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Background: Histo-blood group antigen (HBGA) phenotypes may contribute to poor oral rotavirus vaccine (RVV) immunogenicity, since rotavirus binds intestinal epithelial HBGA glycans, while maternal HBGA status shapes breastmilk composition, which influences the composition of the infant microbiome. We investigated associations between maternal/infant HBGA phenotypes and RVV immunogenicity in rural Zimbabwe., Methods: We undertook salivary FUT2/FUT3 phenotyping in mother-infant pairs. Serum anti-rotavirus immunoglobulin A was measured by enzyme-linked immunosorbent assay. We explored adjusted associations between FUT2/FUT3 status and RVV seroconversion (primary outcome, n = 322) and seropositivity and geometric mean titer (secondary outcomes, n = 776)., Results: Infants of FUT2- or FUT3-positive women were less likely to seroconvert post-RVV than infants of FUT2- or FUT3-negative women (FUT2 positive [20.1%] vs FUT2 negative [27.5%]: adjusted relative risk [aRR], 0.47; 95% CI, .26-.82; P = .008; FUT3 positive [18.1%] vs FUT3 negative [30.0%]: aRR, 0.45; 95% CI, .25-.78; P = .005). When compared with FUT2-positive infants with FUT2-positive mothers, FUT2-positive infants with FUT2-negative mothers were twice as likely to seroconvert (36.8% vs 21.9%; aRR, 2.12; 95% CI, 1.23-3.63; P = .006). When compared with FUT3-positive infants with FUT3-positive mothers, FUT3-positive infants with FUT3-negative mothers were 3 times as likely to seroconvert (48.3% vs 18.2%; aRR, 2.99; 95% CI, 1.82-4.90; P < .001)., Conclusions: Maternal and infant FUT2 and FUT3 status influences infant RVV immunogenicity., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Children hospitalised for severe acute malnutrition (SAM) have a high risk of mortality, relapse and rehospitalisation following hospital discharge. Current approaches fail to promote convalescence, or to address the underlying social determinants of SAM, meaning that restoration of long-term health, growth and neurodevelopment is not achieved. Although guidelines recommend play and stimulation to promote recovery, most caregivers are not supported to do this at home. We set out to evaluate the feasibility and acceptability of a codesigned intervention package aimed at providing child stimulation through play, and strengthening caregiver capabilities through problem-solving skills, peer support and income-generating activities. We evaluated the intervention in two phases, enroling 30 caregiver-child pairs from paediatric wards in Harare, Zimbabwe, once children who had been hospitalised with SAM were ready for discharge. Children were median 17.8 months old, and 28.6% had human immunodeficiency virus. Trained intervention facilitators (IFs)-lay workers whose own children had previously had SAM-delivered the intervention over 12 weeks with nurse supervision. Qualitative interviews with caregivers and IFs showed that the intervention was feasible and acceptable. Participants reported benefiting from the psychosocial support and counselling, and several started income-generating projects. Caregivers appreciated the concept of play and caregiver-child interaction, and all reported practising what they had learned. By Week 12, caregiver mental health and caregiver-child interaction improved significantly. Overall, the intervention was feasible, acceptable and showed promise in modifying caregiver knowledge, attitudes and practice. An efficacy trial is now needed to evaluate whether the intervention can improve child convalescence following complicated SAM., (© 2024 The Author(s). Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of interests RJP was previously an external consultant to Colostrum UK which provided the bovine colostrum used in these studies. RJP has also been an external consultant to Sterling Technology (USA) and an employee of Pantheryx Inc (USA) who produce and distribute bovine colostrum. There was no bovine colostrum company involvement in the production of this article or editing of its content. SH has had funding for teduglutide studies and lectured and participated in advisory boards on behalf of Takeda., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In sub-Saharan Africa, children with severe malnutrition (SM) and HIV have substantially worse outcomes than children with SM alone, facing higher mortality risk and impaired nutritional recovery post-hospitalisation. Biological mechanisms underpinning this risk remain incompletely understood. This case-control study nested within the CHAIN cohort in Kenya, Uganda, Malawi, and Burkina Faso examined effect of HIV on six months post-discharge growth among children with SM and those at risk of malnutrition, assessed proteomic signatures associated with HIV in these children, and investigated how these systemic processes impact post-discharge growth in children with SM. Using SomaScan TM assay, 7335 human plasma proteins were quantified. Linear mixed models identified HIV-associated biological processes and their associations with post-discharge growth. Using structural equation modelling, we examined directed paths explaining how HIV influences post-discharge growth. Here, we show that at baseline, HIV is associated with lower anthropometry. Additionally, HIV is associated with protein profiles indicating increased complement activation and decreased insulin-like growth factor signalling and bone mineralisation. HIV indirectly affects post-discharge growth by influencing baseline anthropometry and modulating proteins involved in bone mineralisation and humoral immune responses. These findings suggest specific biological pathways linking HIV to poor growth, offering insights for targeted interventions in this vulnerable population., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Few trials have explored long-term effects of interventions designed to reduce child stunting. We evaluated school-age outcomes in rural Zimbabwean children who received cluster-randomised water, sanitation and hygiene (WASH) and/or infant and young child feeding (IYCF) interventions from pregnancy up to 18 months of age., Methods: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial enrolled pregnant women from two rural Zimbabwean districts (Chirumanzu and Shurugwi) between 2012 and 2015, and cluster-randomised them using a 2 × 2 factorial design to standard-of-care, WASH, IYCF, or combined WASH & IYCF, with a co-primary outcome of height-for-age Z-score and haemoglobin at 18 months (clinicaltrials.govNCT01824940). Children who were HIV-unexposed, age 7 years, and still living in Shurugwi district were eligible for this follow-up study (registered at PACTR 202201828512110) and measured between 1st April 2021 and 30th September 2022. The primary outcome at 7 years was cognitive function using the Kaufman Assessment Battery for Children (KABC-II). Secondary outcomes were executive function, literacy and numeracy, fine motor skills, socioemotional function, handgrip strength, broad jump distance, shuttle-run test distance, anthropometry, lean mass index, and skinfold thicknesses. Study nurses conducting assessments were blinded to intervention arm. Analysis followed a pre-registered statistical analysis plan. Intention-to-treat analyses using generalized estimating equations were used to assess the long-term effects of WASH and IYCF on each outcome, leveraging the factorial trial design. A pre-specified subgroup analysis by child sex was also performed., Findings: Among 3989 HIV-negative women, 3676 children were assessed at age 18 months; of these, 1002 (510 female) were assessed at mean (SD) age 7.3 (0.2) years. There was no effect of IYCF or WASH on the KABC-II score or secondary cognitive outcomes, except a small improvement in socioemotional function in WASH arms (-0.98 points, 95% CI -1.73, -0.22, p = 0.01). Children in IYCF arms had higher handgrip strength (0.28 Kg, 95% CI 0.02, 0.53, p = 0.03); however, in the pre-specified subgroup analysis, improved handgrip strength was seen only in boys (0.53 Kg, 95% CI 0.19, 0.87 p = 0.002). There were no significant effects of either intervention on other outcomes., Interpretation: Early-life IYCF and WASH led to few functional benefits by school-age. Interventions that are more comprehensive, delivered for longer, and include nurturing care should be considered to improve long-term cognitive and physical function., Funding: Wellcome [220671/Z/20/Z, 108065/Z/15/Z]; NIH [R61HD103101]; Thrasher [15250]; and IMMANA [3.02]., Competing Interests: There are no interests to declare from any authors., (© 2024 The Authors.)

