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Background Children are particularly susceptible to tuberculosis. However, most children exposed to Mycobacterium tuberculosis are able to control the pathogen without evidence of infection. Correlates of human protective immunity against tuberculosis infection are lacking, and their identification would aid vaccine design. Methods We recruited pairs of asymptomatic children with discordant tuberculin skin test status but the same sleeping proximity to the same adult with sputum smear-positive tuberculosis in a matched case-control study in The Gambia. Participants were classified as either Highly TB-Exposed Uninfected or Highly TB-Exposed Infected children. Serial luminescence measurements using an in vitro functional auto-luminescent Bacillus Calmette–Guerin (BCG) whole blood assay quantified the dynamics of host control of mycobacterial growth. Assay supernatants were analysed with a multiplex cytokine assay to measure associated inflammatory responses. Findings 29 pairs of matched Highly TB-Exposed Uninfected and Highly TB-Exposed Infected children aged 5 to 15 years old were enroled. Samples from Highly TB-Exposed Uninfected children had higher levels of mycobacterial luminescence at 96 hours than Highly TB-Exposed Infected children. Highly TB-Exposed Uninfected children also produced less BCG-specific interferon-γ than Highly TB-Exposed Infected children at 24 hours and at 96 hours. Interpretation Highly TB-Exposed Uninfected children showed less control of mycobacterial growth compared to Highly TB-Exposed Infected children in a functional assay, whilst cytokine responses mirrored infection status. Funding Clinical Research Training Fellowship funded under UK Medical Research Council/Department for International Development Concordat agreement and part of EDCTP2 programme supported by European Union (MR/K023446/1). Also MRC Program Grants (MR/K007602/1, MR/K011944/1, MC_UP_A900/1122).

Background This paper reports on the baseline prevalence and associated risk factor findings of a pilot, longitudinal study exploring community-wide treatment of schistosomiasis and soil-transmitted helminthiasis, using albendazole plus praziquantel in the Greater Accra region of Ghana. Method From three communities, at least, 658 individuals were enrolled into the study via random household selection. Prevalence and intensity of schistosomiasis and STH infection were determined from stool and urine samples with a questionnaire being administered in order to explore other morbidities and risk factors. Factor analysis of household demographic variables was undertaken to generate a socioeconomic score; this was then further categorised into tertiles. Proportional-odds cumulative logit generalised estimating equation (GEE) models were used to investigate categorical ordinal intensity of infection associations with morbidity. Separately, logistic GEE models were used to investigate risk factor associations with infection prevalence. Results Both Schistosoma haematobium and S. mansoni were prevalent in the three communities, with the prevalence of S. haematobium ranging from 3.3% (24/679; 95% CI = 1.9–4.7) to 19% (114/632; 95% CI = 15.8–22.2) and S. mansoni ranging from 30% (202/679; 95% CI = 26.5–33.5) to 78.3% (409/536; 95% CI = 74.7–81.9). The total prevalence of STH across all three sites was negligible at 1.3% (24/1847; 95% CI = 0.8–1.9) comprising mainly hookworm (10/1847). Multivariable statistical models indicated males to be 2.3 (95% CI = 1.7–3.3) times more likely to have a high intensity S. mansoni infection and 1.5 (95% CI = 1.1–2) times more likely to have a high intensity of S. haematobium infection compared to females. There was no significant difference in the likelihood of infection with S. mansoni between adults and school age children (SAC), however S. haematobium infections were found to be 2.5 (95% CI = 1.8–3.5) times more likely to occur in school age children than in adults. Multivariable statistical models (adjusted for age and sex) indicated an association between schistosomiasis and a number of self-reported morbidity indicators (notably diarrhoea and blood in stool and urine). Low socio-economic status was also associated with SCH infection (OR: 2; 95% CI = 1.3–3.2). Conclusion The communities targeted by this study showed a range of Schistosoma prevalence’s of infection, from hypo-endemic through to meso-endemic and hyper-endemic. The prevalence of SCH across the different age groups in the study locations highlights the large number of individuals currently being left out of the standard morbidity control method of annual treatment of the SAC., Author summary In this manuscript we detail the baseline results of a broader study investigating the feasibility of expanding access of albendazole and praziquantel to additional at-risk groups in three communities (Tomefa, Maheam and Torgahkope-Adakope) located around the Weija reservoir in the Greater Accra district of Ghana. Our results show that intestinal schistosomiasis was the most common form of disease across all three sites (44.2%) with Tomefa possessing the highest prevalence at 78.3%. The prevalence of urinary schistosomiasis was found to be 11.9% with the highest prevalence found in Torgahkope-Adakope (19%). STH was found to have a very low prevalence across the three communities with only 1.3% of participants found to be positive. No significant difference in STH prevalence was observed between males (0.92%; 95% CI = 0.4–1.81) and females (1.07%; 95% CI = 0.51–1.95). Statistical analysis revealed that males were more likely to be infected and to have high intensity infections of both forms of schistosomiasis. Pre-school age children (PSAC) were found to be less likely to be infected for either form of schistosomiasis in communities with low to medium prevalence of disease, however in Tomefa, where prevalence of intestinal schistosomiasis is high, there was little difference in the prevalence of disease between PSAC, school-age children (SAC) and adults. Our study shows that there is a need to treat the wider community outside of the current morbidity control strategy of mass-drug administration to SAC.

Objective To describe the rates and risk factors for stillbirth and pre-discharge neonatal mortality (PDNM), and impact on quality of life (QoL) among women with postpartum hemorrhage (PPH). Methods A secondary analysis was conducted of the WOMAN trial, which evaluated the use of tranexamic acid for PPH and collected infant outcome data to assess drug safety. The analysis was restricted to singletons (n=18 942). Overall and country-level rates of stillbirth and PDNM were calculated. Multilevel logistic regression models examined the association of stillbirth and PDNM with selected risks, and the association of mother's QoL at discharge after stillbirth or PDNM. Results For women with PPH, the rate of stillbirths was 104.42 per 1000 births (n=1978) and the rate of PDNM was 15.56 per 1000 live births (n=264). Cesarean delivery, increasing blood loss, maternal complications, and maternal death were strongly associated with these adverse outcomes. Women with stillbirth and PDNM were significantly more likely to report poorer QoL. Conclusion Women with PPH experience an extremely high rate of stillbirth and slightly elevated PDNM, which is associated with markers of the severity of their condition and impacts on their QoL.

