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1.  Modifiable early-life risk factors for childhood adiposity and overweight: an analysis of their combined impact and potential for prevention1234 
Background: Early life may be a “critical period” when appetite and regulation of energy balance are programmed, with lifelong consequences for obesity risk. Insight into the potential impact of modifying early-life risk factors on later obesity can be gained by evaluating their combined effects.
Objective: The objective was to examine the relation between the number of early-life risk factors and obesity outcomes among children in a prospective birth cohort (Southampton Women's Survey).
Design: Five risk factors were defined: maternal obesity [prepregnant body mass index (BMI; in kg/m2) >30], excess gestational weight gain (Institute of Medicine, 2009), smoking during pregnancy, low maternal vitamin D status (<64 nmol/L), and short duration of breastfeeding (none or <1 mo). Obesity outcomes examined when the children were aged 4 and 6 y were BMI, dual-energy X-ray absorptiometry–assessed fat mass, overweight, or obesity (International Obesity Task Force). Data were available for 991 mother-child pairs, with children born between 1998 and 2003.
Results: Of the children, 148 (15%) had no early-life risk factors, 330 (33%) had 1, 296 (30%) had 2, 160 (16%) had 3, and 57 (6%) had 4 or 5. At both 4 and 6 y, there were positive graded associations between number of early-life risk factors and each obesity outcome (all P < 0.001). After taking account of confounders, the relative risk of being overweight or obese for children who had 4 or 5 risk factors was 3.99 (95% CI: 1.83, 8.67) at 4 y and 4.65 (95% CI: 2.29, 9.43) at 6 y compared with children who had none (both P < 0.001).
Conclusions: Having a greater number of early-life risk factors was associated with large differences in adiposity and risk of overweight and obesity in later childhood. These findings suggest that early intervention to change these modifiable risk factors could make a significant contribution to the prevention of childhood obesity.
PMCID: PMC4307207  PMID: 25646335
adiposity; childhood obesity; early life; obesity; lifecourse; prevention
2.  The association between MTHFR 677C>T genotype and folate status and genomic and gene-specific DNA methylation in the colon of individuals without colorectal neoplasia1234 
Background: Decreased genomic and increased gene-specific DNA methylation predispose to colorectal cancer. Dietary folate intake and the methylenetetrahydrofolate reductase polymorphism (MTHFR 677C>T) may influence risk by modifying DNA methylation.
Objective: We investigated the associations between MTHFR 677C>T genotype, folate status, and DNA methylation in the colon.
Design: We conducted a cross-sectional study of 336 men and women (age 19–92 y) in the United Kingdom without colorectal neoplasia. We obtained blood samples for measurement of serum and red blood cell folate, plasma homocysteine, and MTHFR 677C>T genotype and colonic tissue biopsies for measurement of colonic tissue folate and DNA methylation (genomic- and gene-specific, estrogen receptor 1, ESR1; myoblast determination protein 1, MYOD1; insulin-like growth factor II, IGF2; tumor suppressor candidate 33, N33; adenomatous polyposis coli, APC; mut-L homolog 1, MLH1; and O6-methylguanine-DNA methyltransferase, MGMT) by liquid chromatography/electrospray ionization mass spectrometry and pyrosequencing, respectively.
Results: Of the 336 subjects recruited, 185 (55%) carried the CC, 119 (35%) the CT, and 32 (10%) the TT alleles. No significant differences in systemic markers of folate status and colonic tissue folate between genotypes were found. The MTHFR TT genotype was not associated with genomic or gene-specific DNA methylation. Biomarkers of folate status were not associated with genomic DNA methylation. Relations between biomarkers of folate status and gene-specific methylation were inconsistent. However, low serum folate was associated with high MGMT methylation (P = 0.001).
Conclusion: MTHFR 677C>T genotype and folate status were generally not associated with DNA methylation in the colon of a folate-replete population without neoplasia. This trial was registered at as ISRCTN43577261.
PMCID: PMC3831541  PMID: 24108782
3.  Postinfancy growth, schooling, and cognitive achievement: Young Lives1234 
Background: Early life growth failure and resulting cognitive deficits are often assumed to be very difficult to reverse after infancy.
