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.

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.

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.

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.

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).

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.

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 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.

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.

Associations of Lifestyle Behaviour and Healthy Ageing in Five Latin American and the Caribbean Countries-A 10/66 Population-Based Cohort Study.

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: 2.20⁻3.03; OR: 1.24, 95% CI: 1.06⁻1.44, 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: 1.40⁻1.84; OR: 2.29, 95% CI: 1.94⁻2.69; OR: 2.46, 95% CI: 1.54⁻3.92, respectively). Our findings highlight the importance of awareness of a healthy lifestyle behaviour among older people.

Transrenal DNA-based diagnosis of Strongyloides stercoralis (Grassi, 1879) infection: Bayesian latent class modeling of test accuracy.

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.

Associations of smoking and alcohol consumption with healthy ageing: a systematic review and meta-analysis of longitudinal studies.

OBJECTIVES: The number of older people is growing across the world; however, quantitative synthesis of studies examining the impact of lifestyle factors on the ageing process is rare. We conducted a systematic review and meta-analysis of longitudinal studies to synthesise the associations of smoking and alcohol consumption with healthy ageing (HA). METHODS: Major electronic databases were searched from inception to March 2017 (prospectively registered systematic reviews registration number CRD42016038130). Studies were assessed for methodological quality. Random-effect meta-analysis was performed to calculate pooled ORs and 95% CI. RESULTS: In total, we identified 28 studies (n=184 543); 27 studies reported results on smoking, 22 on alcohol consumption. 23 studies reported a significant positive association of never or former smoking with HA and 4 non-significant. 12 studies reported a significant positive association of alcohol consumption with HA, 9 no association and 1 negative. Meta-analysis revealed increased pooled OR of HA for never smokers compared with current smokers (2.36, 95% CI 2.03 to 2.75), never smokers compared with former smokers (1.32, 95% CI 1.23 to 1.41), former or never smokers compared with current smokers (1.72, 95% CI 1.20 to 2.47), never smokers compared with past or current smokers (1.29, 95% CI 1.16 to 1.43); drinkers compared with non-drinkers (1.28, 95% CI 1.08 to 1.52), light drinkers compared with non-drinkers (1.12, 95% CI 1.03 to 1.22), moderate drinkers compared with non-drinkers (1.35, 95% CI 0.93 to 1.97) and high drinkers compared with non-drinkers (1.25, 95% CI 1.09 to 1.44). There was considerable heterogeneity in the definition and measurement of HA and alcohol consumption. CONCLUSIONS: There is consistent evidence from longitudinal studies that smoking is negatively associated with HA. The associations of alcohol consumption with HA are equivocal. Future research should focus on the implementation of a single metric of HA, on the use of consistent drinking assessment among studies and on a full-range of confounding adjustment. Our research also highlighted the limited research on ageing in low-and-middle-income countries.

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.

Evaluating diagnostic indicators of urogenital Schistosoma haematobium infection in young women: A cross sectional study in rural South Africa.

BACKGROUND: Urine 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. METHODS: In 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. RESULTS: The 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). CONCLUSION: All 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.

The COUNTDOWN Study Protocol for Expansion of Mass Drug Administration Strategies against Schistosomiasis and Soil-Transmitted Helminthiasis in Ghana.

(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.