Supplementary Feeding of Moderately Wasted Children in Sierra Leone Reduces Severe Acute Malnutrition and Death When Compared with Nutrition Counseling: A Retrospective Cohort Study.

BACKGROUND: There is uncertainty about whether children with moderate wasting should receive supplementary feeding. OBJECTIVES: We examined whether supplementary feeding compared with counseling alone in children with moderate wasting prevented progression to severe acute malnutrition (SAM) or death. METHODS: This was a retrospective, dual-cohort study in which 1791 children with moderate wasting were drawn from 2 prior randomized controlled trials that took place in the same location in rural Sierra Leone. A total of 1077 children received supplementary feeding, whereas 714 children received counseling alone. Children in both cohorts were followed for ≥24 wk from enrollment. The primary outcome was time to SAM or death using Kaplan-Meier analysis. Secondary outcomes included time to death as well as proportions of children with healthy midupper arm circumference (MUAC), moderate wasting, SAM, or death at 6, 12, and 24 wk from enrollment. RESULTS: Children who received supplementary feeding were less likely to develop SAM or die across the entire follow-up period (HR: 0.53; 95% CI: 0.44, 0.65; P < 0.001). Time to event for death alone also revealed a lower risk for children who received supplementary feeding (HR: 0.52; 95% CI: 0.28, 0.94; P = 0.03). Children who received supplementary feeding were more likely to have a healthy MUAC at 6 wk (RR: 2.0; 95% CI: 1.7, 2.2) and 12 wk (RR: 1.3; 95% CI: 1.2, 1.5), were less likely to develop SAM at 6 (RR: 0.7; 95% CI: 0.6, 0.9), 12 (RR: 0.5; 95% CI: 0.3, 0.8), and 24 wk (RR: 0.2; 95% CI: 0.1, 0.5), and had higher rates of gain in weight and MUAC at 6 and 12 wk. CONCLUSIONS: Supplementary feeding of children with moderate wasting reduces risk of SAM and death across 24 wk of follow-up.

Low linoleic acid foods with added DHA given to Malawian children with severe acute malnutrition improve cognition: a randomized, triple-blinded, controlled clinical trial.

BACKGROUND: There is concern that the PUFA composition of ready-to-use therapeutic food (RUTF) for the treatment of severe acute malnutrition (SAM) is suboptimal for neurocognitive recovery. OBJECTIVES: We tested the hypothesis that RUTF made with reduced amounts of linoleic acid, achieved using high-oleic (HO) peanuts without added DHA (HO-RUTF) or with added DHA (DHA-HO-RUTF), improves cognition when compared with standard RUTF (S-RUTF). METHODS: A triple-blind, randomized, controlled clinical feeding trial was conducted among children with uncomplicated SAM in Malawi with 3 types of RUTF: DHA-HO-RUTF, HO-RUTF, and S-RUTF. The primary outcomes, measured in a subset of subjects, were the Malawi Developmental Assessment Tool (MDAT) global z-score and a modified Willatts problem-solving assessment (PSA) intention score for 3 standardized problems, measured 6 mo and immediately after completing RUTF therapy, respectively. MDAT domain z-scores, plasma fatty acid content, anthropometry, and eye tracking were secondary outcomes. Comparisons were made between the novel PUFA RUTFs and S-RUTF. RESULTS: Among the 2565 SAM children enrolled, mean global MDAT z-scores were -0.69 ± 1.19 and -0.88 ± 1.27 for children receiving DHA-HO-RUTF and S-RUTF, respectively (difference 0.19, 95% CI: 0.01, 0.38). Children receiving DHA-HO-RUTF had higher gross motor and social domain z-scores than those receiving S-RUTF. The PSA problem 3 scores did not differ by dietary group (OR: 0.92, 95% CI: 0.67, 1.26 for DHA-HO-RUTF). After 4 wk of treatment, plasma phospholipid EPA and α-linolenic acid were greater in children consuming DHA-HO-RUTF or HO-RUTF when compared with S-RUTF (for all 4 comparisons P values < 0.001), but only plasma DHA was greater in DHA-HO-RUTF than S-RUTF (P < 0.001). CONCLUSIONS: Treatment of uncomplicated SAM with DHA-HO-RUTF resulted in an improved MDAT score, conferring a cognitive benefit 6 mo after completing diet therapy. This treatment should be explored in operational settings. This trial was registered at clinicaltrials.gov as NCT03094247.

