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Abstract Artemisinin‐based combination therapy (ACT) is the first‐line recommended treatment for uncomplicated malaria. Pharmacokinetic (PK) properties in pregnant women are often based on small studies and need to be confirmed and validated in larger pregnant patient populations. This study aimed to evaluate the PK properties of amodiaquine and its active metabolite, desethylamodiaquine, and piperaquine in women in their second and third trimester of pregnancy with uncomplicated P. falciparum infections. Eligible pregnant women received either artesunate‐amodiaquine (200/540 mg daily, n = 771) or dihydroartemisinin‐piperaquine (40/960 mg daily, n = 755) for 3 days (NCT00852423). Population PK properties were evaluated using nonlinear mixed‐effects modeling, and effect of gestational age and trimester was evaluated as covariates. 1071 amodiaquine and 1087 desethylamodiaquine plasma concentrations, and 976 piperaquine plasma concentrations, were included in the population PK analysis. Amodiaquine concentrations were described accurately with a one‐compartment disposition model followed by a two‐compartment disposition model of desethylamodiaquine. The relative bioavailability of amodiaquine increased with gestational age (1.25% per week). The predicted exposure to desethylamodiaquine was 2.8%–32.2% higher in pregnant women than that reported in non‐pregnant women, while day 7 concentrations were comparable. Piperaquine concentrations were adequately described by a three‐compartment disposition model. Neither gestational age nor trimester had significant impact on the PK of piperaquine. The predicted exposure and day 7 concentrations of piperaquine were similar to that reported in non‐pregnant women. In conclusion, the exposure to desethylamodiaquine and piperaquine was similar to that in non‐pregnant women. Dose adjustment is not warranted for women in their second and their trimester of pregnancy.

Abstract Normal respiratory rates (RR) for children under five in the tropics are well-documented, but data for older children are limited. This study tracked RR changes with age and examined associations with nutritional status and environmental factors. We monitored rural Gambian children aged 6 months to 14 years, recording RR during home visits twice weekly over two rainy seasons. Using a generalized additive model, we constructed RR reference curves, and a linear mixed-effect model identified factors influencing RR. A total of 830 children provided 67,512 RR measurements. Their median age was 6.07 years (interquartile range 4.21–8.55) and 400 (48.2%) were female. Age, stunting, ambient temperature, and time of RR measurement were independent predictors of respiratory rate. Strikingly, children showing signs of illness had greater variability in repeat RR measurements. We constructed a RR reference chart for children aged one to 13 years and proposed a cutoff of > 26 breaths/min for raised RR among children aged > 5 years bridging an important gap in this age group. Although the time of data collection, nutritional status, and ambient temperature were predictors of RR, their effect size is not clinically significant enough to warrant a change in the current WHO guidelines owing to the prevailing uncertainty in the measurement of RR. The finding that RRs between repeat measurements were more variable among children with signs of illness suggests that a single RR measurement may be inadequate to reliably assess the status of sick children—a population in which accurate diagnosis is essential to enable targeted interventions with lifesaving treatment.

Abstract Ivermectin (IVM) has been proposed as a new tool for malaria control as it is toxic on vectors feeding on treated humans or cattle. Nevertheless, IVM may have a direct mosquitocidal effect when applied on bed nets or sprayed walls. The potential for IVM application as a new insecticide for long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) was tested in this proof-of-concept study in a laboratory and semi-field environment. Laboratory-reared, insecticide-susceptible Kisumu Anopheles gambiae were exposed to IVM on impregnated netting materials and sprayed plastered- and mud walls using cone bioassays. The results showed a direct mosquitocidal effect of IVM on this mosquito strain as all mosquitoes died by 24 h after exposure to IVM. The effect was slower on the IVM-sprayed walls compared to the treated nettings. Further work to evaluate possibility of IVM as a new insecticide formulation in LLINs and IRS will be required.

BackgroundPoint of care hemoglobin meters play key roles in increasing access to anemia screening in antenatal care especially in settings with limited access to laboratories. We aimed to determine the diagnostic accuracy of a non-invasive spot-check hemoglobin (SpHb) meter, Masimo Rad-67® Pulse CO-Oximeter®, in the diagnosis of anemia in pregnant women attending antenatal care clinics in Kilifi, Kenya.MethodsThis was a diagnostic accuracy study that retrospectively evaluated SpHb against a validated reference standard of laboratory assessed hemoglobin (Lab Hb) by a SYSMEX XN-330 automated hematology analyzer. The study was nested within a prospective pregnancy cohort study that recruited unselected pregnant women from antenatal care clinics in two public hospitals in Kilifi County, coastal Kenya. Records with both SpHb and Lab Hb were selected from pregnancy visits between May 2021 and December 2022. Linear regression and Bland-Altman analysis were performed to compare the two tests and diagnostic accuracy parameters obtained for the diagnosis of anemia.ResultsA total of 2,975 records (from 2,203 unique participants), with paired SpHb and Lab Hb were analyzed. Linear regression showed a significant but weak positive correlation, a proportional bias of 0.44 (95% CI 0.41–0.47) and a constant of 7.59 (95% CI 7.30–7.87, p

Abstract Background In 2022 the WHO recommended the discretionary expansion of the eligible age range for seasonal malaria chemoprevention (SMC) to children older than 4 years. Older children are at lower risk of clinical disease and severe malaria so there has been uncertainty about the cost-benefit for national control programmes. However, emerging evidence from laboratory studies suggests protecting school-age children reduces the infectious reservoir for malaria and may significantly impact on transmission. This study aimed to assess whether these effects were detectable in the context of a routinely delivered SMC programme. Methods In 2021 the Gambia extended the maximum eligible age for SMC from 4 to 9 years. We conducted a prospective population cohort study over the 2021 malaria transmission season covering 2210 inhabitants of 10 communities in the Upper River Region, and used a household-level mixed modelling approach to quantify impacts of SMC on malaria transmission. Results We demonstrate that the hazard of clinical malaria in older participants aged 10+ years ineligible for SMC decreases by 20% for each additional SMC round per child 0–9 years in the same household. Older inhabitants also benefit from reduced risk of asymptomatic infections in high SMC coverage households. Spatial autoregression tests show impacts are highly localised, with no detectable spillover from nearby households. Conclusions Evidence for the transmission-reducing effects of extended-age SMC from routine programmes implemented at scale has been previously limited. Here we demonstrate benefits to the entire household, indicating such programmes may be more cost-effective than previously estimated.

Abstract Background Anopheles gambiae, the major malaria mosquito in sub-Saharan Africa, feed largely indoors at night. Raising a house off the ground with no barriers underneath reduces mosquito-house entry. This experiment tested whether walling off the space under an elevated hut affects mosquito-hut entry. Methods Four inhabited experimental huts, each of which could be moved up and down, were used in rural Gambia. Nightly collections of mosquitoes were made using light traps and temperature and carbon dioxide levels monitored indoors and outdoors using loggers. Each night, a reference hut was kept at ground level and three huts raised 2 m above the ground; with the space under the hut left open, walled with air-permeable walls or solid walls. Treatments were rotated every four nights using a randomized block design. The experiment was conducted for 32 nights. Primary measurements were mosquito numbers and indoor temperature in each hut. Results A total of 1,259 female Anopheles gambiae sensu lato were collected in the hut at ground level, 655 in the hut with an open ground floor, 981 in the hut with air-permeable walls underneath and 873 in the hut with solid walls underneath. Multivariate analysis, adjusting for confounders, showed that a raised hut open underneath had 53% fewer mosquitoes (95% CI 47–58%), those with air-permeable walls underneath 24% fewer (95% CI 9–36%) and huts with solid walls underneath 31% fewer (95% CI 24–37%) compared with a hut on the ground. Similar results were found for Mansonia spp. and total number of female mosquitoes, but not for Culex mosquitoes where hut entry was unaffected by height or barriers. Indoor temperature and carbon dioxide levels were similar in all huts. Conclusion Raising a house 2 m from the ground reduces the entry of An. gambiae and Mansonia mosquitoes, but not Culex species. The protective effect of height is reduced if the space underneath the hut is walled off.

Background Over 250 million children are not reaching their developmental potential globally. The impact of prenatal factors and their interplay with postnatal environmental factors on child neurodevelopment, is still unclear—particularly in low- and middle-income settings. This study aims to understand the impact of pregnancy complications as well as environmental, psychosocial, and biological predictors on neurodevelopmental trajectories. Methods This is an observational cohort study of female and male children (≈3,950) born to women (≈4,200) with and without pregnancy complications (pregnancy-induced hypertension, foetal growth restriction, and premature birth) previously recruited into PREgnancy Care Integrating Translational Science, Everywhere study with detailed biological data collected in intrapartum and post-partum periods. Children will be assessed at six weeks to 6 months, 11-13 months, 23-25 months and 35-37 months in rural and semi-urban Gambia (Farafenni, Illiasa, and Ngayen Sanjal) and Kenya (Mariakani and Rabai). We will assess children's neurodevelopment using Prechtls General Movement Assessment, the Malawi Development Assessment Tool (primary outcome), Observation of Maternal-Child Interaction, the Neurodevelopmental Disorder Screening Tool, and the Epilepsy Screening tool. Children screening positive will be assessed with Cardiff cards (vision), Modified Checklist for Autism in Toddlers Revised, and Pediatric Quality of Life Inventory Family Impact. We will use multivariate logistic regression analysis to investigate the impact of pregnancy complications on neurodevelopment and conduct structural equation modelling using latent class growth to study trajectories and relationships between biological, environmental, and psychosocial factors on child development. Conclusions We aim to provide information regarding the neurodevelopment of infants and children born to women with and without pregnancy complications at multiple time points during the first three years of life in two low-resource African communities. A detailed evaluation of developmental trajectories and their predictors will provide information on the most strategic points of intervention to prevent and reduce the incidence of neurodevelopmental impairments.

