BACKGROUND:Severe acute malnutrition (SAM) is the most critical form of undernutrition, associated with high inpatient and postdischarge mortality. It is hypothesized that malnutrition enteropathy contributes to systemic inflammation by allowing translocation of intestinal pathogen-associated molecular patterns across the damaged epithelium. OBJECTIVES:Assess intestinal permeability, markers of bacterial translocation, and correlate these with inflammatory markers in children admitted with SAM and during 1 y after discharge. METHODS:In a substudy of the longitudinal Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition observational study, we recruited 264 children with complicated SAM on admission to hospital at 3 centers in Zimbabwe and Zambia. We measured gut permeability by urinary lactulose:mannitol ratio (LMR); plasma lipopolysaccharide (LPS) using the limulus amoebocyte lysate assay; and plasma inflammatory biomarkers by enzyme-linked immunosorbent assay and Luminex, at admission, discharge, 12- and 48-wk postdischarge. Values were compared with 173 adequately nourished community controls. Data were analyzed using mixed effects models for longitudinal data, regression for associations between groups, and Cox proportional hazards models for survival. RESULTS:Gut permeability, as measured by LMR, was 2.5-fold higher in children with SAM compared with community controls [95% confidence interval (CI): 1.4, 4.5], and only resolved by 48-wk postdischarge. Higher inpatient gut permeability was associated with increased risk of death or readmission over the following year [hazard ratio 6.14 (95% CI: 1.03, 36.8) per 10-fold increase in LMR]. Children with high gut permeability had higher levels of the intestinal biomarker glucagon-like peptide-2 and lower L-selectin. Children with higher plasma LPS had independently higher concentrations of circulating inflammatory markers [tumor necrosis factor-α, interleukin (IL)-6, IL-1ra, C-reactive protein, IL-8, chemokine ligand 3, and chemokine ligand 4]. CONCLUSIONS:Collectively, these results highlight the central role of the gut in children with SAM. Malnutrition enteropathy may represent a suitable target for therapeutic interventions to improve clinical outcomes in this high-risk population.

We compared neurodevelopment at age 24-months among children born to mothers with or without CMV viraemia in the third trimester of pregnancy in rural Zimbabwe, using the Malawi Developmental Assessment Tool (MDAT) for gross motor, fine motor, language and social development. Among 209 children, 49 (23%) were exposed to third trimester CMV viraemia. The mean total MDAT score was 91.0 (SD 9.4) in CMV-exposed children versus 94.1 (8.8) in CMV-unexposed children (adjusted difference -4.02 points (95% confidence interval -7.01, -1.04, P=0.008). CMV exposure in utero, without evidence of congenital infection, may impair child neurodevelopment, providing a potential antenatal intervention target.

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.

Abstract Children recovering from complicated severe acute malnutrition (SAM) have a high risk of infectious mortality and morbidity, which could reflect impaired anti-microbial defence. We used blood samples from a cross-sectional cohort of children under 5 years’ old admitted to hospital with SAM in Zambia and Zimbabwe (cases, n = 125) and adequately nourished non-hospitalised children from the same communities (controls, n = 73) to characterise anti-bacterial innate immune cell function. We did not find evidence that inpatient immune function differed between cases who experienced subsequent adverse clinical outcomes (death, readmission, SAM at 48 weeks) versus those who did not. However, pro-inflammatory cytokine (IL-6, IL-8 and TNF) responses to E. coli lipopolysaccharide and heat-killed Salmonella typhimurium were positively associated with subsequent gains in mid-upper arm circumference, an indicator of nutritional recovery. We then characterised how innate immune cell function changed during post-discharge rehabilitation in a longitudinal sub-cohort of cases who provided repeat blood samples at discharge, 12, 24 and/or 48 weeks post-discharge ( n = 83). Relative to inpatient immune function, bacterial binding capacity declined whilst anti-bacterial pro-inflammatory cytokine secretion increased in the cases over the post-discharge follow-up period with both normalising towards control ranges. These changes were also evident in cases who had recovered to a healthy nutritional status (weight-for-height Z score ≥ −2). Collectively, our data suggest that restoration of anti-bacterial innate immune cell function following complicated SAM lags behind nutritional recovery. Thus, children who are no longer wasted may continue to have deficient anti-bacterial innate immunity months after hospital admission for SAM.

