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Objectives: To assess (a) the impact of daily preventive zinc tablets (7 mg; PZ), zinc-containing multiple micronutrient powder (10 mg zinc, and 13 other micronutrients; MNP) or placebo, delivered for 9 months, on Insulin-like Growth Factor 1 (IGF1) and IGF Binding Protein 3 (IGFBP3) among Laotian children 6–23 months, and (b) whether the effects of PZ and MNP on length-for-age z-scores (LAZ) and weight-for-age z-scores (WAZ) are modified by baseline IGF1 and IGFBP3. Design: A double-blind, placebo-controlled trial (N = 419). Methods: Plasma IGF1 and IGFBP3 concentrations at baseline and 36 weeks were analyzed by automated chemiluminescent assay. Anthropometry was assessed at baseline, at 18 and 36 weeks. Intervention effects were estimated using ANCOVA. Results: At 36 weeks, geometric mean IGF1 (~39.0–39.2 ng/mL; p = 0.99) and IGFBP3 (2038–2076 ng/mL; p = 0.83) did not differ by group. At 18 weeks (but not at 36 weeks), LAZ in the PZ group (−1.45) was higher than the MNP (−1.70) and control (−1.55) groups (p = 0.01) among children in the highest baseline IGF1 tertile (p for interaction = 0.006). At 36 weeks (but not at 18 weeks), WAZ in the PZ group (−1.55) was significantly higher than the MNP (−1.75) and control (−1.65) groups (p = 0.03), among children in the lowest baseline IGFBP3 tertile (p for interactions = 0.06). Conclusions: Although IGF1 and IGFBP3 did not respond to PZ and MNP, baseline IGF1 and IGFBP3 significantly modified the impact of PZ on linear and ponderal growth, suggesting that IGF1 bioavailability may drive catch-up growth in zinc-supplemented children

Purpose To assess the effects of intervention with a daily multiple micronutrient powder (MNP) on thiamine, riboflavin, folate, and B12 status among young Laotian children. Methods Children (n = 1704) aged 6–23 mo, participating in a double-blind placebo-controlled randomized trial were individually randomized to receive daily either MNP (containing 0.5 mg of thiamine, 0.5 mg riboflavin, 150 μg folic acid, and 0.9 μg vitamin B12 along with 11 other micronutrients) or placebo and followed for ~ 36 weeks. In a randomly selected sub-sample of 260 children, erythrocyte thiamine diphosphate (eThDP), plasma folate and B12 concentrations, and erythrocyte glutathione reductase activation coefficient (EGRac; riboflavin biomarker) were assessed at baseline and endline. Results There was no treatment effect on endline eThDP concentrations (110.6 ± 8.9 nmol/L in MNP vs. 109.4 ± 8.9 nmol/L in placebo group; p = 0.924), EGRac (1.46 ± 0.3 vs. 1.49 ± 0.3; p = 0.184) and B12 concentrations (523.3 ± 24.6 pmol/L vs. 515.9 ± 24.8 pmol/L; p = 0.678). Likewise, the prevalence of thiamine, riboflavin, and B12 deficiencies did not differ significantly between the two groups. However, endline folate concentration was significantly higher in the MNP compared to the placebo group (28.2 ± 0.8 nmol/L vs 19.9 ± 0.8 nmol/L, respectively; p p = 0.015). Conclusions Compared to a placebo, daily MNP for 9 months increased only folate but not thiamine, riboflavin, or B12 status in young Laotian children. Trial registration The trial was registered at www.clinicaltrials.gov (NCT02428647) on April 29 2015.

Zinc deficiency impairs the antibody-mediated immune response and is common in children from lower-income countries. This study aimed to investigate the impact of different zinc supplementation regimens (7, 10 or 20 mg/day elemental zinc)—therapeutic dispersible zinc tablets (TZ), daily multiple micronutrient powder (MNP), daily preventive zinc tablets (PZ) and placebo powder (control)—and compare between baseline and endline antibody production against pathogenic Escherichia coli in Laotian children (aged 6–23 months). Fifty representative plasma samples of each treatment group were randomly selected from 512 children to determine anti-E. coli IgG antibody levels and avidity. Of the 200 children, 78.5% had zinc deficiency (plasma zinc concentration E. coli IgG levels were significantly increased compared with baseline; the effect on the antibody level was more pronounced in children with zinc deficiency. Interestingly, there was increased anti-E. coli IgG avidity in the control and PZ groups. This study suggests that PZ might be the optimal zinc supplementation regimen to increase both the quantity and quality of antibody responses in children with zinc deficiency. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT02428647 (NCT02428647, 29/04/2015).

