An Alternative Oat-Containing, Ready-To-Use, Therapeutic Food Does Not Alter Intestinal Permeability or the 16S Ribosomal RNA Fecal Microbiome Configuration Among Children With Severe Malnutrition in Sierra Leone: A Randomized Controlled Trial.

BACKGROUND: Previously, a novel oat ready-to-use therapeutic food (o-RUTF) resulted in improved recovery from severe acute malnutrition (SAM) when compared to a standard RUTF (s-RUTF). The o-RUTF contained 18% oat, while the s-RUTF has no cereal ingredients. OBJECTIVES: We determined the effects of o-RUTF on intestinal permeability, as measured by lactulose permeability, and the 16S ribosomal RNA (rRNA) fecal microbiome configuration of children with SAM. METHODS: This was a prospective, randomized, double-blinded, controlled clinical trial. Sierra Leonean children aged 6-59 mo with SAM, defined by a midupper arm circumference < 11.5 cm, were randomized to receive o-RUTF or s-RUTF. All children received 7 d of amoxicillin per guidelines. Lactulose permeability testing and fecal 16S rRNA sequencing were performed at baseline and after 4 wk of therapy. The change in lactulose permeability was the primary outcome, while the fecal 16S rRNA configuration at 4 wk was a secondary outcome. RESULTS: Of the 129 children enrolled, lactulose permeability testing was completed by 100 at baseline and 82 at week 4. After 4 wk of therapeutic feeding, there were no differences in lactulose permeability between the o-RUTF and s-RUTF groups (P = 0.84), and over half of children had increased lactulose permeability (50% s-RUTF compared with 58% o-RUTF, mean difference = -7.5%; 95% CI: -29.2, 15.2; P = 0.50). After 4 wk of feeding, there were no differences in the 16S rRNA configurations between the o-RUTF and s-RUTF groups (Permanova, 999 permutations; P = 0.648; pseudo-F = 0.581), nor were there differences in α or ß diversity. CONCLUSIONS: Despite remarkably different compositions of o-RUTF and s-RUTF, no differences were identified in lactulose permeability or the fecal 16S rRNA configuration among children with SAM receiving these foods. These results suggest that the o-RUTF exerts its beneficial effects through mechanisms other than reducing intestinal permeability or altering the fecal 16S configuration. This trial was registered at clinicaltrials.gov as NCT04334538.

Effectiveness and cost-effectiveness of 4 supplementary foods for treating moderate acute malnutrition: results from a cluster-randomized intervention trial in Sierra Leone.

BACKGROUND: Moderate acute malnutrition (MAM) affects 33 million children annually. Investments in formulations of corn-soy blended flours and lipid-based nutrient supplements have effectively improved MAM recovery rates. Information costs and cost-effectiveness differences are still needed. OBJECTIVES: We assessed recovery and sustained recovery rates of MAM children receiving a supplementary food: ready-to-use supplementary food (RUSF), corn soy whey blend with fortified vegetable oil (CSWB w/oil), or Super Cereal Plus with amylase (SC + A) compared to Corn Soy Blend Plus with fortified vegetable oil (CSB+ w/oil). We also estimated differences in costs and cost effectiveness of each supplement. METHODS: In Sierra Leone, we randomly assigned 29 health centers to provide a supplement containing 550 kcal/d for ∼12 wk to 2691 children with MAM aged 6-59 mo. We calculated cost per enrollee, cost per child who recovered, and cost per child who sustained recovery each from 2 perspectives: program perspective and caregiver perspective, combined. RESULTS: Of 2653 MAM children (98.6%) with complete data, 1676 children (63%) recovered. There were no significant differences in the odds of recovery compared to CSB+ w/oil [0.83 (95% CI: 0.64-1.08) for CSWB w/oil, 1.01 (95% CI: 0.78-1.3) for SC + A, 1.05 (95% CI: 0.82-1.34) for RUSF]. The odds of sustaining recovery were significantly lower for RUSF (0.7; 95% CI 0.49-0.99) but not CSWB w/oil or SC + A [1.08 (95% CI: 0.73-1.6) and 0.96 (95% CI: 0.67-1.4), respectively] when compared to CSB+ w/oil. Costs per enrollee [US dollars (USD)/child] ranged from $105/child in RUSF to $112/child in SC + A and costs per recovered child (USD/child) ranged from $163/child in RUSF to $179/child in CSWB w/oil, with overlapping uncertainty ranges. Costs were highest per sustained recovery (USD/child), ranging from $214/child with the CSB+ w/oil to $226/child with the SC + A, with overlapping uncertainty ranges. CONCLUSIONS: The 4 supplements performed similarly across recovery (but not sustained recovery) and costed measures. Analyses of posttreatment outcomes are necessary to estimate the full cost of MAM treatment. This trial was registered at clinicaltrials.gov as NCT03146897.

