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Additional file 1: Supplementary Table 1a: Pattern coefficients from EFA showing the one-factor solution for CES-D. Supplementary Table 1b: Pattern coefficients from EFA showing the four-factor solution for the BAI. Supplementary Table 1c: Pattern coefficients from EFA showing the four-factor solution for the RAND SF-36.

Additional file 1: Table S1. The adjusted associations between food insecurity score and food/nutrient intake, diet quality, and HEI component scores in females.

Additional file 1 Additional file 1 contains the baseline values of the iron biomarkers, separated by sex; procedural details for each of the cognitive tasks; and the details of the pre-processing of the EEG data.

Key Points Question What are the pooled prevalence of congenital cytomegalovirus infection and factors associated with the rates in high-income and low- and middle-income countries? Findings In this systematic review and meta-analysis including 77 studies from 36 countries comprising 515 646 infants younger than 3 weeks, the pooled overall prevalence of congenital cytomegalovirus was 0.67%. The infection burden was 3-fold greater in low- and middle-income countries than in high-income countries. Lower rates were reported in screening methods using blood compared with urine or saliva. Meaning The findings of this study suggest that low- and middle-income countries incur the greatest infection burden of congenital cytomegalovirus; a global effort to address congenital cytomegalovirus in regions with the greatest prevalence is needed to reduce disease incidence and morbidity., Importance Congenital cytomegalovirus (cCMV) infection is the most common congenital infection and the leading acquired cause of developmental disabilities and sensorineural deafness, yet a reliable assessment of the infection burden is lacking. Objectives To estimate the birth prevalence of cCMV in low- and middle-income countries (LMICs) and high-income countries (HICs), characterize the rate by screening methods, and delineate associated risk factors of the infection. Data Sources MEDLINE/PubMed, Scopus, and Cochrane Database of Systematic Reviews databases were searched from January 1, 1960, to March 1, 2021, and a total of 1322 studies were identified. Study Selection Studies that provided data on the prevalence of cCMV derived from universal screening of infants younger than 3 weeks were included. Targeted screening studies were excluded. Data Extraction and Synthesis Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Extraction was performed independently by 3 reviewers. Quality was assessed using the Newcastle-Ottawa Scale for cohort studies. Random-effects meta-analysis was undertaken. Metaregression was conducted to evaluate the association of sociodemographic characteristics, maternal seroprevalence, population-level HIV prevalence, and screening methods with the prevalence of cCMV. Main Outcomes and Measures Birth prevalence of cCMV ascertained through universal screening of infants younger than 3 weeks for CMV from urine, saliva, or blood samples. Results Seventy-seven studies comprising 515 646 infants met the inclusion criteria from countries representative of each World Bank income level. The estimated pooled overall prevalence of cCMV was 0.67% (95% CI, 0.54%-0.83%). The pooled birth prevalence of cCMV was 3-fold greater in LMICs (1.42%; 95% CI, 0.97%-2.08%; n = 23 studies) than in HICs (0.48%; 95% CI, 0.40%-0.59%, n = 54 studies). Screening methods with blood samples demonstrated lower rates of cCMV than urine or saliva samples (odds ratio [OR], 0.38; 95% CI, 0.23-0.66). Higher maternal CMV seroprevalence (OR, 1.19; 95% CI, 1.11-1.28), higher population-level HIV prevalence (OR, 1.22; 95% CI, 1.05-1.40), lower socioeconomic status (OR, 3.03; 95% CI, 2.05-4.47), and younger mean maternal age (OR, 0.85; 95% CI, 0.78-0.92, older age was associated with lower rates) were associated with higher rates of cCMV. Conclusions and Relevance In this meta-analysis, LMICs appeared to incur the most significant infection burden. Lower rates of cCMV were reported by studies using only blood or serum as a screening method., This systematic review and meta-analysis examines the prevalence of congenital cytomegalovirus (cCMV) in young infants by economic status of countries as well as factors contributing to the diagnosis and prevalence.

