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Preterm birth (PTB) is the leading cause of death in children under five, yet comprehensive studies are hindered by its multiple complex etiologies. Epidemiological associations between PTB and maternal characteristics have been previously described. This work used multiomic profiling and multivariate modeling to investigate the biological signatures of these characteristics. Maternal covariates were collected during pregnancy from 13,841 pregnant women across five sites. Plasma samples from 231 participants were analyzed to generate proteomic, metabolomic, and lipidomic datasets. Machine learning models showed robust performance for the prediction of PTB (AUROC = 0.70), time-to-delivery ( r = 0.65), maternal age ( r = 0.59), gravidity ( r = 0.56), and BMI ( r = 0.81). Time-to-delivery biological correlates included fetal-associated proteins (e.g., ALPP, AFP, and PGF) and immune proteins (e.g., PD-L1, CCL28, and LIFR). Maternal age negatively correlated with collagen COL9A1, gravidity with endothelial NOS and inflammatory chemokine CXCL13, and BMI with leptin and structural protein FABP4. These results provide an integrated view of epidemiological factors associated with PTB and identify biological signatures of clinical covariates affecting this disease.

Background: Sensitive diagnostics are needed for effective management and surveillance of schistosomiasis so that current transmission interruption goals set by WHO can be achieved. We aimed to screen the Schistosoma haematobium secretome to find antibody biomarkers of schistosome infection, validate their diagnostic performance in samples from endemic populations, and evaluate their utility as point of care immunochromatographic tests (POC-ICTs) to diagnose urogenital schistosomiasis in the field. Methods: We did a biomarker identification study, in which we constructed a proteome array containing 992 validated and predicted proteins from S haematobium and screened it with serum and urine antibodies from endemic populations in Gabon, Tanzania, and Zimbabwe. Arrayed antigens that were IgG-reactive and a select group of antigens from the worm extracellular vesicle proteome, predicted to be diagnostically informative, were then evaluated by ELISA using the same samples used to probe arrays, and samples from individuals residing in a low-endemicity setting (ie, Pemba and Unguja islands, Zanzibar, Tanzania). The two most sensitive and specific antigens were incorporated into POC-ICTs to assess their ability to diagnose S haematobium infection from serum in a field-deployable format. Findings: From array probing, in individuals who were infected, 208 antigens were the targets of significantly elevated IgG responses in serum and 45 antigens were the targets of significantly elevated IgG responses in urine. Of the five proteins that were validated by ELISA, Sh-TSP-2 (area under the curve [AUC]serum=0·98 [95% CI 0·95-1·00]; AUCurine=0·96 [0·93-0·99]), and MS3_01370 (AUCserum=0·93 [0·89-0·97]; AUCurine=0·81 [0·72-0·89]) displayed the highest overall diagnostic performance in each biofluid and exceeded that of S haematobium-soluble egg antigen in urine (AUC=0·79 [0·69-0·90]). When incorporated into separate POC-ICTs, Sh-TSP-2 showed absolute specificity and a sensitivity of 75% and MS3_01370 showed absolute specificity and a sensitivity of 89%. Interpretation: We identified numerous biomarkers of urogenital schistosomiasis that could form the basis of novel antibody diagnostics for this disease. Two of these antigens, Sh-TSP-2 and MS3_01370, could be used as sensitive, specific, and field-deployable diagnostics to support schistosomiasis control and elimination initiatives, with particular focus on post-elimination surveillance. This study received financial support from Merck Global Health Institute and the Australian Trade and Investment Commission (Australian Tropical Medicine Commercialisation grants programme ATMC50322). Research for the Zanzibar Elimination of Schistosomiasis Transmission project was funded by the University of Georgia Research Foundation, which is funded by the Bill & Melinda Gates Foundation for the Schistosomiasis Consortium for Operational Research and Evaluation projects (prime award number 50816, sub-award number RR374-053/4893206). SK received financial support by sub-award number RR374-053/4893196 and via direct grants from the Gates Foundation (investment identification numbers OPP1191423 and OPP1198086). AL was funded by a National Health and Medical Research Council Senior Principal Research Fellowship (number APP1117504). BAT was funded by a James Cook University Postgraduate Scholarship. GGM was funded by an Australian Institute of Tropical Health and Medicine postgraduate scholarship. Funding was granted to AAA by a European and Developing Countries Clinical Trials Partnership senior fellowship training award (number TA_11_40200). FM was funded by the Thrasher Research Fund (number 12440) and the Wellcome Trust (number 108061/Z/15/Z). Sí

