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Background A large proportion of infants in low- and middle-income countries are stunted. These infants are often fed complementary foods that are low-quality, primarily in terms of protein and micronutrients. Objectives We aimed to test 2 milk–cereal mixes supplemented with modest and high amounts of protein during 6–12 mo of age, compared with no supplementation, for their effect on length-for-age z score (LAZ) at 12 mo of age. Methods Eligible infants (6 mo plus ≤29 d) were randomly assigned to either of the 2 interventions (modest- and high-protein) or a no supplement group. The milk–cereal mixes provided ∼125 kcal, 30%–45% energy from fats, and 80%–100% RDA of multiple micronutrients (MMN). The modest-protein group received 2.5 g protein [protein energy ratio (PER): 8%; 0.75 g from milk source] and the high-protein group received 5.6 g protein (PER: 18%, 1.68 g from milk source). One packet was given daily for 180 d. Counseling on continued breastfeeding and optimal infant-care practices was provided to all. Results We enrolled 1548 infants (high-protein: n = 512; modest-protein: n = 519; and no supplement: n = 517). Compared with the no supplement group, there was an improvement in LAZ [adjusted mean difference (MD): 0.08; 95% CI: 0.01, 0.15], weight-for-age z score (MD: 0.12; 95% CI: 0.06, 0.19), weight-for-length z score (MD: 0.11; 95% CI: 0.02, 0.19), and midupper arm circumference z score (MD: 0.10; 95% CI: 0.02, 0.18) in the high-protein group at 12 mo of age. No significant differences for these anthropometric indicators were noted between the modest-protein and no supplement groups or between the high- and modest-protein groups. Conclusions Cereal mixes with higher amounts of milk-based protein and MMN may lead to improvement in linear growth and other anthropometric indexes in infants, compared with no supplementation. This trial was registered at ctri.nic.in as CTRI/2018/04/012932.

Background In lower-middle-income settings, growth faltering in the first 6 mo of life occurs despite exclusive breastfeeding. Objective The aim was to test the efficacy of an approach to improve the dietary adequacy of mothers during lactation and thus improve the growth of their infants. Methods Eligible mother–infant dyads (infants ≤7 d of age) were randomly assigned to either intervention or control groups. Mothers in the intervention group received snacks that were to be consumed daily, which provided 600 kcal of energy—with 25–30% of energy derived from fats (150–180 kcal) and 13% of energy from protein (80 kcal). Micronutrients were supplemented as daily tablets. We provided counseling on breastfeeding and infant-care practices to mothers in both groups. The primary outcome was attained infant length-for-age z scores (LAZ) at 6 mo of age. Secondary outcomes included exclusive breastfeeding proportion reported by the mother, maternal BMI and midupper arm circumference (MUAC), hemoglobin concentrations in mothers and infants, and the proportion of anemic infants at 6 mo of age. Results We enrolled 816 mother–infant dyads. The intervention did not achieve a significant effect on LAZ at 6 mo (adjusted mean difference: 0.09; 95% CI: −0.03, 0.20). Exclusive breastfeeding at 5 mo was higher (45.1% vs. 34.5%; RR: 1.31; 95% CI: 1.04, 1.64) in the intervention group compared with the controls. There were no significant effects on mean hemoglobin concentration or the proportion of anemic infants at 6 mo of age compared with the control group. We noted significant effects on maternal nutritional status (BMI, MUAC, hemoglobin concentration, and proportion anemic). Conclusions Postnatal supplementation of 600 kcal energy, 20 g protein, and multiple micronutrients daily to lactating mothers did not affect infant LAZ at age 6 mo. Such supplementation may improve maternal nutritional status. This trial was registered at Clinical Trials Registry–India as CTRI/2018/04/013095.