Reducing Oil Separation in Ready-to-Use Therapeutic Food.

Ready-to-use therapeutic food (RUTF) is a shelf-stable, low moisture, energy dense medicinal food composed of peanut butter, vegetable oils, milk powder, a multiple micronutrient premix and sugar. RUTF is used by millions of children annually to treat malnutrition. After mixing, RUTF is a semisolid covered with oil. To produce a homogenous RUTF, hydrogenated vegetable oils are incorporated in small quantities. This study utilized a benchtop methodology to test the effect of RUTF ingredients on oil separation. An acceptable oil separation was <4%. This method compared 15 different vegetable oil stabilizers with respect to oil separation. The dynamic progression of oil separation followed a Michaelis-Menten pattern, reaching a maximum after 60 days when stored at 30 °C. Hydrogenated vegetable oils with triglyceride or 50% monoglycerides reduced the oil separation to acceptable levels. The additive showing the largest reduction in oil separation was used in an industrial trial, where it also performed acceptably. In conclusion, fully hydrogenated soybean and rapeseed oil added as 1.5% controlled oil separation in RUTF.

Ready-to-Use Supplemental Food for Nutritional Supplementation in Cystic Fibrosis.

Undernutrition is common in cystic fibrosis (CF) and is correlated with long-term outcomes, yet current nutritional interventions have not demonstrated consistent improvements in energy intake, and subsequently, growth. Development of novel nutritional interventions to increase energy intake is essential to improve clinical outcomes of individuals with CF. Ready-to-use supplemental food (RUSF) is a modifiable, inexpensive, palatable, safe, and nutrient-dense food for treatment or prevention of acute malnutrition in developing countries. Utilizing a linear-programming tool we identified 6 RUSF formulations with sufficient nutrient density (495 kcal/100 g), protein, and fat for children with CF. Palatability was established by a taste-trial and affirmed by a 2-wk tolerability assessment that demonstrated consistent consumption and tolerance of the RUSF. Although preliminary, this study demonstrates the potential for developing RUSF as a nutritional supplement for increasing energy intake in children with CF.

Children with Poor Linear Growth Are at Risk for Repeated Relapse to Wasting after Recovery from Moderate Acute Malnutrition.

Background: Nutrition programs frequently approach wasting and stunting as 2 separate conditions with distinct causes and effects. Although several cross-sectional studies have identified an association between the 2 conditions, longitudinal studies are useful to quantify the risk of acute malnutrition based on the trajectory of linear growth. Objective: We analyzed data from a longitudinal study to explore associations between linear growth and relapse to acute malnutrition in high-risk children during the year after recovery from moderate acute malnutrition (MAM). Methods: This was a secondary data analysis from a cluster randomized trial involving 1487 Malawian children 6-62 mo old treated for MAM and enrolled upon recovery. Children were followed for 1 y, during which data were collected on anthropometric progress, symptoms of illness, and household food security. Multivariate fixed-effects logistic regression was used to identify associations between linear growth and relapse to acute malnutrition. Results: Children who have recovered from MAM proved to be a high-risk population, with nearly half experiencing a decrease in height-for-age z score (HAZ) for 12 mo. Children whose HAZ was declining were more likely to relapse to MAM or SAM than were those whose linear growth rate maintained or increased their HAZ (P < 0.001). Mean changes of +0.15, -0.03, -0.17, and -0.53 in HAZ were observed for those who sustained recovery, relapsed to MAM once, relapsed to MAM multiple times, and developed SAM, respectively. Conclusion: Our results add to the body of evidence suggesting that acute wasting is a harbinger of subsequent stunting. Children who experience poor linear growth after MAM are more likely to experience relapse. Given this bidirectional relation between wasting and stunting, supplementary feeding programs should consider both when designing protocols, aiming to optimize linear growth and achieve acute weight gain, as a means of reducing relapse. This trial was registered at clinicaltrials.gov as NCT02351687.

Use of a novel supplementary food and measures to control inflammation in malnourished pregnant women in Sierra Leone to improve birth outcomes: study protocol for a prospective, randomized, controlled clinical effectiveness trial.