Introduction The burden of severe maternal morbidity is highest in sub-Saharan Africa, and its relative contribution to maternal (ill) health may increase as maternal mortality continues to fall. Women’s perspective of their long-term recovery following severe morbidity beyond the standard 42-day postpartum period remains largely unexplored.Methods This woman-centred, grounded theory study was nested within the Pregnancy Care Integrating Translational Science Everywhere (PRECISE) study in Kilifi, Kenya. Purposive and theoretical sampling was used to recruit 20 women who experienced either a maternal near-miss event (n=11), potentially life-threatening condition (n=6) or no severe morbidity (n=3). Women were purposively selected between 6 and 36 months post partum at the time of interview to compare recovery trajectories. Using a constant comparative approach of line-by-line open codes, focused codes, super-categories and themes, we developed testable hypotheses of women’s postpartum recovery trajectories after severe maternal morbidity.Results Grounded in women’s accounts of their lived experience, we identify three phases of recovery following severe maternal morbidity: ‘loss’, ‘transition’ and ‘adaptation to a new normal’. These themes are supported by multiple, overlapping super-categories: loss of understanding of own health, functioning and autonomy; transition in women’s identity and relationships; and adaptation to a new physical, psychosocial and economic state. This recovery process is multidimensional, potentially cyclical and extends far beyond the standard 42-day postpartum period.Conclusion Women’s complex needs following severe maternal morbidity require a reconceptualisation of postpartum recovery as extending far beyond the standard 42-day postpartum period. Women’s accounts expose major deficiencies in the provision of postpartum and mental healthcare. Improved postpartum care provision at the primary healthcare level, with reach extended through community health workers, is essential to identify and treat chronic mental or physical health problems following severe maternal morbidity.

Abstract Background Mass Drug Administration (MDA) has become a mainstay for the control of several diseases over the last two decades. Successful implementation of MDA programmes requires community participation and can be threatened by systematic non-participation. Such concerns are particularly pertinent for MDA programmes against malaria, as they require multi-day treatment over several consecutive months. Factors associated with non-participation to the MDA campaign with ivermectin (IVM) and dihydroartemisinin-piperaquine (DHP) implemented within the MASSIV cluster randomized trial were determined. Methods Coverage data was extracted from the MASSIV trial study database, with every datapoint being a directly observed therapy (DOT). A complete month of MDA was classified as receiving all three daily doses of treatment. For both ivermectin and DHP, ordinal logistic regression was used to identify individual and household level variables associated with non-participation. Results For ivermectin, 51.5% of eligible participants received all 3 months of treatment while 30.7% received either one or two complete months. For DHP, 56.7% of eligible participants received all 3 months of treatment and 30.5% received either one or two complete months. Children aged 5–15 years and adults aged more than 50 years were more likely to receive at least one complete month of MDA than working age adults, both for ivermectin (aOR 4.3, 95% CI 3.51–5.28 and aOR of 2.26, 95% CI 1.75–2.95) and DHP (aOR 2.47, 95%CI 2.02–3.02 and aOR 1.33, 95%CI 1.01–1.35), respectively. Members of households where the head received a complete month of MDA were more likely to themselves have received a complete month of MDA, both for ivermectin (aOR 1.71, 95%CI 1.35–2.14) and for DHP (aOR 1.64, 95%CI 1.33–2.04). Conclusion Personal and household-level variables were associated with participation in the MDA programme for malaria control. Specific strategies to (increase participation amongst some groups may be important to ensure maximum impact of MDA strategies in achieving malaria elimination. Trial registration: The MASSIV trial is registered under NCT03576313.

Abstract Background Chronic carriage of asymptomatic low-density Plasmodium falciparum parasitaemia in the dry season may support maintenance of acquired immunity that protects against clinical malaria. However, the relationship between chronic low-density infections and subsequent risk of clinical malaria episodes remains unclear. Methods In a 2-years study (December 2014 to December 2016) in eastern Gambia, nine cross-sectional surveys using molecular parasite detection were performed in the dry and wet season. During the 2016 malaria transmission season, passive case detection identified episodes of clinical malaria. Results Among the 5256 samples collected, 444 (8.4%) were positive for P. falciparum. A multivariate model identified village of residence, male sex, age ≥ 5 years old, anaemia, and fever as independent factors associated with P. falciparum parasite carriage. Infections did not cluster over time within the same households or recurred among neighbouring households. Asymptomatic parasite carriage at the end of dry season was associated with a higher risk of infection (Hazard Ratio, HR = 3.0, p

The GeneXpert HBV Viral Load test is a simplified tool to scale up screening and HBV monitoring in resource-limited settings, where HBV is endemic and where molecular techniques to quantify HBV DNA are expensive and scarce. However, the accuracy of field diagnostics compared to gold standard assays in HBV-endemic African countries has not been well understood. We aim to validate the diagnostic performance of the GeneXpert HBV Viral Load test in freshly collected and stored plasma and dried blood spot (DBS) samples to assess turn-around-time (TAT) for sample processing and treatment initiation, to map GeneXpert machines and to determine limitations to its use in The Gambia. Freshly collected paired plasma and DBS samples (n = 56) were analyzed by the GeneXpert test. Similarly, stored plasma and DBS samples (n = 306, n = 91) were analyzed using the GeneXpert HBV test, in-house qPCR and COBAS TaqMan Roche. The correlation between freshly collected plasma and DBS is r = 0.88 with a mean bias of −1.4. The GeneXpert HBV test had the highest quantifiable HBV DNA viremia of 81.4% (n = 249/306), and the lowest was detected by in-house qPCR at 37.9% (n = 116/306) for stored plasma samples. Bland–Altman plots show strong correlation between GeneXpert and COBAS TaqMan and between GeneXpert and in-house qPCR with a mean bias of +0.316 and −1.173 log10 IU/mL, respectively. However, paired stored plasma and DBS samples had a lower mean bias of 1.831 log10 IU/mL, which is almost significant (95% limits of agreement: 0.66–3.001). Patients (n = 3) were enrolled in the study within a TAT of 6 days. The GeneXpert HBV test displayed excellent diagnostic accuracy by detecting HBV viremia in less than 10 IU/mL.

Objectives: SARS-CoV-2 transmission in sub-Saharan Africa has probably been underestimated. Population-based seroprevalence studies are needed to determine the extent of transmission in the continent. Methods: Blood samples from a cohort of Gambian pregnant women were tested for SARS-CoV-2 total receptor binding domain (RBD) immunoglobulin (Ig) M/IgG before (Pre-pandemic: October-December 2019) and during the pandemic (Pre-wave 1: February-June 2020; Post-wave 1: October-December 2020, Post-wave 2: May-June 2021; and Post-wave 3: October-December 2021). Samples reactive for SARS-CoV-2 total RBD IgM/IgG were tested in specific S1- and nucleocapsid (NCP) IgG assays. Results: SARS-CoV-2 total RBD IgM/IgG seroprevalence was 0.9% 95% confidence interval (0.2, 4.9) in Pre-pandemic; 4.1% (1.4, 11.4) in Pre-wave 1; 31.1% (25.2, 37.7) in Post-wave 1; 62.5% (55.8, 68.8) in Post-wave 2 and 90.0% (85.1, 93.5) in Post-wave 3. S-protein IgG and NCP-protein IgG seroprevalence also increased at each Post-wave period. Although S-protein IgG and NCP-protein IgG seroprevalence was similar at Post-wave 1, S-protein IgG seroprevalence was higher at Post-wave 2 and Post-wave 3, (prevalence difference 13.5 [0.1, 26.8] and prevalence ratio 1.5 [1.0, 2.3] in Post-wave 2; and 22.9 [9.2, 36.6] and 1.4 [1.1, 1.8] in Post-wave 3 respectively, P

