Evaluating hybrid controls methodology in early-phase oncology trials: A simulation study based on the MORPHEUS-UC trial.

Phase Ib/II oncology trials, despite their small sample sizes, aim to provide information for optimal internal company decision-making concerning novel drug development. Hybrid controls (a combination of the current control arm and controls from one or more sources of historical trial data [HTD]) can be used to increase statistical precision. Here we assess combining two sources of Roche HTD to construct a hybrid control in targeted therapy for decision-making via an extensive simulation study. Our simulations are based on the real data of one of the experimental arms and the control arm of the MORPHEUS-UC Phase Ib/II study and two Roche HTD for atezolizumab monotherapy. We consider potential complications such as model misspecification, unmeasured confounding, different sample sizes of current treatment groups, and heterogeneity among the three trials. We evaluate two frequentist methods (with both Cox and Weibull accelerated failure time [AFT] models) and three different commensurate priors in Bayesian dynamic borrowing (with a Weibull AFT model), and modifications within each of those, when estimating the effect of treatment on survival outcomes and measures of effect such as marginal hazard ratios. We assess the performance of these methods in different settings and the potential of generalizations to supplement decisions in early-phase oncology trials. The results show that the proposed joint frequentist methods and noninformative priors within Bayesian dynamic borrowing with no adjustment on covariates are preferred, especially when treatment effects across the three trials are heterogeneous. For generalization of hybrid control methods in such settings, we recommend more simulation studies.

Maternal immunisation against Group B Streptococcus: A global analysis of health impact and cost-effectiveness.

BACKGROUND: Group B Streptococcus (GBS) can cause invasive disease (iGBS) in young infants, typically presenting as sepsis or meningitis, and is also associated with stillbirth and preterm birth. GBS vaccines are under development, but their potential health impact and cost-effectiveness have not been assessed globally. METHODS AND FINDINGS: We assessed the health impact and value (using net monetary benefit (NMB), which measures both health and economic effects of vaccination into monetary units) of GBS maternal vaccination in an annual cohort of 140 million pregnant women across 183 countries in 2020. Our analysis uses a decision tree model, incorporating risks of GBS-related health outcomes from an existing Bayesian disease burden model. We extrapolated country-specific GBS-related healthcare costs using data from a previous systematic review and calculated quality-adjusted life years (QALYs) lost due to infant mortality and long-term disability. We assumed 80% vaccine efficacy against iGBS and stillbirth, following the WHO Preferred Product Characteristics, and coverage based on the proportion of pregnant women receiving at least 4 antenatal visits. One dose was assumed to cost $50 in high-income countries, $15 in upper-middle income countries, and $3.50 in low-/lower-middle-income countries. We estimated NMB using alternative normative assumptions that may be adopted by policymakers. Vaccinating pregnant women could avert 127,000 (95% uncertainty range 63,300 to 248,000) early-onset and 87,300 (38,100 to 209,000) late-onset infant iGBS cases, 31,100 deaths (14,400 to 66,400), 17,900 (6,380 to 49,900) cases of moderate and severe neurodevelopmental impairment, and 23,000 (10,000 to 56,400) stillbirths. A vaccine effective against GBS-associated prematurity might also avert 185,000 (13,500 to 407,000) preterm births. Globally, a 1-dose vaccine programme could cost $1.7 billion but save $385 million in healthcare costs. Estimated global NMB ranged from $1.1 billion ($-0.2 to 3.8 billion) under the least favourable normative assumptions to $17 billion ($9.1 to 31 billion) under the most favourable normative assumptions. The main limitation of our analysis was the scarcity of data to inform some of the model parameters such as those governing health-related quality of life and long-term costs from disability, and how these parameters may vary across country contexts. CONCLUSIONS: In this study, we found that maternal GBS vaccination could have a large impact on infant morbidity and mortality. Globally, a GBS maternal vaccine at reasonable prices is likely to be a cost-effective intervention.

Estimation of country-level incidence of early-onset invasive Group B Streptococcus disease in infants using Bayesian methods.

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.

The impact of physical activity on healthy ageing trajectories: evidence from eight cohort studies.

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.

Healthy ageing and the prediction of mortality and incidence dependence in low- and middle- income countries: a 10/66 population-based cohort study.

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.

Development of a healthy ageing index in Latin American countries - a 10/66 dementia research group population-based study.