Objective: We used data from Young Lives, which is an observational cohort of 8062 children in Ethiopia, India, Peru, and Vietnam, to determine whether changes in growth after infancy are associated with schooling and cognitive achievement at age 8 y.
Design: We represented the growth by height-for-age z score at 1 y [HAZ(1)] and height-for-age z score at 8 y that was not predicted by the HAZ(1). We also characterized growth as recovered (stunted at age 1 y and not at age 8 y), faltered (not stunted at age 1 y and stunted at age 8 y), persistently stunted (stunted at ages 1 and 8 y), or never stunted (not stunted at ages 1 and 8 y). Outcome measures were assessed at age 8 y.
Results: The HAZ(1) was inversely associated with overage for grade and positively associated with mathematics achievement, reading comprehension, and receptive vocabulary. Unpredicted growth from 1 to 8 y of age was also inversely associated with overage for grade (OR range across countries: 0.80–0.84) and positively associated with mathematics achievement (effect-size range: 0.05–0.10), reading comprehension (0.02–0.10), and receptive vocabulary (0.04–0.08). Children who recovered in linear growth had better outcomes than did children who were persistently stunted but were not generally different from children who experienced growth faltering.
Conclusions: Improvements in child growth after early faltering might have significant benefits on schooling and cognitive achievement. Hence, although early interventions remain critical, interventions to improve the nutrition of preprimary and early primary school–age children also merit consideration.
PMCID: PMC3831540  PMID: 24067665
4.  Variation in the SLC23A1 gene does not influence cardiometabolic outcomes to the extent expected given its association with l-ascorbic acid1234 
Background: Observational studies showed that circulating l-ascorbic acid (vitamin C) is inversely associated with cardiometabolic traits. However, these studies were susceptible to confounding and reverse causation.
Objectives: We assessed the relation between l-ascorbic acid and 10 cardiometabolic traits by using a single nucleotide polymorphism in the solute carrier family 23 member 1 (SLC23A1) gene (rs33972313) associated with circulating l-ascorbic acid concentrations. The observed association between rs33972313 and cardiometabolic outcomes was compared with that expected given the rs33972313-l-ascorbic acid and l-ascorbic acid–outcome associations.
Design: A meta-analysis was performed in the following 5 independent studies: the British Women's Heart and Health Study (n = 1833), the MIDSPAN study (n = 1138), the Ten Towns study (n = 1324), the British Regional Heart Study (n = 2521), and the European Prospective Investigation into Cancer (n = 3737).
Results: With the use of a meta-analysis of observational estimates, inverse associations were shown between l-ascorbic acid and systolic blood pressure, triglycerides, and the waist-hip ratio [the strongest of which was the waist-hip ratio (−0.13-SD change; 95% CI: −0.20-, −0.07-SD change; P = 0.0001) per SD increase in l-ascorbic acid], and a positive association was shown with high-density lipoprotein (HDL) cholesterol. The variation at rs33972313 was associated with a 0.18-SD (95% CI: 0.10-, 0.25-SD; P = 3.34 × 10−6) increase in l-ascorbic acid per effect allele. There was no evidence of a relation between the variation at rs33972313 and any cardiometabolic outcome. Although observed estimates were not statistically different from expected associations between rs33972313 and cardiometabolic outcomes, estimates for low-density lipoprotein cholesterol, HDL cholesterol, triglycerides, glucose, and body mass index were in the opposite direction to those expected.
Conclusions: The nature of the genetic association exploited in this study led to limited statistical application, but despite this, when all cardiometabolic traits were assessed, there was no evidence of any trend supporting a protective role of l-ascorbic acid. In the context of existing work, these results add to the suggestion that observational relations between l-ascorbic acid and cardiometabolic health may be attributable to confounding and reverse causation.
PMCID: PMC4266888  PMID: 25527764
l-ascorbic acid; cardiometabolic traits; confounding; genetic variants; reverse causation
5.  Rice consumption and risk of cardiovascular disease: results from a pooled analysis of 3 U.S. cohorts1234 
Background: Health concerns have been raised about rice consumption, which may significantly contribute to arsenic exposure. However, little is known regarding whether habitual rice consumption is associated with cardiovascular disease (CVD) risk.
Objective: We examined prospectively the association of white rice and brown rice consumption with CVD risk.