Background: Children are particularly susceptible to tuberculosis. However, most children exposed to Mycobacterium tuberculosis are able to control the pathogen without evidence of infection. Correlates of human protective immunity against tuberculosis infection are lacking, and their identification would aid vaccine design. Methods: We recruited pairs of asymptomatic children with discordant tuberculin skin test status but the same sleeping proximity to the same adult with sputum smear-positive tuberculosis in a matched case-control study in The Gambia. Participants were classified as either Highly Exposed Uninfected [HEU] or Highly Exposed Infected [HEI] children. Serial luminescence measurements using an in vitro functional auto-luminescent Bacillus Calmette–Guerin (BCG) whole blood assay quantified the dynamics of host control of mycobacterial growth. Assay supernatants were analysed with a multiplex cytokine assay to measure associated inflammatory responses. Findings: 29 pairs of matched HEI and HEU children aged 5 to 15 years old were enrolled. Samples from HEU children had higher levels of mycobacterial luminescence at 96H than HEI children. HEU children also produced less BCG-specific interferon-γ than HEI children at 24 hours and at 96 hours. Interpretation: HEI children showed superior control of mycobacterial growth compared to HEU children in a functional assay whilst cytokine responses mirrored infection status. Funding: Clinical Research Training Fellowship jointly funded by UK Medical Research Council (MRC) and UK Department for International Development (DFID) under MRC/DFID Concordat agreement and part of the EDCTP2 programme supported by the European Union (MR/K023446/1). Also enabled by MRC Program Grants (MR/K007602/1, MR/K011944/1, MC_UP_A900/1122). Declaration of Interests: BK holds a patent for a paediatric TB diagnostic biosignature. The authors do not have any other commercial or other association that might pose a conflict of interest. The data presented here form part of RB’s PhD thesis “Protection from Mycobacterium tuberculosis infection: Learning from exposed but uninfected children” awarded March 2018 by Imperial College London. Ethics Approval Statement: The study was approved by The Gambia Government/MRC Joint Ethics Committee (SCC1405 and SCC1273) and the Imperial College Healthcare Tissue Bank (R13071).

Sepsis and meningitis due to invasive group B Streptococcus (iGBS) disease during early infancy is a leading cause of child mortality. Recent systematic estimates of the worldwide burden of GBS suggested that there are 319,000 cases of infant iGBS disease each year, and an estimated 147,000 stillbirths and young-infant deaths, with the highest burden occurring in Sub-Saharan Africa. The following priority data gaps were highlighted: (1) long-term outcome data after infant iGBS, including mild disability, to calculate quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs) and (2) economic burden for iGBS survivors and their families. Geographic data gaps were also noted with few studies from low- and middle- income countries (LMIC), where the GBS burden is estimated to be the highest. In this paper we present the protocol for a multi-country matched cohort study designed to estimate the risk of long-term neurodevelopmental impairment (NDI), socioemotional behaviors, and economic outcomes for children who survive invasive GBS disease in Argentina, India, Kenya, Mozambique, and South Africa. Children will be identified from health demographic surveillance systems, hospital records, and among participants of previous epidemiological studies. The children will be aged between 18 months to 17 years. A tablet-based custom-designed application will be used to capture data from direct assessment of the child and interviews with the main caregiver. In addition, a parallel sub-study will prospectively measure the acute costs of hospitalization due to neonatal sepsis or meningitis, irrespective of underlying etiology. In summary, these data are necessary to characterize the consequences of iGBS disease and enable the advancement of effective strategies for survivors to reach their developmental and economic potential. In particular, our study will inform the development of a full public health value proposition on maternal GBS immunization that is being coordinated by the World Health Organization.

Neonatal invasive disease caused by Group B Streptococcus (GBS) is responsible for much acute mortality and long-term morbidity. To guide development of better prevention strategies, including maternal vaccines that protect neonates against GBS, it is necessary to estimate the burden of this condition globally and in different regions. Here, we present a Bayesian model that estimates country-specific invasive GBS (iGBS) disease incidence in children aged 0 to 6 days. The model combines different types of epidemiological data, each of which has its own limitations: GBS colonization prevalence in pregnant women, risk of iGBS disease in children born to GBS-colonized mothers and direct estimates of iGBS disease incidence where available. In our analysis, we present country-specific maternal GBS colonization prevalence after adjustment for GBS detection assay used in epidemiological studies. We then integrate these results with other epidemiological data and estimate country-level incidence of iGBS disease including in countries with no studies that directly estimate incidence. We are able to simultaneously estimate two key epidemiological quantities: the country-specific incidence of early-onset iGBS disease, and the risk of iGBS disease in babies born to GBS-colonized women. Overall, we believe our method will contribute to a more comprehensive quantification of the global burden of this disease, inform cost-effectiveness assessments of potential maternal GBS vaccines and identify key areas where data are necessary., Author summary Invasive disease caused by Group B Streptococcus (GBS) in young infants continues to be a major public health problem in both developed and developing countries. However, data on the incidence of this infection during the first week of life are only available for a small number of countries, which has complicated the quantification of the burden of this disease globally. In this paper, we develop a Bayesian framework to estimate the incidence of invasive GBS infection that combines data from multiple types of epidemiological studies, with adjustment for relevant factors such as diagnostic methods used in the studies. We present estimates from a series of models, and our results highlight the potential weaknesses of different types of studies and the importance to consider the entire evidence when estimating global burden of invasive neonatal infections. We believe this model is a step toward better quantification of the number of cases in different regions.