BACKGROUND: Our population is ageing and in 2050 more than one out of five people will be 60 years or older; 80% of whom will be living in a low-and-middle income country. Living longer does not entail living healthier; however, there is not a widely accepted measure of healthy ageing hampering policy and research. The World Health Organization defines healthy ageing as the process of developing and maintaining functional ability that will enable well-being in older age. We aimed to create a healthy ageing index (HAI) in a subset of six low-and-middle income countries, part of the 10/66 study, by using items of functional ability and intrinsic capacity. METHODS: The study sample included residents 65-years old and over (n = 12,865) from catchment area sites in Cuba, Dominican Republic, Peru, Venezuela, Mexico and Puerto Rico. Items were collected by interviewing participants or key informants between 2003 and 2010. Two-stage factor analysis was employed and we compared one-factor, second-order and bifactor models. The psychometric properties of the index, including reliability, replicability, unidimensionality and concurrent convergent validity as well as measurement invariance per ethnic group and gender were further examined in the best fit model. RESULTS: The bifactor model displayed superior model fit statistics supporting that a general factor underlies the various items but other subdomain factors are also needed. The HAI indicated excellent reliability (ω = 0.96, ωΗ = 0.84), replicability (H = 0.96), some support for unidimensionality (Explained Common Variance = 0.65) and some concurrent convergent validity with self-rated health. Scalar measurement invariance per ethnic group and gender was supported. CONCLUSIONS: A HAI with excellent psychometric properties was created by using items of functional ability and intrinsic capacity in a subset of six low-and-middle income countries. Further research is needed to explore sub-population differences and to validate this index to other cultural settings.

Surveillance of intestinal schistosomiasis during control: a comparison of four diagnostic tests across five Ugandan primary schools in the Lake Albert region.

Programmatic surveillance of intestinal schistosomiasis during control can typically use four diagnostic tests, either singularly or in combination, but these have yet to be cross-compared directly. Our study assembled a complete diagnostic dataset, inclusive of infection intensities, from 258 children from five Ugandan primary schools. The schools were purposely selected as typical of the endemic landscape near Lake Albert and reflective of high- and low-transmission settings. Overall prevalence was: 44.1% (95% CI 38.0-50.2) by microscopy of duplicate Kato-Katz smears from two consecutive stools, 56.9% (95% CI 50.8-63.0) by urine-circulating cathodic antigen (CCA) dipstick, 67.4% (95% CI 61.6-73.1) by DNA-TaqMan® and 75.1% (95% CI 69.8-80.4) by soluble egg antigen enzyme-linked immunosorbent assay (SEA-ELISA). A cross-comparison of diagnostic sensitivities, specificities, positive and negative predictive values was undertaken, inclusive of a latent class analysis (LCA) with a LCA-model estimate of prevalence by each school. The latter ranged from 9.6% to 100.0%, and prevalence by school for each diagnostic test followed a static ascending order or monotonic series of Kato-Katz, urine-CCA dipstick, DNA-TaqMan® and SEA-ELISA. We confirm that Kato-Katz remains a satisfactory diagnostic standalone in high-transmission settings but in low-transmission settings should be augmented or replaced by urine-CCA dipsticks. DNA-TaqMan® appears suitable in both endemic settings though is only implementable if resources permit. In low-transmission settings, SEA-ELISA remains the method of choice to evidence an absence infection. We discuss the pros and cons of each method concluding that future surveillance of intestinal schistosomiasis would benefit from a flexible, context-specific approach both in choice and application of each diagnostic method, rather than a single one-size fits all approach.

A latent Markov modelling approach to the evaluation of circulating cathodic antigen strips for schistosomiasis diagnosis pre- and post-praziquantel treatment in Uganda.

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.

Using a nonparametric multilevel latent Markov model to evaluate diagnostics for trachoma.

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.

Group B streptococcus infection during pregnancy and infancy: estimates of regional and global burden.

