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Albuminuria Among Virally Suppressed HIV-infected Patients in Botswana: Longitudinal Changes, and Association with Inflammation and ACEI/ARB Use in a Clinical Setting
No full textPregnancy Risk, Infant Surveillance, and Measurement Alliance (PRISMA) Maternal and Newborn Health Study:Protocol for a multisite, prospective, open cohort study of pregnancy and postpartum health outcomes in South Asia and sub-Saharan Africa
Full text linkIntroduction Maternal and child mortality has markedly decreased worldwide over the past few decades. Despite this success, the decline remains unequal across countries and is overall insufficient to meet the Sustainable Development Goals. South Asia and sub-Saharan Africa bear most of the burden of maternal and child morbidity and mortality. Major gaps persist in our understanding of the causes, timing, diagnostic thresholds and risk factors for adverse outcomes in these regions. Addressing these gaps requires new ways to prevent and treat disease, from novel diagnostics to precision public health strategies, all of which rely on high-quality clinical data from diverse populations. The Pregnancy Risk, Infant Surveillance, and Measurement Alliance (PRISMA) Maternal and Newborn Health Study aims to estimate population-level prevalence of morbidities and mortality and to assess biological, clinical and sociodemographic risk among mother-infant pairs in India, Pakistan, Kenya, Ghana and Zambia. Methods and analysis This study is a prospective, open cohort study with a planned recruitment of about 6000 women annually across six research sites in five countries. Participants are pregnant women enrolled less than 20 weeks gestation, as determined by ultrasound, identified through active house-to-house and facility-based surveillance. Robust clinical data will be collected at 12 scheduled study visits during antenatal care, labour and delivery, and through 1 year postpartum. A total of 34 outcomes will be captured. The primary analysis will estimate the burden of adverse outcomes and examine associated risk factors to inform future intervention strategies. Data will also be used to develop normative values for pregnant and postpartum women, as well as predictive models to assess pregnancy risk. Ethics and dissemination PRISMA received institutional and national ethical approvals. Findings will be published in peer-reviewed open-access journals and disseminated at national and international forums to inform clinical guidelines and public health practice.</p
Harnessing real-world evidence in paediatric randomised controlled trials
No full textRandomised controlled trials (RCTs) provide the highest level of evidence by rigorously evaluating treatments to ensure clinical decisions are grounded in robust data that improve patient outcomes. However, in paediatrics, certain factors can make their conduct more difficult, including recruitment challenges and ethical complexities. There is growing interest in using real-world evidence through routinely collected data (RCD) to improve the design, delivery and applicability of paediatric RCTs across diverse healthcare settings worldwide.This editorial is part of a series on RCD-enabled studies and their analysis. Other articles will explore the use of real-world evidence in observational research and examine specific analytical methods, including interrupted time series and difference in differences
Cluster minimal sufficient balance (CMSB) an efficient covariate balancing randomization method for cluster randomized trials
Full text linkBACKGROUND: Cluster randomized trials (CRTs) require balanced baseline covariates to yield unbiased estimates of treatment effects. Existing approaches such as constrained randomization can improve balance but may compromise allocation randomness. We introduce Cluster Minimal Sufficient Balance (CMSB), a cluster randomization method designed to enhance covariate balance while preserving allocation randomness and computational efficiency. METHODS: CMSB integrates dynamic imbalance monitoring with conditional biased randomization into a single procedure. The method accommodates both continuous and categorical covariates and was evaluated through simulation studies comparing its performance with constrained randomization, simple randomization, block randomization, stratified randomization, and minimization across varying numbers of clusters and covariate dimensions. An empirical application further assessed its practical utility. RESULTS: In high-dimensional settings with 10 covariates, CMSB achieved a 45% greater improvement in covariate balance compared to constrained randomization, while maintaining near-optimal allocation randomness (correct guess probability: 49.79% versus 61.03% for minimization). CMSB reduced mean allocation time from over 100 s under constrained randomization to 0.116 s per allocation, even when simulating up to 2,000 randomization schemes. In the empirical application, CMSB demonstrated a 76% improvement in covariate balance relative to simple randomization. CONCLUSIONS: CMSB effectively balances the competing demands of covariate balance, allocation randomness, and computational efficiency in cluster randomized trials. Its ability to handle high-dimensional covariates makes it particularly suitable for large-scale trials.</p
