Nutritional quality of calorie restricted diets in the CALERIE™ 1 trial.

OBJECTIVES: The aim was to determine the nutritional adequacy of calorie restricted (CR) diets during CR interventions up to 12 months. METHODS: The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE™) phase 1 trial consisted of 3 single-site studies to test the feasibility and effectiveness of CR in adults without obesity. After baseline assessments, participants who were randomized to a CR intervention received education and training from registered dietitians on how to follow a healthful CR diet. Food diaries were completed at baseline and during the CR interventions (~6, 9, and 12 months) when participants were self-selecting CR diets. Diaries were analyzed for energy, macronutrients, fiber, 11 vitamins, and 9 minerals. Nutritional adequacy was defined by sex- and age-specific Estimated Average Requirement (EAR) or Adequate Intake (AI) criteria for each nutrient. Diet quality was evaluated using the PANDiet diet quality index. RESULTS: Eighty-eight CR participants (67% women, age 40 ± 9 y, BMI 27.7 ± 1.5 kg/m2) were included in the analysis. Dietary intake of fiber and most vitamins and minerals increased during CR. More than 90% of participants achieved 100% of EAR or AI during CR for 2 of 4 macronutrients (carbohydrate and protein), 6 of 11 vitamins (A, B1, B2, B3, B6, B12), and 6 of 9 minerals assessed (copper, iron, phosphorus, selenium, sodium, zinc). Nutrients for which <90% of participants achieved adequacy included fiber, omega-3 fatty acids, vitamins B5, B9, C, E, and K, and the minerals calcium, magnesium, and potassium. The PANDiet diet quality index improved from 72.9 ± 6.0% at baseline to 75.7 ± 5.2% during CR (p < 0.0001). CONCLUSION: Long-term, calorie-restricted diets were nutritionally equal or superior to baseline ad libitum diets among adults without obesity. Our results support modest calorie restriction as a safe strategy to promote healthy aging without compromising nutritional adequacy or diet quality.

Randomized controlled trial of early, small-volume formula supplementation among newborns: A study protocol.

Childhood undernutrition is a major health burden worldwide that increases childhood morbidity and mortality and causes impairment in infant growth and developmental delays that can persist into adulthood. The first weeks and months after birth are critical to the establishment of healthy growth and development during childhood. The World Health Organization recommends immediate and exclusive breastfeeding (EBF). In infants for whom EBF may not meet nutritional and caloric demands, early, daily, small-volume formula supplementation along with breastfeeding may more effectively avoid underweight wasting and stunting in early infancy than breastfeeding alone. The primary objective of this randomized controlled trial is to evaluate the efficacy of formula for 30 days among low birth weight (LBW) infants <6 hours of age and those not LBW with weights <2600 grams at 4 days of age. We will compare breastfeeding and formula (up to 59 milliliters administered daily) through 30 days of infant age vs recommendations for frequent EBF without supplementation, and test the hypothesis that formula increases weight-for-age z-score at 30 days of infant age. The trial will enroll and randomize 324 mother-infant pairs in Guinea-Bissau and Uganda, and follow them for 6 months for outcomes including growth, intestinal microbiota, breastfeeding duration, infant dietary intake, and adverse events. Conservatively estimating 20% loss to follow up, this sample size provides ≥80% power per weight stratum for intervention group comparison to detect a difference of 0.20 with respect to the outcome of WAZ at day 30. This trial was approved by the University of California, San Francisco Institutional Review Board (19-29405); the Guinea-Bissau National Committee on Ethics in Health (Comite Nacional de Etica na Saude, 075/CNES/INASA/2020); the Higher Degrees, Research and Ethics Committee of Makerere University (871); and the Uganda National Council of Science and Technology (HS1226ES). We plan to disseminate study results in peer-reviewed journals and international conferences. Trial registration number: NCT04704076.

Transient Effect of Infant Formula Supplementation on the Intestinal Microbiota.