Identifying dietary nutrient gaps and interpreting their public health significance are essential for improving poor diets and reducing malnutrition. Evidence indicative of the burden of nutrient deficiencies and inadequate nutrient intake or availability exists in many countries yet is often misinterpreted or underused in decision-making. Clear guidance is lacking on how to synthesize and interpret the relevant evidence, which comes in many forms. To fill this methodological gap, an approach called Comprehensive Nutrient Gap Assessment was created to enable use of existing evidence to assess the public health significance of nutrient gaps and identify evidence gaps. Comprehensive Nutrient Gap Assessment requires ≥ 2 experts in nutritional assessment but does not require primary data collection or secondary quantitative data analysis. It can be implemented relatively quickly with low costs, for specific countries and subnational regions, and updated on the basis of new data with minimal effort. The findings from a Comprehensive Nutrient Gap Assessment are easily interpretable by nontechnical decision makers yet include clear justification for technical audiences.

Insufficient quantity and inadequate quality of foods in early life are key causes of all forms of malnutrition. Identification of nutrient and dietary gaps in the diets of infants and young children is essential to inform policies and programs designed to improve child diets. A Comprehensive Nutrient Gap Assessment was used to assess the public health significance of nutrient gaps during the complementary feeding period and to identify evidence gaps in 6 countries in Eastern and Southern Africa. Important gaps were identified in iron, vitamin A, zinc, and calcium and, to a lesser extent, vitamin B12 and folate. The best whole-food sources of these micronutrients available in part or all of the countries studied include beef liver, chicken liver, small dried fish, beef, and eggs. Investment is needed in many countries to collect data on micronutrient biomarkers and dietary intake. Strategic actions to improve child diets will require engagement and intervention across relevant systems to accelerate progress on improving the diets of infants and young children.

The objective of this study was to assess the impact of different strategies for delivering supplemental zinc on fecal myeloperoxidase (MPO), neopterin (NEO), and calprotectin (CAL) among young Laotian children. In a double-blind controlled trial, children aged 6–23 months were randomized to receive either daily preventive zinc (PZ) tablets (7 mg/day), daily micronutrient powder (MNP; containing 10 mg zinc and 14 other micronutrients), therapeutic zinc (TZ) supplements for diarrhea treatment (20 mg/day for 10 days), or daily placebo powder and followed for ∼36 weeks. Stool samples were collected at baseline and endline. Fecal MPO, NEO, and CAL concentrations were determined in a randomly selected subsample of 720 children using commercially available ELISA kits. At baseline, the mean age was 14.1 ± 4.9 months and prevalence of stunting was 39%. The endline prevalence of stunting was 43%; there was no overall treatment effect on physical growth in the parent trial. At endline, the mean (95% CI) MPO in the PZ group was 1,590 [1,396; 1,811] ng/mL and did not differ from that in the MNP (1,633 [1,434; 1,859] ng/mL), TZ (1,749 [1,535; 1,992] ng/mL), and control (1,612 [1,415; 1,836] ng/mL) groups (P = 0.749). Similarly, there was no overall treatment effect on NEO and CAL concentrations (P = 0.226 and 0.229, respectively). In this population, the provision of PZ or TZ supplements or MNP had no impact on growth or environmental enteric dysfunction (EED) as assessed by fecal MPO, NEO, and CAL. Additional research is needed to better understand the etiology and proposed mechanisms of EED pathogenesis.

Plasma zinc concentrations (PZC) have been shown to significantly increase during zinc supplementation. This study investigated the effects of daily preventive zinc supplementation on hair and nail zinc concentrations compared with a control group. In a randomized controlled trial, 6- to 23-month-old children (n = 3407) in Lao PDR were randomly assigned to one of four groups and followed for ~ 36 weeks: daily preventive zinc dispersible tablet (7 mg/d; PZ), daily micronutrient powder (10 mg zinc/d; MNP), therapeutic zinc supplements for diarrhea treatment (20 mg/d for 10 days; TZ), or daily placebo powder (Control). Plasma, hair, and nail zinc concentrations were assessed in a sub-sample of participants (n = 457) at baseline and endline. At baseline, 75% of children had low PZC (P P = 0.99). Nail zinc concentrations were marginally higher in the PZ (115.8 (111.6, 119.9) μg/g) and the MNP (117.8 (113.3, 122.3) μg/g) groups than in the TZ group (110.4 (106.0, 114.8) μg/g; P = 0.055) at endline. This study does not support the use of hair zinc as a biomarker of zinc exposure in young children. However, it provides some evidence that zinc concentrations in nails may respond to supplemental zinc interventions and supports the need for collecting additional data on this emerging biomarker.