Background:Sixteen million children are HIV-exposed but uninfected (HEU) due to the prevention of vertical transmission. Despite avoiding HIV, children who are HEU face higher risks of infections and poorer growth and development than children HIV-unexposed (HU), though mechanisms remain unclear. We hypothesized that systemic and vascular inflammations contribute to disparities. Methods:The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial recruited pregnant women at ∼12 gestational weeks between 2012 and 2015 in rural Zimbabwe (∼15% HIV prevalence, >80% antiretroviral therapy coverage). Plasma biomarkers were measured using enzyme-linked immunosorbent assay (ELISA) and multiplex assays in a subgroup of children at 1 month of age and compared using generalized estimating equations adjusted for trial arm, maternal age, birthweight, prematurity, sex, and age. Principal component analysis was used to reduce dimensionality of biomarkers. Results:Seventy-one children who are HEU and 62 who are HU were included. Twenty-two of 27 biomarkers were raised in HEU versus HU. Systemic inflammatory markers (IL-1β/interferon-γ/TNF-α/sCD14) and vascular activation markers (L-selectin/VCAM-1) were significantly higher. HIV-exposed but uninfected infants gained 6.1 g/day less than HU infants in the first month after birth. Although one principal component, primarily driven by vascular endothelial growth factor, was associated with increased growth rate, the difference between HEU and HU growth trajectories was not affected by differences in any principal components, suggesting that inflammation does not explain lower growth amongst HEU children. Conclusions:Children who are HEU have significantly elevated systemic and vascular inflammatory biomarkers compared with those who are HU. Understanding causes and consequences of this inflammatory imbalance may identify new intervention targets for improving outcomes in this vulnerable group.

Mortality following severe acute malnutrition (SAM) remains high in Africa. Some children with SAM have altered immune responses and impaired neurodevelopment; however, whether vitamin D deficiency contributes to these poor outcomes remains unclear. We conducted a cross-sectional analysis of circulating 25-hydroxyvitamin D [25(OH)D] concentrations at hospital discharge (25(OH)D) in 442 children aged 0-59 months with SAM at one hospital in Lusaka, Zambia, and two hospitals in Harare, Zimbabwe. Also, we investigated the relationship between 25(OH)D concentrations and host factors. In 442 children, plasma 25(OH)D concentrations were measured using ELISA. Vitamin D deficiency was identified in 33/442 (7.5%; 95% CI: 5.2-10.3) children, all of whom were from Zimbabwe. A multivariable regression model that included age, sex, HIV status, season, oedema, cerebral palsy, and country demonstrated significantly higher 25(OH)D levels among children aged 6-11 months (adjusted (adj) ratio; 1.3; 95% CI: 1.1, 1.6; P = 0.003), 12-23 months (adj ratio; 1.5; 95% CI: 1.3, 1.8; P < 0.001), and 24-59 months (adj ratio; 1.5; 95% CI: 1.3, 1.8; P < 0.001) compared with those <6 months. Sampling during the cool season (adj ratio; 1.2; 95% CI: 1.1, 1.3; P = 0.002), absence of cerebral palsy (adj ratio; 1.2; 95% CI: 1.1, 1.4; P = 0.002) and residence in Zambia (adj ratio; 1.2; 95% CI: 1.1, 1.2; P < 0.001) were associated with higher concentrations of 25(OH)D, even after excluding children <6 months. These findings indicate that vitamin D status among children with SAM is significantly influenced by age, seasonality, cerebral palsy, and geographical location. To facilitate management and improve clinical outcomes in these children, we recommend further investigation into whether the current vitamin D content in ready-to-use therapeutic foods is sufficient for all children and whether additional supplementation improves clinical outcomes, especially in high-risk groups. If deficiency is present, we recommend that children be managed in accordance with local guidelines and policies.