BACKGROUND: Group B streptococcus (GBS) colonisation during pregnancy can lead to invasive GBS disease (iGBS) in infants, including meningitis or sepsis, with a high mortality risk. Other outcomes include stillbirths, maternal infections, and prematurity. There are data gaps, notably regarding neurodevelopmental impairment (NDI), especially after iGBS sepsis, which have limited previous global estimates. In this study, we aimed to address this gap using newly available multicountry datasets. METHODS: We collated and meta-analysed summary data, primarily identified in a series of systematic reviews published in 2017 but also from recent studies on NDI and stillbirths, using Bayesian hierarchical models, and estimated the burden for 183 countries in 2020 regarding: maternal GBS colonisation, iGBS cases and deaths in infants younger than 3 months, children surviving iGBS affected by NDI, and maternal iGBS cases. We analysed the proportion of stillbirths with GBS and applied this to the UN-estimated stillbirth risk per country. Excess preterm births associated with maternal GBS colonisation were calculated using meta-analysis and national preterm birth rates. FINDINGS: Data from the seven systematic reviews, published in 2017, that informed the previous burden estimation (a total of 515 data points) were combined with new data (17 data points) from large multicountry studies on neurodevelopmental impairment (two studies) and stillbirths (one study). A posterior median of 19·7 million (95% posterior interval 17·9-21·9) pregnant women were estimated to have rectovaginal colonisation with GBS in 2020. 231 800 (114 100-455 000) early-onset and 162 200 (70 200-394 400) late-onset infant iGBS cases were estimated to have occurred. In an analysis assuming a higher case fatality rate in the absence of a skilled birth attendant, 91 900 (44 800-187 800) iGBS infant deaths were estimated; in an analysis without this assumption, 58 300 (26 500-125 800) infant deaths from iGBS were estimated. 37 100 children who recovered from iGBS (14 600-96 200) were predicted to develop moderate or severe NDI. 40 500 (21 500-66 200) maternal iGBS cases and 46 200 (20 300-111 300) GBS stillbirths were predicted in 2020. GBS colonisation was also estimated to be potentially associated with considerable numbers of preterm births. INTERPRETATION: Our analysis provides a comprehensive assessment of the pregnancy-related GBS burden. The Bayesian approach enabled coherent propagation of uncertainty, which is considerable, notably regarding GBS-associated preterm births. Our findings on both the acute and long-term consequences of iGBS have public health implications for understanding the value of investment in maternal GBS immunisation and other preventive strategies. FUNDING: Bill & Melinda Gates Foundation.

Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis.

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 <5 y and 5-14 y (relative risk [RR] = 3.3 and 3.2, respectively, compared to the general population), whereas the highest risk of death per capita was in the age groups 50-64 y and ≥65 y (RR = 1.5 and 1.6, respectively, compared to the general population). Similarly, the ratio of H1N1pdm deaths to hospitalizations increased with age and was the highest in the ≥65-y-old age group, indicating that while infection rates have been observed to be very low in the oldest age group, risk of death in those over the age of 64 y who became infected was higher than in younger groups. The proportion of H1N1pdm patients with one or more reported chronic conditions increased with severity (median = 31.1%, 52.3%, and 61.8% of hospitalized, ICU-admitted, and fatal H1N1pdm cases, respectively). With the exception of the risk factors asthma, pregnancy, and obesity, the proportion of patients with each risk factor increased with severity level. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. Our findings suggest that morbid obesity might be a risk factor for ICU admission and fatal outcome (RR = 36.3). CONCLUSIONS: Our results demonstrate that risk factors for severe H1N1pdm infection are similar to those for seasonal influenza, with some notable differences, such as younger age groups and obesity, and reinforce the need to identify and protect groups at highest risk of severe outcomes. Please see later in the article for the Editors' Summary.

Integrated monitoring and evaluation and environmental risk factors for urogenital schistosomiasis and active trachoma in Burkina Faso before preventative chemotherapy using sentinel sites.

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.

Latent Class Analysis: Insights about design and analysis of schistosomiasis diagnostic studies.

Various global health initiatives are currently advocating the elimination of schistosomiasis within the next decade. Schistosomiasis is a highly debilitating tropical infectious disease with severe burden of morbidity and thus operational research accurately evaluating diagnostics that quantify the epidemic status for guiding effective strategies is essential. Latent class models (LCMs) have been generally considered in epidemiology and in particular in recent schistosomiasis diagnostic studies as a flexible tool for evaluating diagnostics because assessing the true infection status (via a gold standard) is not possible. However, within the biostatistics literature, classical LCM have already been criticised for real-life problems under violation of the conditional independence (CI) assumption and when applied to a small number of diagnostics (i.e. most often 3-5 diagnostic tests). Solutions of relaxing the CI assumption and accounting for zero-inflation, as well as collecting partial gold standard information, have been proposed, offering the potential for more robust model estimates. In the current article, we examined such approaches in the context of schistosomiasis via analysis of two real datasets and extensive simulation studies. Our main conclusions highlighted poor model fit in low prevalence settings and the necessity of collecting partial gold standard information in such settings in order to improve the accuracy and reduce bias of sensitivity and specificity estimates.

