Effect of multiple micronutrient-fortified bouillon on micronutrient status among women and children in the Northern Region of Ghana: Protocol for the Condiment Micronutrient Innovation Trial (CoMIT), a community-based randomized controlled trial.

INTRODUCTION: Micronutrient deficiencies are prevalent in West Africa, particularly among women of reproductive age (WRA) and young children. Bouillon is a promising food fortification vehicle due to its widespread consumption. This study aims to evaluate the impact of multiple micronutrient-fortified bouillon cubes, compared to control bouillon cubes (fortified with iodine only), on micronutrient status and hemoglobin concentrations among lactating and non-lactating WRA and young children in northern Ghana. METHODS: This randomized, controlled doubly-masked trial will be conducted in the Kumbungu and Tolon districts in the Northern Region of Ghana, where prior data indicate multiple micronutrient deficiencies are common. Participants will be: 1) non-pregnant non-lactating WRA (15-49 y), 2) children 2-5 y, and 3) non-pregnant lactating women 4-18 months postpartum. Eligible participants will be randomly assigned to receive household rations of one of two types of bouillon cubes: 1) a multiple micronutrient-fortified bouillon cube containing vitamin A, folic acid, vitamin B12, iron, zinc, and iodine, or 2) a control cube containing iodine only. Each participant's household will receive a ration of bouillon cubes every 2 weeks, and households will be advised to prepare meals as usual, using the study-provided cubes. The trial duration will be 9 months for non-pregnant non-lactating WRA and children, and 3 months for lactating women. The primary outcomes will be changes in biomarkers of micronutrient status and hemoglobin among WRA and children and milk micronutrient concentrations among lactating women. Secondary outcomes will include change in prevalence of micronutrient deficiency and anemia; dietary intake of bouillon and micronutrients; inflammation, malaria, and morbidity symptoms; and child growth and development. DISCUSSION: Evidence from this study will inform discussions about bouillon fortification in Ghana and West Africa. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov (NCT05178407) and the Pan-African Clinical Trial Registry (PACTR202206868437931). This manuscript reflects protocol version 4 (August 29, 2022).

Acceptability of Multiple Micronutrient-Fortified Bouillon Cubes among Women and Their Households in 2 Districts in The Northern Region of Ghana.

Background: Bouillon is a promising large-scale food fortification vehicle, but there is uncertainty regarding the types and concentrations of micronutrients that are feasible to add without compromising consumer acceptability. Objective: The objective of this study was to evaluate the acceptability of 2 different multiple micronutrient-fortified bouillon cube formulations, compared with a bouillon cube fortified with iodine only. Methods: We conducted a double-blind, randomized, controlled acceptability study in 2 districts in northern Ghana. Two nonproprietary, noncommercialized formulations of multiple micronutrient-fortified bouillon cubes containing iron, zinc, folic acid, vitamins A and B12, and iodine at "upper-level" (45-125% CODEX NRV/2.5g) or "lower-level" (15-50% CODEX NRV/2.5g) concentrations, and a control cube that contained iodine only (50% CODEX NRV/2.5g) were evaluated. Eligible women (n = 84) were invited to participate in 1) center-based sensory evaluations designed to permit within-individual comparisons among the different study products; and 2) in-home evaluation of bouillon acceptability and use, in which participants were randomized to receive 1 of the 3 study products to use in household cooking for a 2-wk period. Acceptance test ratings were based on a 5-point Likert scale (1 = dislike very much, 5 = like very much). Results: In the center-based evaluations, overall liking of the 3 bouillon cube formulations both dry and in prepared dishes ranged from 4.3 to 4.6 on the 5-point Likert scale and did not differ among formulations (P > 0.05). After the 2-wk in-home trial, 93.8% of index participants (n = 75/80) rated their overall liking of the bouillon product formulation to which they were randomly assigned as "like" or "like very much" (4-5 on the 5-point Likert scale) and median apparent intake of study-provided bouillon over 2 wk was 3.6 g/capita/d; neither value differed by study group (P = 0.91 for both). Conclusions: All 3 formulations of bouillon cubes assessed were acceptable to women and their households in 2 districts in northern Ghana.This trial was registered at www.clinicaltrials.gov as NCT05177614.

Consumption of Discretionary Salt and Salt from Bouillon among Households, Women, and Young Children in Northern Region, Ghana: A Mixed-Methods Study with the Condiment Micronutrient Innovation Trial (CoMIT) Project.