Summary Background Coverage of kangaroo mother care remains very low despite WHO recommendations for its use for babies with low birthweight in health facilities for over a decade. Initiating kangaroo mother care at the community level is a promising strategy to increase coverage. However, knowledge of the efficacy of community-initiated kangaroo mother care is still lacking. We aimed to assess the effect of community-initiated kangaroo mother care provided to babies weighing 1500–2250 g on neonatal and infant survival. Methods In this randomised controlled, superiority trial, undertaken in Haryana, India, we enrolled babies weighing 1500–2250 g at home within 72 h of birth, if not already initiated in kangaroo mother care, irrespective of place of birth (ie, home or health facility) and who were stable and feeding. The first eligible infants in households were randomly assigned (1:1) to the intervention (community-initiated kangaroo mother care) or control group by block randomisation using permuted blocks of variable size. Twins were allocated to the same group. For second eligible infants in the same household as an enrolled infant, if the first infant was assigned to the intervention group the second infant was also assigned to this group, whereas if the first infant was assigned to the control group the second infant was randomly assigned (1:1) to the intervention or control group. Mothers and infants in the intervention group were visited at home (days 1–3, 5, 7, 10, 14, 21, and 28) to support kangaroo mother care (ie, skin-to-skin contact and exclusive breastfeeding). The control group received routine care. The two primary outcomes were mortality between enrolment and 28 days and between enrolment and 180 days. Analysis was by intention to treat and adjusted for clustering within households. The effect of the intervention on mortality was assessed with person-time in the denominator using Cox proportional hazards model. This study is registered with ClinicalTrials.gov , NCT02653534 and NCT02631343 , and is now closed to new participants. Findings Between July 30, 2015, and Oct 31, 2018, 8402 babies were enrolled, of whom 4480 were assigned to the intervention group and 3922 to the control group. Most births (6837 [81·4%]) occurred at a health facility, 36·2% (n=3045) had initiated breastfeeding within 1 h of birth, and infants were enrolled at an average of about 30 h (SD 17) of age. Vital status was known for 4470 infants in the intervention group and 3914 in the control group at age 28 days, and for 3653 in the intervention group and 3331 in the control group at age 180 days. Between enrolment and 28 days, 73 infants died in 4423 periods of 28 days in the intervention group and 90 deaths in 3859 periods of 28 days in the control group (hazard ratio [HR] 0·70, 95% CI 0·51–0·96; p=0·027). Between enrolment and 180 days, 158 infants died in 3965 periods of 180 days in the intervention group and 184 infants died in 3514 periods of 180 days in the control group (HR 0·75, 0·60–0·93; p=0·010). The risk ratios for death were almost the same as the HRs (28-day mortality 0·71, 95% CI 0·52– 0·97; p=0·032; 180-day mortality 0·76, 0·60–0·95; p=0·017). Interpretation Community-initiated kangaroo mother care substantially improves newborn baby and infant survival. In low-income and middle-income countries, incorporation of kangaroo mother care for all infants with low birthweight, irrespective of place of birth, could substantially reduce neonatal and infant mortality. Funding Research Council of Norway and University of Bergen.

The aim of this study was to examine the association between vitamin D deficiency and anemia status among young children in the resource-poor setting of northern urban India.We used data from a randomized controlled trial of daily supplementation with folic acid, vitamin B25-Hydroxyvitamin-D (25 OHD) concentration was measured for 960 (96%) children. Of the children, 331 (34.5%) were vitamin-D deficient (10 ng/mL). Approximately 70% of the enrolled children were anemic, with ∼46% having moderate (Hgb 7-9.9 g/dL) and 24% mild (Hgb 10-10.9 g/dL) anemia. There was no association between vitamin D and anemia status after adjusting for confounders; however, the risk for moderate anemia was significantly higher among vitamin D-deficient children than those who were vitamin-D replete (relative risk, 1.58; 95% confidence interval, 1.09-2.31).Vitamin D deficiency was associated with moderate anemia among young children and the effect was independent of iron deficiency. The causal association of vitamin D deficiency with anemia risk remains debatable. The role of vitamin D in risk for anemia needs to be examined in further studies.

