Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is used to treat type 2 diabetes and manage weight in individuals with obesity or who are overweight. Semaglutide was found to reduce COVID-19-related mortality risk in a secondary analysis of the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial. We previously demonstrated that diabetes and obesity are associated with higher risks of COVID-19-related mortality in the general population. Using this existing cohort, we found that semaglutide use was associated with a significant 49% reduction in the risk of COVID-19-related death. Diabetes and obesity were linked to higher mortality risk, but an E-value of 3.31 suggests that unmeasured confounders would need to be strong to negate the observed association. These findings suggest that further investigation is warranted into the potential role of semaglutide in reducing risks associated with other causes of death.

This study evaluates 12-month outcomes from a clinical trial comparing adjunctive rose bengal photodynamic therapy vs sham in treatment of fungal, acanthamoeba, and smear/culture-negative infectious keratitis. QuestionDoes adjunctive rose bengal photodynamic therapy (RB-PDT) improve outcomes at 12 months in patients with infectious keratitis?FindingsIn this randomized clinical trial including 330 participants with fungal, acanthamoeba, or smear/culture-negative keratitis, the primary outcome was best spectacle-corrected visual acuity (BSCVA) measured at 6 months. Overall, there was no difference in prespecified secondary outcomes of BSCVA, infiltrate/scar size, or adverse outcomes between the RB-PDT and sham control groups at 12 months.MeaningIn this study, adjunctive RB-PDT did not appear to confer a long-term clinical benefit over standard antimicrobial therapy for these forms of infectious keratitis. ImportanceInfectious keratitis results in poor outcomes despite maximal medical therapy. While rose bengal photodynamic therapy (RB-PDT) has not been shown to be beneficial at improving best spectacle-corrected visual acuity (BSCVA) or cure rate, decreasing scar size, or complication rate at a shorter period of 6 months, long-term results are essential to evaluate clinically relevant scarring and visual recovery.ObjectiveTo evaluate 12-month outcomes from the clinical trial (REAGIR) comparing adjunctive rose bengal photodynamic therapy (RB-PDT) vs sham in treatment of fungal, acanthamoeba, and smear/culture-negative infectious keratitis.Design, Setting, and ParticipantsThis international multicenter, randomized, double-masked, sham-controlled clinical trial took place at Aravind Eye Hospitals in India (Madurai, Coimbatore, and Pondicherry) and the Federal University of S & atilde;o Paulo in Brazil. The study included a total of 330 participants with corneal ulcers who were randomized to the above groups. These data were analyzed from June 1, 2025, to July 15, 2025.InterventionParticipants were randomized to receive (1) a standardized loading dose of topical 0.1% rose bengal, followed by 15 minutes of green light irradiation (RB-PDT) or (2) identical procedure without activating the green light source (sham). All participants received standard antimicrobial therapy.Main Outcomes and MeasuresPrespecified primary outcome was BSCVA (logarithm of the minimum angle of resolution) at 6 months. Prespecified secondary outcomes included BSCVA, infiltrate and/or scar size at 12 months, corneal perforation (CP) and/or the rate of therapeutic penetrating keratoplasty (TPK), and microbiological cure rate at 12 months.ResultsOf 330 enrolled patients (mean [SD] age, 50 [13] years; 213 male [65%] and 117 female [35%]), 282 (85%) had BSCVA measurements and 250 (75%) had 12-month infiltrate/scar measurements. There was no evidence of benefit of RB-PDT vs sham for BSCVA at 12 months (mean difference, 0.01; 95% CI -0.13 to 0.14; P = .91). Scar size was not different at 12 months (mean difference, 0.006 mm; 95% CI, -0.32 to 0.33; P = .97). CP/TPK rates were 31 vs 34 events at 12 months (hazard ratio, 1.21; 95% CI, 0.74-1.98; P = .44), indicating no difference. There was no difference in outcomes by organism subgroup.Conclusions and RelevanceIn this study, at 12 months, RB-PDT did not confer a benefit over sham therapy for BSCVA, infiltrate/scar size, or rates of CP/TPK. These findings support 6-month REAGIR results, supporting the likelihood that there is no benefit to adjunctive RB-PDT for infectious keratitis at 1 year. These findings do not rule out the possibility that alternative photosensitizers or treatment algorithms might be beneficial.Trial RegistrationClinicalTrials.gov Identifier: NCT05110001