Purpose of Review: Differences in health outcomes between children who are HIV-exposed but uninfected (CHEU) compared to children who are HIV-unexposed (CHU) have been reported both before and since the availability of antiretroviral therapy (ART) during pregnancy and breastfeeding. This review highlights recent studies investigating the impact of ART on the health, growth and development of CHEU., Recent Findings: Several meta-analyses confirm higher rates of adverse birth outcomes among pregnant women with HIV compared to pregnant women without HIV. The highest risk of adverse birth outcomes is among women with HIV not receiving ART, and generally studies indicate that more time on ART is associated with lower risk of adverse birth outcomes; however, most data are from observational cohorts. Where studies have compared historic regimens, prior to dolutegravir use, adverse birth outcomes are more commonly associated with exposure to protease inhibitors. Recent population-based studies have not demonstrated an association between neural tube defects and dolutegravir exposure. In a recent, multisite randomized trial, infants born to mothers receiving dolutegravir vs. efavirenz had lower neonatal mortality, possibly mediated through reductions in small-for-gestational age and preterm birth. Neurodevelopment, neuroimaging and growth studies suggest a protective effect of earlier maternal ART initiation., Summary: Dolutegravir continues to appear safe in pregnancy. Randomized trials of specific regimens during pregnancy and breastfeeding, including long-acting and newer ART drugs with long-term follow-up of children, are critical to understand the contribution of ART exposure to CHEU outcomes., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Piper et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

It is widely recognised that children recovering from Severe Acute Malnutrition (SAM), remain vulnerable to risk of death following hospital discharge due to a wide range of biological and social factors. In light of this heightened risk, we report here on a qualitative study which aimed to better understand the caring contexts that children recovering from SAM were recuperating in within the high density urban and suburban districts of Harare, Zimbabwe. Undertaken with the mothers and other primary caregivers of 10 children enrolled on a large observational cohort study (HOPE-SAM), this paper identifies several dimensions of the women's lives that impede their caring capabilities. Given the country's status as a global 'hunger hotspot' (FAO/WFP, 2022), it should not be surprising that food insecurity featured prominently amongst these. Beyond this, the paper highlights the women's uneven access to informal social protection, experiences that are reflective of what recent scholarship refers to as examples of 'uncaring' or 'noncaring,' as well as their responses to discourses of shame and stigma within the community and hospital settings. The paper concludes by considering what this means for understanding of, and responses to, the bodies encountered in the place of global health research and interventions., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Small-quantity lipid-based nutrient supplements (SQ-LNS), which has been widely tested to reduce child stunting, has largely modest effects to date, but the mechanisms underlying these modest effects are unclear. Child stunting is a longstanding indicator of chronic undernutrition and it remains a prevalent public health problem. The infant gut microbiome may be a key contributor to stunting; and mother and infant fucosyltransferase (FUT) phenotypes are important determinants of infant microbiome composition., Methods: We investigated whether mother-infant FUT status (n = 792) and infant gut microbiome composition (n = 354 fecal specimens from 172 infants) modified the impact of an infant and young child feeding (IYCF) intervention, that included SQ-LNS, on stunting at age 18 months in secondary analysis of a randomized trial in rural Zimbabwe., Findings: We found that the impact of the IYCF intervention on stunting was modified by: (i) mother-infant FUT2+/FUT3- phenotype (difference-in-differences -32.6% [95% CI: -55.3%, -9.9%]); (ii) changes in species composition that reflected microbiome maturation (difference-in-differences -68.1% [95% CI: -99.0%, -28.5%); and (iii) greater relative abundance of B. longum (differences-in-differences 49.1% [95% CI: 26.6%, 73.6%]). The dominant strains of B. longum when the intervention started were most similar to the proficient milk oligosaccharide utilizer subspecies infantis, which decreased with infant age and differed by mother-infant FUT2+/FUT3- phenotypes., Interpretation: These findings indicate that a persistently "younger" microbiome at initiation of the intervention reduced its benefits on stunting in areas with a high prevalence of growth restriction., Funding: Bill and Melinda Gates Foundation, UK DFID/Aid, Wellcome Trust, Swiss Agency for Development and Cooperation, US National Institutes of Health, UNICEF, and Nutricia Research Foundation., Competing Interests: Declaration of interests AJP was supported by Wellcome Trust grant 108065/Z/15/Z. ARM was supported by Bill & Melinda Gates Foundation grant OPP1021542 and OPP1143707, with a subcontract to the University of British Columbia 20R25498 EKG was supported by The Nutricia Research Foundation grant 2021-52. T.J.E. was paid a scientific consulting fee in relation to the analysis of the data presented here by the Zvitambo Institute for Maternal and Child Health Research. RCR declares remittance from Abbott Nutrition Health Institute and Nutricia for public conference talks outside of the submitted work in the past 36 months. All other authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The Healthy Child Programme (HCP) in England, delivered by Health Visitors (HV) and Nursery Nurses (NN), aims to assess growth and development in pre-school age children. This qualitative analysis aimed to evaluate the perceptions and experiences of HCP providers and parents located in a London borough., Methods: This qualitative analysis is part of a larger study piloting an automated growth screening algorithm in a London borough. We conducted three focus group discussions; two with parents of pre-school children participating in the pilot study, one in English (n = 6) and one in Sylheti (n = 5), and one with HVs and NNs (n = 11). Sampling was purposeful, and written informed consent was obtained. Groups were facilitated by the same bilingual researcher using semi-structured topic guides. Data were analysed using reflexive thematic analysis and assessed for intercoder reliability., Results: Three broad themes were identified in the data: (1) lack of clarity around the role of the HV and NN; (2) a lack of resources; and (3) a desire for a preventative service. Underlying these themes was a sense of disempowerment shown by HVs/NNs and parents, as well as systemic issues in terms of the accessibility and practicality of the service. Nevertheless, parents and HVs/NNs all stressed the importance of the service in providing information, reassurance and advice., Conclusions: Various challenges prevent the HCP from providing equitable and effective care to every child. However, the service was recognised as very valuable by users and providers despite systemic difficulties., (© 2024. The Author(s).)

