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Background: While the high prevalence of preterm births and its impact on infant mortality in the US have been widely acknowledged, recent data suggest that even full-term births in the US face substantially higher mortality risks compared to European countries with low infant mortality rates. In this paper, we use the most recent birth records in the US to more closely analyze the primary causes underlying mortality rates among full-term births.Methods and Findings: Linked birth and death records for the period 2010-2012 were used to identify the state- and cause-specific burden of infant mortality among full-term infants (born at 37-42 weeks of gestation). Multivariable logistic models were used to assess the extent to which state-level differences in full-term infant mortality (FTIM) were attributable to observed differences in maternal and birth characteristics. Random effects models were used to assess the relative contribution of state-level variation to FTIM. Hypothetical mortality outcomes were computed under the assumption that all states could achieve the survival rates of the best-performing states. A total of 10,175,481 infants born full-term in the US between January 1, 2010, and December 31, 2012, were analyzed. FTIM rate (FTIMR) was 2.2 per 1,000 live births overall, and ranged between 1.29 (Connecticut, 95% CI 1.08, 1.53) and 3.77 (Mississippi, 95% CI 3.39, 4.19) at the state level. Zero states reached the rates reported in the 6 low-mortality European countries analyzed (FTIMR < 1.25), and 13 states had FTIMR > 2.75. Sudden unexpected death in infancy (SUDI) accounted for 43% of FTIM; congenital malformations and perinatal conditions accounted for 31% and 11.3% of FTIM, respectively. The largest mortality differentials between states with good and states with poor FTIMR were found for SUDI, with particularly large risk differentials for deaths due to sudden infant death syndrome (SIDS) (odds ratio [OR] 2.52, 95% CI 1.86, 3.42) and suffocation (OR 4.40, 95% CI 3.71, 5.21). Even though these mortality differences were partially explained by state-level differences in maternal education, race, and maternal health, substantial state-level variation in infant mortality remained in fully adjusted models (SIDS OR 1.45, suffocation OR 2.92). The extent to which these state differentials are due to differential antenatal care standards as well as differential access to health services could not be determined due to data limitations. Overall, our estimates suggest that infant mortality could be reduced by 4,003 deaths (95% CI 2,284, 5,587) annually if all states were to achieve the mortality levels of the best-performing state in each cause-of-death category. Key limitations of the analysis are that information on termination rates at the state level was not available, and that causes of deaths may have been coded differentially across states.Conclusions: More than 7,000 full-term infants die in the US each year. The results presented in this paper suggest that a substantial share of these deaths may be preventable. Potential improvements seem particularly large for SUDI, where very low rates have been achieved in a few states while average mortality rates remain high in most other areas. Given the high mortality burden due to SIDS and suffocation, policy efforts to promote compliance with recommended sleeping arrangements could be an effective first step in this direction. [ABSTRACT FROM AUTHOR]

Background: Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IYCF) on early child development (ECD) among children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe.Methods and Findings: SHINE was a cluster-randomized community-based 2×2 factorial trial. A total of 5,280 pregnant women were enrolled from 211 clusters (defined as the catchment area of 1-4 village health workers [VHWs] employed by the Zimbabwean Ministry of Health and Child Care). Clusters were randomly allocated to standard of care, IYCF (20 g of small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counseling), WASH (ventilated improved pit latrine, handwashing stations, chlorine, liquid soap, and play yard), and WASH + IYCF. Primary outcomes were child length-for-age Z-score and hemoglobin concentration at 18 months of age. Children who completed the 18-month visit and turned 2 years (102-112 weeks) between March 1, 2016, and April 30, 2017, were eligible for the ECD substudy. We prespecified that primary inferences would be drawn from findings of children born to HIV-negative mothers; these results are presented in this paper. A total of 1,655 HIV-unexposed children (64% of those eligible) were recruited into the ECD substudy from 206 clusters and evaluated for ECD at 2 years of age using the Malawi Developmental Assessment Tool (MDAT) to assess gross motor, fine motor, language, and social skills; the MacArthur-Bates Communicative Development Inventories (CDI) to assess vocabulary and grammar; the A-not-B test to assess object permanence; and a self-control task. Outcomes were analyzed in the intention-to-treat population. For all ECD outcomes, there was not a statistical interaction between the IYCF and WASH interventions, so we estimated the effects of the interventions by comparing the 2 IYCF groups with the 2 non-IYCF groups and the 2 WASH groups with the 2 non-WASH groups. The mean (95% CI) total MDAT score was modestly higher in the IYCF groups compared to the non-IYCF groups in unadjusted analysis: 1.35 (0.24, 2.46; p = 0.017); this difference did not persist in adjusted analysis: 0.79 (-0.22, 1.68; p = 0.057). There was no evidence of impact of the IYCF intervention on the CDI, A-not-B, or self-control tests. Among children in the WASH groups compared to those in the non-WASH groups, mean scores were not different for the MDAT, A-not-B, or self-control tests; mean CDI score was not different in unadjusted analysis (0.99 [95% CI -1.18, 3.17]) but was higher in children in the WASH groups in adjusted analysis (1.81 [0.01, 3.61]). The main limitation of the study was the specific time window for substudy recruitment, meaning not all children from the main trial were enrolled.Conclusions: We found little evidence that the IYCF and WASH interventions implemented in SHINE caused clinically important improvements in child development at 2 years of age. Interventions that directly target neurodevelopment (e.g., early stimulation) or that more comprehensively address the multifactorial nature of neurodevelopment may be required to support healthy development of vulnerable children.Trial Registration: ClinicalTrials.gov NCT01824940. [ABSTRACT FROM AUTHOR]

Background: The development of cognitive and socioemotional skills early in life influences later health and well-being. Existing estimates of unmet developmental potential in low- and middle-income countries (LMICs) are based on either measures of physical growth or proxy measures such as poverty. In this paper we aim to directly estimate the number of children in LMICs who would be reported by their caregivers to show low cognitive and/or socioemotional development.Methods and Findings: The present paper uses Early Childhood Development Index (ECDI) data collected between 2005 and 2015 from 99,222 3- and 4-y-old children living in 35 LMICs as part of the Multiple Indicator Cluster Survey (MICS) and Demographic and Health Surveys (DHS) programs. First, we estimate the prevalence of low cognitive and/or socioemotional ECDI scores within our MICS/DHS sample. Next, we test a series of ordinary least squares regression models predicting low ECDI scores across our MICS/DHS sample countries based on country-level data from the Human Development Index (HDI) and the Nutrition Impact Model Study. We use cross-validation to select the model with the best predictive validity. We then apply this model to all LMICs to generate country-level estimates of the prevalence of low ECDI scores globally, as well as confidence intervals around these estimates. In the pooled MICS and DHS sample, 14.6% of children had low ECDI scores in the cognitive domain, 26.2% had low socioemotional scores, and 36.8% performed poorly in either or both domains. Country-level prevalence of low cognitive and/or socioemotional scores on the ECDI was best represented by a model using the HDI as a predictor. Applying this model to all LMICs, we estimate that 80.8 million children ages 3 and 4 y (95% CI 48.1 million, 113.6 million) in LMICs experienced low cognitive and/or socioemotional development in 2010, with the largest number of affected children in sub-Saharan Africa (29.4.1 million; 43.8% of children ages 3 and 4 y), followed by South Asia (27.7 million; 37.7%) and the East Asia and Pacific region (15.1 million; 25.9%). Positive associations were found between low development scores and stunting, poverty, male sex, rural residence, and lack of cognitive stimulation. Additional research using more detailed developmental assessments across a larger number of LMICs is needed to address the limitations of the present study.Conclusions: The number of children globally failing to reach their developmental potential remains large. Additional research is needed to identify the specific causes of poor developmental outcomes in diverse settings, as well as potential context-specific interventions that might promote children's early cognitive and socioemotional well-being. [ABSTRACT FROM AUTHOR]

Bryce and colleagues, reflect on lessons that can be learned from the Real-Time Monitoring of Under-Five Mortality Collection. [ABSTRACT FROM AUTHOR]

Background: Preterm infants are a group at high risk of having experienced placental insufficiency. It is unclear which growth charts perform best in identifying infants at increased risk of stillbirth and other adverse perinatal outcomes. We compared 2 birthweight charts (population centiles and INTERGROWTH-21st birthweight centiles) and 3 fetal growth charts (INTERGROWTH-21st fetal growth charts, World Health Organization fetal growth charts, and Gestation Related Optimal Weight [GROW] customised growth charts) to identify which chart performed best in identifying infants at increased risk of adverse perinatal outcome in a preterm population.Methods and Findings: We conducted a retrospective cohort study of all preterm infants born at 24.0 to 36.9 weeks gestation in Victoria, Australia, from 2005 to 2015 (28,968 records available for analysis). All above growth charts were applied to the population. Proportions classified as <5th centile and <10th centile by each chart were compared, as were proportions of stillborn infants considered small for gestational age (SGA, <10th centile) by each chart. We then compared the relative performance of non-overlapping SGA cohorts by each chart to our low-risk reference population (infants born appropriate size for gestational age [>10th and <90th centile] by all intrauterine charts [AGAall]) for the following perinatal outcomes: stillbirth, perinatal mortality (stillbirth or neonatal death), Apgar <4 or <7 at 5 minutes, neonatal intensive care unit admissions, suspicion of poor fetal growth leading to expedited delivery, and cesarean section. All intrauterine charts classified a greater proportion of infants as <5th or <10th centile than birthweight charts. The magnitude of the difference between birthweight and fetal charts was greater at more preterm gestations. Of the fetal charts, GROW customised charts classified the greatest number of infants as SGA (22.3%) and the greatest number of stillborn infants as SGA (57%). INTERGROWTH classified almost no additional infants as SGA that were not already considered SGA on GROW or WHO charts; however, those infants classified as SGA by INTERGROWTH had the greatest risk of both stillbirth and total perinatal mortality. GROW customised charts classified a larger proportion of infants as SGA, and these infants were still at increased risk of mortality and adverse perinatal outcomes compared to the AGAall population. Consistent with similar studies in this field, our study was limited in comparing growth charts by the degree of overlap, with many infants classified as SGA by multiple charts. We attempted to overcome this by examining and comparing sub-populations classified as SGA by only 1 growth chart.Conclusions: In this study, fetal charts classified greater proportions of preterm and stillborn infants as SGA, which more accurately reflected true fetal growth restriction. Of the intrauterine charts, INTERGROWTH classified the smallest number of preterm infants as SGA, although it identified a particularly high-risk cohort, and GROW customised charts classified the greatest number at increased risk of perinatal mortality. [ABSTRACT FROM AUTHOR]