Background:Testing blood samples with multiplex bead assays can assess elimination and identify residual foci of transmission for multiple pathogens simultaneously. In Ecuador, onchocerciasis and yaws are presumed eliminated, and the status of trachoma is unknown. We assessed their elimination status by measuring IgG antibodies in children 6-24 months. Methods:In a birth cohort of 404 children measured between 2021-2024 in Esmeraldas province, Ecuador, we tested dried blood spots at ages 6, 9, 12, 18, and 24 months using a multiplex IgG assay that included antigens to Onchocerca volvulus (Ov16), Treponema pallidum (rp17, tmpa), and Chlamydia trachomatis (Pgp3, Ct694). We estimated seroprevalence and incident seroconversion rates across an urban-rural gradient. Results:Of 404 children enrolled, 370 contributed 1,606 samples. Seroprevalence was near zero for onchocerciasis (0.4%, 95% CI: 0.2% to 0.8%) and yaws (0.2%, 95% CI: 0.0% to 0.5%). Conversely, C. trachomatis Pgp3 seroprevalence increased along the urban-rural gradient from Esmeraldas city (3.4%, 95% CI: 1.8% to 5.8%) to remote, river-accessible rural villages (22.4%, 95% CI: 16.0% to 30.1%), and incident seroconversion was common in rural villages (16.1 per 100 child-years, 95% CI: 11.3 to 21.9). Conclusions:Serologic surveillance found no evidence of O. volvulus or T. pallidum transmission, consistent with elimination. High Pgp3 seroconversion rates suggest ongoing C. trachomatis transmission in rural villages. Results highlight the value of integrated serologic surveillance and motivate in-depth trachoma surveillance in Esmeraldas.

PURPOSE:Patients with noninfectious uveitis (NIU) may be more susceptible to complications of COVID-19, including long COVID, yet limited research has evaluated this outcome in NIU populations. This study aimed to assess the prevalence and risk factors of long COVID among individuals with NIU in the United States. METHODS:A retrospective cohort analysis was conducted using de-identified data from a large healthcare claims database. A time-varying Cox proportional hazard regression analysis was performed to estimate the effects of various risk factors on the development of long COVID. Models were adjusted for use of systemic corticosteroids and other immunosuppressive medications, comorbidities, COVID-19 vaccination status, and demographic variables. RESULTS:The study population consisted of 63 220 individuals with NIU (mean age (SD) = 62.9 (17.4) years, 60.7% female). There were 621 (0.096%) documented cases of long COVID across 100 105.6 person-years, representing an incidence rate of 6.2 cases of long COVID per 1000 person-years. Exposure to systemic corticosteroids was associated with an average increased risk of long COVID (hazard ratio (HR) = 3.45, 95% CI: 2.68-4.46, p < 0.001). Additionally, COVID-19-related hospitalizations, increased healthcare utilization, and having baseline asthma and mental health disorders were also associated with an average increased risk of long COVID (all p < 0.003). Male sex, topical or local corticosteroid exposure, and COVID-19 vaccination were associated with an average decreased risk of long COVID (all p < 0.001). CONCLUSION:This large population-based study identified key risk and protective factors for long COVID among patients with NIU. Findings suggest that systemic corticosteroid-induced immune dysregulation may increase vulnerability to long COVID in individuals with severe uveitis.

Programmatic decisions regarding surveillance and intervention for trachoma are made at the district level, reflecting an implicit assumption that transmission within districts is sufficiently homogeneous. However, as transmission declines, residual pockets of transmission may become spatially heterogeneous at sub-district scales. Using cluster-level data from 12 districts in Amhara, Ethiopia (2019-2023), we assess the spatial structure of Pgp3 antibody responses, a sensitive measure of infection transmission. Spatial clustering was evident in higher prevalence districts but diminished as populations approached elimination. We show that as districts approach elimination sub-district heterogeneity likely disappears, and district-level summaries may be sufficient to guide decision-making.