Background In the absence of a consensus on definition and measurement of healthy ageing, we created a healthy ageing index tallying with the functional ability framework provided by the World Health Organization. To create this index, we employed items of functional ability and intrinsic capacity. The current study aims to establish the predictive validity and discrimination properties of this healthy ageing index in settings in Latin American, part of the 10/66 cohort. Methods Population-based cohort studies including 12,865 people ≥65 years old in catchment areas of Cuba, Dominican Republic, Venezuela, Mexico and Peru. We employed latent variable modelling to estimate the healthy ageing scores of each participant. We grouped participants according to the quintiles of the healthy ageing score distribution. Cox’s proportional hazard models for mortality and sub-hazard (competing risks) models for incident dependence (i.e. needing care) were calculated per area after a median of 3.9 years and 3.7 years, respectively. Results were pooled together via fixed-effects meta-analysis. Our findings were compared with those obtained from self-rated health. Results Participants with lowest levels, compared to participants with highest level of healthy ageing, had increased risk of mortality and incident dependence, even after adjusting for sociodemographic and health conditions (HR: 3.25, 95%CI: 2.63–4.02; sub-HR: 5.21, 95%CI: 4.02–6.75). Healthy ageing scores compared to self-rated health had higher population attributable fractions (PAFs) for mortality (43.6% vs 19.3%) and incident dependence (58.6% vs 17.0%), and better discriminative power (Harrell’s c-statistic: mortality 0.74 vs 0.72; incident dependence 0.76 vs 0.70). Conclusion These results provide evidence that our healthy ageing index could be a valuable tool for prevention strategies as it demonstrated predictive and discriminative properties. Further research in other cultural settings will assist moving from a theoretical conceptualisation of healthy ageing to a more practical one.

The widely used nasally-administered Live Attenuated Influenza Vaccine (LAIV) alters the dynamics of naturally occurring nasopharyngeal carriage ofStreptococcus pneumoniaein animal models. Using a human experimental model (serotype 6B) we tested two hypotheses: 1) LAIV increased the density ofS. pneumoniaein those already colonised; 2) LAIV administration promoted colonisation. Randomised, blinded administration of LAIV or nasal placebo either preceded bacterial inoculation or followed it, separated by a 3-day interval. The presence and density ofS. pneumoniaewas determined from nasal washes by bacterial culture and PCR. Overall acquisition for bacterial carriage were not altered by prior LAIV administration vs. controls (25/55 [45.5%] vs 24/62 [38.7%] respectively, p=0.46). Transient increase in acquisition was detected in LAIV recipients at day 2 (33/55 [60.0%] vs 25/62 [40.3%] in controls, p=0.03). Bacterial carriage densities were increased approximately 10-fold by day 9 in the LAIV recipients (2.82 vs 1.81 log10titers, p=0.03). When immunisation followed bacterial acquisition (n=163), LAIV did not change area under the bacterial density-time curve (AUC) at day 14 by conventional microbiology (primary endpoint), but significantly reduced AUC to day 27 by PCR (p=0.03). These studies suggest that LAIV may transiently increase nasopharyngeal density ofS. pneumoniae.Transmission effects should therefore be considered in the timing design of vaccine schedules.Trial registrationThe study was registered on EudraCT (2014-004634-26)FundingThe study was funded by the Bill and Melinda Gates Foundation and the UK Medical Research Council.

For epidemiological work with soil transmitted helminths the recommended diagnostic approaches are to examine fecal samples for microscopic evidence of the parasite. In addition to several logistical and processing issues, traditional diagnostic approaches have been shown to lack the sensitivity required to reliably identify patients harboring low-level infections such as those associated with effective mass drug intervention programs. In this context, there is a need to rethink the approaches used for helminth diagnostics. Serological methods are now in use, however these tests are indirect and depend on individual immune responses, exposure patterns and the nature of the antigen. However, it has been demonstrated that cell-free DNA from pathogens and cancers can be readily detected in patient’s urine which can be collected in the field, filtered in situ and processed later for analysis. In the work presented here, we employ three diagnostic procedures—stool examination, serology (NIE-ELISA) and PCR-based amplification of parasite transrenal DNA from urine–to determine their relative utility in the diagnosis of S. stercoralis infections from 359 field samples from an endemic area of Argentina. Bayesian Latent Class analysis was used to assess the relative performance of the three diagnostic procedures. The results underscore the low sensitivity of stool examination and support the idea that the use of serology combined with parasite transrenal DNA detection may be a useful strategy for sensitive and specific detection of low-level strongyloidiasis. Fil: Krolewiecki, Alejandro Javier. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Koukounari, Artemis. Liverpool School of Tropical Medicine; Reino Unido Fil: Romano, Miryam de Los Angeles. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina. University Johns Hopkins; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Caro, Reynaldo N.. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina Fil: Scott, Alan L. University Johns Hopkins; Estados Unidos Fil: Fleitas, Pedro Emanuel. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cimino, Rubén Oscar. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Shiff, Clive J.. University Johns Hopkins; Estados Unidos

Latin American and the Caribbean countries exhibit high life expectancy and projections show that they will experience the fastest growth of older people in the following years. As people live longer, it is important to maximise the opportunity to age healthily. We aimed to examine the associations of lifestyle behaviours with healthy ageing in Cuba, Dominican Republic, Peru, Mexico and Puerto Rico, part of the 10/66 study. Residents 65 years old and over (n = 10,900) were interviewed between 2003 and 2010. In the baseline survey, we measured four healthy behaviours: Physical activity, non-smoking, moderate drinking and fruits or vegetables consumption. Healthy ageing was conceptualised within the functional ability framework over a median of 4 years follow-up. Logistic models were calculated per country and then pooled together with fixed-effects meta-analysis. People engaging in physical activity and consuming fruits or vegetables had increased odds of healthy ageing in the follow-up (OR: 2.59, 95% CI: 2.20&ndash, 3.03, OR: 1.24, 95% CI: 1.06&ndash, 1.44, respectively). Compared with participants engaging in none or one healthy behaviour, the ORs of participants engaging in two, three or four healthy behaviours increased in a linear way (OR: 1.60, 95% CI: 1.40&ndash, 1.84, OR: 2.29, 95% CI: 1.94&ndash, 2.69, OR: 2.46, 95% CI: 1.54&ndash, 3.92, respectively). Our findings highlight the importance of awareness of a healthy lifestyle behaviour among older people.