Safety and efficacy of the monoclonal antibody L9LS for malaria prevention in children exposed to perennial malaria transmission: a randomised, double-blind, placebo-controlled phase 2 trial
No full textBackground: Malaria remains a major cause of mortality globally, especially among young children in sub-Saharan Africa. The long-acting monoclonal antibody L9LS has shown high efficacy in preventing malaria in school-age children exposed to seasonal transmission but remains untested in perennial transmission settings and younger children. Methods: We conducted a double-blind, placebo-controlled randomised phase 2 trial assessing safety, tolerability, and efficacy of L9LS in healthy infants and children in a high perennial malaria transmission setting in western Kenya. In parts 1a/1b, we tested safety and tolerability, using an age de-escalation and dose escalation approach and randomising 96 children (5–10 years and 5–59 months) 3:1 to L9LS at 5, 10, 20, 30, or 40 mg/kg subcutaneously or to placebo (normal saline). In part 2, 324 children aged 5–59 months were randomised 1:1:1 using centralised computer-generated lists to receive two doses of L9LS at 10–20 mg/kg at baseline and month 6, one dose of L9LS at baseline and placebo at month 6, or placebo at both timepoints. Children were followed for 12 months with monthly clinic visits and blood smear collections. The primary endpoint was Plasmodium falciparum infection detected by blood smear over 12 months. This completed trial was registered at clinicaltrials.gov (NCT05400655).Findings: Across all study parts, grade 3 or worse treatment-related adverse events (AEs) occurred after 4/384 (1·0%) L9LS injections and 1/235 (0·4%) placebo injections; these events all resolved by study end. The proportion of solicited and unsolicited AEs was similar across all L9LS dose groups. There were no serious adverse events (SAEs) related to the trial. In part 2, 70 of 106 (66%) children who received two doses of L9LS were infected over 12 months versus 91 of 110 (83%) who received placebo at both timepoints (protective efficacy [PE] = 42·7% [95% CI: 22·5–57·7], p=0·0003). At 6 months, after a single dose of L9LS or placebo, infections occurred in 103/214 (48%) after L9LS and 69/110 (63%) after placebo (PE = 45·9% (95% CI: 26·5–60·1). Interpretation: L9LS was protective against malaria in young children in western Kenya without evident safety concerns over 6–12 months. A higher dose of L9LS may be needed to achieve high-level efficacy against malaria in young children exposed to intense perennial P. falciparum transmission.Funding: Bill and Melinda Gates Foundation<br/
Editorial: Tips for early career researchers (ECRs) in searching the literature and in academic publishing
Full text linkGenomic population structure and insecticide resistance mechanisms in the malaria vector An. coluzzii across contrasting bioclimatic zones in West Africa
Full text linkBackground: Environmental barriers influencing the movement of insect vectors can govern adaptive gene flow, including the dispersal of insecticide resistance mechanisms that compromise population control. We sought to understand population connectivity of the major malaria vector, An. coluzzii, across the different bioclimatic zones of West Africa including Ghana, Mali and Côte d’Ivoire using SNPs from whole genomes and inversion karyotypes previously associated with environmental adaptation. Methods: We used Ghana as a case study to investigate how adaptive alleles are shared across geographical space. Paired-end 100–150 bp sequencing reads were aligned to the AgamP4 reference genome using BWA version 0.7.15 and single nucleotide polymorphisms (SNP) called using GATK version 3.7.0. We characterised known target site and metabolic insecticide resistance markers, including amino acid substitutions and copy number variants. We also performed genome-wide scans for novel signals of selection with a potential link to insecticide resistance