Effects of improved complementary feeding and improved water, sanitation and hygiene on early child development among HIV-exposed children: substudy of a cluster randomised trial in rural Zimbabwe.

Introduction: HIV-exposed uninfected children may be at risk of poor neurodevelopment. We aimed to test the impact of improved infant and young child feeding (IYCF) and improved water, sanitation and hygiene (WASH) on early child development (ECD) outcomes. Methods: Sanitation Hygiene Infant Nutrition Efficacy was a cluster randomised 2×2 factorial trial in rural Zimbabwe ClinicalTrials.gov NCT01824940). Pregnant women were eligible if they lived in study clusters allocated to standard-of-care (SOC; 52 clusters); IYCF (20 g small-quantity lipid-based nutrient supplement/day from 6 to 18 months, complementary feeding counselling; 53 clusters); WASH (pit latrine, 2 hand-washing stations, liquid soap, chlorine, play space, hygiene counselling; 53 clusters) or IYCF +WASH (53 clusters). Participants and fieldworkers were not blinded. ECD was assessed at 24 months using the Malawi Developmental Assessment Tool (MDAT; assessing motor, cognitive, language and social skills); MacArthur Bates Communication Development Inventory (assessing vocabulary and grammar); A-not-B test (assessing object permanence) and a self-control task. Intention-to-treat analyses were stratified by maternal HIV status. Results: Compared with SOC, children randomised to combined IYCF +WASH had higher total MDAT scores (mean difference +4.6; 95% CI 1.9 to 7.2) and MacArthur Bates vocabulary scores (+8.5 words; 95% CI 3.7 to 13.3), but there was no evidence of effects from IYCF or WASH alone. There was no evidence that that any intervention impacted object permanence or self-control. Conclusions: Combining IYCF and WASH interventions significantly improved motor, language and cognitive development in HIV-exposed children. Trial registration number: NCT01824940

Formative research on hygiene behaviors and geophagy among infants and young children and implications of exposure to fecal bacteria.

We conducted direct observation of 23 caregiver-infant pairs for 130 hours and recorded wash-related behaviors to identify pathways of fecal-oral transmission of bacteria among infants. In addition to testing fingers, food, and drinking water of infants, three infants actively ingested 11.3 ± 9.2 (mean ± SD) handfuls of soil and two ingested chicken feces 2 ± 1.4 times in 6 hours. Hand washing with soap was not common and drinking water was contaminated with Escherichia coli in half (12 of 22) of the households. A one-year-old infant ingesting 1 gram of chicken feces in a day and 20 grams of soil from a laundry area of the kitchen yard would consume 4,700,000-23,000,000 and 440-4,240 E. coli, respectively, from these sources. Besides standard wash and nutrition interventions, infants in low-income communities should be protected from exploratory ingestion of chicken feces, soil, and geophagia for optimal child health and growth

Design of an Intervention to Minimize Ingestion of Fecal Microbes by Young Children in Rural Zimbabwe.

We sought to develop a water, sanitation, and hygiene (WASH) intervention to minimize fecal-oral transmission among children aged 0-18 months in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial. We undertook 4 phases of formative research, comprising in-depth interviews, focus group discussions, behavior trials, and a combination of observations and microbiological sampling methods. The resulting WASH intervention comprises material inputs and behavior change communication to promote stool disposal, handwashing with soap, water treatment, protected exploratory play, and hygienic infant feeding. Nurture and disgust were found to be key motivators, and are used as emotional triggers. The concept of a safe play space for young children was particularly novel, and families were eager to implement this after learning about the risks of unprotected exploratory play. An iterative process of formative research was essential to create a sequenced and integrated longitudinal intervention for a SHINE household as it expects (during pregnancy) and then cares for a new child

Mother to child transmission of HIV among Zimbabwean women who seroconverted postnatally: prospective cohort study

Objectives To estimate the rates and timing of mother to infant transmission of HIV associated with breast feeding in mothers who seroconvert postnatally, and their breast milk and plasma HIV loads during and following seroconversion, compared with women who tested HIV positive at delivery

The impact of antibiotics on growth in children in low and middle income countries: systematic review and meta-analysis of randomised controlled trials