Background: Low birthweight (LBW) is when an infant is born too soon or too small, and it affects one in seven infants in low- and middle-income countries. LBW has a significant impact on short-term morbidity and mortality, and it impairs long-term health and human capital. Antenatal microbial and inflammatory exposure may contribute to LBW., Methods: Ovid-Medline, Embase and Cochrane databases were searched for English-language articles evaluating inflammatory, microbial or infective causes of LBW, small-for-gestational age, intra-uterine growth restriction or prematurity. Inclusion criteria were human studies including published data; conference abstracts and grey literature were excluded. A narrative synthesis of the literature was conducted., Results: Local infections may drive the underlying causes of LBW: for example, vaginitis and placental infection are associated with a greater risk of prematurity. Distal infection and inflammatory pathways are also associated with LBW, with an association between periodontitis and preterm delivery and environmental enteric dysfunction and reduced intra-uterine growth. Systemic maternal infections such as malaria and HIV are associated with LBW, even when infants are exposed to HIV but not infected. This latter association may be driven by chronic inflammation, co-infections and socio-economic confounders. Antimicrobial prophylaxis against other bacteria in pregnancy has shown minimal impact in most trials, though positive effects on birthweight have been found in some settings with a high infectious disease burden., Conclusion: Maternal inflammatory and infective processes underlie LBW, and provide treatable pathways for interventions. However, an improved understanding of the mechanisms and pathways underlying LBW is needed, given the impact of LBW on life-course.

One-third of people with HIV in sub-Saharan Africa start antiretroviral therapy (ART) with advanced disease. We investigated associations between immune biomarkers and mortality in participants with advanced HIV randomised to cotrimoxazole or enhanced antimicrobial prophylaxis in the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial (ISRCTN43622374). Biomarkers were assayed using ELISA and Luminex. Associations between baseline values and all-cause 24-week mortality were analysed using Cox models, and for cause-specific mortality used Fine & Gray models, including prophylaxis randomisation, viral load, CD4, WHO stage, age, BMI, and site as covariates; and weighted according to inverse probability of selection into the substudy. Higher baseline CRP, IFN-γ, IL-6 and IP-10 were associated with higher all-cause mortality; and higher IL-23, IL-2 and RANTES with lower all-cause mortality. Associations varied by cause of death: tuberculosis-associated mortality was most strongly associated with higher CRP and sST2, and cryptococcosis-associated mortality with higher IL-4 and lower IL-8. Changes in I-FABP (p = 0.002), faecal alpha-1 antitrypsin (p = 0.01) and faecal myeloperoxidase (p = 0.005) between baseline and 4 weeks post-ART were greater in those receiving enhanced versus cotrimoxazole prophylaxis. Our findings highlight how the immune milieu shapes outcomes following ART initiation, and how adjunctive antimicrobials can modulate the gut environment in advanced HIV., (© 2024. The Author(s).)

The 'double burden of malnutrition' is a global health challenge that increasingly affects populations in both low- and middle-income countries (LMICs). This phenomenon refers to the coexistence of undernutrition and overweight or obesity, as well as other diet-related non-communicable diseases, in the same population, household or even individual. While noteworthy progress has been made in reducing undernutrition in some parts of the world, in many of these areas, the prevalence of overweight and obesity is increasing, particularly in urban areas, resulting in greater numbers of people who were undernourished in childhood and have overweight or obesity in adulthood. This creates a complex and challenging situation for research experts and policymakers who must simultaneously address the public health burdens of undernutrition and overweight/obesity. This review identifies key challenges and limitations in the current research on the double burden of malnutrition in individuals, including the need for a more comprehensive and nuanced understanding of the drivers of malnutrition, the importance of context-specific interventions and the need for greater attention to the food environment and food systems. We advocate for the re-evaluation of research strategies and focus, with a greater emphasis on multidisciplinary and systems approaches and greater attention to the synergistic relationship between the biological, environmental, commercial and socio-economic determinants of malnutrition. Addressing these key challenges can enable us to better comprehend and tackle the multifaceted and dynamic issues of the double burden of malnutrition, particularly in individuals and work towards more effective and sustainable solutions., (© 2024 The Authors. Nutrition Bulletin published by John Wiley & Sons Ltd on behalf of British Nutrition Foundation.)