BACKGROUND: The negative synergy between poor nutritional status and infectious diseases is doubly detrimental in pregnancy. In Sierra Leone, maternal malnutrition is amongst the highest in the world, while maternal mortality is high at 1320/100,000 live births and stunting in under-five is 37.9%, ranked 110/132 worldwide. Maternal malnutrition has been associated with preterm birth, small-for-gestational age infants, and poor maternal outcomes. Infants born prematurely or small-for-gestational age experience higher mortality and are at risk for stunting and decreased cognitive performance. Nutritional interventions alone during pregnancy may not be as effective in the setting of increased inflammation from repeated infections. Interventions are needed to improve maternal outcomes and reduce stunting in this population. METHODS/DESIGN: This will be a prospective, randomized, controlled clinical effectiveness trial of an improved supplementary food plus anti-infective therapies compared to standard therapy in malnourished pregnant women. Pregnant women will be randomized to receive a low water activity, ready-to-use supplementary food plus five anti-infective interventions or the standard of care which is 3.5 kg corn/ soy blended flour with 350 mL vegetable oil every two weeks. The five anti-infective interventions are 1) insecticide-treated mosquito net at the time of enrollment into the study, 2) sulfadoxine-pyrimethamine given every 4 weeks, beginning at enrollment or at 13 weeks' gestation, whichever is later, 3)azithromycin at a dose of 1 g given once at enrollment (after first trimester)and again during 28-34 weeks of gestation, 4)single dose 400 mg albendazole given in second trimester, and 5) testing and treatment for bacterial vaginosis at enrollment and again at 28-34 weeks of gestation. Treatment will be provided for the duration of the pregnancy. The primary outcome measure will be birth length. Secondary outcomes in the mothers will include rates of maternal weight gain and increase in mid-upper arm circumference, and time to maternal anthropometric recovery. Secondary outcomes in the infants will include birth weight, birth head circumference, and linear and ponderal growth. DISCUSSION: Malnutrition remains a major problem in the developing world with lasting maternal and infant consequences. Maternal malnutrition has been associated with intrauterine growth retardation, low birth weight (LBW), pre-term delivery and poor cognitive development. Nutritional interventions alone have not been successful in reducing stunting. By bundling nutritional and anti-infective interventions, we aim to reduce intrauterine growth restriction and low birth weight in moderately malnourished pregnant women in Sierra Leone. If successful, this bundle can easily be implemented by governments or non-governmental organizations. TRIAL REGISTRATION: Clinicaltrials.gov NCT03079388; Date: March 5, 2017.

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.

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.

The association of serum choline with linear growth failure in young children from rural Malawi.

BACKGROUND: Choline is an essential nutrient for cell structure, cell signaling, neurotransmission, lipid transport, and bone formation. Choline can be irreversibly converted to betaine, a major source of methyl groups. Trimethylene N-oxide (TMAO), a proatherogenic molecule, is produced from the metabolism of dietary choline by the gut microbiome. The relation between serum choline and its closely related metabolites with linear growth in children is unknown. OBJECTIVE: The aim was to characterize the relation between serum choline and its closely related metabolites, betaine and TMAO, with linear growth and stunting in young children. DESIGN: We measured serum choline, betaine, and TMAO concentrations by using liquid chromatography isotopic dilution tandem mass spectrometry in a cross-sectional study in 325 Malawian children, aged 12-59 mo, of whom 62% were stunted. RESULTS: Median (25th, 75th percentile) serum choline, betaine, and TMAO concentrations were 6.4 (4.8, 8.3), 12.4 (9.1, 16.3), and 1.2 (0.7, 1.8) µmol/L, respectively. Spearman correlation coefficients of age with serum choline, betaine, and TMAO were -0.57 (P < 0.0001), -0.26 (P < 0.0001), and -0.10 (P = 0.07), respectively. Correlation coefficients of height-for-age z score with serum choline, betaine-to-choline ratio, and TMAO-to-choline ratio were 0.31 (P < 0.0001), -0.24 (P < 0.0001), and -0.29 (P < 0.0001), respectively. Serum choline concentrations were strongly and significantly associated with stunting. Children with and without stunting had median (25th, 75th percentile) serum choline concentrations of 5.6 (4.4, 7.4) and 7.3 (5.9, 9.1) µmol/L (P < 0.0001). CONCLUSIONS: Linear growth failure in young children is associated with low serum choline and elevated betaine-to-choline and TMAO-to-choline ratios. Further work is needed to understand whether low dietary choline intake explains low circulating choline among stunted children living in low-income countries and whether increasing choline intake may correct choline deficiency and improve growth and development. This trial was registered in the ISRCTN registry (www.isrctn.com) as ISRCTN14597012.