Objectives To determine whether antibiotic treatment leads to improvements in growth in prepubertal children in low and middle income countries, to determine the magnitude of improvements in growth, and to identify moderators of this treatment effect.Design Systematic review and meta-analysis.Data sources Medline, Embase, Scopus, the Cochrane central register of controlled trials, and Web of Science.Study selection Randomised controlled trials conducted in low or middle income countries in which an orally administered antibacterial agent was allocated by randomisation or minimisation and growth was measured as an outcome. Participants aged 1 month to 12 years were included. Control was placebo or non-antimicrobial intervention.Results Data were pooled from 10 randomised controlled trials representing 4316 children, across a variety of antibiotics, indications for treatment, treatment regimens, and countries. in random effects models, antibiotic use increased height by 0.04 cm/month (95% confidence interval 0.00 to 0.07) and weight by 23.8 g/month (95% confidence interval 4.3 to 43.3). After adjusting for age, effects on height were larger in younger populations and effects on weight were larger in African studies compared with other regions.Conclusion Antibiotics have a growth promoting effect in prepubertal children in low and middle income countries. This effect was more pronounced for ponderal than for linear growth. the antibiotic growth promoting effect may be mediated by treatment of clinical or subclinical infections or possibly by modulation of the intestinal microbiota. Better definition of the mechanisms underlying this effect will be important to inform optimal and safe approaches to achieving healthy growth in vulnerable populations.Vanier Canada Graduate ScholarshipMcGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, CanadaZvitambo Inst Maternal Child Hlth Res, Harare, ZimbabweQueen Mary Univ London, Blizard Inst, Ctr Paediat, London, EnglandMRC, Clin Trials Unit, London, EnglandJohns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USACornell Univ, Div Nutr Sci, Program Int Nutr, Ithaca, NY 14853 USAWashington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USAUniv Malawi, Blantyre, MalawiUniv Cambridge, Dept Archaeol & Anthropol, Div Biol Anthropol, Cambridge CB2 1TN, EnglandUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo, BrazilUniv British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V6T 1Z3, CanadaUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo, BrazilWeb of Scienc

Modelling stunting in LiST: the effect of applying smoothing to linear growth data.

BACKGROUND: The Lives Saved Tool (LiST) is a widely used resource for evidence-based decision-making regarding health program scale-up in low- and middle-income countries. LiST estimates the impact of specified changes in intervention coverage on mortality and stunting among children under 5 years of age. We aimed to improve the estimates of the parameters in LiST that determine the rate at which the effects of interventions to prevent stunting attenuate as children get older. METHODS: We identified datasets with serial measurements of children's lengths or heights and used random effects models and restricted cubic splines to model the growth trajectories of children with at least six serial length/height measurements. We applied WHO growth standards to both measured and modelled (smoothed) lengths/heights to determine children's stunting status at multiple ages (1, 6, 12, 24 months). We then calculated the odds ratios for the association of stunting at one age point with stunting at the next ("stunting-to-stunting ORs") using both measured and smoothed data points. We ran analyses in LiST to compare the impact on intervention effect attenuation of using smoothed rather than measured stunting-to-stunting ORs. RESULTS: A total of 21,786 children with 178,786 length/height measurements between them contributed to our analysis. The odds of stunting at a given age were strongly related to whether a child is stunted at an earlier age, using both measured and smoothed lengths/heights, although the relationship was stronger for smoothed than measured lengths/heights. Using smoothed lengths/heights, we estimated that children stunted at 1 month have 45 times the odds of being stunted at 6 months, with corresponding odds ratios of 362 for the period 6 to 12 months and 175 for the period 12 to 24 months. Using the odds ratios derived from the smoothed data in LiST resulted in a somewhat slower attenuation of intervention effects over time, but substantial attenuation was still observed in the LiST outputs. For example, in Mali the effect of effectively eliminating SGA births reduced prevalence of stunting at age 59 months from 44.4% to 43.7% when using odds ratios derived from measured lengths/heights and from 44.4% to 41.9% when using odds ratios derived from smoothed lengths/heights. CONCLUSIONS: Smoothing of children's measured lengths/heights increased the strength of the association between stunting at a given age and stunting at an earlier age. Using odds ratios based on smoothed lengths/heights in LiST resulted in a small reduction in the attenuation of intervention effects with age and thus some increase in the estimated benefits, and may better reflect the true benefits of early nutritional interventions

Performance of the UNICEF/UN Washington Group tool for identifying functional difficulty in rural Zimbabwean children.