Background: Information on salt consumption patterns is needed to inform the need for and design of salt reduction strategies. Objectives: In northern Ghana, this study aimed to estimate household consumption of salt, including salt from bouillon, and compare (estimated) women and children's salt intake to global recommendations; to estimate the proportion of salt consumed from bouillon; and to identify factors, including knowledge, attitudes, and practices, associated with household salt consumption. Methods: Employing mixed-methods methodology, we conducted a pilot survey (n = 369 households enrolled) and focus group discussions (FGDs; n = 20) in Tolon and Kumbungu districts (14 urban, 14 rural clusters) (clinicaltrials.gov registry: NCT04632771). Households reported purchases of discretionary salt (DS, "table salt") and bouillon cubes. DS and total salt (TS; DS+salt from bouillon) consumption for women (15-49 y) and children (2-5 y) were estimated using the Adult Male Equivalent method and compared with global recommendations (<5 g/d women; <3.75 g/d children). Women's salt intake was also predicted from urinary sodium excretion (INTERSALT equation). Associations between DS and TS consumption, as well as household and women's characteristics, were tested with minimally adjusted and multivariable linear mixed-effects models. Qualitative FGD themes were generated using the Framework Method. Results: From household purchase data, estimated TS consumption exceeded global recommendations for 44% of children [median: 2.9 (IQR: 1.9, 5.2) g/d] and 60% of women [6.0 (4.0, 10.2) g/d]; 35% of children and 50% of women exceeded recommendations from DS alone. Bouillon contributed <25% of households' TS consumption. Few characteristics were associated with DS or TS consumption. Salient qualitative themes that shaped salt consumption behaviors included salt's ubiquity as a seasoning, key household members' influence on food procurement and preparation, and perceptions about health. Conclusions: Purchase data suggest salt consumption among women and children exceeds recommendations, even when excluding salt from bouillon; food prepared outside the home likely further contributes. Salt reduction interventions may be warranted in this context.

Evaluation of a tablet-based assessment tool for measuring cognition among children 4-6 years of age in Ghana.

OBJECTIVES: To investigate several basic psychometric properties, including construct, convergent and discriminant validity, of the tablet-based Rapid Assessment of Cognitive and Emotional Regulation (RACER) among children aged 4-6 years in Ghana. METHODS: We investigated whether RACER tasks administered to children in Ghana could successfully reproduce expected patterns of performance previously found in high-income countries on similar tasks assessing inhibitory control (e.g., slower responses on inhibition trials), declarative memory (e.g., higher accuracy on previously seen items), and procedural memory (e.g., faster responses on sequence blocks). Next, we assessed the validity of declarative memory and inhibitory control scores by examining associations of these scores with corresponding paper-based test scores and increasing child age. Lastly, we examined whether RACER was more sensitive than paper-based tests to environmental risk factors common in low- and middle-income countries (LMICs). RESULTS: Of the 966 children enrolled, more than 96% completed the declarative memory and inhibitory control tasks; however, around 30% of children were excluded from data analysis on the procedural memory task due to missing more than half of trials. The performance of children in Ghana replicated previously documented patterns of performance. RACER inhibitory control accuracy score was significantly correlated with child age (r (929) = .09, p = .007). However, our findings did not support other hypotheses. CONCLUSIONS: The high task completion rates and replication of expected patterns support that certain RACER sub-tasks are feasible for measuring child cognitive development in LMIC settings. However, this study did not provide evidence to support that RACER is a valid tool to capture meaningful individual differences among children aged 4-6 years in Ghana.

The impact of maternal supplementation during pregnancy and the first 6 months postpartum on the growth status of the next child born after the intervention period: Follow-up results from Bangladesh and Ghana.

Pregnancy and breastfeeding make demands on maternal nutrient stores. The extent of depletion and the degree to which nutrient stores are replenished between pregnancies has implications for a mother's nutritional status at conception of the subsequent child and therefore that child's birth outcomes and growth. Using follow-up data collected several years after a randomized effectiveness trial conducted in rural Bangladesh and a randomized efficacy trial conducted in semiurban Ghana, we evaluated the impact of maternal supplementation with small-quantity lipid-based nutrient supplements (LNS) or multiple micronutrients (MMN) through pregnancy (the index pregnancy) and 6 months postpartum on the growth status of the next living younger sibling conceived and born after the index pregnancy. In both Bangladesh (n = 472 younger siblings) and Ghana (n = 327 younger siblings), there were no overall differences in the growth status or the prevalence of undernutrition among younger siblings whose mothers had received LNS (or MMN, Ghana only) during and after the index pregnancy compared with the younger siblings of mothers who had received iron plus folic acid (IFA) during the index pregnancy (Ghana) or during and for 3 months after the index pregnancy (Bangladesh). These findings do not indicate that preconception nutrition interventions do not improve child growth. Rather, they suggest that any benefits of maternal LNS or MMN supplementation during one pregnancy and for 6 months postpartum are unlikely to extend to the growth of her next child beyond any effects due to IFA alone.