Background:Niger has one of the highest maternal mortality rates, and facility delivery can help prevent these deaths. While distance to health facilities predicts home delivery in other sub-Saharan African settings, few studies have examined this relationship in Niger. Methods:This cross-sectional survey, an ancillary study to the AVENIR trial, included women aged 12-59 years old with a child participating in a sub-trial of AVENIR. Trained workers collected survey data on potential predictors of a home-based delivery, and separately documented primary health care centre (Centre de Santé Integré, CSI) services through site visits. Distance from household to CSI was split into three categories: less than five km, 5-10 km, and over 10 km. Generalised estimating equations (GEE) evaluated the association between distance to CSI and likelihood of a home-based delivery, adjusting for clustering by community. As a secondary analysis, backwards stepwise model selection determined the best set of predictors for a home-based delivery. Results:49.2% of women indicated their last birth occurred at home. Compared with women living <5 km from a CSI, those living 5-10 km away had 1.72 times the odds of home delivery (95% confidence interval (CI) = 1.00-2.96), and those >10 km away had 2.67 times the odds (95% CI = 1.44-4.95). Model selection identified three significant predictors: number of prenatal care visits, distance to CSI, and number of living children. Conclusions:Home delivery remains highly prevalent in rural Niger. Access to prenatal consultations, the number of living children a mother has, and distance from the household to the local CSI are key predictors of delivery location. Interventions for women who prefer or must give birth at home along with those aimed to increase facility-based delivery may support efforts to decrease maternal mortality in rural Niger. Trial registration:This trial was registered at clinicaltrials.gov (NCT04224987) on 13 January 2020.

PURPOSE:To evaluate the effect of a digital mindfulness-based program (Calm Health) on mental health outcomes in adults with noninfectious uveitis (NIU). DESIGN:Single-center, single-masked, waitlist-controlled, randomized clinical trial. PARTICIPANTS:One hundred adults aged ≥18 years with active or inactive NIU and baseline mild or greater anxiety or depression were randomized 1:1 to immediate access to a mindfulness application (app) (Calm Health) or to a waitlist control group. METHODS:Participants in the intervention group were instructed to use the Calm Health mobile app for ≥10 minutes daily for 8 weeks. Controls received no new mindfulness intervention during this period. Outcomes were assessed at baseline and 8 weeks using validated surveys. MAIN OUTCOME MEASURES:The primary outcome was the mean difference in the anxiety symptom severity score measured by the Generalized Anxiety Disorder-7 (GAD-7) at 8 weeks. Secondary outcomes included changes in depression (Patient Health Questionnaire-9 [PHQ-9]), perceived stress (Perceived Stress Scale-10 [PSS-10]), and vision-related quality of life (National Eye Institute Visual Function Questionnaire-25 [NEI VFQ-25]). Outcomes were analyzed using linear analysis of covariance (ANCOVA) models, adjusting for baseline scores. RESULTS:Of 100 randomized participants (median age 43.5 years; 75% female), 70 completed the primary endpoint assessment. Median [Q1, Q3] total app use among intervention participants was 578.62 [397.79, 923.00] minutes over 8 weeks. After adjustment for baseline scores, the intervention group had a significantly lower GAD-7 score at 8 weeks compared with controls (mean difference -1.7 points; 95% CI, -3.17 to -0.23, P = 0.02). Secondary analyses showed significantly greater reductions in PHQ-9 scores (-1.90 points; 95% CI, -3.04 to -0.76, P = 0.001) and PSS-10 scores (-3.69 points; 95% CI, -6.00 to -1.37, P = 0.002) in the intervention group. Changes in NEI VFQ-25 scores were not statistically significant between groups (mean difference 1.98 points; 95% CI, -0.90 to 4.86, P = 0.18). Sensitivity analyses accounting for missing data and clinical covariates yielded similar results. CONCLUSIONS:A digital mindfulness-based intervention (Calm Health) significantly reduced anxiety, depression, and perceived stress in adults with NIU. Digital mindfulness tools may serve as a feasible, scalable adjunct to uveitis care, particularly in settings with limited access to traditional mental health services. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found after the references.