Background: Approximately 250 million (43%) children under the age of 5 years in low- and middle-income countries (LMICs) are failing to meet their developmental potential. Risk factors are recognised to contribute to this loss of human potential. Expanding understanding of the risks that lead to poor outcomes and which protective factors contribute to resilience in children may be critical to improving disparities.Methods and Findings: The Drakenstein Child Health Study is a population-based birth cohort in the Western Cape, South Africa. Pregnant women were enrolled between 20 and 28 weeks' gestation from two community clinics from 2012 to 2015; sociodemographic and psychosocial data were collected antenatally. Mothers and children were followed through birth until 2 years of age. Developmental assessments were conducted by trained assessors blinded to background, using the Bayley-III Scales of Infant and Toddler Development (BSID-III), validated for use in South Africa, at 24 months of age. The study assessed all available children at 24 months; however, some children were not able to attend, because of loss to follow-up or unavailability of a caregiver or child at the correct age. Of 1,143 live births, 1,002 were in follow-up at 24 months, and a total of 734 children (73%) had developmental assessments, of which 354 (48.2%) were girls. This sample was characterised by low household employment (n = 183; 24.9%) and household income (n = 287; 39.1% earning 1 domain affected, and 75 (10.2%) had delay in all domains. Bivariate and multivariable analyses revealed several factors that were associated with developmental outcomes. These included protective factors (maternal education, higher birth weight, and socioeconomic status) and risk factors (maternal anaemia in pregnancy, depression or lifetime intimate partner violence, and maternal HIV infection). Boys consistently performed worse than girls (in cognition [β = -0.74; 95% CI -1.46 to -0.03, p = 0.042], receptive language [β = -1.10; 95% CI -1.70 to -0.49, p < 0.001], expressive language [β = -1.65; 95% CI -2.46 to -0.84, p < 0.001], and fine motor [β = -0.70; 95% CI -1.20 to -0.20, p = 0.006] scales). There was evidence that child sex interacted with risk and protective factors including birth weight, maternal anaemia in pregnancy, and socioeconomic factors. Important limitations of the study include attrition of sample from birth to assessment age and missing data in some exposure areas from those assessed.Conclusions: This study provides reliable developmental data from a sub-Saharan African setting in a well-characterised sample of mother-child dyads. Our findings highlight not only the important protective effects of maternal education, birth weight, and socioeconomic status for developmental outcomes but also sex differences in developmental outcomes and key risk and protective factors for each group. [ABSTRACT FROM AUTHOR]

Background: In Bangladesh, neonatal sepsis is the cause of 24% of neonatal deaths, over 65% of which occur in the early-newborn stage (0-6 days). Only 50% of newborns in Bangladesh initiated breastfeeding within 1 hour of birth. The mechanism by which early initiation of breastfeeding reduces neonatal deaths is unclear, although the most likely pathway is by decreasing severe illnesses leading to sepsis. This study explores the effect of breastfeeding initiation time on early newborn danger signs and severe illness.Methods and Findings: We used data from a community-based trial in Bangladesh in which we enrolled pregnant women from 2013 through 2015 covering 30,646 newborns. Severe illness was defined using newborn danger signs reported by The Young Infants Clinical Science Study Group. We categorized the timing of initiation as within 1 hour, 1 to 24 hours, 24 to 48 hours, ≥48 hours of birth, and never breastfed. The analysis includes descriptive statistics, risk attribution, and multivariable mixed-effects logistic regression while adjusting for the clustering effects of the trial design, and maternal/infant characteristics. In total, 29,873 live births had information on breastfeeding among whom 19,914 (66.7%) initiated within 1 hour of birth, and 4,437 (14.8%) neonates had a severe illness by the seventh day after birth. The mean time to initiation was 3.8 hours (SD 16.6 hours). The proportion of children with severe illness increased as the delay in initiation increased from 1 hour (12.0%), 24 hours (15.7%), 48 hours (27.7%), and more than 48 hours (36.7%) after birth. These observations would correspond to a possible reduction by 15.9% (95% CI 13.2-25.9, p < 0.001) of severe illness in a real world population in which all newborns had breastfeeding initiated within 1 hour of birth. Children who initiated after 48 hours (odds ratio [OR] 4.13, 95% CI 3.48-4.89, p < 0.001) and children who never initiated (OR 4.77, 95% CI 3.52-6.47, p < 0.001) had the highest odds of having severe illness. The main limitation of this study is the potential for misclassification because of using mothers' report of newborn danger signs. There could be a potential for recall bias for mothers of newborns who died after being born alive.Conclusions: Breastfeeding initiation within the first hour of birth is significantly associated with severe illness in the early newborn period. Interventions to promote early breastfeeding initiation should be tailored for populations in which newborns are delivered at home by unskilled attendants, the rate of low birth weight (LBW) is high, and postnatal care is limited.Trial Registration: Trial Registration number: anzctr.org.au ID ACTRN12612000588897. [ABSTRACT FROM AUTHOR]

Background: Community management of acute malnutrition (CMAM) is a highly efficacious approach for treating acute malnutrition (AM) in children who would otherwise be at significantly increased risk of mortality. In program settings, however, CMAM's effectiveness is limited because of low screening coverage of AM, in part because of the lack of perceived benefits for caregivers. In Burkina Faso, monthly screening for AM of children <2 years of age is conducted during well-baby consultations (consultation du nourrisson sain [CNS]) at health centers. We hypothesized that the integration of a preventive package including age-appropriate behavior change communication (BCC) on nutrition, health, and hygiene practices and a monthly supply of small-quantity lipid-based nutrient supplements (SQ-LNSs) to the monthly screening would increase AM screening and treatment coverage and decrease the incidence and prevalence of AM.Methods and Findings: We used a cluster-randomized controlled trial and allocated 16 health centers to the intervention group and 16 to a comparison group. Both groups had access to standard CMAM and CNS services; caregivers in the intervention group also received age-appropriate monthly BCC and SQ-LNS for children >6 months of age. We used two study designs: (1) a repeated cross-sectional study of children 0-17 months old (n = 2,318 and 2,317 at baseline and endline 2 years later) to assess impacts on AM screening coverage, treatment coverage, and prevalence; (2) a longitudinal study of 2,113 children enrolled soon after birth and followed up monthly for 18 months to assess impacts on AM screening coverage, treatment coverage, and incidence. Data were analyzed as intent to treat. Level of significance for primary outcomes was α = 0.016 after adjustment for multiple testing. Children's average age was 8.8 ± 4.9 months in the intervention group and 8.9 ± 5.0 months in the comparison group at baseline and, respectively, 0.66 ± 0.32 and 0.67 ± 0.33 months at enrollment in the longitudinal study. Relative to the comparison group, the intervention group had significantly higher monthly AM screening coverage (cross-sectional study: +18 percentage points [pp], 95% CI 10-26, P < 0.001; longitudinal study: +23 pp, 95% CI 17-29, P < 0.001). There were no impacts on either AM treatment coverage (cross-sectional study: +8.0 pp, 95% CI 0.09-16, P = 0.047; longitudinal study: +7.7 pp, 95% CI -1.2 to 17, P = 0.090), AM incidence (longitudinal study: incidence rate ratio = 0.98, 95% CI 0.75-1.3, P = 0.88), or AM prevalence (cross-sectional study: -0.46 pp, 95% CI -4.4 to 3.5, P = 0.82). A study limitation is the referral of AM cases (for ethical reasons) by study enumerators as part of the monthly measurement in the longitudinal study that may have attenuated the detectable impact on AM treatment coverage.Conclusions: Adding a preventive package to CMAM delivered at health facilities in Burkina Faso increased participation in monthly AM screening, thus overcoming a major impediment to CMAM effectiveness. The lack of impact on AM treatment coverage and on AM prevalence and incidence calls for research to address the remaining barriers to uptake of preventive and treatment services at the health center and to identify and test complementary approaches to bring integrated preventive and CMAM services closer to the community while ensuring high-quality implementation and service delivery.Trial Registration: ClinicalTrials.gov NCT02245152. [ABSTRACT FROM AUTHOR]

Amita Gupta and colleagues discuss priorities in clinical research aimed at improving tuberculosis prevention and treatment in pregnant women, children, and people with HIV. [ABSTRACT FROM AUTHOR]

Background: Metformin is increasingly offered as an acceptable and economic alternative to insulin for treatment of gestational diabetes mellitus (GDM) in many countries. However, the impact of maternal metformin treatment on the trajectory of fetal, infant, and childhood growth is unknown.Methods and Findings: PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov, and the Cochrane database were systematically searched (from database inception to 26 February 2019). Outcomes of GDM-affected pregnancies randomised to treatment with metformin versus insulin were included (randomised controlled trials and prospective randomised controlled studies) from cohorts including European, American, Asian, Australian, and African women. Studies including pregnant women with pre-existing diabetes or non-diabetic women were excluded, as were trials comparing metformin treatment with oral glucose-lowering agents other than insulin. Two reviewers independently assessed articles for eligibility and risk of bias, and conflicts were resolved by a third reviewer. Outcome measures were parameters of fetal, infant, and childhood growth, including weight, height, BMI, and body composition. In total, 28 studies (n = 3,976 participants) met eligibility criteria and were included in the meta-analysis. No studies reported fetal growth parameters; 19 studies (n = 3,723 neonates) reported measures of neonatal growth. Neonates born to metformin-treated mothers had lower birth weights (mean difference -107.7 g, 95% CI -182.3 to -32.7, I2 = 83%, p = 0.005) and lower ponderal indices (mean difference -0.13 kg/m3, 95% CI -0.26 to 0.00, I2 = 0%, p = 0.04) than neonates of insulin-treated mothers. The odds of macrosomia (odds ratio [OR] 0.59, 95% CI 0.46 to 0.77, p < 0.001) and large for gestational age (OR 0.78, 95% CI 0.62 to 0.99, p = 0.04) were lower following maternal treatment with metformin compared to insulin. There was no difference in neonatal height or incidence of small for gestational age between groups. Two studies (n = 411 infants) reported measures of infant growth (18-24 months of age). In contrast to the neonatal phase, metformin-exposed infants were significantly heavier than those in the insulin-exposed group (mean difference 440 g, 95% CI 50 to 830, I2 = 4%, p = 0.03). Three studies (n = 520 children) reported mid-childhood growth parameters (5-9 years). In mid-childhood, BMI was significantly higher (mean difference 0.78 kg/m2, 95% CI 0.23 to 1.33, I2 = 7%, p = 0.005) following metformin exposure than following insulin exposure, although the difference in absolute weights between the groups was not significantly different (p = 0.09). Limited evidence (1 study with data treated as 2 cohorts) suggested that adiposity indices (abdominal [p = 0.02] and visceral [p = 0.03] fat volumes) may be higher in children born to metformin-treated compared to insulin-treated mothers. Study limitations include heterogeneity in metformin dosing, heterogeneity in diagnostic criteria for GDM, and the scarcity of reporting of childhood outcomes.Conclusions: Following intrauterine exposure to metformin for treatment of maternal GDM, neonates are significantly smaller than neonates whose mothers were treated with insulin during pregnancy. Despite lower average birth weight, metformin-exposed children appear to experience accelerated postnatal growth, resulting in heavier infants and higher BMI by mid-childhood compared to children whose mothers were treated with insulin. Such patterns of low birth weight and postnatal catch-up growth have been reported to be associated with adverse long-term cardio-metabolic outcomes. This suggests a need for further studies examining longitudinal perinatal and childhood outcomes following intrauterine metformin exposure. This review protocol was registered with PROSPERO under registration number CRD42018117503. [ABSTRACT FROM AUTHOR]