Maternal and child factors associated with child body fatness in a Ghanaian cohort.

OBJECTIVE: We aimed to identify factors (child diet, physical activity; maternal BMI) associated with body composition of Ghanaian pre-school children. DESIGN: Longitudinal analysis of the International Lipid-Based Nutrient Supplements (iLiNS)-DYAD-Ghana randomized trial, which enrolled 1320 pregnant women at ≤20 weeks' gestation and followed them and their infants until 6 and 18 months postpartum, respectively. At follow-up, child age 4-6 years, we collected data on body composition (by 2H dilution), physical activity and diet, extracted dietary patterns using factor analysis, and examined the association of children's percentage body fat with maternal and child factors by regression analysis. SETTING: Eastern Region, Ghana. PARTICIPANTS: Children 4-6 years of age. RESULTS: The analysis included 889 children with percentage body fat and dietary data at follow-up. We identified two major dietary patterns, a snacking and a cooked foods pattern. Percentage body fat was positively associated (standardized ß (se)) with maternal BMI at follow-up (0·10 (0·03); P = 0·003) and negatively associated with physical activity (-0·15 (0·05); P = 0·003, unadjusted for child gender), but not associated with the snacking (0·06 (0·03); P = 0·103) or cooked foods (-0·05 (0·07); P = 0·474) pattern. Boys were more active than girls (1470 v. 1314 mean vector magnitude counts/min; P < 0·0001) and had lower percentage body fat (13·8 v. 16·9 %; P < 0·0001). CONCLUSIONS: In this population, maternal overweight and child physical activity, especially among girls, may be key factors for addressing child overweight/obesity. We did not demonstrate a relationship between the dietary patterns and body fatness, which may be related to limitations of the dietary data available.

The effects of supplementing maternal and infant diets with lipid-based nutrient supplements on physical activity and sedentary behaviour at preschool age in Ghana.

Evidence on whether nutritional supplementation affects physical activity (PA) during early childhood is limited. We examined the long-term effects of lipid-based nutrient supplements (LNS) on total PA, moderate-to-vigorous PA (MVPA) and sedentary behaviour (SB) of children at 4-6 years using an accelerometer for 1 week. Their mothers were enrolled in the International Lipid-based Nutrient Supplement-DYAD randomised controlled trial in Ghana, assigned to daily LNS or multiple micronutrients (MMN) during pregnancy through 6 months postpartum or Fe and folic acid (IFA) during pregnancy and placebo for 6 months postpartum. From 6 to 18 months, children in the LNS group received LNS; the other two groups received no supplements. Analysis was done with intention to treat comparing two groups: LNS v. non-LNS (MMN+ IFA). Of the sub-sample of 375 children fitted with accelerometers, 353 provided sufficient data. Median vector magnitude (VM) count was 1374 (interquartile range (IQR) 309), and percentages of time in MVPA and SB were 4·8 (IQR 2) and 31 (IQR 8) %, respectively. The LNS group (n 129) had lower VM (difference in mean -73 (95 % CI -20, -126), P = 0·007) and spent more time in SB (LNS v. non-LNS: 32·3 v. 30·5 %, P = 0·020) than the non-LNS group (n 224) but did not differ in MVPA (4·4 v. 4·7 %, P = 0·198). Contrary to expectations, provision of LNS in early life slightly reduced the total PA and increased the time in SB but did not affect time in MVPA. Given reduced social-emotional difficulties in the LNS group previously reported, including hyperactivity, one possible explanation is less restless movement in the LNS group.

Replacing iron-folic acid with multiple micronutrient supplements among pregnant women in Bangladesh and Burkina Faso: costs, impacts, and cost-effectiveness.

Consumption of multiple micronutrient supplements (MMS) during pregnancy offers additional benefits compared with iron-folic acid (IFA) supplementation, but the tablets are more expensive. We estimated the effects, costs, and cost-effectiveness of hypothetically replacing IFA supplements with MMS for 1 year in Bangladesh and Burkina Faso. Using baseline demographic characteristics from LiST and effect sizes from a meta-analysis, we estimated the marginal effects of replacing IFA with MMS on mortality, adverse birth outcomes, and disability-adjusted life years (DALYs) averted. We calculated the marginal tablet costs of completely replacing MMS with IFA (assuming 180 tablets per covered pregnancy). Replacing IFA with MMS could avert over 15,000 deaths and 30,000 cases of preterm birth annually in Bangladesh and over 5000 deaths and 5000 cases of preterm birth in Burkina Faso, assuming 100% coverage and adherence. We estimated the cost per death averted to be US$175-185 in Bangladesh and $112-125 in Burkina Faso. Cost per DALY averted ranged from $3 to $15, depending on the country and consideration of subgroup effects. Our estimates suggest that this policy change would cost-effectively save lives and reduce life-long disabilities. Improvements in program delivery and supplement adherence would be expected to improve the cost-effectiveness of replacing IFA with MMS.