Breastfeeding is the gold standard for feeding infants because of its long-term benefits to health and development, but most infants in the United States are not exclusively breastfed in the first six months. We enrolled 24 infants who were either exclusively breastfed or supplemented with formula by the age of one month. We collected diet information, stool samples for evaluation of microbiotas by 16S rRNA sequencing, and blood samples for assessment of immune development by flow cytometry from birth to 6 months of age. We further typed the Bifidobacterium strains in stool samples whose 16S rRNA sequencing showed the presence of Bifidobacteriaceae. Supplementation with formula during breastfeeding transiently changed the composition of the gut microbiome, but the impact dissipated by six months of age. For example, Bifidobacterium longum, a bacterial species highly correlated with human milk consumption, was found to be significantly different only at 1 month of age but not at later time points. No immunologic differences were found to be associated with supplementation, including the development of T-cell subsets, B cells, or monocytes. These data suggest that early formula supplementation, given in addition to breast milk, has minimal lasting impact on the gut microbiome or immunity.

Physiology of Energy Intake in the Weight-Reduced State.

Physiological adaptations to intentional weight loss can facilitate weight regain. This review summarizes emerging findings on hypothalamic and brainstem circuitry in the regulation of body weight and identifies promising areas for research to improve therapeutic interventions for sustainable weight loss. There is good evidence that body weight is actively regulated in a homeostatic fashion similar to other physiological parameters. However, the defended level of body weight is not fixed but rather depends on environmental conditions and genetic background in an allostatic fashion. In an environment with plenty of easily available energy-dense food and low levels of physical activity, prone individuals develop obesity. In a majority of individuals with obesity, body weight is strongly defended through counterregulatory mechanisms, such as hunger and hypometabolism, making weight loss challenging. Among the options for treatment or prevention of obesity, those directly changing the defended body weight would appear to be the most effective ones. There is strong evidence that the mediobasal hypothalamus is a master sensor of the metabolic state and an integrator of effector actions responsible for the defense of adequate body weight. However, other brain areas, such as the brainstem and limbic system, are also increasingly implicated in body weight defense mechanisms and may thus be additional targets for successful therapies.

Effects of food supplementation on cognitive function, cerebral blood flow, and nutritional status in young children at risk of undernutrition: randomized controlled trial.

OBJECTIVE: To assess the effects of food supplementation on improving working memory and additional measures including cerebral blood flow in children at risk of undernutrition. DESIGN: Randomized controlled trial. SETTING: 10 villages in Guinea-Bissau. PARTICIPANTS: 1059 children aged 15 months to 7 years; children younger than 4 were the primary population. INTERVENTIONS: Supervised isocaloric servings (≈1300 kJ, five mornings each week, 23 weeks) of a new food supplement (NEWSUP, high in plant polyphenols and omega 3 fatty acids, within a wide variety and high fortification of micronutrients, and a high protein content), or a fortified blended food (FBF) used in nutrition programs, or a control meal (traditional rice breakfast). MAIN OUTCOME MEASUREMENTS: The primary outcome was working memory, a core executive function predicting long term academic achievement. Additional outcomes were hemoglobin concentration, growth, body composition, and index of cerebral blood flow (CBFi). In addition to an intention-to-treat analysis, a predefined per protocol analysis was conducted in children who consumed at least 75% of the supplement (820/925, 89%). The primary outcome was assessed by a multivariable Poisson model; other outcomes were assessed by multivariable linear mixed models. RESULTS: Among children younger than 4, randomization to NEWSUP increased working memory compared with the control meal (rate ratio 1.20, 95% confidence interval 1.02 to 1.41, P=0.03), with a larger effect in the per protocol population (1.25, 1.06 to 1.47, P=0.009). NEWSUP also increased hemoglobin concentration among children with anemia (adjusted mean difference 0.65 g/dL, 95% confidence interval 0.23 to 1.07, P=0.003) compared with the control meal, decreased body mass index z score gain (-0.23, -0.43 to -0.02, P=0.03), and increased lean tissue accretion (2.98 cm2, 0.04 to 5.92, P=0.046) with less fat (-5.82 cm2, -11.28 to -0.36, P=0.04) compared with FBF. Additionally, NEWSUP increased CBFi compared with the control meal and FBF in both age groups combined (1.14 mm2/s×10-8, 0.10 to 2.23, P=0.04 for both comparisons). Among children aged 4 and older, NEWSUP had no significant effect on working memory or anemia, but increased lean tissue compared with FBF (4.31 cm2, 0.34 to 8.28, P=0.03). CONCLUSIONS: Childhood undernutrition is associated with long term impairment in cognition. Contrary to current understanding, supplementary feeding for 23 weeks could improve executive function, brain health, and nutritional status in vulnerable young children living in low income countries. Further research is needed to optimize nutritional prescriptions for regenerative improvements in cognitive function, and to test effectiveness in other vulnerable groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT03017209.