(1) Background: Current international policy for schistosomiasis and soil-transmitted helminthiasis (STH) control emphasises mass administration of deworming drugs in school-based programmes. However, this approach is insufficient to control the transmission of these diseases, and their burden in non-school cohorts is recognised, albeit under-researched. This research will investigate the feasibility and acceptability of expanding access to praziquantel (PZQ) against schistosomiasis, and albendazole (ALB) against STH, to communities in selected transmission settings in Ghana. (2) Methods: A three-site longitudinal study will be implemented to investigate the effectiveness of expanding treatment strategies for PZQ and ALB to community members. In the context of community mass drug administration (to preschool children, school non-attending children, and adults, including pregnant women), the intervention will be assessed in a random sample of community members, at baseline with follow-up at 6, 12, and 18 months. In each community, 658 participants will be enrolled, and 314 followed up at each time point. The primary outcome measure is the prevalence of infection of Schistosoma haematobium and/or S. mansoni at study endpoint, as assessed by longitudinal surveys. Secondary outcomes are to quantify the infection of schistosomiasis and STH infections in non-treated cohorts, reductions in prevalence of STH, and intensity of schistosomiasis and STH, and treatment coverage. Nested within this study will be qualitative, cost-benefit, and cost-effectiveness evaluations that will explore accessibility, feasibility, and economic impact of expanded treatment from different complementary perspectives. (3) Discussion: Using a multidisciplinary approach, this study will generate evidence for improved availability, acceptability, affordability, and accessibility to deworming drugs against schistosomiasis and STH to individuals and communities in Ghana. This is likely to have considerable research, programmatic, and political value to contribute evidence for national programme policy development within Ghana, and, more broadly, World Health Organization policy development.

Soil-transmitted helminths, a group of three intestinal parasitic worms, are estimated to affect about a billion people worldwide, predominantly in low-income settings. The world's largest deworming programme is the lymphatic filariasis elimination programme, which combines community-wide treatment with drugs that target soil-transmitted helminths. As these programmes are scaled back because of successful control of lymphatic filariasis, the question of whether and how to continue or expand deworming for soil-transmitted helminths, usually delivered through school-based deworming programmes, remains to be answered.

In disease control or elimination programs, diagnostics are essential for assessing the impact of interventions, refining treatment strategies, and minimizing the waste of scarce resources. Although high-performance tests are desirable, increased accuracy is frequently accompanied by a requirement for more elaborate infrastructure, which is often not feasible in the developing world. These challenges are pertinent to mapping, impact monitoring, and surveillance in trachoma elimination programs. To help inform rational design of diagnostics for trachoma elimination, we outline a nonparametric multilevel latent Markov modeling approach and apply it to 2 longitudinal cohort studies of trachoma-endemic communities in Tanzania (2000-2002) and The Gambia (2001-2002) to provide simultaneous inferences about the true population prevalence of Chlamydia trachomatis infection and disease and the sensitivity, specificity, and predictive values of 3 diagnostic tests for C. trachomatis infection. Estimates were obtained by using data collected before and after mass azithromycin administration. Such estimates are particularly important for trachoma because of the absence of a true "gold standard" diagnostic test for C. trachomatis. Estimated transition probabilities provide useful insights into key epidemiologic questions about the persistence of disease and the clearance of infection as well as the required frequency of surveillance in the post-elimination setting.

International audience; BACKGROUND: The global impact of the 2009 influenza A(H1N1) pandemic (H1N1pdm) is not well understood. OBJECTIVES: We estimate overall and age-specific prevalence of cross-reactive antibodies to H1N1pdm virus and rates of H1N1pdm infection during the first year of the pandemic using data from published and unpublished H1N1pdm seroepidemiological studies.METHODS: Primary aggregate H1N1pdm serologic data from each study were stratified in standardized age groups and evaluated based on when sera were collected in relation to national or subnational peak H1N1pdm activity. Seropositivity was assessed using well-described and standardized hemagglutination inhibition (HI titers ≥ 32 or ≥ 40) and microneutralization (MN ≥ 40) laboratory assays. The prevalence of cross-reactive antibodies to the H1N1pdm virus was estimated for studies using sera collected prior to the start of the pandemic (between 2004 and April 2009); H1N1pdm cumulative incidence was estimated for studies in which collected both pre- and post-pandemic sera; and H1N1pdm seropositivity was calculated from studies with post-pandemic sera only (collected between December 2009-June 2010).RESULTS: Data from 27 published/unpublished studies from 19 countries/administrative regions - Australia, Canada, China, Finland, France, Germany, Hong Kong SAR, India, Iran, Italy, Japan, Netherlands, New Zealand, Norway, Reunion Island, Singapore, United Kingdom, United States, and Vietnam - were eligible for inclusion. The overall age-standardized pre-pandemic prevalence of cross-reactive antibodies was 5% (95%CI 3-7%) and varied significantly by age with the highest rates among persons ≥ 65 years old (14% 95%CI 8-24%). Overall age-standardized H1N1pdm cumulative incidence was 24% (95%CI 20-27%) and varied significantly by age with the highest in children 5-19 (47% 95%CI 39-55%) and 0-4 years old (36% 95%CI 30-43%).CONCLUSIONS: Our results offer unique insight into the global impact of the H1N1 pandemic and highlight the need for standardization of seroepidemiological studies and for their inclusion in pre-pandemic preparedness plans. Our results taken together with recent global pandemic respiratory-associated mortality estimates suggest that the case fatality ratio of the pandemic virus was approximately 0.02%.