The association of early linear growth and haemoglobin concentration with later cognitive, motor, and social-emotional development at preschool age in Ghana.

It is important to identify the periods during childhood when exposure to environmental risk factors results in long-term neurodevelopmental deficits. Stunting and anaemia may be sensitive indicators of exposure to such risks. In a prospective cohort enrolled before birth, we investigated the association of developmental scores at 4-6 years with (a) birth length and linear growth during three postnatal periods and (2) haemoglobin (Hb) concentration at three time points. Children were participants in a follow-up study of a randomized controlled trial of nutritional supplementation in Ghana. At 4-6 years, cognitive, motor, and social-emotional developments were assessed using standard tests adapted for this population. We estimated the associations of length-for-age z-score (LAZ) at birth and postnatal linear growth (n = 710) and Hb (n = 617) with developmental scores in regression models, using multistage least squares analysis to calculate uncorrelated residuals for postnatal growth. Cognitive development at 4-6 years was significantly associated with LAZ at birth (ß = 0.12, 95% CI = 0.05, 0.19), ΔLAZ from 6 to 18 months (ß = 0.16, 95% CI = 0.04, 0.28), and Hb at 18 months (ß = 0.13, 95% CI = 0.06, 0.20), but not with ΔLAZ during 0-6 months, ΔLAZ from 18 months to 4-6 years, Hb at 6 months, or Hb at 4-6 years. No evidence of associations with motor or social-emotional development were found. These results suggest that in similar contexts, the earlier periods prior to birth and up to 18 months are more sensitive to risk factors for long-term cognitive development associated with LAZ and Hb compared with later childhood. This may inform the optimal timing of interventions targeting improved cognitive development.

Maternal and Infant Lipid-Based Nutritional Supplementation Increases Height of Ghanaian Children at 4-6 Years Only if the Mother Was Not Overweight Before Conception.

BACKGROUND: Few studies have evaluated the long-term effects of nutritional supplementation during the first 1000 d of life. We previously reported that maternal and child lipid-based nutrient supplements (LNS) increased child length by 18 mo. OBJECTIVE: The aim of this study was to examine the effects of LNS on later growth and body composition at 4-6 y of age. DESIGN: This was a follow-up of children in the International Lipid-based Nutrient Supplements (iLiNS)-DYAD trial in Ghana. Women (n = 1320) at ≤20 weeks of gestation were randomly assigned to: 1) iron and folic acid during pregnancy and 200 mg calcium/d for 6 mo postpartum, 2) multiple micronutrients (1-2 RDA of 18 vitamins and minerals) during both periods, or 3) maternal LNS during both periods plus child LNS from 6 to 18 mo. At 4-6 y, we compared height, height-for-age z score (HAZ), and % body fat (deuterium dilution method) between the LNS group and the 2 non-LNS groups combined. RESULTS: Data were available for 961 children (76.5% of live births). There were no significant differences between LNS compared with non-LNS groups in height [106.7 compared with 106.3 cm (mean difference, MD, 0.36; P = 0.226)], HAZ [-0.49 compared with -0.57 (MD = 0.08; P = 0.226)], stunting (< -2 SD) [6.5 compared with 6.3% (OR = 1.00; P = 0.993)], or % body fat [15.5 compared with 15.3% (MD = 0.16; P = 0.630)]. However, there was an interaction with maternal prepregnancy BMI (kg/m2) (P-interaction = 0.046 before correction for multiple testing): among children of women with BMI < 25 , LNS children were taller than non-LNS children (+1.1 cm, P = 0.017), whereas there was no difference among children of women with BMI ≥ 25 (+0.1 cm; P = 0.874). CONCLUSIONS: There was no overall effect of LNS on height at 4-6 y in this cohort, which had a low stunting rate, but height was greater in the LNS group among children of nonoverweight/obese women. There was no adverse impact of LNS on body composition. This trial was registered at clinicaltrials.gov as NCT00970866.

Exposure to a slightly sweet lipid-based nutrient supplement during early life does not increase the level of sweet taste most preferred among 4- to 6-year-old Ghanaian children: follow-up of a randomized controlled trial.