Introduction Determination of hemoglobins (Hbs) F, A2, and E is crucial for diagnosis of thalassemia. This study determined the levels of Hbs F, A2, and E in children aged 6‐23 months and investigated the effect of age, sex, and types of thalassemia on the expression of these Hbs. Methods A total of 698 blood samples of Laotian children including 272 non‐Hb E, 271 Hb E heterozygotes, and 155 Hb E homozygotes were collected. Hb profiles were determined using the capillary zone electrophoresis. Coinheritance of α‐thalassemia and the homozygosity for Hb E mutation were checked by PCR‐based assay. Results Children heterozygous and homozygous for Hb E had significantly higher Hb F and A2 levels than non‐Hb E children (median Hb F = 1.1% for non‐Hb E group, 2.7% for Hb E heterozygotes, and 9.4% for Hb E homozygotes; median Hb A2 = 2.6% for non‐Hb E group, 3.8% for Hb E heterozygotes, and 5.2% for Hb E homozygotes). The median Hb E levels were 21.9% for Hb E heterozygotes and 85.3% for Hb E homozygotes. Comparing within group, there was a statistically significant difference between children with and without an α‐gene defect for Hb A2 and E, but not Hb F. Based on a multiple regression analysis, age and sex were significantly associated with the expression of Hb F and A2 but not Hb E. Conclusions Our findings can guide the development of a diagnostic approach to thalassemia in children aged 6‐23 months.

To assess the effects of intervention with a daily multiple micronutrient powder (MNP) on thiamine, riboflavin, folate, and BChildren (n = 1704) aged 6-23 mo, participating in a double-blind placebo-controlled randomized trial were individually randomized to receive daily either MNP (containing 0.5 mg of thiamine, 0.5 mg riboflavin, 150 μg folic acid, and 0.9 μg vitamin BThere was no treatment effect on endline eThDP concentrations (110.6 ± 8.9 nmol/L in MNP vs. 109.4 ± 8.9 nmol/L in placebo group; p = 0.924), EGRac (1.46 ± 0.3 vs. 1.49 ± 0.3; p = 0.184) and BCompared to a placebo, daily MNP for 9 months increased only folate but not thiamine, riboflavin, or BThe trial was registered at www.gov (NCT02428647) on April 29 2015.

Micronutrient malnutrition is a key driver of morbidity and mortality for millions of children in South Asia. Understanding the specific micronutrients lacking in the diet during the complementary feeding period is essential for addressing undernutrition caused by inadequate diets. A Comprehensive Nutrient Gap Assessment was used to synthesize diverse evidence and estimate the public health significance of complementary-feeding micronutrient gaps and identify evidence gaps in 8 countries in South Asia. There were important gaps across the region in iron, zinc, vitamin A, folate, vitamin B12, and, to a lesser extent, calcium and vitamin C. The most nutrient-dense, whole-food sources of these micronutrients include liver, small fish, eggs, ruminant meat, and dark leafy greens. Investment is needed in some countries to collect data on micronutrient biomarkers and dietary intakes. A food systems approach is essential for improving child diets and reducing malnutrition, which affects millions of children, their futures, and society at large across South Asia and beyond.

BackgroundDiarrhea and respiratory tract infections are leading causes of childhood morbidity and mortality. This individually randomized, double-blind placebo-controlled trial was designed to evaluate the effects of different zinc supplementation regimens on the incidence and duration of diarrhea and acute lower (ALRI) and upper (AURI) respiratory tract infections among rural Laotian children. The study included 3407 children, 6-23 months at enrollment.MethodsChildren were randomized to one of four study groups: therapeutic zinc supplements for diarrhea treatment (20 mg/d for 10 days with each episode; TZ), daily preventive zinc tablets (7 mg/d; PZ), daily multiple micronutrient powder (10 mg/d zinc, 6 mg/d iron and 13 other micronutrients; MNP), or daily placebo powder for 9 months. Incidence and duration of diarrhea (≥3 liquid stools/24 hours), ALRI (persistent cough with wheezing, stridor or chest in-drawing) and AURI (purulent nasal discharge with cough) were assessed by parental report during weekly home visits and analyzed using negative binomial models.ResultsBaseline mean age was 14.2 ± 5.1 months, and 71% had low plasma zinc (18 months, TZ reduced diarrhea incidence by 24% vs MNP (P = 0.035), and 36% vs Control (P = 0.004), but there was no difference with PZ. This patterned remained when analyses were restricted to diarrhea episode occurring after the first treatment with TZ. Also, in children >18 months, TZ reduced diarrhea duration by 15% vs PZ (P = 0.03), and 16% vs Control (P = 0.03), but there was no difference with MNP. There were no overall effects of study group on incidence of ALRI (overall mean 0.005 ± 0.001 episodes/100 days, P = 0.14) or AURI (overall mean 0.09 ± 0.01 episodes/100 days, P = 0.72).ConclusionsThere was no overall impact of TZ, PZ or MNP on diarrhea, ALRI and AURI. However, in children >18 months, TZ significantly reduced both the duration of diarrhea episodes and the incidence of future diarrhea episodes compared with placebo.Trial registrationClinicalTrials.gov: NCT02428647.