Abstract Background Thanks to the scale up of malaria control interventions, the malaria burden in Senegal has decreased substantially to the point that the National Malaria Control Programme plans to achieve malaria elimination by 2030. To guide such efforts, measuring and monitoring parasite population evolution and anti-malarial drugs resistance is extremely important. Information on the prevalence of parasite mutations related to drug resistance can provide a first signal of emergence, introduction and selection that can help with refining drug interventions. The aim of this study was to analyse the prevalence of anti-malarial drug resistance-associated markers before and after the implementation of artemisinin-based combination therapy (ACT) from 2005 to 2014 in Dielmo, a model site for malaria intervention studies in Senegal. Methods Samples from both malaria patients and Plasmodium falciparum asymptomatic carriers were analysed with high resolution melting (HRM) technique to genotype P. falciparum chloroquine resistance transporter (Pfcrt) gene haplotypes and multidrug-resistant protein 1 (Pfmdr1) gene at codons N86 and Y184. Results Among the 539 samples analysed, 474, 486, and 511 were successfully genotyped for Pfmdr1 N86, Y184, and Pfcrt, respectively. The prevalence of drug resistance markers was high, particularly during the malaria upsurges. Following the scale-up in bed net distribution, only the mutant (86F-like) variant of Pfmdr1 86 was present while during the malaria upsurges the predominance of two types 86Y-86N (43%) and 86F-like (56%) were observed. Most infections (87%) carried the wild type Y-allele at Pfmdr1 184 during the period of nets scale-up while during the malaria upsurges only 16% of infections had wild type and 79% of infections had mixed (mutant/wild) type. The frequency of the mixed genotypes SVMNT-like_CVMNK and SVMNT-like_CVIET within Pfcrt gene was particularly low during bednet scale up. Their frequency increased significantly (P

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83–0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

Further understanding of the molecular mediators of alternative RBC invasion phenotypes in endemic malaria parasites will support malaria blood-stage vaccine or drug development. This study investigated the prevalence of sialic acid (SA)-dependent and SA-independent RBC invasion pathways in endemic Plasmodium falciparum parasites from Cameroon and compared the schizont stage transcriptomes in these two groups to uncover the wider repertoire of transcriptional variation associated with the use of alternative RBC invasion pathway phenotypes. A two-color flow cytometry-based invasion-inhibition assay against RBCs treated with neuraminidase, trypsin, and chymotrypsin and deep RNA sequencing of schizont stages harvested in the first ex vivo replication cycle in culture were employed in this investigation. RBC invasion phenotypes were determined for 63 isolates from asymptomatic children with uncomplicated malaria. Approximately 80% of the isolates invaded neuraminidase-treated but not chymotrypsin-treated RBCs, representing SA-independent pathways of RBC invasion. The schizont transcriptome profiles of 16 isolates with invasion phenotypes revealed a total of 5,136 gene transcripts, with 85% of isolates predicted at schizont stages. Two distinct transcriptome profile clusters belonging to SA-dependent and SA-independent parasites were obtained by data reduction with principal component analysis. Differential analysis of gene expression between the two clusters implicated, in addition to the well-characterized adhesins, the upregulation of genes encoding proteins mediating merozoite organelle discharges as well as several conserved, virulent, merozoite-associated, and exported proteins. The latter majority have been shown to have structural and physiological relevance to RBC surface remodeling and immune evasion in malaria and thus have potential as anti-invasion targets.

Background PRECISE-DYAD is an observational cohort study of mother-child dyads running in urban and rural communities in The Gambia and Kenya. The cohort is being followed for two years and includes uncomplicated pregnancies and those that suffered pregnancy hypertension, fetal growth restriction, preterm birth, and/or stillbirth. Methods The PRECISE-DYAD study will follow up ~4200 women and their children recruited into the original PRECISE study. The study will add to the detailed pregnancy information and samples in PRECISE, collecting additional biological samples and clinical information on both the maternal and child health. Women will be asked about both their and their child’s health, their diets as well as undertaking a basic cardiology assessment. Using a case-control approach, some mothers will be asked about their mental health, their experiences of care during labour in the healthcare facility. In a sub-group, data on financial expenditure during antenatal, intrapartum, and postnatal periods will also be collected. Child development will be assessed using a range of tools, including neurodevelopment assessments, and evaluating their home environment and quality of life. In the event developmental milestones are not met, additional assessments to assess vision and their risk of autism spectrum disorders will be conducted. Finally, a personal environmental exposure model for the full cohort will be created based on air and water quality data, combined with geographical, demographic, and behavioural variables. Conclusions The PRECISE-DYAD study will provide a greater epidemiological and mechanistic understanding of health and disease pathways in two sub-Saharan African countries, following healthy and complicated pregnancies. We are seeking additional funding to maintain this cohort and to gain an understanding of the effects of pregnancies outcome on longer-term health trajectories in mothers and their children.

Development of resistance to deployed antimalarial drugs is inevitable and needs prompt and continuous discovery of novel candidate drugs. Therefore, the antimalarial activity of 125 compounds from the Medicine for Malaria Ventures (MMV) pathogen box was determined. Combining standard IC50 and normalised growth rate inhibition (GR50) analyses, we found 16 and 22 compounds had higher potencies than CQ respectively. Seven compounds with relatively high potencies (low GR50 and IC50) against P. falciparum 3D7 were further analysed. Three of these were tested on 10 natural P. falciparum isolates from The Gambia using our newly developed parasite survival rate assay (PSRA).According to the IC50, GR50 and PSRA analyses, compound MMV667494 was most potent and highly cytotoxic to parasites. MMV010576 was slow acting but more potent than dihydroartemisinin (DHA) 72 h after exposure. MMV634140 was potent against the laboratory-adapted 3D7 isolate, but 4 out of 10 natural Gambian isolates survived and replicated slowly despite 72 h of exposure to the compound, suggesting potential drug tolerance and risk of resistance development.These results emphasise the usefulness of in vitro testing as a starting point for drug discovery. Improved approaches to data analyses and the use of natural isolates will facilitate the prioritisation of compounds for further clinical development.

Abstract Background The malaria parasite Plasmodium falciparum utilizes multiple alternative receptor-ligand interactions for the invasion of human erythrocytes. While some P. falciparum clones make use of sialic acid (SA) residues on the surface of the human glycophorin receptors to invade the erythrocyte, others use alternative receptors independent of sialic acid residues. We hypothesized that over the years, intensified malaria control interventions and declining prevalence in The Gambia have resulted in a selection of parasites with a dominant invasion pathways and ligand expression profiles. Methods Blood samples were collected from 65 malaria-infected participants with uncomplicated malaria across 3 years (2015, 2016, and 2021). Genetic diversity was determined by genotyping the merozoite surface protein 2 (msp2) polymorphic gene of P. falciparum. Erythrocyte invasion phenotypes were determined using neuraminidase, trypsin, and chymotrypsin enzymes, known to cleave different receptors from the surface of the erythrocyte. Schizont-stage transcript levels were obtained for a panel of 6 P. falciparum invasion ligand genes (eba175, eba181, Rh2b, Rh4, Rh5, and clag2) using 48 successfully cultured isolates. Results Though the allelic heterozygosity of msp2 repeat region decreased as expected with reduced transmission, there was an increase in infections with more than a single msp2 allelotype from 2015 to 2021. The invasion phenotypes of these isolates were mostly SA independent with a continuous increase from 2015 to 2021. Isolates from 2021 were highly inhibited by chymotrypsin treatment compared to isolates from 2015 and 2016. Higher invasion inhibition for 2021 isolates was further obtained following erythrocyte treatment with a combination of chymotrypsin and trypsin. The transcript levels of invasion ligand genes varied across years. However, levels of clag2, a rhoptry-associated protein, were higher in 2015 and 2016 isolates than in 2021 isolates, while Rh5 levels were higher in 2021 compared to other years. Conclusions Overall, these findings suggest increasing mixed infections with an increase in the use of sialic-acid independent invasion pathways by P. falciparum clinical isolates in the Western part of Gambia. Graphical Abstract

Abstract In areas of moderate to intense Plasmodium falciparum transmission, malaria in pregnancy remains a significant cause of low birth weight, stillbirth, and severe anaemia. Previously, fetal sex has been identified to modify the risks of maternal asthma, pre-eclampsia, and gestational diabetes. One study demonstrated increased risk of placental malaria in women carrying a female fetus. We investigated the association between fetal sex and malaria in pregnancy in 11 pregnancy studies conducted in sub-Saharan African countries and Papua New Guinea through meta-analysis using log binomial regression fitted to a random-effects model. Malaria infection during pregnancy and delivery was assessed using light microscopy, polymerase chain reaction, and histology. Five studies were observational studies and six were randomised controlled trials. Studies varied in terms of gravidity, gestational age at antenatal enrolment and bed net use. Presence of a female fetus was associated with malaria infection at enrolment by light microscopy (risk ratio 1.14 [95% confidence interval 1.04, 1.24]; P = 0.003; n = 11,729). Fetal sex did not associate with malaria infection when other time points or diagnostic methods were used. There is limited evidence that fetal sex influences the risk of malaria infection in pregnancy.