Importance:Infectious keratitis results in poor outcomes despite maximal medical therapy. While rose bengal photodynamic therapy (RB-PDT) has not been shown to be beneficial at improving best spectacle-corrected visual acuity (BSCVA) or cure rate, decreasing scar size, or complication rate at a shorter period of 6 months, long-term results are essential to evaluate clinically relevant scarring and visual recovery. Objective:To evaluate 12-month outcomes from the clinical trial (REAGIR) comparing adjunctive rose bengal photodynamic therapy (RB-PDT) vs sham in treatment of fungal, acanthamoeba, and smear/culture-negative infectious keratitis. Design, Setting, and Participants:This international multicenter, randomized, double-masked, sham-controlled clinical trial took place at Aravind Eye Hospitals in India (Madurai, Coimbatore, and Pondicherry) and the Federal University of São Paulo in Brazil. The study included a total of 330 participants with corneal ulcers who were randomized to the above groups. These data were analyzed from June 1, 2025, to July 15, 2025. Intervention:Participants were randomized to receive (1) a standardized loading dose of topical 0.1% rose bengal, followed by 15 minutes of green light irradiation (RB-PDT) or (2) identical procedure without activating the green light source (sham). All participants received standard antimicrobial therapy. Main Outcomes and Measures:Prespecified primary outcome was BSCVA (logarithm of the minimum angle of resolution) at 6 months. Prespecified secondary outcomes included BSCVA, infiltrate and/or scar size at 12 months, corneal perforation (CP) and/or the rate of therapeutic penetrating keratoplasty (TPK), and microbiological cure rate at 12 months. Results:Of 330 enrolled patients (mean [SD] age, 50 [13] years; 213 male [65%] and 117 female [35%]), 282 (85%) had BSCVA measurements and 250 (75%) had 12-month infiltrate/scar measurements. There was no evidence of benefit of RB-PDT vs sham for BSCVA at 12 months (mean difference, 0.01; 95% CI -0.13 to 0.14; P = .91). Scar size was not different at 12 months (mean difference, 0.006 mm; 95% CI, -0.32 to 0.33; P = .97). CP/TPK rates were 31 vs 34 events at 12 months (hazard ratio, 1.21; 95% CI, 0.74-1.98; P = .44), indicating no difference. There was no difference in outcomes by organism subgroup. Conclusions and Relevance:In this study, at 12 months, RB-PDT did not confer a benefit over sham therapy for BSCVA, infiltrate/scar size, or rates of CP/TPK. These findings support 6-month REAGIR results, supporting the likelihood that there is no benefit to adjunctive RB-PDT for infectious keratitis at 1 year. These findings do not rule out the possibility that alternative photosensitizers or treatment algorithms might be beneficial. Trial Registration:ClinicalTrials.gov Identifier: NCT05110001.

