relative risk, but this bias is relatively small.

The distribution of antibody levels to Legionella (L.) pneumophila (serotypes 1-7) was compared between subjects who worked near the source of a large outbreak of Legionnaires' disease (n=668) and a population sample of comparable age (n=480). In a previous analysis of these data, it was estimated that 80% of those working near the source were infected with L. pneumophila. However, the estimation procedure implicitly assumes that the probability of infection does not depend on the antibody level of a person before exposure. This is questionable, as antibodies could protect against infection. We have now estimated the minimum value consistent with the data on the number of infected persons. We observed that a minimum of 40% [95% confidence interval (CI) 32-48] of those working near the source and 13% (95% CI 8-18) of those working further away were infected with L. pneumophila. Implications of these findings for design options in future research are discussed.

The susceptibility to and the severity of Bordetella pertussis infections in infants and children varies widely, suggesting that genetic differences between individuals influence the course of infection. We have previously identified three novel loci that influence the severity of whooping cough by using recombinant congenic strains of mice: Bordetella pertussis susceptibility loci 1, 2, and 3 (Bps1, -2, and -3). Because these loci could not account for all genetic differences between mice, we extended our search for additional susceptibility loci. We therefore screened 11 inbred strains of mice for susceptibility to a pertussis infection after intranasal infection. Susceptibility was defined by the number of bacteria in the lungs, being indicative of the effect between the clearance and replication of bacteria. The most resistant (A/J) and the most susceptible (C3H/HeJ) strains were selected for further genetic and phenotypic characterization. The link between bacterial clearance and chromosomal location was investigated with 300 F2 mice, generated by crossing A/J and C3H/HeJ mice. We found a link between the delayed clearance of bacteria from the lung and a large part of chromosome 4 in F2 mice with a maximum log of the odds score of 33.6 at 65.4 Mb, which is the location of Tlr4. C3H/HeJ mice carry a functional mutation in the intracellular domain of Tlr4. This locus accounted for all detectable genetic differences between these strains. Compared to A/J mice, C3H/HeJ mice showed a delayed clearance of bacteria from the lung, a higher relative lung weight, and increased body weight loss. Splenocytes from infected C3H/HeJ mice produced almost no interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) upon ex vivo restimulation with B. pertussis compared to A/J mice and also showed a delayed gamma interferon (IFN-gamma) production. TNF-alpha expression in the lungs 3 days after infection was increased fivefold compared to uninfected controls in A/J mice and was not affected in C3H/HeJ mice. In conclusion, Tlr4 is a major host factor explaining the differences in the course of infection between these inbred strains of mice. Functional Tlr4 is essential for an efficient IL-1-beta, TNF-alpha, and IFN-gamma response; efficient clearance of bacteria from the lung; and reduced lung pathology.