Environmental enteric dysfunction (EED) may be ameliorated by zinc supplementation. The objective of this study was to investigate the impact of different forms of zinc supplementation on biomarkers of EED (i.e., plasma citrulline, kynurenine, and tryptophan concentrations and the kynurenine:tryptophan [KT] ratio) among young Laotian children. In a double-blind randomized controlled trial, 3,407 children aged 6–23 months were randomized into one of four groups: daily preventive zinc dispersible tablets (PZ; 7 mg zinc), daily multiple micronutrient powders (MNP; 10 mg zinc, 6 mg iron, and 13 other micronutrients), therapeutic zinc supplements for diarrhea treatment (TZ; 20 mg/day for 10 days), or daily placebo powder, and followed up for ∼36 weeks. Plasma samples at baseline and endline for 359 children were analyzed for citrulline, kynurenine, and tryptophan concentrations. At baseline, the prevalence of stunting and zinc deficiency was 37% and 76.5%, respectively. The mean plasma citrulline, kynurenine, and tryptophan concentrations were 24.6 ± 5.4 µmol/L, 3.27 ± 0.83 µmol/L, and 72.3 ± 12.9 µmol/L, respectively; the mean KT ratio (×1,000) was 45.9 ± 12.0. At endline, neither plasma citrulline, kynurenine, or tryptophan concentrations, nor the KT ratio differed among intervention groups (P > 0.05). In this population, PZ, MNP, and TZ had no overall effect on plasma concentrations of citrulline, kynurenine, and tryptophan, or the KT ratio. The need remains to better understand the etiology of EED, and the development of biomarkers to diagnose EED and evaluate the impact of interventions.

Author(s): Kewcharoenwong, Chidchamai; Schuster, Gertrud U; Wessells, K Ryan; Hinnouho, Guy-Marino; Barffour, Maxwell A; Kounnavong, Sengchanh; Brown, Kenneth H; Hess, Sonja Y; Samer, Waraporn; Tussakhon, Inthira; Peerson, Janet M; Lertmemongkolchai, Ganjana; Stephensen, Charles B | Abstract: BACKGROUND:Zinc deficiency impairs immune function and is common among children in South-East Asia. OBJECTIVES:The effect of zinc supplementation on immune function in young Laotian children was investigated. METHODS:Children (n = 512) aged 6-23 mo received daily preventive zinc tablets (PZ; 7 mg Zn/d), daily multiple micronutrient powder (MNP; 10 mg Zn/d, 6 mg Fe/d, plus 13 other micronutrients), therapeutic dispersible zinc tablets only in association with diarrhea episodes (TZ; 20 mg Zn/d for 10 d after an episode), or daily placebo powder (control). These interventions continued for 9 mo. Cytokine production from whole blood cultures, the concentrations of T-cell populations, and a complete blood count with differential leukocyte count were measured at baseline and endline. Endline means were compared via ANCOVA, controlling for the baseline value of the outcome, child age and sex, district, month of enrollment, and baseline zinc status (below, or above or equal to, the median plasma zinc concentration). RESULTS:T-cell cytokines (IL-2, IFN-γ, IL-13, IL-17), LPS-stimulated cytokines (IL-1β, IL-6, TNF-α, and IL-10), and T-cell concentrations at endline did not differ between intervention groups, nor was there an interaction with baseline zinc status. However, mean ± SE endline lymphocyte concentrations were significantly lower in the PZ than in the control group (5018 ± 158 compared with 5640 ± 160 cells/μL, P = 0.032). Interactions with baseline zinc status were seen for eosinophils (Pixn = 0.0036), basophils (Pixn = 0.023), and monocytes (P = 0.086) but a significant subgroup difference was seen only for eosinophils, where concentrations were significantly lower in the PZ than in the control group among children with baseline plasma zinc concentrations below the overall median (524 ± 44 compared with 600 ± 41 cells/μL, P = 0.012). CONCLUSIONS:Zinc supplementation of rural Laotian children had no effect on cytokines or T-cell concentrations, although zinc supplementation affected lymphocyte and eosinophil concentrations. These cell subsets may be useful as indicators of response to zinc supplementation.This trial was registered at clinicaltrials.gov as NCT02428647.