Stillbirths and neonatal deaths among 18 942 women with postpartum hemorrhage: Analysis of perinatal outcomes in the WOMAN trial.

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.

The impact of single versus mixed schistosome species infections on liver, spleen and bladder morbidity within Malian children pre- and post-praziquantel treatment.

BACKGROUND: In the developing world co-infections and polyparasitism within humans appear to be the rule rather than the exception, be it any combination of inter-specific and/or inter- and intra-Genera mixed infections. Mixed infections might generate synergistic or antagonistic interactions and thereby clinically affect individuals and/or impact parasite epidemiology. METHODS: The current study uniquely assesses both Schistosoma mansoni- and Schistosoma haematobium-related morbidity of the liver and the bladder as assessed by ultrasound as well as spleen and liver morbidity through clinical exams. The impact of praziquantel (PZQ) treatment on such potential inter-specific schistosome interactions and resulting morbidity using uniquely detailed longitudinal data (pre- and one year post-PZQ treatment) arising from the National Schistosomiasis Control Program in three areas of Mali: Ségou, Koulikoro and Bamako, is also evaluated. At baseline, data were collected from up to 2196 children (aged 7-14 years), 844 of which were infected with S. haematobium only, 124 with S. mansoni only and 477 with both. Follow-up data were collected from up to 1265 children. RESULTS: Results suggested lower liver morbidity in mixed compared to single S. mansoni infections and higher bladder morbidity in mixed compared to single S. haematobium infections. Single S. haematobium or S. mansoni infections were also associated with liver and spleen morbidity whilst only single S. haematobium infections were associated with bladder morbidity in these children (light S. haematobium infection OR: 4.3, p < 0.001 and heavy S. haematobium infection OR: 19, p < 0.001). PZQ treatment contributed to the regression of some of the forms of such morbidities. CONCLUSIONS: Whilst the precise biological mechanisms for these observations remain to be ascertained, the results illustrate the importance of considering mixed species infections in any analyses of parasite-induced morbidity, including that for the proposed Disability Adjusted Life Years (DALYs) revised estimates of schistosomiasis morbidity.

Protection against mycobacterial infection: A case-control study of mycobacterial immune responses in pairs of Gambian children with discordant infection status despite matched TB exposure.

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-Guérin (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).

Assessing expanded community wide treatment for schistosomiasis: Baseline infection status and self-reported risk factors in three communities from the Greater Accra region, Ghana.

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.

Quantifying long-term health and economic outcomes for survivors of group B Streptococcus invasive disease in infancy: protocol of a multi-country study in Argentina, India, Kenya, Mozambique and South Africa.

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.

Healthy ageing trajectories and lifestyle behaviour: the Mexican Health and Aging Study.

Projections show that the number of people above 60 years old will triple by 2050 in Mexico. Nevertheless, ageing is characterised by great variability in the health status. In this study, we aimed to identify trajectories of health and their associations with lifestyle factors in a national representative cohort study of older Mexicans. We used secondary data of 14,143 adults from the Mexican Health and Aging Study (MHAS). A metric of health, based on the conceptual framework of functional ability, was mapped onto four waves (2001, 2003, 2012, 2015) and created by applying Bayesian multilevel Item Response Theory (IRT). Conditional Growth Mixture Modelling (GMM) was used to identify latent classes of individuals with similar trajectories and examine the impact of physical activity, smoking and alcohol on those. Conditional on sociodemographic and lifestyle behaviour four latent classes were suggested: high-stable, moderate-stable, low-stable and decliners. Participants who did not engage in physical activity, were current or previous smokers and did not consume alcohol at baseline were more likely to be in the trajectory with the highest deterioration (i.e. decliners). This study confirms ageing heterogeneity and the positive influence of a healthy lifestyle. These results provide the ground for new policies.