A Randomized Controlled Trial of Two Ready-to-Use Supplementary Foods Demonstrates Benefit of the Higher Dairy Supplement for Reduced Wasting in Mothers, and Differential Impact in Infants and Children Associated With Maternal Supplement Response.

BACKGROUND: There is no consensus over best approaches to reliably prevent malnutrition in rural communities in low-income countries. OBJECTIVE: We compared the effectiveness of 2 lipid-based ready-to-use supplementary foods (RUSFs) differing in dairy protein content to improve the nutritional status of mothers and at-risk infants and young children in rural Guinea-Bissau. METHODS: A 3-month cluster-randomized controlled pilot trial of 2 RUSFs was conducted with 692 mothers and 580 mildly or moderately malnourished infants (6-23 months) and children (24-59 months) from 13 villages. The RUSFs contained either 478 (mothers, children) or 239 kcal/d (infants) with 15% or 33% of protein from dairy and were distributed at community health centers 5 d/wk. Controls were wait-listed to receive RUSF. Primary outcomes were mid-upper arm circumference (MUAC) in mothers, and weight-for-age and height-for-age z-scores (WAZ and HAZ) in infants and children. RESULTS: There was a significant effect of the RUSF-33% on MUAC in mothers ( P = .03). The WAZ and HAZ increased substantially, by ≈1 z-score, in infants and children ( P < .01) independent of group randomization. In children, but not infants, baseline WAZ and change in maternal MUAC were associated with change in WAZ (ß = .07, P = .02). CONCLUSION: Ready-to-use supplementary foods with higher dairy protein content had a significant benefit in village mothers, supporting a comparable recent finding in preschool children. In addition, supplementation of children <2 years resulted in improved growth independent of family nutritional status, whereas success in older children was associated with change in maternal nutrition, suggesting the need for community-level education about preventing malnutrition in older, as well as younger, children.

Discovery and preclinical evaluation of potent, orally bioavailable, metabolically stable cyclopropylindolobenzazepine acylsulfonamides as thumb site 1 inhibitors of the hepatitis c virus NS5B RNA-dependent, RNA polymerase.

Herein, we describe the synthesis, antiviral structure-activity relationships (SAR), metabolic stability, and pharmacokinetic (PK) properties for a series of cyclopropylindolobenzazepine acylsulfonamide HCV NS5B polymerase inhibitors. Optimization of SAR, metabolic stability and PK led to the identification of compound 19 which was advanced into pre-IND enabling toxicology studies.

A Randomized Controlled Trial Offering Higher- Compared with Lower-Dairy Second Meals Daily in Preschools in Guinea-Bissau Demonstrates an Attendance-Dependent Increase in Weight Gain for Both Meal Types and an Increase in Mid-Upper Arm Circumference for the Higher-Dairy Meal.

BACKGROUND: Controversy remains over the most effective approaches to prevent childhood malnutrition. OBJECTIVES: We tested the feasibility and effectiveness of delivering ready-to-use supplementary foods (RUSFs) as a second daily meal in preschool children aged 3-5 y in Guinea-Bissau, and compared RUSFs with different levels of dairy protein. METHODS: This study was a 3 mo cluster-randomized controlled pilot trial of 2 RUSFs differing in dairy protein in 533 boys and girls from 9 preschools. Children receiving RUSFs were compared with wait-listed controls, and all students received a daily school lunch. The RUSFs were delivered 5 d/wk for 3 mo and contained 478 kcal and 11.5 g protein per 92-g daily serving. Deliveries included a ready-to-use supplementary food with 15% of protein from dairy sources (RUSF-15%) or one with 33% of protein from dairy sources (RUSF-33%). Intention-to-treat (ITT) and per-protocol analyses (>50 d of RUSF consumption) were conducted. Changes in the weight-for-age z score (WAZ) and height-for-age z score were primary outcomes. Additional outcomes included changes in mid-upper arm circumference (MUAC), hemoglobin, and retinol binding protein. RESULTS: Baseline anthropometry was not different between groups (WAZ, -0.48 ± 1.04) and increased significantly over time (P < 0.01) with no effects of the RUSFs in ITT analyses. However, children consuming RUSFs for >50 d had a significantly greater increase in WAZ relative to the increase in controls (+0.40 and +0.32 for RUSF-15% and RUSF-33%, respectively, compared with +0.24 in controls, P < 0.01 and P < 0.05, respectively). RUSF-33%, but not RUSF-15%, also eliminated a decrease in MUAC observed in controls (-0.01 cm in RUSF-33% compared with -0.34 cm in controls, P < 0.05). The only difference between RUSF-15% and RUSF-33% was a mean decrease in hemoglobin in children receiving RUSF-15% (-0.5 compared with -0.002 g/dL, P = 0.05). CONCLUSIONS: Implementation of 2-meal preschool feeding programs is feasible in low-income countries, and there are measurable benefits relative to 1-meal programs in children attending preschool regularly. In addition, MUAC and hemoglobin measurements indicate that meals with 33% compared with 15% of protein from dairy may help prevent wasting and anemia.