The effect of bovine colostrum/egg supplementation compared with corn/soy flour in young Malawian children: a randomized, controlled clinical trial.

BACKGROUND: Bovine colostrum with egg powder (BC/egg) is rich in essential amino acids and immunoactive compounds. OBJECTIVES: This trial tested the hypothesis that a daily supplement of BC/egg would reduce linear growth faltering and environmental enteric dysfunction (EED) in Malawian infants when compared with an isoenergetic ration of corn/soy flour used as a control. EED was defined by a lactulose permeability test. METHODS: This was a prospective, randomized, blinded, placebo-controlled clinical trial in which 9-mo-old infants received BC/egg or a control for 3 mo. The primary outcomes were change in length-for-age z-score (ΔLAZ) and urinary lactulose excretion (%L) at 12-mo-old. Secondary outcomes included episodes of diarrhea, stunting, EED, and the 16S configuration of the fecal microbiota. RESULTS: Of the 277 children enrolled, 267 completed the intervention phase of the study. LAZ decreased in all children from 9 to 17 mo, although ΔLAZ was less in children receiving BC/egg from 9 to 12 mo (difference = 0.12 z-scores; P = 0.0011). This difference persisted after feeding was completed, with less ΔLAZ (difference = 0.09 z-scores). A lower prevalence of stunting was seen in the intervention group (n = 47/137) than the control group (n = 62/127) at 17 mo (RR = 0.70; 95% CI: 0.52, 0.94).The median %L at 12 mo of age in the children receiving BC/egg was 0.14%, compared with 0.17% in the control group (P = 0.74). In children with %L >0.45% at enrollment (severe EED), the BC/egg group had more children with normal %L at 12 mo of age (10/20, 50%) than was seen in controls (2/15, 13%; P = 0.024). Episodes of diarrhea and ß-diversity of the 16S configuration of fecal microbiota did not differ between the 2 groups. CONCLUSIONS: Addition of BC/egg to complementary feeding in Malawian infants resulted in less linear growth faltering. This trial was registered at clinicaltrials.gov as NCT03801317.

Circulating Insulin-Like Growth Factor-1 Is Positively Associated with Growth and Cognition in 6- to 9-Year-Old Schoolchildren from Ghana.

BACKGROUND: Milk intake stimulates linear growth and improves cognition in children from low-income countries. These effects may be mediated through insulin-like growth factor-1 (IGF-1). OBJECTIVE: The objective was to assess the effect of milk supplement on circulating IGF-1 and to assess IGF-1 as a correlate of growth and cognition in children. METHODS: Secondary data on blood spot IGF-1 from a randomized, double-blind, controlled trial in 6-9-y-old children from rural Ghana were analyzed. Intervention groups received porridge with non-energy-balanced supplements: 8.8 g milk protein/d, 100 kcal/d (Milk8); 4.4 g milk and 4.4 g rice protein/d, 100 kcal/d (Milk/rice); 4.4 g milk protein/d, 48 kcal/d (Milk4); or a control (no protein, 10 kcal/d). IGF-1, length, body composition, and Cambridge Neuropsychological Test Automated Battery (CANTAB) were measured at 3.5 or 8.5 mo. Linear regressions were used to assess the effect of milk interventions on IGF-1 and IGF-1 as a correlate of growth and cognition. RESULTS: The increase in IGF-1 was 15.3 (95% CI: 3.3, 27.3) ng/mL higher in children receiving Milk8 compared with the control. The IGF-1 increases in the isonitrogenous, isoenergetic Milk/rice or the Milk4 groups were not different from the control (P ≥ 0.49). The increase in IGF-1 was associated with improvements in 4 out of 5 CANTAB domains. The strongest associations included reductions in "mean correct latency" from Pattern Recognition Memory and "pre-extradimensional (pre-ED) shift errors" from Intra/Extradimensional Set Shift (P ≤ 0.005). In addition, change in IGF-1 was positively associated with changes in height, weight, and fat-free mass (P ≤ 0.001). CONCLUSIONS: Intake of skimmed milk powder corresponding to one, but not half a glass of milk on school days stimulates IGF-1 in 6-9-y-old Ghanian children. IGF-1 seems to mediate the effect of milk intake on growth and cognition. The association between IGF-1 and cognition in relation to milk intake is novel and opens possibilities for dietary interventions to improve cognition.

Treatment of severe acute malnutrition with oat or standard ready-to-use therapeutic food: a triple-blind, randomised controlled clinical trial.