BACKGROUND: The impact of feeding a slightly sweet nutrient supplement early in life on later sweet taste preference is unknown. OBJECTIVE: We tested the hypothesis that the level of sucrose most preferred by 4-6-y-old children exposed to a slightly sweet lipid-based nutrient supplement (LNS) early in life would not be higher than that of children never exposed to LNS. DESIGN: We followed up children born to women (n = 1,320) who participated in a randomized trial in Ghana. In one group, LNS was provided to women on a daily basis during pregnancy and the first 6 mo postpartum and to their infants from age 6 to 18 mo (LNS group). The control groups received daily iron and folic acid or multiple micronutrients during pregnancy and the first 6 mo postpartum, with no infant supplementation (non-LNS group). At age 4-6 y, we randomly selected a subsample of children (n = 775) to assess the concentration of sucrose most preferred using the Monell 2-series, forced-choice, paired-comparison tracking procedure. We compared LNS with non-LNS group differences using a noninferiority margin of 5% weight/volume (wt/vol). RESULTS: Of the 624 children tested, most (61%) provided reliable responses. Among all children, the mean ± SD sucrose solution most preferred (% wt/vol) was 14.6 ± 8.6 (LNS group 14.9 ± 8.7; non-LNS group 14.2 ± 8.4). However, among children with reliable responses, it was 17.0 ± 10.2 (LNS group 17.5 ± 10.4; non-LNS group 16.5 ± 10.0). The upper level of the 95% CI of the difference between groups did not exceed the noninferiority margin in either the full sample or those with reliable responses, indicating that the LNS group did not have a higher sweet preference than the non-LNS group. CONCLUSION: Exposure to a slightly sweet nutrient supplement early in life did not increase the level of sweet taste most preferred during childhood. This trial was registered at clinicaltrials.gov as NCT00970866.

Maternal-Infant Supplementation with Small-Quantity Lipid-Based Nutrient Supplements Does Not Affect Child Blood Pressure at 4-6 Y in Ghana: Follow-up of a Randomized Trial.

BACKGROUND: In the International Lipid-Based Nutrient Supplements (iLiNS)-DYAD-Ghana trial, prenatal small-quantity lipid-based nutrient supplements (LNSs) had a positive effect on birth weight. Birth weight may be inversely related to blood pressure (BP) later in life. OBJECTIVES: We examined the effect of the intervention on BP at 4-6 y of age, and maternal and child factors related to BP. METHODS: The iLiNS-DYAD-Ghana study was a partially double-blind, randomized controlled trial which assigned women (n = 1320) ≤20 weeks of gestation to daily supplementation with: 1) iron and folic acid during pregnancy and 200 mg Ca for 6 mo postpartum , 2) multiple micronutrients during pregnancy and postpartum, or 3) LNSs during pregnancy and postpartum plus LNSs for infants from 6 to 18 mo of age. At 4-6 y of age (n = 858, 70% of live births), we compared BP, a secondary outcome, between non-LNS and LNS groups and examined whether BP was related to several factors including maternal BP, child weight-for-age z score (WAZ), and physical activity. RESULTS: Non-LNS and LNS groups did not differ in systolic (99.2 ± 0.4 compared with 98.5 ± 0.6 mm Hg; P = 0.317) or diastolic (60.1 ± 0.3 compared with 60.0 ± 0.4 mm Hg; P = 0.805) BP, or prevalence of high BP (systolic or diastolic BP ≥90th percentile of the US National Heart, Lung, and Blood Institute reference: 31% compared with 28%; P = 0.251). BP at 4-6 y of age was positively related to birth weight; this relation was largely mediated through concurrent WAZ in a path model. Concurrent WAZ and maternal BP were the factors most strongly related to child BP. CONCLUSIONS: Despite greater birth weight in the LNS group, there was no intervention group difference in BP at 4-6 y. In this preschool population at high risk of adult hypertension based on BP at 4-6 y, high maternal BP and child WAZ were key factors related to BP. This trial was registered at clinicaltrials.gov as NCT00970866.

Exposure to a Slightly Sweet Lipid-Based Nutrient Supplement During Early Life Does Not Increase the Preference for or Consumption of Sweet Foods and Beverages by 4-6-y-Old Ghanaian Preschool Children: Follow-up of a Randomized Controlled Trial.