BACKGROUND: Control efforts against soil-transmitted helminths focus on preventive chemotherapy with albendazole and mebendazole, however these drugs yield unsatisfactory results against Trichuris trichiura infections. We aimed to assess the efficacy and safety of moxidectin and albendazole compared with ivermectin and albendazole against T trichiura in adolescents living on Pemba Island, Tanzania. METHODS: This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done in four secondary schools (Kilindi, Kwale, Ndagoni [Chake Chake District], and Kiuyu [Wete District]) on Pemba Island, Tanzania. Adolescents aged 12-19 years who tested positive for T trichiura in at least two of four Kato-Katz slides with a mean infection intensity of 48 eggs per gram (EPG) of stool or higher were considered for inclusion. Participants were randomly assigned (21:21:2:2:8) to five treatment groups (8 mg moxidectin and 400 mg albendazole [group 1], 200 mug/kg ivermectin and 400 mg albendazole [group 2], 400 mg albendazole [group 3], 200 mug/kg ivermectin [group 4], or 8 mg moxidectin [group 5]) using a computer-generated randomisation code, stratified by baseline T trichiura infection intensity. Study site investigators and participants were not masked to study treatment; however, allocation was concealed to participants. The primary outcome was egg reduction rate (ERR) of T trichiura 14-21 days after treatment in the available case population. Moxidectin and albendazole was considered non-inferior to ivermectin and albendazole (control group) when the lower limit of the two-sided 95% CI of the difference was higher than the non-inferiority margin of -2 percentage points. This study is registered with ClinicalTrials.gov, NCT04700423. FINDINGS: Between March 1 and April 30, 2021, 771 participants were assessed for eligibility. 221 (29%) of 771 participants were ineligible and a further 14 (2%) were excluded. 207 (39%) of 536 participants were randomly assigned to moxidectin and albendazole, 211 (39%) to ivermectin and albendazole, 19 (4%) to albendazole, 19 (4%) to ivermectin, and 80 (15%) to moxidectin. Primary outcome data were available for all 536 participants. The geometric mean ERR of T trichiura after 14-21 days was 96.8% (95% CI 95.8 to 97.6) with moxidectin and albendazole and 99.0% (98.7 to 99.3) with ivermectin and albendazole (difference of -2.2 percentage points [-4.2 to -1.4]). No serious adverse events were reported during the study. The most reported adverse events were headache (160 [34%] of 465), abdominal pain (78 [17%]), itching (44 [9%]), and dizziness (26 [6%]). INTERPRETATION: Our findings show inferiority of moxidectin and albendazole to ivermectin and albendazole against T trichiura. However, given the high efficacy, moxidectin coadministration might complement treatment progammes, particularly in areas in which ivermectin is not available FUNDING: Bill and Melinda Gates Foundation, reference number OPP1153928.

We estimated the financial costs of different interventions against urogenital schistosomiasis, implemented by the Zanzibar Elimination of Schistosomiasis Transmission (ZEST) project, on Pemba and Unguja islands, Tanzania. We used available data on project activities, resources used, and costs reported in the accounting information systems of ZEST partners. The costs were estimated for all the activities related to snail control, behavior change interventions, the impact assessment surveys, and management of the whole program. Costs are presented in US$ for the full duration of the ZEST project from 2011/2012 to 2017. The total financial costs of implementing snail control activities over 5 years, excluding the costs for donated Bayluscide, were US$55,796 on Pemba and US$73,581 on Unguja, mainly driven by personnel costs. The total financial costs of implementing behavior change activities were US$109,165 on Pemba and US$155,828 on Unguja, with costs for personnel accounting for 47% on Pemba and 69% on Unguja. Costs of implementing biannual mass drug administration refer to the estimated 2.4 million treatments provided on Pemba over 4 years (2013–2016), and do not include the costs of donated praziquantel. The total cost per provided treatment was, on average, US$0.21. This study showed the value of exploiting administrative data to estimate costs of major global health interventions. It also provides an evidence base for financial costs and main cost drivers of implementing multiple combinations of intervention sets that inform decisions regarding the feasibility and affordability of implementing schistosomiasis control and elimination strategies.

As part of its diverse portfolio, the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) included two cluster-randomized trials evaluating interventions that could potentially lead to interruption of schistosomiasis transmission (elimination) in areas of Africa with low prevalence and intensity of infection. These studies, conducted in Zanzibar and Côte d’Ivoire, demonstrated that multiyear mass drug administration (MDA) with praziquantel failed to interrupt the transmission of urogenital schistosomiasis, even when provided biannually and/or supplemented by small-scale implementation of additional interventions. Other SCORE activities related to elimination included a feasibility and acceptability assessment of test–treat–track–test–treat (T5) strategies and mathematical modeling. Future evaluations of interventions to eliminate schistosomiasis should recognize the difficulties inherent in conducting randomized controlled trials on elimination and in measuring small changes where baseline prevalence is low. Highly sensitive and specific diagnostic tests for use in very low–prevalence areas for schistosomiasis are not routinely available, which complicates accurate measurement of infection rates and assessment of changes resulting from interventions in these settings. Although not encountered in these two studies, as prevalence and intensity decrease, political and community commitment to population-wide MDA may decrease. Because of this potential problem, SCORE developed and funded the T5 strategy implemented in Egypt, Kenya, and Tanzania. It is likely that focal MDA campaigns, along with more targeted approaches, including a T5 strategy and snail control, will need to be supplemented with the provision of clean water and sanitation and behavior change communications to achieve interruption of schistosome transmission.

We investigated the vaginal microbiota (VMB) composition, prevalence of genital pathogens and their association among pregnant and post-delivery women in Pemba Island, Tanzania. Vaginal swabs were collected from 90 women, at two time points during pregnancy (

