How Can Nutrition Research Better Reflect the Relationship Between Wasting and Stunting in Children? Learnings from the Wasting and Stunting Project.

Childhood wasting and stunting affect large numbers of children globally. Both are important risk factors for illness and death yet, despite the fact that these conditions can share common risk factors and are often seen in the same child, they are commonly portrayed as relatively distinct manifestations of undernutrition. In 2014, the Wasting and Stunting project was launched by the Emergency Nutrition Network. Its aim was to better understand the complex relationship and associations between wasting and stunting and examine whether current separations that were apparent in approaches to policy, financing, and programs were justified or useful. Based on the project's work, this article aims to bring a wasting and stunting lens to how research is designed and financed in order for the nutrition community to better understand, prevent, and treat child undernutrition. Discussion of lessons learnt focuses on the synergy and temporal relationships between children's weight loss and linear growth faltering, the proximal and distal factors that drive diverse forms of undernutrition, and identifying and targeting people most at risk. Supporting progress in all these areas requires research collaborations across interest groups that highlight the value of research that moves beyond a focus on single forms of undernutrition, and ensures that there is equal attention given to wasting as to other forms of malnutrition, wherever it is present.

The Role of Nutrition in COVID-19 Susceptibility and Severity of Disease: A Systematic Review.

BACKGROUND: Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to coronavirus disease 2019 (COVID-19) infection, progression to symptoms, likelihood of severe disease, and survival. OBJECTIVE: The aim was to review the latest evidence on how malnutrition across all its forms (under- and overnutrition and micronutrient status) may influence both susceptibility to, and progression of, COVID-19. METHODS: We synthesized information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity, and diabetes; protein-energy malnutrition; anemia; vitamins A, C, D, and E; PUFAs; iron; selenium; zinc; antioxidants; and nutritional support. For each section we provide: 1) a landscape review of pertinent material; 2) a systematic search of the literature in PubMed and EMBASE databases, including a wide range of preprint servers; and 3) a screen of 6 clinical trial registries. All original research was considered, without restriction to study design, and included if it covered: 1) severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV), or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16 May and 11 August 2020. RESULTS: Across the 13 searches, 2732 articles from PubMed and EMBASE, 4164 articles from the preprint servers, and 433 trials were returned. In the final narrative synthesis, we include 22 published articles, 38 preprint articles, and 79 trials. CONCLUSIONS: Currently there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery. However, results of clinical trials are eagerly awaited. Given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. Furthermore, there is strong evidence that prevention of obesity and type 2 diabetes will reduce the risk of serious COVID-19 outcomes. This review is registered at PROSPERO as CRD42020186194.

A novel nutritional supplement to reduce plasma homocysteine in nonpregnant women: A randomised controlled trial in The Gambia.