BackgroundUrine microscopy is the standard diagnostic method for urogenital S. haematobium infection. However, this may lead to under-diagnosis of urogenital schistosomiasis, as the disease may present itself with genital symptoms in the absence of ova in the urine. Currently there is no single reliable and affordable diagnostic method to diagnose the full spectrum of urogenital S. haematobium infection. In this study we explore the classic indicators in the diagnosis of urogenital S. haematobium infection, with focus on young women.MethodsIn a cross-sectional study of 1237 sexually active young women in rural South Africa, we assessed four diagnostic indicators of urogenital S. haematobium infection: microscopy of urine, polymerase chain reaction (PCR) of cervicovaginal lavage (CVL), urogenital symptoms, and sandy patches detected clinically in combination with computerised image analysis of photocolposcopic images. We estimated the accuracy of these diagnostic indicators through the following analyses: 1) cross tabulation (assumed empirical gold standard) of the tests against the combined findings of sandy patches and/or computerized image analysis and 2) a latent class model of the four indicators without assuming any gold standard.ResultsThe empirical approach showed that urine microscopy had a sensitivity of 34.7% and specificity of 75.2% while the latent class analysis approach (LCA) suggested a sensitivity of 81.0% and specificity of 85.6%. The empirical approach and LCA showed that Schistosoma PCR in CVL had low sensitivity (14.1% and 52.4%, respectively) and high specificity (93.0% and 98.0, respectively). Using LCA, the presence of sandy patches showed a sensitivity of 81.6 and specificity of 42.4%. The empirical approach and LCA showed that urogenital symptoms had a high sensitivity (89.4% and 100.0%, respectively), whereas specificity was low (10.6% and 12.3%, respectively).ConclusionAll the diagnostic indicators used in the study had limited accuracy. Using urine microscopy or Schistosoma PCR in CVL would only confirm a fraction of the sandy patches found by colposcopic examination.

SUMMARYSchistosomiasis remains one of the most prevalent parasitic diseases in developing countries. After malaria, schistosomiasis is the most important tropical disease in terms of human morbidity with significant economic and public health consequences. Although schistosomiasis has recently attracted increased focus and funding for control, it has been estimated that less than 20% of the funding needed to control the disease in Africa is currently available. In this article the following issues are discussed: the rationale, development and objectives of the Schistosomiasis Control Initiative (SCI)-supported programmes; the management approaches followed to achieve implementation by each country; mapping, monitoring and evaluation activities with quantifiable impact of control programmes; monitoring for any potential drug resistance; and finally exit strategies within each country. The results have demonstrated that morbidity due to schistosomiasis has been reduced by the control programmes. While challenges remain, the case for the control of schistosomiasis has been strengthened by research by SCI teams and the principle that a national programme using ‘preventive chemotherapy’ can be successfully implemented in sub-Saharan Africa, whenever the resources are available. SCI and partners are now actively striving to raise further funds to expand the coverage of integrated control of neglected tropical diseases (NTDs) in sub-Saharan Africa.

SUMMARYA primary objective of schistosomiasis control programmes is to achieve, and hence also demonstrate, a quantifiable reduction in schistosome-associated morbidity as a consequence of chemotherapeutic intervention. Inherent within such an objective, it is necessary to define and validate direct and indirect indicators of schistosome-related morbidity. However, to define and thereby document such morbidity, and its reduction following treatment, may not be straightforward, particularly for intestinal schistosomiasis-induced morbidity, which is often not apparent in all but the most severe or chronic cases. Within all ‘Schistosomiasis Control Initiative’ activities, across selected sub-Saharan African countries since 2002, a range of standard and novel potential morbidity markers have been monitored and evaluated. Parasitological intensity measures, combined with haemoglobin/anaemia counts and ultrasonography, proved valuable schistosomiasis-related morbidity indicators, being both logistically practical and informative. Additional measures tested, such as albumin excretion profiles, were promising, and are subject to ongoing research, whilst some measures, such as distended stomach/umbilical circumference, anthropometrics and health questionnaires proved less reliable. These results serve to both illustrate the success of current control activities in reducing schistosome-induced morbidity, and to highlight key tools and techniques for continued application within ongoing and future mass drug administration programmes.

Substantial uncertainties surround the sensitivities and specificities of diagnostic techniques for urinary schistosomiasis. We used latent class (LC) modeling to address this problem. In this study, 220 adults in three villages northwest of Accra, Ghana were examined using five Schistosoma haematobium diagnostic measures: microscopic examination of urine for detection of S. haematobium eggs, dipsticks for detection of hematuria, tests for circulating antigens, antibody tests, and ultrasound scans of the urinary system. Testing of the LC model indicated non-invariance of the performance of the diagnostic tests across different age groups, and measurement invariance held for males and females and for the three villages. We therefore recommend the use of LC models for comparison between and the identification of the most accurate schistosomiasis diagnostic tests. Furthermore, microscopy and hematuria dipsticks were indicated through these models as the most appropriate techniques for detection of S. haematobium infection.

The potential relationship between Schistosoma mansoni and anemia was examined using data obtained by the Schistosomiasis Control Initiative (SCI) before (baseline) and 1 year after (follow-up) a chemotherapeutic treatment program in Uganda. Changes in hemoglobin (Hb) levels in 2,788 children in relation to their schistosomiasis and/or hookworm infection intensity category and baseline anemia status were analyzed. At baseline, significant predictors of childhood anemia were intensities of S. mansoni and hookworm infection. At follow-up, moderate or heavy hookworm as well as heavy S. mansoni infections were important. Children heavily infected with S. mansoni or hookworm had significantly lower Hb counts at baseline compared with those not infected. Among anemic children at the baseline survey, a significant increase in Hb counts of 0.834 g/dL after treatment was found. Our results suggest that anemia is associated with schistosomiasis and hookworm in Ugandan children and that such anemia shows a significant improvement after chemotherapy.