To address the disproportionate burden of preterm birth (PTB) in low- and middle-income countries, this study aimed to (1) verify the performance of the United States-validated spontaneous PTB (sPTB) predictor, comprised of the IBP4/SHBG protein ratio, in subjects from Bangladesh, Pakistan and Tanzania enrolled in the Alliance for Maternal and Newborn Health Improvement (AMANHI) biorepository study, and (2) discover biomarkers that improve performance of IBP4/SHBG in the AMANHI cohort. The performance of the IBP4/SHBG biomarker was first evaluated in a nested case control validation study, then utilized in a follow-on discovery study performed on the same samples. Levels of serum proteins were measured by targeted mass spectrometry. Differences between the AMANHI and U.S. cohorts were adjusted using body mass index (BMI) and gestational age (GA) at blood draw as covariates. Prediction of sPTB < 37 weeks and < 34 weeks was assessed by area under the receiver operator curve (AUC). In the discovery phase, an artificial intelligence method selected additional protein biomarkers complementary to IBP4/SHBG in the AMANHI cohort. The IBP4/SHBG biomarker significantly predicted sPTB < 37 weeks (n = 88 vs. 171 terms ≥ 37 weeks) after adjusting for BMI and GA at blood draw (AUC= 0.64, 95% CI: 0.57–0.71, p < .001). Performance was similar for sPTB < 34 weeks (n = 17 vs. 184 ≥ 34 weeks): AUC = 0.66, 95% CI: 0.51–0.82, p = .012. The discovery phase of the study showed that the addition of endoglin, prolactin, and tetranectin to the above model resulted in the prediction of sPTB < 37 with an AUC= 0.72 (95% CI: 0.66–0.79, p-value < .001) and prediction of sPTB < 34 with an AUC of 0.78 (95% CI: 0.67–0.90, p < .001). A protein biomarker pair developed in the U.S. may have broader application in diverse non-U.S. populations.

IntroductionPreterm birth is the leading cause of child mortality. This study aimed to develop and validate programmatically feasible and accurate approaches to estimate newborn gestational age (GA) in low resource settings.MethodsThe WHO Alliance for Maternal and Newborn Health Improvement (AMANHI) study recruited pregnant women from population-based cohorts in five countries (Bangladesh, Ghana, Pakistan, Tanzania and Zambia). Women Results7428 liveborn infants were included (n=536 preterm, ConclusionThe best machine-learning model (10 neonatal characteristics and LMP) estimated GA within ±15.7 days of early ultrasound dating. Simpler models performed reasonably well with marginal increases in prediction error. These models hold promise for newborn GA estimation when ultrasound dating is unavailable.

Background: Infections with soil-transmitted helminths (STHs) predominantly affect impoverished populations in tropical environments. The periodic administration of single dose benzimidazoles (i.e., albendazole, mebendazole) to at-risk individuals in endemic regions is at the center of STH control strategies. Given the low efficacy of these drugs against trichuriasis, investigation of drug combinations including moxidectin and ivermectin has recently been initiated, yet the identification of the best treatment option requires more research. We present the protocol for a trial investigating the efficacy and safety of co-administered moxidectin and albendazole compared to co-administered ivermectin and albendazole against Trichuris trichiura. Methods: We will conduct a randomized controlled trial enrolling 540 T. trichiura-infected adolescents aged 12-19 years on Pemba Island (Tanzania). The primary objective is to demonstrate non-inferiority of orally co-administered single-dose moxidectin (8 mg)/albendazole (400 mg) compared to orally co-administered single-dose ivermectin (200 µg/kg)/albendazole (400 mg) in terms of egg reduction rates (ERRs) against T. trichiura infections assessed by Kato-Katz at 14-21 days post-treatment. Secondary objectives include the assessment of the drug combinations’ superiority compared to their respective monotherapies, of the cure rates (CRs) against T. trichiura, and the safety and tolerability of all treatments, as well as CRs and ERRs against concomitant STH infections (Ascaris lumbricoides and hookworm). Potential effects of the treatment regimens on follow-up prevalences of STH at 5-6 weeks and 3 months post-treatment, infection status derived by quantitative polymerase chain reaction (qPCR), and pharmacokinetic/ pharmacodynamic parameters will also be assessed. Furthermore, a subsample of stool specimens will be analyzed by an updated version of the FECPAKG2 platform. Conclusions: Results from this trial will help to inform decision- and policymakers on which anthelminthic combination therapy might improve existing deworming programs and provide a valuable adjunct tool for interrupting STH transmission. Clinicaltrials.gov registration: NCT04700423 (07/01/2021)

Background: Infections with soil-transmitted helminths (STHs) predominantly affect impoverished populations in tropical environments. The periodic administration of single dose benzimidazoles (i.e., albendazole, mebendazole) to at-risk individuals in endemic regions is at the center of STH control strategies. Given the low efficacy of these drugs against trichuriasis, investigation of drug combinations including moxidectin and ivermectin has recently been initiated, yet the identification of the best treatment option requires more research. We present the protocol for a trial investigating the efficacy and safety of co-administered moxidectin and albendazole compared to co-administered ivermectin and albendazole against Trichuris trichiura. Methods: We will conduct a randomized controlled trial enrolling 540 T. trichiura-infected adolescents aged 12-19 years on Pemba Island (Tanzania). The trial will be open-label with blinded outcome assessors. The primary objective is to demonstrate non-inferiority of orally co-administered single-dose moxidectin (8 mg)/albendazole (400 mg) compared to orally co-administered single-dose ivermectin (200 µg/kg)/albendazole (400 mg) in terms of egg reduction rates (ERRs) against T. trichiura infections assessed by Kato-Katz at 14-21 days post-treatment. Secondary objectives include the assessment of the drug combinations’ superiority compared to their respective monotherapies, of the cure rates (CRs) against T. trichiura, and the safety and tolerability of all treatments, as well as CRs and ERRs against concomitant STH infections ( Ascaris lumbricoides and hookworm). Potential effects of the treatment regimens on follow-up prevalences of STH at 5-6 weeks and 3 months post-treatment and pharmacokinetic/ pharmacodynamic parameters will also be assessed. Conclusions: Results from this trial will help to inform decision- and policymakers on which anthelminthic combination therapy might improve existing deworming programs and provide a valuable adjunct tool for interrupting STH transmission. Clinicaltrials.gov registration: NCT04700423 (07/01/2021)