Summary: Background: Global elimination of hepatitis B virus (HBV) requires expanded uptake of antiviral therapy, potentially by simplifying testing algorithms, especially in resource-limited countries. We evaluated the effectiveness, cost-effectiveness, and budget impact of three strategies that determine eligibility for anti-HBV treatment, as compared with the WHO 2015 treatment eligibility criteria, in The Gambia. Methods: We developed a microsimulation model of natural history using data from the Prevention of Liver Fibrosis and Cancer in Africa programme (known as PROLIFICA) in The Gambia, for an HBV-infected cohort of individuals aged 20 years. The algorithms included in the model were a conventional strategy using the European Association for the Study of the Liver (EASL) 2017 criteria, a simplified algorithm using hepatitis B e antigen and alanine aminotransferase (the Treatment Eligibility in Africa for the Hepatitis B Virus [TREAT-B] score), a Treat All approach for all HBV-infected individuals, and the WHO 2015 criteria. Outcomes to measure effectiveness were disability-adjusted life years (DALYs) and years of life saved (YLS), which were used to calculate incremental cost-effectiveness ratios (ICERs) with the WHO 2015 criteria as the base-case scenario. Costs were assessed from a modified social perspective. A budget impact analysis was also done. We tested the robustness of results with a range of sensitiviy analyses including probabilistic sensitivity analysis. Findings: Compared with the WHO criteria, TREAT-B resulted in 4877 DALYs averted and Treat All resulted in 9352 DALYs averted, whereas the EASL criteria led to an excess of 795 DALYs. TREAT-B was cost-saving, whereas the ICER for Treat All (US$2149 per DALY averted) was higher than the cost-effectiveness threshold for The Gambia (0·5 times the country's gross domestic product per capita: $352). These patterns did not change when YLS was the outcome. In a modelled cohort of 5000 adults (aged 20 years) with chronic HBV infection from The Gambia, the 5-year budget impact was $1·14 million for Treat All, $0·66 million for TREAT-B, $1·03 million for the WHO criteria, and $1·16 million for the EASL criteria. Probabilistic sensitivity analysis indicated that among the Treat All, EASL, and TREAT-B algorithms, Treat All would become the most preferred strategy only with a willingness-to-pay threshold exceeding approximately $72 000 per DALY averted or $110 000 per YLS. Interpretation: Although the Treat All strategy might be the most effective, it is unlikely to be cost-effective in The Gambia. A simplified strategy such as TREAT-B might be a cost-saving alternative. Funding: UK Research and Innovation (Medical Research Council). Translation: For the French translation of the abstract see Supplementary Materials section.

Tuberculosis (TB) and non-communicable diseases (NCD) share predisposing risk factors. TB-associated NCD might cluster within households affected with TB requiring shared prevention and care strategies. We conducted an individual participant data meta-analysis of national TB prevalence surveys to determine whether NCD cluster in members of households with TB. We identified eligible surveys that reported at least one NCD or NCD risk factor through the archive maintained by the World Health Organization and searching in Medline and Embase from 1 January 2000 to 10 August 2021, which was updated on 23 March 2023. We compared the prevalence of NCD and their risk factors between people who do not have TB living in households with at least one person with TB (members of households with TB), and members of households without TB. We included 16 surveys (n = 740,815) from Asia and Africa. In a multivariable model adjusted for age and gender, the odds of smoking was higher among members of households with TB (adjusted odds ratio (aOR) 1.23; 95% CI: 1.11-1.38), compared with members of households without TB. The analysis did not find a significant difference in the prevalence of alcohol drinking, diabetes, hypertension, or BMI between members of households with and without TB. Studies evaluating household-wide interventions for smoking to reduce its dual impact on TB and NCD may be warranted. Systematically screening for NCD using objective diagnostic methods is needed to understand the actual burden of NCD and inform comprehensive interventions.

BackgroundSeroprevalence studies are an alternative approach to estimating the extent of transmission of SARS-CoV-2 and the evolution of the pandemic in different geographical settings. We aimed to determine the SARS-CoV-2 seroprevalence from March 2020 to March 2022 in a rural and urban setting in Kilifi County, Kenya.MethodsWe obtained representative random samples of stored serum from a pregnancy cohort study for the period March 2020 to March 2022 and tested for antibodies against the spike protein using a qualitative SARS-CoV-2 ELISA kit (Wantai, total antibodies). All positive samples were retested for anti-SARS-CoV-2 anti-nucleocapsid antibodies (Euroimmun, ELISA kits, NCP, qualitative, IgG) and anti-spike protein antibodies (Euroimmun, ELISA kits, QuantiVac; quantitative, IgG).ResultsA total of 2,495 (of 4,703 available) samples were tested. There was an overall trend of increasing seropositivity from a low of 0% [95% CI 0–0.06] in March 2020 to a high of 89.4% [95% CI 83.36–93.82] in Feb 2022. Of the Wantai test-positive samples, 59.7% (95% CI 57.06–62.34) tested positive by the Euroimmun anti-SARS-CoV-2 NCP test and 75.9% (95% CI 73.55–78.17) tested positive by the Euroimmun anti-SARS-CoV-2 QuantiVac test. No differences were observed between the urban and rural hospital but villages adjacent to the major highway traversing the study area had a higher seroprevalence.ConclusionAnti-SARS-CoV-2 seroprevalence rose rapidly, with most of the population exposed to SARS-CoV-2 within 23 months of the first cases. The high cumulative seroprevalence suggests greater population exposure to SARS-CoV-2 than that reported from surveillance data.

Abstract Controlled human malaria infection (CHMI) studies, i.e. the deliberate infection of healthy volunteers with malaria parasites to study immune response and/or test drug or vaccine efficacy, are increasingly being conducted in malaria endemic countries, including in sub-Saharan Africa. However, there have been few studies on the perceptions and acceptability of CHMI by the local communities. This qualitative study assessed the perception and acceptability of such studies in The Gambia following the first CHMI study conducted in the country in March–May 2018. Data were collected through non-participant observation, in-depth interviews and focus group discussions and analyzed using NVivo 12 software with an inductive-deductive approach. Sixty-seven participants were involved, including volunteers enrolled in the CHMI, community stakeholders and members of the Gambian Ethics Committee. Respondents expressed a positive view about CHMI. Key motivating factors for participation were the financial compensation, comprehensive health checks, and willingness to support malaria research. Risks associated with participation were considered low. Concerns raised included the frequency of bleeding and the blood volume collected.

Abstract Following integrated malaria control interventions, malaria burden on the Bijagós Archipelago has significantly decreased. Understanding the genomic diversity of circulating Plasmodium falciparum malaria parasites can assist infection control, through identifying drug resistance mutations and characterising the complexity of population structure. This study presents the first whole genome sequence data for P. falciparum isolates from the Bijagós Archipelago. Amplified DNA from P. falciparum isolates sourced from dried blood spot samples of 15 asymptomatic malaria cases were sequenced. Using 1.3 million SNPs characterised across 795 African P. falciparum isolates, population structure analyses revealed that isolates from the archipelago cluster with samples from mainland West Africa and appear closely related to mainland populations; without forming a separate phylogenetic cluster. This study characterises SNPs associated with antimalarial drug resistance on the archipelago. We observed fixation of the PfDHFR mutations N51I and S108N, associated with resistance to sulphadoxine-pyrimethamine, and the continued presence of PfCRT K76T, associated with chloroquine resistance. These data have relevance for infection control and drug resistance surveillance; particularly considering expected increases in antimalarial drug use following updated WHO recommendations, and the recent implementation of seasonal malaria chemoprevention and mass drug administration in the region.

Abstract Background Carriers of persistent asymptomatic Plasmodium falciparum infections constitute an infectious reservoir that maintains malaria transmission. Understanding the extent of carriage and characteristics of carriers specific to endemic areas could guide use of interventions to reduce infectious reservoir. Methods In eastern Gambia, an all-age cohort from four villages was followed up from 2012 to 2016. Each year, cross-sectional surveys were conducted at the end of the malaria transmission season (January) and just before the start of the next one (June) to determine asymptomatic P. falciparum carriage. Passive case detection was conducted during each transmission season (August to January) to determine incidence of clinical malaria. Association between carriage at the end of the season and at start of the next one and the risk factors for this were assessed. Effect of carriage before start of the season on risk of clinical malaria during the season was also examined. Results A total of 1403 individuals—1154 from a semi-urban village and 249 from three rural villages were enrolled; median age was 12 years (interquartile range [IQR] 6, 30) and 12 years (IQR 7, 27) respectively. In adjusted analysis, asymptomatic P. falciparum carriage at the end of a transmission season and carriage just before start of the next one were strongly associated (adjusted odds ratio [aOR] = 19.99; 95% CI 12.57–31.77, p

Objectives: Ivermectin, used to control several neglected tropical diseases, may also reduce malaria transmission. Mass drug administration (MDA) for malaria control therefore might have off-target impacts on neglected tropical diseases. Methods: In The Gambia, nested in a trial of ivermectin MDA, cross-sectional surveys measuring ectoparasites and soil-transmitted helminths in children aged 3 to 14 years took place in June and November 2019 and in November 2021. Results: After MDA, scabies prevalence was 41.2% (237/576) in the control and 38.2% (182/476) in the intervention arm (odds ratio [OR] 0.89 (95% confidence interval [CI] 0 67-1.2), P-value = 0.471) but by 2021, had rebounded to 38.8% (180/464) in the control and 53.2% (245/458) in the intervention arm. After MDA, prevalence of Strongyloides stercoralis was 16.8% (87/518) in the control and 9.1% (40/440) in the intervention arm (OR 0.4 (95% CI 0.16-0.94), P-value = 0.039). In 2021, it was 9.2% (38/413) in the control and 11.3% (45/399) in the intervention arm (OR 1.31 (95% CI 0.74-2.28), P-value = 0.35). Conclusion: Scabies prevalence was similar between the two study arms. S. stercoralis prevalence was reduced. However, this effect did not last long: the prevalence 2 years after MDA was similar between study arms.