BACKGROUND: Infant DNA methylation profiles are associated with their mother's periconceptional nutritional status. DNA methylation relies on nutritional inputs for one-carbon metabolic pathways, including the efficient recycling of homocysteine. This randomised controlled trial in nonpregnant women in rural Gambia tests the efficacy of a novel nutritional supplement designed to improve one-carbon-related nutrient status by reducing plasma homocysteine, and assesses its potential future use in preconception trials. METHODS AND FINDINGS: We designed a novel drink powder based on determinants of plasma homocysteine in the target population and tested it in a three-arm, randomised, controlled trial. Nonpregnant women aged between 18 and 45 from the West Kiang region of The Gambia were randomised in a 1:1:1 allocation to 12 weeks daily supplementation of either (a) a novel drink powder (4 g betaine, 800 µg folic acid, 5.2 µg vitamin B12, and 2.8 mg vitamin B2), (b) a widely used multiple micronutrient tablet (United Nations Multiple Micronutrient Preparation [UNIMMAP]) containing 15 micronutrients, or (c) no intervention. The trial was conducted between March and July 2018. Supplementation was observed daily. Fasted venepuncture samples were collected at baseline, midline (week 5), and endline (week 12) to measure plasma homocysteine. We used linear regression models to determine the difference in homocysteine between pairs of trial arms at midline and endline, adjusted for baseline homocysteine, age, and body mass index (BMI). Blood pressure and pulse were measured as secondary outcomes. Two hundred and ninety-eight eligible women were enrolled and randomised. Compliance was >97.8% for both interventions. At endline (our primary endpoint), the drink powder and UNIMMAP reduced mean plasma homocysteine by 23.6% (-29.5 to -17.1) and 15.5% (-21.2 to -9.4), respectively (both p < 0.001), compared with the controls. Compared with UNIMMAP, the drink powder reduced mean homocysteine by 8.8% (-15.8 to -1.2; p = 0.025). The effects were stronger at midline. There was no effect of either intervention on blood pressure or pulse compared with the control at endline. Self-reported adverse events (AEs) were similar in both intervention arms. There were two serious AEs reported over the trial duration, both in the drink powder arm, but judged to be unrelated to the intervention. Limitations of the study include the use of a single targeted metabolic outcome, homocysteine. CONCLUSIONS: The trial confirms that dietary supplements can influence metabolic pathways that we have shown in previous studies to predict offspring DNA methylation. Both supplements reduced homocysteine effectively and remain potential candidates for future epigenetic trials in pregnancy in rural Gambia. TRIAL REGISTRATION: Clinicaltrials.gov Reference NCT03431597.

Low-dose RUTF protocol and improved service delivery lead to good programme outcomes in the treatment of uncomplicated SAM: a programme report from Myanmar.

The treatment of uncomplicated severe acute malnutrition (SAM) requires substantial amounts of ready-to-use therapeutic food (RUTF). In 2009, Action Contre la Faim anticipated a shortfall of RUTF for their nutrition programme in Myanmar. A low-dose RUTF protocol to treat children with uncomplicated SAM was adopted. In this protocol, RUTF was dosed according to beneficiary's body weight, until the child reached a Weight-for-Height z-score of ≥-3 and mid-upper arm circumference ≥110 mm. From this point, the child received a fixed quantity of RUTF per day, independent of body weight until discharge. Specific measures were implemented as part of this low-dose RUTF protocol in order to improve service quality and beneficiary support. We analysed individual records of 3083 children treated from July 2009 to January 2010. Up to 90.2% of children recovered, 2.0% defaulted and 0.9% were classified as non-responders. No deaths were recorded. Among children who recovered, median [IQR] length of stay and weight gain were 42 days [28; 56] and 4.0 g kg(-1) day(-1) [3.0; 5.7], respectively. Multivariable logistic regression showed that children older than 48 months had higher odds of non-response to treatment than younger children (adjusted odds ratio: 3.51, 95% CI: 1.67-7.42). Our results indicate that a low-dose RUTF protocol, combined with specific measures to ensure good service quality and beneficiary support, was successful in treating uncomplicated SAM in this setting. This programmatic experience should be validated by randomised studies aiming to test, quantify and attribute the effect of the protocol adaptation and programme improvements presented here.

Integrating Women and Girls' Nutrition Services into Health Systems in Low- and Middle-Income Countries: A Systematic Review.

Women's nutrition has been highlighted as a global priority to ensure the health and well-being of both them and future generations. This systematic review summarises the available literature on the integration of nutrition services for girls and women of reproductive age (GWRA) into existing public health systems across low- and middle-income countries, as well as any barriers to integration. We searched PubMed and Cochrane Database of Systematic Reviews for articles published since 2011 according to eligibility criteria. A total of 69 articles were included. Evidence suggested that several services for GWRA are well integrated into public health systems, including antenatal care services, nutrition education and counselling, and micronutrient supplementation programmes. However, there was limited evidence on the integration of family planning, adolescent health, and reproductive health services. Barriers to integration fell into five main themes: lack of training and capacity building, poor multisectoral linkages and coordination, weak advocacy, lack of M&E systems, and inequity. We identified a lack of evidence and services for non-pregnant GWRA and for women postpartum. Addressing barriers to integration and gaps in nutrition services for GWRA would increase service coverage and contribute to improving health outcomes for GWRA and future generations.