Background Soil-transmitted helminthiasis affects almost 2 billion people worldwide in tropical climates. Preventive chemotherapy, using the benzimidazoles (albendazole and mebendazole) is the current main recommended control strategy. Nevertheless, there is limited efficacy of these drugs against hookworm infection and, to a greater extent, against trichuriasis. We describe a protocol for a trial investigating the efficacy and safety of the co-administration of ivermectin and albendazole against trichuriasis. Methods A double-blind, placebo-controlled randomized controlled trial will be conducted in three countries (Côte d’Ivoire, Tanzania and Lao PDR) with the aim to determine the efficacy, safety and extended effects of co-administered ivermectin and albendazole compared to standard albendazole monotherapy. We will enroll 600 participants aged 6–60 years in each setting. The primary outcome is cure rate (CR) against Trichuris trichiura infection as assessed by Kato-Katz 14–21 days after treatment. Secondary outcomes include CRs against concomitant soil-transmitted helminth (STH) infections (Ascaris lumbricoides, hookworm and Strongyloides stercoralis) and egg reduction rates (ERRs) against STH at 14–21 days, 180 days and 360 days. Tolerability of treatment, infection status assessed by polymerase chain reaction (PCR), and potential benefits of deworming on nutritional and morbidity indicators will be assessed. The primary analysis will include an available-case set and use logistic regression models adjusted for age, sex and weight. Discussion This trial will provide robust results on the efficacy and safety of co-administration of ivermectin and albendazole with the aim to better inform WHO recommendations on control of STHs. Furthermore, secondary and explanatory outcomes will provide direct evidence on the extended effects of combination therapy and insight on the relationship between nutrition and morbidity parameters and infection status and intensity. Trial registration NCT03527732 (date assigned: 17 May 2018). Electronic supplementary material The online version of this article (10.1186/s12879-019-3882-x) contains supplementary material, which is available to authorized users.

Background Globally, 15 million infants are born preterm and another 23.2 million infants are born small for gestational age (SGA). Determining burden of preterm and SGA births, is essential for effective planning, modification of health policies and targeting interventions for reducing these outcomes for which accurate estimation of gestational age (GA) is crucial. Early pregnancy ultrasound measurements, last menstrual period and post-natal neonatal examinations have proven to be not feasible or inaccurate. Proposed algorithms for GA estimation in western populations, based on routine new-born screening, though promising, lack validation in developing country settings. We evaluated the hypothesis that models developed in USA, also predicted GA in cohorts of South Asia (575) and Sub-Saharan Africa (736) with same precision. Methods Dried heel prick blood spots collected 24-72 hours after birth from 1311 new-borns, were analysed for standard metabolic screen. Regression algorithm based, GA estimates were computed from metabolic data and compared to first trimester ultrasound validated, GA estimates (gold standard). Results Overall Algorithm (metabolites + birthweight) estimated GA to within an average deviation of 1.5 weeks. The estimated GA was within the gold standard estimate by 1 and 2 weeks for 70.5% and 90.1% new-borns respectively. Inclusion of birthweight in the metabolites model improved discriminatory ability of this method, and showed promise in identifying preterm births. Receiver operating characteristic (ROC) curve analysis estimated an area under curve of 0.86 (conservative bootstrap 95% confidence interval (CI) = 0.83 to 0.89); P