OBJECTIVE: We hypothesised that an alternative RUTF (ready-to-use therapeutic food) made with oats (oat-RUTF) would be non-inferior to standard RUTF (s-RUTF). DESIGN: This was a randomised, triple-blind, controlled, clinical non-inferiority trial comparing oat-RUTF to s-RUTF in rural Sierra Leone. Children aged 6-59 months with severe acute malnutrition (SAM) were randomised to oat-RUTF or s-RUTF. s-RUTF was composed of milk powder, sugar, peanut paste and vegetable oil, with a hydrogenated vegetable oil additive. Oat-RUTF contained oats and no hydrogenated vegetable oil additives. The primary outcome was graduation, an increase in anthropometric measurements such that the child was not acutely malnourished. Secondary outcomes were rates of growth, time to graduation and presence of adverse events. Intention to treat analyses was used. RESULTS: Of the 1406 children were enrolled, graduation was attained in 404/721 (56%) children receiving oat-RUTF and 311/685 (45%) receiving s-RUTF (difference 10.6%, 95% CI 5.4% to 15.8%). Death, hospitalisation or remaining with SAM was seen in 87/721 (12%) receiving oat-RUTF and in 125/685 (18%) receiving s-RUTF (difference 6.2%, 95% CI 2.3 to 10.0, p=0.001). Time to graduation was less for children receiving oat RUTF; 3.9±1.8 versus 4.5±1.8 visits, respectively (p<0.001). Rates of weight in the oat-RUTF group were greater than in the s-RUTF group; 3.4±2.7 versus 2.5±2.3 g/kg/d, p<0.001. CONCLUSION: Oat-RUTF is superior to s-RUTF in the treatment of SAM in Sierra Leone. We speculate that might be because of beneficial bioactive components or the absence of hydrogenated vegetable oil in oat-RUTF. TRIAL REGISTRATION NUMBER: NCT03407326.

Alternative Ready-To-Use Therapeutic Food Yields Less Recovery Than the Standard for Treating Acute Malnutrition in Children From Ghana.

BACKGROUND: Only 20% of children with severe acute malnutrition (SAM) have access to ready-to-use therapeutic food (RUTF), and RUTF cost limits its accessibility. METHODS: This randomized, double-blind controlled study involved a clinical equivalence trial comparing the effectiveness of an alternative RUTF with standard RUTF in the home-based treatment of uncomplicated SAM and moderate malnutrition in Ghanaian children aged 6 to 59 months. The primary outcome was recovery, equivalence was defined as being within 5 percentage points of the control group, and an intention-to-treat analysis was used. Alternative RUTF was composed of whey protein, soybeans, peanuts, sorghum, milk, sugar, and vegetable oil. Standard RUTF included peanuts, milk, sugar, and vegetable oil. The cost of alternative RUTF ingredients was 14% less than standard RUTF. Untargeted metabolomics was used to characterize the bioactive metabolites in the RUTFs. RESULTS: Of the 1,270 children treated for SAM or moderate malnutrition, 554 of 628 (88%) receiving alternative RUTF recovered (95% confidence interval [CI]=85% to 90%) and 516 of 642 (80%) receiving standard RUTF recovered (95% CI=77% to 83%). The difference in recovery was 7.7% (95% CI=3.7% to 11.7%). Among the 401 children with SAM, the recovery rate was 130 of 199 (65%) with alternative RUTF and 156 of 202 (77%) with standard RUTF (P=.01). The default rate in SAM was 60 of 199 (30%) for alternative RUTF and 41 of 202 (20%) for standard RUTF (P=.04). Children enrolled with SAM who received alternative RUTF had less daily weight gain than those fed standard RUTF (2.4 ± 2.4 g/kg vs. 2.9 ± 2.6 g/kg, respectively; P<.05). Among children with moderate wasting, recovery rates were lower for alternative RUTF, 386 of 443 (87%), than standard RUTF, 397 of 426 (93%) (P=.003). More isoflavone metabolites were found in alternative RUTF than in the standard. CONCLUSION: The lower-cost alternative RUTF was less effective than standard RUTF in the treatment of severe and moderate malnutrition in Ghana.

Development of Acute Malnutrition Despite Nutritional Supplementation in Malawi.

