The double burden of malnutrition in individuals: Identifying key challenges and re-thinking research focus.

The 'double burden of malnutrition' is a global health challenge that increasingly affects populations in both low- and middle-income countries (LMICs). This phenomenon refers to the coexistence of undernutrition and overweight or obesity, as well as other diet-related non-communicable diseases, in the same population, household or even individual. While noteworthy progress has been made in reducing undernutrition in some parts of the world, in many of these areas, the prevalence of overweight and obesity is increasing, particularly in urban areas, resulting in greater numbers of people who were undernourished in childhood and have overweight or obesity in adulthood. This creates a complex and challenging situation for research experts and policymakers who must simultaneously address the public health burdens of undernutrition and overweight/obesity. This review identifies key challenges and limitations in the current research on the double burden of malnutrition in individuals, including the need for a more comprehensive and nuanced understanding of the drivers of malnutrition, the importance of context-specific interventions and the need for greater attention to the food environment and food systems. We advocate for the re-evaluation of research strategies and focus, with a greater emphasis on multidisciplinary and systems approaches and greater attention to the synergistic relationship between the biological, environmental, commercial and socio-economic determinants of malnutrition. Addressing these key challenges can enable us to better comprehend and tackle the multifaceted and dynamic issues of the double burden of malnutrition, particularly in individuals and work towards more effective and sustainable solutions.

Three-arm clinical trial of improved flour targeting intestinal microbiota (MALINEA).

The main objective of this project was to compare in the field conditions two strategies of re-nutrition of children with moderate acute malnutrition (MAM) aged from 6 to 24 months, targeting the microbiota in comparison with a standard regimen. A three-arm, open-label, pragmatic randomised trial was conducted in four countries (Niger, CAR, Senegal and Madagascar). Children received for 12 weeks either fortified blended flour (FBF control) = arm 1, or FBF + azithromycin (oral suspension of 20 mg/kg/day daily given with a syringe) for the first 3 days at inclusion = arm 2 or mix FBF with inulin/fructo-oligosaccharides (6 g/day if age ≥12 months and 4 g if age <12 months) = arm 3. For each arm, children aged from 6 to 11 months received 100 g x 2 per day of flours and those aged from 12 to 24 months received 100 g × 3 per day of FBF. The primary endpoint was nutritional recovery, defined by reaching a weight-for-height z-score (WHZ) ≥ -1.5 within 12 weeks. Overall, 881 children were randomised (297, 290 and 294 in arm 1, arm 2 and arm 3, respectively). Three hundred and forty-four children were males (39%) and median/mean age were 14.6/14.4 months (SD = 4.9, IQR = 10.5-18.4). At inclusion, the three arms were comparable for all criteria, but differences were observed between countries. Overall, 44% (390/881) of the children recovered at week 12 from MAM, with no significant difference between the three arms (41.4%, 45.5% and 45.9%, in arm 1, arm 2 and arm 3, respectively, p = 0.47). This study did not support the true advantages of adding a prebiotic or antibiotic to flour. When using a threshold of WHZ ≥ -2 as an exploratory endpoint, significant differences were observed between the three arms, with higher success rates in arms with antibiotics or prebiotics compared to the control arm (66.9%, 66.0% and 55.2%, respectively, p = 0.005).

Developmental and Nutritional Changes in Children with Severe Acute Malnutrition Provided with n-3 Fatty Acids Improved Ready-to-Use Therapeutic Food and Psychosocial Support: A Pilot Study in Tanzania.

Children with severe acute malnutrition (SAM) are at high risk of impaired development. Contributing causes include the inadequate intake of specific nutrients such as polyunsaturated fatty acids (PUFAs) and a lack of adequate stimulation. We conducted a pilot study assessing developmental and nutritional changes in children with SAM provided with a modified ready-to-use therapeutic food and context-specific psychosocial intervention in Mwanza, Tanzania. We recruited 82 children with SAM (6-36 months) and 88 sex- and age-matched non-malnourished children. We measured child development, using the Malawi Development Assessment Tool (MDAT), measures of family and maternal care for children, and whole-blood PUFA levels. At baseline, the mean total MDAT z-score of children with SAM was lower than non-malnourished children; -2.37 (95% confidence interval: -2.92; -1.82), as were their total n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels. After 8 weeks of intervention, MDAT z-scores improved in all domains, especially fine motor, among children with SAM. Total n-3 and EPA levels increased, total n-6 fatty acids decreased, and DHA remained unchanged. Family and maternal care also improved. The suggested benefits of the combined interventions on the developmental and nutritional status of children with SAM will be tested in a future trial.