Regular treatment with praziquantel (PZQ) is the strategy for human schistosomiasis control aiming to prevent morbidity in later life. With the recent resolution on schistosomiasis elimination by the 65th World Health Assembly, appropriate diagnostic tools to inform interventions are keys to their success. We present a discrete Markov chains modelling framework that deals with the longitudinal study design and the measurement error in the diagnostic methods under study. A longitudinal detailed dataset from Uganda, in which one or two doses of PZQ treatment were provided, was analyzed through Latent Markov Models (LMMs). The aim was to evaluate the diagnostic accuracy of Circulating Cathodic Antigen (CCA) and of double Kato-Katz (KK) faecal slides over three consecutive days for Schistosoma mansoni infection simultaneously by age group at baseline and at two follow-up times post treatment. Diagnostic test sensitivities and specificities and the true underlying infection prevalence over time as well as the probabilities of transitions between infected and uninfected states are provided. The estimated transition probability matrices provide parsimonious yet important insights into the re-infection and cure rates in the two age groups. We show that the CCA diagnostic performance remained constant after PZQ treatment and that this test was overall more sensitive but less specific than single-day double KK for the diagnosis of S. mansoni infection. The probability of clearing infection from baseline to 9 weeks was higher among those who received two PZQ doses compared to one PZQ dose for both age groups, with much higher re-infection rates among children compared to adolescents and adults. We recommend LMMs as a useful methodology for monitoring and evaluation and treatment decision research as well as CCA for mapping surveys of S. mansoni infection, although additional diagnostic tools should be incorporated in schistosomiasis elimination programs., Author Summary Schistosomiasis remains one of the most prevalent parasitic diseases in developing countries, with Schistosoma mansoni being the most widespread of the human-infecting schistosomes. For the routine surveillance of human S. mansoni infection more “field-applicable,” sensitive, and cost-effective diagnostics that replicate faecal samples over several consecutive days [the Kato-Katz (KK) method], are needed. We propose a statistical modelling framework in order to evaluate the diagnostic performance of the urine strip test for Circulating Cathodic Antigen (CCA) and single-day double KK measurements over three consecutive days for the diagnosis of S. mansoni infection in two different age groups from Uganda pre- and post- praziquantel (PZQ) treatment. We demonstrate that CCA is an appropriate tool for mapping surveys of S. mansoni infection. Our findings should allow for evaluation of the risk of potential misinterpretation with regards to diagnosis of S. mansoni infection through CCA or KK in this endemic setting pre- and post- PZQ treatment as the numbers and infection intensities are brought down, bridging existing important gaps in schistosomiasis diagnostics research. More generally, the proposed statistical analysis can reveal important biological insights from other diseases without gold standard diagnostic tools whenever longitudinal data are available.

Background Over 1 billion of the world's poorest inhabitants are afflicted by neglected tropical diseases (NTDs). Integrated control programmes aimed at tackling these debilitating NTDs have been recently initiated, mainly using preventative chemotherapy. Monitoring and evaluation (M&E) of these integrated programs presents particular challenges over and above those required for single disease vertical programmes. We used baseline data from the National NTD Control Programme in Burkina Faso in order to assess the feasibility of an integrated survey design, as well as to elucidate the contribution of environmental variables to the risk of either Schistosoma haematobium, trachoma, or both among school-aged children. Methods S. haematobium infection was diagnosed by detecting eggs in urine. A trachoma case was defined by the presence of Trachomatous inflammation-Follicular (TF) and/or Trachomatous inflammation-Intense (TI) in either eye. Baseline data collected from 3,324 children aged 7-11 years in 21 sentinel sites across 11 regions of Burkina Faso were analyzed using simple and multivariable hierarchical binomial logistic regression models fitted by Markov Chain Monte Carlo estimation methods. Probabilities of the risk of belonging to each infection/disease category were estimated as a function of age, gender (individual level), and environmental variables (at sentinel site level, interpolated from national meteorological stations). Results Overall prevalence at the sentinel sites was 11.79% (95% CI: 10.70-12.89) for S. haematobium; 13.30% (12.14-14.45) for trachoma and 0.84% (0.53-1.15) for co-infections. The only significant predictor of S. haematobium infection was altitude. There were significant negative associations between the prevalence of active trachoma signs and minimum temperature, and air pressure. Conditional upon these predictors, these data are consistent with the two pathogens being independent. Conclusions Urogenital schistosomiasis and trachoma constitute public health problems in Burkina Faso. Sentinel site (at school level) surveys for these two NTDs can be implemented simultaneously. However, to support MDA treatment decisions in Burkina Faso, the protocol used in this study would only be applicable to hypoendemic trachoma areas. More research is needed to confirm if these findings can be generalized to West Africa and beyond.

AIM: To study impact of once weekly iron supplementation on praziquantel cure rate, Schistosoma haematobium reinfection, and haematological parameters in pupils aged between 9 and 15 years of age in Nchelenge district, Zambia. METHODS: Pupils in the intervention group received once weekly dose of ferrous sulphate at 200 mg while those in the control received once weekly vitamin C at 100 mg for up to 9 months. Both study groups received a single dose of praziquantel at baseline. RESULTS: S haematobium reinfection intensity was significantly lower in boys in the intervention group than in boys in the control group at 6 months (P < 0.001) and 9 months (P < 0.001) of supplementation. Significantly lower S haematobium reinfection intensity was found in girls in the intervention group than in girls in the control group only at 6 months of supplementation (P = 0.018). Boys in the intervention group were 42% (Adjusted Risk Ratio = 0.58, 95% confidence interval 0.39, 0.86) less likely to be reinfected with S haematobium than in the control group at 6 months follow up. CONCLUSION: Once weekly iron supplementation can decrease S haematobium reinfection after 6 months and should be incorporated into school based schistosomiasis control programs in highly endemic areas.