Relapse to acute malnutrition after recovery from severe acute malnutrition (SAM) is common. However, most programmatic resources are devoted to the acute phase of recovery, and fewer interventions are available for children recently discharged from outpatient nutritional programs. We evaluated the feasibility of training caregivers to screen for relapse using mid-upper arm circumference (MUAC) tapes for reducing time to detection of relapse among children recently recovered from SAM in Burkina Faso. Caregiver-child dyads were enrolled and randomized in a 1:1 fashion to either caregiver MUAC screening or local standard of care (SOC), which consists of monthly clinic-based follow-up visits for 3 months following discharge. In the MUAC screening group, caregivers were trained on how to use a standard MUAC tape and asked to screen their child weekly with a provided MUAC tape for the 6-month duration of the study. The primary outcome was time to relapse detection, defined as MUAC < 12.5 cm and/or weight-for-height Z-score < -2. Secondary outcomes included hospitalization and/or death over the 6-month study period. Of 200 caregiver-child dyads enrolled in the trial, 99 were randomized to the MUAC screening group and 101 to the SOC group. By 6 months after enrollment, the hazard of relapse detection was lower in the MUAC screening group compared to the SOC group (hazard ratio, HR, 0.65, 95% confidence interval, CI, 0.38-1.12). Fewer hospitalizations and/or deaths occurred in the MUAC screening group compared to the SOC group (MUAC: 3%; SOC: 14%, risk ratio 0.23, 95% CI, 0.07-0.79). Training caregivers to screen for relapse after recovery from SAM was feasible and may lead to modestly reduced time to detection of relapse, suggesting a full-scale trial is warranted. Trial Registration: This study was prospectively registered on clinicaltrials.gov (NCT05932992, registered June 27, 2023).

Introduction The WHO cut-offs to define anaemia among children (haemoglobin, Hb <105 g/L in 6–23 months and <110 g/L in 24–59 months) are based on the distribution of Hb concentrations in a healthy population. Our objective was to identify Hb values that best discriminate functional outcomes among children aged 6–30 months.Methods We used previously compiled datasets from an individual participant data meta-analysis of effects of small quantity lipid-based nutrient supplements. Participants were eligible for this pooled analysis if they had Hb measured at 6–30 months and data on at least one functional outcome of interest, which included physical activity and sleep patterns, and language, socioemotional and motor development. We stratified the datasets by child age in 3-month intervals and analysed associations of Hb with both concurrent and subsequently measured (longitudinal) outcomes. If Hb significantly discriminated the 25th, 50th or 75th percentile of the outcome based on the pooled area under the receiver operating characteristic curve (AUC), we identified the Hb value with the highest concordance probability as the best discriminatory threshold.Results 11 datasets from 8 countries including 27 626 children were analysed. Hb significantly discriminated 21 of 47 concurrent and 11 of 32 longitudinal Hb-outcome associations. Best Hb discriminatory thresholds ranged from 102 to 111 g/L for concurrent physical activity outcomes, 103–116 g/L for concurrent developmental outcomes, and 109–117 g/L for longitudinal developmental outcomes. The I2 for the pooled AUC analysis indicated generally low to moderate heterogeneity across studies.Conclusions The current WHO cut-offs to define anaemia among children are in the middle to upper range of Hb values that best discriminate concurrent physical activity and development, and are in the lower range of values that best discriminate subsequent child development. Along with other types of evidence, this study provides additional evidence to inform Hb cut-offs to define anaemia among young children.

We studied the effects of a combined water, sanitation, handwashing, and nutritional supplementation (WSH + N) intervention on Shigella/EIEC IgG immune development among Bangladeshi children enrolled in a cluster-randomized trial. We used a bacterial display assay to measure IgG-specific binding to Shigella/EIEC Ipa proteins (IpaA, IpaB, IpaC, IpaD, and IpaH) from a substudy of 120 children (60 intervention, 60 control) at median ages 3, 14, and 28 months. We found that the WSH + N intervention did not impact IgG seroprevalence (56% vs 53%, P = 0.6) or IgG epitope repertoire development (P = 0.15-0.97), but there were distinct age-based patterns of IgG linear epitopes and motifs charting the development of the immune repertoire. Samples from before age 6 months, reflecting predominantly maternal IgG, had higher epitope breadth and magnitude compared with samples from older ages. A modeling analysis of maternal-child IgG dynamics suggests that peak susceptibility occurs between 6 and 9 months of age. With this methodology, we found that intensive, household-based WASH interventions were insufficient to impact early childhood immune development to Shigella/EIEC. Our results motivate complementary interventions, such as vaccines, to prevent Shigella/EIEC infection in the first 2 years of life.IMPORTANCEShigella/EIEC is a leading cause of global diarrheal deaths, especially in low-resource settings. Current interventions against childhood Shigella/EIEC infection focus on reducing exposure, such as through improved water, sanitation, handwashing, and nutritional supplementation (WSH + N). It is unclear how these interventions impact childhood immune development against pathogens. In the present study, we characterize the null impact of a WSH + N intervention on IgG immune responses to Shigella/EIEC in a birth cohort and demonstrate the development of immune responses over the first 2 years of life. We found that maternal IgG wanes between 6 and 9 months, and that peak susceptibility to infection is during this time. From our findings, we provide a modeling framework that can be used to inform vaccination schedules in early childhood after 6 months.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT01590095.