OBJECTIVES: To investigate the impact of different forms of zinc supplementation on plasma citrulline (CIT), kynurenine (KYN) and tryptophan (TRP) concentrations and the kynurenine: tryptophan ratio (KTR), considered as markers of intestinal function and systemic inflammatory response, among young Lao children. METHODS: In a randomized controlled double-blind trial, 3407 children aged 6–23 mo were randomized into one of four groups and followed for ∼36 weeks: daily preventive zinc dispersible tablet (7 mg zinc; PZ), daily multiple micronutrient powder (10 mg zinc, 6 mg iron and 13 other micronutrients; MNP), therapeutic zinc supplements for the treatment of diarrhea (20 mg/d for 10 days with each diarrhea episode; TZ), or daily placebo powder (Control). Plasma samples at baseline and endline for 359 children participating in the parent trial were analyzed at the NIH West Coast Metabolomics Center (UC Davis); plasma CIT, KYN and TRP concentrations were determined by hydrophilic interaction chromatography (HILIC) quadrupole time of flight mass spectrometer (QTOF) tandem mass spectrometry (MS/MS). Linear regression models were used to assess the treatment effect, controlling for baseline value, child age and district. RESULTS: The parent trial found no overall group-wise effects on linear growth or diarrhea outcomes. In the subgroup included in the present analyses, mean age at enrollment was 16.0 ± 4.9 mo, 37% were stunted and 83% were zinc deficient. At baseline, mean plasma CIT, KYN and TRP concentrations were 24.6 ± 5.4 µM, 3.27 ± 0.83 µM and 72.3 ± 12.9 µM, respectively; the mean KT ratio was 0.046 ± 0.013. 5% of children had low CIT (

Zinc supplementation has been shown to reduce the morbidity burden among young children, and may reduce chronic stress. Hair cortisol has been promoted as an indicator of chronic stress. We assessed the impact of different strategies for delivering supplementary zinc on hair cortisol concentrations (HCC) in young Laotian children and examined risk factors associated with HCC. In a randomized double-blind controlled trial (NCT02428647), children aged 6–23 mo were randomized to one of four intervention groups and followed for ~36 weeks: daily preventive zinc (PZ) tablets (7 mg/day), daily multiple micronutrient powder (MNP) sachets (containing 10 mg zinc and 14 other micronutrients), therapeutic zinc (TZ) supplements for diarrhea treatment (20 mg/day for 10 days) or daily placebo powder. HCC of 512 children was assessed at baseline and endline. ANCOVA and linear regression models were used to assess group differences in HCC and to examine the risk factors associated with HCC, respectively. At enrollment, mean HCC was 28.8 ± 43.9 pg/mg. In models adjusted for age at enrollment, health district, and baseline HCC there was no overall effect of the interventions on endline HCC and change in HCC. When controlling for additional predetermined covariates, there was a marginally significant effect on change in HCC (p = 0.075) with a slightly lower reduction of HCC in TZ compared to PZ (mean change (95% CI): −4.6 (−7.0; −2.3) vs. −9.4 (−11.7; −7.0) pg/mg; p = 0.053). At baseline, consumption of iron rich foods was negatively associated with HCC, whereas AGP (α1-acid glycoprotein) levels, elevated AGP and C-reactive protein and high soluble transferrin receptor were positively associated with HCC. In young Laotian children, MNP, PZ and TZ had no impact on HCC. The marginal difference in change in HCC between the PZ and TZ groups was too small to be considered of health significance.

Background: Measurements of mid-upper arm circumference (MUAC) may result in measurement error due to incorrect placement along the arm or tight pulling of tape. To reduce the risk of these measurement errors, a new wider tape was developed. Objective: To compare the measurement agreement and precision and the ease of use of the standard and wide MUAC tapes. Methods: Mid-upper arm circumference was measured in 814 children aged 9 to 32 months with both tapes. The midpoint of the upper arm was measured with the standard tape and estimated with the wide tape. Standardization sessions were implemented to assess intra- and interobserver precision. Results: Mid-upper arm circumference with the wide MUAC tape was significantly larger than the standard tape (mean [standard deviation]: 14.3 [1.0] cm vs 13.9 [1.0] cm; P < .001), resulting in a consistent bias of +0.41 cm. Forty-six (5.7%) children were identified with low MUAC Conclusions: Despite simplifying the measurement by approximating the midpoint of the upper arm, the wide MUAC tape tended to have better precision than the standard MUAC tape. However, there was a consistent measurement bias of +0.41 cm in mean MUAC. This first field test yielded promising results and led to further product adjustments.