Gavin Yamey and co-authors discuss approaches to providing support for middle-income countries transitioning away from health aid. [ABSTRACT FROM AUTHOR]

Background: College affirmative action programs seek to expand socioeconomic opportunities for underrepresented minorities. Between 1996 and 2013, 9 US states-including California, Texas, and Michigan-banned race-based affirmative action in college admissions. Because economic opportunity is known to motivate health behavior, banning affirmative action policies may have important adverse spillover effects on health risk behaviors. We used a quasi-experimental research design to evaluate the association between college affirmative action bans and health risk behaviors among underrepresented minority (Black, Hispanic, and Native American) adolescents.Methods and Findings: We conducted a difference-in-differences analysis using data from the 1991-2015 US national Youth Risk Behavior Survey (YRBS). We compared changes in self-reported cigarette smoking and alcohol use in the 30 days prior to survey among underrepresented minority 11th and 12th graders in states implementing college affirmative action bans (Arizona, California, Florida, Michigan, Nebraska, New Hampshire, Oklahoma, Texas, and Washington) versus outcomes among those residing in states not implementing bans (n = 35 control states). We also assessed whether underrepresented minority adults surveyed in the 1992-2015 Tobacco Use Supplement to the Current Population Survey (TUS-CPS) who were exposed to affirmative action bans during their late high school years continued to smoke cigarettes between the ages of 19 and 30 years. Models adjusted for individual demographic characteristics, state and year fixed effects, and state-specific secular trends. In the YRBS (n = 34,988 to 36,268, depending on the outcome), cigarette smoking in the past 30 days among underrepresented minority 11th-12th graders increased by 3.8 percentage points after exposure to an affirmative action ban (95% CI: 2.0, 5.7; p < 0.001). In addition, there were also apparent increases in past-30-day alcohol use, by 5.9 percentage points (95% CI: 0.3, 12.2; p = 0.041), and past-30-day binge drinking, by 3.5 percentage points (95% CI: -0.1, 7.2, p = 0.058), among underrepresented minority 11th-12th graders, though in both cases adjustment for multiple comparisons resulted in failure to reject the null hypothesis (adjusted p = 0.083 for both outcomes). Underrepresented minority adults in the TUS-CPS (n = 71,575) exposed to bans during their late high school years were also 1.8 percentage points more likely to report current smoking (95% CI: 0.1, 3.6; p = 0.037). Event study analyses revealed a discrete break for all health behaviors timed with policy discussion and implementation. No substantive or statistically significant effects were found for non-Hispanic White adolescents, and the findings were robust to a number of additional specification checks. The limitations of the study include the continued potential for residual confounding from unmeasured time-varying factors and the potential for recall bias due to the self-reported nature of the health risk behavior outcomes.Conclusions: In this study, we found evidence that some health risk behaviors increased among underrepresented minority adolescents after exposure to state-level college affirmative action bans. These findings suggest that social policies that shift socioeconomic opportunities could have meaningful population health consequences. [ABSTRACT FROM AUTHOR]

Background: Despite the sharp decline in global under-5 deaths since 1990, uneven progress has been achieved across and within countries. In sub-Saharan Africa (SSA), the Millennium Development Goals (MDGs) for child mortality were met only by a few countries. Valid concerns exist as to whether the region would meet new Sustainable Development Goals (SDGs) for under-5 mortality. We therefore examine further sources of variation by assessing age patterns, trends, and forecasts of mortality rates.Methods and Findings: Data came from 106 nationally representative Demographic and Health Surveys (DHSs) with full birth histories from 31 SSA countries from 1990 to 2017 (a total of 524 country-years of data). We assessed the distribution of age at death through the following new demographic analyses. First, we used a direct method and full birth histories to estimate under-5 mortality rates (U5MRs) on a monthly basis. Second, we smoothed raw estimates of death rates by age and time by using a two-dimensional P-Spline approach. Third, a variant of the Lee-Carter (LC) model, designed for populations with limited data, was used to fit and forecast age profiles of mortality. We used mortality estimates from the United Nations Inter-agency Group for Child Mortality Estimation (UN IGME) to adjust, validate, and minimize the risk of bias in survival, truncation, and recall in mortality estimation. Our mortality model revealed substantive declines of death rates at every age in most countries but with notable differences in the age patterns over time. U5MRs declined from 3.3% (annual rate of reduction [ARR] 0.1%) in Lesotho to 76.4% (ARR 5.2%) in Malawi, and the pace of decline was faster on average (ARR 3.2%) than that observed for infant (IMRs) (ARR 2.7%) and neonatal (NMRs) (ARR 2.0%) mortality rates. We predict that 5 countries (Kenya, Rwanda, Senegal, Tanzania, and Uganda) are on track to achieve the under-5 sustainable development target by 2030 (25 deaths per 1,000 live births), but only Rwanda and Tanzania would meet both the neonatal (12 deaths per 1,000 live births) and under-5 targets simultaneously. Our predicted NMRs and U5MRs were in line with those estimated by the UN IGME by 2030 and 2050 (they overlapped in 27/31 countries for NMRs and 22 for U5MRs) and by the Institute for Health Metrics and Evaluation (IHME) by 2030 (26/31 and 23/31, respectively). This study has a number of limitations, including poor data quality issues that reflected bias in the report of births and deaths, preventing reliable estimates and predictions from a few countries.Conclusions: To our knowledge, this study is the first to combine full birth histories and mortality estimates from external reliable sources to model age patterns of under-5 mortality across time in SSA. We demonstrate that countries with a rapid pace of mortality reduction (ARR ≥ 3.2%) across ages would be more likely to achieve the SDG mortality targets. However, the lower pace of neonatal mortality reduction would prevent most countries from achieving those targets: 2 countries would reach them by 2030, 13 between 2030 and 2050, and 13 after 2050. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that airway obstruction and increased bronchial reactivity are present in early life in children developing asthma, which challenges the dogma that airway inflammation leads to low lung function. Further studies are needed to explore whether low lung function and bronchial hyperreactivity are inherent traits increasing the risk of developing airway inflammation and asthmatic symptoms in order to establish timely primary preventive initiatives.Methods and Findings: We investigated 367 (89%) of the 411 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort born to mothers with asthma, who were assessed by spirometry and bronchial reactivity to methacholine from age 1 month, plethysmography and bronchial reversibility from age 3 years, cold dry air hyperventilation from age 4 years, and exercise challenge at age 7 years. The COPSAC pediatricians diagnosed and treated asthma based on symptom load, response to inhaled corticosteroid, and relapse after treatment withdrawal according to a standardized algorithm. Repeated measures mixed models were applied to analyze lung function trajectories in children with asthma ever or never at age 1 month to 13 years. The number of children ever versus never developing asthma in their first 13 years of life was 97 (27%) versus 270 (73%), respectively. Median age at diagnosis was 2.0 years (IQR 1.2-5.7), and median remission age was 6.2 years (IQR 4.2-7.8). Children with versus without asthma had reduced lung function (z-score difference, forced expiratory volume, -0.31 [95% CI -0.47; -0.15], p < 0.001), increased airway resistance (z-score difference, specific airway resistance, +0.40 [95% CI +0.24; +0.56], p < 0.001), increased bronchial reversibility (difference in change in forced expiratory volume in the first second [ΔFEV1], +3% [95% CI +2%; +4%], p < 0.001), increased reactivity to methacholine (z-score difference for provocative dose, -0.40 [95% CI -0.58; -0.22], p < 0.001), decreased forced expiratory volume at cold dry air challenge (ΔFEV1, -4% [95% CI -7%; -1%], p < 0.01), and decreased forced expiratory volume after exercise (ΔFEV1, -4% [95% CI -7%; -1%], p = 0.02). Both airway obstruction and bronchial hyperreactivity were present before symptom debut, independent of disease duration, and did not improve with symptom remission. The generalizability of these findings may be limited by the high-risk nature of the cohort (all mothers had a diagnosis of asthma), the modest study size, and limited ethnic variation.Conclusions: Children with asthma at some point at age 1 month to 13 years had airway obstruction and bronchial hyperreactivity before symptom debut, which did not worsen with increased asthma symptom duration or attenuate with remission. This suggests that airway obstruction and bronchial hyperreactivity are stable traits of childhood asthma since neonatal life, implying that symptomatic disease may in part be a consequence of these traits but not their cause. [ABSTRACT FROM AUTHOR]

Background: The addition of neonatal (NN) mortality targets in the Sustainable Development Goals highlights the increased need for age-specific quantification of mortality trends, detail that is not provided by summary birth histories (SBHs). Several methods exist to indirectly estimate trends in under-5 mortality from SBHs; however, efforts to monitor mortality trends in important age groups such as the first month and first year of life have yet to utilize the vast amount of SBH data available from household surveys and censuses.Methods and Findings: We analyzed 243 Demographic and Health Surveys (DHS) from 76 countries, which collected both complete and SBHs from 8.5 million children from 2.3 million mothers to develop a new empirically based method to indirectly estimate time trends in age-specific mortality. We used complete birth history (CBH) data to train a discrete hazards generalized additive model in order to predict individual hazard functions for children based on individual-, mother-, and country-year-level covariates. Individual-level predictions were aggregated over time by assigning probability weights to potential birth years from mothers from SBH data. Age-specific estimates were evaluated in three ways: using cross-validation, using an external database of an additional 243 non-DHS census and survey data sources, and comparing overall under-5 mortality to existing indirect methods. Our model was able to closely approximate trends in age-specific child mortality. Depending on age, the model was able to explain between 80% and 95% of the variation in the validation data. Bias was close to zero in every age, with median relative errors spanning from 0.96 to 1.09. For trends in all under-5s, performance was comparable to the methods used for the Global Burden of Disease (GBD) study and significantly better than the standard indirect (Brass) method, especially in the 5 years preceding a survey. For the 15 years preceding surveys, the new method and GBD methods could explain more than 95% of the variation in the validation data for under-5s, whereas the standard indirect variants tested could only explain up to 88%. External validation using census and survey data found close agreement with concurrent direct estimates of mortality in the NN and infant age groups. As a predictive method based on empirical data, one limitation is that potential issues in these training data could be reflected in the resulting application of the method out of sample.Conclusions: This new method for estimating child mortality produces results that are comparable to current best methods for indirect estimation of under-5 mortality while additionally producing age-specific estimates. Use of such methods allows researchers to utilize a massive amount of SBH data for estimation of trends in NN and infant mortality. Systematic application of these methods could further improve the evidence base for monitoring of trends and inequalities in age-specific child mortality. [ABSTRACT FROM AUTHOR]