Nutrition status and morbidity of Ethiopian children after recovery from severe acute malnutrition: Prospective matched cohort study.

After recovery, children with severe acute malnutrition (SAM) remain vulnerable to sub-optimal growth and malnutrition relapse. Although there is an increased interest in understanding these problems, data are scarce, and contextual factors can cause variability. We prospectively followed a cohort of Ethiopian children (215 post-SAM cases and 215 non-wasted controls), monthly for one year. The post-SAM cases were: age 6-59 months at admission into the community management of acute malnutrition (CMAM) program and being successfully discharged from CMAM (MUAC>11.0cm, weight gain of 20%, absence of oedema and clinically stable for two consecutive weeks). The controls were apparently healthy children from same village who had no history of an episode of AM and were matched 1:1 to a post-SAM child by age and sex. The primary outcomes were: cumulative incidence of acute malnutrition; growth trajectory; cumulative incidence of reported common morbidities, and cumulative proportion and incidence of deaths. The burden of common morbidities was higher among post-SAM than controls; post-SAM children had more frequent illness episodes (Incidence Rate Ratio of any illness 1.39, 95% CI: 1.14, 1.71; p<0.001). The prevalence of SAM was consistently higher among post-SAM cases than the control group, having a 14 times higher risk of developing SAM (Incidence Rate Ratio: 14.1; 95% CI: 3.5, 122.5; p<0.001). The divergence in weight and growth trajectory remained the same during the study period. Our results advocate for the design of post-discharge interventions that aim to prevent the reoccurrence of acute malnutrition, reduce morbidity and promote catch-up growth. Research is needed to define the appropriate package of post-discharge interventions.

Environmentally sensitive hotspots in the methylome of the early human embryo.

In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed three datasets covering two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin-specific methylation and germline differentially methylated regions, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 embryonic stem cells and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental 'hotspots' providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease.

The weight lowering effect of sibutramine and its impact on serum lipids in cardiovascular high risk patients with and without type 2 diabetes mellitus - an analysis from the SCOUT lead-in period.

BACKGROUND: Obesity, type 2 diabetes mellitus (T2D) and unhealthy blood lipid profile are strongly associated with the risk of developing cardiovascular disease (CVD). We examined whether blood lipid changes with short term administration of the weight lowering drug, sibutramine and lifestyle modification in obese and overweight high-risk patients was associated with T2D status at screening. METHODS: The Sibutramine Cardiovascular OUTcomes (SCOUT) trial included obese and overweight patients at increased risk of cardiovascular events. All patients received guidance on diet and exercise plus once-daily 10 mg sibutramine during the 6-week, single blind lead-in period. Multivariable regression models were used to investigate factors associated with changes in lipid levels during the first four weeks of treatment. RESULTS: A total of 10 742 patients received at least one dose of sibutramine during the 6-week lead-in period of SCOUT. After four weeks, patients experienced mean reductions in low density lipoprotein (LDL-C) 0.19 mmol/L, high density lipoprotein (HDL-C) 0.019 mmol/L, very low density lipoprotein (VLDL-C) 0.08 mmol/L, total cholesterol (TC) 0.31 mmol/L and triglycerides 0.24 mmol/L (p < 0.0001 for each). Four week changes in LDL-C, HDL-C and total cholesterol for patients without vs. with T2D were: LDL-C:-0.25 mmol/L vs. -0.18 mmol/L, P = 0.0004; HDL-C: -0.03 mmol/L vs. -0.02 mmol/L, P = 0.0014; total cholesterol: -0.37 mmol/l vs. -0.29 mmol/l, P = 0.0009. Multivariable regression analysis showed that similar decreases in body mass index (BMI) affected lipid changes differently according to diabetes status. A 1 kg/m2 decrease in BMI in patients with T2D was associated with -0.09 mmol/L in LDL-C (P < 0.0001) and -0.01 mmol/L in HDL-C (P = 0.0001) but larger changes of -0.16 mmol/L LDL-C and -0.03 mmol/L in HDL-C (P < 0.0001 for both) in patients without T2D. CONCLUSION: Short term weight management with sibutramine therapy in obese or overweight high-risk patients induced significant mean reductions for all lipids. Those without T2D benefited most. Patients with hyperlipidaemia and the less obese patients also had greater falls in LDL-C and TC during weight loss. The trial is registered at ClinicalTrial.gov number: NCT00234832.