Summary COVID-19 has had negative repercussions on the entire global population. Despite there being a common goal that should have unified resources and efforts, there have been an overwhelmingly large number of clinical trials that have been registered that are of questionable methodological quality. As the final paper of this Series, we discuss how the medical research community has responded to COVID-19. We recognise the incredible pressure that this pandemic has put on researchers, regulators, and policy makers, all of whom were doing their best to move quickly but safely in a time of tremendous uncertainty. However, the research community's response to the COVID-19 pandemic has prominently highlighted many fundamental issues that exist in clinical trial research under the current system and its incentive structures. The COVID-19 pandemic has not only re-emphasised the importance of well designed randomised clinical trials but also highlighted the need for large-scale clinical trials structured according to a master protocol in a coordinated and collaborative manner. There is also a need for structures and incentives to enable faster data sharing of anonymised datasets, and a need to provide similar opportunities to those in high-income countries for clinical trial research in low-resource regions where clinical trial research receives considerably less research funding.

Summary Background & aims The main objective of this report is to measure to what extent folate or vitamin B12 given daily for 6 months to young North Indian Children improves hemoglobin (Hb) concentration. Methods In a randomized placebo controlled trial in low-to-middle income neighborhoods in New Delhi, India, children were randomized into four groups in a 1:1:1:1 ratio and supplemented daily for 6 months with 2 RDAs of vitamin B12, folic acid, both, or placebo. All children with anemia at baseline were given iron supplementation daily for 2 months. We measured the plasma concentrations of soluble transferrin receptor (sTfR), folate, vitamin B12, total homocysteine (tHcy) and Hb in 262 children. Results Mean Hb concentration decreased in all four study groups during the six months of follow up and supplementation of either or both of the vitamins did not improve the Hb concentration. Iron supplements for the initial 2 mo had limited effect on anemia at 6 mo as almost 90% were still anemic at study end. Conclusion Supplementation of folic acid and/or vitamin B12 for 6 months does not improve Hb concentration in young children. Our findings do not argue for widespread vitamin B12 or folic acid supplementation to combat anemia. Our results also call for alternative strategies to improve iron status and treat iron deficiency anemia. Clinical trial registry NCT00717730 at www.clinicaltrials.gov , CTRI No.: CTRI/2010/091/001090 at www.ctri.nic.in .

Background: Kangaroo Mother Care (KMC), defined as prolonged skin-to-skin contact of the low birth weight baby with the mother and exclusive breastfeeding, is highly effective in reducing neonatal mortality. Yet the coverage of KMC globally is 8 hours of skin to skin contact per day and exclusive breastfeeding) before discharge, and 7 days after discharge, among infants with birth weight

Background: Linear growth faltering in the first 2 y contributes greatly to a high stunting burden, and prevention is hampered by the limited capacity in primary health care for timely screening and intervention. Objective: This study aimed to determine an approach to predicting long-term stunting from consecutive 1-mo weight increments in the first year of life. Methods: By using the reference sample of the WHO velocity standards, the analysis explored patterns of consecutive monthly weight increments among healthy infants. Four candidate screening thresholds of successive increments that could predict stunting were considered, and one was selected for further testing. The selected threshold was applied in a cohort of Bangladeshi infants to assess its predictive value for stunting at ages 12 and 24 mo. Results: Between birth and age 12 mo, 72.6% of infants in the WHO sample tracked within 1 SD of their weight and length. The selected screening criterion ("event") was 2 consecutive monthly increments below the 15th percentile. Bangladeshi infants were born relatively small and, on average, tracked downward from approximately age 6 to

Summary Background Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India. Methods We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6–7 weeks were randomly assigned (2:1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6–7 weeks, 10 weeks, and 14 weeks. Infants' families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (≥11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry–India (CTRI/2010/091/000102) and ClinicalTrials.gov (NCT01305109). Findings 4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53·6% (95% CI 35·0–66·9; p=0·0013) and 56·4% (36·6–70·1; p Interpretation Monovalent human-bovine (116E) rotavirus vaccine is effective and well tolerated in Indian infants. Funding Department of Biotechnology and the Biotechnology Industry Research Assistance Council, Government of India; Bill & Melinda Gates Foundation to PATH, USA; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; and Bharat Biotech International, Hyderabad, India.