Background Intestinal schistosomiasis and soil-transmitted helminth (STH) infections constitute major public health problems in many parts of sub-Saharan Africa. In this study we examined the functional significance of such polyparasite infections in anemia and undernutrition in Rwandan individuals. Methods Three polyparasite infection profiles were defined, in addition to a reference profile that consisted of either no infections or low-intensity infection with only one of the focal parasite species. Logistic regression models were applied to data of 1,605 individuals from 6 schools in 2 districts of the Northern Province before chemotherapeutic treatment in order to correctly identify individuals who were at higher odds of being anaemic and/or undernourished. Findings Stunted relative to nonstunted, and males compared to females, were found to be at higher odds of being anaemic independently of polyparasite infection profile. The odds of being wasted were 2-fold greater for children with concurrent infection of at least 2 parasites at M+ intensity compared to those children with the reference profile. Males compared to females and anaemic compared to nonanaemic children were significantly more likely to be stunted. None of the three polyparasite infection profiles were found to have significant effects on stunting. Conclusion The present data suggest that the levels of polyparasitism, and infection intensities in the Rwandan individuals examined here may be lower as compared to other recent similar epidemiological studies in different regions across sub-Saharan Africa. Neither the odds of anaemia nor the odds of stunting were found to be significantly different in the three-polyparasite infection profiles. However, the odds of wasting were higher in those children with at least two parasites at M+ intensity compared to those children with the reference profile. Nevertheless, despite the low morbidity levels indicated in the population under study here, we recommend sustainable efforts for the deworming of affected populations to be continued in order to support the economic development of the country., Author Summary The helminth infections—schistosomiasis, hookworm, ascariasis and trichuriasis—are the main neglected tropical diseases (NTDs) to thrive in sub-Saharan Africa. Here we assess the distribution and the intensities of such polyparasite infections in two districts of the Northern Province in Rwanda and determine whether these are associated with anaemia, lowered haemoglobin levels and recent and/or chronic undernutrition. Rwanda is a small landlocked country in Central Africa where no research or control efforts on NTDs has been conducted since before the genocide in 1994. The current study aimed to elucidate, for the first time post-genocide, the burden of NTDs on the health of the Rwandan people and potential associated morbidity. Despite the fact that we observed low morbidity levels and intensities of polyparasite helminth infections, we recommend sustainable efforts for the deworming of the Rwandan people to be continued in order to offer a worm-free physical and cognitive development to the children of Rwanda and hence support the economic development of the country.

Background. In sub-Saharan Africa, 112 million people are infected with Schistosoma haematobium, with the most intense infections in children 5–15 years old. Methods. We describe a longitudinal epidemiological study that evaluates the relationship between S. haematobium infection and associated morbidity in children before and after the large-scale administration of praziquantel for schistosomiasis and albendazole for soil-transmitted helminths. Results. At baseline, higher intensities of S. haematobium infection were observed in children with anemia and/or severe microhematuria, but there was no apparent association between the risk of undernutrition and intensity of S. haematobium infection. Significant reductions in the prevalence and intensity of S. haematobium infection 1 year after treatment were, however, observed. Children who benefited the most from anthelmintic treatment in terms of increased hemoglobin concentrations were those who had anemia at baseline and those with highly positive microhematuria scores at baseline. Conclusions. This study suggests that even a single round of mass chemotherapy can have a substantial impact on S. haematobium infection and its associated morbidity in children.

OBJECTIVE: We aimed to assess the health impact of a national control programme targeting schistosomiasis and intestinal nematodes in Uganda, which has provided population-based anthelmintic chemotherapy since 2003. METHODS: We conducted longitudinal surveys on infection status, haemoglobin concentration and clinical morbidity in 1871 randomly selected schoolchildren from 37 schools in eight districts across Uganda at three time points - before chemotherapy and after one year and two years of annual mass chemotherapy. FINDINGS: Mass treatment with praziquantel and albendazole led to a significant decrease in the intensity of Schistosoma mansoni - 70% (95% confidence interval (CI): 66-73%) after one year and 82% (95% CI: 80-85%) after two years of treatment. Intensity of hookworm infection also decreased (75% and 93%; unadjusted). There was a significant increase in haemoglobin concentration after one (0.135 g/dL (95% CI: 0.126-0.144)) and two years (0.303 g/dL (95% CI: 0.293-0.312)) of treatment, and a significant decrease in signs of early clinical morbidity. The impact of intervention on S. mansoni prevalence and intensity was similar to that predicted by mathematical models of the impact of chemotherapy on human schistosomiasis. Improvements in haemoglobin concentration were greatest among children who were anaemic or harbouring heavy S. mansoni infection at baseline. CONCLUSION: Anthelmintic treatment delivered as part of a national helminth control programme can decrease infection and morbidity among schoolchildren and improve haemoglobin concentration.