Background: Somalia has been affected by conflict since 1991, with children aged <5 years presenting a high acute malnutrition prevalence. Cash-based interventions (CBIs) have been used in this context since 2011, despite sparse evidence of their nutritional impact. We aimed to understand whether a CBI would reduce acute malnutrition and its risk factors.Methods and Findings: We implemented a non-randomised cluster trial in internally displaced person (IDP) camps, located in peri-urban Mogadishu, Somalia. Within 10 IDP camps (henceforth clusters) selected using a humanitarian vulnerability assessment, all households were targeted for the CBI. Ten additional clusters located adjacent to the intervention clusters were selected as controls. The CBI comprised a monthly unconditional cash transfer of US$84.00 for 5 months, a once-only distribution of a non-food-items kit, and the provision of piped water free of charge. The cash transfers started in May 2016. Cash recipients were female household representatives. In March and September 2016, from a cohort of randomly selected households in the intervention (n = 111) and control (n = 117) arms (household cohort), we collected household and individual level data from children aged 6-59 months (155 in the intervention and 177 in the control arms) and their mothers/primary carers, to measure known malnutrition risk factors. In addition, between June and November 2016, data to assess acute malnutrition incidence were collected monthly from a cohort of children aged 6-59 months, exhaustively sampled from the intervention (n = 759) and control (n = 1,379) arms (child cohort). Primary outcomes were the mean Child Dietary Diversity Score in the household cohort and the incidence of first episode of acute malnutrition in the child cohort, defined by a mid-upper arm circumference < 12.5 cm and/or oedema. Analyses were by intention-to-treat. For the household cohort we assessed differences-in-differences, for the child cohort we used Cox proportional hazards ratios. In the household cohort, the CBI appeared to increase the Child Dietary Diversity Score by 0.53 (95% CI 0.01; 1.05). In the child cohort, the acute malnutrition incidence rate (cases/100 child-months) was 0.77 (95% CI 0.70; 1.21) and 0.92 (95% CI 0.53; 1.14) in intervention and control arms, respectively. The CBI did not appear to reduce the risk of acute malnutrition: unadjusted hazard ratio 0.83 (95% CI 0.48; 1.42) and hazard ratio adjusted for age and sex 0.94 (95% CI 0.51; 1.74). The CBI appeared to increase the monthly household expenditure by US$29.60 (95% CI 3.51; 55.68), increase the household Food Consumption Score by 14.8 (95% CI 4.83; 24.8), and decrease the Reduced Coping Strategies Index by 11.6 (95% CI 17.5; 5.96). The study limitations were as follows: the study was not randomised, insecurity in the field limited the household cohort sample size and collection of other anthropometric measurements in the child cohort, the humanitarian vulnerability assessment data used to allocate the intervention were not available for analysis, food market data were not available to aid results interpretation, and the malnutrition incidence observed was lower than expected.Conclusions: The CBI appeared to improve beneficiaries' wealth and food security but did not appear to reduce acute malnutrition risk in IDP camp children. Further studies are needed to assess whether changing this intervention, e.g., including specific nutritious foods or social and behaviour change communication, would improve its nutritional impact.Trial Registration: ISRCTN Registy ISRCTN29521514. [ABSTRACT FROM AUTHOR]

Background: Early childhood interventions have potential to offset the negative impact of early adversity. We evaluated the impact of a community-based parenting group intervention on child development in Zambia.Methods and Findings: We conducted a non-masked cluster-randomized controlled trial in Southern Province, Zambia. Thirty clusters of villages were matched based on population density and distance from the nearest health center, and randomly assigned to intervention (15 clusters, 268 caregiver-child dyads) or control (15 clusters, 258 caregiver-child dyads). Caregivers were eligible if they had a child 6 to 12 months old at baseline. In intervention clusters, caregivers were visited twice per month during the first year of the study by child development agents (CDAs) and were invited to attend fortnightly parenting group meetings. Parenting groups selected "head mothers" from their communities who were trained by CDAs to facilitate meetings and deliver a diverse parenting curriculum. The parenting group intervention, originally designed to run for 1 year, was extended, and households were visited for a follow-up assessment at the end of year 2. The control group did not receive any intervention. Intention-to-treat analysis was performed for primary outcomes measured at the year 2 follow-up: stunting and 5 domains of neurocognitive development measured using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). In order to show Cohen's d estimates, BSID-III composite scores were converted to z-scores by standardizing within the study population. In all, 195/268 children (73%) in the intervention group and 182/258 children (71%) in the control group were assessed at endline after 2 years. The intervention significantly reduced stunting (56/195 versus 72/182; adjusted odds ratio 0.45, 95% CI 0.22 to 0.92; p = 0.028) and had a significant positive impact on language (β 0.14, 95% CI 0.01 to 0.27; p = 0.039). The intervention did not significantly impact cognition (β 0.11, 95% CI -0.06 to 0.29; p = 0.196), motor skills (β -0.01, 95% CI -0.25 to 0.24; p = 0.964), adaptive behavior (β 0.21, 95% CI -0.03 to 0.44; p = 0.088), or social-emotional development (β 0.20, 95% CI -0.04 to 0.44; p = 0.098). Observed impacts may have been due in part to home visits by CDAs during the first year of the intervention.Conclusions: The results of this trial suggest that parenting groups hold promise for improving child development, particularly physical growth, in low-resource settings like Zambia.Trial Registration: ClinicalTrials.gov NCT02234726. [ABSTRACT FROM AUTHOR]

Background: In recent decades, there has been a shift to later childbearing in high-income countries. There is limited large-scale evidence of the relationship between maternal age and child outcomes beyond the perinatal period. The objective of this study is to quantify a child's risk of developmental vulnerability at age five, according to their mother's age at childbirth.Methods and Findings: Linkage of population-level perinatal, hospital, and birth registration datasets to data from the Australian Early Development Census (AEDC) and school enrolments in Australia's most populous state, New South Wales (NSW), enabled us to follow a cohort of 99,530 children from birth to their first year of school in 2009 or 2012. The study outcome was teacher-reported child development on five domains measured by the AEDC, including physical health and well-being, emotional maturity, social competence, language and cognitive skills, and communication skills and general knowledge. Developmental vulnerability was defined as domain scores below the 2009 AEDC 10th percentile cut point. The mean maternal age at childbirth was 29.6 years (standard deviation [SD], 5.7), with 4,382 children (4.4%) born to mothers aged <20 years and 20,026 children (20.1%) born to mothers aged ≥35 years. The proportion vulnerable on ≥1 domains was 21% overall and followed a reverse J-shaped distribution according to maternal age: it was highest in children born to mothers aged ≤15 years, at 40% (95% CI, 32-49), and was lowest in children born to mothers aged between 30 years and ≤35 years, at 17%-18%. For maternal ages 36 years to ≥45 years, the proportion vulnerable on ≥1 domains increased to 17%-24%. Adjustment for sociodemographic characteristics significantly attenuated vulnerability risk in children born to younger mothers, while adjustment for potentially modifiable factors, such as antenatal visits, had little additional impact across all ages. Although the multi-agency linkage yielded a broad range of sociodemographic, perinatal, health, and developmental variables at the child's birth and school entry, the study was necessarily limited to variables available in the source data, which were mostly recorded for administrative purposes.Conclusions: Increasing maternal age was associated with a lesser risk of developmental vulnerability for children born to mothers aged 15 years to about 30 years. In contrast, increasing maternal age beyond 35 years was generally associated with increasing vulnerability, broadly equivalent to the risk for children born to mothers in their early twenties, which is highly relevant in the international context of later childbearing. That socioeconomic disadvantage explained approximately half of the increased risk of developmental vulnerability associated with younger motherhood suggests there may be scope to improve population-level child development through policies and programs that support disadvantaged mothers and children. [ABSTRACT FROM AUTHOR]

Background: Poor early childhood development (ECD) in low- and middle-income countries is a major concern. There are calls to universalise access to ECD interventions through integrating them into existing government services but little evidence on the medium- or long-term effects of such scalable models. We previously showed that a psychosocial stimulation (PS) intervention integrated into a cash transfer programme improved Colombian children's cognition, receptive language, and home stimulation. In this follow-up study, we assessed the medium-term impacts of the intervention, 2 years after it ended, on children's cognition, language, school readiness, executive function, and behaviour.Methods and Findings: Study participants were 1,419 children aged 12-24 months at baseline from beneficiary households of the cash transfer programme, living in 96 Colombian towns. The original cluster randomised controlled trial (2009-2011) randomly allocated the towns to control (N = 24, n = 349), PS (N = 24, n = 357), multiple micronutrient (MN) supplementation (N = 24, n = 354), and combined PS and MN (N = 24, n = 359). Interventions lasted 18 months. In this study (26 September 2013 to 11 January 2014), we assessed impacts on cognition, language, school readiness, executive function, and behaviour 2 years after intervention, at ages 4.5-5.5 years. Testers, but not participants, were blinded to treatment allocation. Analysis was on an intent-to-treat basis. We reassessed 88.5% of the children in the original study (n = 1,256). Factor analysis of test scores yielded 2 factors: cognitive (cognition, language, school readiness, executive function) and behavioural. We found no effect of the interventions after 2 years on the cognitive factor (PS: -0.031 SD, 95% CI -0.229-0.167; MN: -0.042 SD, 95% CI -0.249-0.164; PS and MN: -0.111 SD, 95% CI -0.311-0.089), the behavioural factor (PS: 0.013 SD, 95% CI -0.172-0.198; MN: 0.071 SD, 95% CI -0.115-0.258; PS and MN: 0.062 SD, 95% CI -0.115-0.239), or home stimulation. Study limitations include that behavioural development was measured through maternal report and that very small effects may have been missed, despite the large sample size.Conclusions: We found no evidence that a scalable PS intervention benefited children's development 2 years after it ended. It is possible that the initial effects on child development were too small to be sustained or that the lack of continued impact on home stimulation contributed to fade out. Both are likely related to compromises in implementation when going to scale and suggest one should not extrapolate from medium-term effects of small efficacy trials to scalable interventions. Understanding the salient differences between small efficacy trials and scaled-up versions will be key to making ECD interventions effective tools for policymakers.Trial Registration: ISRCTN18991160. [ABSTRACT FROM AUTHOR]