BACKGROUND: Whether consuming sweet foods early in life affects sweet food preferences and consumption later in childhood is unknown. OBJECTIVE: We tested the hypothesis that exposure to a slightly sweet lipid-based nutrient supplement (LNS) early in life would not increase preference for or consumption of sweet items at preschool age. METHODS: We followed up children who had participated in a randomized trial in Ghana in which LNS was provided to 1 group of women during pregnancy and 6 mo postpartum and to their infants from ages 6-18 mo (LNS group). The control group (non-LNS group) received iron and folic acid during pregnancy or multiple micronutrients during pregnancy and 6 mo postpartum, with no infant supplementation. At 4-6 y, we obtained data from caregivers on children's food and beverage preferences and consumption (n = 985). For a randomly selected subsample (n = 624), we assessed preference for sweet items using a photo game (range in potential scores, 0-15). For the photo game and reported consumption of sweet items, we examined group differences using predetermined noninferiority margins equivalent to an effect size of 0.2. RESULTS: Median (quartile 1, quartile 3) reported consumption of sweet items (times in previous week) was 14 (8, 23) in the LNS group and 16 (9, 22) in the non-LNS group; in the photo game, the number of sweet items selected was 15 (11, 15) and 15 (11, 15), respectively. The upper level of the 95% CI of the mean difference between LNS and non-LNS groups did not exceed the noninferiority margins for these outcomes. Caregiver-reported preferences for sweet items also did not differ between groups (P = 0.9). CONCLUSION: In this setting, where child consumption of sweet foods was common, exposure to a slightly sweet LNS early in life did not increase preference for or consumption of sweet foods and beverages at preschool age. This trial was registered at clinicaltrials.gov as NCT00970866.

Prenatal and postnatal lipid-based nutrient supplementation and cognitive, social-emotional, and motor function in preschool-aged children in Ghana: a follow-up of a randomized controlled trial.

Background: Adequate nutrition is necessary for brain development during pregnancy and infancy. Few randomized controlled trials of supplementation during these periods have measured later developmental outcomes. Objective: Our objective was to investigate the effects of provision of prenatal and postnatal lipid-based nutrient supplements (LNS) on child development at preschool age. Methods: We conducted a follow-up study of 966 children aged 4-6 y in 2016, born to women who participated in the International Lipid-Based Nutrient Supplements-DYAD trial conducted in Ghana in 2009-2014, representing 79% of eligible children. Women ≤20 weeks of gestation were randomized to daily LNS or multiple micronutrient (MMN) capsules during pregnancy through 6 mo postpartum or iron and folic acid (IFA) capsules during pregnancy and calcium placebo capsules during 6 mo postpartum. Children in the LNS group received LNS from 6 to 18 mo. Primary outcomes of this follow-up study were (1) a cognitive factor score based on a test battery adapted from several standard tests, 2) fine motor score (9-hole pegboard test), and (3) social-emotional difficulties (Strengths and Difficulties Questionnaire; SDQ). Eight secondary outcomes were calculated in specific domains (e.g., language, SDQ prosocial). Analysis was by a complete case intention to treat in a 2-group comparison: LNS compared with non-LNS (MMN + IFA). Results: Children in the LNS group had significantly lower social-emotional difficulties z-scores than children in the non-LNS group (adjusted for child age ß = -0.12, 95% CI: -0.25, 0.02, P = 0.087; fully adjusted ß = -0.16, 95% CI: -0.29, -0.03, P = 0.013). The effect of LNS on social-emotional difficulties score was larger among children living in households with lower home environment scores (P-interaction = 0.081). No other outcomes differed between the 2 intervention groups. Conclusions: Provision of LNS during the first 1000 d of development improved behavioral function, particularly for children from low nurturing and stimulation households, but did not affect cognition at preschool age in this setting. Trial Registration: clinicaltrials.gov, Identifier NCT00970866.

Comparison of cross-sectional renal function measurements in African Americans with hypertensive nephrosclerosis and of primary formulas to estimate glomerular filtration rate.

Renal function measurements were obtained in 1,703 African Americans with presumed hypertensive nephrosclerosis who were screened for entry into the African-American Study of Hypertension and Kidney Disease (AASK). We examined the effect of race on relationships involving renal variables by comparing African Americans enrolled into the AASK with non-African Americans enrolled into the Modification of Diet in Renal Disease (MDRD) study. We examined the effect of gender on renal variables by comparing African American men and women. We compared various methods for estimating glomerular filtration rate (GFR) with iodine 125-labeled ((125)I)-iothalamate GFR. AASK data were also used to derive a new formula for estimating GFR in African Americans. After adjusting for age, sex, and baseline GFR, African American patients on the AASK study were heavier and had larger body surface areas and body mass indices than either MDRD African Americans or non-African Americans. African Americans had greater serum creatinine levels and urinary creatinine excretions for any given level of GFR. Mean GFR was greater in African American men than African American women (59.7 versus 51.7 mL/min/1.73 m(2)), although serum creatinine levels were also greater in men (1.91 versus 1.73 mg/dL). Seventy-eight percent of women with serum creatinine levels between 1.2 and 1.5 mg/dL had GFRs less than 65 mL/min/1.73 m(2). For African Americans in the AASK, GFR was overestimated by the 24-hour creatinine clearance and underestimated by the Cockcroft-Gault formula. A prediction formula developed in the MDRD study more accurately predicted GFR in AASK patients than these measurements. AASK data were also used to derive a new five-term formula for estimating GFR that was slightly more accurate in the African Americans in the AASK than the MDRD formula (median percentage of error, 12.4% for the MDRD formula versus 12.1% for the AASK formula). Important differences exist in renal variables between African Americans and non-African Americans and between African American men and African American women. Formulas using demographic data and readily measured serum values estimate (125)I-iothalamate GFR.