OBJECTIVES: The extent to which vitamin-D deficiency (

Background: Young children in low- and middle-income countries frequently have inadequate vitamin B-12 (cobalamin) status. Poor folate status is also common and is associated with increased diarrheal and respiratory morbidity. Objective: The objective was to measure the effect of folic acid and/or vitamin B-12 administration on the incidence of diarrhea and acute lower respiratory tract infections. Design: One thousand North Indian children (6230 mo of age) were enrolled in a randomized, double-blind, placebo-controlled trial to receive 2 times the Recommended Dietary Allowance of folic acid and/or vitamin B-12 or placebo daily for 6 mo. Children were individually randomly assigned in a 1:1:1:1 ratio in blocks of 16. Primary outcomes were the number of episodes of acute lower respiratory infections, diarrhea, and prolonged diarrhea. Results: Folic acid and vitamin B-12 supplementation significantly improved vitamin B-12 and folate status, respectively. Neither folic acid nor vitamin B-12 administration reduced the incidence of diarrhea or lower respiratory infections. In comparison with placebo, children treated with folic acid alone or in combination with vitamin B-12 had a significantly higher risk of persistent diarrhea (OR: 2.1; 95% CI: 1.1, 3.8). Conclusions: Folic acid or vitamin B-12 supplementation did not reduce the burden of common childhood infections. In view of the increased risk of diarrhea, the safety of folic acid supplements in young children should be further assessed. This trial was registered at www.clinicaltrials.gov as NCT00717730 and at www.ctri.nic.in as CTRI/2010/091/001090. Am J Clin Nutr doi: 10.3945/ajcn. 113.059592.

Poor micronutrient status is associated with diarrheal illness, but it is not known whether low folate and/or cobalamin status are independent risk factors for diarrhea. We measured the association between plasma folate and cobalamin and subsequent diarrheal morbidity in a prospective cohort study of 2296 children aged 6-30 mo in New Delhi, India. Plasma concentrations of folate, cobalamin, total homocysteine (tHcy), and methylmalonic acid were determined at baseline. Whether a child had diarrhea was recorded during weekly visits in a 4-mo zinc supplementation trial. Diarrhea episodes lasting7, ≥7, and ≥14 d were classified as acute, prolonged, and persistent, respectively. There was a total of 4596 child periods with acute, 633 with prolonged, and 117 with persistent diarrhea during follow-up. Children with plasma folate concentrations in the lowest quartile had higher odds of persistent diarrhea than children in the other quartiles [adjusted OR = 1.77 (95% CI = 1.14, 2.75); P = 0.01]. This effect differed between boys [adjusted OR = 2.51 (95% CI = 1.47, 4.28)] and girls [adjusted OR = 1.03 (95% CI = 0.53, 2.01); P-interaction = 0.030]. We found a small but significant association between high plasma tHcy concentration and acute diarrhea [adjusted OR = 1.14 (95% CI = 1.04, 1.24); P = 0.006]. Plasma cobalamin concentration was not a predictor of diarrheal morbidity. In conclusion, poor folate status was an independent predictor of persistent diarrhea in this population.

BACKGROUND Pneumonia is a leading cause of illness and death in young children. Interventions to improve case management of pneumonia are needed. OBJECTIVE Our objective was to measure the effect of zinc supplementation in children with pneumonia in a population in which zinc deficiency is common. DESIGN In a double-blind, placebo-controlled clinical trial, children aged 2-35 mo with severe (n = 149) or nonsevere (n = 2479) pneumonia defined according to criteria established by the World Health Organization were randomly assigned to receive zinc (10 mg for children aged 2-11 mo, 20 mg for children aged > or =12 mo) or placebo daily for 14 d as an adjuvant to antibiotics. The primary outcomes were treatment failure, defined as a need for change in antibiotics or hospitalization, and time to recovery from pneumonia. RESULTS One of 5 children did not respond adequately to antibiotic treatment; the odds ratios between zinc and placebo groups for treatment failure were 0.95 (95% CI: 0.78, 1.2) for nonsevere pneumonia and 0.97 (95% CI: 0.42, 2.2) for severe pneumonia. There was no difference in time to recovery between zinc and placebo groups for nonsevere (median: 2 d; hazard ratio: 1.0; 95% CI: 0.96, 1.1) or severe (median: 4 d; hazard ratio: 1.1; 95% CI: 0.79, 1.5) pneumonia. Regurgitation or vomiting < or =15 min after supplementation was observed more frequently among children in the zinc group than among those in the placebo group during the supplementation period (37% compared with 13%; odds ratio: 0.25; 95% CI: 0.20, 0.30). CONCLUSION Adjuvant treatment with zinc neither reduced the risk of treatment failure nor accelerated recovery in episodes of nonsevere or severe pneumonia. This trial was registered at clinicaltrials.gov as NCT00148733.