Background: Neurodevelopment assessment tools for low-resource settings are urgently needed. However, most available tools were developed in high-income settings and may lack cross-cultural validity., Methods: We piloted and adapted two subtests within the planning domain of the Kaufman Assessment Battery for Children-2nd edition (KABC-II) for use in rural Zimbabwean children aged 7years. After initial assessments of face validity, we created 4 substitutions for the story completion subtest and 7 additions for the pattern reasoning subtest through a co-design process with fieldworkers and child development experts. To assess how successful the changes were, T-tests adjusting for unequal variances were used to compare scores between the original and adapted versions of the same subtest. ANOVA and pairwise analysis was performed to compare the performance of KABC-II subtests across domains. Intraclass correlation coefficient was calculated to explore the variability between domains., Results: Initial test scores on the planning domain were significantly lower than the other three domains of learning, sequential memory and simultaneous reasoning (P<0.001) in 50 children (mean age 7.6(SD 0.2) years). Modified subtests were administered to another 20 children (mean age 7.6(SD 0.2) years), who showed story completion scores that were 0.7 marks higher (95% CI 0.0, 1.4; P=0.05) and pattern reasoning scores 1.8 marks higher (95% CI 0.5, 3.2; P=0.01). Overall, the planning domain mean score increased from 8.1 (SD 2.9) to 10.6 (SD 3.4). The intra class correlation coefficient between all four KABC-II domains was initially 0.43 (95% CI 0.13, 0.64) and after modification was 0.69 (95% CI 0.37, 0.87), suggesting an increase in the construct validity., Conclusions: The KABC-II planning domain was successfully adapted to improve cross-cultural validity. Construct validity was enhanced, based on increased inter-correlations among scales. The process of co-design to modify tests for new settings may be beneficial for other commonly used neurodevelopmental tools., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Piper JD et al.)

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, α 1 -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., (© 2024. The Author(s).)

Children who are HIV-exposed but uninfected have increased infectious mortality compared to HIV-unexposed children, raising the possibility of immune abnormalities following exposure to maternal viraemia, immune dysfunction, and co-infections during pregnancy. In a secondary analysis of the SHINE trial in rural Zimbabwe we explored biological pathways underlying infant mortality, and maternal factors shaping immune development in HIV-exposed uninfected infants. Maternal inflammation and cytomegalovirus viraemia were independently associated with infant deaths: mortality doubled for each log 10 rise in maternal C-reactive protein (adjusted hazard ratio (aHR) 2.09; 95% CI 1.33-3.27), and increased 1.6-fold for each log 10 rise in maternal cytomegalovirus viral load (aHR 1.62; 95% CI 1.11-2.36). In girls, mortality was more strongly associated with maternal C-reactive protein than cytomegalovirus; in boys, mortality was more strongly associated with cytomegalovirus than C-reactive protein. At age one month, HIV-exposed uninfected infants had a distinct immune milieu, characterised by raised soluble CD14 and an altered CD8 + T-cell compartment. Alterations in immunophenotype and systemic inflammation were generally greater in boys than girls. Collectively, these findings show how the pregnancy immune environment in women with HIV underlies mortality and immune development in their offspring in a sex-differentiated manner, and highlights potential new intervention strategies to transform outcomes of HIV-exposed children. ClinicalTrials.gov/NCT01824940., (© 2023. The Author(s).)

Stunting affects almost one-quarter of children globally, leading to reduced human capacity and increased long-term risk of chronic disease. Despite intensive infant and young child feeding (IYCF) interventions, many children do not meet their requirements for essential nutrients. This study aimed to assess the feasibility of implementing an IYCF intervention utilizing nutrient-dense powders from egg, biofortified sugar beans and Moringa oleifera leaf in rural Zimbabwe. A mixed-methods formative study was conducted comprising the following: (i) a recipe formulation trial, (ii) trials of improved practices to assess acceptability of the intervention, and (iii) a participatory message formulation process to develop counselling modules for the IYCF-plus intervention. Twenty-seven mother-baby pairs were recruited between November 2019 and April 2020. Key domains affecting IYCF practices that emerged were time, emotional and physical space, cultural and religious beliefs, indigenous knowledge systems and gender dynamics. Household observations and sensory evaluation indicated high acceptability of the new ingredients. Recipe formulation and participatory message formulation by participants instilled community ownership and served to demystify existing misconceptions about the new food products. Families noted the potential for intervention sustainability because the foods could be grown locally. Supplementing complementary foods with nutrient-dense local food ingredients as powders has the potential to sustainably address nutrient-gaps in the diets of young children living in rural lower- and middle-income countries. Comprehensive IYCF counselling utilizing a gender-lens approach, family support and indigenous knowledge systems or resources are key elements to support positive behaviour change in complementary feeding interventions., (© 2023 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

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.

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.