BACKGROUND:Cytomegalovirus (CMV) co-infection is associated with mortality in adults with HIV, but whether CMV is associated with mortality in children with HIV remains uncertain. METHODS:In 498 children (median age 6.3 years, interquartile range 2.3-9.6) enrolled in the ARROW trial (ISRCTN24791884) in Uganda (336/498) and Zimbabwe (162/498) selected using a case-cohort design, CMV was quantified using real-time polymerase chain reaction at initiation of non-nucleotide reverse transcriptase inhibitor-based antiretroviral therapy (ART), 12-weeks post-ART, and 84-weeks post-ART. Associations between baseline CMV viraemia and mortality were evaluated using multivariable models, adjusting for baseline HIV viral load, CD4+ percentage, and IL-6 concentrations. RESULTS:Baseline CMV viraemia was associated with mortality, with relationships differing by country and assay. In Zimbabwe (assay limit of detection 20 copies/mL), 119/162 (73%) children had detectable CMV, and each log10 higher CMV viral load was associated with over 2-fold higher mortality (adjusted hazard ratio (aHR)=2.74; 95% confidence interval (CI) 1.57-4.77). In Uganda (assay limit of detection 120 copies/mL), 89/336 (26%) children had detectable CMV viraemia, which was associated with 3-fold higher mortality compared to undetectable CMV (aHR=3.15; 95%CI 1.11-8.93). In a subset of 48 children with immunophenotyping data, we found no evidence that CMV was associated with immune activation. CONCLUSIONS:CMV viraemia is independently associated with mortality in children with HIV starting ART in sub-Saharan Africa. Future studies should define the underlying mechanisms and evaluate whether suppressing CMV viraemia reduces mortality in children with HIV.

Childhood severe acute malnutrition (SAM) occurs as either classical wasting (non-oedematous-SAM; NO-SAM) or with the presence of oedema (oedematous SAM; O-SAM). Both forms of SAM have distinct mortality and nutritional recovery rates, however, the underlying pathophysiology is poorly understood. We collected stool for whole metagenome shotgun sequencing and plasma for metabolic phenotyping from 238 children (79 NO-SAM, 159 O-SAM) hospitalised with complicated SAM and 141 adequately-nourished controls (ANC) from an observational, prospective cohort in Zimbabwe and Zambia. Children with SAM were followed up at 12-, 24- and 48-weeks post-discharge. During hospitalisation, there were significant alterations in taxonomic and functional microbiome diversity between O-SAM and NO-SAM. Lancefieldella parvula , a potent producer of hydrogen-sulfide from cysteine, was one of three species significantly elevated in O-SAM versus NO-SAM. Metagenomic analysis showed an overabundance of pathways involved in sulfur amino-acid and one-carbon metabolism in O-SAM compared to NO-SAM. Consistently, the sulfur amino acids cysteine and homocysteine were significantly depleted in the plasma of O-SAM versus NO-SAM, while histidine and various phosphatidylcholines were more abundant. During follow-up, O-SAM and NO-SAM microbiomes remained divergent up to 24 weeks post-discharge whilst alpha diversity recovery was delayed in NO-SAM. Plasma metabolomes also remained significantly different between O-SAM, NO-SAM and ANC throughout 48 weeks of follow-up. These findings demonstrate that distinct microbiome profiles may drive disturbance of systemic one-carbon metabolism in O-SAM and highlight persistent microbiome and metabolic dysfunction during nutritional recovery. This work supports further studies targeting the gut microbiome to correct metabolic disturbances and improve long-term clinical outcomes in complicated SAM. One Sentence Summary Children hospitalised with oedematous versus non-oedematous severe acute malnutrition have altered gut microbiomes and disrupted one-carbon metabolism, which remain distinct up to 48 weeks post-discharge. ### Competing Interest Statement RCR is on the scientific advisory board of Biostime Institute Nutrition and Care and declares remittance from Abbott Nutrition Health Institute, Nutricia and Nestle for public conference talks outside the submitted work. All other authors declare that they have no competing interests. ### Clinical Protocols ### Funding Statement HOPE-SAM was funded by the Medical Research Council (MR/K012711/1), Wellcome (107634/Z/15/Z to MB, 206455/Z/17/Z to RCR, and 093768/Z/10/Z and 108065/Z/15/Z to AJP), a joint award from Wellcome and the Royal Society (206225/Z/17/Z to CDB), and UNICEF Zimbabwe (ZIM/PCA201721/PD2019158). JRS is supported by NIHR Southampton Biomedical Research Centre (NIHR203319) and BBSRC (UKRI775; BB/W00139X/1). Funding bodies had no role in the study design, implementation, analysis and interpretation of the data. ### 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: University of Zambia Biomedical Research Ethics Committee (010-02-16) and the Medical Research Council of Zimbabwe (MRCZ/A/2044) gave ethical approval for this work 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 The raw metagenome sequencing data generated in this study have been deposited in the European Bioinformatics Database