Background Maternal morbidity occurs several times more frequently than mortality, yet data on morbidity burden and its effect on maternal, foetal, and newborn outcomes are limited in low- and middle-income countries. We aimed to generate prospective, reliable population-based data on the burden of major direct maternal morbidities in the antenatal, intrapartum, and postnatal periods and its association with maternal, foetal, and neonatal death in South Asia and sub-Saharan Africa. Methods and findings This is a prospective cohort study, conducted in 9 research sites in 8 countries of South Asia and sub-Saharan Africa. We conducted population-based surveillance of women of reproductive age (15 to 49 years) to identify pregnancies. Pregnant women who gave consent were include in the study and followed up to birth and 42 days postpartum from 2012 to 2015. We used standard operating procedures, data collection tools, and training to harmonise study implementation across sites. Three home visits during pregnancy and 2 home visits after birth were conducted to collect maternal morbidity information and maternal, foetal, and newborn outcomes. We measured blood pressure and proteinuria to define hypertensive disorders of pregnancy and woman’s self-report to identify obstetric haemorrhage, pregnancy-related infection, and prolonged or obstructed labour. Enrolled women whose pregnancy lasted at least 28 weeks or those who died during pregnancy were included in the analysis. We used meta-analysis to combine site-specific estimates of burden, and regression analysis combining all data from all sites to examine associations between the maternal morbidities and adverse outcomes. Among approximately 735,000 women of reproductive age in the study population, and 133,238 pregnancies during the study period, only 1.6% refused consent. Of these, 114,927 pregnancies had morbidity data collected at least once in both antenatal and in postnatal period, and 114,050 of them were included in the analysis. Overall, 32.7% of included pregnancies had at least one major direct maternal morbidity; South Asia had almost double the burden compared to sub-Saharan Africa (43.9%, 95% CI 27.8% to 60.0% in South Asia; 23.7%, 95% CI 19.8% to 27.6% in sub-Saharan Africa). Antepartum haemorrhage was reported in 2.2% (95% CI 1.5% to 2.9%) pregnancies and severe postpartum in 1.7% (95% CI 1.2% to 2.2%) pregnancies. Preeclampsia or eclampsia was reported in 1.4% (95% CI 0.9% to 2.0%) pregnancies, and gestational hypertension alone was reported in 7.4% (95% CI 4.6% to 10.1%) pregnancies. Prolonged or obstructed labour was reported in about 11.1% (95% CI 5.4% to 16.8%) pregnancies. Clinical features of late third trimester antepartum infection were present in 9.1% (95% CI 5.6% to 12.6%) pregnancies and those of postpartum infection in 8.6% (95% CI 4.4% to 12.8%) pregnancies. There were 187 pregnancy-related deaths per 100,000 births, 27 stillbirths per 1,000 births, and 28 neonatal deaths per 1,000 live births with variation by country and region. Direct maternal morbidities were associated with each of these outcomes. Conclusions Our findings imply that health programmes in sub-Saharan Africa and South Asia must intensify their efforts to identify and treat maternal morbidities, which affected about one-third of all pregnancies and to prevent associated maternal and neonatal deaths and stillbirths. Trial registration The study is not a clinical trial., Author summary Why was this study done? Estimates of severe direct maternal morbidity are largely based on hospital-based studies with inconsistent definitions and varying selection criteria. Limited data are available from South Asia and sub-Saharan Africa, the 2 regions with the highest maternal and newborn morbidity and mortality, where a larger proportion of births occur at home. What did the researchers do and find? We collected data on maternal morbidities from a cohort of women in the community in multiple sites in sub-Saharan Africa and in South Asia. Out of a cohort of >114,000 women, we found that about 1 in 3 women suffer a maternal morbidity, which was notably higher than the previously reported data. We found that the prevalence of preeclampsia and eclampsia was about 1%, which was lower than previously reported. About 11% of women reported having prolonged or obstructed labour, which was somewhat higher than published estimates. The burden of pregnancy-related infection in postpartum period was higher in South Asia than in sub-Saharan Africa. This is the first study, to our knowledge, to describe the burden of antepartum haemorrhage and late antepartum infection and to clearly demonstrate the association of direct maternal morbidity with adverse pregnancy outcomes. What do these findings mean? Higher burden of direct maternal morbidity and its association with adverse outcomes highlights the need for improving health of women and mothers, including promotion of preconception health and nutrition, and high-quality antepartum, intrapartum and postpartum care.

This study aimed to determine the persistence of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG) infections during pregnancy and after delivery in vaginal swabs of women from Pemba Island, Tanzania. In the context of an earlier biobanking effort, vaginal swabs were collected at two timepoints during pregnancy and once post-delivery. Detection of CT, NG, TV, and MG was performed by PCR using validated detection kits in samples from 441 pregnant women aged 16–48 years old. Among those, 202 samples were matched during pregnancy and 38 at the second timepoint of the pregnancy and post-delivery CT infection persistence during pregnancy was 100% (n = 11) after an average of eight weeks, that of TV infection 82% (n = 11) after ten weeks, and that of MG infection 75% (n = 4) after ten weeks. Post-delivery (after approximately 22 weeks) infection persistence was 100% for CT (n = 1) and 20% for TV (n = 5). NG was only detected at the last collection timepoint, its persistence rate could not be determined. These results show persistence and clearance of curable infections during and after pregnancy. Analysis of biobanked samples is a valuable approach in the investigation of the natural history of curable pathogens.

Background Preventive chemotherapy is the cornerstone of soil-transmitted helminth (STH) control. Long-term outcomes and adequate treatment frequency of the recently recommended albendazole-ivermectin have not been studied to date. Methodology/principal findings Double-blind randomized controlled trials were conducted in Lao PDR, Pemba Island, Tanzania and Côte d’Ivoire between 2018 and 2020 to evaluate the efficacy and safety of ivermectin-albendazole versus albendazole-placebo in Trichuris trichiura-infected individuals aged 6 to 60. In the framework of this study, in Lao PDR 466 and 413 participants and on Pemba Island, 558 and 515 participants were followed-up six and 12 months post-treatment, respectively. From each participant at least one stool sample was processed for Kato-Katz diagnosis and cure rates (CRs), egg reduction rates (ERRs) and apparent reinfection rates were calculated. If found helminth-positive at six months, participants were re-treated according to their allocated treatment. Long-term outcomes against T. trichiura based on CRs and ERRs of ivermectin-albendazole compared to albendazole were significantly higher at six months in Lao PDR (CR, 65.8 vs 13.4%, difference; 52.4; 95% CI 45.0–60.0; ERRs, 99.0 vs 79.6, difference 19.4; 95% CI 14.4–24.4) and Pemba Island (CR, 17.8 vs 1.4%, difference; 16.4; 95% CI 11.6–21.0; ERRs, 84.9 vs 21.2, difference 63.8; 95% CI 50.6–76.9) and also at 12 months in Lao PDR (CR, 74.0 vs 23.4%, difference; 50.6; 95% CI 42.6–61.0; ERRs, 99.6 vs 91.3, difference 8.3; 95% CI 5.7–10.8) and Pemba Island (CR, 19.5 vs 3.4%, difference; 16.1; 95% CI 10.7–21.5; ERRs, 92.9 vs 53.6, difference 39.3; 95% CI 31.2–47.4) respectively. Apparent reinfection rates with T. trichiura were considerably higher on Pemba Island (100.0%, 95% CI, 29.2–100.0) than in Lao PDR (10.0%, 95% CI, 0.2–44.5) at 12 months post-treatment for participants treated with albendazole alone. Conclusions/significance The long-term outcomes against T. trichiura of ivermectin-albendazole are superior to albendazole in terms of CRs and ERRs and in reducing infection intensities. Our results will help to guide decisions on how to best use ivermectin-albendazole in the context of large-scale PC programs tailored to the local context to sustainably control STH infections. Trial registration ClinicalTrials.gov registered with clinicaltrials.gov, reference: NCT03527732, date assigned: 17 May 2018., Author summary Around 1.5 billion people are infected with the gastrointestinal dwelling nematodes, the so-called soil-transmitted helminths (STHs). Especially chronic high-intensity infections with these parasites can cause substantial morbidity in endemic regions. Preventive chemotherapy, which is the regular administration of a single dose of an anthelmintic drug to at-risk populations, aims to reduce morbidity by lowering the prevalence and intensity of STH infections. Due to the suboptimal efficacy of these recommended single dose monotherapies, particularly against Trichuris trichiura, the use of drug combinations with dissimilar modes of action may enhance treatment efficacy. In double-blind randomized controlled trials in Lao PDR and on Pemba Island, Tanzania, we examined the long-term outcomes of ivermectin-albendazole versus albendazole alone, against T. trichiura. We assessed the infection status, apparent reinfections, new infections and the change of infection intensity for the three major STH species six and 12 months post-treatment. The long-term outcomes (in terms of cure and egg-reduction rates) of the ivermectin-albendazole combination therapy against T. trichiura were significantly higher than that of albendazole alone at all-time points and in both countries. Bi-annual treatment intervals using the ivermectin-albendazole combination might be necessary to sustainably decrease transmission of STH infections.