Background: Evidence on the long-term effect of breastfeeding on neurocognitive development is based almost exclusively on observational studies. In the 16-year follow-up study of a large, cluster-randomized trial of a breastfeeding promotion intervention, we evaluated the long-term persistence of the neurocognitive benefits of the breastfeeding promotion intervention previously observed at early school age.Methods and Findings: A total of 13,557 participants (79.5% of the 17,046 randomized) of the Promotion of Breastfeeding Intervention Trial (PROBIT) were followed up at age 16 from September 2012 to July 2015. At the follow-up, neurocognitive function was assessed in 7 verbal and nonverbal cognitive domains using a computerized, self-administered test battery among 13,427 participants. Using an intention-to-treat (ITT) analysis as our prespecified primary analysis, we estimated cluster- and baseline characteristic-adjusted mean differences between the intervention (prolonged and exclusive breastfeeding promotion modelled on the Baby-Friendly Hospital Initiative) and control (usual care) groups in 7 cognitive domains and a global cognitive score. In our prespecified secondary analysis, we estimated mean differences by instrumental variable (IV) analysis to account for noncompliance with the randomly assigned intervention and estimate causal effects of breastfeeding. The 16-year follow-up rates were similar in the intervention (79.7%) and control groups (79.3%), and baseline characteristics were comparable between the two. In the cluster-adjusted ITT analyses, children in the intervention group did not show statistically significant differences in the scores from children in the control group. Prespecified additional adjustment for baseline characteristics improved statistical precision and resulted in slightly higher scores among children in the intervention for verbal function (1.4 [95% CI 0.3-2.5]) and memory (1.2 [95% CI 0.01-2.4]). IV analysis showed that children who were exclusively breastfed for ≥3 (versus <3) months had a 3.5-point (95% CI 0.9-6.1) higher verbal function, but no differences were observed in other domains. While our computerized, self-administered cognitive testing reduced the cluster-level variability in the scores, it may have increased individual-level measurement errors in adolescents.Conclusions: We observed no benefit of a breastfeeding promotion intervention on overall neurocognitive function. The only beneficial effect was on verbal function at age 16. The higher verbal ability is consistent with results observed at early school age; however, the effect size was substantially smaller in adolescence.Probit Trial Registration: ClinicalTrials.gov NCT01561612. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization's integrated community case management (iCCM) guidelines recommend that all children presenting with uncomplicated fever and no danger signs return for follow-up on day 3 following the initial consultation on day 1. Such fevers often resolve rapidly, however, and previous studies suggest that expectant home care for uncomplicated fever can be safely recommended. We aimed to determine if a conditional follow-up visit was non-inferior to a universal follow-up visit for these children.Methods and Findings: We conducted a cluster-randomized, community-based non-inferiority trial among children 2-59 months old presenting to community health workers (CHWs) with non-severe unclassified fever in Tanganyika Province, Democratic Republic of the Congo. Clusters (n = 28) of CHWs were randomized to advise caregivers to either (1) return for a follow-up visit on day 3 following the initial consultation on day 1, regardless of illness resolution (as per current WHO guidelines; universal follow-up group) or (2) return for a follow-up visit on day 3 only if illness continued (conditional follow-up group). Children in both arms were assessed again at day 8, and classified as a clinical failure if fever (caregiver-reported), malaria, diarrhea, pneumonia, or decline of health status (development of danger signs, hospitalization, or death) was noted (failure definition 1). Alternative failure definitions were examined, whereby caregiver-reported fever was first restricted to caregiver-reported fever of at least 3 days (failure definition 2) and then replaced with fever measured via axillary temperature (failure definition 3). Study participants, providers, and investigators were not masked. Among 4,434 enrolled children, 4,141 (93.4%) met the per-protocol definition of receipt of the arm-specific advice from the CHW and a timely day 8 assessment (universal follow-up group: 2,210; conditional follow-up group: 1,931). Failure was similar (difference: -0.7%) in the conditional follow-up group (n = 188, 9.7%) compared to the universal follow-up group (n = 230, 10.4%); however, the upper bound of a 1-sided 95% confidence interval around this difference (-∞, 5.1%) exceeded the prespecified non-inferiority margin of 4.0% (non-inferiority p = 0.089). When caregiver-reported fever was restricted to fevers lasting ≥3 days, failure in the conditional follow-up group (n = 159, 8.2%) was similar to that in the universal follow-up group (n = 200, 9.1%) (difference: -0.8%; 95% CI: -∞, 4.1%; p = 0.053). If caregiver-reported fever was replaced by axillary temperature measurement in the definition of failure, failure in the conditional follow-up group (n = 113, 5.9%) was non-inferior to that in the universal follow-up group (n = 160, 7.2%) (difference: -1.4%; 95% CI: -∞, 2.5%; p = 0.012). In post hoc analysis, when the definition of failure was limited to malaria, diarrhea, pneumonia, development of danger signs, hospitalization, or death, failure in the conditional follow-up group (n = 108, 5.6%) was similar to that in the universal follow-up group (n = 147, 6.7%), and within the non-inferiority margin (95% CI: -∞, 2.9%; p = 0.017). Limitations include initial underestimation of the proportion of clinical failures as well as substantial variance in cluster-specific failure rates, reducing the precision of our estimates. In addition, heightened security concerns slowed recruitment in the final months of the study.Conclusions: We found that advising caregivers to return only if children worsened or remained ill on day 3 resulted in similar rates of caregiver-reported fever and other clinical outcomes on day 8, compared to advising all caregivers to return on day 3. Policy-makers could consider revising guidelines for management of uncomplicated fever within the iCCM framework.Trial Registration: ClinicalTrials.gov NCT02595827. [ABSTRACT FROM AUTHOR]

In this essay, Julie Freccero and colleagues discuss resources to prevent the sexual exploitation of unaccompanied and separated refugee boys in Greece. [ABSTRACT FROM AUTHOR]

V. Jordan Greenbaum discusses ways healthcare providers can identify children trafficked for sex to provide for their physical and mental health and their social and educational needs. [ABSTRACT FROM AUTHOR]

Pamela Collins and colleagues explain the research and policy approaches needed globally to ensure children with developmental delays and disabilities are fully included in health and education services. [ABSTRACT FROM AUTHOR]

Background: Children living with HIV who are not diagnosed in infancy often remain undiagnosed until they present with advanced disease. Provider-initiated testing and counselling (PITC) in health facilities is recommended for high-HIV-prevalence settings, but it is unclear whether this approach is sufficient to achieve universal coverage of HIV testing. We aimed to investigate the change in community burden of undiagnosed HIV infection among older children and adolescents following implementation of PITC in Harare, Zimbabwe.Methods and Findings: Over the course of 2 years (January 2013-January 2015), 7 primary health clinics (PHCs) in southwestern Harare implemented optimised, opt-out PITC for all attendees aged 6-15 years. In February 2015-December 2015, we conducted a representative cross-sectional survey of 8-17-year-olds living in the 7 communities served by the study PHCs, who would have had 2 years of exposure to PITC. Knowledge of HIV status was ascertained through a caregiver questionnaire, and anonymised HIV testing was carried out using oral mucosal transudate (OMT) tests. After 1 participant taking antiretroviral therapy was observed to have a false negative OMT result, from July 2015 urine samples were obtained from all participants providing OMTs and tested for antiretroviral drugs to confirm HIV status. Children who tested positive through PITC were identified from among survey participants using gender, birthdate, and location. Of 7,146 children in 4,251 eligible households, 5,486 (76.8%) children in 3,397 households agreed to participate in the survey, and 141 were HIV positive. HIV prevalence was 2.6% (95% CI 2.2%-3.1%), and over a third of participants with HIV were undiagnosed (37.7%; 95% CI 29.8%-46.2%). Similarly, among the subsample of 2,643 (48.2%) participants with a urine test result, 34.7% of those living with HIV were undiagnosed (95% CI 23.5%-47.9%). Based on extrapolation from the survey sample to the community, we estimated that PITC over 2 years identified between 18% and 42% of previously undiagnosed children in the community. The main limitation is that prevalence of undiagnosed HIV was defined using a combination of 3 measures (OMT, self-report, and urine test), none of which were perfect.Conclusions: Facility-based approaches are inadequate in achieving universal coverage of HIV testing among older children and adolescents. Alternative, community-based approaches are required to meet the Joint United Nations Programme on HIV/AIDS (UNAIDS) target of diagnosing 90% of those living with HIV by 2020 in this age group. [ABSTRACT FROM AUTHOR]

Community efforts and peer support programs are needed in addition to provider-initiated and opt-out HIV testing in adolescents, Sheri Weiser and colleagues discuss. [ABSTRACT FROM AUTHOR]

Background: Cash-based interventions (CBIs), offer an interesting opportunity to prevent increases in wasting in humanitarian aid settings. However, questions remain as to the impact of CBIs on nutritional status and, therefore, how to incorporate them into emergency programmes to maximise their success in terms of improved nutritional outcomes. This study evaluated the effects of three different CBI modalities on nutritional outcomes in children under 5 y of age at 6 mo and at 1 y.Methods and Findings: We conducted a four-arm parallel longitudinal cluster randomised controlled trial in 114 villages in Dadu District, Pakistan. The study included poor and very poor households (n = 2,496) with one or more children aged 6-48 mo (n = 3,584) at baseline. All four arms had equal access to an Action Against Hunger-supported programme. The three intervention arms were as follows: standard cash (SC), a cash transfer of 1,500 Pakistani rupees (PKR) (approximately US$14; 1 PKR = US$0.009543); double cash (DC), a cash transfer of 3,000 PKR; or a fresh food voucher (FFV) of 1,500 PKR; the cash or voucher amount was given every month over six consecutive months. The control group (CG) received no specific cash-related interventions. The median total household income for the study sample was 8,075 PKR (approximately US$77) at baseline. We hypothesized that, compared to the CG in each case, FFVs would be more effective than SC, and that DC would be more effective than SC-both at 6 mo and at 1 y-for reducing the risk of child wasting. Primary outcomes of interest were prevalence of being wasted (weight-for-height z-score [WHZ] < -2) and mean WHZ at 6 mo and at 1 y. The odds of a child being wasted were significantly lower in the DC arm after 6 mo (odds ratio [OR] = 0.52; 95% CI 0.29, 0.92; p = 0.02) compared to the CG. Mean WHZ significantly improved in both the FFV and DC arms at 6 mo (FFV: z-score = 0.16; 95% CI 0.05, 0.26; p = 0.004; DC: z-score = 0.11; 95% CI 0.00, 0.21; p = 0.05) compared to the CG. Significant differences on the primary outcome were seen only at 6 mo. All three intervention groups showed similar significantly lower odds of being stunted (height-for-age z-score [HAZ] < -2) at 6 mo (DC: OR = 0.39; 95% CI 0.24, 0.64; p < 0.001; FFV: OR = 0.41; 95% CI 0.25, 0.67; p < 0.001; SC: OR = 0.36; 95% CI 0.22, 0.59; p < 0.001) and at 1 y (DC: OR = 0.53; 95% CI 0.35, 0.82; p = 0.004; FFV: OR = 0.48; 95% CI 0.31, 0.73; p = 0.001; SC: OR = 0.54; 95% CI 0.36, 0.81; p = 0.003) compared to the CG. Significant improvements in height-for-age outcomes were also seen for severe stunting (HAZ < -3) and mean HAZ. An unintended outcome was observed in the FFV arm: a negative intervention effect on mean haemoglobin (Hb) status (-2.6 g/l; 95% CI -4.5, -0.8; p = 0.005). Limitations of this study included the inability to mask participants or data collectors to the different interventions, the potentially restrictive nature of the FFVs, not being able to measure a threshold effect for the two different cash amounts or compare the different quantities of food consumed, and data collection challenges given the difficult environment in which this study was set.Conclusions: In this setting, the amount of cash given was important. The larger cash transfer had the greatest effect on wasting, but only at 6 mo. Impacts at both 6 mo and at 1 y were seen for height-based growth variables regardless of the intervention modality, indicating a trend toward nutrition resilience. Purchasing restrictions applied to food-based voucher transfers could have unintended effects, and their use needs to be carefully planned to avoid this.Trial Registration: ISRCTN registry ISRCTN10761532. [ABSTRACT FROM AUTHOR]