Background Breastfeeding is known to reduce risk of enteropathogen infections, but protection from specific enteropathogens is not well characterized. Objective To estimate the association between full breastfeeding (days fed breast milk exclusively or with non-nutritive liquids) and enteropathogen detection. Design 2,145 newborns were enrolled in eight sites, of whom 1,712 had breastfeeding and key enteropathogen data through 6 months. We focused on eleven enteropathogens: adenovirus 40/41, norovirus, sapovirus, astrovirus, and rotavirus, enterotoxigenic Escherichia coli (ETEC), Campylobacter spp, and typical enteropathogenic E. coli as well as entero-aggregative E. coli, Shigella and Cryptosporidium. Logistic regression was used to estimate the risk of enteropathogen detection in stools and survival analysis to estimate the timing of first detection of an enteropathogen. Results Infants with 10% more days of full breastfeeding within the preceding 30 days of a stool sample were less likely to have the three E. Coli and Campylobacter spp detected in their stool (mean odds 0.92���0.99) but equally likely (0.99���1.02) to have the viral pathogens detected in their stool. A 10% longer period of full breastfeeding from birth was associated with later first detection of the three E. Coli, Campylobacter, adenovirus, astrovirus, and rotavirus (mean hazard ratios of 0.52���0.75). The hazards declined and point estimates were not statistically significant at 3 months. Conclusions In this large multi-center cohort study, full breastfeeding was associated with lower likelihood of detecting four important enteric pathogens in the first six months of life. These results also show that full breastfeeding is related to delays in the first detection of some bacterial and viral pathogens in the stool. As several of these pathogens are risk factors for poor growth during childhood, this work underscores the importance of exclusive or full breastfeeding during the first six months of life to optimize early health., Accepted for publication in AJCN

Background Poor growth in early childhood has been associated with increased risk of mortality and morbidity, as well as long-term deficits in cognitive development and economic productivity. Objectives Data from the MAL-ED cohort study were used to identify factors in the first 2 y of life that are associated with height-for-age, weight-for-age, and body mass index z-scores (HAZ, WAZ, BMIZ) at 5 y of age. Methods A total of 1017 children were followed from near birth until 5 y of age at sites in Bangladesh, Brazil, India, Nepal, Peru, South Africa, and Tanzania. Data were collected on their growth, environmental enteric dysfunction (EED), micronutrient status, enteric pathogen burden, illness prevalence, dietary intake, and various other socio-economic and environmental factors. Results EED biomarkers were related to size at 5 y. Mean lactulose:mannitol z-scores during the first 2 y of life were negatively associated with all of the growth measures (HAZ: −0.11 [95% CI: −0.19, −0.03]; WAZ: −0.16 [95% CI: −0.26, −0.06]; BMIZ: −0.11 [95% CI: −0.23, 0.0]). Myeloperoxidase was negatively associated with weight (WAZ: −0.52 [95% CI: −0.78, −0.26] and BMIZ: −0.56 [95% CI: −0.86, −0.26]); whereas α-1-antitrypsin had a negative association with HAZ (−0.28 [95% CI: −0.52, −0.04]). Transferrin receptor was positively related to HAZ (0.18 [95% CI: 0.06, 0.30]) and WAZ (0.21 [95% CI: 0.07, 0.35]). Hemoglobin was positively related to HAZ (0.06 [95% CI: 0.00, 0.12]), and ferritin was negatively related to HAZ (−0.08 [95% CI: −0.12, −0.04]). Bacterial density in stool was negatively associated with HAZ (−0.04 [95% CI: −0.08, 0.00]), but illness symptoms did not have any effect on size at 5 y. Conclusions EED markers, bacterial density, and iron markers are associated with growth at 5 y of age. Interventions to reduce bacterial burden and EED may improve long-term growth in low-income settings.

Background Evidence suggests that iron deficiency (ID) affects cognitive performance, as measured in behavior. Although such effects must be mediated by changes in the brain, very few studies have included measures of brain activity to assess this relation. Objective We tested the hypothesis that provision of iron-biofortified beans would result in improvements in measures of iron status, brain dynamics, and behavior. Methods A double-blind, randomized, intervention study was conducted in 55 women aged 18–27 y with low iron status (serum ferritin

Additional file 1.

Background: Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and systemic inflammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Methods: Non-diarrheal stool samples (N = 22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) (N = 6363) and plasma alpha-1-acid glycoprotein (AGP) (N = 2797) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0–2 years of age. Findings: Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic inflammation than for gut inflammation; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. Interpretation: The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic inflammation. Funding: Bill & Melinda Gates Foundation.

The home environment provides the context for much of a child's early development. Examples of important aspects of the home environment include safety, cleanliness, and opportunities for cognitive stimulation. This study sought to examine the psychometric properties of an adapted form of the Home Observation for the Measurement of the Environment (HOME; Caldwell & Bradley, 1984, 2003) across the eight international sites of the MAL-ED project (Dhaka, Bangladesh; Vellore, India; Bhakatapur, Nepal; Naushahro Feroze, Pakistan; Fortaleza, Brazil; Loreto, Peru; Venda, South Africa; Haydom, Tanzania), to identify a factor structure that fit the data at all sites, and to derive a subset of items that could be used to examine home environmental characteristics across sites. A three-factor structure (i.e., Emotional and Verbal Responsivity; Clean and Safe Environment; Child Cleanliness) was identified, and partial measurement equivalence/invariance across sites was supported. Overall, these findings lend support for the use of portions of this abbreviated and adapted version of the HOME for use among heterogeneous, cross-cultural groups in low- and middle-income nations.

Background: Child cognitive development is influenced by early-life insults and protective factors. To what extent these factors have a long-term legacy on child development and hence fulfillment of cognitive potential is unknown. Objective: The aim of this study was to examine the relation between early-life factors (birth to 2 y) and cognitive development at 5 y. Methods: Observational follow-up visits were made of children at 5 y, previously enrolled in the community-based MAL-ED longitudinal cohort. The burden of enteropathogens, prevalence of illness, complementary diet intake, micronutrient status, and household and maternal factors from birth to 2 y were extensively measured and their relation with the Wechsler Preschool Primary Scales of Intelligence at 5 y was examined through use of linear regression. Results: Cognitive T-scores from 813 of 1198 (68%) children were examined and 5 variables had significant associations in multivariable models: mean child plasma transferrin receptor concentration (β: −1.81, 95% CI: −2.75, −0.86), number of years of maternal education (β: 0.27, 95% CI: 0.08, 0.45), maternal cognitive reasoning score (β: 0.09, 95% CI: 0.03, 0.15), household assets score (β: 0.64, 95% CI: 0.24, 1.04), and HOME child cleanliness factor (β: 0.60, 95% CI: 0.05, 1.15). In multivariable models, the mean rate of enteropathogen detections, burden of illness, and complementary food intakes between birth and 2 y were not significantly related to 5-y cognition. Conclusions: A nurturing home context in terms of a healthy/clean environment and household wealth, provision of adequate micronutrients, maternal education, and cognitive reasoning have a strong and persistent influence on child cognitive development. Efforts addressing aspects of poverty around micronutrient status, nurturing caregiving, and enabling home environments are likely to have lasting positive impacts on child cognitive development. publishedVersion