Our objective in this trial was to assess the impact of daily zinc supplementation on growth in young children. A double-blind, randomized, placebo-controlled trial was conducted in New Delhi, India. We enrolled 2482 children aged 6-30 mo who were supplemented daily with placebo or zinc (10 mg elemental zinc to infants and 20 mg to older children) for 4 mo. At enrollment, all children also received a single dose of vitamin A (104.7 micromol for infants and 209.4 micromol for older children). Weight and length were measured at enrollment and 4 mo later. Weekly visits were conducted by field workers to ascertain morbidity in the previous 7 d. Change in length, weight, length-for-age Z-scores (LAZ), and weight-for-length Z-scores (WLZ) after 4 mo of supplementation were assessed in the zinc and placebo groups. After 4 mo of supplementation, the weight and length gains in the 2 groups did not differ and there was no impact on LAZ, weight-for-age, and WLZ in the 2 groups. There was no substantial effect in any of the subgroups defined for age, income, gender, zinc levels in the crude analysis nor after adjusting for age, gender, income, breast-feeding status, and baseline anthropometric status. Despite successful zinc supplementation reflected in increased plasma zinc concentration and a substantially reduced incidence of diarrhea and pneumonia in zinc-supplemented children, the intervention did not have a beneficial effect on growth.

Background: Low-birth-weight infants may have impaired zinc status, but little is known about the effect of zinc supplementation. Objective: The objective was to investigate the effect of daily zinc supplementation on morbidity and anthropometric status in hospitalborn, low-birth-weight infants. Design: In a double-blind, randomized, placebo-controlled trial, 2052 hospital-born term infants with a birth weight 2500 g were randomly assigned to receive zinc or placebo. The zinc group received elemental zinc: 5 mg/d for those infants between ages 2 wk and 6 mo and 10 mg/d for those infants aged .6 mo. All-cause hospitalizations, prevalence of diarrhea, acute lower respiratory tract infections, visits to health care providers, weights, and lengths were ascertained at 3, 6, 9, and 12 mo of age. Results: The supplement was consumed for .85% of the follow-up period. Mean plasma zinc at 12 mo of age was higher in the zinc group (100.2 lg/dL) than in the control group (73.3 lg/dL) (difference in means: 26.9; 95% CI: 19.6, 34.2). The 24-h and 7-d prevalence of diarrhea and acute lower respiratory tract infections was similar at 3, 6, 9, and 12 mo. Care-seeking for illness was significantly lower in the zinc group (difference in proportions: 25.7; 95% CI: 29.9, 21.4; P , 0.05) at 9 mo. The numbers of hospitalizations, weights, and lengths were all similar at all 4 assessments. Conclusion: Hospital-born, term, low-birth-weight infants do not seem to benefit substantially from zinc supplementation that meets the Recommended Dietary Allowance for zinc in terms of morbidity or physical growth during infancy in this setting. This trial was registered at www.clinicaltrials.gov as NCT00272142. Am J Clin Nutr 2009;90:385‐91.