using the H12 homozygosity statistic across defined windows of the genome. Results: Based on analysis of population connectivity, we identified restricted gene flow between An. coluzzii from the northern savannah and southern forested regions of West Africa. We further found marked differences in insecticide resistance profiles across the different bioclimatic zones in Ghana, suggesting that population connectivity impacts on adaptive allele sharing. Greater evidence for target site pyrethroid resistance substitutions at the Vgsc gene and metabolic resistance markers at carboxylesterases and Gste2 in the North reflected differences in insecticide use across the country. Based on insecticide resistance marker profiles and selection scans, we also observed distinct resistance mechanisms in the coastal region of Greater Accra which may result from intense urban agricultural activity. These included a unique selection signal on the 3R chromosome at a cytochrome P450 gene, Cyp12f and a UDP glucuronosyltransferase. Conclusion: Overall, findings suggest that environmental conditions restrict An. coluzzii gene flow to impact the geographical distribution of molecular insecticide resistance.</p
Artemether-lumefantrine versus pyronaridine-artesunate for the treatment of malaria in patients with mild to moderate COVID-19 in Kenya and Burkina Faso: a randomised open-label trial (MALCOV)
Full text linkBackground: It is unknown whether the choice of malaria treatment for uncomplicated malaria affects coronavirus disease 2019 (COVID-19) severity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load, or duration of viral shedding. Several antimalarials exhibit antiviral activity against SARS-CoV-2 in-vitro and have been suggested as potential therapeutic candidates for COVID-19, particularly pyronaridine-artesunate (PA), despite disappointing clinical results with chloroquine and hydroxychloroquine.Methods: We conducted an open-label randomised trial comparing standard 3-day treatment with PA and artemether-lumefantrine (AL) in newly diagnosed SARS-CoV-2 infected patients aged >=6 months with rapid diagnostic test or microscopy-confirmed non-severe malaria in Kenya and Burkina Faso. SARS-CoV-2 was assessed by RT-PCR on days 3, 7, 14, and 28, and symptom resolution was assessed daily for 14 days using FLU-PRO-Plus. The primary endpoint was the proportion of participants with SARS-CoV-2 clearance by day 7. Secondary endpoints included SARS-CoV-2 clearance by days 14, 21, and 28, time to SARS-CoV-2 clearance over 28 days, median viral load on day 7, and time to symptom resolution. Complete case analysis was conducted using log-binomial regression for binary outcomes, Cox-regression for time-to-event outcomes, and negative binomial regression for count outcomes, all adjusted for disease severity and viral load at enrolment. The trial is registered with ClinicalTrials.gov NCT04695197.Findings: From January 2021 to January 2022, 143 participants were randomised (PA=69, AL=74, intention-to-treat [ITT] population), including 117 with reverse transcription polymerase chain reaction (RT-PCR) confirmed (PA=58, AL=59, modified intention-to-treat [mITT] population) and 26 with rapid-antigen test confirmed SARS-CoV-2 infection. The median age was 19 years (interquartile range [IQR] 13-38), 66% were aged >=15 years. Baseline characteristics were comparable. SARS-CoV-2 clearance by day-7 (primary endpoint) was 41% (22/54) with PA versus 58% (33/57) with AL (adjusted risk ratio [aRR]=0.78, 95% confidence interval [CI] 0.45-1.35, p=0.37); by day-14: PA=80% (44/55) versus AL=96% (55/57) AL (aRR=0.86, 0.58-1.29, p=0.47). Median (IQR) viral load on day-7 was higher with PA (855 [30-2883] versus AL:81 [12-209] copies/mL, p=0.023). Time to SARS-CoV-2 clearance over 28 days was slower with PA (adjusted hazard ratio [aHR]: 0.55, 0.37-0.83, p=0.004). Time to symptom clearance between treatments was similar (aHR=1.01, 0.91-1.13, p=0.79). Parasitological cure rates by day 42 were PA=100% and AL=99%. Five serious adverse events occurred (PA=2, AL=3) in three participants (PA=1, AL=2), including three hospitalisations (PA=1, AL=2), resulting in two deaths, both from respiratory failure (PA=1, AL=1). No serious adverse events (SAEs) were considered treatment-related. Interpretation: Pyronaridine-artesunate in COVID-19 patients co-infected with malaria was associated with slower viral clearance than standard treatment with artemether-lumefantrine but similar symptom resolution. Both treatments were highly effective as antimalarials and should continue to be considered first- or second-line treatments options for uncomplicated malaria in patients with mild to moderate COVID-19.<br/