The effect of nutritional and hormonal supplementation on protein synthesis immediately after liver transplantation.

We have previously shown that immediately after liver transplantation (LT) the porcine recipient exhibits elevated plasma glucagon, increased fractional synthetic rate (FSR) of fibrinogen, and decreased FSR of fixed or structural liver proteins. The purpose of this study was to evaluate the effect of nutritional and hormonal supplementation on these observations 24 h after LT. Two groups of nine pigs were studied 1 day after LT using radioisotopic and arteriovenous difference techniques. A control group underwent LT with saline infusion and a supplemented group underwent LT with infusion of glucose, amino acids (6 and 1.06 mg/kg. min, respectively), and intraportal insulin (0.6 mU/kg. min) and glucagon (1.3 ng/kg. min). Primed constant infusions of [3H]leucine were used to determine leucine flux, an estimate of whole body protein breakdown, and fractional synthetic rates (FSR). The following changes were noted with supplementation: elevated plasma insulin (6 +/- 1 versus 29 +/- 4 microU/ml, control versus supplemented, respectively, P < 0.05), decreased glucagon to normal levels (323 +/- 65 versus 102 +/- 12 pg/ml, P < 0.05), decreased fibrinogen FSR (108 +/- 15 versus 70 +/- 6%/day, P < 0.025), and increased fixed liver protein FSR (8 +/- 1 versus 13 +/- 2%/day, P < 0.05, respectively). Albumin FSR was unaltered by supplementation (8 +/- 2 versus 6 +/- 1%/day, respectively). Nutritional and hormonal supplementation immediately after LT restored the measured protein synthesis in the allograft to near normal levels 1 day after transplantation.

Net hepatic glucose output is normal on postoperative day 1 after liver transplantation.

The liver plays a central role in carbohydrate metabolism and glucose homeostasis; therefore, the rapid recovery of glucose homeostasis after liver transplantation (LT) is important. The purpose of this study was to evaluate hepatic and whole-body glucose production (WBGP) on postoperative day 1 after LT using a combination of arteriovenous differences and radioisotope techniques. Two groups of female commercially bred pigs with an average body weight of 31.9 +/- 1.4 kg were studied. A control group (n = 6) underwent laparotomy. A transplanted group (n = 6) was submitted to LT. All pigs were instrumented with catheters placed in the carotid artery and the hepatic, portal, and jugular vein, and flow probes were placed around the hepatic artery and portal vein. WBGP was measured by a primed constant infusion of 3-[3H]glucose 1 day postoperatively. Plasma glucose was 89 +/- 6 versus 98 +/- 7 mg/dL in the control and transplanted groups, respectively. WBGP was increased by 42 per cent in the transplanted group (2.54 +/- 0.17 vs 3.62 +/- 0.39 mg/kg.min), but the net hepatic glucose output was not different between the control and the transplanted groups (1.53 +/- 0.28 vs 1.68 +/- 0.31 mg/kg.min). These results demonstrate that net hepatic glucose output was not different between the control and transplanted pigs, suggesting that LT does not compromise the ability of the liver to produce glucose. However, the WBGP was increased by 42 per cent in the transplanted group, suggesting either a significant contribution from another organ or a significant intrahepatic utilization of glucose.

Hepatic uptake of amino acids immediately after liver transplantation is well preserved despite altered plasma profiles.