Sodium, saturated fat, and trans fat content per 1,000 kilocalories: temporal trends in fast-food restaurants, United States, 2000-2013.

INTRODUCTION: Intakes of sodium, saturated fat, and trans fat remain high despite recommendations to limit these nutrients for cardiometabolic risk reduction. A major contributor to intake of these nutrients is foods prepared outside the home, particularly from fast-food restaurants. METHODS: We analyzed the nutrient content of frequently ordered items from 3 US national fast-food chains: fried potatoes (large French fries), cheeseburgers (2-oz and 4-oz), and a grilled chicken sandwich. We used an archival website to obtain data on sodium, saturated fat, and trans fat content for these items from 2000 through 2013. The amount of each nutrient per 1,000 kcal was calculated to determine whether there were trends in product reformulation. RESULTS: Sodium content per 1,000 kcal differed widely among the 3 chains by food item, precluding generalizations across chains. During the 14-year period, sodium content per 1,000 kcal for large French fries remained high for all 3 chains, although the range narrowed from 316-2,000 mg per 1,000 kcal in 2000 to 700-1,420 mg per 1,000 kcal in 2013. Among the items assessed, cheeseburgers were the main contributor of saturated fat, and there was little change in content per 1,000 kcal for this item during the 14-year period. In contrast, there was a sharp decline in saturated and trans fat content of large French fries per 1,000 kcal. Post-2009, the major contributor of trans fat per 1,000 kcal was cheeseburgers; trans fat content of this item remained stable during the 14-year period. CONCLUSION: With the exception of French fries, little evidence was found during the 14-year period of product reformulation by restaurants to become more consistent with dietary guidance to reduce intakes of sodium and saturated fat.

Temporal trends in fast-food restaurant energy, sodium, saturated fat, and trans fat content, United States, 1996-2013.

INTRODUCTION: Excess intakes of energy, sodium, saturated fat, and trans fat are associated with increased risk for cardiometabolic syndrome. Trends in fast-food restaurant portion sizes can inform policy decisions. We examined the variability of popular food items in 3 fast-food restaurants in the United States by portion size during the past 18 years. METHODS: Items from 3 national fast-food chains were selected: French fries, cheeseburgers, grilled chicken sandwich, and regular cola. Data on energy, sodium, saturated fat, and trans fat content were collated from 1996 through 2013 using an archival website. Time trends were assessed using simple linear regression models, using energy or a nutrient component as the dependent variable and the year as the independent variable. RESULTS: For most items, energy content per serving differed among chain restaurants for all menu items (P ≤ .04); energy content of 56% of items decreased (ß range, -0.1 to -5.8 kcal) and the content of 44% increased (ß range, 0.6-10.6 kcal). For sodium, the content of 18% of the items significantly decreased (ß range, -4.1 to -24.0 mg) and the content for 33% increased (ß range, 1.9-29.6 mg). Absolute differences were modest. The saturated and trans fat content, post-2009, was modest for French fries. In 2013, the energy content of a large-sized bundled meal (cheeseburger, French fries, and regular cola) represented 65% to 80% of a 2,000-calorie-per-day diet, and sodium content represented 63% to 91% of the 2,300-mg-per-day recommendation and 97% to 139% of the 1,500-mg-per-day recommendation. CONCLUSION: Findings suggest that efforts to promote reductions in energy, sodium, saturated fat, and trans fat intakes need to be shifted from emphasizing portion-size labels to additional factors such as total calories, frequency of eating, number of items ordered, menu choices, and energy-containing beverages.