OBJECTIVES: To assess a) the impact of daily preventive zinc tablets (7 mg; PZ), multiple micronutrient powder (10 mg zinc, 6 mg iron and 13 other micronutrients; MNP) or placebo on Insulin-like Growth Factor 1 (IGF1), IGF Binding Protein 3 (IGFBP3) and IGF1 bioavailability (indexed by molar IGF1: IGFBP3 ratio), among Laotian children aged 6–23 mo; b) potential effect modification by baseline physical growth status. METHODS: Plasma samples from 419 children participating in the parent trial (n = 3407) were collected at baseline and after ∼9 mo (endline). Determination of IGF1 and IGFBP3 were done via an automated chemiluminescent assay. Linear regression models were used to assess main and modifying effects of PZ and MNP on IGF1 and IGFBP3, controlling for age, sex, district and baseline values of each biomarker. RESULTS: The parent trial found no overall treatment effects on physical growth. In this subgroup, mean age at baseline was 14.2 ± 5.1 mo and ∼38% were stunted. IGF1 and IGFBP3 at baseline were 45.9 ng/ml and 2143.0 ng/ml, respectively. At endline, geometric mean IGF1 (∼39.0–39.2 ng/ml; P = 0.99), IGFBP3 (2038–2076 ng/ml; P = 0.83) and molar IGF1: IGFBP3 ratio (0.071–0.073; P = 0.74) did not differ by group. Baseline weight-for-age z-score (WAZ) modified the treatment effect on IGFBP3 (p for interaction = 0.05) and molar IGF1: IGFBP3 (p for interaction = 0.04). In non-underweight children (WAZ ≥ -2), mean IGFBP3 in the PZ group (2000 ng/ml) was significantly lower than in the placebo (2148 ng/ml; P = 0.03) and MNP (2157 ng/ml; P = 0.03) groups. In underweight children, however, the IGFBP3 in the PZ group (2039 ng/ml) was higher than the placebo (1774 ng/ml; P = 0.05) but not the MNP (1881 ng/ml; P = 0.15) group. PZ (relative to placebo and MNP) appeared to reduce the bioavailability of IGF1 in underweight children, while increasing IGF1 bioavailability in non-underweight children (p interaction = 0.04). CONCLUSIONS: IGF1 in this population did not respond to PZ or MNP. PZ (relative to placebo and MNP) was associated with higher endline IGFBP3 concentrations in underweight children but lower values in non-underweight children. These results suggest that PZ affected activity in the GH-IGF axis in these children, but additional evidence is needed to understand long term implications for growth in this population. FUNDING SOURCES: By The Thrasher Research Fund, with support from the Mathile Institute for the Advancement of Human Nutrition, Nutrition International and the Bill & Melinda Gates Foundation.

OBJECTIVES: Determine if children (6 to 23 mo) who received daily preventive zinc (PZ; 7 mg/d), daily high-zinc, low-iron micronutrient powder (MNP; 10 mg/d zinc, 6 mg/d iron) or therapeutic zinc during episodes of diarrhea (TZ; 20 mg/d for 10 d per episode) have improved markers of innate and adaptive immune function, compared to placebo (PL). METHODS: Rural Laotian children were recruited into a double-blind, randomized, controlled intervention trial for 9 mo. Venous blood was collected at baseline (BL) and endline (EL) for analysis. Primary outcomes included T-cell subsets (naïve and memory CD4, CD8, Tregs) measured by flow cytometry and production of T-cell cytokines (IL-2, IL-10, IL-13, IL-17A, INF-γ) and LPS-induced cytokines (IL-1β, IL-6, IL-10, TNF-α by whole blood cultures. Blood leukocytes (including lymphocytes, neutrophils, monocytes and eosinophils) were measured as secondary outcome variables. Group means at EL were compared by analysis of covariance (controlling for BL values of the outcome, sex, child age, district, month of enrollment and plasma zinc concentration). If an interaction with BL plasma zinc (above/below median) was observed, group means were compared separately in children above and below the median. RESULTS: Mean BL plasma zinc in all children (N = 574) was 0.55 ± 0.12 mg/L. No significant group differences were seen at EL in the primary outcomes. For secondary outcomes, the counts (^10(3)/μL) of lymphocytes from the PZ group (5.02 ± 0.16) were significantly lower than the PL group (5.64 ± 0.16; P = 0.032). The EL counts (^10(3)/μL) of from the PZ group (0.144 ± 0.026) were significantly lower than in the PL (0.279 ± 0.048; P = 0.036) and TZ (0.285 ± 0.047; P = 0.025) groups among children with baseline zinc below the median. CONCLUSIONS: Primary outcomes (T-cell subsets, and cytokine production) were not affected by the zinc intervention. Lymphocyte and eosinophil concentrations may be affected by zinc treatment but this result requires confirmation. FUNDING SOURCES: ARS Project 2032-53000-001-00-D, Mathile Institute for the Advancement of Human Nutrition.