New insights into environmental enteric dysfunction.

Environmental enteric dysfunction (EED) has been recognised as an important contributing factor to physical and cognitive stunting, poor response to oral vaccines, limited resilience to acute infections and ultimately global childhood mortality. The aetiology of EED remains poorly defined but the epidemiology suggests a multifactorial combination of prenatal and early-life undernutrition and repeated infectious and/or toxic environmental insults due to unsanitary and unhygienic environments. Previous attempts at medical interventions to ameliorate EED have been unsatisfying. However, a new generation of imaging and '-omics' technologies hold promise for developing a new understanding of the pathophysiology of EED. A series of trials designed to decrease EED and stunting are taking novel approaches, including improvements in sanitation, hygiene and nutritional interventions. Although many challenges remain in defeating EED, the global child health community must redouble their efforts to reduce EED in order to make substantive improvements in morbidity and mortality worldwide.

Effect of emulsifier and viscosity on oil separation in ready-to-use therapeutic food.

Oil separation is a common food quality problem in ready-to-use therapeutic food (RUTF), the shelf-stable, peanut-based food used to treat severe acute malnutrition in home settings. Our objective was to evaluate the effect on oil separation of three emulsifiers at different concentrations in RUTF. We also assessed two viscosity measurements. A scale-up experiment was carried out during full-scale RUTF production in Malawi. Results indicate that viscosity is inversely correlated with oil separation, and that the Bostwick consistometer is a simple, useful tool to predict viscosity. Oil separation in RUTF may be mitigated by use of an emulsifier, which increases the viscosity of the product. The emulsifier that reduced oil separation to the greatest extent was a mixture of high and low monoacylglycerol (MAG) emulsifiers. Proper raw material quality control to achieve consistent ingredient fat level and fat type, and production temperature and shearing control should be a focus in RUTF manufacturing.

Discovery of STL polyomavirus, a polyomavirus of ancestral recombinant origin that encodes a unique T antigen by alternative splicing.

The family Polyomaviridae is comprised of circular double-stranded DNA viruses, several of which are associated with diseases, including cancer, in immunocompromised patients. Here we describe a novel polyomavirus recovered from the fecal microbiota of a child in Malawi, provisionally named STL polyomavirus (STLPyV). We detected STLPyV in clinical stool specimens from USA and The Gambia at up to 1% frequency. Complete genome comparisons of two STLPyV strains demonstrated 5.2% nucleotide divergence. Alternative splicing of the STLPyV early region yielded a unique form of T antigen, which we named 229T, in addition to the expected large and small T antigens. STLPyV has a mosaic genome and shares an ancestral recombinant origin with MWPyV. The discovery of STLPyV highlights a novel alternative splicing strategy and advances our understanding of the complex evolutionary history of polyomaviruses.

Identification of MW polyomavirus, a novel polyomavirus in human stool.

We have discovered a novel polyomavirus present in multiple human stool samples. The virus was initially identified by shotgun pyrosequencing of DNA purified from virus-like particles isolated from a stool sample collected from a healthy child from Malawi. We subsequently sequenced the virus' 4,927-bp genome, which has been provisionally named MW polyomavirus (MWPyV). The virus has genomic features characteristic of the family Polyomaviridae but is highly divergent from other members of this family. It is predicted to encode the large T antigen and small T antigen early proteins and the VP1, VP2, and VP3 structural proteins. A real-time PCR assay was designed and used to screen 514 stool samples from children with diarrhea in St. Louis, MO; 12 specimens were positive for MWPyV. Comparison of the whole-genome sequences of the index Malawi case and one St. Louis case demonstrated that the two strains of MWPyV varied by 5.3% at the nucleotide level. The number of polyomaviruses found in the human body continues to grow, raising the question of how many more species have yet to be identified and what roles they play in humans with and without manifest disease.

Children consuming cassava as a staple food are at risk for inadequate zinc, iron, and vitamin A intake.