This study analyzes data from 19 countries (from April 2009 to Jan 2010), comprising some 70,000 hospitalized patients with severe H1N1 infection, to reveal risk factors for severe pandemic influenza, which include chronic illness, cardiac disease, chronic respiratory disease, and diabetes., Background Since the start of the 2009 influenza A pandemic (H1N1pdm), the World Health Organization and its member states have gathered information to characterize the clinical severity of H1N1pdm infection and to assist policy makers to determine risk groups for targeted control measures. Methods and Findings Data were collected on approximately 70,000 laboratory-confirmed hospitalized H1N1pdm patients, 9,700 patients admitted to intensive care units (ICUs), and 2,500 deaths reported between 1 April 2009 and 1 January 2010 from 19 countries or administrative regions—Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong SAR, Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom—to characterize and compare the distribution of risk factors among H1N1pdm patients at three levels of severity: hospitalizations, ICU admissions, and deaths. The median age of patients increased with severity of disease. The highest per capita risk of hospitalization was among patients, Editors' Summary Background In April 2009, a new strain of influenza A H1N1 was first identified in Mexico and the United States and subsequently spread around the world. In June 2009, the World Health Organization (WHO) declared a pandemic alert phase 6, which continued until August 2010. Throughout the pandemic, WHO and member states gathered information to characterize the patterns of risk associated with the new influenza A H1N1 virus infection and to assess the clinical picture. Although risk factors for severe disease following seasonal influenza infection have been well documented in many countries (for example, pregnancy; chronic medical conditions such as pulmonary, cardiovascular, renal, hepatic, neuromuscular, hematologic, and metabolic disorders; some cognitive conditions; and immunodeficiency), risk factors for severe disease following infection early in the 2009 H1N1 pandemic were largely unknown. Why Was This Study Done? Many countries have recently reported data on the association between severe H1N1 influenza and a variety of underlying risk factors, but because these data are presented in different formats, making direct comparisons across countries is difficult, with no clear consensus for some conditions. Therefore, to assess the frequency and distribution of known and new potential risk factors for severe H1N1 infection, this study was conducted to collect data (from 1 April 2009 to 1 January 2010) from surveillance programs of the Ministries of Health or National Public Health Institutes in 19 countries―Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong (special administrative region), Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom. What Did the Researchers Do and Find? As part of routine surveillance, countries were asked to provide risk factor data on laboratory-confirmed H1N1 in patients who were admitted to hospital, admitted to the intensive care unit (ICU), or had died because of their infection, using a standardized format. The researchers grouped potential risk conditions into four categories: age, chronic medical illnesses, pregnancy (by trimester), and other conditions that were not previously considered as risk conditions for severe influenza outcomes, such as obesity. For each risk factor (except pregnancy), the researchers calculated the percentage of each group of patients using the total number of cases reported in each severity category (hospitalization, admission to ICU, and death). To evaluate the risk associated with pregnancy, the researchers used the ratio of pregnant women to all women of childbearing age (age 15–49 years) at each level of severity to describe the differences between levels. The researchers were able to collect data on approximately 70,000 patients requiring hospitalization, 9,700 patients admitted to the ICU, and 2,500 patients who died from H1N1 infection. The proportion of patients with H1N1 with one or more reported chronic conditions increased with severity—the median was 31.1% of hospitalized patients, 52.3% of patients admitted to the ICU, and 61.8% of patients who died. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. The proportion of patients with obesity increased with increasing disease severity—median of 6% of hospitalized patients, 11.3% of patients admitted to the ICU, and 12.0% of all deaths from H1N1. What Do These Findings Mean? These findings show that risk factors for severe H1N1 infection are similar to those for seasonal influenza, with some notable differences: a substantial proportion of people with severe and fatal cases of H1N1 had pre-existing chronic illness, which indicates that the presence of chronic illness increases the likelihood of death. Cardiac disease, chronic respiratory disease, and diabetes are important risk factors for severe disease that will be especially relevant for countries with high rates of these illnesses. Approximately 2/3 of hospitalized people and 40% of people who died from H1N1 infection did not have any identified pre-existing chronic illness, but this study was not able to comprehensively assess how many of these cases had other risk factors, such as pregnancy, obesity, smoking, and alcohol misuse. Because of large differences between countries, the role of risk factors such as obesity and pregnancy need further study—although there is sufficient evidence to support vaccination and early intervention for pregnant women. Overall, the findings of this study reinforce the need to identify and target high-risk groups for interventions such as immunization, early medical advice, and use of antiviral medications. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001053. WHO provides a Global Alert and Response (GAR) with updates on a number of influenza-related topics The US Centers for Disease Control and Prevention provides information on risk factors and H1N1

Objective To evaluate the impact on schistosomiasis of biennial treatment with praziquantel (PZQ) among school-age children in Burkina Faso, the first country that achieved full national coverage with treatment of more than 90% of the school-age population. Methods A cohort of 1727 schoolchildren (6–14 years old) was monitored at yearly intervals through a longitudinal survey. Additional groups of schoolchildren were monitored in cross-sectional surveys. Parasitological examinations for Schistosoma haematobium and Schistosoma mansoni were performed, and prevalence and intensity of infection before and after treatment were analysed. Findings Data from the longitudinal cohort show that a single round of PZQ treatment significantly reduced prevalence of S. haematobium infection by 87% (from 59.6% to 7.7%) and intensity of infection by 92.8% (from 94.2 to 6.8 eggs/10 ml of urine) 2 years posttreatment. The impact on infection was also confirmed by a cross-sectional survey 2 years post-treatment. Importantly, the proportion of school-age children with heavy S. haematobium infection decreased from around 25% before treatment to around 2–3% 2 years post-treatment. Cross-sectional comparison of S. haematobium infection in 7-year-old children in their first year at school, who received treatment through community-based drug delivery, also showed significant reduction in both prevalence (65.9%) and intensity of S. haematobium infection (78.4%) 2 years after single treatment. A significant reduction in S. mansoni infection was also achieved. Conclusion Significant and sustained reduction in S. haematobium infection was achieved by biennial treatment in school-age children in Burkina Faso. This may provide a cost-effective treatment strategy for similar national schistosomiasis control programmes in sub-Saharan Africa. Bulletin of the World Health Organization 2008;86:780–787.

Background Research has suggested the positive impact of physical activity on health and wellbeing in older age, yet few studies have investigated the associations between physical activity and heterogeneous trajectories of healthy ageing. We aimed to identify how physical activity can influence healthy ageing trajectories using a harmonised dataset of eight ageing cohorts across the world. Methods Based on a harmonised dataset of eight ageing cohorts in Australia, USA, Mexico, Japan, South Korea, and Europe, comprising 130,521 older adults (Mage = 62.81, SDage = 10.06) followed-up up to 10 years (Mfollow-up = 5.47, SDfollow-up = 3.22), we employed growth mixture modelling to identify latent classes of people with different trajectories of healthy ageing scores, which incorporated 41 items of health and functioning. Multinomial logistic regression modelling was used to investigate the associations between physical activity and different types of trajectories adjusting for sociodemographic characteristics and other lifestyle behaviours. Results Three latent classes of healthy ageing trajectories were identified: two with stable trajectories with high (71.4%) or low (25.2%) starting points and one with a high starting point but a fast decline over time (3.4%). Engagement in any level of physical activity was associated with decreased odds of being in the low stable (OR: 0.18; 95% CI: 0.17, 0.19) and fast decline trajectories groups (OR: 0.44; 95% CI: 0.39, 0.50) compared to the high stable trajectory group. These results were replicated with alternative physical activity operationalisations, as well as in sensitivity analyses using reduced samples. Conclusions Our findings suggest a positive impact of physical activity on healthy ageing, attenuating declines in health and functioning. Physical activity promotion should be a key focus of healthy ageing policies to prevent disability and fast deterioration in health.