Children with tuberculosis have increased platelet count and platelet/lymphocyte ratio along with decreased mean platelet volume, suggesting that these indices may be useful as adjunct tools in diagnosis of paediatric tuberculosis https://bit.ly/3Ga4AWT., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: World Health Organization (WHO) guidelines recommend cotrimoxazole prophylaxis for children who are HIV-exposed until infection is excluded and vertical transmission risk has ended. While cotrimoxazole has benefits for children with HIV, there is no mortality benefit for children who are HIV-exposed but uninfected, prompting a review of global guidelines. Here, we model the potential impact of alternative cotrimoxazole strategies on mortality in children who are HIV-exposed., Methods and Findings: Using a deterministic compartmental model, we estimated mortality in children who are HIV-exposed from 6 weeks to 2 years of age in 4 high-burden countries: Côte d'Ivoire, Mozambique, Uganda, and Zimbabwe. Vertical transmission rates, testing rates, and antiretroviral therapy (ART) uptake were derived from UNAIDS data, trial evidence, and meta-analyses. We explored 6 programmatic strategies: maintaining current recommendations; shorter cotrimoxazole provision for 3, 6, 9, or 12 months; and starting cotrimoxazole only for children diagnosed with HIV. Modelled alternatives to the current strategy increased mortality to varying degrees; countries with high vertical transmission had the greatest mortality. Compared to current recommendations, starting cotrimoxazole only after a positive HIV test had the greatest predicted increase in mortality: Mozambique (961 excess annual deaths; excess mortality 339 per 100,000 HIV-exposed children; risk ratio (RR) 1.06), Uganda (491; 221; RR 1.04), Zimbabwe (352; 260; RR 1.05), and Côte d'Ivoire (125; 322; RR 1.06). Similar effects were observed for 3-, 6-, 9-, and 12-month strategies. Increased mortality persisted but was attenuated when modelling lower cotrimoxazole uptake, smaller mortality benefits, higher testing coverage, and lower vertical transmission rates. The study is limited by uncertain estimates of cotrimoxazole coverage in programmatic settings; an inability to model increases in mortality arising from antimicrobial resistance due to limited surveillance data in sub-Saharan Africa; and lack of a formal health economic analysis., Conclusions: Changing current guidelines from universal cotrimoxazole provision for children who are HIV-exposed increased predicted mortality across the 4 modelled high-burden countries, depending on test-to-treat cascade coverage and vertical transmission rates. These findings can help inform policymaker deliberations on cotrimoxazole strategies, recognising that the risks and benefits differ across settings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mathur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Congenital syphilis is a major global cause of fetal loss, stillbirth, neonatal death, and congenital infection. In 2020, the global rate of congenital syphilis was 425 cases per 100 000 livebirths-substantially higher than WHO's elimination target of 50 cases per 100 000 livebirths. Case rates are rising in many high-income countries, but remain low compared with those in low-income and middle-income settings. This Review aims to summarise the current epidemiology and knowledge on transmission and treatment of syphilis in pregnancy, and proposes measures to reduce the rising incidence seen worldwide. We also describe emerging diagnostic and treatment tools to prevent vertical transmission and improve management of congenital syphilis. Finally, we outline a programme of public health priorities, which include research, clinical, and preventive strategies., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition and underlies at least 10% of all deaths among children younger than 5 years in low-income countries. SAM is a complex, multisystem disease, with physiological perturbations observed in conjunction with the loss of lean mass, including structural and functional changes in many organ systems. Despite the high mortality burden, predominantly due to infections, the underlying pathogenic pathways remain poorly understood. Intestinal and systemic inflammation is heightened in children with SAM. Chronic inflammation and its consequent immunomodulation may explain the increased morbidity and mortality from infections in children with SAM, both during hospitalization and in the longer term after discharge. Recognition of the role of inflammation in SAM is critical in considering new therapeutic targets in this disease, which has not seen a transformational approach to treatment for several decades. This review highlights the central role of inflammation in the wide-ranging pathophysiology of SAM, as well as identifying potential interventions that have biological plausibility based on evidence from other inflammatory syndromes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Life Sciences Institute.)

Children with severe acute malnutrition (SAM) have high infectious mortality and morbidity, implicating defects in their immune defenses. We hypothesized that circulating innate immune cells from children (0 to 59 months) hospitalized with SAM in Zambia and Zimbabwe ( n = 141) have distinct capacity to respond to bacteria relative to adequately nourished healthy controls ( n = 92). SAM inpatients had higher neutrophil and monocyte Escherichia coli binding capacity but lower monocyte activation and proinflammatory mediator secretion in response to lipopolysaccharide or heat-killed Salmonella typhimurium than controls. Among SAM cases, wasting severity was negatively associated with cytokine secretion, children with HIV had lower monocyte activation, and the youngest children released the least myeloperoxidase upon stimulation. Inpatient bacterial binding capacity and monocyte activation were associated with higher odds of persistent SAM at discharge, a risk factor for subsequent mortality. Thus, SAM shifts innate immune cell function, favoring bacterial containment over proinflammatory activation, which may contribute to health deficits after discharge.

Background: Growth screening in early childhood can help identify children with a range of medical and psychosocial vulnerabilities. In the UK, childhood growth and development up to age 5 years are assessed through the Healthy Child Programme, delivered by health visitors. However, formal criteria to trigger referrals for onward investigation are unclear. There is a lack of qualitative data on the acceptability and feasibility of formal growth screening programmes. This study aimed to build understanding of the perceptions and motivations of caregivers and health visitors in relation to child growth and growth screening., Methods: This longitudinal observational study was part of a larger study piloting an automated growth screening algorithm in Tower Hamlets, London. We conducted three separate qualitative focus group interviews with health visitors (n=10), English-speaking parents (n=6), and Sylheti-speaking parents (n=5). Participants were purposively sampled, and written informed consent was obtained. A bilingual researcher facilitated each group, using a semi-structured interview guide. Data were analysed by two researchers using thematic analysis and assessed for intercoder reliability. The interview guide was translated into Sylheti, and data from the Sylheti group were translated into English by the same bilingual researcher., Findings: Findings suggest that parents desire holistic care in which health visitors are empowered to refer to other health professionals and council services. Parents also want easier access to health visitors, frequent visits with the same health-care provider, and advice on raising their children. Health visitors were seen as well positioned to play an essential role in educating parents on health and developmental milestones and in helping them identify when their child might need additional support. Both parents and health visitors stressed that resources need to be in place not only to assess children but also to provide access to services when problems are identified., Interpretation: These findings suggest that implementing growth screening through health visitors is feasible and acceptable, provided health visitors are given the resources and capabilities to refer children to appropriate services. Interpretation is limited by the purposive nature of the sampling and possible response bias., Funding: Barts Charity., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