Dietary variety predicts low body mass index and inadequate macronutrient and micronutrient intakes in community-dwelling older adults.

BACKGROUND: Low body mass index (BMI) and micronutrient deficiencies are associated with increased morbidity and mortality rates in old age. Whether adverse patterns of dietary variety predict both low BMI and low micronutrient intakes in older adults was investigated. METHODS: A cross-sectional analysis of national survey data was conducted in 1174 healthy adult men and women (ages 21 to 90 years) who provided physiologically plausible dietary data in the 1994-1996 Continuing Survey of Food Intakes by Individuals. Measurements included reported energy intake, protein intake (percentage meeting Recommended Dietary Allowance), micronutrient intakes (percentage meeting Estimated Average Requirements for 14 micronutrients), and BMI. RESULTS: Adults who were 61 years or older consumed a greater total variety of foods, chose foods from a wider range of food groups, had a greater variety of micronutrient-dense foods and energy-weak foods, and had a lower variety of micronutrient-weak foods compared with adults ages 21 to 60 years (p < .05 to.001). However, older adults with low BMIs (< 22 kg/m2) consumed a lower variety of energy-dense foods compared with older adults with higher BMIs (p < .05). The variety of energy-dense foods predicted both energy intake and BMI at all ages in multiple regression models controlling for confounding variables (R2 = .124 for energy, R2 = .574 for BMI, p < .001). A higher percentage of older persons had inadequate micronutrient intakes compared with younger persons (p < .05), especially vitamin E, calcium, and magnesium, but consumption of a particularly wide variety of micronutrient-rich foods helped counterbalance these trends (p < .05). Older adults who had a low BMI and consumed a low variety of micronutrient-dense foods were particularly at nutritional risk, with only 65.4% consuming the Recommended Dietary Allowance for protein and none meeting the Estimated Average Requirements for all 14 micronutrients. CONCLUSIONS: In contrast to previous suggestions that older persons consume a monotonous diet, this study showed that adults who were 61 years or older consumed a greater total food variety, and a greater variety of micronutrient-dense and energy-weak foods, compared with adults who were 60 years or younger. Although consumption of a low variety of energy-dense foods may contribute to reduced energy intake and body weight at any age, the variety of micronutrient-dense foods consumed needs to increase in old age to prevent micronutrient deficiencies. These findings suggest that all adults need advice on the changing needs for dietary variety with aging to maintain health, and that older persons with low BMI are particularly vulnerable to dietary shortfalls.

Hydroxytriamides as potent gamma-secretase inhibitors.

Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.

Fermentable and nonfermentable fiber supplements did not alter hunger, satiety or body weight in a pilot study of men and women consuming self-selected diets.

Little is known about the relative effects of fermentable fiber (FF) vs. nonfermentable fiber (NFF) on energy regulation in humans. We compared 27 +/- 0.6 g/d supplements of FF (pectin, beta-glucan) and NFF (methylcellulose) for their ability to decrease ad libitum energy intake (EI) and hunger, increase satiety and cause spontaneous body weight and fat losses. Men and women (n = 11) aged 23-46 y, BMI 20.0-34.4 kg/m2, consumed first NFF and then FF for 3 wk each, with a 4-wk washout period between phases. Daily satiety assessed with analog scales was higher with NFF than FF (60.7 +/- 1.0 vs. 57.7 +/- 0.8 mm, P = 0.01). However, there were no differences in reported EI (NFF < FF by 7%, P = 0.31, NFF < baseline by 9.5%, P = 0.11), body weight (NFF 0.13 kg, P = 0.73; FF 0.13 kg, P = 0.60) or fat percentage (NFF -0.3%, P = 0.56; FF -0.1%, P = 0.66) within either phase. In contrast to findings in animals, NFF was more, rather than less satiating than FF, and use of neither NFF nor FF preparations was associated with body weight or fat loss. These pilot results suggest no role for short-term use of FF and NFF supplements in promoting weight loss in humans consuming a diet ad libitum.