Sub-optimal menstrual materials and vaginal microbiome disruption in women relying on sex for livelihood
No full textBackground: Sub-optimal menstrual materials (MM), such as using cloths, cotton balls, or tissues, can adversely affect the vaginal microbiome (VMB). Women who rely on sex for economic livelihood often use sub-optimal materials to conceal menstruation and avoid loss of income. We hypothesized that among women who rely on sex for economic livelihood, those using sub-optimal MM would be more likely to have non-optimal VMB than those with adequate MM.Methods: This cross-sectional analysis used baseline data from women participating in a trial assessing the impact of reusable menstrual discs on the VMB, Bacterial vaginosis (BV), and sexually transmitted infections (STIs). Data on sociodemographics, menstrual materials, and sexual practices were collected via interviewer-administered survey. Clinician-collected vaginal samples were tested for BV, STI, and VMB. VMB was assessed via 16S rRNA gene amplicon sequencing. A suite of statistical approaches identified factors associated with sub-optimal MM (use of cotton balls, tissue, or cloth) and VMB composition. Results: 407 women were enrolled February through October 2023, with median age 27 years, 24.7% were HIV-positive, 42.2% had BV, and 21.9% had STI (composite of chlamydia, gonorrhea, trichomoniasis). Vaginal community state type (CST) was primarily diverse (CST-IV; 63.5%), or Lactobacillus iners dominated (CST-III; 28.1%), while CST-I (L. crispatus dominated) was uncommon (7.9%). Sub-optimal MM was reported by 42.0% of participants and in multivariable modeling, was more common among women with indicators of economic strain. In multivariable analyses, alpha diversity was higher with sub-optimal MM and indicators of economic strain. Sub-optimal MM was associated with CST-IV in crude analyses but was attenuated and non-significant when adjusted for age, educational attainment, amount paid at last sexual encounter, number of sex partners, and HSV-2. Non-targeted machine learning algorithms identified non-optimal VMB taxa with greater relative abundance among women with sub-optimal MM.Discussion: Sub-optimal menstrual materials were used commonly and associated with non-optimal VMB composition. Reusable menstrual discs that may be worn during sex may address the economic factors driving sub-optimal MM that are associated with non-optimal VMB.<br/
Attenuated viral strains of priority pathogens for potential use in controlled human infection model studies: A scoping review
No full textBackgroundThere are several known pathogens and families identified as high risk for pandemic potential. It is essential to study these pathogens and develop medical countermeasures to mitigate disease prior to potential pandemics. Controlled human infection models (CHIMs) using attenuated viral strains may offer an efficient and safe way to do this.ObjectiveOur aim was to systematically examine the literature for attenuated, but replication competent, strains of Coalition for Epidemic Preparedness Innovations (CEPI) identified priority pathogens (Ebola, Lassa virus, Nipah virus, Rift Valley fever virus, chikungunya virus and Middle East respiratory syndrome-related coronavirus) that have been administered to humans.DesignA comprehensive literature search of multiple databases was performed by an information specialist. All search results were screened by two authors against inclusion/exclusion criteria from a pre-specified protocol. The primary outcome was confirmation that the administered viral strain could subsequently be recovered from participants. The secondary outcome was attenuated virus safety.ResultsOur searches yielded 13078 results and 5998 articles remained for screening after removing duplicates and animal studies. Subsequently, 351 articles were selected for full text review and nine were included for data extraction. Four distinct attenuated strains were identified across two priority pathogens – TSI-GSD-218 and VLA1553 for chikungunya virus and MP-12 and hRVFV-4s for Rift Valley Fever virus. Attenuated virus was recovered for each strain except hRVFV-4s. There were no major safety concerns for these identified strains in Phase 1–3 studies.ConclusionsWe have identified three attenuated viral strains that may be amenable to development into novel CHIMs for two priority pathogens. Of these, VLA1553 for chikungunya is a licenced and commercially available vaccine product suitable for use in CHIM. There is a research gap for the creation of new attenuated mutants that could be utilised in CHIM for other priority pathogens