This study aimed to determine the persistence of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG) infections during pregnancy and after delivery in vaginal swabs of women from Pemba Island, Tanzania. In the context of an earlier biobanking effort, vaginal swabs were collected at two timepoints during pregnancy and once post-delivery. Detection of CT, NG, TV, and MG was performed by PCR using validated detection kits in samples from 441 pregnant women aged 16–48 years old. Among those, 202 samples were matched during pregnancy and 38 at the second timepoint of the pregnancy and post-delivery CT infection persistence during pregnancy was 100% (n = 11) after an average of eight weeks, that of TV infection 82% (n = 11) after ten weeks, and that of MG infection 75% (n = 4) after ten weeks. Post-delivery (after approximately 22 weeks) infection persistence was 100% for CT (n = 1) and 20% for TV (n = 5). NG was only detected at the last collection timepoint, its persistence rate could not be determined. These results show persistence and clearance of curable infections during and after pregnancy. Analysis of biobanked samples is a valuable approach in the investigation of the natural history of curable pathogens.

BACKGROUND: Preventive chemotherapy with albendazole or mebendazole remains one of the cornerstones of soil-transmitted helminth control. However, these drugs are less effective against Trichuris trichiura. Combined ivermectin-albendazole is a promising treatment alternative, yet robust evidence is lacking. We aimed to demonstrate superiority of co-administered ivermectin-albendazole over albendazole monotherapy in three distinct epidemiological settings. METHODS: We conducted a double-blind, parallel-group, phase 3, randomised controlled trial in community members aged 6-60 years infected with T trichiura in Cote d'Ivoire, Laos, and Pemba Island, Tanzania, between Sept 26, 2018, and June 29, 2020. Participants with at least 100 T trichiura eggs per g of stool at baseline were randomly assigned (1:1) using computer-generated randomisation sequences in varying blocks of four, six, and eight, stratified by baseline T trichiura infection intensity, to orally receive either a single dose of ivermectin (200 mug/kg) plus albendazole (400 mg) or albendazole (400 mg) plus placebo. Patients, field staff, and outcome assessors were masked to treatment assignment. The primary outcome was cure rate against T trichiura, defined as the proportion of participants with no eggs in their faeces 14-21 days after treatment, assessed by Kato-Katz thick smears, and analysed in the available-case population according to intention-to-treat principles. Safety was a secondary outcome and was assessed 3 h and 24 h after drug administration. The trial is registered at ClinicalTrials.gov, NCT03527732. FINDINGS: Between Sept 13 and Dec 18, 2019, Jan 12 and April 5, 2019, and Sept 26 and Nov 5, 2018, 3737, 3694, and 1435 community members were screened for trial eligibility in Cote d'Ivoire, Laos, and Pemba Island, respectively. In Cote d'Ivoire, Laos, and Pemba Island, 256, 274, and 305 participants, respectively, were randomly assigned to the albendazole group, and 255, 275, and 308, respectively, to the ivermectin-albendazole group. Primary outcome data were available for 722 participants treated with albendazole and 733 treated with ivermectin-albendazole. Ivermectin-albendazole showed significantly higher cure rates against T trichiura than albendazole in Laos (66% [140 of 213]vs 8% [16 of 194]; difference 58 percentage points, 95% CI 50 to 65, p

There is only limited scientific literature on trial methodology, trial procedures and mitigation strategies to overcome challenges faced during clinical research taking place in resource constrained healthcare environments. Organisational, cultural, infrastructural and ethical challenges may vary between settings although conduct of clinical trials for the same disease (in our case soil-transmitted helminth (STH) infections) share similar risks for implementation. We use the example of a phase III randomised controlled trial, conducted between 2018 and 2020 in Côte d'Ivoire, Lao PDR and Pemba Island (Tanzania), to share challenges faced and mitigation strategies to guide future planning of studies in similar settings. We describe the planning, screening, enrolment and implementation phases in each of the three settings. Our findings indicate that involvement of local staff and close collaboration are essential factors for successful trial preparation and implementation. A strategic plan adapted to each setting with a distinct focus on community engagement and workforce is crucial to proceed efficiently. Mutual trust between the trial population and the trial team is of utmost importance and allows for early reaction and adaption to emerging issues.