BACKGROUND: The liver is one of the principal organs responsible for the uptake and release of amino acids in the body. The ability of the transplanted liver to clear plasma amino acids is associated with a functioning allograft. However, clinical assessment is limited by the inability to access the portal vein postoperatively. Therefore, using a porcine liver transplant model, we examined (1) the plasma levels of amino acids presented to the new hepatic allograft and (2) the capacity of the new allograft to clear these amino acids from the circulation. MATERIALS AND METHODS: Two groups of commercially bred pigs were studied: a control group (n = 8) underwent laparotomy and a transplanted group (n = 6) underwent orthotopic liver transplantation (LT) using veno-venous bypass. All pigs had catheters placed in the carotid artery and portal and hepatic veins and ultrasonic transit time flow probes placed around the hepatic artery and portal vein. Plasma profiles of 23 amino acids were analyzed by high-pressure liquid chromatography. Hepatic balances of amino acids, using arteriovenous difference techniques coupled with hepatic blood flows, were also analyzed on postoperative day 1. RESULTS: Neither portal vein blood flow (703 +/- 74 ml/min vs 666 +/- 82 ml/min) nor hepatic artery blood flow (322 +/- 43 ml/min vs 209 +/- 59 ml/min) was significantly different between the control and the transplanted groups, respectively. The transplanted group had significantly increased plasma levels of alanine (135 +/- 13 mumol/l vs 382 +/- 72 mumol/l), hydroxyproline (30 +/- 5 mumol/l vs 60 +/- 9 mumol/l), methionine (25 +/- 2 mumol/l vs 55 +/- 10 mumol/l), ornithine (36 +/- 5 mumol/l vs 141 +/- 33 mumol/l), phenylalanine (84 +/- 5 mumol/l vs 120 +/- 12 mumol/l), threonine (75 +/- 9 mumol/l vs 159 +/- 27 mumol/l), and tryptophan (17 +/- 2 mumol/l vs 31 +/- 4 mumol/l). The transplanted group also had significantly decreased plasma levels of isoleucine (122 +/- 12 mumol/l vs 85 +/- 8 mumol/l) and taurine (71 +/- 7 mumol/l vs 35 +/- 7 mumol/l). These individual amino acid changes were not accompanied by impairment in the net hepatic amino acid balance or the hepatic fractional extraction of amino acids between the two groups. CONCLUSION: These results suggest that the circumstances associated with liver transplantation alter the fasting amino acid profile immediately postoperatively. However, liver transplantation does not impair the normal hepatic allograft uptake of most plasma amino acids. Thus, the changes observed in the circulating levels of amino acids may represent alterations in nonhepatic production and/or utilization. Furthermore, altered plasma amino acid profiles following liver transplantation are not necessarily indicative of impaired hepatic allograft amino acid metabolism.

Mechanisms of hyperinsulinemia and hyperglucagonemia after liver transplantation.

These studies were undertaken to evaluate the mechanisms for changes in plasma insulin and glucagon levels observed post-liver transplantation. Two groups of pigs were studied: a control group (n = 8) underwent laparotomy and catheter placement in the carotid artery and portal and hepatic veins. Hepatic blood flow was measured by ultrasonic flow probes placed around the hepatic artery and portal vein. An experimental group (n = 8) underwent orthotopic liver transplantation and similar instrumentation. On Day 1 after surgery, an estimate of insulin and glucagon secretion and hepatic extraction was determined using arteriovenous difference techniques. Serum assays were performed for markers of hepatic and renal function. Plasma insulin levels of the transplanted pigs were higher in the carotid artery (4 +/- 1 microU/ml vs 7 +/- 1 microU/ml), but not in the hepatic vein (5 +/- 1 microU/ml vs 7 +/- 1 microU/ml) and in the portal vein (10 +/- 2 microU/ml vs 12 +/- 2 microU/ml). Arterial plasma C-peptide was significantly greater in the transplanted group (0.23 +/- 0.02 ng/ml vs 0.42 +/- 0.03 ng/ml); however, the molar ratio of C-peptide and insulin was not different between the two groups (3.6 +/- 0.9 vs 3.4 +/- 0.4). Plasma glucagon levels of the transplanted pigs were significantly elevated in the carotid artery (111 +/- 11 pg/ml vs 323 +/- 65 pg/ml), portal vein (221 +/- 27 pg/ml vs 495 +/- 69 pg/ml), and hepatic vein (142 +/- 15 pg/ml vs 395 +/- 58 pg/ml). The estimate of pancreatic secretion of insulin (115 +/- 28 microU/kg.min) vs 71 +/- 21 microU/kg.min) and glucagon (2.0 +/- 0.4 ng/kg.min vs 2.7 +/- 0.7 ng/kg.min) and the fractional hepatic extraction rate of insulin (35 +/- 8% vs 32 +/- 5%) were not different between the two groups. However, the hepatic fractional extraction rate of glucagon was significantly decreased in the transplanted group (25 +/- 5% vs 11 +/- 3%). Therefore, the hyperglucagonemia observed 24 hr following liver transplantation is partly due to reduced hepatic fractional extraction of glucagon while the hyperinsulinemia is mainly due to the nonhepatic clearance of insulin. We speculate that decreased renal function may contribute to the hyperinsulinemia, elevated C-peptide concentrations, and hyperglucagonemia.