Effect of lipid-based nutrient supplements on micronutrient status and hemoglobin among children with stunting: secondary analysis of a randomized controlled trial in Uganda.

BACKGROUND: Micronutrient deficiencies and anemia are widespread among children with stunting. OBJECTIVES: We assessed the effects of lipid-based nutrient supplements (LNS) containing milk protein (MP) and/or whey permeate (WP) on micronutrient status and hemoglobin (Hb) among children with stunting. METHODS: This was a secondary analysis of a randomized controlled trial. Children aged 12-59 mo with stunting were randomly assigned to LNS (100 g/d) with milk or soy protein and WP or maltodextrin for 12 wk, or no supplement. Hb, serum ferritin (S-FE), serum soluble transferrin receptor (S-TfR), plasma cobalamin (P-Cob), plasma methylmalonic acid (P-MMA), plasma folate (P-Fol), and serum retinol-binding protein (S-RBP) were measured at inclusion and at 12 wk. Data were analyzed using linear and logistic mixed-effects models. RESULTS: Among 750 children, with mean age ± SD of 32 ± 11.7 mo, 45% (n = 338) were female and 98% (n = 736) completed follow-up. LNS, compared with no supplementation, resulted in 43% [95% confidence interval (CI): 28, 60] greater increase in S-FE corrected for inflammation (S-FEci), 2.4 (95% CI: 1.2, 3.5) mg/L greater decline in S-TfR, 138 (95% CI: 111, 164) pmol/L greater increase in P-Cob, 33% (95% CI: 27, 39) reduction in P-MMA, and 8.5 (95% CI: 6.6, 10.3) nmol/L greater increase in P-Fol. There was no effect of LNS on S-RBP. Lactation modified the effect of LNS on markers of cobalamin status, reflecting improved status among nonbreastfed and no effects among breastfed children. LNS increased Hb by 3.8 (95% CI: 1.7, 6.0) g/L and reduced the odds of anemia by 55% (odds ratio: 0.45, 95% CI: 0.29, 0.70). MP compared with soy protein increased S-FEci by 14% (95% CI: 3, 26). CONCLUSIONS: LNS supplementation increases Hb and improves iron, cobalamin, and folate status, but not vitamin A status among children with stunting. LNS should be considered for children with stunting. This trial was registered at ISRCTN as 13093195.

Correlates of early child development among children with stunting: A cross-sectional study in Uganda.

Many children in low- and middle-income countries are not attaining their developmental potential. Stunting is associated with poor child development, but it is not known which correlates of stunting are impairing child development. We explored potential socioeconomic, nutritional, clinical, and household correlates of early child development among 12-59-month-old children with stunting in a cross-sectional study in Uganda. Development was assessed using the Malawi Development Assessment Tool (MDAT) across four domains of gross and fine motor, language, and social skills. Linear regression analysis was used to assess correlates of development in the four domains and total MDAT score. Of 750 children included, the median [interquartile range] age was 30 [23-41] months, 55% of the children resided in rural settings with 21% from female-headed households and 47% of mothers had no schooling. The mean ± standard deviation height-for-age z-score (HAZ) was -3.02 ± 0.74, 40% of the children had a positive malaria test and 65% were anaemic (haemoglobin < 110 g/L). One-third had children's books at home, majority (96%) used household objects to play with and most of them (70%) used toys as pretence items like those to mimic cooking. After age, sex, and site adjustments, HAZ (0.24, 95% confidence interval [CI]: 0.14-0.33) and head circumference (0.07, 95% CI: 0.02-0.12) were positive correlates of total MDAT score, whereas weight-for-height z-score (WHZ) was not. Current breastfeeding was associated with 0.41 (95% CI: 0.17-0.65) lower total MDAT score. Children from households with a single income earner had 0.22 (95% CI: 0.06-0.37) lower total MDAT score. Furthermore, severe food insecurity, inflammation and positive malaria test were associated with lower scores for motor development. All family care indicator subscales (FCIs) positively correlated with the total MDAT score and this association was independent of household's socioeconomic status. In conclusion, stunting degree, head circumference, number of household income earners and stimulation by improved FCIs correlate with early child development among stunted children. The negative association with prolonged breastfeeding is likely due to reverse causality. Identified correlates may inform initiatives to support children with stunting attain their development potential.