HIV and severe wasting are associated with post-discharge mortality and hospital readmission among children with complicated severe acute malnutrition (SAM); however, the reasons remain unclear. We assessed body composition at hospital discharge, stratified by HIV and oedema status, in a cohort of children with complicated SAM in three hospitals in Zambia and Zimbabwe. We measured skinfold thicknesses and bioelectrical impedance analysis (BIA) to investigate whether fat and lean mass were independent predictors of time to death or readmission. Cox proportional hazards models were used to estimate the association between death/readmission and discharge body composition. Mixed effects models were fitted to compare longitudinal changes in body composition over 1 year. At discharge, 284 and 546 children had complete BIA and skinfold measurements, respectively. Low discharge lean and peripheral fat mass were independently associated with death/hospital readmission. Each unit Z -score increase in impedance index and triceps skinfolds was associated with 48 % (adjusted hazard ratio 0·52, 95 % CI (0·30, 0·90)) and 17 % (adjusted hazard ratio 0·83, 95 % CI (0·71, 0·96)) lower hazard of death/readmission, respectively. HIV-positive v . HIV-negative children had lower gains in sum of skinfolds (mean difference -1·49, 95 % CI (-2·01, -0·97)) and impedance index Z -scores (-0·13, 95 % CI (-0·24, -0·01)) over 52 weeks. Children with non-oedematous v . oedematous SAM had lower mean changes in the sum of skinfolds (-1·47, 95 % CI (-1·97, -0·97)) and impedance index Z -scores (-0·23, 95 % CI (-0·36, -0·09)). Risk stratification to identify children at risk for mortality or readmission, and interventions to increase lean and peripheral fat mass, should be considered in the post-discharge care of these children.

Background/objectives: Malnutrition underlies 45% of deaths in children under-5 years annually. Children hospitalised with complicated severe acute malnutrition (SAM) have unacceptably high mortality. We aimed to identify variables from early hospital admission (baseline factors) independently associated with inpatient mortality in this cohort to identify those most at risk., Subjects/methods: Observational study of 745 children aged 0-59 months admitted with complicated SAM at three hospitals in Zimbabwe/Zambia. Children underwent anthropometry and clinical assessment by a study physician within 72 h of enrolment, and caregivers provided sociodemographic data. Children were followed-up daily until discharge/death. A multivariable survival analysis identified the baseline factors independently associated with mortality., Results: 70/745 (9.4%) children died in hospital. Age between 6-23 months [aHR 6.53, 95%CI 2.24-19.02], higher mid-upper arm circumference [aHR 0.73, 95%CI 0.59-0.89], presence of oedema [aHR 2.22, 95%CI 1.23-4.05], shock [aHR 8.18, 95%CI 3.79-17.65], sepsis [aHR 3.13, 95%CI 1.44-6.80], persistent diarrhoea [aHR 2.27, 95%CI 1.18-4.37], lack of a toilet at home [aHR 4.35, 95%CI 1.65-11.47], and recruitment at one Harare site [aHR 0.38, 95%CI 0.18-0.83] were all independently associated with inpatient mortality. Oedematous children had a significantly higher birthweight [2987 g vs 2757 g, p < 0.001] than those without oedema; higher birthweight was weakly associated with mortality [aHR 1.50 95%CI 0.97-2.31]., Conclusions: Children with oedema, low MUAC, baseline infections, shock and lack of home sanitation had a significantly increased risk of inpatient mortality following hospitalisation for complicated SAM. Children with high-risk features may require additional care. A better understanding of the pathophysiology of SAM is needed to identify adjunctive interventions., (© 2023. The Author(s).)

Background : There is a need for follow-up of early-life stunting intervention trials into childhood to determine their long-term impact. A holistic school-age assessment of health, growth, physical and cognitive function will help to comprehensively characterise the sustained effects of early-life interventions. Methods: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe assessed the effects of improved infant and young child feeding (IYCF) and/or improved water, sanitation and hygiene (WASH) on stunting and anaemia at 18 months. Among children enrolled to SHINE, 1,275 have been followed up at 7-8 years of age (1,000 children who have not been exposed to HIV, 268 exposed to HIV antenatally who remain HIV negative and 7 HIV positive children). Children were assessed using the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox, to measure their growth, body composition, cognitive and physical function. In parallel, a caregiver questionnaire assessed household demographics, socioeconomic status, adversity, nurturing, caregiver support, food and water insecurity. A monthly morbidity questionnaire is currently being administered by community health workers to evaluate school-age rates of infection and healthcare-seeking. The impact of the SHINE IYCF and WASH interventions, the early-life 'exposome', maternal HIV, and contemporary exposures on each school-age outcome will be assessed. We will also undertake an exploratory factor analysis to generate new, simpler metrics for assessment of cognition (COG-SAHARAN), growth (GROW-SAHARAN) and combined growth, cognitive and physical function (SUB-SAHARAN). The SUB-SAHARAN toolbox will be used to conduct annual assessments within the SHINE cohort from ages 8-12 years. Ethics and dissemination: Approval was obtained from Medical Research Council of Zimbabwe (08/02/21) and registered with Pan-African Clinical Trials Registry (PACTR202201828512110, 24/01/22). Primary caregivers provided written informed consent and children written assent. Findings will be disseminated through community sensitisation, peer-reviewed journals and stakeholders including the Zimbabwean Ministry of Health and Child Care., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Piper JD et al.)