Periconceptional environment predicts leukocyte telomere length in a cross-sectional study of 7-9 year old rural Gambian children.

Early life exposures are important predictors of adult disease risk. Although the underlying mechanisms are largely unknown, telomere maintenance may be involved. This study investigated the relationship between seasonal differences in parental exposures at time of conception and leukocyte telomere length (LTL) in their offspring. LTL was measured in two cohorts of children aged 2 yrs (N = 487) and 7-9 yrs (N = 218). The association between date of conception and LTL was examined using Fourier regression models, adjusted for age, sex, leukocyte cell composition, and other potential confounders. We observed an effect of season in the older children in all models [likelihood ratio test (LRT) χ²2 = 7.1, p = 0.03; fully adjusted model]. LTL was greatest in children conceived in September (in the rainy season), and smallest in those conceived in March (in the dry season), with an effect size (LTL peak-nadir) of 0.60 z-scores. No effect of season was evident in the younger children (LRT χ²2 = 0.87, p = 0.65). The different results obtained for the two cohorts may reflect a delayed effect of season of conception on postnatal telomere maintenance. Alternatively, they may be explained by unmeasured differences in early life exposures, or the increased telomere attrition rate during infancy.

Guts, Germs, and Iron: A Systematic Review on Iron Supplementation, Iron Fortification, and Diarrhea in Children Aged 4-59 Months.

BACKGROUND: The impact of iron supplements and iron fortification on diarrhea in children is controversial, with some studies reporting an increase and others reporting no effect. OBJECTIVE: The aim of the study was systematically assess the published literature on oral iron supplementation and fortification to evaluate its impact on diarrhea incidence among children aged 4-59 mo. METHODS: Randomized controlled trials of oral iron supplementation or iron fortification that reported diarrheal outcomes in children aged 4-59 mo were identified from a systematic search of 5 databases. RESULTS: Of the 906 records identified, 19 studies were found to fit the inclusion criteria for this systematic review. However, variable case definitions for diarrhea made meta-analysis impossible. Of the 19 studies, 7 (37%) studies showed a significant increase, either in overall diarrhea incidence or within a specific subgroup of the population, between iron-supplemented and control groups. Subgroups included children who were iron-replete and children undergoing their first month of iron intervention. Two studies reported an increase in bloody diarrhea. The remaining 12 (63%) studies showed no difference between iron-supplemented and control groups. CONCLUSIONS: Studies on iron supplementation and fortification use divergent case definitions for diarrhea. A number of studies (37%) showed an increase in overall diarrhea incidence or within a specific subgroup of the population, between iron-supplemented and control groups, but the majority (63%) did not. In addition, there was no clear relation between diarrhea and type of intervention or amount of iron administered observed. In future studies, we recommend that diarrhea be clearly defined and consistently recorded as a secondary outcome. Antibiotic status of participants receiving iron should also be collected to help assess possible drug interactions resulting in a "red stool effect." Finally, further microbiome research is required to better understand the effects of oral iron on specific bacterial species in the colon.

Obesity: the worldwide epidemic.