Malnutrition in children is most often attributed to inadequate nutrient intake. Utilizing data from 2 prospective, randomized controlled trials of complimentary feeding with supplemental legumes (n = 693, ages 6-24 months) in 2 Malawian villages, Masenjere, and Limera, we document a high rate 70/693 (10.1%) of acute malnutrition (AM). Risks for AM in this setting, as determined by Cox regression analysis, include study village (hazard ratio [HR] 3.0), prior malnutrition (HR 4.12), stunting (HR 2.87), and a marker of food insecurity (HR 1.89). Comparison of Masenjere to Limera demonstrate adequate and similar nutritional intake yet an increased rate of AM in Masenjere, 56 of 400 (14.0%) versus 14 of 293 (4.8%), and stunting, 140 of 400 (35%) versus 80 of 293 (27%), environmental enteric dysfunction 246 of 400 (71%) versus 181/293 (67%), and infectious symptoms (cough and diarrhea). Masenjere did have cleaner water and less food insecurity 200 of 399 (50.5%) versus 204 of 293 (69.6%). These findings suggest adequate complementary nutrient intake does not protect young children against AM.

Supplementation With Lactoferrin and Lysozyme Ameliorates Environmental Enteric Dysfunction: A Double-Blind, Randomized, Placebo-Controlled Trial.

INTRODUCTION: Environmental enteric dysfunction (EED) predisposes children throughout the developing world to high rates of systemic exposure to enteric pathogens and stunting. Effective interventions that treat or prevent EED may help children achieve their full physical and cognitive potential. The objective of this study is to test whether 2 components of breast milk would improve a biomarker of EED and linear growth during the second year of life. METHODS: A prospective, randomized, double-blind, placebo-controlled clinical trial among children aged 12-23 months was conducted in rural Malawi. The experimental group received a daily supplement of 1.5 g of lactoferrin and 0.2 g of lysozyme for 16 weeks. The primary outcome was an improvement in EED, as measured by the change in the percentage of ingested lactulose excreted into the urine (Δ%L). RESULTS: Among 214 children who completed the study, there was a significant difference in Δ%L between the control and experimental groups over 8 weeks (an increase of 0.23% vs 0.14%, respectively; P = 0.04). However, this relative improvement was not as strongly sustained over the full 16 weeks of the study (an increase of 0.16% vs 0.11%, respectively; P = 0.17). No difference in linear growth over this short period was observed. The experimental intervention group had significantly lower rates of hospitalization and the development of acute malnutrition during the course of the study (2.5% vs 10.3%, relative risk 0.25; P < 0.02). DISCUSSION: Supplementation with lactoferrin and lysozyme in a population of agrarian children during the second year of life has a beneficial effect on gut health. This intervention also protected against hospitalization and the development of acute malnutrition, a finding with a significant clinical and public health importance. This finding should be pursued in larger studies with longer follow-up and optimized dosing.

Consumption of Animal-Source Protein is Associated with Improved Height-for-Age z Scores in Rural Malawian Children Aged 12⁻36 Months.

Linear growth faltering, caused by insufficient diet, recurrent infections and environmental enteric dysfunction (EED), continues to plague young children in low- and middle-income countries (LMICs). Diets in LMICs are primarily plant based, and thus have poor-quality protein and low levels of essential micronutrients. The aim of this study was to assess the association of the type and protein quality of food consumed with stunting, EED and acute malnutrition in children aged 6⁻36 months in Limera and Masenjere, two rural Southern Malawian communities. This is a secondary analysis of two randomized controlled trials that tested the effects of common bean and cowpea flour on stunting in children aged 6⁻36 months. We used data from two interactive 24-h dietary recalls conducted 12 weeks after enrolment into each trial. Food intakes were compared between the regions using Chi-square and Student's t-test. There were 355 children that participated in the dietary recalls. The diets of children were of poor quality, but the children from Limera consumed more fish (54% vs. 35%, p = 0.009) and more bioavailable protein (26.0 ± 10.3 g/day vs. 23.1 ± 8.1 g/day, p = 0.018, respectively) than children in Masenjere. Food type and protein quality were not associated with any of the outcomes except an association between animal protein consumption and improvement in height-for-age z scores in children aged 12⁻36 months (p = 0.047). These findings support the notion that animal-source food (ASF) consumption in this vulnerable population promotes linear growth.

Effect of Nutritional Interventions on Micronutrient Status in Pregnant Malawian Women with Moderate Malnutrition: A Randomized, Controlled Trial.