Abstract Plasmodium malariae, a neglected human malaria parasite, contributes up to 10% of malaria infections in sub-Saharan Africa (sSA). Though P. malariae infection is considered clinically benign, it presents mostly as coinfections with the dominant P. falciparum. Completion of its reference genome has paved the way to further understand its biology and interactions with the human host, including responses to antimalarial interventions. We characterized 75 P. malariae isolates from seven endemic countries in sSA using highly divergent microsatellites. The P. malariae infections were highly diverse and five subpopulations from three ancestries (independent of origin of isolates) were determined. Sequences of 11 orthologous antimalarial resistance genes, identified low frequency single nucleotide polymorphisms (SNPs), strong linkage disequilibrium between loci that may be due to antimalarial drug selection. At least three sub-populations were detectable from a subset of denoised SNP data from mostly the mitochondrial cytochrome b coding region. This evidence of diversity and selection calls for including P. malariae in malaria genomic surveillance towards improved tools and strategies for malaria elimination.

Introduction Malaria infection during pregnancy increases the risk of low birth weight and infant mortality and should be prevented and treated. Artemisinin-based combination treatments are generally well tolerated, safe and effective; the most used being artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Pyronaridine-artesunate (PA) is a new artemisinin-based combination. The main objective of this study is to determine the efficacy and safety of PA versus AL or DP when administered to pregnant women with confirmed Plasmodium falciparum infection in the second or third trimester. The primary hypothesis is the pairwise non-inferiority of PA as compared with either AL or DP.Methods and analysis A phase 3, non-inferiority, randomised, open-label clinical trial to determine the safety and efficacy of AL, DP and PA in pregnant women with malaria in five sub-Saharan, malaria-endemic countries (Burkina Faso, Democratic Republic of the Congo, Mali, Mozambique and the Gambia). A total of 1875 pregnant women will be randomised to one of the treatment arms. Women will be actively monitored until Day 63 post-treatment, at delivery and 4–6 weeks after delivery, and infants’ health will be checked on their first birthday. The primary endpoint is the PCR-adjusted rate of adequate clinical and parasitological response at Day 42 in the per-protocol population.Ethics and dissemination This protocol has been approved by the Ethics Committee for Health Research in Burkina Faso, the National Health Ethics Committee in the Democratic Republic of Congo, the Ethics Committee of the Faculty of Medicine and Odontostomatology/Faculty of Pharmacy in Mali, the Gambia Government/MRCG Joint Ethics Committee and the National Bioethics Committee for Health in Mozambique. Written informed consent will be obtained from each individual prior to her participation in the study. The results will be published in peer-reviewed open access journals and presented at (inter)national conferences and meetings.Trial registration number PACTR202011812241529.

Summary: Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016–2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92–5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07–7.59), Group A streptococcus (OR 2.73, 95% CI 1.13–6.09) and E. coli (OR 2.7, 95% CI 1.02–6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11–0.46), influenza B (OR 0.12, 95% CI 0.02–0.37) and RSV (OR 0.16, 95% CI: 0.06–0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23–0.72) and EBV (OR 0.71, 95% CI 0.56–0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics. Funding: EU Horizon 2020 grant 668303.

Summary: Background: Non-communicable diseases (NCDs) and NCD risk factors, such as smoking, increase the risk for tuberculosis (TB). Data are scarce on the risk of prevalent TB associated with these factors in the context of population-wide systematic screening and on the association between NCDs and NCD risk factors with different manifestations of TB, where ∼50% being asymptomatic but bacteriologically positive (subclinical). We did an individual participant data (IPD) meta-analysis of national and sub-national TB prevalence surveys to synthesise the evidence on the risk of symptomatic and subclinical TB in people with NCDs or risk factors, which could help countries to plan screening activities. Methods: In this systematic review and IPD meta-analysis, we identified eligible prevalence surveys in low-income and middle-income countries that reported at least one NCD (e.g., diabetes) or NCD risk factor (e.g., smoking, alcohol use) through the archive maintained by the World Health Organization and by searching in Medline and Embase from January 1, 2000 to August 10, 2021. The search was updated on March 23, 2023. We performed a one-stage meta-analysis using multivariable multinomial models. We estimated the proportion of and the odds ratio for subclinical and symptomatic TB compared to people without TB for current smoking, alcohol use, and self-reported diabetes, adjusted for age and gender. Subclinical TB was defined as microbiologically confirmed TB without symptoms of current cough, fever, night sweats, or weight loss and symptomatic TB with at least one of these symptoms. We assessed heterogeneity using forest plots and I2 statistic. Missing variables were imputed through multi-level multiple imputation. This study is registered with PROSPERO (CRD42021272679). Findings: We obtained IPD from 16 national surveys out of 21 national and five sub-national surveys identified (five in Asia and 11 in Africa, N = 740,815). Across surveys, 15.1%–56.7% of TB were subclinical (median: 38.1%). In the multivariable model, current smoking was associated with both subclinical (OR 1.67, 95% CI 1.27–2.40) and symptomatic TB (OR 1.49, 95% CI 1.34–1.66). Self-reported diabetes was associated with symptomatic TB (OR 1.67, 95% CI 1.17–2.40) but not with subclinical TB (OR 0.92, 95% CI 0.55–1.55). For alcohol drinking ≥ twice per week vs no alcohol drinking, the estimates were imprecise (OR 1.59, 95% CI 0.70–3.62) for subclinical TB and OR 1.43, 95% CI 0.59–3.46 for symptomatic TB). For the association between current smoking and symptomatic TB, I2 was high (76.5% (95% CI 62.0–85.4), while the direction of the point estimates was consistent except for three surveys with wide CIs. Interpretation: Our findings suggest that current smokers are more likely to have both symptomatic and subclinical TB. These individuals can, therefore, be prioritised for intensified screening, such as the use of chest X-ray in the context of community-based screening. People with self-reported diabetes are also more likely to have symptomatic TB, but the association is unclear for subclinical TB. Funding: None.

Abstract Background Vector control interventions in sub-Saharan Africa rely on insecticide-treated nets and indoor residual spraying. Insecticide resistance, poor coverage of interventions, poor quality nets and changes in vector behavior threaten the effectiveness of these interventions and, consequently, alternative tools are needed. Mosquitoes die after feeding on humans or animals treated with ivermectin (IVM). Mass drug administration (MDA) with IVM could reduce vector survival and decrease malaria transmission. The entomological impact of MDA of combined IVM and dihydroartemisinin-piperaquine was assessed in a community-based, cluster-randomized trial. Methods A cluster-randomized trial was implemented in 2018 and 2019 in 32 villages in the Upper River Region, The Gambia. The with the inhabitants of 16 intervention villages eligible to receive three monthly rounds of MDA at the beginning of the malaria transmission season. Entomological surveillance with light traps and human landing catches (HLC) was carried out during a 7- to 14-day period after each round of MDA, and then monthly until the end of the year. The mosquitocidal effect of IVM was determined by direct membrane feeding assays. Results Of the 15,017 mosquitoes collected during the study period, 99.65% (n = 14,965) were Anopheles gambiae sensu lato (An. gambiae s.l.), comprising Anopheles arabiensis (56.2%), Anopheles coluzzii (24.5%), Anopheles gambiae sensu stricto (An. gembiae s.s.; 16.0%) and Anopheles funestus sensu lato (An. funestus s.l.; 0.35%). No effect of the intervention on vector parity was observed. Vector density determined on light trap collections was significantly lower in the intervention villages in 2019 (adjusted incidence rate ratio: 0.39; 95% confidence interval [CI]: 0.20, 0.74; P = 0.005) but not in 2018. However, vector density determined in HLC collections was similar in both the intervention and control villages. The entomological inoculation rate was significantly lower in the intervention villages than in the control villages (odds ratio: 0.36, 95% CI: 0.19, 0.70; P = 0·003). Mosquito mortality was significantly higher when blood fed on IVM-treated individuals up to 21 days post-treatment, particularly in adults and individuals with a higher body mass index. Conclusion Mass drug administration with IVM decreased vector density and the entomological inoculation rate while the effect on vector parity was less clear. Survival of mosquitoes fed on blood collected from IVM-treated individuals was significantly lower than that in mosquitoes which fed on controls. The influence of host characteristics on mosquito survivorship indicated that dose optimization could improve IVM efficacy. Future detailed entomological evaluation trials in which IVM is administered as stand-alone intervention may elucidate the contribution of this drug to the observed reduction in transmission. Graphical Abstract