Introduction: Co-trimoxazole prophylaxis is recommended for children born to women with HIV to protect those who acquire HIV from opportunistic infections, severe bacterial infections and malaria. With scale-up of maternal antiretroviral therapy, most children remain HIV-exposed uninfected (HEU) and the benefits of universal co-trimoxazole are uncertain. We assessed the effect of co-trimoxazole on mortality and morbidity of children who are HEU., Methods: We performed a systematic review (PROSPERO number: CRD42021215059). We systematically searched MEDLINE, Embase, Cochrane CENTRAL, Global Health, CINAHL Plus, Africa-Wide Information, SciELO and WHO Global Index Medicus for peer-reviewed articles from inception to 4th January 2022 without limits. Ongoing randomized controlled trials (RCTs) were identified through registries. We included RCTs reporting mortality or morbidity in children who are HEU receiving co-trimoxazole versus no prophylaxis/placebo. The risk of bias was assessed using the Cochrane 2.0 tool. Data were summarized using narrative synthesis and findings were stratified by malaria endemicity., Results: We screened 1257 records and included seven reports from four RCTs. Two trials from Botswana and South Africa of 4067 children who are HEU found no difference in mortality or infectious morbidity in children randomized to co-trimoxazole prophylaxis started at 2-6 weeks of age compared to those randomized to placebo or no treatment, although event rates were low. Sub-studies found that antimicrobial resistance was higher in infants receiving co-trimoxazole. Two trials in Uganda investigating prolonged co-trimoxazole after breastfeeding cessation showed protection against malaria but no other morbidity or mortality differences. All trials had some concerns or a high risk of bias, which limited the certainty of evidence., Discussion: Studies show no clinical benefit of co-trimoxazole prophylaxis in children who are HEU, except to prevent malaria. Potential harms were identified for co-trimoxazole prophylaxis leading to antimicrobial resistance. The trials in non-malarial regions were conducted in populations with low mortality potentially reducing generalizability to other settings., Conclusions: In low-mortality settings with few HIV transmissions and well-performing early infant diagnosis and treatment programmes, universal co-trimoxazole may not be required., (© 2023 World Health Organization; licensed by International AIDS Society. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

The pathway to a thriving newborn begins before conception and continues in utero with a healthy placenta and the right balance of nutrients and growth factors that are timed and sequenced alongside hormonal suppression of labour until a mature infant is ready for birth. Optimal nutrition that includes adequate quantities of quality protein, energy, essential fats, and an extensive range of vitamins and minerals not only supports fetal growth but could also prevent preterm birth by supporting the immune system and alleviating oxidative stress. Infection, illness, undernourishment, and harmful environmental exposures can alter this trajectory leading to an infant who is too small due to either poor growth during pregnancy or preterm birth. Systemic inflammation suppresses fetal growth by interfering with growth hormone and its regulation of insulin-like growth factors. Evidence supports the prevention and treatment of several maternal infections during pregnancy to improve newborn health. However, microbes, such as Ureaplasma species, which are able to ascend the cervix and cause membrane rupture and chorioamnionitis, require new strategies for detection and treatment. The surge in fetal cortisol late in pregnancy is essential to parturition at the right time, but acute or chronically high maternal cortisol levels caused by psychological or physical stress could also trigger labour onset prematurely. In every pathway to the small vulnerable newborn, there is a possibility to modify the course of pregnancy by supporting improved nutrition, protection against infection, holistic maternal wellness, and healthy environments., Competing Interests: Declaration of interests PA reports a grant from the Children's Investment Fund Foundation in support of the preparation of this manuscript (grant number 2004-04635). ALD is an unpaid Scientific Trustee of Tommy's Charity. CPD reports grant support from WHO, the US Agency for International Development, and National Institutes of Health (NIH; P30 DK040561); royalties from UpToDate; and grant support on behalf of his institution from Takeda and the American Society for Nutrition in work unrelated to this paper. UR receives honoraria from NIH for educational activities and her institution receives funding from NIH. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: We developed the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox to address the shortage of school-age assessment tools that combine growth, physical and cognitive function. Here we present i) development, acceptability and feasibility of the SAHARAN toolbox; ii) characteristics of a pilot cohort; and iii) associations between the domains measured in the cohort., Methods: Growth was measured with anthropometry, knee-heel length and skinfold thicknesses. Bioimpedance analysis measured lean mass index and phase angle. Cognition was assessed using the mental processing index, derived from the Kaufman Assessment Battery for Children version 2, a fine motor finger-tapping task, and School Achievement Test (SAT). Physical function combined grip strength, broad jump and the 20m shuttle-run test to produce a total physical score. A caregiver questionnaire was performed in parallel., Results: The SAHARAN toolbox was feasible to implement in rural Zimbabwe, and highly acceptable to children and caregivers following some minor modifications. Eighty children with mean (SD) age 7.6 (0.2) years had mean height-for-age (HAZ) and weight-for-age Z-scores (WAZ) of -0.63 (0.81) and -0.55 (0.85), respectively. Lean mass index and total skinfold thicknesses were related to WAZ and BMI Z-score, but not to HAZ. Total physical score was associated with unit rises in HAZ (1.29, 95% CI 0.75, 1.82, p<0.001), and lean mass index (0.50, 95% CI 0.16, 0.83, p = 0.004), but not skinfold thicknesses. The SAT was associated with unit increases in the mental processing index and child socioemotional score. The caregiver questionnaire identified high levels of adversity and food insecurity., Conclusions: The SAHARAN toolbox provided a feasible and acceptable holistic assessment of child growth and function in mid-childhood. We found clear associations between growth, height-adjusted lean mass and physical function, but not cognitive function. The SAHARAN toolbox could be deployed to characterise school-age growth, development and function elsewhere in sub-Saharan Africa., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2023 Piper et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Diarrhoeal disease is a leading cause of childhood illness and death globally, and Shigella is a major aetiological contributor for which a vaccine might soon be available. The primary objective of this study was to model the spatiotemporal variation in paediatric Shigella infection and map its predicted prevalence across low-income and middle-income countries (LMICs)., Methods: Individual participant data for Shigella positivity in stool samples were sourced from multiple LMIC-based studies of children aged 59 months or younger. Covariates included household-level and participant-level factors ascertained by study investigators and environmental and hydrometeorological variables extracted from various data products at georeferenced child locations. Multivariate models were fitted and prevalence predictions obtained by syndrome and age stratum., Findings: 20 studies from 23 countries (including locations in Central America and South America, sub-Saharan Africa, and south and southeast Asia) contributed 66 563 sample results. Age, symptom status, and study design contributed most to model performance followed by temperature, wind speed, relative humidity, and soil moisture. Probability of Shigella infection exceeded 20% when both precipitation and soil moisture were above average and had a 43% peak in uncomplicated diarrhoea cases at 33°C temperatures, above which it decreased. Compared with unimproved sanitation, improved sanitation decreased the odds of Shigella infection by 19% (odds ratio [OR]=0·81 [95% CI 0·76-0·86]) and open defecation decreased them by 18% (OR=0·82 [0·76-0·88])., Interpretation: The distribution of Shigella is more sensitive to climatological factors, such as temperature, than previously recognised. Conditions in much of sub-Saharan Africa are particularly propitious for Shigella transmission, although hotspots also occur in South America and Central America, the Ganges-Brahmaputra Delta, and the island of New Guinea. These findings can inform prioritisation of populations for future vaccine trials and campaigns., Funding: NASA, National Institutes of Health-The National Institute of Allergy and Infectious Diseases, and Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests JG and MM report grants from PanTheryx, during the conduct of the study; NP reports grants from GlaxoSmithKline, during the conduct of the study; the remaining authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Stunting affects one-in-five children globally and is associated with greater infectious morbidity, mortality and neurodevelopmental deficits. Recent evidence suggests that the early-life gut microbiome affects child growth through immune, metabolic and endocrine pathways. Using whole metagenomic sequencing, we map the assembly of the gut microbiome in 335 children from rural Zimbabwe from 1-18 months of age who were enrolled in the Sanitation, Hygiene, Infant Nutrition Efficacy Trial (SHINE; NCT01824940), a randomized trial of improved water, sanitation and hygiene (WASH) and infant and young child feeding (IYCF). Here, we show that the early-life gut microbiome undergoes programmed assembly that is unresponsive to the randomized interventions intended to improve linear growth. However, maternal HIV infection is associated with over-diversification and over-maturity of the early-life gut microbiome in their uninfected children, in addition to reduced abundance of Bifidobacterium species. Using machine learning models (XGBoost), we show that taxonomic microbiome features are poorly predictive of child growth, however functional metagenomic features, particularly B-vitamin and nucleotide biosynthesis pathways, moderately predict both attained linear and ponderal growth and growth velocity. New approaches targeting the gut microbiome in early childhood may complement efforts to combat child undernutrition., (© 2023. The Author(s).)