Micronutrient deficiencies during pregnancy are common in Africa and can cause adverse outcomes. The objective was to measure micronutrient status and change in moderately malnourished pregnant Malawian women randomized to one of three nutritional interventions. Serum vitamin B12, 25-hydroxyvitamin D, folate, retinol, ferritin, zinc, albumin and C-reactive protein were measured in pregnant women with MUAC ≥20.6 cm and ≤23.0 cm at enrollment (n = 343) and after 10 weeks (n = 229) of receiving: (1) ready-to-use supplementary food (RUSF); (2) fortified corn-soy blend (CSB+) with multiple-micronutrient supplement (CSB+UNIMMAP); or (3) CSB+ with iron and folic acid (CSB+IFA). Each provided 100⁻300% Recommended Dietary Allowance of most micronutrients and 900 kcal/day. Birth length was measured in 272 infants. Enrollment measurements indicated deficiencies in vitamin B12 (20.9%) and zinc (22.3%), low values of ferritin (25.1%) and albumin (33.7%), and elevated CRP (46.0%). Vitamin B12 is known to decrease in the third trimester; the RUSF group had the smallest decrease from enrollment to week 10 (3%), compared to 20% decrease in the CSB+IFA group and 8% decrease in the CSB+UNIMMAP group (p = 0.001). Mean serum 25-hydroxyvitamin D increased most in the RUSF group (+6.4 ng/mL), compared to CSB+IFA (+1.7 ng/mL) and CSB+UNIMMAP (+2.7 ng/mL) (p < 0.001). Micronutrient deficiencies and inflammation are common among moderately malnourished pregnant women and had little improvement despite supplementation above the RDA, with the exception of vitamins B12 and D.

Effect of cowpea flour processing on the chemical properties and acceptability of a novel cowpea blended maize porridge.

Childhood growth stunting is a pervasive problem in Malawi and is in large part due to low quality complementary foods and chronic gut inflammation. Introducing legumes such as cowpea (Vigna unguiculata) into the complementary diet has the potential to improve childhood growth by improving diet quality through improvements in macro- and micronutrients and also by reducing gut inflammation. However, cowpea is relatively underutilized in complementary feeding in Malawi due to its strong taste, long processing time, and high energy requirements for processing. Effective utilization of cowpea in complementary feeding requires processing which may affect chemical composition as well as sensory quality. The present study evaluated the effect of processing on the retention of zinc, crude fibre, and flavonoid in roasted, boiled, and dehulled cowpea flours, and assessed the acceptability of maize porridge (70%) enriched with one of the three cowpea flours (30%). Roasting, dehulling, and boiling did not have any effect on zinc content. Crude fibre content increased after processing by all methods. Processing had no effect on measurable flavonoids. Roasted, boiled, and dehulled cowpea blended maize porridges were acceptable to children with mean quantities of leftover food of less than 3g from the given 100g. Caregivers also rated the blended flours to be highly acceptable to them as well, with maize porridge blended with dehulled cowpea flour the most acceptable to both children and caregivers. These results demonstrate that cowpea flour, processed by any of these three different methods, could serve as a useful addition to maize porridge for complementary feeding of children in sub-Saharan Africa.

Milk Powder Added to a School Meal Increases Cognitive Test Scores in Ghanaian Children.

Background: The inclusion of milk in school feeding is accepted as good nutritional practice, but specific benefits remain uncertain. Objective: The objective was to determine whether consumption of 8.8 g milk protein/d given as milk powder with a multiple micronutrient-enriched porridge resulted in greater increases in linear growth and Cambridge Neuropsychological Test Automated Battery (CANTAB) scores in Ghanaian schoolchildren when compared with 1 of 3 control groups. Methods: A randomized, double-blind, placebo-controlled clinical trial in healthy children aged 6-9 y was conducted comparing 8.8 g milk protein/d with 4.4 g milk protein/d or 4.4 g milk protein + 4.4 g rice protein/d (isonitrogenous, half of the protein from milk and half from rice) or a non-nitrogenous placebo. Primary outcomes were changes in length after 9 mo and CANTAB scores after 4.5 mo; secondary outcomes were body-composition measures. Supplements were added to porridge each school day and consumed for 9 mo. Anthropometric and body-composition measures and CANTAB tests were completed upon enrollment and after 4.5 and 9 mo. Group results were compared by using ANCOVA for anthropometric measures and the Kruskal-Wallis test for CANTAB scores. Results: Children receiving 8.8 g milk protein/d showed greater increases on percentage correct in Pattern Recognition Memory (mean ± SD: 5.5% ± 16.8%; P < 0.05) and Intra/Extradimensional Set Shift completed stages compared with all other food groups (0.6 ± 2.3; P < 0.05). No differences were seen in linear growth between the groups. The children receiving either 4.4 or 8.8 g milk protein/d had a higher fat-free body mass index than those who received no milk, with an effect size of 0.34 kg/m2. Conclusion: Among schoolchildren, the consumption of 8.8 g milk protein/d improved executive cognitive function compared with other supplements and led to the accretion of more lean body mass, but not more linear growth. This trial was registered at www.clinicaltrials.gov">www.clinicaltrials.gov as NCT02757508.