Over the last decade, the prevalence of obesity in Western and Westernizing countries has more than doubled. A standardized classification of overweight and obesity, based on the body mass index now allows a comparison of prevalence rates worldwide for the first time. In children, the International Obesity Taskforce age, sex, and BMI specific cut-off points are increasingly being used. BMI data are being evaluated as part of a new analysis of the Global Burden of Disease. Prevalence rates for overweight and obese people are very different in each region with the Middle East, Central and Eastern Europe and North American having higher prevalence rates. Obesity is usually now associated with poverty even in developing countries. Relatively new data suggest that abdominal obesity in adults, with its associated enhanced morbidity, occurs particularly in those who had lower birth weights and early childhood stunting.

Differential changes in serum uric acid concentrations in sibutramine promoted weight loss in diabetes: results from four weeks of the lead-in period of the SCOUT trial.

BACKGROUND AND AIMS: Elevated levels of serum uric acid are associated with an increased risk of cardiovascular morbidity and mortality. The response of uric acid to weight loss therapy (lifestyle plus sibutramine) in an overweight and obese cardiovascular high risk population was studied. METHODS AND RESULTS: Data from a four week single-blind lead-in period of the Sibutramine Cardiovascular OUTcomes (SCOUT) study were analyzed. 2584 patients (24%) had diabetes mellitus (DM) only, 1748 (16%) had cardiovascular disease (CVD) only and 6397 (60%) had both DM + CVD. Uric acid concentrations (mean +/- standard deviation) at screening were significantly higher among patients with CVD compared to patients without CVD (p < 0.0001): 369 +/- 86 mumol/L, 374 +/- 98 mumol/L and 342 +/- 87 mumol/L in CVD only, CVD+DM and DM only groups, respectively. During treatment uric acid decreased significantly more in patients without DM (p < 0.0001): -15.0 mumol/L (95% confidence interval -17.7;-12.4), -4.6 mumol/L (-6.2;-3.0), and -6.6 mumol/L (-8.7;-4.5) in CVD only, CVD+DM, and DM only groups, respectively. In patients who failed to lose weight, sibutramine induced lower uric acid levels, but greater weight loss and diabetes were associated with smaller falls in blood uric acid levels; decreasing fasting and urinary glucose concentrations in diabetes were associated with increases in uric acid levels. CONCLUSION: A four week daily intake of sibutramine and life style changes was associated with significant reductions in mean uric acid levels. Changes in renal glucose load in diabetes seem to counteract a potential uricosuric effect of sibutramine. TRIAL REGISTRATION: The trial is registered at ClinicalTrial.gov number: NCT00234832.

The obesity epidemic, metabolic syndrome and future prevention strategies.

UNLABELLED: The epidemic of obesity and overweight poses a major challenge to the prevention of chronic noncommunicable diseases throughout the world. In some developing countries it presents a double burden alongside enduring problems of undernutrition. Current IOTF estimates suggest that at least 1.1 billion adults are overweight including 312 million who are obese. The prevalence of obesity has doubled or even risen threefold in less than two decades, while in children this is rising at an even faster rate in some regions of Europe to levels of up to 36% in parts of Italy and elsewhere. The comparative burden of disease due to raised body mass index is among the top five leading risk factors in both developed and low mortality developing countries. When viewed in conjunction with the burden of raised cholesterol and hypertension, these components of the metabolic syndrome form the major cause of mortality and disease in Europe and are guaranteed to increase with the rising trend in overweight and obesity while amplifying the burden of cardiovascular disease. The increase in childhood obesity will, unchecked, accentuate the rise in early adult type 2 diabetes and cardiovascular disease. CONCLUSIONS: A fundamental policy shift is required to widen responsibility for the prevention of diet, activity and weight-related ill health across the whole of Europe's population. Only such a comprehensive approach offers any realistic prospect of averting a public health catastrophe for Europe and indeed for the whole world.