Background: Rotavirus vaccines are now globally recommended by the World Health Organization (WHO), but in early 2009 WHO's Strategic Advisory Group of Experts on Immunization reviewed available data and concluded that there was no evidence for the efficacy or effectiveness of a two-dose schedule of the human rotavirus vaccine (HRV; Rotarix) given early at 6 and 10 wk of age. Additionally, the effectiveness of programmatic rotavirus vaccination, including possible indirect effects, has not been assessed in low-resource populations in Asia.Methods and Findings: In Bangladesh, we cluster-randomized (1:1) 142 villages of the Matlab Health and Demographic Surveillance System to include two doses of HRV with the standard infant vaccines at 6 and 10 wk of age or to provide standard infant vaccines without HRV. The study was initiated November 1, 2008, and surveillance was conducted concurrently at Matlab Diarrhoea Hospital and two community treatment centers to identify children less than 2 y of age presenting with acute rotavirus diarrhea (ARD) through March 31, 2011. Laboratory confirmation was made by enzyme immunoassay detection of rotavirus antigen in stool specimens. Overall effectiveness of the HRV vaccination program (primary objective) was measured by comparing the incidence rate of ARD among all children age-eligible for vaccination in villages where HRV was introduced to that among such children in villages where HRV was not introduced. Total effectiveness among vaccinees and indirect effectiveness were also evaluated. In all, 6,527 infants were age-eligible for vaccination in 71 HRV villages, and 5,791 in 71 non-HRV villages. In HRV villages, 4,808 (73.7%) infants received at least one dose of HRV. The incidence rate of ARD was 4.10 cases per 100 person-years in non-HRV villages compared to 2.8 per 100 person-years in HRV villages, indicating an overall effectiveness of 29.0% (95% CI, 11.3% to 43.1%). The total effectiveness of HRV against ARD among vaccinees was 41.4% (95% CI, 23.2% to 55.2%). The point estimate for total effectiveness was higher against ARD during the first year of life than during the second (45.2% versus 28.9%), but estimates for the second year of life lacked precision and did not reach statistical significance. Indirect effects were not detected. To check for bias in presentation to treatment facilities, we evaluated the effectiveness of HRV against acute diarrhea associated with enterotoxigenic Escherichia coli; it was 4.0% (95% CI, -46.5% to 37.1%), indicating that bias likely was not introduced. Thirteen serious adverse events were identified among recipients of HRV, but none were considered related to receipt of study vaccine. The main limitation of this study is that it was an open-label study with an observed-only control group (no placebo).Conclusions: The two-dose HRV rotavirus vaccination program significantly reduced medically attended ARD in this low-resource population in Asia. Protection among vaccinees was similar to that in other low-resource settings. In low-resource populations with high rotavirus incidence, large-scale vaccination across a wide population may be required to obtain the full benefit of rotavirus vaccination, including indirect effects.Trial Registration: ClinicalTrials.gov NCT00737503. [ABSTRACT FROM AUTHOR]

Background: Clear recognition of the damaging effects of poverty on early childhood development has fueled an interest in interventions aimed at mitigating these harmful consequences. Psychosocial interventions aimed at alleviating the negative impacts of poverty on children are frequently shown to be of benefit, but effect sizes are typically small to moderate. However, averaging outcomes over an entire sample, as is typically done, could underestimate efficacy because weaker effects on less susceptible individuals would dilute estimation of effects on those more disposed to respond. This study investigates whether a genetic polymorphism of the serotonin transporter gene moderates susceptibility to a psychosocial intervention.Methods and Findings: We reanalyzed data from a randomized controlled trial of a home-visiting program delivered by community health workers in a black, isiXhosa-speaking population in Khayelitsha, South Africa. The intervention, designed to enhance maternal-infant attachment, began in the third trimester and continued until 6 mo postpartum. Implemented between April 1999 and February 2003, the intervention comprised 16 home visits delivered to 220 mother-infant dyads by specially trained community health workers. A control group of 229 mother-infant dyads did not receive the intervention. Security of maternal-infant attachment was the main outcome measured at infant age 18 mo. Compared to controls, infants in the intervention group were significantly more likely to be securely attached to their primary caregiver (odds ratio [OR] = 1.7, p = 0.029, 95% CI [1.06, 2.76], d = 0.29). After the trial, 162 intervention and 172 control group children were reenrolled in a follow-up study at 13 y of age (December 2012-June 2014). At this time, DNA collected from 279 children (134 intervention and 145 control) was genotyped for a common serotonin transporter polymorphism. There were both genetic data and attachment security data for 220 children (110 intervention and 110 control), of whom 40% (44 intervention and 45 control) carried at least one short allele of the serotonin transporter gene. For these 220 individuals, carrying at least one short allele of the serotonin transporter gene was associated with a 26% higher rate of attachment security relative to controls (OR = 3.86, p = 0.008, 95% CI [1.42, 10.51], d = 0.75), whereas there was a negligible (1%) difference in security between intervention and control group individuals carrying only the long allele (OR = 0.95, p = 0.89, 95% CI [0.45, 2.01], d = 0.03). Expressed in terms of absolute risk, for those with the short allele, the probability of secure attachment being observed in the intervention group was 84% (95% CI [73%, 95%]), compared to 58% (95% CI [43%, 72%]) in the control group. For those with two copies of the long allele, 70% (95% CI [59%, 81%]) were secure in the intervention group, compared to 71% (95% CI [60%, 82%]) of infants in the control group. Controlling for sex, maternal genotype, and indices of socioeconomic adversity (housing, employment, education, electricity, water) did not change these results. A limitation of this study is that we were only able to reenroll 49% of the original sample randomized to the intervention and control conditions. Attribution of the primary outcome to causal effects of intervention in the present subsample should therefore be treated with caution.Conclusions: When infant genotype for serotonin transporter polymorphism was taken into account, the effect size of a maternal-infant attachment intervention targeting impoverished pregnant women increased more than 2.5-fold when only short allele carriers were considered (from d = 0.29 for all individuals irrespective of genotype to d = 0.75) and decreased 10-fold when only those carrying two copies of the long allele were considered (from d = 0.29 for all individuals to d = 0.03). Genetic differential susceptibility means that averaging across all participants is a misleading index of efficacy. The study raises questions about how policy-makers deal with the challenge of balancing equity (equal treatment for all) and efficacy (treating only those whose genes render them likely to benefit) when implementing psychosocial interventions.Trial Registration: Current Controlled Trials ISRCTN25664149. [ABSTRACT FROM AUTHOR]

In January's Guest Editorial, Sarah Stock and Jenny Myers discuss approaches to fetal and neonatal growth assessment. [ABSTRACT FROM AUTHOR]

In a Perspective, Gordon Schiff discusses the importance of appropriately analyzing adverse event reports. [ABSTRACT FROM AUTHOR]

Background: Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ), given each month during the transmission season, is recommended for children living in areas of the Sahel where malaria transmission is highly seasonal. The recommendation for SMC is currently limited to children under five years of age, but, in many areas of seasonal transmission, the burden in older children may justify extending this age limit. This study was done to determine the effectiveness of SMC in Senegalese children up to ten years of age.Methods and Findings: SMC was introduced into three districts over three years in central Senegal using a stepped-wedge cluster-randomised design. A census of the population was undertaken and a surveillance system was established to record all deaths and to record all cases of malaria seen at health facilities. A pharmacovigilance system was put in place to detect adverse drug reactions. Fifty-four health posts were randomised. Nine started implementation of SMC in 2008, 18 in 2009, and a further 18 in 2010, with 9 remaining as controls. In the first year of implementation, SMC was delivered to children aged 3-59 months; the age range was then extended for the latter two years of the study to include children up to 10 years of age. Cluster sample surveys at the end of each transmission season were done to measure coverage of SMC and the prevalence of parasitaemia and anaemia, to monitor molecular markers of drug resistance, and to measure insecticide-treated net (ITN) use. Entomological monitoring and assessment of costs of delivery in each health post and of community attitudes to SMC were also undertaken. About 780,000 treatments were administered over three years. Coverage exceeded 80% each month. Mortality, the primary endpoint, was similar in SMC and control areas (4.6 and 4.5 per 1000 respectively in children under 5 years and 1.3 and 1.2 per 1000 in children 5-9 years of age; the overall mortality rate ratio [SMC: no SMC] was 0.90, 95% CI 0.68-1.2, p = 0.496). A reduction of 60% (95% CI 54%-64%, p < 0.001) in the incidence of malaria cases confirmed by a rapid diagnostic test (RDT) and a reduction of 69% (95% CI 65%-72%, p < 0.001) in the number of treatments for malaria (confirmed and unconfirmed) was observed in children. In areas where SMC was implemented, incidence of confirmed malaria in adults and in children too old to receive SMC was reduced by 26% (95% CI 18%-33%, p < 0.001) and the total number of treatments for malaria (confirmed and unconfirmed) in these older age groups was reduced by 29% (95% CI 21%-35%, p < 0.001). One hundred and twenty-three children were admitted to hospital with a diagnosis of severe malaria, with 64 in control areas and 59 in SMC areas, showing a reduction in the incidence rate of severe disease of 45% (95% CI 5%-68%, p = 0.031). Estimates of the reduction in the prevalence of parasitaemia at the end of the transmission season in SMC areas were 68% (95% CI 35%-85%) p = 0.002 in 2008, 84% (95% CI 58%-94%, p < 0.001) in 2009, and 30% (95% CI -130%-79%, p = 0.56) in 2010. SMC was well tolerated with no serious adverse reactions attributable to SMC drugs. Vomiting was the most commonly reported mild adverse event but was reported in less than 1% of treatments. The average cost of delivery was US$0.50 per child per month, but varied widely depending on the size of the health post. Limitations included the low rate of mortality, which limited our ability to detect an effect on this endpoint.Conclusions: SMC substantially reduced the incidence of outpatient cases of malaria and of severe malaria in children, but no difference in all-cause mortality was observed. Introduction of SMC was associated with an overall reduction in malaria incidence in untreated age groups. In many areas of Africa with seasonal malaria, there is a substantial burden in older children that could be prevented by SMC. SMC in older children is well tolerated and effective and can contribute to reducing malaria transmission.Trial Registration: ClinicalTrials.gov NCT00712374. [ABSTRACT FROM AUTHOR]