ObjectiveTo examine how child mortality among children aged 1-59 months varies by asset-based wealth status in rural Burkina Faso, and to assess the interaction between mass azithromycin (AZ) distribution and wealth status on child mortality at both the household and community levels.MethodsWe used data from a cluster-randomized trial and population census data on household characteristics and assets. A wealth index score for each household, used to classify the population by wealth, was generated using principal component analysis. We used the Relative Index of Inequality (RII), the Slope Index of Inequality (SII), and the concentration index to assess wealth-related inequalities in mortality, and the Gini Index to assess variability in child mortality across households and communities. Poisson regression models were used, with person-time at risk included as an offset, and robust standard error to estimate changes in mortality rates by wealth and treatment arm. Interaction was assessed on both the multiplicative and additive scales.ResultsMortality declined with increasing wealth at both the household and community levels, with a significant gradient at the community level (RII = 1.17, 95% CI: 1.05-1.29; SII = 2.3 per 1,000 person-years, 95% CI: 0.2-4.4), reflecting higher mortality among the poorest. The effect of AZ did not vary significantly by wealth index, and changes in mortality rates across wealth levels were similar between the two treatment arms. There was no evidence of a statistically significant interaction between AZ and asset-based wealth on either the multiplicative or additive scale at the household or cluster level.ConclusionOur findings demonstrate a wealth gradient in child mortality, with the highest mortality rates observed among households and communities in the lowest wealth quintiles. These disparities were consistent across both AZ-treated and placebo groups, suggesting that the role of AZ in health disparities may be limited to addressing gaps in treatment access rather than broader wealth-related disparities. While the study may have been underpowered to detect modest interaction effects, AZ appeared to offer similar benefits across economically diverse communities, with no evidence suggesting enhanced benefits for disadvantaged communities or for prioritizing treatment based on wealth status. Further work is needed to address the wealth-related disparities in child mortality in these communities.Trial registrationClinicalTrials.gov NCT03676764.

The World Health Organization recommends biannual azithromycin mass drug administration (MDA) to infants aged 1-11 months to reduce mortality, following promising results from trials in West Africa. High coverage seen in well-resourced trials may decline as the intervention transitions to a real-world program. As a result, the most vulnerable children facing the highest risk of mortality may be missed. We aimed to identify predictors of non-participation in an azithromycin MDA program to inform programmatic delivery strategies to improve coverage. We conducted a coverage evaluation survey after azithromycin MDA to children aged 1-11 months in Niger's Tahoua region. Data collection teams visited households to assess caregiver-reported participation, reasons for participation and non-participation, and adverse events. Mixed effects logistic regression models were used to analyze community-, household-, and child-level predictors associated with non-participation in azithromycin MDA. Among 40 communities with 811 unique households and 871 children ages 2-12 months old included in analyses, 76% of eligible children received treatment based on caregiver report compared to 96% community health worker-reported coverage. The most frequently stated reasons for non-receipt of treatment were absence (34%), nobody coming to the house (31%), and not receiving enough information (17.2%). In an adjusted model, older children experienced higher odds of receiving treatment (aOR 1.22, 95% CI 1.15 - 1.30, P ≤ 0.0001), as did children living in more densely populated areas (aOR 1.15, 95% CI 1.04 - 1.28, P = 0.01). Adverse events were reported among 6.8% of children who received treatment, with fever being the most reported symptom. Strengthening community sensitization and preparation activities before MDA is essential to address common reasons for non-participation. Future research to understand why younger children and those living in sparsely populated communities were less likely to be included may help target specific interventions in these populations. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT05288023 (AVENIR) ### Funding Statement This work was supported by the Bill & Melinda Gates Foundation grants OPP1210548 and INV-002454. The funders had no role in study implementation, data collection, analysis, or preparation of this manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Boards (IRB) at the Niger Ministry of Health (Comité Nationale Éthique pour la Recherche en Santé, N 041/2020/CNERS) and the University of California, San Francisco (19-28287) provided ethical approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data can be accessed at publication at: https://osf.io/47jkd/overview?view_only=69ab394303594f00bf6c2eda662a5584