Background Babies born early and/or small for gestational age in Low and Middle-income countries (LMICs) contribute substantially to global neonatal and infant mortality. Tracking this metric is critical at a population level for informed policy, advocacy, resources allocation and program evaluation and at an individual level for targeted care. Early prenatal ultrasound examination is not available in these settings, gestational age (GA) is estimated using new-born assessment, last menstrual period (LMP) recalls and birth weight, which are unreliable. Algorithms in developed settings, using metabolic screen data, provided GA estimates within 1–2 weeks of ultrasonography-based GA. We sought to leverage machine learning algorithms to improve accuracy and applicability of this approach to LMICs settings. Methods This study uses data from AMANHI-ACT, a prospective pregnancy cohorts in Asia and Africa where early pregnancy ultrasonography estimated GA and birth weight are available and metabolite screening data in a subset of 1318 new-borns were also available. We utilized this opportunity to develop machine learning (ML) algorithms. Random Forest Regressor was used where data was randomly split into model-building and model-testing dataset. Mean absolute error (MAE) and root mean square error (RMSE) were used to evaluate performance. Bootstrap procedures were used to estimate confidence intervals (CI) for RMSE and MAE. For pre-term birth identification ROC analysis with bootstrap and exact estimation of CI for area under curve (AUC) were performed. Results Overall model estimated GA had MAE of 5.2 days (95% CI 4.6–6.8), which was similar to performance in SGA, MAE 5.3 days (95% CI 4.6–6.2). GA was correctly estimated to within 1 week for 85.21% (95% CI 72.31–94.65). For preterm birth classification, AUC in ROC analysis was 98.1% (95% CI 96.0–99.0; p p = 0.002). Conclusions Machine learning algorithms and models applied to metabolomic gestational age dating offer a ladder of opportunity for providing accurate population-level gestational age estimates in LMICs settings. These findings also point to an opportunity for investigation of region-specific models, more focused feasible analyte models, and broad untargeted metabolome investigation.

Background Soil-transmitted helminthiases are important neglected tropical diseases that result in a notably high number of disability-adjusted life years worldwide. Characterizing the interactions between the human intestinal microbiome and helminths is of interest in the development of alternative treatments that do not rely on chemotherapeutics and do not lead to drug resistance. Methods We recruited and obtained fecal samples from 32 pairs of mothers and children on Pemba Island and monitored their intestinal microbiota using 16S rRNA gene sequencing. Results We observed that microbial changes occur in the gut microbiota of infected mothers and children. Some short-chain fatty acid (SCFA)-producing bacteria and carbohydrate-degrading bacteria exhibited lower abundance in the infected individuals. Potentially pathogenic Campylobacter and proinflammatory Methanobrevibacter in infected mothers and opportunistic Enterococcus in infected children exhibited greater abundance. Conclusions Our findings could reveal the microbiota profiling in T. trichiura-infected individuals, indicate the potential roles of key microbiota in the host and aid to the development of novel strategies to control T. trichiura infection. Graphical Abstract

Background Considerable progress towards the elimination of urogenital schistosomiasis was made by the Zanzibar Elimination of Schistosomiasis Transmission project from 2012 till 2016, when biannual praziquantel mass drug administration (MDA) alone or with additional snail control or behaviour change interventions were implemented. Annual MDA was continued in 2017 and 2018, but not in 2019, imposing a 16-month treatment gap. We monitored the Schistosoma haematobium prevalence from 2012 till 2020 and assessed recrudescence patterns with focus on 2020. Methodology Repeated cross-sectional surveys were conducted from 2011/12 till 2020 in 90 communities and 90 schools in Zanzibar. Annually, around 4,500 adults and up to 20,000 schoolchildren were surveyed. The S. haematobium prevalence was detected by urine filtration and reagent strips. In 2020, risk factors for infection were investigated using generalized estimated equation models. Principal findings In adults, the apparent S. haematobium prevalence was 3.9% in 2011 and 0.4% in 2020. In schoolchildren, the prevalence decreased from 6.6% in 2012 to 1.2% in 2019 with vicissitudes over the years. Prominent recrudescence of infection from 2.8% in 2019 to 9.1% (+225%) in 2020 was observed in 29 schools with historically moderate prevalences (≥10%). Compared with 2019, reinfection in 2020 was particularly striking in boys aged 9–16 years. Being male was a risk factor for infection in 2020 (adults: odds ratio (OR): 6.24, 95% confidence interval (95% CI): 1.96–19.60; schoolchildren: OR: 2.06, 95% CI: 1.52–2.78). Living near to a natural freshwater body significantly increased the odds of infection in adults (OR: 2.90, CI: 1.12–7.54). Conclusions/Significance After 11 rounds of MDA over 7 years and a 16-month treatment gap, the urogenital schistosomiasis prevalence considerably rebounded in hotspot areas. Future elimination efforts in Zanzibar should focus on re-intensifying MDA plus additional interventions in hotspot areas. In low-prevalence areas, the strategy might be adapted from MDA to targeted surveillance-response., Author summary Schistosomiasis is a neglected tropical disease caused by parasitic blood flukes of the genus Schistosoma. On the Zanzibar islands, United Republic of Tanzania, interventions to eliminate urogenital schistosomiasis commenced in 2012. From 2012 to 2016, the population was treated biannually with praziquantel and, additionally, some areas received mollusciciding against the intermediate host snail, or educational measures for behavior change. Mass drug administration (MDA) with praziquantel was continued annually in 2017 and 2018, but not in 2019. As a result of the interventions, the overall S. haematobium prevalence was reduced to 0.4% in adults and 3.4% in schoolchildren in 2020. However, in some areas, the MDA gap in 2019 resulted in a considerable rebound of infections. The recrudescence in 2020 was particularly striking for boys aged 9–16 years. In general, in 2020, male participants had higher odds of infection than females. Adults living near to a natural freshwater body also showed an increased risk of S. haematobium infection. Future elimination efforts in Zanzibar should focus on re-intensifying elimination interventions, including MDA, snail control and behavior change in hotspot areas. In low-prevalence areas, the strategy might be adapted from MDA to targeted interventions, such as surveillance-response.