Vitamin deficiencies are often part of malnutrition, which predisposes to acute lower respiratory tract infections.The objective was to measure the association between cobalamin and folate status and subsequent respiratory morbidity.A prospective cohort study was conducted in 2482 children aged 6-30 mo nested in a zinc supplementation trial. We measured plasma concentrations of folate, cobalamin, methylmalonic acid, and total homocysteine (tHcy) and followed the children for 4 mo.We observed 1176 episodes of acute lower respiratory tract infections. Children with folate concentrations in the lowest quartile (interquartile range: 6.4-20.0 nmol/L) had a 44% higher incidence [adjusted incidence rate ratio (IRR): 1.44; 95% CI: 1.23, 1.70] of acute lower respiratory tract infections than did children in the other 3 quartiles. For tHcy, the IRR was 1.24 (1.07, 1.40) in a comparison of those in the highest quartile with those in the other quartiles. Breastfeeding was associated with high folate concentrations and protection against subsequent respiratory tract infections. This protection was significantly and substantially reduced after adjustment for plasma folate concentrations at baseline. Compared with the children in the other 3 quartiles, the IRR for being in the lowest quartile of cobalamin was 1.13 (0.76, 1.03) and for being in the highest quartile of methylmalonic acid was 1.12 (0.96, 1.31).Poor folate status appears to be an independent risk factor for lower respiratory tract infections in young children. This study also suggests that the protective effect of breastfeeding is partly mediated by folate provided through breast milk.

Exclusive breastfeeding is recommended until age 6 months. We assessed the feasibility, effectiveness, and safety of an educational intervention to promote exclusive breastfeeding for this length of time in India.We developed the intervention through formative research, pair-matched eight communities on their baseline characteristics, and randomised one of each pair to receive the intervention and the other to no specific intervention. We trained health and nutrition workers in the intervention communities to counsel mothers for exclusive breastfeeding at multiple opportunities. We enrolled 1115 infants born in the 9 months after training-552 in the intervention and 473 in the control communities. Feeding at age 3 months, and anthropometry and of diarrhoea prevalence at age 3 months and 6 months were assessed. All analyses were by intention to treat.We assessed 483 and 412 individuals at 3 months in the intervention and control groups, respectively, and 468 and 412 at 6 months. At 3 months, exclusive breastfeeding rates were 79% (381) in the intervention and 48% (197) in the control communities (odds ratio 4.02, 95% CI 3.01-5.38, p0.0001). The 7-day diarrhoea prevalence was lower in the intervention than in the control communities at 3 months (0.64, 0.44-0.95, p=0.028) and 6 months (0.85, 0.72-0.99, p=0.04). The mean weights and lengths, and the proportion with weight-for-height or height-for-age Z scores of 2 or less, at age 3 months and 6 months did not differ much between groups. Intervention effect on exclusive breastfeeding, diarrhoeal morbidity, and anthropometry at age 6 months in the low-birthweight subgroup was similar to that for all births.Promotion of exclusive breastfeeding until age 6 months in a developing country through existing primary health-care services is feasible, reduces the risk of diarrhoea, and does not lead to growth faltering.

The association between low initial plasma zinc concentration and risk of morbidity over the subsequent 3 mo was examined in a cohort of 116 children aged 12-59 mo recovering from acute diarrhea. Children with low initial plasma zinc (or = 8.4 micromol/L) had more episodes of diarrhea [risk ratio (RR): 1.47; 95% CI: 1.03, 2.49) and severe diarrhea, defined as passage ofor = 5 liquid stools in a 24-h period, (RR: 1.70; 95% CI: 1.06, 2.72) than did children with normal plasma zinc (8.4 micromol/L). The mean prevalence rate of diarrhea associated with fever was 4 times higher in the zinc-deficient group (P = 0.01). Overall, the difference in the number of episodes of acute lower respiratory tract infections (ALRIs) between the two groups was not statistically significant (RR: 1.76; 95% CI: 0.88-3.53) but the mean prevalence rate of ALRIs was 3.5 times higher in children with low plasma zinc (P = 0.05). The increased risk of diarrhea and ALRIs episodes in zinc-deficient children was larger in boys than in girls. These results show that children with low plasma zinc concentrations are at risk for increased diarrheal and respiratory morbidity.