Lactoferrin and lysozyme to reduce environmental enteric dysfunction and stunting in Malawian children: study protocol for a randomized controlled trial.

BACKGROUND: Chronic childhood malnutrition, as manifested by stunted linear growth, remains a persistent barrier to optimal child growth and societal development. Environmental enteric dysfunction (EED) is a significant underlying factor in the causal pathway to stunting, delayed cognitive development, and ultimately morbidity and mortality. Effective therapies against EED and stunting are lacking and further clinical trials are warranted to effectively identify and operationalize interventions. METHODS/DESIGN: A prospective randomized placebo-controlled parallel-group randomized controlled trial will be conducted to determine if a daily supplement of lactoferrin and lysozyme, two important proteins found in breast milk, can decrease the burden of EED and stunting in rural Malawian children aged 12-23 months old. The intervention and control groups will have a sample size of 86 subjects each. All field and laboratory researchers will be blinded to the assigned intervention group, as will the subjects and their caregivers. The percentage of ingested lactulose excreted in the urine (Δ%L) after 4 h will be used as the biomarker for EED and linear growth as the measure of chronic malnutrition (stunting). The primary outcomes of interest will be change in Δ%L from baseline to 8 weeks and to 16 weeks. Intention-to-treat analyses will be used. DISCUSSION: A rigorous clinical trial design will be used to assess the biologically plausible use of lactoferrin and lysozyme as dietary supplements for children at high risk for EED. If proven effective, these safe proteins may serve to markedly reduce the burden of childhood malnutrition and improve survival. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02925026 . Registered on 4 October 2016.

Low serum ω-3 and ω-6 polyunsaturated fatty acids and other metabolites are associated with poor linear growth in young children from rural Malawi.

Background: Stunting affects ∼25% of children <5 y of age and is associated with impaired cognitive and motor development and increased morbidity and mortality. The pathogenesis of stunting is poorly understood.Objective: The purpose of this study was to identify altered metabolic pathways associated with child stunting.Design: We measured 677 serum metabolites using liquid chromatography-tandem mass spectrometry in a cross-sectional study of 400 Malawian children aged 12-59 mo, of whom 62% were stunted.Results: A low height-for-age z score (HAZ) was associated with lower serum concentrations of 1) ω-3 (n-3) and ω-6 (n-6) polyunsaturated fatty acids (PUFAs), 2) sulfated neurosteroids, which play a role in brain development, 3) carnitine, a conditionally essential nutrient with an important role in the carnitine shuttle for the metabolism of fatty acids and energy production, and 4) γ-glutamyl amino acids, which represent an altered γ-glutamyl cycle of glutathione metabolism. A low HAZ was associated with significantly higher serum concentrations of 5 biomarkers related to cigarette smoke exposure.Conclusions: This metabolomics study shows a cross-sectional association between stunting and low serum ω-3 and ω-6 long-chain PUFAs, which are essential for growth and development; low sulfated neurosteroids, which play a role in brain development; low carnitine, which is essential for ß-oxidation of fatty acids; alterations in glutathione metabolism; and increased serum metabolites that are associated with secondhand tobacco smoke exposure. This trial was registered at www.controlled-trials.com as ISRCTN14597012.

Trial of ready-to-use supplemental food and corn-soy blend in pregnant Malawian women with moderate malnutrition: a randomized controlled clinical trial.

Background: Malnutrition during pregnancy in sub-Saharan Africa is associated with poor birth outcomes. Objective: This study compared maternal and offspring anthropometry for moderately malnourished pregnant women receiving ready-to-use supplemental food (RUSF), a fortified corn-soy blend (CSB+) with a daily multiple micronutrient antenatal supplement [United Nations International Multiple Micronutrient Preparation (UNIMMAP)], or standard of care comprising CSB+ and iron and folic acid (IFA). Design: A single-blind randomized controlled clinical trial was conducted in southern Malawi among 1828 pregnant women with moderate malnutrition, defined as a midupper arm circumference (MUAC) ≥20.6 and ≤23.0 cm. Women received 1 of 3 dietary treatment regimens that provided ∼900 kcal/d and 33-36 g protein/d. Maternal and infant anthropometry were followed until the child was 3 mo old. Results: Newborns had a mean length-for-age z score of -1.3 ± 1.2 and 22% were stunted at birth. Mothers receiving RUSF had the highest weight gain during supplementation (3.4 ± 2.6, 3.0 ± 2.2, and 3.2 ± 2.4 kg for the RUSF, CSB+ with UNIMMAP, and CSB+ with IFA groups, respectively; P = 0.03). Newborn birth weights and lengths were similar across intervention groups, but the incidence of newborns with a birth weight <2.4 kg (weight-for-age z score <-2) was higher in the CSB+ with UNIMMAP group than the other groups (17%, 18%, and 24% for the CSB+ with IFA, RUSF, and CSB+ with UNIMMAP groups, respectively; P = 0.02). At birth, HIV-exposed newborns had a similar length and weight as newborns without HIV exposure, but their head circumference was smaller (34.0 ± 1.5 and 34.3 ± 1.6 cm, respectively; P = 0.02). At 3 mo of age, HIV-exposed infants had smaller weights, lengths, and head and arm circumferences than infants without HIV exposure. Conclusions: RUSF improved maternal weight gain compared with CSB+ with UNIMMAP. The large amount of food given and the modest effect on linear growth in newborns suggests that stunting in utero is unlikely to be reduced by supplemental food alone. This trial was registered at clinicaltrials.gov as NCT02120599.

Effect of a package of health and nutrition services on sustained recovery in children after moderate acute malnutrition and factors related to sustaining recovery: a cluster-randomized trial.

Background: Children who recover from moderate acute malnutrition (MAM) have high rates of relapse in the year after nutritional recovery. Interventions to decrease these adverse outcomes are needed to maximize the overall effectiveness of supplemental feeding programs (SFPs).Objective: We evaluated the effectiveness of a package of health and nutrition interventions on improving the proportion of children who sustained recovery for 1 y after MAM treatment. We further explored factors related to sustained recovery.Design: We conducted a cluster-randomized clinical effectiveness trial involving rural Malawian children aged 6-62 mo who were enrolled on discharge from an SFP for MAM. We enrolled 718 children at 10 control sites and 769 children at 11 intervention sites. In addition to routine health and nutrition counseling, the intervention group received a package of health and nutrition interventions that consisted of a lipid nutrient supplement, deworming medication, zinc supplementation, a bed net, and malaria chemoprophylaxis. A survival analysis was used to determine the effectiveness of the intervention as well as to identify factors associated with sustained recovery.Results: Of 1383 children who returned for the full 12-mo follow-up period, 407 children (56%) and 347 children (53%) sustained recovery in the intervention and control groups, respectively. There was no significant difference in relapse-free survival curves between the treatment and control groups (P = 0.380; log-rank test). The risk factors for relapse or death after initial recovery were a smaller midupper arm circumference on SFP admission (P = 0.01) and discharge (P < 0.001), a lower weight-for-height z score on discharge (P < 0.01), and the receipt of ready-to-use supplementary food as opposed to ready-to-use therapeutic food during treatment (P < 0.05).Conclusion: The provision of a package of health and nutrition services in addition to traditional SFP treatment has no significant effect on improving sustained recovery in children after treatment of MAM. This trial was registered at clinicaltrials.gov as NCT02351687.

Drug-development concepts as guides for optimizing clinical trials of supplemental zinc for populations at risk of deficiency or diarrhea.

Studies on the efficacy of zinc supplementation for treatment or prevention of diarrhea have shown an inconsistent effect in populations at risk for zinc deficiency. Unlike drugs, which have no preexisting presence in the body, endogenous zinc must be assessed pharmacokinetically by isotope tracer studies. Although such methods have produced much data, very few studies have estimated the dose and the timing of dosing of zinc supplementation. This review examines drug kinetics used to establish the best dose, the timing of such doses, and the mechanism of action through pharmacodynamic markers and applies them, where possible, to zinc supplements. The findings reveal that little is known, especially in children at highest risk of zinc deficiency. Key data missing to inform proper dosing, whether for treatment of disease or for preventive nutrient supplementation, are noted. Addressing these uncertainties could improve study design, leading to future studies of zinc supplements that might be of greater benefit.

The Nutrient and Metabolite Profile of 3 Complementary Legume Foods with Potential to Improve Gut Health in Rural Malawian Children.

Background: Environmental enteric dysfunction (EED), frequently seen in rural Malawian children, causes chronic inflammation and increases the risk of stunting. Legumes may be beneficial for improving nutrition and reducing the risk of developing EED in weaning children. Objective: The objectives of this study were to determine the nutritional value, verify the food safety, and identify metabolite profiles of 3 legume-based complementary foods: common bean (CB), cowpea (CP), and traditional corn-soy blend (CSB). Methods: Foods were prepared by using local ingredients and analyzed for nutrient composition with the use of Association of Official Analytical Chemists (AOAC) standards (950.46, 991.43, 992.15, 996.06, and 991.36) for macro- and micronutrient proximate analysis. Food safety analysis was conducted in accordance with the Environmental Protection Agency (7471B) and AOAC (2008.02) standards. The metabolite composition of foods was determined with nontargeted ultra-performance LC-tandem mass spectrometry metabolomics. Results: All foods provided similar energy; CB and CP foods contained higher protein and dietary fiber contents than did the CSB food. Iron and zinc were highest in the CSB and CP foods, whereas CB and CP foods contained higher amounts of magnesium, phosphorus, and potassium. A total of 652 distinct metabolites were identified across the 3 foods, and 23, 14, and 36 metabolites were specific to the CSB, CB, and CP foods, respectively. Among the potential dietary biomarkers of intake to distinguish legume foods were pipecolic acid and oleanolic acid for CB; arabinose and serotonin for CSB; and quercetin and α- and γ-tocopherol acid for CP. No heavy metals were detected, and aflatoxin was measured only in the CSB (5.2 parts per billion). Conclusions: Legumes in the diet provide a rich source of protein, dietary fiber, essential micronutrients, and phytochemicals that may reduce EED. These food metabolite analyses identified potential dietary biomarkers of legume intake for stool, urine, and blood detection that can be used in future studies to assess the relation between the distinct legumes consumed and health outcomes. This trial was registered at clinicaltrials.gov as NCT02472262 and NCT02472301.

Perspective: The Potential Role of Essential Amino Acids and the Mechanistic Target of Rapamycin Complex 1 (mTORC1) Pathway in the Pathogenesis of Child Stunting.

Stunting is the best summary measure of chronic malnutrition in children. Approximately one-quarter of children under age 5 worldwide are stunted. Lipid-based or micronutrient supplementation has little to no impact in reducing stunting, which suggests that other critical dietary nutrients are missing. A dietary pattern of poor-quality protein is associated with stunting. Stunted children have significantly lower circulating essential amino acids than do nonstunted children. Inadequate dietary intakes of essential amino acids could adversely affect growth, because amino acids are required for synthesis of proteins. The master growth regulation pathway, the mechanistic target of rapamycin complex 1 (mTORC1) pathway, is exquisitely sensitive to amino acid availability. mTORC1 integrates cues such as nutrients, growth factors, oxygen, and energy to regulate growth of bone, skeletal muscle, nervous system, gastrointestinal tract, hematopoietic cells, immune effector cells, organ size, and whole-body energy balance. mTORC1 represses protein and lipid synthesis and cell and organismal growth when amino acids are deficient. Over the past 4 decades, the main paradigm for child nutrition in developing countries has been micronutrient malnutrition, with relatively less attention paid to protein. In this Perspective, we present the view that essential amino acids and the mTORC1 pathway play a key role in child growth. The current assumption that total dietary protein intake is adequate for growth among most children in developing countries needs re-evaluation.

Including whey protein and whey permeate in ready-to-use supplementary food improves recovery rates in children with moderate acute malnutrition: a randomized, double-blind clinical trial.

BACKGROUND: The utility of dairy ingredients in the supplementary foods used in the treatment of childhood moderate acute malnutrition (MAM) remains unsettled. OBJECTIVE: We evaluated the effectiveness of a peanut-based ready-to-use supplementary food (RUSF) with soy protein compared with a novel RUSF containing dairy ingredients in the form of whey permeate and whey protein concentrate in the treatment of children with MAM. DESIGN: We conducted a randomized, double-blind clinical effectiveness trial involving rural Malawian and Mozambican children 6-59 mo of age with MAM treated with either soy RUSF or a novel whey RUSF treatment of ~75 kcal · kg(-1) · d(-1) for up to 12 wk. RESULTS: The proportion of children that recovered from MAM was significantly higher in the group that received whey RUSF (960 of 1144; 83.9%) than in the group that received soy RUSF (874 of 1086; 80.5%; P < 0.04; risk difference 3.4%, 95% CI: 0.3%, 6.6%). Children who consumed whey RUSF also demonstrated better growth markers, with a higher mean midupper arm circumference (MUAC) at the time of discharge (P < 0.009), greater MUAC gain during the course of treatment (P < 0.003), higher mean weight-for-height z score at discharge (P < 0.008), and greater weight gain (P < 0.05). No significant differences were identified in length gain or time to recovery between the 2 groups. CONCLUSION: This study highlights the importance of milk protein in the treatment of MAM, because the use of a novel whey RUSF resulted in higher recovery rates and improved growth than did soy RUSF, although the whey RUSF supplement provided less total protein and energy than the soy RUSF. This study was registered at clinicaltrials.gov as NCT01790048.