Abstract Malaria remains a major health problem and vector control is an essential approach to decrease its burden, although it is threatened by insecticide resistance. New approaches for vector control are needed. The females of Anopheles gambiae s.l. mate once in their life and in the swarms formed by males. Trapping swarms of Anopheles gambiae s.l. males is a potential new intervention for vector control, alternative to the use of insecticides, as it would disrupt mating . The proof-of-concept pilot study aiming at investigating swarm trapping as a potential vector control intervention, was carried out in 6 villages as in eastern Gambia. Swarms of Anopheles gambiae s.l. were identified and their size, height, and duration determined during the baseline year. Swarm trapping by local volunteers was implemented the following transmission season in 4 villages while the other 2 villages were taken as controls. Entomological outcomes were monitored by Human Landing Catches and Pyrethrum Spray Catches. A cross-sectional survey to determine malaria prevalence was carried out at the peak of the malaria transmission season for two consecutive years. At baseline, 23 swarming sites of Anopheles gambiae s.l. were identified. Before the intervention, mean indoor resting density per house and malaria prevalence were similar between control and intervention villages. Following the intervention, Anopheles gambiae s.l. indoor resting density was 44% lower in intervention than in control villages (adj IRR: 0.0.56; 95% CI 0.47–0.68); the odds of malaria infections were 68% lower in intervention than in control villages (OR: 0.32; 95% CI 0.11–0.97). Swarm trapping seems to be a promising, community-based vector control intervention that could reduce malaria prevalence by reducing vector density. Such results should be further investigated and confirmed by larger cluster-randomized trials.

Abstract Background The housing stock of rural sub-Saharan Africa is changing rapidly. With millions of new homes required over the coming decades, there is an opportunity to protect residents by screening homes from malaria mosquitoes. This study, undertaken in the Upper River Region of The Gambia, explores local perceptions of what a good house should provide for its inhabitants and responses to living in a house that has been modified as part of a randomized control trial designed to assess whether improved housing provided additional protection against clinical malaria in children (the RooPfs trial). Methods This descriptive, exploratory study was undertaken over 22 months using mixed-methods (informal conversations, observations, focus group discussions, photovoice, and a questionnaire survey) in a parallel convergent design. Analysis was conducted across the data sets using a framework approach. Following coding, the textual data were charted by a priori and emerging themes. These themes were compared with the quantitative survey results. The nature and range of views about housing and the RooPfs study modifications and the relationships among them were identified and described. Results The data were derived from a total of 35 sets of observations and informal conversations in 10 villages, 12 discussions with the photovoice photographers, 26 focus group discussions (across 13 villages) and 391 completed questionnaires. The study participants described a ‘good house’ as one with a corrugate-metal roof, cement walls (preferably cement block, but mud block covered with cement plaster was also an acceptable and cheaper substitute) and well-fitting doors. These features align with local perceptions of a modern house that provides social status and protection from physical harms. The RooPfs modifications were largely appreciated, although poor workmanship caused concerns that houses had become insecure. However, the long-term trusting relationship with the implementing institution and the actions taken to rectify problems provided reassurance and enhanced acceptability. Conclusion In developing housing to address population needs in Africa, attention should be paid to local perceptions of what is required to make a house secure for its inhabitants, as well as providing a healthy environment.

Abstract Background In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns. Methods A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models. Results Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17–0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19–0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms. Conclusions Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients. Trial registration PROSPERO, CRD42019128185

Summary: Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection.

Introduction As malaria declines, innovative tools are required to further reduce transmission and achieve elimination. Mass drug administration (MDA) of artemisinin-based combination therapy (ACT) is capable of reducing malaria transmission where coverage of control interventions is already high, though the impact is short-lived. Combining ACT with ivermectin, an oral endectocide shown to reduce vector survival, may increase its impact, while also treating ivermectin-sensitive co-endemic diseases and minimising the potential impact of ACT resistance in this context.Methods and analysis MATAMAL is a cluster-randomised placebo-controlled trial. The trial is being conducted in 24 clusters on the Bijagós Archipelago, Guinea-Bissau, where the peak prevalence of Plasmodium falciparum (Pf) parasitaemia is approximately 15%. Clusters have been randomly allocated to receive MDA with dihydroartemisinin–piperaquine and either ivermectin or placebo. The primary objective is to determine whether the addition of ivermectin MDA is more effective than dihydroartemisinin–piperaquine MDA alone in reducing the prevalence of P. falciparum parasitaemia, measured during peak transmission season after 2 years of seasonal MDA. Secondary objectives include assessing prevalence after 1 year of MDA; malaria incidence monitored through active and passive surveillance; age-adjusted prevalence of serological markers indicating exposure to P. falciparum and anopheline mosquitoes; vector parous rates, species composition, population density and sporozoite rates; prevalence of vector pyrethroid resistance; prevalence of artemisinin resistance in P. falciparum using genomic markers; ivermectin’s impact on co-endemic diseases; coverage estimates; and the safety of combined MDA.Ethics and dissemination The trial has been approved by the London School of Hygiene and Tropical Medicine’s Ethics Committee (UK) (19156) and the Comite Nacional de Eticas de Saude (Guinea-Bissau) (084/CNES/INASA/2020). Results will be disseminated in peer-reviewed publications and in discussion with the Bissau-Guinean Ministry of Public Health and participating communities.Trial registration number NCT04844905.

Abstract Background Subclinical infection with Plasmodium falciparum remains highly prevalent, yet diagnosing these often low-density infections remains a challenge. Infections can be subpatent, falling below the limit of detection for conventional thick-film microscopy and rapid diagnostic testing (RDT). In this study, the prevalence of subclinical P. falciparum infections in school-aged children was characterised at the start of the dry season in the Upper River Region of The Gambia in 2017/2018, with a goal to also compare the utility of different diagnostic tools. Methods In a cross-sectional survey of children living in 29 villages on the south bank of the Gambia river (median age of 10 years), matched microscopy, rapid diagnostic test (RDT, detecting histidine-rich protein 2) and polymerase chain reaction (PCR, targeting either 18S rRNA or var gene acidic terminal sequence) were used to determine the prevalence of patent and subpatent infections and to compare the performance of the different diagnostic methods. Results The prevalence of var gene acidic terminal sequence (varATS) qPCR-detectable infections was 10.2% (141/1381) with a median density of 3.12 parasites/µL. Malaria prevalence was highly heterogeneous across the region, ranging from 98%). Samples that were positive by all three tests (varATS qPCR, RDT and microscopy) had significantly higher parasite densities (median = 1705 parasites/µL) than samples that were positive by varATS qPCR only (median = 2.4 parasites/µL). Conclusions The majority of subclinical malaria infections in school-aged children were of extremely low parasite density and detectable only by ultra-sensitive PCR analysis. Understanding the duration of these low density infections, their physiological impact and their contribution to sustained parasite transmission is necessary to inform malaria elimination strategies.

For the first time in over 20 years, an Enterotoxigenic Escherichia coli (ETEC) vaccine candidate, ETVAX®, has advanced into a phase 2b field efficacy trial for children 6–18 months of age in a low-income country. ETVAX® is an inactivated whole cell vaccine that has gone through a series of clinical trials to provide a rationale for the design elements of the Phase 2b trial. This trial is now underway in The Gambia and will be a precursor to an upcoming pivotal phase 3 trial. To reach this point, numerous findings were brought together to define factors such as safe and immunogenic doses for children, and the possible benefit of a mucosal adjuvant, double mutant labile toxin (dmLT). Considering the promising but still underexplored potential of inactivated whole cells in oral vaccination, we present a perspective compiling key observations from past ETVAX® trials that informed The Gambian trial design. This report will update the trial’s status and explore future directions for ETEC vaccine trials. Our aim is to provide not only an update on the most advanced ETEC vaccine candidate but also to offer insights beneficial for the development of other much-needed oral whole-cell vaccines against enteric and other pathogens.

Abstract Background Some people produce specific body odours that make them more attractive than others to mosquitoes, and consequently are at higher risk of contracting vector-borne diseases. The skin microbiome can break down carbohydrates, fatty acids and peptides on the skin into volatiles that mosquitoes can differentiate. Results Here, we examined how skin microbiome composition of women differs in relation to level of attractiveness to Anopheles coluzzii mosquitoes, to identify volatiles in body odour and metabolic pathways associated with individuals that tend to be poorly-attractive to mosquitoes. We used behavioural assays to measure attractiveness of participants to An. coluzzii mosquitoes, 16S rRNA amplicon sequencing of the bacteria sampled from the skin and gas chromatography of volatiles in body odour. We found differences in skin microbiome composition between the poorly- and highly-attractive groups, particularly eight Amplicon Sequence Variants (ASVs) belonging to the Proteobacteria, Actinobacteria and Firmicutes phyla. Staphylococcus 2 ASVs are four times as abundant in the highly-attractive compared to poorly-attractive group. Associations were found between these ASVs and volatiles known to be attractive to Anopheles mosquitoes. Propanoic pathways are enriched in the poorly-attractive participants compared to those found to be highly-attractive. Conclusions Our findings suggest that variation in attractiveness of people to mosquitoes is related to the composition of the skin microbiota, knowledge that could improve odour-baited traps or other next generation vector control tools.