Background Clinical trial participants are required to sign an informed consent form (ICF). However, information is lacking on the most effective methods to convey trial relevant information prior to inviting participants to sign the ICF, being particularly pertinent in low-income countries. A previous study on Pemba Island, Tanzania, found that a verbal information session (IS) was significantly better than providing an ICF alone. However, knowledge gaps remained. Building on these findings, we investigated the effect of adding a slideshow or a theater to the IS in the informed consent procedure of an anthelminthic clinical trial. Methodology/principal findings A total of 604 caregivers were randomized into the control group that only received an ICF (n = 150) or an ICF plus one of three intervention strategies: (i) verbal IS (n = 135), (ii) verbal IS with a slideshow (n = 174) or (iii) verbal IS followed by a theater (n = 145). All modes of information covered the same key messages. Participants’ understanding was assessed using a semi-structured questionnaire. The mean score of caregivers in the control group (ICF only) was 4.41 (standard deviation = 1.47). Caregivers attending the IS alone were more knowledgeable than those in the control group (estimated difference in mean scores: 2.40, 95% confidence interval (CI) 1.95 to 2.86, p < 0.01). However, there was no evidence of an improvement compared to the IS only when participants attended a slideshow (0.09, 95% CI -0.53 to 0.35, p = 0.68) or a theater (0.28, 95% CI -0.27 to 0.82, p = 0.32). Three out of 10 key messages remained largely misunderstood, regardless of the mode of information group. Conclusions/significance Our study confirmed that, in this setting, an ICF alone was not sufficient to convey clinical trial-related information. An IS was beneficial, however, additional theater and slideshows did not further improve understanding. Future research should explore methods to improve communication between study teams and participants for different key messages, study types and settings., Author summary Legally, participants of clinical trials must sign an informed consent form prior to the start of a trial. To be truly informed, participants (or their caregivers, if underaged) need to understand the trial objectives, procedures, benefits, potential risks and their rights throughout the study. However, in regions where literacy and health literacy are still quite low, delivering information exclusively in written format using an informed consent form is not the best way to convey information. A previous study on Pemba Island, Tanzania, found that a spoken information session in addition to the informed consent form alone, significantly improved the clinical trial-related knowledge of the caregivers of participants. However, not all questions could be answered correctly. In the current study, we explored the addition of two further modes of information to the information session: a slideshow or a theater show. Caregivers’ understanding was measured using a questionnaire. We confirmed that having an oral information session is significantly better than only receiving the informed consent form. However, adding a slideshow and theater did not further improve caregivers’ knowledge. We conclude that future studies should work on improving these modes of information or explore new ones.

Highlights • Children self-reported changes in urogenital schistosomiasis risk taking behaviours. • Children self-reported an increase in swallowing anthelmintic drugs during MDA. • Rebranding the concept of “worm” to “blood fluke” created a critical perceived health threat. • The Health Belief Model was a viable foundation for the behavioural intervention., Urogenital schistosomiasis is a common experience among children in Zanzibar. There is a paucity of behavioural science-based, health education and behaviour change (HEBC) interventions for school-aged children, those at greatest risk for urogenital schistosomiasis. We assessed the influence of a HEBC intervention, guided by the Health Belief model, among rural schoolchildren on Pemba and Unguja islands in Zanzibar, Tanzania. From 2012 to 2016, a cluster-randomized trial to assess three different interventions against urogenital schistosomiasis was conducted in 90 schools and shehias across Zanzibar. The HEBC intervention was implemented in 15 schools per island. In 2017, at the trial conclusion, we administered written questionnaires to schoolchildren from 4 HEBC intervention schools and 4 not HEBC exposed schools on each island, respectively. Responses were compared between students that were exposed or not exposed to the HEBC intervention using a Fisher's exact test. A total of 1451 students, 708 from intervention and 743 from non-intervention schools completed the questionnaire. Noting some between island differences, students who had received the HEBC interventions reported significant improvements in knowledge about Schistosoma haematobium transmission and personal risk, strategies for schistosomiasis prevention, and self-reported changes in risk behaviours: stopped washing laundry/dishes 49.4% (350/708) versus 5.8% (43/743), stopped bathing in streams/ponds 49.4% (350/708) versus 4.2% (31/743), and stopped playing in streams/ponds 40.8% (289/708) versus 10.8% (80/743). HEBC exposed children also reported a significant increase in swallowing tablets during mass drug administration (MDA) campaigns (when they had not before) 30.2% (214/708) versus 4.6% (34/743). The school based HEBC interventions were associated with desirable positive behaviour change among students. Data suggest that scaling up HEBC interventions to all schools in high-risk areas, augmented with bi-annual MDA, can help to reduce prevalence of urogenital schistosomiasis in Zanzibar, strengthening the possibility for future disease elimination.