Children recovering after hospitalisation with complicated severe acute malnutrition (SAM) have a high risk of infectious mortality and morbidity. In a cross-sectional cohort of SAM inpatients in Zambia and Zimbabwe (cases, n=125) and well-nourished children from the same communities (controls, n=73) we evaluate anti-bacterial innate immune cell function to determine whether abnormalities may be an underlying factor in subsequent adverse clinical outcomes and ponderal growth gains. We go on to characterise how innate immune cell function changes over 48 weeks of post-discharge rehabilitation in a longitudinal cohort (n=83). We find that blood immune cell composition, monocyte and neutrophil bacterial binding capacity, and upregulation of monocyte surface marker expression and soluble immune mediator secretion in response to bacterial antigen stimulation are dysregulated by complicated SAM. We did not find evidence that inpatient immune function differed in cases who experienced subsequent adverse clinical outcomes (clinic visits or death, readmission, persistent SAM at 48 weeks). However, pro-inflammatory cytokine (IL-6, IL-8 and TNFα) secretion in response to E. coli lipopolysaccharide and heat-killed Salmonella typhimurium during hospitalisation was positively associated with subsequent gains in mid-upper arm circumference, an indicator of nutritional recovery. Relative to initial immune function during hospitalisation, bacterial binding capacity and anti-bacterial pro-inflammatory cytokine secretion of cases had reciprocal patterns; the former declined whilst the latter increased over the post-discharge follow-up period with both normalising towards ranges in controls. These changes continued to be evident in cases who had recovered from SAM to a healthy nutritional status (weight-for-height Z score≥-2). Collectively, our data suggest that restoration of immune function following complicated SAM lags behind nutritional recovery. Thus, children who are no longer wasted may nevertheless continue to have deficient anti-bacterial innate immunity weeks to months after hospital admission for SAM.

INTRODUCTION:Children discharged from hospital following management of complicated severe acute malnutrition (SAM) have a high risk of mortality, readmission and failed nutritional recovery. Current management approaches fail to sufficiently promote convalescence after inpatient nutritional rehabilitation. Novel interventions during the post-discharge period could enhance convalescence to help children survive and thrive. METHODS AND ANALYSIS:The Co-SAM trial is an adaptive, multicountry, phase III, individually randomised clinical trial, based on the principles that (i) interacting biological and social factors drive multimorbidity in children with SAM, and (ii) both medical and psychosocial interventions may therefore ameliorate underlying causal pathways to reduce morbidity and mortality and improve recovery. Children aged 6-59 months with complicated SAM, who have stabilised and started the transition to ready-to-use therapeutic food (RUTF), will be enrolled and randomised to one of five trial arms (standard-of-care alone; antimicrobials; reformulated RUTF; psychosocial support; or a combination of all strategies). Standard-of-care, which is provided in all trial arms, includes RUTF until nutritional recovery (defined as weight-for-height Z-score >-2, mid-upper arm circumference >12.5 cm and oedema-free since the last study visit), and other management recommended in WHO guidelines. The 12-week antimicrobial package provides daily co-formulated rifampicin and isoniazid (with pyridoxine) and 3 days of azithromycin monthly. The reformulated RUTF, which incorporates medium-chain triglycerides and hydrolysed protein to increase nutrient bioavailability and reduce metabolic stress, is provided at the same dose and duration as standard RUTF. The 12-week psychosocial package includes caregiver problem-solving therapy, educational modules, peer support groups and child play. The combined arm includes all interventions. Children start their intervention package prior to hospital discharge, with follow-up data collection in study clinics at 2, 4, 6, 8, 12 and 24 weeks. The primary composite outcome is death, hospitalisation or failed nutritional recovery within 24 weeks post-randomisation. An interim analysis will allow unpromising arms to be dropped, while the final analysis will be conducted when 1266 children have completed the study. Embedded process evaluation and laboratory substudies will explore the mechanisms of action of the interventions. ETHICS AND DISSEMINATION:The trial has been approved by ethics committees in Zimbabwe, Zambia, Kenya and UK. Dissemination will be via community advisory boards in each country; Ministries of Health; and dialogue with policymakers including UNICEF. TRIAL REGISTRATION NUMBER:Clinicaltrials.gov: NCT05994742; Pan African Clinical Trials Registry: PACTR202311478928378.