Background: Despite recommendations supporting optimal breastfeeding, the number of women practicing exclusive breastfeeding (EBF) remains low, and few interventions have demonstrated implementation and impact at scale. Alive & Thrive was implemented over a period of 6 y (2009-2014) and aimed to improve breastfeeding practices through intensified interpersonal counseling (IPC), mass media (MM), and community mobilization (CM) intervention components delivered at scale in the context of policy advocacy (PA) in Bangladesh and Viet Nam. In Bangladesh, IPC was delivered through a large non-governmental health program; in Viet Nam, it was integrated into government health facilities. This study evaluated the population-level impact of intensified IPC, MM, CM, and PA (intensive) compared to standard nutrition counseling and less intensive MM, CM, and PA (non-intensive) on breastfeeding practices in these two countries.Methods and Findings: A cluster-randomized evaluation design was employed in each country. For the evaluation sample, 20 sub-districts in Bangladesh and 40 communes in Viet Nam were randomized to either the intensive or the non-intensive group. Cross-sectional surveys (n ~ 500 children 0-5.9 mo old per group per country) were implemented at baseline (June 7-August 29, 2010, in Viet Nam; April 28-June 26, 2010, in Bangladesh) and endline (June 16-August 30, 2014, in Viet Nam; April 20-June 23, 2014, in Bangladesh). Difference-in-differences estimates (DDEs) of impact were calculated, adjusting for clustering. In Bangladesh, improvements were significantly greater in the intensive compared to the non-intensive group for the proportion of women who reported practicing EBF in the previous 24 h (DDE 36.2 percentage points [pp], 95% CI 21.0-51.5, p < 0.001; prevalence in intensive group rose from 48.5% to 87.6%) and engaging in early initiation of breastfeeding (EIBF) (16.7 pp, 95% CI 2.8-30.6, p = 0.021; 63.7% to 94.2%). In Viet Nam, EBF increases were greater in the intensive group (27.9 pp, 95% CI 17.7-38.1, p < 0.001; 18.9% to 57.8%); EIBF declined (60.0% to 53.2%) in the intensive group, but less than in the non-intensive group (57.4% to 40.6%; DDE 10.0 pp, 95% CI -1.3 to 21.4, p = 0.072). Our impact estimates may underestimate the full potential of such a multipronged intervention because the evaluation lacked a "pure control" area with no MM or national/provincial PA.Conclusions: At-scale interventions combining intensive IPC with MM, CM, and PA had greater positive impacts on breastfeeding practices in Bangladesh and Viet Nam than standard counseling with less intensive MM, CM, and PA. To our knowledge, this study is the first to document implementation and impacts of breastfeeding promotion at scale using rigorous evaluation designs. Strategies to design and deliver similar programs could improve breastfeeding practices in other contexts.Trial Registration: ClinicalTrials.gov NCT01678716 (Bangladesh) and NCT01676623 (Viet Nam). [ABSTRACT FROM AUTHOR]

Background: The Joint United Nations Programme on HIV and AIDS (UNAIDS) 90-90-90 targets have reinforced the importance of functioning laboratory services to ensure prompt diagnosis and to assess treatment efficacy. We surveyed the availability and utilization of technologies for HIV treatment monitoring and early infant diagnosis (EID) in World Health Organization (WHO) Member States.Methods and Findings: The survey questionnaire included 14 structured questions focusing on HIV testing, cluster of differentiation 4 (CD4) testing, HIV viral load (VL) testing, and EID and was administered annually from 2012 to 2014 through WHO country offices, with each survey covering the previous 12-mo period. Across 127 targeted countries, survey response rates were 60% in 2012, 67% in 2013, and 78% in 2014. There were encouraging trends towards increased procurement of CD4 and VL/EID instruments in reporting countries. Globally, the capacity of available CD4 instruments was sufficient to meet the demand of all people living with HIV/AIDS (PLWHA), irrespective of treatment status (4.62 theoretical tests per PLWHA in 2013 [median 7.33; interquartile range (IQR) 3.44-17.75; median absolute deviation (MAD) 4.35]). The capacity of VL instruments was inadequate to cover all PLWHA in many reporting countries (0.44 tests per PLWHA in 2013 [median 0.90; IQR 0.30-2.40; MAD 0.74]). Of concern, only 13.7% of existing CD4 capacity (median 4.3%; IQR 1.1%-12.1%; MAD 3.8%) and only 36.5% of existing VL capacity (median 9.4%; IQR 2.3%-28.9%; MAD 8.2%) was being utilized across reporting countries in 2013. By the end of 2013, 7.4% of all CD4 instruments (5.8% CD4 conventional instruments and 11.0% of CD4 point of care [POC]) and 10% of VL/EID instruments were reportedly not in use because of lack of reagents, the equipment not being installed or deployed, maintenance, and staff training requirements. Major limitations of this survey included under-reporting and/or incomplete reporting in some national programmes and noncoverage of the private sector.Conclusion: This is the first attempt to comprehensively gather information on HIV testing technology coverage in WHO Member States. The survey results suggest that major operational changes will need to be implemented, particularly in low- and middle-income countries, if the 90-90-90 targets are to be met. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is the leading cause of disability and mortality in children and young adults worldwide. It remains unclear, however, how TBI in childhood and adolescence is associated with adult mortality, psychiatric morbidity, and social outcomes.Methods and Findings: In a Swedish birth cohort between 1973 and 1985 of 1,143,470 individuals, we identified all those who had sustained at least one TBI (n = 104,290 or 9.1%) up to age 25 y and their unaffected siblings (n = 68,268) using patient registers. We subsequently assessed these individuals for the following outcomes using multiple national registries: disability pension, specialist diagnoses of psychiatric disorders and psychiatric inpatient hospitalisation, premature mortality (before age 41 y), low educational attainment (not having achieved secondary school qualifications), and receiving means-tested welfare benefits. We used logistic and Cox regression models to quantify the association between TBI and specified adverse outcomes on the individual level. We further estimated population attributable fractions (PAF) for each outcome measure. We also compared differentially exposed siblings to account for unobserved genetic and environmental confounding. In addition to relative risk estimates, we examined absolute risks by calculating prevalence and Kaplan-Meier estimates. In complementary analyses, we tested whether the findings were moderated by injury severity, recurrence, and age at first injury (ages 0-4, 5-9, 6-10, 15-19, and 20-24 y). TBI exposure was associated with elevated risks of impaired adult functioning across all outcome measures. After a median follow-up period of 8 y from age 26 y, we found that TBI contributed to absolute risks of over 10% for specialist diagnoses of psychiatric disorders and low educational attainment, approximately 5% for disability pension, and 2% for premature mortality. The highest relative risks, adjusted for sex, birth year, and birth order, were found for psychiatric inpatient hospitalisation (adjusted relative risk [aRR] = 2.0; 95% CI: 1.9-2.0; 6,632 versus 37,095 events), disability pension (aRR = 1.8; 95% CI: 1.7-1.8; 4,691 versus 29,778 events), and premature mortality (aRR = 1.7; 95% CI: 1.6-1.9; 799 versus 4,695 events). These risks were only marginally attenuated when the comparisons were made with their unaffected siblings, which implies that the effects of TBI were consistent with a causal inference. A dose-response relationship was observed with injury severity. Injury recurrence was also associated with higher risks-in particular, for disability pension we found that recurrent TBI was associated with a 3-fold risk increase (aRR = 2.6; 95% CI: 2.4-2.8) compared to a single-episode TBI. Higher risks for all outcomes were observed for those who had sustained their first injury at an older age (ages 20-24 y) with more than 25% increase in relative risk across all outcomes compared to the youngest age group (ages 0-4 y). On the population level, TBI explained between 2%-6% of the variance in the examined outcomes. Using hospital data underestimates milder forms of TBI, but such misclassification bias suggests that the reported estimates are likely conservative. The sibling-comparison design accounts for unmeasured familial confounders shared by siblings, including half of their genes. Thus, residual genetic confounding remains a possibility but will unlikely alter our main findings, as associations were only marginally attenuated within families.Conclusions: Given our findings, which indicate potentially causal effects between TBI exposure in childhood and later impairments across a range of health and social outcomes, age-sensitive clinical guidelines should be considered and preventive strategies should be targeted at children and adolescents. [ABSTRACT FROM AUTHOR]

Background: Exclusive breastfeeding (EBF) is associated with early child health; its longer-term benefits for child development remain inconclusive. We examine the associations between EBF, HIV exposure, and other maternal/child factors and the cognitive and emotional-behavioural development of children aged 7-11 y.Methods and Findings: The Vertical Transmission Study (VTS) supported EBF in HIV-positive and HIV-negative women; between 2012 and 2014, HIV-negative VTS children (332 HIV exposed, 574 HIV unexposed) were assessed in terms of cognition (Kaufman Assessment Battery for Children Second Edition [KABC-II]), executive function (Developmental Neuropsychological Assessment Second Edition [NEPSY-II]), and emotional-behavioural functioning (parent-reported Child Behaviour Checklist, [CBCL]). We developed population means by combining the VTS sample with 629 same-aged HIV-negative children from the local demographic platform. For each outcome, we split the VTS sample into scores above or at/below each population mean and modelled each outcome using logistic regression analyses, overall and stratified by child sex. There was no demonstrated effect of EBF on overall cognitive functioning. EBF was associated with fewer conduct disorders overall (adjusted odds ratio [aOR] 0.44 [95% CI 0.3-0.7], p ≤ 0.01), and there was weak evidence of better cognition in boys who had been exclusively breastfed for 2-5 mo versus ≤1 mo (Learning subscale aOR 2.07 [95% CI 1.0-4.3], p = 0.05). Other factors associated with better child cognition were higher maternal cognitive ability (aOR 1.43 [95% CI 1.1-1.9], p = 0.02, Sequential; aOR 1.74 [95% CI 1.3-2.4], p < 0.001, Planning subscales) and crèche attendance (aOR 1.96 [95% CI 1.1-3.5], p = 0.02, Sequential subscale). Factors positively associated with executive function were home stimulation (aOR 1.36 [95% CI 1.0-1.8], p = 0.04, Auditory Attention; aOR 1.35 [95% CI 1.0-1.8], p = 0.05, Response Set) and crèche (aOR 1.74 [95% CI 1.0-3.0], p = 0.05, Animal Sorting). Maternal mental health problems and parenting stress were associated with increased emotional-behavioural problems on the total CBCL (aOR 2.44 [95% CI 1.3-4.6], p = 0.01; aOR 7.04 [95% CI 4.2-11.9], p < 0.001, respectively). Maternal HIV status was not associated with any outcomes in the overall cohort. Limitations include the nonrandomised study design and lack of maternal mental health assessment at the child's birth.Conclusions: EBF was associated with fewer than average conduct disorders and weakly associated with improved cognitive development in boys. Efforts to improve stimulation at home, reduce maternal stress, and enable crèche attendance are likely to improve executive function and emotional-behavioural development of children. [ABSTRACT FROM AUTHOR]