OBJECTIVES: To assess the impact of different strategies for delivering supplemental zinc on fecal myeloperoxidase (MPO), neopterin (NEO) and calprotectin (CAL) among young Laotian children and explore modifying effects of MPO, CAL and NEO on growth METHODS: In a double-blind controlled trial, children 6–23 mo of age were randomized to receive either daily preventive zinc tablets (PZ; 7 mg/d), daily micronutrient powder sachets (MNP; containing 10 mg zinc and 14 other micronutrients), therapeutic zinc supplements for diarrhea treatment (TZ; 20 mg/d for 10 days) or daily placebo powder and followed for ∼36 weeks. Stool samples were collected at baseline and endline. Fecal MPO, NEO and CAL were determined in a randomly selected sub-sample of 720 children using commercially available ELISA kits. Linear regression models were used to assess main and modifying effects while controlling for baseline value, age and district RESULTS: The baseline prevalence of stunting was 39.3%, and there was no overall treatment effect on physical growth in the parent trial. At endline, geometric mean fecal MPO, NEO and CAL concentrations did not differ among the 4 groups (all P > 0.23). There was an effect modification by baseline concentrations of NEO and CAL on endline stunting (p for interaction = 0.01 and 0.02, respectively). Among children in the lowest quintile of NEO concentrations, there was a trend towards a higher stunting prevalence at endline in the TZ [47.1% (35.6, 58.7)] and the MNP [45.3% (32.7, 57.9)] groups compared to the PZ [33.6% (21.0, 46.3)] and the control [33.9% (22.8, 44.9)] groups. Similar results were found among children in the lowest quintile of CAL concentrations. Moreover, baseline concentration of CAL, modified the impact of the interventions on weight-for-height z-scores (WHZ) (p for interaction = 0.074). Among children in the lowest quintile of CAL concentrations, there was a trend towards a higher WHZ at endline in the MNP [−0.57 (−0.73, −0.42)] and TZ [−0.68 (−0.86, −0.51)] groups compared to the control [−0.79 (−0.97, −0.61)] and the PZ [−0.88 (−1.05, −0.72)] groups. CONCLUSIONS: In this population of young Laotian children PZ, MNP and TZ had no overall impact on EED or growth, but intestinal function modified the growth response to supplementation suggesting its potential role in the pathways of growth impairment. FUNDING SOURCES: Funded by the Bill & Melinda Gates Foundation, Nutrition International and the Mathile Institute for the Advancement of Human Nutrition.

OBJECTIVE To assess the association of a “metabolically healthy obese” phenotype with mortality using five definitions of metabolic health. RESEARCH DESIGN AND METHODS Adults (n = 5,269; 71.7% men) aged 39–62 years in 1991 through 1993 provided data on BMI and metabolic health, defined using data from the Adult Treatment Panel-III (ATP-III); criteria from two studies; and the Matsuda and homeostasis model assessment (HOMA) indices. Cross-classification of BMI categories and metabolic status (healthy/unhealthy) created six groups. Cox proportional hazards regression models were used to analyze associations with all-cause and cardiovascular disease (CVD) mortality during a median follow-up of 17.7 years. RESULTS A total of 638 individuals (12.1% of the cohort) were obese, of whom 9–41% were metabolically healthy, depending on the definition. Regardless of the definition, compared with metabolically healthy, normal-weight individuals, both the metabolically healthy obese (hazard ratios [HRs] ranged from 1.81 [95% CI 1.16–2.84] for ATP-III to 2.30 [1.13–4.70] for the Matsuda index) and the metabolically abnormal obese (HRs ranged from 1.57 [1.08–2.28] for the Matsuda index to 2.05 [1.44–2.92] for criteria defined in a separate study) had an increased risk of mortality. The only exception was the lack of excess risk using the HOMA criterion for the metabolically healthy obese (1.08; 0.67–1.74). Among the obese, the risk of mortality did not vary as a function of metabolic health apart from when using the HOMA criterion (1.93; 1.15–3.22). Similar results were obtained for cardiovascular mortality. CONCLUSIONS For most definitions of metabolic health, both metabolically healthy and unhealthy obese patients carry an elevated risk of mortality.