INTRODUCTION: Over one billion people live with disability worldwide, of whom 80% are in developing countries. Robust childhood disability data are limited, particularly as tools for identifying disability function poorly at young ages. METHODS: A subgroup of children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial (a cluster-randomised, community-based, 2x2 factorial trial in two rural districts in Zimbabwe) had neurodevelopmental assessments at 2 years of age. We evaluated functional difficulty prevalence in HIV-exposed and HIV-unexposed children using the Washington Group Child Functioning Module (WGCFM), comparing absolute difference using chi-squared or Fisher's exact tests. Concurrent validity with the Malawi Developmental Assessment Tool (MDAT) was assessed using logistic regression with cohort MDAT score quartiles, linear regression for unit-increase in raw scores and a Generalised Estimating Equation approach (to adjust for clusters) to compare MDAT scores of those with and without functional difficulty. A 3-step, cluster-adjusted multivariable regression model was then carried out to examine risk factors for functional difficulty. FINDINGS: Functional Difficulty prevalence was 4.2% (95%CI: 3.2%, 5.2%) in HIV-unexposed children (n = 1606) versus 6.1% (95%CI: 3.5%, 8.9%) in HIV-exposed children (n = 314) (absolute difference 1.9%, 95%CI: -0.93%, 4.69%; p = 0.14). Functional difficulty score correlated negatively with MDAT: for each unit increase in WGCFM score, children completed 2.6 (95%CI: 2.2, 3.1) fewer MDAT items (p = 0.001). Children from families with food insecurity and poorer housing were more at risk of functional difficulty. INTERPRETATION: Functional difficulty was identified in approximately 1-in-20 children in rural Zimbabwe, which is comparable to prevalence in previous studies. WGCFM showed concurrent validity with the MDAT, supporting its use in early childhood

Functional Genetic Variants in DC-SIGNR Are Associated with Mother-to-Child Transmission of HIV-1

BACKGROUND: Mother-to-child transmission (MTCT) is the main cause of HIV-1 infection in children worldwide. Given that the C-type lectin receptor, dendritic cell-specific ICAM-grabbing non-integrin-related (DC-SIGNR, also known as CD209L or liver/lymph node-specific ICAM-grabbing non-integrin (L-SIGN)), can interact with pathogens including HIV-1 and is expressed at the maternal-fetal interface, we hypothesized that it could influence MTCT of HIV-1. METHODS AND FINDINGS: To investigate the potential role of DC-SIGNR in MTCT of HIV-1, we carried out a genetic association study of DC-SIGNR in a well-characterized cohort of 197 HIV-infected mothers and their infants recruited in Harare, Zimbabwe. Infants harbouring two copies of DC-SIGNR H1 and/or H3 haplotypes (H1-H1, H1-H3, H3-H3) had a 3.6-fold increased risk of in utero (IU) (P = 0.013) HIV-1 infection and a 5.7-fold increased risk of intrapartum (IP) (P = 0.025) HIV-1 infection after adjusting for a number of maternal factors. The implicated H1 and H3 haplotypes share two single nucleotide polymorphisms (SNPs) in promoter region (p-198A) and intron 2 (int2-180A) that were associated with increased risk of both IU (P = 0.045 and P = 0.003, respectively) and IP (P = 0.025, for int2-180A) HIV-1 infection. The promoter variant reduced transcriptional activity in vitro. In homozygous H1 infants bearing both the p-198A and int2-180A mutations, we observed a 4-fold decrease in the level of placental DC-SIGNR transcripts, disproportionately affecting the expression of membrane-bound isoforms compared to infant noncarriers (P = 0.011). CONCLUSION: These results suggest that DC-SIGNR plays a crucial role in MTCT of HIV-1 and that impaired placental DC-SIGNR expression increases risk of transmission

Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance

Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance