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Vitamin B12 deficiency is common and affects cell division and differentiation, erythropoiesis, and the central nervous system. Several observational studies have demonstrated associations between biomarkers of vitamin B12 status with growth, neurodevelopment, and anemia. The objective of this study was to measure the effects of daily supplementation of vitamin B12 for 1 year on neurodevelopment, growth, and hemoglobin concentration in infants at risk of deficiency. This is a community-based, individually randomized, double-blind placebo-controlled trial conducted in low- to middle-income neighborhoods in Bhaktapur, Nepal. We enrolled 600 marginally stunted, 6- to 11-month-old infants between April 2015 and February 2017. Children were randomized in a 1:1 ratio to 2 μg of vitamin B12, corresponding to approximately 2 to 3 recommended daily allowances (RDAs) or a placebo daily for 12 months. Both groups were also given 15 other vitamins and minerals at around 1 RDA. The primary outcomes were neurodevelopment measured by the Bayley Scales of Infant and Toddler Development 3rd ed. (Bayley-III), attained growth, and hemoglobin concentration. Secondary outcomes included the metabolic response measured by plasma total homocysteine (tHcy) and methylmalonic acid (MMA). A total of 16 children (2.7%) in the vitamin B12 group and 10 children (1.7%) in the placebo group were lost to follow-up. Of note, 94% of the scheduled daily doses of vitamin B12 or placebo were reported to have been consumed (in part or completely). In this study, we observed that there were no effects of the intervention on the Bayley-III scores, growth, or hemoglobin concentration. Children in both groups grew on an average 12.5 cm (SD: 1.8), and the mean difference was 0.20 cm (95% confidence interval (CI): -0.23 to 0.63, P = 0.354). Furthermore, at the end of the study, the mean difference in hemoglobin concentration was 0.02 g/dL (95% CI: -1.33 to 1.37, P = 0.978), and the difference in the cognitive scaled scores was 0.16 (95% CI: -0.54 to 0.87, P = 0.648). The tHcy and MMA concentrations were 23% (95% CI: 17 to 30, P < 0.001) and 30% (95% CI: 15 to 46, P < 0.001) higher in the placebo group than in the vitamin B12 group, respectively. We observed 43 adverse events in 36 children, and these events were not associated with the intervention. In addition, 20 in the vitamin B12 group and 16 in the placebo group were hospitalized during the supplementation period. Important limitations of the study are that the strict inclusion criteria could limit the external validity and that the period of vitamin B12 supplementation might not have covered a critical window for infant growth or brain development. In this study, we observed that vitamin B12 supplementation in young children at risk of vitamin B12 deficiency resulted in an improved metabolic response but did not affect neurodevelopment, growth, or hemoglobin concentration. Our results do not support widespread vitamin B12 supplementation in marginalized infants from low-income countries. ClinicalTrials.gov NCT02272842 Universal Trial Number: U1111-1161-5187 (September 8, 2014) Trial Protocol: Original trial protocol: PMID: 28431557 (reference [18]; study protocols and plan of analysis included as Supporting information).

Background The Ages and Stages Questionnaire 3rd edition (ASQ-3) could be a feasible tool in resource-poor settings. Little is known on the relationship between scores on the ASQ-3 and later intellectual abilities in these settings. Aims To examine the relationship between ASQ-3 scores during the first and second year of life and intellectual abilities at 4 years of age in Nepalese children. Methods In a cohort of 600 children at-risk of stunting, the ASQ-3 was performed at 6–11 and 18–23 months, and the Wechsler Preschool and Primary Scales of Intelligence, fourth edition (WPPSI-IV) at 4 years. We examined the relationship between the ASQ-3 scores and WPPSI-IV full scale IQ (FSIQ) using Spearman correlation coefficients and linear regression models. Results Correlations between ASQ-3 total scores and FSIQ was 0.17 (95% CI 0.07, 0.27) at 6–11 and 0.34 (95% CI 0.26, 0.44) at 18–23 months explaining 2 and 12% of the variance respectively. Except for the communication subscale at 18–23 months with moderate correlations, correlations between the ASQ-3 subscales and FSIQ were weak. Conclusion Our findings suggest a modest relationship between ASQ-3 scores in early childhood and intellectual abilities at 4 years.

Children in low and middle-income countries have a high burden of pneumonia. Measuring the cytokine responses may be useful to identify novel markers for diagnosing, monitoring, and treating pneumonia. To describe and compare a wide range of inflammatory mediators in plasma from children with WHO-defined severe and non-severe community acquired pneumonia (CAP), and explore to what extent certain mediators are associated with severity and viral detection. We collected blood samples from 430 children with severe (n = 43) and non-severe (n = 387) CAP. Plasma from these children were analysed for 27 different cytokines, and we measured the association with age, disease severity and viral detection. There were generally higher plasma concentrations of several cytokines with both pro-inflammatory and anti-inflammatory effects among children with severe CAP than in children with non-severe CAP. We found significantly higher concentrations of interleukin (IL)-1, IL-4, IL-6, IL-8, IL-9, IL-15, eotaxin, basic fibroblast growth factor (b-FGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-α) in the group of severe CAP. Most of these associations persisted when adjusting for age in linear regression analyses. The cytokine response was strongly associated with age but to a lesser extent with viral etiology. The plasma concentrations of several cytokines, both with pro-inflammatory and anti-inflammatory effects, were higher among children with severe illness. In particular G-CSF and IL-6 reflected severity and might provide complementary information on the severity of the infection. ClinicalTrials.gov NCT00148733.

Background Social withdrawal in infants may be a signal of distress and a precursor for non-optimal development. Objective To examine the relationship between infant social withdrawal and neurodevelopment up to 4 years in Nepalese children. Methods A total of 597 Nepalese infants 6–11 months old were assessed with the modified Alarm Distress Baby Scale (m-ADBB), and of these, 527 with the Bayley Scales of Infant and Toddler Development 3rd edition (Bayley-III) during early childhood, and the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) and NEPSY-II subtests at 4 years. We examined whether social withdrawal defined by the m-ADBB was associated with neurodevelopmental scores in regression models. Results Children socially withdrawn in infancy had lower Bayley-III language scores (-2.6 (95% CI -4.5, -0.7)) in early childhood. This association seems to be driven by the expressive communication subscale (-0.7 (95% CI -1.0, -0.3)), but not the receptive communication subscale (-0.2 (95% CI -0.6, 0.1)). There were no differences in the other Bayley-III scores or the WPPSI-IV and NEPSY-II scores at 4 years in children who were socially withdrawn or not. Conclusion Social withdrawal in infancy was reflected in early language development but not cognitive functioning at 4 years.

Cobalamin and folate are essential micronutrients and are important in DNA and RNA synthesis, cell proliferation, growth, hematopoiesis, and cognitive function. However, data on cobalamin and folate status are lacking particularly from young children residing in low and middle income countries. To measure cobalamin and folate status and identifies their predictors among 6 to 35 months old children presenting with acute diarrhea. This was a cross-sectional study in 823 children presenting with acute diarrhea. We measured plasma cobalamin, folate, methylmalonic acid and total homocysteine who sought treatment for acute diarrhea between June 1998 and August 2000. The mean (SD) plasma concentrations of cobalamin, folate, total homocysteine and methylmalonic acid were 206 (124) pmol/L, 55 (32) nmol/L, 11.4 (5.6) µmol/L and 0.79 (1.2) µmol/L, respectively. The prevalence of low plasma cobalamin (<150 pmol/L) was 41% but less than 2% (15) children had low folate concentration (<10 nmol/L). Plasma homocysteine and methylmalonic acid concentrations were negatively associated with cobalamin concentration but not associated with folate status. The prevalence of cobalamin deficiency was higher in breastfed than non-breastfed children (44% vs 24%; p = <0.001). The prevalence of hyperhomocysteinemia (>10 µmol/L) and elevated methylmalonic acid (>0.28 µmol/L) were 73% and 52%, respectively. In the regression analyses, the plasma cobalamin concentration was positively associated with age, and introduction of animal or formula milk. Our study indicated that poor cobalamin status was common particularly among breastfed children. Folate deficiency was virtually none existent. Possible consequences of cobalamin deficiency in young children need to be explored.

We sought to identify predictors of extended duration of diarrhea in young children, which contributes substantially to the nearly 1 1/2 million annual diarrheal deaths globally. We followed 6-35 month old Nepalese children enrolled in the placebo-arm of a randomized controlled trial with 391 episodes of acute diarrhea from the day they were diagnosed until cessation of the episode. Using multiple logistic regression analysis, we identified independent risk factors for having diarrhea for more than 7 days after diagnosis. Infants had a 17 (95% CI 3.5, 83)-fold and toddlers (12 to 23 month olds) a 9.9 (95% CI 2.1, 47)-fold higher odds of having such illness duration compared to the older children. Not being breastfed was associated with a 9.3 (95% CI 2.4, 35.7)-fold increase in the odds for this outcome. The odds also increased with increasing stool frequency. Furthermore, having diarrhea in the monsoon season also increased the risk of prolonged illness. We found that high stool frequency, not being breastfed, young age and acquiring diarrhea in the rainy season were risk factors for prolonged diarrhea. In populations such as ours, breastfeeding may be the most important modifiable risk factor for extended duration of diarrhea.

Background Chronic obstructive pulmonary disease (COPD) is the end result of a susceptible individual being exposed to sufficiently deleterious environmental stimuli. More than 90% of COPD-related deaths occur in low- and middle-income countries (LMICs). LMICs face unique challenges in managing COPD; for example, deficient primary care systems present challenges for proper diagnosis and management. Formal diagnosis of COPD requires quality-assured spirometry, which is often limited to urban health centres. Similarly, standard treatment options for COPD remain limited where few providers are trained to manage COPD. The Global Excellence in COPD Outcomes (GECo) studies aim to assess the performance of a COPD case-finding questionnaire with and without peak expiratory flow (PEF) to diagnose COPD, and inform the effectiveness and implementation of COPD self-management Action Plans in LMIC settings. The ultimate goal is to develop simple, low-cost models of care that can be implemented in LMICs. This study will be carried out in Nepal, Peru and Uganda, three distinct LMIC settings. Methods/design We aim to assess the diagnostic accuracy of a simple questionnaire with and without PEF to case-find COPD (GECo1), and examine the effectiveness, cost-effectiveness and implementation of a community-health-worker-supported self-management Action Plan strategy for managing exacerbations of COPD (GECo2). To achieve the first aim, we will enrol a randomly selected sample of up to 10,500 adults aged ≥ 40 years across our three sites, with the goal to enrol 240 participants with moderate-to-severe COPD in to GECo2. We will apply two case-finding questionnaires (Lung Function Questionnaire and CAPTURE) with and without PEF and compare performance against spirometry. We will report ROC areas, sensitivity and specificity. Individuals who are identified as having COPD grades B–D will be invited to enrol in an effectiveness-implementation hybrid randomised trial of a multi-faceted COPD self-management Action Plan intervention delivered by CHWs. The intervention group will receive (1) COPD education, (2) facilitated-self management Action Plans for COPD exacerbations and (3) monthly visits by community health workers. The control group will receive COPD education and standard of care treatment provided by local health providers. Beginning at baseline, we will measure quality of life with the EuroQol-5D (EQ-5D) and St. George’s Respiratory Questionnaire (SGRQ) every 3 months over a period of 1 year. The primary endpoint is SGRQ at 12 months. Quality-adjusted life years (QALYs) using the Short-Form 36 version 2 will also be calculated. We will additionally assess the acceptability and feasibility of implementing COPD Action Plans in each setting among providers and individuals with COPD. Discussion This study should provide evidence to inform the use of pragmatic models of COPD diagnosis and management in LMIC settings. Trial registration NCT03359915 (GECo1). Registered on 2 December 2017 and NCT03365713 (GECo2). Registered on 7 December 2017. Trial acronym: Global Excellence in COPD Outcomes (GECo1; GECo2).

Background Vitamin B 12 deficiency is one of the most common micronutrient deficiencies and is associated with poor cognitive development and growth. Vitamin B 12 is crucial for normal cell division and differentiation, and it is necessary for the development and myelination of the central nervous system. The aim of the present study is to measure the effect of daily supplementation of vitamin B 12 on the neurodevelopment and growth of young children in Nepal. Methods/design We are conducting an individually randomized, double-blind, placebo-controlled trial with 600 marginally stunted children 6–11 months old (length for age less than −1 z-score). Children are randomized to receive a lipid-based paste containing vitamin B 12 or placebo daily for 12 months. The main outcomes are changes in growth (z-scores) and in neurodevelopment measured by the Bayley Scales of Infant and Toddler Development, Third Edition, from baseline until the end of the study. Discussion If vitamin B 12 supplementation benefits early child development and growth, this will have consequences for dietary recommendations for malnourished children worldwide. Trial registrations ClinicalTrials.gov Identifier: NCT02272842 . Registered on 21 October 2014. Universal Trial Number: U1111-1161-5187. Registered on 8 September 2014.

The WHO recommends exclusive breastfeeding for the first 6 months of life. However, the transition of the infants' diet to partial breastfeeding with the addition of animal milks and/or solids typically occurs earlier than this. Here, we explored factors associated with the timing of an early transition to partial breastfeeding across seven sites of a birth cohort study in which twice weekly information on infant feeding practices was collected. Infant (size, sex, illness and temperament), maternal (age, education, parity and depressive symptoms), breastfeeding initiation practices (time of initiation, colostrum and pre‐lacteal feeding) and household factors (food security, crowding, assets, income and resources) were considered. Three consecutive caregiver reports of feeding animal milks and/or solids (over a 10‐day period) were characterized as a transition to partial breastfeeding, and Cox proportional hazard models with time (in days) to partial breastfeeding were used to evaluate associations with both fixed and time‐varying characteristics. Overall, 1470 infants were included in this analysis. Median age of transition to partial breastfeeding ranged from 59 days (South Africa and Tanzania) to 178 days (Bangladesh). Overall, higher weight‐for‐length z‐scores were associated with later transitions to partial breastfeeding, as were food insecurity, and infant cough in the past 30 days. Maternal depressive symptoms (evaluated amongst 1227 infants from six sites) were associated with an earlier transition to partial breastfeeding. Relative thinness or heaviness within each site was related to breastfeeding transitions, as opposed to absolute z‐scores. Further research is needed to understand relationships between local perceptions of infant body size and decisions about breastfeeding.