Cassava contains little zinc, iron, and beta-carotene, yet it is the primary staple crop of over 250 million Africans. This study used a 24-hour dietary recall to test the hypothesis that among healthy children aged 2-5 years in Nigeria and Kenya, cassava's contribution to the childrens' daily diets is inversely related to intakes of zinc, iron, and vitamin A. Dietary and demographic data and anthropometric measurements were collected from 449 Kenyan and 793 Nigerian children. Among Kenyan children 89% derived at least 25% of their dietary energy from cassava, while among the Nigerian children 31% derived at least 25% of energy from cassava. Spearman's correlation coefficient between the fraction of dietary energy obtained from cassava and vitamin A intake was r = -0.15, P < 0.0001, zinc intake was r = -0.11, P < 0.0001 and iron intake was r = -0.36, P < 0.0001. In Kenya, 59% of children consumed adequate vitamin A, 22% iron, and 31% zinc. In Nigeria, 17% of children had adequate intake of vitamin A, 57% iron, and 41% zinc. Consumption of cassava is a risk factor for inadequate vitamin A, zinc and/or iron intake.

Cortisol and its action on the glucocorticoid receptor in malnutrition and acute infection.

Severe malnutrition alone is believed to cause hypercortisolemia. Cortisol's effects are mediated through the glucocorticoid receptor, which binds the hormone in the cytosol, translocates to the nucleus, and promotes gene transcription. This observational study in marasmic children with and without acute infection tested the hypothesis that marasmus is associated with hypercortisolemia, less glucocorticoid receptor, and less receptor translocation to the nucleus. Twenty-eight Malawian children participated; 14 with marasmus and infection, 6 with marasmus without infection, and 8 well nourished with infection. Free serum cortisol, interleukin 6 and tumor necrosis factor alpha, leucine derived from whole-body proteolysis, and the amount of whole-cell and nuclear leukocyte glucocorticoid receptor were measured upon admission. Free serum cortisol concentration was increased in marasmic and well-nourished children with infection compared with uninfected children with marasmus (14.2 [8.5, 16.3], 24.4 [15.0, 39.2], 5.1 [3.5, 7.0] microg/L, median [25th, 75th percentiles]; P < .05 by Kruskal-Wallis test). The amount of whole-cell leukocyte glucocorticoid receptor was similar in all children (0.48 +/- 0.33 signal units), but the amount in the nucleus was greatest in marasmic children with infection, followed by the amount in uninfected marasmic children, and then in well-nourished infected children (0.54 +/- 0.58, 0.19 +/- 0.13, 0.02 +/- 0.5 signal units [mean +/- SD]; P < .05 for all comparisons by analysis of variance). These findings suggest that hypercortisolemia is not associated with malnutrition alone, but does occur appropriately with acute infection. The increased nuclear glucocorticoid receptor abundance in marasmus demonstrates that nutritional status modulates glucocorticoid receptor action by mechanisms in addition to circulating glucocorticoid concentrations.

Whole-body leucine kinetics and the acute phase response during acute infection in marasmic Malawian children.

This study compared leucine kinetics and acute-phase protein and cytokine concentrations in three groups of Malawian children who were fed an isoenergetic, isonitrogenous diet: children with marasmus with (n = 25) and without (n = 17) infection and well-nourished children with infection (n =13). The hypotheses tested were that whole-body leucine kinetics will be less in marasmic acutely infected children than in well-nourished acutely infected children but greater than in marasmic uninfected children. Children were studied after 24 h of therapy using standard (13)C-leucine stable isotope tracer techniques. Well-nourished children with acute infection had greater leucine kinetic rates than did marasmic children with acute infection; nonoxidative leucine disposal was 153 +/- 31 versus 118 +/- 43 micromol leucine. kg(-1). h(-1), leucine derived from whole-body proteolysis was 196 +/- 34 versus 121 +/- 47, and leucine oxidation was 85 +/- 31 versus 45 +/- 13 (p < 0.01 for all comparisons). Leucine kinetic rates were similar in marasmic children with and without acute infection. Well-nourished children with acute infection increased their serum concentration of five of six acute-phase proteins during the first 24 h, whereas marasmic children with infection did not have any increases. The serum concentrations of IL-6 were elevated in well-nourished and marasmic children with infection. These data suggest that the cytokine stimulus for the acute-phase protein kinetic response to acute infection is present in marasmic children but that the acute-phase protein metabolic response is blunted by malnutrition.

Community-based dietary phytate reduction and its effect on iron status in Malawian children.

This study describes a community-based method used in rural Malawi to remove dietary phytate, an inhibitor of iron absorption, and notes an improvement in the iron status of ten children who participated in the trial. Phytate was removed by soaking maize flour in excess water with phytase and decanting the water before cooking the flour. Iron status, as measured by soluble transferrin receptor and zinc protoporphyrin, was improved but not normal.