BACKGROUND:Biannual mass azithromycin distribution to children aged 1-59 months reduces all-cause child mortality but selects for antimicrobial resistance (AMR). The World Health Organization (WHO) recommends ongoing surveillance of AMR in the context of azithromycin distribution. We evaluated the impact of twice-yearly distribution of azithromycin compared to placebo on AMR in the gut of children in Burkina Faso. METHODS:The Community Health with Azithromycin Trial (CHAT) was a 1:1 cluster randomized placebo-controlled trial in Nouna District, Burkina Faso, from 2019 to 2023. Communities were randomized in a 1:1 fashion to twice-yearly azithromycin (20 mg/kg) or matching placebo. At 36 months, rectal swabs were collected from a random sample of 15 children per community in 48 communities participating in the trial and assessed for AMR genetic resistance determinants using next-generation DNA sequencing (DNA-seq). We assessed the fold-change in macrolide and nonmacrolide resistance determinants between treatment groups after 36 months. RESULTS:A total of 483 samples from 41 communities were analyzed at 36 months. There was no evidence of a difference in macrolide resistance determinants in the azithromycin group compared to the placebo group (fold-change, 1.21; 95% confidence interval [CI], .96-1.52; P = .62). There was no evidence of a difference in nonmacrolide resistance genes; for example, beta-lactam resistance was similar between treatment groups (fold-change, 1.05; 95% CI, .79-1.40; P = .81). CONCLUSIONS:In this setting in Burkina Faso, twice-yearly azithromycin distributions to children aged 1-59 months did not lead to statistically significant differences in macrolide or nonmacrolide genetic resistance determinants at 36 months. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT03676764.

Children with severe acute malnutrition (SAM) have a high risk of mortality and morbidity. After recovery from an initial episode of SAM, the risk of relapse can be high, although estimates vary across settings. Post-recovery surveillance for relapsed SAM in Burkina Faso consists of monthly clinic-based follow-up visits. However, adherence to the follow-up schedule can be variable, and children with missed surveillance visits may have delayed diagnoses of relapse. Here, we describe the protocol for a feasibility trial design to provide preliminary evidence to support the training of caregivers to screen for relapsed acute malnutrition using mid-upper arm circumference (MUAC) screening at home. This feasibility trial will enroll 200 caregiver-child dyads in which the child has recovered in the past month from an episode of SAM in Boromo, Burkina Faso. Eligible children had an initial episode of SAM that they recovered from per Burkinabè guidelines (weight-for-height Z-score, WHZ ≥ −2 and/or MUAC ≥ 12.5 cm, depending on the admission criteria). Caregiver-child dyads are randomized to either weekly screening using a standard MUAC tape plus standard of care follow-up or standard of care alone, which consists of monthly clinic-based screening for relapse for 3 months. Caregiver-child dyads are followed for 6 months. Primary feasibility endpoints include acceptability, time for training, enrollment potential and refusals, adherence to the follow-up protocol, and adherence to the screening protocol. Clinical endpoints, measured to inform the design of a full-scale trial, include the proportion of children relapsing, anthropometric measurements at 6 months, hospitalization, and vital status. This feasibility trial will generate data to support the development and full-scale testing of an intervention to train caregivers to screen for relapsed acute malnutrition using MUAC. This trial is registered at clinicaltrials.gov (NCT05932992), first posted 27 June 2023.