BACKGROUND Maternal infections underlie several adverse birth outcomes. Whether trimethoprim-sulfamethoxazole prophylaxis during pregnancy will improve birth outcomes is unknown. METHODS In a double-blind, randomized, placebo-controlled trial in Zimbabwe, we assigned pregnant women to receive trimethoprim-sulfamethoxazole, at a dose of 960 mg daily, or placebo from at least 14 weeks' gestation until delivery. The primary outcome was birth weight. RESULTS Among 993 participants (131 with human immunodeficiency virus infection), 498 were randomly assigned to receive placebo and 495 to receive trimethoprim-sulfamethoxazole, with the first dose received at a median of 21.7 weeks' gestation (interquartile range, 17.3 to 26.4). In intention-to-treat analyses, the mean (SD) birth weight was 3040460 g in the trimethoprim-sulfamethoxazole group and 3019 +/- 526 g in the placebo group (mean difference, 20 g, 95% confidence interval, -43 to 83; P=0.53). The number of adverse events was similar in the two groups. CONCLUSIONS In Zimbabwe, trimethoprim-sulfamethoxazole prophylaxis during pregnancy did not significantly increase infant birth weight.

BACKGROUND:Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition, and children hospitalised with complications have unacceptably high mortality. Complicated SAM is a multisystem disease characterised pathophysiologically by muscle wasting, systemic inflammation, metabolic dysfunction, and malnutrition enteropathy including epithelial barrier dysfunction. There is a clear need for novel interventions to address the underlying pathogenic perturbations of complicated SAM. METHODS:In this analysis of tertiary outcomes from a phase II multi-centre trial in Zambia and Zimbabwe, multiplex biomarkers were measured in 122 children (57% male) with SAM randomised following stabilisation ('baseline') to one of four interventions for 14 days to treat malnutrition enteropathy: budesonide, N-acetylglucosamine, colostrum, or teduglutide, compared with standard-of-care. Following measurement of 35 biomarkers from day 15 plasma samples using Luminex and ELISA, the dimensionality of biomarker data was reduced using principal component analysis. FINDINGS:Both budesonide and colostrum reduced systemic inflammation (as measured by CD14, IL1-ra, CRP, and LBP), while children receiving colostrum had higher GLP2 and angiopoietin, and lower circulating lipopolysaccharide, suggesting better restoration of epithelial barrier function. N-acetylglucosamine, a precursor for epithelial glycosaminoglycan synthesis, increased biomarkers of epithelial regeneration (EGF, VEGF), and circulating growth factors (angiopoietin, IGFBP-3, and GCSF). INTERPRETATION:Interventions aimed at ameliorating malnutrition enteropathy showed plausible effects on biomarkers of inflammation and epithelial regeneration, demonstrating an interdependence of systemic inflammation and enteropathy markers seen in structural analysis. Given the interplay between inflammation and tissue restoration in malnutrition, this mechanism of action supports larger trials to determine the clinical benefits of interventions, either alone or in combination, in children with complicated SAM. FUNDING:This analysis of tertiary outcomes for the TAME trial was funded by a Wellcome grant to JPS (220566/Z/20/Z). The TAME trial was funded by a grant from the Medical Research Council (UK), number MR/P024033/1. AJP is funded by Wellcome (108065/Z/15/Z). Takeda UK provided teduglutide at a discounted price.