Nutritional treatment of children 6-59 months with severely low weight-for-age z-score: a study protocol for a 3-arm randomized controlled trial.

BACKGROUND: Admission criteria that treat children with low mid-upper-arm circumference (MUAC), and low weight-for-height z-score (WHZ) are not aligned with the evidence on which children are at risk of mortality. An analysis of community-based cohort data from Senegal found that a combination of weight-for-age (WAZ) and MUAC criteria identified all children at risk of near-term death associated with severe anthropometric deficits. This study will address whether children with WAZ <-3 but MUAC ≥125 mm benefit from therapeutic feeding with ready-to-use therapeutic foods (RUTF) and whether a simplified protocol is non-inferior to the weight-based standard protocol. METHODS: This is a prospective individually randomized controlled 3-arm trial conducted in the Nara health district in Mali. Children aged 6-59 months presenting with MUAC ≥125 mm and WAZ <-3 will be randomized to (1) control group receiving no treatment, (2) simplified treatment receiving 1 sachet of RUTF daily until WAZ ≥-3 for 2 visits, (3) standard treatment receiving RUTF according to WHZ category: (a) WHZ <-3 receive 200 kcal/kg/day until WHZ ≥-2 for 2 visits, (b) WHZ ≥-3 but <-2 receive 1 sachet daily until WHZ ≥-2 for 2 visits or (c) WHZ ≥-2 receive no treatment. All children will be followed up first fortnightly for 12 weeks and then monthly until 6 months post-enrolment. The primary endpoint will be measured at 2 months with the primary outcome being WAZ as a continuous measure. Other outcomes include other anthropometric measurements and a secondary endpoint will be observed at 6 months. A total of 1397 children will be recruited including 209 in the control and 594 in both the simplified and standard arms. The sample size should enable us to conclude on the superiority of the simplified treatment compared to no treatment and on the non-inferiority of the simplified treatment versus standard treatment with a margin of non-inferiority of 0.2 WAZ. DISCUSSION: This trial aims to generate new evidence on the benefit of treating children with WAZ <-3 but MUAC ≥125 mm in order to guide the choice of admission criteria to malnutrition treatment and build evidence on the most efficient treatment protocol. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov: NCT05248516 on February 21, 2022.

Correlates of Plasma Citrulline, a Potential Marker of Enterocyte Mass, among Children with Stunting: A Cross-Sectional Study in Uganda.

BACKGROUND: Environmental enteric dysfunction (EED) is associated with stunting. Citrulline, produced in mature enterocytes, may be a valuable biomarker of small intestinal enterocyte mass in the context of EED. OBJECTIVES: We aimed to explore the correlates of plasma citrulline (p-cit) in children with stunting. METHODS: In a cross-sectional study using baseline data from the community-based MAGNUS (milk affecting growth, cognition and the gut in child stunting) trial (ISRCTN13093195), we explored potential correlates of p-cit in Ugandan children with stunting aged 12-59 mo. Using linear regression in univariate and multivariate models, we explored associations with socioeconomics, diet, micronutrient status, and water, sanitation, and hygiene characteristics. The influence of covariates age, fasting, and systemic inflammation were also explored. RESULTS: In 750 children, the mean ± standard deviation age was 32.0 ± 11.7 mo, and height-for-age z-score was -3.02 ± 0.74. P-cit, available for 730 children, differed according to time fasted and was 20.7 ± 8.9, 22.3 ± 10.6 and 24.2 ± 13.1 µmol/L if fasted <2, 2-5 and >5 h, respectively. Positive correlates of p-cit were age [0.07; 95% confidence interval (CI): 0.001, 0.15 µmol/L] and log10 serum insulin-like growth factor-1 (8.88; 95% CI: 5.09, 12.67 µmol/L). With adjustment for systemic inflammation, the association with serum insulin-like growth factor-1 reduced (4.98; 95% CI: 0.94, 9.03 µmol/L). Negative correlates of p-cit included food insecurity, wet season (-3.12; 95% CI: -4.97, -1.26 µmol/L), serum C-reactive protein (-0.15; 95% CI: -0.20, -0.10 µmol/L), serum α1-acid glycoprotein (-5.34; 95% CI: -6.98, -3.70 µmol/L) and anemia (-1.95; 95% CI: -3.72, -0.18 µmol/L). Among the negatively correlated water, sanitation, and hygiene characteristics was lack of soap for handwashing (-2.53; 95% CI: -4.82, -0.25 µmol/L). Many associations attenuated with adjustment for inflammation. CONCLUSIONS: Many of the correlates of p-cit are characteristic of populations with a high EED prevalence. Systemic inflammation is strongly associated with p-cit and is implicated in EED and stunting. Adjustment for systemic inflammation attenuates many associations, reflecting either confounding, mediation, or both. This study highlights the complex interplay between p-cit and systemic inflammation.