Enteric pathogen infections are a major global health challenge, influenced by a variety of host and environmental factors, and their clinical presentation and treatment can be complicated by the presence of co-infections. The prevalence of enteric infections and co-infections tend to vary between rural and urban contexts, likely driven by underlying environmental, geographic, and demographic characteristics. To improve understanding of urbanicity and age on enteric pathogen prevalence and on co-infection risk, we measured 22 enteric pathogens in fecal samples collected from children aged 6, 12, and 18 months across a rural-urban gradient within the ECoMiD birth cohort study ( n =473). Enteric pathogen burden was high and increased with age, with at least one pathogen detected in 91% of children at 6 months, 97% at 12 months, and 98% at 18 months. However, prevalence of some pathogens- notably Salmonella enterica, enterovirus, and rotavirus- decreased with age. Co-infections were also common (88%), and children were infected with as many as 11 pathogens simultaneously. The most frequently observed co-infection profiles included enteroaggregative E. coli and atypical enteropathogenic E. coli , followed by combinations with diffusely adherent E. coli , enterovirus, enterotoxigenic E. coli , and/or adenovirus. Enteric pathogen detection generally was higher in more rural settings, though patterns varied by pathogen. These results provide useful information for future examination of pathogen dynamics of co-occurrence. Given the ubiquity of enteric infections in high transmission settings, strategies that aim to reduce overall microbial exposure may be needed to supplement interventions targeting control of individual pathogens. AUTHOR SUMMARY:Children living in low-resource settings are frequently exposed to pathogens that cause enteric infections, which can contribute to diarrhea, poor growth, and long-term health problems. Many children are infected with more than one pathogen at the same time, but we still know relatively little about how these infections occur together or how they vary across different environments. We examined stool samples collected from children during their first 18 months of life in communities ranging from urban to rural areas of northern Ecuador. We found that nearly every child carried at least one pathogen, and most carried several simultaneously. The number of pathogens increased as children grew older, and children living in more rural communities generally had a higher burden of infection. We also found that some pathogens occurred together more often than expected by chance, suggesting they may share common transmission routes or interact in ways that deserve further study. Our findings show that children in high-transmission settings experience a substantial burden of multiple simultaneous infections from an early age. These results support the need for interventions that reduce overall exposure to enteric pathogens, alongside strategies that target individual pathogens such as vaccines.

Background:Giardia is the most common enteric parasite among children in low-resource settings, causing diarrhea and leading to prolonged infection or asymptomatic carriage. We assessed whether the effect of water, sanitation, and handwashing (WSH) interventions on Giardia infection among rural Bangladeshi children varies with seasonal conditions. Methods:We conducted a secondary analysis of the WASH Benefits Bangladesh cluster-randomized trial, with 450 clusters assigned to 4 arms in a 2 × 2 factorial design (WSH: WSH, WSH + Nutrition; no WSH: Control, Nutrition). Giardia infection was measured by multiplex real-time polymerase chain reaction in stool samples after 2 years of intervention. Effects were estimated by marginal treatment and assessed for heterogeneity by season when Giardia was measured. We also assessed heterogeneity by cumulative exposure to dry and monsoon seasons from birth to measurement age to estimate cumulative seasonal exposure history. Results:Giardia prevalence, measured among 2773 children (median age: 30 months, range: 22-38 months), was higher in the dry seasons (32%) than in the monsoon (21%). Improved WSH was associated with a consistent 20% relative reduction and a modest absolute reduction that was slightly greater during the dry season (-6.1%; 95% confidence interval: -10.1 to -2.1), although interaction test did not show strong evidence of effect modification by season. Prevalence remained lower in the WSH group across increasing dry season exposure, with the largest differences among children with more than 17 months of dry-season exposure. Conclusions:We demonstrate how WSH provides resilience to seasonal variation in infection risk and mitigates climate-driven, seasonally varying Giardia transmission.