Background: Under-five mortality is declining in Ghana and many other countries. Very few studies have measured under-five mortality-and its social and environmental risk factors-at fine spatial resolutions, which is relevant for policy purposes. Our aim was to estimate under-five mortality and its social and environmental risk factors at the district level in Ghana.Methods and Findings: We used 10% random samples of Ghana's 2000 and 2010 National Population and Housing Censuses. We applied indirect demographic methods and a Bayesian spatial model to the information on total number of children ever born and children surviving to estimate under-five mortality (probability of dying by 5 y of age, 5q0) for each of Ghana's 110 districts. We also used the census data to estimate the distributions of households or persons in each district in terms of fuel used for cooking, sanitation facility, drinking water source, and parental education. Median district 5q0 declined from 99 deaths per 1,000 live births in 2000 to 70 in 2010. The decline ranged from <5% in some northern districts, where 5q0 had been higher in 2000, to >40% in southern districts, where it had been lower in 2000, exacerbating existing inequalities. Primary education increased in men and women, and more households had access to improved water and sanitation and cleaner cooking fuels. Higher use of liquefied petroleum gas for cooking was associated with lower 5q0 in multivariate analysis.Conclusions: Under-five mortality has declined in all of Ghana's districts, but the cross-district inequality in mortality has increased. There is a need for additional data, including on healthcare, and additional environmental and socioeconomic measurements, to understand the reasons for the variations in mortality levels and trends. [ABSTRACT FROM AUTHOR]

In this Perspective on the GEMS study by Kelly Baker and colleagues, Jonny Crocker and Jamie Bartram consider the implications of associations found and not found between diarrheal disease and sanitation and hygiene. [ABSTRACT FROM AUTHOR]

Background: Diarrheal disease is the second leading cause of disease in children less than 5 y of age. Poor water, sanitation, and hygiene conditions are the primary routes of exposure and infection. Sanitation and hygiene interventions are estimated to generate a 36% and 48% reduction in diarrheal risk in young children, respectively. Little is known about whether the number of households sharing a sanitation facility affects a child's risk of diarrhea. The objective of this study was to describe sanitation and hygiene access across the Global Enteric Multicenter Study (GEMS) sites in Africa and South Asia and to assess sanitation and hygiene exposures, including shared sanitation access, as risk factors for moderate-to-severe diarrhea (MSD) in children less than 5 y of age.Methods/findings: The GEMS matched case-control study was conducted between December 1, 2007, and March 3, 2011, at seven sites in Basse, The Gambia; Nyanza Province, Kenya; Bamako, Mali; Manhiça, Mozambique; Mirzapur, Bangladesh; Kolkata, India; and Karachi, Pakistan. Data was collected for 8,592 case children aged <5 y old experiencing MSD and for 12,390 asymptomatic age, gender, and neighborhood-matched controls. An MSD case was defined as a child with a diarrheal illness <7 d duration comprising ≥3 loose stools in 24 h and ≥1 of the following: sunken eyes, skin tenting, dysentery, intravenous (IV) rehydration, or hospitalization. Site-specific conditional logistic regression models were used to explore the association between sanitation and hygiene exposures and MSD. Most households at six sites (>93%) had access to a sanitation facility, while 70% of households in rural Kenya had access to a facility. Practicing open defecation was a risk factor for MSD in children <5 y old in Kenya. Sharing sanitation facilities with 1-2 or ≥3 other households was a statistically significant risk factor for MSD in Kenya, Mali, Mozambique, and Pakistan. Among those with a designated handwashing area near the home, soap or ash were more frequently observed at control households and were significantly protective against MSD in Mozambique and India.Conclusions: This study suggests that sharing a sanitation facility with just one to two other households can increase the risk of MSD in young children, compared to using a private facility. Interventions aimed at increasing access to private household sanitation facilities may reduce the burden of MSD in children. These findings support the current World Health Organization/ United Nations Children's Emergency Fund (UNICEF) system that categorizes shared sanitation as unimproved. [ABSTRACT FROM AUTHOR]

Background: Homicide of children is a global problem. The under-5-y age group is the second largest homicide age group after 15-19 y olds, but has received little research attention. Understanding age and gender patterns is important for assisting with developing prevention interventions. Here we present an age and gender analysis of homicides among children under 5 y in South Africa from a national study that included a focus on neonaticide and infanticide.Methods and Findings: A retrospective national cross-sectional study was conducted using a random sample of 38 medico-legal laboratories operating in 2009 to identify homicides of children under 5 y. Child data were abstracted from the mortuary files and autopsy reports, and both child and perpetrator data data were collected from police interviews. We erred towards applying a conservative definition of homicide and excluded sudden infant death syndrome cases. We estimated that 454 (95% CI 366, 541) children under the age of 5 y were killed in South Africa in 2009. More than half (53.2%; 95% CI 46.7%, 59.5%) were neonates (0-28 d), and 74.4% (95% CI 69.3%, 78.9%) were infants (under 1 y), giving a neonaticide rate of 19.6 per 100,000 live births and an infanticide rate of 28.4 per 100,000 live births. The majority of the neonates died in the early neonatal period (0-6 d), and abandonment accounted for 84.9% (95% CI 81.5%, 87.8%) of all the neonates killed. Distinct age and gender patterns were found, with significantly fewer boy children killed in rural settings compared to urban settings (odds ratio 0.6; 95% CI 0.4, 0.9; p = 0.015). Abuse-related killings and evidence of sexual assault were more common among older girls than in all other age and gender groups. Mothers were identified as the perpetrators in all of the neonaticides and were the most common perpetrators overall (71.0%; 95% CI 63.9%, 77.2%). Abandoned neonates were mainly term babies, with a mean gestational age of 38 wk. We did not have information on abandonment motives for all newborns and did not know if babies were abandoned with the intention that they would die or with the hope that they would be found alive. We therefore considered all abandoned babies as homicides.Conclusions: Homicide of children is an extreme form or consequence of violence against children. This national study provides one of the first analyses of neonaticide and infanticide by age and gender and shows the failure of reproductive and mental health and social services to identify and help vulnerable mothers. Multi-sectoral prevention strategies are needed. [ABSTRACT FROM AUTHOR]

Amasanti and colleagues consider female genital mutilation in the UK, how overly intrusive efforts to help might make the problem worse, and how best to move forwards. [ABSTRACT FROM AUTHOR]

Background: China accounted for 87% (9.8 million/11.3 million) of all hand, foot, and mouth disease (HFMD) cases reported to WHO during 2010-2014. Enterovirus 71 (EV71) is responsible for most of the severe HFMD cases. Three EV71 vaccines recently demonstrated good efficacy in children aged 6-71 mo. Here we assessed the cost-effectiveness of routine pediatric EV71 vaccination in China.Methods and Findings: We characterized the economic and health burden of EV71-associated HFMD (EV71-HFMD) in China using (i) the national surveillance database, (ii) virological surveillance records from all provinces, and (iii) a caregiver survey on the household costs and health utility loss for 1,787 laboratory-confirmed pediatric cases. Using a static model parameterized with these data, we estimated the effective vaccine cost (EVC, defined as cost/efficacy or simply the cost of a 100% efficacious vaccine) below which routine pediatric vaccination would be considered cost-effective. We performed the base-case analysis from the societal perspective with a willingness-to-pay threshold of one times the gross domestic product per capita (GDPpc) and an annual discount rate of 3%. We performed uncertainty analysis by (i) accounting for the uncertainty in the risk of EV71-HFMD due to missing laboratory data in the national database, (ii) excluding productivity loss of parents and caregivers, (iii) increasing the willingness-to-pay threshold to three times GDPpc, (iv) increasing the discount rate to 6%, and (v) accounting for the proportion of EV71-HFMD cases not registered by national surveillance. In each of these scenarios, we performed probabilistic sensitivity analysis to account for parametric uncertainty in our estimates of the risk of EV71-HFMD and the expected costs and health utility loss due to EV71-HFMD. Routine pediatric EV71 vaccination would be cost-saving if the all-inclusive EVC is below US$10.6 (95% CI US$9.7-US$11.5) and would remain cost-effective if EVC is below US$17.9 (95% CI US$16.9-US$18.8) in the base case, but these ceilings could be up to 66% higher if all the test-negative cases with missing laboratory data are EV71-HFMD. The EVC ceiling is (i) 10%-14% lower if productivity loss of parents/caregivers is excluded, (ii) 58%-84% higher if the willingness-to-pay threshold is increased to three times GDPpc, (iii) 14%-19% lower if the discount rate is increased to 6%, and (iv) 36% (95% CI 23%-50%) higher if the proportion of EV71-HFMD registered by national surveillance is the same as that observed in the three EV71 vaccine phase III trials. The validity of our results relies on the following assumptions: (i) self-reported hospital charges are a good proxy for the opportunity cost of care, (ii) the cost and health utility loss estimates based on laboratory-confirmed EV71-HFMD cases are representative of all EV71-HFMD cases, and (iii) the long-term average risk of EV71-HFMD in the future is similar to that registered by national surveillance during 2010-2013.Conclusions: Compared to no vaccination, routine pediatric EV71 vaccination would be very cost-effective in China if the cost of immunization (including all logistical, procurement, and administration costs needed to confer 5 y of vaccine protection) is below US$12.0-US$18.3, depending on the choice of vaccine among the three candidates. Given that the annual number of births in China has been around 16 million in recent years, the annual costs for routine pediatric EV71 vaccination at this cost range should not exceed US$192-US$293 million. Our results can be used to determine the optimal vaccine when the prices of the three vaccines are known. [ABSTRACT FROM AUTHOR]

As part of the "Grand Convergence: Aligning Technologies and Realities in Global Health" Collection, Cyril Engmann and colleagues discuss promising innovations that have the potential to move the RMNCH agenda forward. [ABSTRACT FROM AUTHOR]

Marni Sommer and colleagues reflect on priorities needed to guide global, national, and local action to address girls' menstrual hygiene management needs in schools. [ABSTRACT FROM AUTHOR]

Noor Giesbertz and colleagues consider different re-contact policy designs that could be used by biobanks to obtain permission for the continued use of samples collected from children. [ABSTRACT FROM AUTHOR]