Aims The health correlates of the metabolically healthy obese (MHO) phenotype, particularly in relation to depressive symptoms remains unclear. Accordingly, we examined the risk of depressive symptoms in this phenotype using a 16-year follow-up prospective study. Methods A sample of 14 475 participants (75% men), aged 44–59 years in 1996, was drawn from the Gazel cohort. Obesity was defined as body mass index (BMI) ≥ 30 kg/m2 and metabolic health as having none of the self-reported following cardiovascular risk factors: hypertension, type 2 diabetes and dyslipidemia. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression (CES-D) scale in 1996, 1999, 2002, 2005, 2008 and 2012. Generalized Estimating Equations (GEE) were used to estimate the risk of depressive symptoms during a follow-up of 16 years. Results In multivariate analyses, metabolically unhealthy normal weight [Odds Ratio (OR) = 1.37; 95% Confidence Interval (CI): 1.25–1.51], overweight [1.44 (1.31–1.59)] and obese [1.30 (1.10–1.54)] but not MHO participants [1.04 (0.81–1.32)] had higher risk of depressive symptoms at the start of follow-up compared to metabolically healthy normal weight individuals. Depressive symptoms decreased over time in metabolically healthy normal weight individuals [0.52 (0.50–0.55)], this decrease was less marked only in metabolically unhealthy obese participants [1.22 (1.07–1.40)]. Compared to MHO participants, metabolically unhealthy obese individuals were at increased risk of depression at the start of follow-up, but with a similar reduction of this risk over time. Conclusion Poor metabolic health, irrespective of BMI was associated with greater depressive symptoms at the start of follow-up, whereas a poorer course of depressive symptoms over time was observed only in those with both obesity and poor metabolic health.

We thank Drs. Doehner and Pfeiffer (1) for their letter in response to our article (2) on the association of metabolically healthy obese (MHO) phenotype with mortality. We used five definitions of metabolic health to show that for most definitions of metabolic health both metabolically healthy and unhealthy obese patients carry a similar, elevated risk of mortality. Doehner and Pfeiffer do not question the validity of our findings in relation to the MHO phenotype, but suggest that overweight and obesity may not be harmful at older ages and in those with a chronic disease. They suggest that “weight management should be …

Objectif Le phenotype « obeses metaboliquement sains » designe les sujets obeses ayant un profil metabolique favorable. Nous avons examine l’association entre ce phenotype et la survenue d’un diabete de type 2 (DT2) d’une part, et d’un evenement cardiovasculaire (ECV) d’autre part. Materiels et methodes L’indice de masse corporelle (IMC) et le statut metabolique defini en utilisant le critere de l’ATP-III ont ete mesures chez 7 122 participants (69,7 % d’hommes) de la cohorte Whitehall II, entre 1991 et 1993. En croisant l’IMC (poids normal, surpoids, obesite) et le statut metabolique (sain/ anormal), six groupes ont ete crees. Leur association avec la survenue d’un DT2 ou d’un ECV incident, chez des sujets indemnes a l’inclusion a ete mesuree jusqu’en 2009 et analysee par des modeles de Cox (HR, IC 95 %). Resultats Au total, 657 participants (9,2 %) etaient obeses et parmi eux 42,5 % etaient metaboliquement sains. Durant le suivi, 828 cas d’ECV et 798 DT2 ont ete denombres. En comparaison aux individus metaboliquement sains de poids normal, les obeses metaboliquement sains avaient un risque eleve d’ECV: 1,97 (1,38–2,80) et de DT2 : 3,25 (2,32–4,54). En comparant les sujets obeses avec anomalies metaboliques aux sujets obeses metaboliquement sains, seul le risque de DT2 etait augmente : 1,98 (1,39–2,83). Conclusion Pour les evenements de sante tels que le DT2, le phenotype obese metaboliquement sain est associe a un risque moindre compare aux obeses avec anomalies metaboliques. En revanche, aucune difference n’etait observee entre les deux groupes pour la survenue d’un evenement cardiovasculaire apres 17 ans de suivi.