How age and sex affect treatment outcomes for children with severe malnutrition: A multi-country secondary data analysis.

Age and sex influence the risk of childhood wasting. We aimed to determine if wasting treatment outcomes differ by age and sex in children under 5 years, enroled in therapeutic and supplementary feeding programmes. Utilising data from stage 1 of the ComPAS trial, we used logistic regression to assess the association between age, sex and wasting treatment outcomes (recovery, death, default, non-response, and transfer), modelling the likelihood of recovery versus all other outcomes. We used linear regression to calculate differences in mean length of stay (LOS) and mean daily weight gain by age and sex. Data from 6929 children from Kenya, Chad, Yemen and South Sudan was analysed. Girls in therapeutic feeding programmes were less likely to recover than boys (pooled odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.72-0.97, p = 0.018). This association was statistically significant in Chad (OR: 0.61, 95% CI: 0.39-0.95, p = 0.030) and Yemen (OR: 0.47, 95% CI: 0.27-0.81, p = 0.006), but not in Kenya and South Sudan. Multinomial analysis, however, showed no difference in recovery between sexes. There was no difference between sexes for LOS, but older children (24-59 months) had a shorter mean LOS than younger children (6-23 months). Mean daily weight gain was consistently lower in boys compared with girls. We found few differences in wasting treatment outcomes by sex and age. The results do not indicate a need to change current programme inclusion requirements or treatment protocols on the basis of sex or age, but future research in other settings should continue to investigate the aetiology of differences in recovery and implications for treatment protocols.

Micronutrient Status and Other Correlates of Hemoglobin among Children with Stunting: A Cross-Sectional Study in Uganda.

In low-income countries, undernutrition and infections play a major role in childhood anemia. Stunted children may be at particular risk of anemia. In a cross-sectional study nested in a nutrition trial among 12-59-month-old stunted children in eastern Uganda, we measured hemoglobin (Hb) and markers of iron, cobalamin, folate and vitamin A status. We assessed low micronutrient status, socio-demography, stunting severity, inflammation and malaria as correlates of Hb and anemia using linear and logistic regression analyses, respectively. Of 750 stunted children, the mean ± SD age was 32.0 ± 11.7 months and 55% (n = 412) were male. The mean Hb was 104 ± 15 g/L and 65% had anemia, Hb < 110 g/L. In a multivariable model with age, sex and inflammation, the following were associated with lower Hb: serum ferritin < 12 µg/L (-5.6 g/L, 95% CI: -8.6; -2.6), transferrin receptors > 8.3 mg/L (-6.2 g/L, 95% CI: -8.4; -4.0), plasma folate <20 nmol/L (-4.6 g/L, 95% CI: -8.1;-1.1), cobalamin < 222 pmol/L (-3.0 g/L, 95% CI: -5.4; -0.7) and serum retinol-binding protein < 0.7 µmol/L (-2.0 g/L, 95% CI: -4.1; 0.2). In addition, severe stunting, inflammation and malaria were negative correlates. Anemia is common among stunted children in eastern Uganda; micronutrient deficiencies, inflammation and malaria are associated with low Hb.