Severe acute malnutrition (SAM) is the most high-risk form of undernutrition, particularly when children require hospitalization for complications. Complicated SAM is a multisystem disease with high inpatient and postdischarge mortality, especially in children with comorbidities such as HIV; however, the underlying pathogenesis of complicated SAM is poorly understood. Targeted multiplex biomarker analysis in children hospitalized with SAM ( n = 264) was conducted on plasma samples, and inflammatory markers were assessed on stool samples taken at recruitment, discharge, and 12 to 24 and 48 weeks after discharge from three hospitals in Zimbabwe and Zambia. Compared with adequately nourished controls ( n = 173), we found that at baseline, complicated SAM was characterized by systemic, endothelial, and intestinal inflammation, which was exacerbated by HIV infection. This persisted over 48 weeks despite nutritional recovery and was associated with children’s outcomes. Baseline plasma concentrations of vascular endothelial growth factor, glucagon-like peptide-2, and intestinal fatty acid–binding protein were independently associated with lower mortality or hospital readmission over the following 48 weeks. Following principal components analysis of baseline biomarkers, higher scores of a component representing growth factors was associated with greater weight-for-height z score recovery and lower mortality or hospital readmission over the 48 weeks. Conversely, components representing higher gut and systemic inflammation were associated with higher mortality or hospital readmission. These findings highlight the interplay between inflammation, which damages tissues, and growth factors, which mediate endothelial and epithelial regeneration, and support further studies investigating interventions to reduce inflammation and promote epithelial repair as an approach to reducing mortality and improving nutritional recovery.

Child stunting is an indicator of chronic undernutrition and reduced human capital. However, it remains a poorly understood public health problem. Small-quantity lipid-based nutrient supplements (SQ-LNS) have been widely tested to reduce stunting, but have modest effects. The infant intestinal microbiome may contribute to stunting, and is partly shaped by mother and infant histo-blood group antigens (HBGA). We investigated whether mother-infant fucosyltransferase status, which governs HBGA, and the infant gut microbiome modified the impact of SQ-LNS on stunting at age 18 months among Zimbabwean infants in the SHINE Trial ( NCT01824940 ). We found that mother-infant fucosyltransferase discordance and Bifidobacterium longum reduced SQ-LNS efficacy. Infant age-related microbiome shifts in B. longum subspecies dominance from infantis , a proficient human milk oligosaccharide utilizer, to suis or longum , proficient plant-polysaccharide utilizers, were partly influenced by discordance in mother-infant FUT2+/FUT3- phenotype, suggesting that a "younger" microbiome at initiation of SQ-LNS reduces its benefits on stunting.

Addressing the hurdles and opportunities associated with omics research in low- and middle-income countries may inform strategies for its effective execution, and thus increase our ability to tackle health challenges that transcend geographical boundaries.