OBJECTIVES: To identify clusters of cognitive developmental trajectories and associated differentiating factors of children aged 6 to 60 months old in 5 low to middle-income sites. METHODS: We followed 835 children and assessed anthropometry at enrolment (≤ 17 d old); bi-weekly illness data (0–24 and 60 mo); non-diarrheal and diarrheal stools (0–24 mo) analyzed for a panel of enteropathogens; quantitative complementary food intakes (9–24 and 60 mo); micronutrient status (Fe, Zn, Vit A; 7, 15, and 24 mo); quality of the child's home environment (6, 24, and 60 mo) and maternal reasoning ability and depressive symptoms via questionnaire. Child cognitive development was assessed by the Bayley Scales of Infant Development III (6, 15 and 24 mo) and Wechsler Preschool and Primary Scale of Intelligence (60 mo). Clusters of trajectories were identified using a latent class mixed model. Differences between clusters were described using discriminant analysis to rank the contribution of each variable using correlation-adjusted t-scores (CAT). RESULTS: Five clusters were identified. From 51 discriminatory factors, 10 had greatest descriptive power: HOME score at 60 mo (mean CAT(2 )± SD: 34.6 ± 0.35), proportion of days ill from 0–24 mo (23.9 ± 0.18), years of maternal schooling (13.8 ± 0.23), mean nutrient densities of zinc (12.3 ± 0.07), protein (8.95 ± 0.09), vitamin B6 (8.2 ± 0.10), phytate (7.91 ± 0.05) and mean energy (7.82 ± 0.04) from complementary foods (9–24 mo), % days of exclusive breastfeeding (0–6 mo; 6.42 ± 0.10) and weight-for-age at enrolment (6.14 ± 0.17). The discriminant analysis model fit was statistically significant (Wilk's λ 0.54, P

Supplemental material, Appendix_A._MALED_Investigators_JPA for Assessing Early Childhood Fluid Reasoning in Low- and Middle-Income Nations: Validity of the Wechsler Preschool and Primary Scale of Intelligence Across Seven MAL-ED Sites by Linda Ruan-Iu, Laura L. Pendergast, Muneera Rasheed, Fahmida Tofail, Erling Svensen, Angelina Maphula, Reeba Roshan, Baitun Nahar, Rita Shrestha, Brittney Williams, Barbara A. Schaefer, Rebecca Scharf, Laura E. Caulfield, Jessica Seidman and Laura E. Murray-Kolb in Journal of Psychoeducational Assessment

In a multisite birth cohort study, we document a high burden of Campylobacter infection using enzyme immunoassay, demonstrate an association between Campylobacter and linear growth shortfalls and both increased intestinal permeability and intestinal and systemic inflammation, and identify potential interventions., Background. Enteropathogen infections have been associated with enteric dysfunction and impaired growth in children in low-resource settings. In a multisite birth cohort study (MAL-ED), we describe the epidemiology and impact of Campylobacter infection in the first 2 years of life. Methods. Children were actively followed up until 24 months of age. Diarrheal and nondiarrheal stool samples were collected and tested by enzyme immunoassay for Campylobacter. Stool and blood samples were assayed for markers of intestinal permeability and inflammation. Results. A total of 1892 children had 7601 diarrheal and 26 267 nondiarrheal stool samples tested for Campylobacter. We describe a high prevalence of infection, with most children (n = 1606; 84.9%) having a Campylobacter-positive stool sample by 1 year of age. Factors associated with a reduced risk of Campylobacter detection included exclusive breastfeeding (risk ratio, 0.57; 95% confidence interval, .47–.67), treatment of drinking water (0.76; 0.70–0.83), access to an improved latrine (0.89; 0.82–0.97), and recent macrolide antibiotic use (0.68; 0.63–0.74). A high Campylobacter burden was associated with a lower length-for-age Z score at 24 months (−1.82; 95% confidence interval, −1.94 to −1.70) compared with a low burden (−1.49; −1.60 to −1.38). This association was robust to confounders and consistent across sites. Campylobacter infection was also associated with increased intestinal permeability and intestinal and systemic inflammation. Conclusions. Campylobacter was prevalent across diverse settings and associated with growth shortfalls. Promotion of exclusive breastfeeding, drinking water treatment, improved latrines, and targeted antibiotic treatment may reduce the burden of Campylobacter infection and improve growth in children in these settings.