Abstract Background Malaria in pregnancy can result in placental infection with fetal implications. This study aimed at assessing placental malaria (PM) prevalence and its associated factors in a cohort of pregnant women with peripheral malaria and their offspring. Method The data were collected in the framework of a clinical trial on treatments for malaria in pregnant women . Placental malaria (PM) was diagnosed by histopathological detection of parasites and/or malaria pigment on placenta biopsies taken at delivery. Factors associated with PM were assessed using logistic regression. Results Out of 745 biopsies examined, PM was diagnosed in 86.8 % of women. Acute, chronic and past PM were retrieved in 11 (1.5 %), 170 (22.8 %), and 466 (62.6 %) women, respectively. A modifying effect was observed in the association of gravidity or anemia at the study start with pooled PM (presence of parasites and/or malaria pigment). In women under 30, gravidity ≤ 2 was associated with an increased prevalence of pooled PM but in women aged 30 years or more, gravidity was no more associated with pooled PM (OR 6.81, 95 % CI 3.18 – 14.60; and OR 0.52, 95 % CI 0.10 – 2.76, respectively). Anemia was associated with pooled PM in women under 30 (OR 1.96, 95 % CI 1.03 – 3.72) but not in women aged 30 years or more (OR 0.68, 95 % CI 0.31 – 1.49). Similarly, the association of gravidity with past-chronic PM depended also on age. A higher prevalence of active PM was observed in women under 30 presenting with symptomatic malaria (OR 3.79, 95 % CI 1.55 – 9.27), while there was no significant increase in the prevalence of active PM (presence of parasites only) in women with symptomatic malaria when aged 30 years or more (OR 0.42, 95 % CI 0.10 – 1.75). In women with chronic PM, the prevalence of low birth weight or prematurity was the highest (31.2 %) as compared with past PM or no PM. Conclusion Despite the rapid diagnosis and efficacious treatment of peripheral infection, the prevalence of placental malaria remained high in women with P. falciparum peripheral infection in Nanoro, especially in younger women This underlines the importance of preventive measures in this specific group.

Abstract Background Despite freely distributed insecticide-treated nets (ITNs) and health information campaigns to increase their use among populations at risk, malaria transmission persists in forested areas in Vietnam, especially among ethnic minority communities. A mixed-methods study was conducted in four villages of Ca Dong and M’nong ethnicity in Central Vietnam between 2009 and 2011 to assess factors limiting the uptake of ITNs. Methods The mixed-methods research design consisted of a qualitative study to explore the context and barriers to ITN use, and a cross-sectional household survey (n = 141) to quantify factors for limited and appropriate net use. Results The Ca Dong and M’nong’s livelihood was dependent on swidden farming in the forest. Poverty-related factors, including the lack of beds, blankets, the practice of sleeping around the kitchen fire and deteriorated ITNs due to open housing structures, were reasons for alternative and non-use of ITNs. When household members stayed overnight in plot huts at fields, ITNs were even more unavailable and easily deteriorated. 72.5% of households reported having received one net for every two persons, and 82.2% of participants reported to have used ITNs the night before the survey. However, only 18.4% of participants were estimated to be effectively protected by ITNs after accounting for the availability of torn ITNs and the way ITNs were used, for example as blankets, at both village and fields. Multi-variable logistic regression showed the effect of four significant factors for appropriate ITN use: i) being female (AOR = 8.08; p = 0.009); ii) aware of mosquito bites as the sole cause of malaria (AOR = 7.43; p = 0.008); iii) not sleeping around the kitchen fire (AOR = 24.57; p = 0.001); and iv) having sufficient number of ITNs in the household (AOR = 21.69; p = 0.001). Conclusion This study showed how social factors rooted in poverty and swidden agriculture limited the effective use of ITNs, despite high coverage, among ethnic minority populations in Central Vietnam. An in-depth understanding of the local context is essential to develop specific indicators for measuring ITN use.

Summary: Background: COVID-19, caused by SARS-CoV-2, is one of the deadliest pandemics of the past 100 years. Genomic sequencing has an important role in monitoring of the evolution of the virus, including the detection of new viral variants. We aimed to describe the genomic epidemiology of SARS-CoV-2 infections in The Gambia. Methods: Nasopharyngeal or oropharyngeal swabs collected from people with suspected cases of COVID-19 and international travellers were tested for SARS-CoV-2 with standard RT-PCR methods. SARS-CoV-2-positive samples were sequenced according to standard library preparation and sequencing protocols. Bioinformatic analysis was done using ARTIC pipelines and Pangolin was used to assign lineages. To construct phylogenetic trees, sequences were first stratified into different COVID-19 waves (waves 1–4) and aligned. Clustering analysis was done and phylogenetic trees constructed. Findings: Between March, 2020, and January, 2022, 11 911 confirmed cases of COVID-19 were recorded in The Gambia, and 1638 SARS-CoV-2 genomes were sequenced. Cases were broadly distributed into four waves, with more cases during the waves that coincided with the rainy season (July–October). Each wave occurred after the introduction of new viral variants or lineages, or both, generally those already established in Europe or in other African countries. Local transmission was higher during the first and third waves (ie, those that corresponded with the rainy season), in which the B.1.416 lineage and delta (AY.34.1) were dominant, respectively. The second wave was driven by the alpha and eta variants and the B.1.1.420 lineage. The fourth wave was driven by the omicron variant and was predominantly associated with the BA.1.1 lineage. Interpretation: More cases of SARS-CoV-2 infection were recorded in The Gambia during peaks of the pandemic that coincided with the rainy season, in line with transmission patterns for other respiratory viruses. The introduction of new lineages or variants preceded epidemic waves, highlighting the importance of implementing well structured genomic surveillance at a national level to detect and monitor emerging and circulating variants. Funding: Medical Research Unit The Gambia at London School of Hygiene & Tropical Medicine, UK Research and Innovation, WHO.

Abstract Background The World Health Organization recommends house screening as a tool for malaria control, yet evidence of the long-term durability, functionality and acceptability of this intervention is lacking. In this study, the sustainability and use of novel types of screened doors and windows was examined 4 years after installation in a Gambian village. Methods A survey of 31 houses, each with two screened doors and two screened windows, was conducted in the rainy season. There were four types of screened door and two types of screened window. Trained staff carried out the survey and interviews of room owners were conducted in the local language before translation into English. Results Structurally, the manufactured doors and windows were highly durable and in excellent condition. Most doors shut smoothly 50/61 (82%), although only 25/61 (41%) shut fully automatically with the latch slotting into the hole on the frame and holding fast. Door locks were less robust, with only (24/61) 39% present and working. Blinds proved especially flimsy, with only 4/109 (4%) of door blinds and 10/56 (18%) of window blinds present and in working order. Householders hung curtains inside most doors 50/61 (82%) and in 26/61 (43%) of the windows. Front doors were commonly found propped open 21/31 (68%) and 23/27 (85%) of those with a front door curtain, put their curtains down at night. Doors and windows were well liked, 19/31 (61%) of respondents were happy with them because they kept mosquitoes out 14/31 (45%) and provided security 12/31 (39%). The main reason given for the use of curtains was to provide privacy 26/28 (93% of those with curtains), especially while the door was open or had ‘see-through’ panels. Conclusions Overall, the screened doors and windows were in full-working order and undamaged after 4 years of use. The doors and windows were well liked, especially for their ability to reduce the entry of mosquitoes and for the security they afforded. Improvements to the lock design are needed before scale-up. Most householders hung curtains behind their doors for privacy. Installation of screening in buildings should be accompanied with recommendations that at night, when doors and windows are closed, curtains be lifted or drawn to one side—to improve ventilation and keep the house cool.

Abstract Background Pneumococcal conjugate vaccines (PCV) effectively prevent pneumococcal disease but the global impact of pneumococcal vaccination is hampered by the cost of PCV. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where PCV has been introduced with good disease control but where transmission of vaccine-type pneumococci persists. We are conducting a large cluster-randomised, non-inferiority, field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. Methods PVS is a prospective, cluster-randomised, non-inferiority, real-world field trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. the alternative ‘1 + 1’ schedule) compared to the standard schedule of three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. the standard ‘3 + 0’ schedule). The intervention will be delivered for 4 years. The primary endpoint is the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in children aged 2 weeks to 59 months with clinical pneumonia in year 4 of the trial. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoint will be masked. Sixty-eight geographic population clusters have been randomly allocated, in a 1:1 ratio, to each schedule and all resident infants are eligible for enrolment. All resident children less than 5 years of age are under continuous surveillance for clinical safety endpoints measured at 11 health facilities; invasive pneumococcal disease, radiological pneumonia, clinical pneumonia, and hospitalisations. Secondary endpoints include the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in years 2 and 4 and vaccine-type carriage prevalence in unimmunised infants aged 6–12 weeks in year 4. The trial includes components of mathematical modelling, health economics, and health systems research. Discussion Analysis will account for potential non-independence of measurements by cluster, comparing the population-level impact of the two schedules with interpretation at the individual level. The non-inferiority margin is informed by the ‘acceptable loss of effect’ of the alternative compared to the standard schedule. The secondary endpoints will provide substantial evidence to support the interpretation of the primary endpoint. PVS will evaluate the effect of transition from a standard 3+ 0 schedule to an alternative 1 + 1 schedule in a setting of high pneumococcal transmission. The results of PVS will inform global decision-making concerning the use of reduced-dose PCV schedules. Trial registration International Standard Randomised Controlled Trial Number 15056916 . Registered on 15 November 2018.