Background Globally, over 16 million children were exposed to HIV during pregnancy but remain HIV-free at birth and throughout childhood by 2022. Children born HIV-free (CBHF) have higher morbidity and mortality and poorer neurodevelopment in early life compared to children who are HIV-unexposed (CHU), but long-term outcomes remain uncertain. We characterised school-age growth, cognitive and physical function in CBHF and CHU previously enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. Methods and findings The SHINE trial enrolled pregnant women between 2012 and 2015 across 2 rural Zimbabwean districts. Co-primary outcomes were height-for-age Z-score and haemoglobin at age 18 months (clinicaltrials.gov NCT01824940). Children were re-enrolled if they were aged 7 years, resident in Shurugwi district, and had known pregnancy HIV-exposure status. From 5,280 pregnant women originally enrolled, 376 CBHF and 2016 CHU reached the trial endpoint at 18 months in Shurugwi; of these, 264 CBHF and 990 CHU were evaluated at age 7 years using the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox. Cognitive function was evaluated using the Kaufman Assessment Battery for Children (KABC-II), with additional tools measuring executive function, literacy, numeracy, fine motor skills, and socioemotional function. Physical function was assessed using standing broad jump and handgrip for strength, and the shuttle-run test for cardiovascular fitness. Growth was assessed by anthropometry. Body composition was assessed by bioimpedance analysis and skinfold thicknesses. A caregiver questionnaire measured demographics, socioeconomic status, nurturing, child discipline, food, and water insecurity. We prespecified the primary comparisons and used generalised estimating equations with an exchangeable working correlation structure to account for clustering. Adjusted models used covariates from the trial (study arm, study nurse, exact child age, sex, calendar month measured, and ambient temperature). They also included covariates derived from directed acyclic graphs, with separate models adjusted for contemporary variables (socioeconomic status, household food insecurity, religion, social support, gender norms, caregiver depression, age, caregiver education, adversity score, and number of children’s books) and early-life variables (length-for-age-Z-score) at 18 months, birthweight, maternal baseline depression, household diet, maternal schooling and haemoglobin, socioeconomic status, facility birth, and gender norms. We applied a Bonferroni correction for the 27 comparisons (0.05/27) with threshold of p < 0.00185 as significant. We found strong evidence that cognitive function was lower in CBHF compared to CHU across multiple domains. The KABC-II mental processing index was 45.2 (standard deviation (SD) 10.5) in CBHF and 48.3 (11.3) in CHU (mean difference 3.3 points [95% confidence interval (95% CI) 2.0, 4.5]; p < 0.001). The school achievement test score was 39.0 (SD 26.0) in CBHF and 45.7 (27.8) in CHU (mean difference 7.3 points [95% CI 3.6, 10.9]; p < 0.001); differences remained significant in adjusted analyses. Executive function was reduced but not significantly in adjusted analyses. We found no consistent evidence of differences in growth or physical function outcomes. The main limitation of our study was the restriction to one of two previous study districts, with possible survivor and selection bias. Conclusions In this study, we found that CBHF had reductions in cognitive function compared to CHU at 7 years of age across multiple domains. Further research is needed to define the biological and psychosocial mechanisms underlying these differences to inform future interventions that help CBHF thrive across the life-course. Trial registration ClinicalTrials.gov The SHINE follow-up study was registered with the Pan-African Clinical Trials Registry (PACTR202201828512110). The original SHINE trial was registered at NCT https://clinicaltrials.gov/study/NCT01824940.

Abstract Malnutrition underlies almost half of all child deaths globally. Severe Acute Malnutrition (SAM) carries unacceptable mortality, particularly if accompanied by infection or medical complications, including enteropathy. We evaluated four interventions for malnutrition enteropathy in a multi-centre phase II multi-arm trial in Zambia and Zimbabwe and completed in 2021. The purpose of this trial was to identify therapies which could be taken forward into phase III trials. Children of either sex were eligible for inclusion if aged 6–59 months and hospitalised with SAM (using WHO definitions: WLZ <−3, and/or MUAC <11.5 cm, and/or bilateral pedal oedema), with written, informed consent from the primary caregiver. We randomised 125 children hospitalised with complicated SAM to 14 days treatment with (i) bovine colostrum (n = 25), (ii) N-acetyl glucosamine (n = 24), (iii) subcutaneous teduglutide (n = 26), (iv) budesonide (n = 25) or (v) standard care only (n = 25). The primary endpoint was a composite of faecal biomarkers (myeloperoxidase, neopterin, α1-antitrypsin). Laboratory assessments, but not treatments, were blinded. Per-protocol analysis used ANCOVA, adjusted for baseline biomarker value, sex, oedema, HIV status, diarrhoea, weight-for-length Z-score, and study site, with pre-specified significance of P < 0.10. Of 143 children screened, 125 were randomised. Teduglutide reduced the primary endpoint of biomarkers of mucosal damage (effect size −0.89 (90% CI: −1.69,−0.10) P = 0.07), while colostrum (−0.58 (−1.4, 0.23) P = 0.24), N-acetyl glucosamine (−0.20 (−1.01, 0.60) P = 0.67), and budesonide (−0.50 (−1.33, 0.33) P = 0.32) had no significant effect. All interventions proved safe. This work suggests that treatment of enteropathy may be beneficial in children with complicated malnutrition. The trial was registered at ClinicalTrials.gov with the identifier NCT03716115.