Paramount among the challenges to our ability to address the role of food and nutrition in health promotion and disease prevention is how to design and implement context-specific interventions and guidance. The Integration to Effective Implementation (I-to-I) concept is intended to address the complexities of the global health context through engagement of the continuum of stakeholders involved in the food and nutrition enterprise. The 2014 Micronutrient Forum (MNF) Global Conference held in Addis Ababa, Ethiopia, in June 2014 offered the opportunity to apply the I-to-I approach with the use of current concerns about the safety and effectiveness of interventions to prevent and treat iron deficiency (ID) as a case study. ID is associated with a range of adverse outcomes, especially in pregnant and nonpregnant women, infants, and primary school-age children. Strategies to combat ID include iron supplementation, multiple micronutrient powders, and food-based interventions to enhance dietary iron intake. Recent reports indicate potential increased adverse risks when iron is provided in areas with high infection burdens (e.g., malaria). This paradox has weakened iron intervention programs. Furthermore, the selection and interpretation of available biomarkers for assessing iron nutrition have been found to be compromised by the inflammatory process. These issues highlight the need for a comprehensive approach that considers basic biology, assessment, interventions, and how these can be translated into appropriate programs and policies. The application of the I-to-I with the use of the MNF offered an opportunity to explore how that might be achieved.

Biofortification is the breeding of crops to increase their nutritional value, including increased contents of micronutrients or their precursors. Biofortification aims to increase nutrient levels in crops during plant growth rather than during processing of the crops into foods. Emerging research from 8 human trials conducted in the past decade with staple food crops that have been biofortified by traditional plant breeding methods were presented in this symposium. Specifically, data from 6 efficacy and 2 effectiveness trials were discussed to assess the effects of regular consumption of these enhanced staple crops on improving population vitamin A and iron status and reducing the burden of micronutrient deficiencies in targeted populations living in South Asia, Sub-Saharan Africa, and Latin America. Biofortified food crops appear to have a positive impact on nutritional and functional health outcomes, as the results from the trials suggest. Additional implementation research will be needed to ensure maximization of the beneficial impact of this intervention and a smooth scaling up to make biofortification a sustainable intervention in public health. The challenge for the global health community remains how to take this efficacious intervention and implement at large scale in the real world.

In Nepal, antenatal iron-folic acid supplementation improved aspects of intellectual, executive, and fine motor function among school-age children. We examined the impact of added zinc to the maternal antenatal supplement (M-IFAZn) and preschool supplementation from 12 to 36 mo with iron-folic acid (C-IFA) ± zinc (C-IFAZn) on cognitive outcomes compared to maternal iron-folic acid (M-IFA) alone. Children 7-9 y old (n = 780) who participated in early childhood micronutrient supplementation trial during 2001-2004 and whose mothers participated in an antenatal micronutrient supplementation between 1999 and 2001 were followed for cognitive assessments in 2007-2009. Using multivariate analysis of variance and adjusting for confounders, M-IFA with child supplementation (either C-IFA or C-IFAZn) did not impact scores on the tests of general intelligence (Universal Nonverbal Intelligence Test), and executive function (Stroop and go/no go tests) relative to the M-IFA alone. However, children in the C-IFAZn group had slightly lower scores on the backward digit span (-0.29, 95% CI: -0.55, -0.04) and Movement Assessment Battery for Children (1.33, 95% CI: 0.26, 2.40) relative to the referent group, whereas both C-IFA (-1.92, 95% CI: -3.12, -0.71) and C-IFAZn (-1.78, 95% CI: -2.63, -0.92) produced somewhat lower finger tapping test scores (fine motor skills). The combination of M-IFAZn and C-IFA or C-IFAZn did not lead to any outcome differences relative to M-IFA alone. Preschool iron-folic acid ± zinc to children exposed to iron-folic acid in utero or addition of zinc to maternal iron-folic acid conferred no additional benefit to cognitive outcomes assessed in early school age. The late timing of supplementation during preschool may explain the lack of impact of iron and/or zinc.

Iron deficiency (ID) anemia is associated with poor neurocognitive development in infants and children. Depending on the stage of development at the time of deficiency, these adverse effects may be reversible. Recent investigations using sensitive measurements have confirmed that the deposition of iron in the brain varies according to brain region and age, and that dopamine-dependent behaviors are among the core deficits in ID. Dr John Beard (1947-2009) has been one of the leading scientists and pioneers in the area of iron and child development. His legacy to this area of science will grow through the continuation of his work by his co-workers and colleagues.