The relationship between wasting and stunting in young children: A systematic review.

In 2014, the Emergency Nutrition Network published a report on the relationship between wasting and stunting. We aim to review evidence generated since that review to better understand the implications for improving child nutrition, health and survival. We conducted a systematic review following PRISMA guidelines, registered with PROSPERO. We identified search terms that describe wasting and stunting and the relationship between the two. We included studies related to children under five from low- and middle-income countries that assessed both ponderal growth/wasting and linear growth/stunting and the association between the two. We included 45 studies. The review found the peak incidence of both wasting and stunting is between birth and 3 months. There is a strong association between the two conditions whereby episodes of wasting contribute to stunting and, to a lesser extent, stunting leads to wasting. Children with multiple anthropometric deficits, including concurrent stunting and wasting, have the highest risk of near-term mortality when compared with children with any one deficit alone. Furthermore, evidence suggests that the use of mid-upper-arm circumference combined with weight-for-age Z score might effectively identify children at most risk of near-term mortality. Wasting and stunting, driven by common factors, frequently occur in the same child, either simultaneously or at different moments through their life course. Evidence of a process of accumulation of nutritional deficits and increased risk of mortality over a child's life demonstrates the pressing need for integrated policy, financing and programmatic approaches to the prevention and treatment of child malnutrition.

A One Health Approach to Child Stunting: Evidence and Research Agenda.

Stunting (low height for age) affects approximately one-quarter of children aged < 5 years worldwide. Given the limited impact of current interventions for stunting, new multisectoral evidence-based approaches are needed to decrease the burden of stunting in low- and middle-income countries (LMICs). Recognizing that the health of people, animals, and the environment are connected, we present the rationale and research agenda for considering a One Health approach to child stunting. We contend that a One Health strategy may uncover new approaches to tackling child stunting by addressing several interdependent factors that prevent children from thriving in LMICs, and that coordinated interventions among human health, animal health, and environmental health sectors may have a synergistic effect in stunting reduction.

Combinatorial Normalization of Liver-Derived Cytokine Pathways Alleviates Hepatic Tumor-Associated Cachexia in Zebrafish.

The role and significance of liver-derived cytokines in cancer-associated cachexia syndrome remain elusive. Here we report that combinatorial counterbalances of the leptin and Igf1 signaling pathways in hepatocellular carcinoma (HCC) models significantly relieves cachexia. Double transgenic zebrafish models of HCC that stably displayed focal lesions, anorexia, and wasting of adipose and muscle tissues were first generated. Knockout of lepr or mc4r from these zebrafish partially restored appetite and exerted moderate or no effect on tissue wasting. However, genetic replenishment of Igf1 in a lepr-mutant background effectively relieved the cachexia-like phenotype without affecting tumor growth. Similarly, administration of napabucasin, a Stat3/Socs3 inhibitor, on the zebrafish HCC model, mammalian cell lines with exogenous IGF1, and two mouse xenograft models restored insulin sensitivity and rescued the wasting of nontumor tissues. Together, these results describe the synergistic impact of leptin and Igf1 normalization in treating certain HCC-associated cachexia as a practical strategy. SIGNIFICANCE: Disruption of leptin signaling with normalized Igf1 expression significantly rescues anorexia, muscle wasting, and adipose wasting in Ras- and Myc-driven zebrafish models of HCC.

Effect of lipid-based nutrient supplement-Medium quantity on reduction of stunting in children 6-23 months of age in Sindh, Pakistan: A cluster randomized controlled trial.

BACKGROUND: Chronic childhood malnutrition, or stunting, remains a persistent barrier to achieve optimal cognitive development, child growth and ability to reach full potential. Almost half of children under-five years of age are stunted in the province of Sindh, Pakistan. OBJECTIVE: The primary objective of this study was to test the hypothesis that the provision of lipid-based nutrient supplement-medium-quantity (LNS-MQ) known as Wawamum will result in a 10% reduction in risk of being stunted at the age of 24 months in the intervention group compared with the control group. DESIGN: A cluster randomized controlled trial was conducted in Thatta and Sujawal districts of Sindh province, Pakistan. A total of 870 (419 in intervention; 451 in control) children between 6-18 months old were enrolled in the study. The unit of randomization was union council and considered as a cluster. A total of 12 clusters, 6 in each study group were randomly assigned to intervention and control group. All children received standard government health services, while children in the intervention group also received 50 grams/day of Wawamum. RESULTS: Children who received Wawamum were found to have a significantly reduced risk of stunting (RR = 0.91, 95% CI; 0.88-0.94, p<0.001) and wasting (RR = 0.78, 95% CI; 0.67-0.92, p = 0.004) as compared to children who received the standard government health services. There was no evidence of a reduction in the risk of underweight (RR = 0.94, 95% CI; 0.85-1.04, p = 0.235) in the intervention group compared to the control group. Statistically significant reduction in anaemia in the intervention group was also found as compared to the control group (RR = 0.97, 95% CI; 0.94-0.99, p = 0.042). The subgroup analysis by age, showed intervention effect is significant in reduction of risk of stunting in younger children of aged 6-12 month (RR = 0.83, 95% CI; 0.81-0.86, p = <0.001) and their older peers aged 13-18 month- (RR = 0.90, 95% CI; 0.83-0.97, p = 0.008). The mean compliance of Wawamum was 60% among children. CONCLUSIONS: The study confirmed that the provision of Wawamum to children 6-23 months of age is effective in reducing the risk of stunting, wasting and anaemia. This approach should be scaled up among the most food insecure areas/households with a high prevalence of stunting to achieve positive outcomes for nutrition and health. This study was registered at clinicaltrials.gov as NCT02422953. Clinical Trial Registration Number: NCT02422953.

Community-level interventions for improving access to food in low- and middle-income countries.

BACKGROUND: After decades of decline since 2005, the global prevalence of undernourishment reverted and since 2015 has increased to levels seen in 2010 to 2011. The prevalence is highest in low- and middle-income countries (LMICs), especially Africa and Asia. Food insecurity and associated undernutrition detrimentally affect health and socioeconomic development in the short and long term, for individuals, including children, and societies. Physical and economic access to food is crucial to ensure food security. Community-level interventions could be important to increase access to food in LMICs. OBJECTIVES: To determine the effects of community-level interventions that aim to improve access to nutritious food in LMICs, for both the whole community and for disadvantaged or at-risk individuals or groups within a community, such as infants, children and women; elderly, poor or unemployed people; or minority groups. SEARCH METHODS: We searched for relevant studies in 16 electronic databases, including trial registries, from 1980 to September 2019, and updated the searches in six key databases in February 2020. We applied no language or publication status limits. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster randomised controlled trials (cRCTs) and prospective controlled studies (PCS). All population groups, adults and children, living in communities in LMICs exposed to community-level interventions aiming to improve food access were eligible for inclusion. We excluded studies that only included participants with specific diseases or conditions (e.g. severely malnourished children). Eligible interventions were broadly categorised into those that improved buying power (e.g. create income-generation opportunities, cash transfer schemes); addressed food prices (e.g. vouchers and subsidies); addressed infrastructure and transport that affected physical access to food outlets; addressed the social environment and provided social support (e.g. social support from family, neighbours or government). DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts, and full texts of potentially eligible records, against the inclusion criteria. Disagreements were resolved through discussion or arbitration by a third author, if necessary. For each included study, two authors independently extracted data and a third author arbitrated disagreements. However, the outcome data were extracted by one author and checked by a biostatistician. We assessed risk of bias for all studies using the Effective Practice and Organization of Care (EPOC) risk of bias tool for studies with a separate control group. We conducted meta-analyses if there was a minimum of two studies for interventions within the same category, reporting the same outcome measure and these were sufficiently homogeneous. Where we were able to meta-analyse, we used the random-effects model to incorporate any existing heterogeneity. Where we were unable to conduct meta-analyses, we synthesised using vote counting based on effect direction. MAIN RESULTS: We included 59 studies, including 214 to 169,485 participants, and 300 to 124, 644 households, mostly from Africa and Latin America, addressing the following six intervention types (three studies assessed two different types of interventions). Interventions that improved buying power: Unconditional cash transfers (UCTs) (16 cRCTs, two RCTs, three PCSs): we found high-certainty evidence that UCTs improve food security and make little or no difference to cognitive function and development and low-certainty evidence that UCTs may increase dietary diversity and may reduce stunting. The evidence was very uncertain about the effects of UCTs on the proportion of household expenditure on food, and on wasting. Regarding adverse outcomes, evidence from one trial indicates that UCTs reduce the proportion of infants who are overweight. Conditional cash transfers (CCTs) (nine cRCTs, five PCSs): we found high-certainty evidence that CCTs result in little to no difference in the proportion of household expenditure on food and that they slightly improve cognitive function in children; moderate-certainty evidence that CCTs probably slightly improve dietary diversity and low-certainty evidence that they may make little to no difference to stunting or wasting. Evidence on adverse outcomes (two PCSs) shows that CCTs make no difference to the proportion of overweight children. Income generation interventions (six cRCTs, 11 PCSs): we found moderate-certainty evidence that income generation interventions probably make little or no difference to stunting or wasting; and low-certainty evidence that they may result in little to no difference to food security or that they may improve dietary diversity in children, but not for households. Interventions that addressed food prices: Food vouchers (three cRCTs, one RCT): we found moderate-certainty evidence that food vouchers probably reduce stunting; and low-certainty evidence that that they may improve dietary diversity slightly, and may result in little to no difference in wasting. Food and nutrition subsidies (one cRCT, three PCSs): we found low-certainty evidence that food and nutrition subsidies may improve dietary diversity among school children. The evidence is very uncertain about the effects on household expenditure on healthy foods as a proportion of total expenditure on food (very low-certainty evidence). Interventions that addressed the social environment: Social support interventions (one cRCT, one PCS): we found moderate-certainty evidence that community grants probably make little or no difference to wasting; low-certainty evidence that they may make little or no difference to stunting. The evidence is very uncertain about the effects of village savings and loans on food security and dietary diversity. None of the included studies addressed the intervention category of infrastructure changes. In addition, none of the studies reported on one of the primary outcomes of this review, namely prevalence of undernourishment. AUTHORS' CONCLUSIONS: The body of evidence indicates that UCTs can improve food security. Income generation interventions do not seem to make a difference for food security, but the evidence is unclear for the other interventions. CCTs, UCTs, interventions that help generate income, interventions that help minimise impact of food prices through food vouchers and subsidies can potentially improve dietary diversity. UCTs and food vouchers may have a potential impact on reducing stunting, but CCTs, income generation interventions or social environment interventions do not seem to make a difference on wasting or stunting. CCTs seem to positively impact cognitive function and development, but not UCTs, which may be due to school attendance, healthcare visits and other conditionalities associated with CCTs.

Community-level interventions for improving access to food in low- and middle-income countries.

BACKGROUND: After decades of decline since 2005, the global prevalence of undernourishment reverted and since 2015 has increased to levels seen in 2010 to 2011. The prevalence is highest in low- and middle-income countries (LMICs), especially Africa and Asia. Food insecurity and associated undernutrition detrimentally affect health and socioeconomic development in the short and long term, for individuals, including children, and societies. Physical and economic access to food is crucial to ensure food security. Community-level interventions could be important to increase access to food in LMICs. OBJECTIVES: To determine the effects of community-level interventions that aim to improve access to nutritious food in LMICs, for both the whole community and for disadvantaged or at-risk individuals or groups within a community, such as infants, children and women; elderly, poor or unemployed people; or minority groups. SEARCH METHODS: We searched for relevant studies in 16 electronic databases, including trial registries, from 1980 to September 2019, and updated the searches in six key databases in February 2020. We applied no language or publication status limits. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster randomised controlled trials (cRCTs) and prospective controlled studies (PCS). All population groups, adults and children, living in communities in LMICs exposed to community-level interventions aiming to improve food access were eligible for inclusion. We excluded studies that only included participants with specific diseases or conditions (e.g. severely malnourished children). Eligible interventions were broadly categorised into those that improved buying power (e.g. create income-generation opportunities, cash transfer schemes); addressed food prices (e.g. vouchers and subsidies); addressed infrastructure and transport that affected physical access to food outlets; addressed the social environment and provided social support (e.g. social support from family, neighbours or government). DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts, and full texts of potentially eligible records, against the inclusion criteria. Disagreements were resolved through discussion or arbitration by a third author, if necessary. For each included study, two authors independently extracted data and a third author arbitrated disagreements. However, the outcome data were extracted by one author and checked by a biostatistician. We assessed risk of bias for all studies using the Effective Practice and Organization of Care (EPOC) risk of bias tool for studies with a separate control group. We conducted meta-analyses if there was a minimum of two studies for interventions within the same category, reporting the same outcome measure and these were sufficiently homogeneous. Where we were able to meta-analyse, we used the random-effects model to incorporate any existing heterogeneity. Where we were unable to conduct meta-analyses, we synthesised using vote counting based on effect direction. MAIN RESULTS: We included 59 studies, including 214 to 169,485 participants, and 300 to 124, 644 households, mostly from Africa and Latin America, addressing the following six intervention types (three studies assessed two different types of interventions). Interventions that improved buying power: Unconditional cash transfers (UCTs) (16 cRCTs, two RCTs, three PCSs): we found high-certainty evidence that UCTs improve food security and make little or no difference to cognitive function and development and low-certainty evidence that UCTs may increase dietary diversity and may reduce stunting. The evidence was very uncertain about the effects of UCTs on the proportion of household expenditure on food, and on wasting. Regarding adverse outcomes, evidence from one trial indicates that UCTs reduce the proportion of infants who are overweight. Conditional cash transfers (CCTs) (nine cRCTs, five PCSs): we found high-certainty evidence that CCTs result in little to no difference in the proportion of household expenditure on food and that they slightly improve cognitive function in children; moderate-certainty evidence that CCTs probably slightly improve dietary diversity and low-certainty evidence that they may make little to no difference to stunting or wasting. Evidence on adverse outcomes (two PCSs) shows that CCTs make no difference to the proportion of overweight children. Income generation interventions (six cRCTs, 11 PCSs): we found moderate-certainty evidence that income generation interventions probably make little or no difference to stunting or wasting; and low-certainty evidence that they may result in little to no difference to food security or that they may improve dietary diversity in children, but not for households. Interventions that addressed food prices: Food vouchers (three cRCTs, one RCT): we found moderate-certainty evidence that food vouchers probably reduce stunting; and low-certainty evidence that that they may improve dietary diversity slightly, and may result in little to no difference in wasting. Food and nutrition subsidies (one cRCT, three PCSs): we found low-certainty evidence that food and nutrition subsidies may improve dietary diversity among school children. The evidence is very uncertain about the effects on household expenditure on healthy foods as a proportion of total expenditure on food (very low-certainty evidence). Interventions that addressed the social environment: Social support interventions (one cRCT, one PCS): we found moderate-certainty evidence that community grants probably make little or no difference to wasting; low-certainty evidence that they may make little or no difference to stunting. The evidence is very uncertain about the effects of village savings and loans on food security and dietary diversity. None of the included studies addressed the intervention category of infrastructure changes. In addition, none of the studies reported on one of the primary outcomes of this review, namely prevalence of undernourishment. AUTHORS' CONCLUSIONS: The body of evidence indicates that UCTs can improve food security. Income generation interventions do not seem to make a difference for food security, but the evidence is unclear for the other interventions. CCTs, UCTs, interventions that help generate income, interventions that help minimise impact of food prices through food vouchers and subsidies can potentially improve dietary diversity. UCTs and food vouchers may have a potential impact on reducing stunting, but CCTs, income generation interventions or social environment interventions do not seem to make a difference on wasting or stunting. CCTs seem to positively impact cognitive function and development, but not UCTs, which may be due to school attendance, healthcare visits and other conditionalities associated with CCTs.

How do nutrition professionals working in low-income countries perceive and prioritize actions to prevent wasting? A mixed-methods study.

Despite a shared commitment to achieving global nutrition targets, development and emergency-humanitarian actors tend to prioritize different nutrition outcomes and actions. New approaches are needed to bridge the divide between these communities and to strengthen the overall evidence base for prevention of wasting. To better understand how these different groups perceive and prioritize actions for wasting prevention, key informant interviews (n = 21) were conducted, and an online survey was fielded among nutrition professionals working in low-income countries (n = 107). Additionally, nutrition policy and strategy documents for select global and country institutions (n = 12) were analysed to identify interventions and approaches for addressing different forms of undernutrition. The findings of this study suggest that at both global and country levels, development actors tend to prioritize stunting prevention, and emergency-humanitarian actors tend to prioritize treatment of acute malnutrition. It was less common for wasting prevention to be mentioned as an explicit priority. Many interventions were perceived by respondents to influence both stunting and wasting despite limited published evidence of effectiveness on wasting for water, sanitation and hygiene, growth monitoring and promotion, breastfeeding promotion and micronutrient supplementation. To help unify the nutrition community around prevention of wasting, the discourse about priority interventions should shift from 'stunting versus wasting' and 'prevention versus treatment' to a life-course framing around child survival, growth and development. Respondents identified a need for more programme and research funding that prioritizes both wasting and stunting as outcomes. They also suggest leveraging existing national coordination bodies that bring development and emergency-humanitarian partners together.

Muscle wasting in the critically ill patient: how to minimise subsequent disability.

Muscle wasting in critically ill patients is the most common complication associated with critical care. It has significant effects on physical and psychological health, mortality and quality of life. It is most severe in the first few days of illness and in the most critically unwell patients, with muscle loss estimated to occur at 2-3% per day. This muscle loss is likely a result of a reduction in protein synthesis relative to muscle breakdown, resulting in altered protein homeostasis. The associated weakness is associated with in an increase in both short- and long-term mortality and morbidity, with these detrimental effects demonstrated up to 5 years post discharge. This article highlights the significant impact that muscle wasting has on critically ill patients' outcomes, how this can be reduced, and how this might change in the future.

Zinc supplementation for the promotion of growth and prevention of infections in infants less than six months of age.

BACKGROUND: Zinc is a vital micronutrient for humans and is essential for protein synthesis, cell growth, and differentiation. Severe zinc deficiency can lead to slower physical, cognitive and sexual growth, cause skin disorders, decrease immunity, increase incidence of acute illnesses in infants and children and contribute to childhood stunting. By estimation, 17.3% of the world population is at risk of inadequate zinc intake. Such nutritional impairment increases the risk of diarrhoea and pneumonia by 20%, as well as leads to a global loss of more than 16 million disability-adjusted life years in children less than five years of age. Not only does zinc deficiency affect lives, it adds to the considerable financial burden on depleted resources in countries that are most affected. By preventing or curing this deficiency, we can improve childhood mortality, morbidity and growth. OBJECTIVES: To assess the effectiveness of zinc supplementation for the promotion of growth, reduction in mortality, and the prevention of infections in infants less than six months of age. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 4), MEDLINE via PubMed (1966 to 18 May 2018), Embase (1980 to 18 May 2018), and CINAHL (1982 to 18 May 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. An updated search from 1 January 2018 to 29 January 2020 was run in the following databases: CENTRAL via CRS Web, MEDLINE via Ovid, and CINAHL via EBSCOhost. SELECTION CRITERIA: All randomised controlled (individual and cluster randomised) and quasi-randomised trials of zinc supplementation in healthy, term infants, less than six months of age comparing infant mortality, incidence of diarrhoea or respiratory illnesses, growth and/or serum zinc levels were eligible. DATA COLLECTION AND ANALYSIS: Two review authors screened search results (title and abstracts) and relevant full texts. Studies fulfilling prespecified inclusion criteria were included with any disagreements resolved by consensus. Extraction and analysis were then conducted. We used the GRADE approach to assess the quality of evidence as indicated by certainty in effect estimates. MAIN RESULTS: Eight studies (with 85,629 infants) were included and five studies were meta-analysed, out of which four studies compared zinc with placebo, and one compared zinc plus riboflavin versus riboflavin. Certain growth outcomes after six months of intervention (Weight for Age Z-scores (WAZ) (standardised mean difference) (SMD) 0.16, 95% CI 0.03 to 0.29; three studies, n = 955; fixed-effect; heterogeneity Chi² P = 0.96); I² = 0%); change in WAZ (SMD 0.16, 95% CI 0.07 to 0.25; one study, n = 386; fixed-effect); (Weight-for-Length Z-score (WLZ) (SMD 0.15, 95% CI 0.02 to 0.28; three studies, n = 955; fixed-effect; heterogeneity: Chi² P = 0.81); I² = 0%); (change in WLZ (SMD 0.17, 95% CI 0.06 to 0.28; one study, n = 386; fixed-effect)) were positively affected by zinc supplementation compared to placebo. A single study reported no difference in the incidence of diarrhoea and lower respiratory tract infection with zinc supplementation. Zinc had no effect on mortality in children younger than 12 months. When zinc plus riboflavin was compared to riboflavin only, significant improvement was observed in the incidence of wasting at 24 months (risk ratio (RR) 0.59, 95% CI 0.37 to 0.96; one study, n = 296; fixed-effect), but significant worsening of incidence of stunting was present at 21 months (RR 1.53, 95% CI 1.09 to 2.16; one study, n = 298; fixed-effect). AUTHORS' CONCLUSIONS: There was a significant positive impact of zinc supplementation on WAZ and WLZ after six months of intervention in infants compared to placebo. When a combined supplement of zinc and riboflavin was compared to riboflavin, there was a significant reduction in wasting at 24 months, but stunting at 21 months was negatively affected. Although included trials were of good-to-moderate quality, evidence that could be meta-analysed was based on a few studies which affected the overall quality of results. Regardless, there is a need for strong trials conducted in infants younger than six months before a strong recommendation can be made supporting zinc supplementation in this age group.

Effect of Intermittent or Continuous Feed on Muscle Wasting in Critical Illness: A Phase 2 Clinical Trial.

BACKGROUND: Acute skeletal muscle wasting in critical illness is associated with excess morbidity and mortality. Continuous feeding may suppress muscle protein synthesis as a result of the muscle-full effect, unlike intermittent feeding, which may ameliorate it. RESEARCH QUESTION: Does intermittent enteral feed decrease muscle wasting compared with continuous feed in critically ill patients? STUDY DESIGN AND METHODS: In a phase 2 interventional single-blinded randomized controlled trial, 121 mechanically ventilated adult patients with multiorgan failure were recruited following prospective informed consultee assent. They were randomized to the intervention group (intermittent enteral feeding from six 4-hourly feeds per 24 h, n = 62) or control group (standard continuous enteral feeding, n = 59). The primary outcome was 10-day loss of rectus femoris muscle cross-sectional area determined by ultrasound. Secondary outcomes included nutritional target achievements, plasma amino acid concentrations, glycemic control, and physical function milestones. RESULTS: Muscle loss was similar between arms (-1.1% [95% CI, -6.1% to -4.0%]; P = .676). More intermittently fed patients received 80% or more of target protein (OR, 1.52 [1.16-1.99]; P < .001) and energy (OR, 1.59 [1.21-2.08]; P = .001). Plasma branched-chain amino acid concentrations before and after feeds were similar between arms on trial day 1 (71 µM [44-98 µM]; P = .547) and trial day 10 (239 µM [33-444 µM]; P = .178). During the 10-day intervention period the coefficient of variation for glucose concentrations was higher with intermittent feed (17.84 [18.6-20.4]) vs continuous feed (12.98 [14.0-15.7]; P < .001). However, days with reported hypoglycemia and insulin usage were similar in both groups. Safety profiles, gastric intolerance, physical function milestones, and discharge destinations did not differ between groups. INTERPRETATION: Intermittent feeding in early critical illness is not shown to preserve muscle mass in this trial despite resulting in a greater achievement of nutritional targets than continuous feeding. However, it is feasible and safe. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02358512; URL: www.clinicaltrials.gov.

MEF2c-Dependent Downregulation of Myocilin Mediates Cancer-Induced Muscle Wasting and Associates with Cachexia in Patients with Cancer.

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer. SIGNIFICANCE: This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia.

Impact of stakeholder perspectives on cost-effectiveness estimates of four specialized nutritious foods for preventing stunting and wasting in children 6-23 months in Burkina Faso.

BACKGROUND: Multiple specialized nutritious food options are programmed for supplementation in humanitarian and development settings. However, comparative cost-effectiveness evidence is lacking, let alone incorporation of perspectives from uncompensated stakeholders. A Burkina Faso trial evaluated the cost-effectiveness of Corn Soy Blend Plus w/ oil (CSB+ w/oil, reference arm), Corn Soy Whey Blend w/oil (CSWB w/oil), Super Cereal Plus (SC+), and Ready-to-Use Supplementary Food (RUSF) in reducing stunting and wasting among children 6-23 months old. This paper presents cost-effectiveness findings from multiple stakeholders' perspectives, including caregivers and program volunteers. METHODS: An activity-based costing with ingredients approach was used to summarize cost of the 18-month-long blanket supplementary feeding for each enrolled child (in 2018 USD). Time data were collected using self-reported and observational instruments. Cost-effectiveness relative to CSB+ w/oil assessed incremental cost per enrolled child against incremental outcomes: prevalence of stunting at 23 months of age and number of months of wasting. Two combined perspectives were compared: program (donor, implementer, and volunteer) versus program and caregiver (adding caregiver). RESULTS: A total of 6112 children were enrolled. While similar effectiveness was found in three arms (CSWB w/oil was less effective), costs differed. Product cost and caregiver time to prepare study foods were major drivers of cross-arm cost differences from the respective combined perspective. The two major drivers were used to construct uncertainty ranges of cost per enrolled child from program and caregiver perspective: $317 ($279- $355) in CSB+ w/oil, $350 ($327- $373) in CSWB w/oil, $387 ($371- $403) in RUSF, and $434 ($365- $503) in SC+. Cost from program and caregiver perspective was a substantial increase from program perspective. CSB+ w/oil was most cost-effective in reducing stunting and wasting, and this main finding was robust to changing perspectives and all corresponding sensitivity analyses when uncompensated time was valued at minimum wage ($0.36/h). The break-even point for uncompensated time valuation is >$0.84/h, where RUSF became the most cost-effective from the program and caregiver perspective. Relative cost-effectiveness rankings among the other three arms depended on choice of perspectives, and were sensitive to values assigned to product cost, international freight cost, opportunity cost of time, and outcomes of a hypothetical control. Volunteer opportunity cost did not affect arm comparisons, but lack of compensation resulted in negative financial consequences for caregivers. CONCLUSIONS: Evaluating cost-effectiveness by incorporating uncompensated stakeholders provided crucial implementation insights around nutrition products and programming. TRIAL REGISTRATION: Trial registration number: NCT02071563. Name of registry: ClinicalTrials.gov URL of registry: https://clinicaltrials.gov/ct2/show/NCT02071563?type=Intr&cond=Malnutrition&cntry=BF&draw=2&rank=9 Date of registration: February 26, 2014. Date of enrollment of first participant: July 2014.

Role of Optimized Plant Protein Combinations as a Low-Cost Alternative to Dairy Ingredients in Foods for Prevention and Treatment of Moderate Acute Malnutrition and Severe Acute Malnutrition.

Tackling the global burden of acute malnutrition in children remains a major public health challenge and is essential for achieving sustainable development. Despite having effective treatment options, most wasted children go untreated; treatment coverage for severe acute malnutrition (SAM) children is only about 20%. Milk is currently an essential component of effective SAM treatment, incorporated into ready-to-use therapeutic food (RUTF). Reaching the untreated children, as well as preventing SAM, requires investment in innovative and cost-efficient approaches. To date, attempts to replace or remove milk from RUTF have been either unsuccessful or unpersuasive. This is likely because milk provides the highest protein quality and density of all typical RUTF ingredients. However, alternative protein sources could provide cost savings. Alternative protein sources, especially plant-based protein alternatives, have had shown more promising progress for the treatment of children with moderate acute malnutrition. Acknowledging that cost is a major barrier to the scale-up of treatment of acute malnutrition and that alternative protein sources are a practical means to reduce cost, continued research focusing on alternative proteins is necessary.

Effects of Propranolol in Accelerating Wound Healing and Attenuation of Hypermetabolism in Adult Burn Patients.

OBJECTIVE: To compare the mean duration of wound healing and attenuation of muscle wasting in adult burn patients treated with propranolol and control group. STUDY DESIGN: A randomised controlled trial. PLACE AND DURATION OF STUDY: Allied Burn and Reconstructive Surgery Center, Faisalabad from March to August 2018. METHODOLOGY: Seventy adult burn patients with 20-40% burn of the total body surface area (TBSA) were included in the study and divided into two groups; propranolol group and control group. Propranolol was administered at dose of 0.5-3 mg/Kg body weight per day along with standard burn care treatment during the entire period of treatment. RESULTS: Faster healing of the superficial burns was noticed in the patients of propranolol group. In superficial burns lesser time was needed for adequate healing; 13.20 ±1.90 days versus 20.34 ±2.32 days (p <0.001). At the same time, lesser time was required for deep burn patients treated with propranolol to be ready for skin grafting; 23.87 ±2.36 versus 33.64 ±3.15 days; p <0.001) comparing control group. Mean mid-arm circumference was 27.57 ±1.62 cm in study group and 24.46 ±1.77 cm in control group (p<0.0001) which was statistically significant. This result showed that hypermetabolic response of burn in terms of muscle wasting was clearly modulated by betablocker therapy. CONCLUSION: Propranolol administration in adult burn patients appears to be beneficial in reducing morbidity, mortality and hospital stay by enhancing earlier wound healing and attenuating the catabolic muscle wasting in response to stress caused by burn.

Rojiroti microfinance and child nutrition: a cluster randomised trial.

OBJECTIVE: To determine whether Rojiroti microfinance, for poor Indian women, improves child nutrition. DESIGN: Cluster randomised trial. SETTING: Tolas (village communities) in Bihar State. PARTICIPANTS: Women and children under 5 years. INTERVENTIONS: With Rojiroti microfinance, women form self-help groups and save their money to provide loans to group members. After 6 months, they receive larger external loans. Tolas were randomised to receive Rojiroti immediately or after 18 months. OUTCOME MEASURES: The primary analysis compared the mean weight for height Z score (WHZ) of children under 5 years in the intervention versus control tolas who attended for weight and height measurement 18 months after randomisation. Secondary outcomes were weight for age Z score (WAZ), height for age Z score, mid-upper arm circumference (MUAC), wasting, underweight and stunting. RESULTS: We randomised 28 tolas to each arm and collected data from 2469 children (1560 mothers) at baseline and 2064 children (1326 mothers) at follow-up. WHZ was calculated for 1718 children at baseline and 1377 (674 intervention and 703 control) at follow-up. At 18 months, mean WHZ was significantly higher for intervention (-1.02) versus controls (-1.37; regression coefficient adjusted for clustering ß=0.38, 95% CI 0.16 to 0.61, p=0.001). Significantly fewer children were wasted in the intervention group (122, 18%) versus control (200, 29%; OR=0.46, 95% CI 0.28 to 0.74, p=0.002). Mean WAZ was better in the intervention group (-2.13 vs -2.37; ß=0.27, 95% CI 0.11 to 0.43, p=0.001) as was MUAC (13.6 cm vs 13.4 cm; ß=0.22, 95% CI 0.03 to 0.40, p=0.02). In an analysis adjusting for baseline nutritional measures (259 intervention children and 300 control), only WAZ and % underweight showed significant differences in favour of the intervention. CONCLUSION: In marginalised communities in rural India, child nutrition was better in those who received Rojiroti microfinance, compared with controls. TRIAL REGISTRATION NUMBER: NCT01845545.

The Effect of the Yingyangbao Complementary Food Supplement on the Nutritional Status of Infants and Children: A Systematic Review and Meta-Analysis.

Yingyangbao (YYB) is a nutrient-dense complementary food supplement for infants and young children in China. There has been considerable interest and research on the potential effects of YYB on hematological and anthropometric outcomes in China, but limited effort has been made to consolidate and synthesize the evidence to inform the research and policy agendas. Eight English databases and three Chinese databases were searched from January 2001 to June 2019 to identify YYB intervention studies. A total of 32 quasi-experimental, post-only, concurrent-control studies or pre-post studies were identified, and 26 were included in the meta-analyses. A pooled analysis of post-only studies with concurrent-control determined that YYB was associated with an increase of 4.43 g/L (95% confidence interval (CI) 1.55, 7.30) hemoglobin concentration, 2.46 cm (CI 0.96, 3.97) in height, and 0.79 kg (CI 0.25, 1.32) weight in infants and young children. YYB was also associated with reductions in the prevalence of anemia (risk ratio (RR) = 0.55; 95% CI: 0.45, 0.67), stunting (RR = 0.60; 95% CI: 0.44, 0.81), and underweight (RR = 0.51; 95% CI: 0.39, 0.65). Overall, YYB was found to be associated with improved hematological and anthropometric indicators among infants and young children in China; however, randomized trials are needed to causally assess the efficacy of YYB due to the inherent risk of bias in existing quasi-experimental studies; rigorous implementation and cost-effectiveness evaluations are also needed.

Neuromuscular electrical stimulation is feasible in patients with acute heart failure.

AIMS: In acute heart failure (AHF), immobilization is caused because of unstable haemodynamics and dyspnoea, leading to protein wasting. Neuromuscular electrical stimulation (NMES) has been reported to preserve muscle mass and improve functional outcomes in chronic disease. NMES may be effective against protein wasting frequently manifested in patients with AHF; however, whether NMES can be implemented safely without any adverse effect on haemodynamics has remained unknown. This study aimed to examine the feasibility of NMES in patients with AHF. METHODS AND RESULTS: Patients with AHF were randomly assigned to the NMES or control group. The intensity of the NMES group was set at 10-20% maximal voluntary contraction level, whereas the control group was limited at a visible or palpable level of muscle contraction. The sessions were performed 5 days per week since the day after admission. Before the study implementation, we set the feasibility criteria with following items: (i) change in systolic blood pressure (BP) > ±20 mmHg during the first session; (ii) increase in heart rate (HR) > +20 b.p.m. during the first session; (iii) development of sustained ventricular arrhythmia, atrial fibrillation (AF), and paroxysmal supraventricular tachycardia during all sessions; (iv) incidence of new-onset AF during the hospitalization period < 40%; and (v) completion of the planned sessions by >70% of patients. The criteria of feasibility were set as follows; the percentage to fill one of (i)-(iii) was <20% of the total subjects, and both (iv) and (v) were satisfied. A total of 73 patients (median age 72 years, 51 men) who completed the first session were analysed (NMES group, n = 34; control group, n = 39). Systolic BP and HR variations were not significantly different between two groups (systolic BP, P = 0.958; HR, P = 0.665). Changes in BP > ±20 mmHg or HR > +20 b.p.m. were observed in three cases in the NMES group (8.8%) and five in the control group (12.8%). New-onset arrhythmia was not observed during all sessions in both groups. During hospitalization, one patient newly developed AF in the NMES group (2.9%), and one developed AF (2.6%) and two lethal ventricular arrhythmia in the control group. Thirty-one patients in the NMES group (91%) and 33 patients in the control group (84%) completed the planned sessions during hospitalization. This study fulfilled the preset feasibility criteria. CONCLUSIONS: NMES is feasible in patients with AHF from immediately after admission.

Estimating the effect of measles vaccination on child growth using 191 DHS from 65 low- and middle-income countries.

BACKGROUND: Childhood vaccinations reduce morbidity and mortality and are highly cost-effective. They may also protect children from malnutrition and lead to improved child growth. Stunting, wasting and underweight are targets used to monitor progress towards the achievement of the sustainable development goals (SDGs). METHODS: We use data from Demographic and Health Surveys (DHS) covering the period from 1990 to 2017 to estimate the effect of measles vaccination at 12 months of age on stunting, wasting, and underweight. For causal estimation, we use household- and mother-fixed effects, which allows us to compare outcomes across siblings while controlling for all observed and unobserved confounders that are shared by the siblings, such as household social characteristics and home location. In addition, we control for a wide range of sibling-varying confounders, including sex, age, birth order and mother's age at birth, as well as vaccination with diphtheria-tetanus-polio (DPT), as a broad indicator of general likelihood to receive vaccinations. RESULTS: Our samples include 347,808 individuals in 132 surveys from 59 countries (for stunting), 430,963 individuals in 190 surveys from 65 countries (for wasting), and 353,520 individuals in 130 surveys from 59 countries (for underweight). Measles vaccination is associated with significantly reduced odds of stunting (odds ratio 0.90 [95% CI 0.86-0.94], p < 0.001) and underweight (odds ratio 0.90 [95% CI 0.86-0.95], p < 0.001). The association with wasting is weaker and not statistically significant (odds ratio 0.95 [95% CI 0.89-1.02], p = 0.143). Our results remain robust across several alternative specifications of our regression models. CONCLUSIONS: Measles vaccination substantially reduces stunting and underweight among children in low- and middle-income countries. Increasing measles coverage from the current low to near-universal levels would provide a large boost to child growth and the attainment of the SDGs.

Is women's empowerment a pathway to improving child nutrition outcomes in a nutrition-sensitive agriculture program?: Evidence from a randomized controlled trial in Burkina Faso.

Nutrition-sensitive programs in low- and middle-income countries often aim to improve child nutrition outcomes in part by empowering women. Although previous studies have found cross-sectional associations linking women's empowerment and child nutritional status, there is limited empirical evidence supporting the hypothesis that empowering women as part of an intervention will, in turn, improve child nutritional outcomes. We tested this hypothesis using two waves of data from a cluster-randomized controlled trial of a nutrition-sensitive agricultural program in Burkina Faso. With structural equation models, we examined whether four domains of women's empowerment-purchasing decisions, healthcare decisions, family planning decisions, and spousal communication-mediated the program's impact on reducing wasting and increasing hemoglobin among children who were three to 12 months old at the start of the two-year program. We found that improvements in women's empowerment in the domains of spousal communication, purchasing decisions, healthcare decisions, and family planning decisions contributed to the program's impact on reducing wasting with the largest share being attributable to spousal communication. Improvements in women's empowerment did not contribute to the increase in hemoglobin. These findings provide the first evidence from a randomized controlled trial that women's empowerment is a pathway by which a nutrition-sensitive program can improve child wasting. Programs that aim to improve child nutritional status should incorporate interventions designed to empower women.

Biochanin A prevents 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced adipocyte dysfunction in cultured 3T3-L1 cells.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant. TCDD accumulates in the food chain, mainly in the fatty tissues of the human body where it causes various toxic effects. Biochanin A is a natural organic compound in the class of phytochemicals known as flavonoids. We investigated whether biochanin A suppresses TCDD-induced loss of adipogenic action using 3T3-L1 adipocytes as a cell culture model of wasting syndrome. In the present study, biochanin A suppressed TCDD-induced loss of lipid accumulation. Pretreating the cells with biochanin A increased the levels of the adipogenesis-associated factors peroxisome proliferator-activated receptor γ and adiponectin, which were inhibited by TCDD. TCDD decreased insulin-stimulated glucose uptake, which was effectively restored by pretreatment with biochanin A. Biochanin A also inhibited the TCDD-driven decrease in production of insulin receptor substrate-1 and glucose transporter 4. These results suggest a preventive effect of biochanin A against TCDD in the development of insulin resistance and diabetes. TCDD increased production of intracellular calcium ([Ca2+]i), prostaglandin E2, cytosolic phospholipase A2, and cyclooxygenase-1, while reducing the level of peroxisome proliferator-activated receptor gamma coactivator 1-alpha. However, biochanin A inhibited these TCDD-induced effects. We conclude that biochanin A is an attractive compound for preventing TCDD-induced wasting syndrome.