A protocol for a proof-of-concept randomized control trial testing increased protein quantity and quality in ready-to-use therapeutic food in improving linear growth among 6-23-month-old children with severe wasting in Malawi.

INTRODUCTION: Ready-to-use therapeutic foods (RUTFs) have successfully promoted recovery from severe wasting and increased treatment coverage. However, RUTFs do not sufficiently improve linear growth, leaving many survivors of severe wasting at risk of persistent stunting, which is associated with high mortality risk, poor child development and non-communicable diseases in adulthood. High protein quantity and quality can stimulate linear growth. AIM: The trial aims to assess whether higher-protein-RUTF leads to higher concentrations of markers of linear growth compared to standard RUTF among 6-23 months old children with severe wasting. METHODS: We designed a higher protein quantity and quality RUTF for a proof-of-concept (PoC) double-blind randomized controlled trial. OUTCOMES: The primary outcome is a change in insulin-like growth factor-1 (IGF-1), a hormone positively associated with linear growth after four weeks of treatment. Secondary outcomes include changes in ponderal and linear growth and in body composition from baseline to eight weeks later; plasma amino acid profile at four weeks; acceptability and safety. IMPLICATIONS: These findings will help in informing the potential impact of increased protein in RUTF on linear growth when treating severe wasting towards conducting a larger clinical trial. TRIAL REGISTRATION: The trial has been registered on clinicaltrial.gov (NCT05737472).

Correlates of Iron, Cobalamin, Folate, and Vitamin A Status among Stunted Children: A Cross-Sectional Study in Uganda.

Micronutrient deficiencies and stunting are prevalent. We assessed correlates of iron, cobalamin, folate, and vitamin A biomarkers in a cross-sectional study of stunted children aged 12-59 months in eastern Uganda. The biomarkers measured were serum ferritin (S-FE), soluble transferrin receptor (S-TfR), retinol binding protein (S-RBP), plasma cobalamin (P-Cob), methylmalonic acid (P-MMA), and folate (P-Fol). Using linear regression, we assessed socio-demography, stunting severity, malaria rapid test, and inflammation as correlates of micronutrient biomarkers. Of the 750 children, the mean (SD) age was 32.0 (11.7) months, and 45% were girls. Iron stores were depleted (inflammation-corrected S-FE < 12 µg/L) in 43%, and 62% had tissue iron deficiency (S-TfR > 8.3 mg/L). P-Cob was low (<148 pmol/L) and marginal (148-221 pmol/L) in 3% and 20%, and 16% had high P-MMA (>0.75 µmol/L). Inflammation-corrected S-RBP was low (<0.7 µmol/L) in 21% and P-Fol (<14 nmol/L) in 1%. Age 24-59 months was associated with higher S-FE and P-Fol and lower S-TfR. Breastfeeding beyond infancy was associated with lower iron status and cobalamin status, and malaria was associated with lower cobalamin status and tissue iron deficiency (higher S-TfR) despite iron sequestration in stores (higher S-FE). In conclusion, stunted children have iron, cobalamin, and vitamin A deficiencies. Interventions addressing stunting should target co-existing micronutrient deficiencies.

Vitamin B12 Status before and after Outpatient Treatment of Severe Acute Malnutrition in Children Aged 6-59 Months: A Sub-Study of a Randomized Controlled Trial in Burkina Faso.

Severe acute malnutrition (SAM) is treated with ready-to-use therapeutic foods (RUTF) containing a vitamin-mineral premix. Yet little is known about micronutrient status in children with SAM before and after treatment. We aimed to investigate vitamin B12 status in children with uncomplicated SAM, aged 6-59 months in Burkina Faso, before and after treatment with a standard or a reduced dose of RUTF. Blood samples were collected at admission and discharge. Serum B12 was determined with microbiological assay and serum methylmalonic acid (MMA) and total homocysteine (tHcy) were analyzed with gas chromatography-tandem mass spectrometry. B12 status was classified using the combined indicator (3cB12). Among 374 children, the median [interquartile range] age was 11.0 [7.7-16.9] months, and 85.8% were breastfed. Marked or severe B12 deficiency, as judged by 3cB12, decreased from 32% to 9% between admission and discharge (p < 0.05). No differences in B12 status following treatment with either standard (n = 194) or reduced (n = 180) doses of RUTF were observed. Breastfed children showed a lower B12 status (3cB12) than non-breastfed ones (-1.10 vs -0.18, p < 0.001 at admission; -0.44 vs 0.19; p < 0.001 at discharge). In conclusion, treatment of SAM with RUTF improved children's B12 status but did not fully correct B12 deficiency.

Evaluating the Validity of the Responses to Illness Severity Quantification Score to Discriminate Illness Severity and Level of Care Transitions in Hospitalized Children with Severe Acute Malnutrition.

OBJECTIVE: To evaluate the validity of the Responses to Illness Severity Quantification (RISQ) score to discriminate illness severity and transitions between levels of care during hospitalization. STUDY DESIGN: A prospective observational study conducted in Maiduguri, Nigeria, enrolled inpatients aged 1-59 months with severe acute malnutrition. The primary outcome was the RISQ score associated with the patient state. Heart and respiratory rate, oxygen saturation, respiratory effort, oxygen use, temperature, and level of consciousness are summed to calculate the RISQ score. Five states were defined by levels of care and hospital discharge outcome. The states were classified hierarchically, reflecting illness severity: hospital mortality was the most severe state, then intensive care unit (ICU), care in the stabilization phase (SP), care in the rehabilitation phase (RP), and lowest severity, survival at hospital discharge. A multistate statistical model examined performance of the RISQ score in predicting clinical states and transitions. RESULTS: Of 903 children enrolled (mean age, 14.6 months), 63 (7%) died. Mean RISQ scores during care in each phase were 3.5 (n = 2265) in the ICU, 1.7 (n = 6301) in the SP, and 1.5 (n = 2377) in the RP. Mean scores and HRs for a 3-point change in score at transitions: ICU to death, 6.9 (HR, 1.80); SP to ICU, 2.8 (HR, 2.00); ICU to SP, 2.0 (HR, 0.5); and RP to discharge, 1.4 (HR, 0.91). CONCLUSIONS: The RISQ score can discriminate between points of escalation or de-escalation of care and reflects illness severity in hospitalized children with severe acute malnutrition. Evaluation of clinical implementation and demonstration of benefit will be important before widespread adoption.

Effect of Milk Protein and Whey Permeate in Large-Quantity Lipid-Based Nutrient Supplement on Early Child Development among Children with Stunting: A Randomized 2 × 2 Factorial Trial in Uganda.

Stunting affects 22% children globally, putting them at risk of adverse outcomes including delayed development. We investigated the effect of milk protein (MP) vs. soy and whey permeate (WP) vs. maltodextrin in large-quantity, lipid-based nutrient supplement (LNS), and LNS itself vs. no supplementation, on child development and head circumference among stunted children aged 1-5 years. We conducted a randomized, double-blind, community-based 2 × 2 factorial trial in Uganda (ISRCTN1309319). We randomized 600 children to one of four LNS formulations (~535 kcal/d), with or without MP (n = 299 vs. n = 301) or WP (n = 301 vs. n = 299), for 12 weeks or to no supplementation (n = 150). Child development was assessed using the Malawi Development Assessment Tool. Data were analyzed using linear mixed-effects models. Children had a median [interquartile range] age of 30 [23; 41] months and mean ± standard deviation height-for-age z-score of -3.02 ± 0.74. There were no interactions between MP and WP for any of the outcomes. There was no effect of either MP or WP on any developmental domain. Although LNS itself had no impact on development, it resulted in 0.07 (95%CI: 0.004; 0.14) cm higher head circumference. Neither dairy in LNS, nor LNS in itself, had an effect on development among already stunted children.

Effect of milk protein and whey permeate in large quantity lipid-based nutrient supplement on linear growth and body composition among stunted children: A randomized 2 × 2 factorial trial in Uganda.

BACKGROUND: Despite possible benefits for growth, milk is costly to include in foods for undernourished children. Furthermore, the relative effects of different milk components, milk protein (MP), and whey permeate (WP) are unclear. We aimed to assess the effects of MP and WP in lipid-based nutrient supplement (LNS), and of LNS itself, on linear growth and body composition among stunted children. METHODS AND FINDINGS: We performed a randomized, double-blind, 2 × 2 factorial trial among 12 to 59 months old stunted children in Uganda. Children were randomized to 4 formulations of LNS with MP or soy protein isolate and WP or maltodextrin (100 g/day for 12 weeks) or no supplementation. Investigators and outcome assessors were blinded; however, participants were only blinded to the ingredients in LNS. Data were analyzed based on intention-to-treat (ITT) using linear mixed-effects models adjusted for age, sex, season, and site. Primary outcomes were change in height and knee-heel length, and secondary outcomes included body composition by bioimpedance analysis (ISRCTN13093195). Between February and September 2020, we enrolled 750 children with a median age of 30 (interquartile range 23 to 41) months, with mean (± standard deviation) height-for-age z-score (HAZ) -3.02 ± 0.74 and 12.7% (95) were breastfed. The 750 children were randomized to LNS (n = 600) with or without MP (n = 299 versus n = 301) and WP (n = 301 versus n = 299), or no supplementation (n = 150); 736 (98.1%), evenly distributed between groups, completed 12-week follow-up. Eleven serious adverse events occurred in 10 (1.3%) children, mainly hospitalization with malaria and anemia, all deemed unrelated to the intervention. Unsupplemented children had 0.06 (95% confidence interval, CI [0.02, 0.10]; p = 0.015) decline in HAZ, accompanied by 0.29 (95% CI [0.20, 0.39]; p < 0.001) kg/m2 increase in fat mass index (FMI), but 0.06 (95% CI [-0.002; 0.12]; p = 0.057) kg/m2 decline in fat-free mass index (FFMI). There were no interactions between MP and WP. The main effects of MP were 0.03 (95% CI [-0.10, 0.16]; p = 0.662) cm in height and 0.2 (95% CI [-0.3, 0.7]; p = 0.389) mm in knee-heel length. The main effects of WP were -0.08 (95% CI [-0.21, 0.05]; p = 220) cm and -0.2 (95% CI [-0.7; 0.3]; p = 403) mm, respectively. Interactions were found between WP and breastfeeding with respect to linear growth (p < 0.02), due to positive effects among breastfed and negative effects among non-breastfed children. Overall, LNS resulted in 0.56 (95% CI [0.42, 0.70]; p < 0.001) cm height increase, corresponding to 0.17 (95% CI [0.13, 0.21]; p < 0.001) HAZ increase, and 0.21 (95% CI [0.14, 0.28]; p < 0.001) kg weight increase, of which 76.5% (95% CI [61.9; 91.1]) was fat-free mass. Using height-adjusted indicators, LNS increased FFMI (0.07 kg/m2, 95% CI [0.0001; 0.13]; p = 0.049), but not FMI (0.01 kg/m2, 95% CI [-0.10, 0.12]; p = 0.800). Main limitations were lack of blinding of caregivers and short study duration. CONCLUSIONS: Adding dairy to LNS has no additional effects on linear growth or body composition in stunted children aged 12 to 59 months. However, supplementation with LNS, irrespective of milk, supports linear catch-up growth and accretion of fat-free mass, but not fat mass. If left untreated, children already on a stunting trajectory gain fat at the expense of fat-free mass, thus nutrition programs to treat such children should be considered. TRIAL REGISTRATION: ISRCTN13093195.

Anthropometric criteria for best-identifying children at high risk of mortality: a pooled analysis of twelve cohorts.

OBJECTIVE: To understand which anthropometric diagnostic criteria best discriminate higher from lower risk of death in children and explore programme implications. DESIGN: A multiple cohort individual data meta-analysis of mortality risk (within 6 months of measurement) by anthropometric case definitions. Sensitivity, specificity, informedness and inclusivity in predicting mortality, face validity and compatibility with current standards and practice were assessed and operational consequences were modelled. SETTING: Community-based cohort studies in twelve low-income countries between 1977 and 2013 in settings where treatment of wasting was not widespread. PARTICIPANTS: Children aged 6 to 59 months. RESULTS: Of the twelve anthropometric case definitions examined, four (weight-for-age Z-score (WAZ) <-2), (mid-upper arm circumference (MUAC) <125 mm), (MUAC < 115 mm or WAZ < -3) and (WAZ < -3) had the highest informedness in predicting mortality. A combined case definition (MUAC < 115 mm or WAZ < -3) was better at predicting deaths associated with weight-for-height Z-score <-3 and concurrent wasting and stunting (WaSt) than the single WAZ < -3 case definition. After the assessment of all criteria, the combined case definition performed best. The simulated workload for programmes admitting based on MUAC < 115 mm or WAZ < -3, when adjusted with a proxy for required intensity and/or duration of treatment, was 1·87 times larger than programmes admitting on MUAC < 115 mm alone. CONCLUSIONS: A combined case definition detects nearly all deaths associated with severe anthropometric deficits suggesting that therapeutic feeding programmes may achieve higher impact (prevent mortality and improve coverage) by using it. There remain operational questions to examine further before wide-scale adoption can be recommended.

Prognostic value of different anthropometric indices over different measurement intervals to predict mortality in 6-59-month-old children.

OBJECTIVE: To compare the prognostic value of mid-upper arm circumference (MUAC), weight-for-height Z-score (WHZ) and weight-for-age Z-score (WAZ) for predicting death over periods of 1, 3 and 6 months follow-up in children. DESIGN: Pooled analysis of twelve prospective studies examining survival after anthropometric assessment. Sensitivity and false-positive ratios to predict death within 1, 3 and 6 months were compared for three individual anthropometric indices and their combinations. SETTING: Community-based, prospective studies from twelve countries in Africa and Asia. PARTICIPANTS: Children aged 6-59 months living in the study areas. RESULTS: For all anthropometric indices, the receiver operating characteristic curves were higher for shorter than for longer durations of follow-up. Sensitivity was higher for death with 1-month follow-up compared with 6 months by 49 % (95 % CI (30, 69)) for MUAC < 115 mm (P < 0·001), 48 % (95 % CI (9·4, 87)) for WHZ < -3 (P < 0·01) and 28 % (95 % CI (7·6, 42)) for WAZ < -3 (P < 0·005). This was accompanied by an increase in false positives of only 3 % or less. For all durations of follow-up, WAZ < -3 identified more children who died and were not identified by WHZ < -3 or by MUAC < 115 mm, 120 mm or 125 mm, but the use of WAZ < -3 led to an increased false-positive ratio up to 16·4 % (95 % CI (12·0, 20·9)) compared with 3·5 % (95 % CI (0·4, 6·5)) for MUAC < 115 mm alone. CONCLUSIONS: Frequent anthropometric measurements significantly improve the identification of malnourished children with a high risk of death without markedly increasing false positives. Combining two indices increases sensitivity but also increases false positives among children meeting case definitions.

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.

How do children with severe underweight and wasting respond to treatment? A pooled secondary data analysis to inform future intervention studies.

Children with weight-for-age z-score (WAZ) <-3 have a high risk of death, yet this indicator is not widely used in nutrition treatment programming. This pooled secondary data analysis of children aged 6-59 months aimed to examine the prevalence, treatment outcomes, and growth trajectories of children with WAZ <-3 versus children with WAZ ≥-3 receiving outpatient treatment for wasting and/or nutritional oedema, to inform future protocols. Binary treatment outcomes between WAZ <-3 and WAZ ≥-3 admissions were compared using logistic regression. Recovery was defined as attaining mid-upper-arm circumference ≥12.5 cm and weight-for-height z-score ≥-2, without oedema, within a period of 17 weeks of admission. Data from 24,829 children from 9 countries drawn from 13 datasets were included. 55% of wasted children had WAZ <-3. Children admitted with WAZ <-3 compared to those with WAZ ≥-3 had lower recovery rates (28.3% vs. 48.7%), higher risk of death (1.8% vs. 0.7%), and higher risk of transfer to inpatient care (6.2% vs. 3.8%). Growth trajectories showed that children with WAZ <-3 had markedly lower anthropometry at the start and end of care, however, their patterns of anthropometric gains were very similar to those with WAZ ≥-3. If moderately wasted children with WAZ <-3 were treated in therapeutic programmes alongside severely wasted children, we estimate caseloads would increase by 32%. Our findings suggest that wasted children with WAZ <-3 are an especially vulnerable group and those with moderate wasting and WAZ <-3 likely require a higher intensity of nutritional support than is currently recommended. Longer or improved treatment may be necessary, and the timeline and definition of recovery likely need review.