Abstract Background Group A Streptococcus (GAS) is a major human pathogen and an important cause of maternal and neonatal sepsis. Asymptomatic bacterial colonization is considered a necessary step towards sepsis. Intra-partum azithromycin may reduce GAS carriage. Methods A posthoc analysis of a double-blind, placebo-controlled randomized-trial was performed to determine the impact of 2 g oral dose of intra-partum azithromycin on maternal and neonatal GAS carriage and antibiotic resistance. Following screening, 829 mothers were randomized who delivered 843 babies. GAS was determined by obtaining samples from the maternal and newborn nasopharynx, maternal vaginal tract and breastmilk. Whole Genome Sequencing (WGS) of GAS isolates was performed using the Illumina Miseq platform. Results GAS carriage was lower in the nasopharynx of both mothers and babies and breast milk among participants in the azithromycin arm. No differences in GAS carriage were found between groups in the vaginal tract. The occurrence of azithromycin-resistant GAS was similar in both arms, except for a higher prevalence in the vaginal tract among women in the azithromycin arm. WGS revealed all macrolide-resistant vaginal tract isolates from the azithromycin arm were Streptococcus dysgalactiae subspecies equisimilis expressing Lancefield group A carbohydrate (SDSE(A)) harbouring macrolide resistant genes msr(D) and mef(A). Ten of the 45 GAS isolates (22.2%) were SDSE(A). Conclusions Oral intra-partum azithromycin reduced GAS carriage among Gambian mothers and neonates however carriage in the maternal vaginal tract was not affected by the intervention due to azithromycin resistant SDSE(A). SDSE(A) resistance must be closely monitored to fully assess the public health impact of intrapartum azithromycin on GAS. Trial registration ClinicalTrials.gov Identifier NCT01800942

Abstract Background Pneumococcal conjugate vaccines (PCVs) effectively prevent pneumococcal disease, but the global impact of pneumococcal vaccination is hampered by its cost. The evaluation of reduced dose schedules of PCV includes measurement of effects on immunogenicity and carriage acquisition compared to standard schedules. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where the introduction of PCV resulted in good disease control but where transmission of vaccine-type pneumococci persists. We designed a large cluster-randomised field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. We will also conduct a sub-study to evaluate the individual-level effect of the two schedules on carriage acquisition, immunogenicity, and co-administration of PCV with yellow fever vaccine, the PVS-AcqImm trial. Methods PVS-AcqImm is a prospective, cluster-randomised trial of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. alternative ‘1+1’ schedule) compared to three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. standard ‘3+0’ schedule). Sub-groups within the alternative schedule group will receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 9 to 14 months of age, (b) geometric mean concentration of vaccine-type pneumococcal IgG at 18 months of age, and (c) proportions with yellow fever neutralising antibody titre ≥8 four weeks after administration of yellow fever vaccine. Participants and field staff will not be masked to group allocation while the measurement of laboratory endpoints will be masked. Approximately equal numbers of participants will be resident in each of 28 geographic clusters (14 clusters in alternative and standard schedule groups); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. Discussion Analysis will account for potential non-independence of measurements by cluster and so interpretation of effects will be at the individual level (i.e. a population of individuals). PVS-AcqImm will evaluate whether acquisition of vaccine-type pneumococci is reduced by the alternative compared to the standard schedule, which is required if the alternative schedule is to be effective. Likewise, evidence of superior immune response at 18 months of age and safety of PCV co-administration with yellow fever vaccine will support decision-making regarding the use of the alternative 1+1 schedule. Acquisition and immunogenicity outcomes will be essential for the interpretation of the results of the large field trial comparing the two schedules. Trial registration International Standard Randomised Controlled Trial Number 72821613 .

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network. It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented. For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations. We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent. We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines. Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website.

Abstract Background In rural sub-Saharan Africa, thatch roofs are being replaced by metal roofs. Metal roofing, however, increases indoor temperatures above human comfort levels, and thus makes it more likely that residents will not use an insecticide-treated bed net (ITN) at night. Whether the colour of a metal roof affects indoor temperature and human comfort was assessed. Methods Two identical, experimental houses were constructed with metal roofs in rural Gambia. Roof types were: (1) original bare-metal, (2) painted with red oxide primer or (3) white gloss, to reflect solar radiation. Pairwise comparisons were run in six, five-night blocks during the malaria season 2018. Indoor climate was measured in each house and multivariate analysis used to compare indoor temperatures during the day and night. Results From 21.00 to 23.59 h, when most residents decide whether to use an ITN or not, the indoor temperature of a house with a bare metal roof was 31.5 °C (95% CI 31.2–31.8 °C), a red roof, 30.3 °C (95% CI 30.0–30.6) and a white roof, 29.8 °C (95% CI 29.4–30.1). During the same period, red-roofed houses were 1.23 °C cooler (95% CI 1.22–1.23) and white roofs 1.74 °C cooler (95% CI 1.70–1.79) than bare-metal roofed houses (p

Abstract Background Single low-dose primaquine (SLD-PQ) is recommended in combination with artemisinin-based combination therapy to reduce Plasmodium falciparum transmission in areas threatened by artemisinin resistance or aiming for malaria elimination. SLD-PQ may be beneficial in mass drug administration (MDA) campaigns to prevent malaria transmission but uptake is limited by concerns of hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The aim of this study was to improve the evidence on the safety of MDA with SLD-PQ in a sub-Saharan African setting. Methods A nonlinear mixed-effects model describing the pharmacokinetics and treatment-induced hemolysis of primaquine was developed using data from an adult (n = 16, G6PD deficient) and pediatric study (n = 38, G6PD normal). The relationship between primaquine pharmacokinetics and hemolysis was modeled using an established erythrocyte lifespan model. The safety of MDA with SLD-PQ was explored through Monte Carlo simulations for SLD-PQ at 0.25 or 0.4 mg/kg using baseline data from a Tanzanian setting with detailed information on hemoglobin concentrations and G6PD status. Results The predicted reduction in hemoglobin levels following SLD-PQ was small and returned to pre-treatment levels after 25 days. G6PD deficiency (African A- variant) was associated with a 2.5-fold (95% CI 1.2–8.2) larger reduction in hemoglobin levels. In the Tanzanian setting where 43% of the population had at least mild anemia (hemoglobin

Abstract Background Rheumatic heart disease (RHD) remains the leading cause of cardiac-related deaths and disability in children and young adults worldwide. In The Gambia, the RHD burden is thought to be high although no data are available and no control programme is yet implemented. We conducted a pilot study to generate baseline data on the clinical and valvular characteristics of RHD patients at first presentation, adherence to penicillin prophylaxis and the evolution of lesions over time. Methods All patients registered with acute rheumatic fever (ARF) or RHD at two Gambian referral hospitals were invited for a clinical review that included echocardiography. In addition, patients were interviewed about potential risk factors, disease history, and treatment adherence. All clinical and echocardiography information at first presentation and during follow-up was retrieved from medical records. Results Among 255 registered RHD patients, 35 had died, 127 were examined, and 111 confirmed RHD patients were enrolled, 64% of them females. The case fatality rate in 2017 was estimated at 19.6%. At first presentation, median age was 13 years (IQR [9; 18]), 57% patients had late stage heart failure, and 84.1% a pathological heart murmur. Although 53.2% of them reported history of recurrent sore throat, only 32.2% of them had sought medical treatment. A history suggestive of ARF was reported by 48.7% patients out of whom only 15.8% were adequately treated. Two third of the patients (65.5%) to whom it was prescribed were fully adherent to penicillin prophylaxis. Progressive worsening and repeated hospitalisation was experienced by 46.8% of the patients. 17 patients had cardiac surgery, but they represented only 18.1% of the 94 patients estimated eligible for cardiac surgery. Conclusion This study highlights for the first time in The Gambia the devastating consequences of RHD on the health of adolescents and young adults. Our findings suggest a high burden of disease that remains largely undetected and without appropriate secondary prophylaxis. There is a need for the urgent implementation of an effective national RHD control programto decrease the unacceptably high mortality rate, improve case detection and management, and increase community awareness of this disease.