HIV nonprogression despite persistent viremia is rare among adults who are naive to antiretroviral therapy (ART) but relatively common among ART-naive children. Previous studies indicate that ART-naive pediatric slow progressors (PSPs) adopt immune evasion strategies similar to those described in natural hosts of SIV. However, the mechanisms underlying this immunophenotype are not well understood. In a cohort of early-treated infants who underwent analytical treatment interruption (ATI) after 12 months of ART, expression of PD-1 on CD8+ T cells immediately before ATI was the main predictor of slow progression during ATI. PD-1+CD8+ T cell frequency was also negatively correlated with CCR5 and HLA-DR expression on CD4+ T cells and predicted stronger HIV-specific T lymphocyte responses. In the CD8+ T cell compartment of PSPs, we identified an enrichment of stem-like TCF-1+PD-1+ memory cells, whereas pediatric progressors and viremic adults had a terminally exhausted PD-1+CD39+ population. TCF-1+PD-1+ expression on CD8+ T cells was associated with higher proliferative activity and stronger Gag-specific effector functionality. These data prompted the hypothesis that the proliferative burst potential of stem-like HIV-specific cytotoxic cells could be exploited in therapeutic strategies to boost the antiviral response and facilitate remission in infants who received early ART with a preserved and nonexhausted T cell compartment.

Prior to widespread availability of antiretroviral therapy (ART) in sub-Saharan Africa, children who were HIV-exposed but uninfected (HEU) had increased mortality, morbidity and undernutrition compared with children who were HIV-unexposed. Scale-up of ART has led to impressive declines in vertical HIV transmission, but over 15 million children are now HEU, 90% of whom live in sub-Saharan Africa. There are ongoing health disparities among children who are HEU, with higher mortality, morbidity and stunting and modest impairments in early child development, which collectively hamper health and human capital in high prevalence countries. The underlying causes are multifactorial and include exposure to HIV, co-infections and a skewed antenatal inflammatory milieu, particularly if mothers start ART once they have advanced disease, as well as socioeconomic risk factors, which may cluster in HIV-affected households. Improving maternal health through early and sustained ART, ensuring optimal breastfeeding, and implementing evidence-based priority interventions for all children in areas of high HIV prevalence, will likely improve outcomes. A more comprehensive intervention package based on the Nurturing Care Framework may have particular benefits for children who are HEU, to close health gaps and ensure that the next generation of HIV-free children survive and thrive, and lead healthy and productive lives., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)