Design: We followed a total of 207,556 women and men [73,228 women from the Nurses’ Health Study (1984–2010), 92,158 women from the Nurses’ Health Study II (1991–2011), and 42,170 men from the Health Professionals Follow-Up Study (1986–2010)] who were free of CVD and cancer at baseline. Validated semiquantitative food-frequency questionnaires were used to assess consumption of white rice, brown rice, and other food items. Fatal and nonfatal CVD (coronary artery disease and stroke) was confirmed by medical records or self-reports.
Results: During 4,393,130 person-years of follow-up, 12,391 cases of CVD were identified. After adjustment for major CVD risk factors, including demographics, lifestyle, and other dietary intakes, rice consumption was not associated with CVD risk. The multivariable-adjuted HR of developing CVD comparing ≥5 servings/wk with <1 serving/wk was 0.98 (95% CI: 0.84, 1.14) for white rice, 1.01 (0.79, 1.28) for brown rice, and 0.99 (0.90, 1.08) for total rice. To minimize the potential impact of racial difference in rice consumption, we restricted the analyses to whites only and obtained similar results: the HRs of CVD for ≥5 servings/wk compared with <1 serving/wk were 1.04 (95% CI: 0.88, 1.22) for white rice and 1.01 (0.78, 1.31) for brown rice.
Conclusions: Greater habitual consumption of white rice or brown rice is not associated with CVD risk. These findings suggest that rice consumption may not pose a significant CVD risk among the U.S. population when consumed at current amounts. More prospective studies are needed to explore these associations in other populations.
PMCID: PMC4266886  PMID: 25527760
cardiovascular disease; coronary artery disease; longitudinal study; rice; stroke
6.  Effect of mastication on lipid bioaccessibility of almonds in a randomized human study and its implications for digestion kinetics, metabolizable energy, and postprandial lipemia1234 
Background: The particle size and structure of masticated almonds have a significant impact on nutrient release (bioaccessibility) and digestion kinetics.
Objectives: The goals of this study were to quantify the effects of mastication on the bioaccessibility of intracellular lipid of almond tissue and examine microstructural characteristics of masticated almonds.
Design: In a randomized, subject-blind, crossover trial, 17 healthy subjects chewed natural almonds (NAs) or roasted almonds (RAs) in 4 separate mastication sessions. Particle size distributions (PSDs) of the expectorated boluses were measured by using mechanical sieving and laser diffraction (primary outcome). The microstructure of masticated almonds, including the structural integrity of the cell walls (i.e., dietary fiber), was examined with microscopy. Lipid bioaccessibility was predicted by using a theoretical model, based on almond particle size and cell dimensions, and then compared with empirically derived release data.
Results: Intersubject variations (n = 15; 2 subjects withdrew) in PSDs of both NA and RA samples were small (e.g., laser diffraction; CV: 12% and 9%, respectively). Significant differences in PSDs were found between these 2 almond forms (P < 0.05). A small proportion of lipid was released from ruptured cells on fractured surfaces of masticated particles, as predicted by using the mathematical model (8.5% and 11.3% for NAs and RAs, respectively). This low percentage of lipid bioaccessibility is attributable to the high proportion (35–40%) of large particles (>500 μm) in masticated almonds. Microstructural examination of the almonds indicated that most intracellular lipid remained undisturbed in intact cells after mastication. No adverse events were recorded.
Conclusions: Following mastication, most of the almond cells remained intact with lipid encapsulated by cell walls. Thus, most of the lipid in masticated almonds is not immediately bioaccessible and remains unavailable for early stages of digestion. The lipid encapsulation mechanism provides a convincing explanation for why almonds have a low metabolizable energy content and an attenuated impact on postprandial lipemia. This trial was registered at as ISRCTN58438021.
PMCID: PMC4266890  PMID: 25527747
almonds; lipid bioaccessibility; mastication; mathematical model; microstructure
7.  Adult consequences of growth failure in early childhood123 
Background: Growth failure is associated with adverse consequences, but studies need to control adequately for confounding.
Objective: We related height-for-age z scores (HAZs) and stunting at age 24 mo to adult human capital, marriage, fertility, health, and economic outcomes.
Design: In 2002–2004, we collected data from 1338 Guatemalan adults (aged 25–42 y) who were studied as children in 1969–1977. We used instrumental variable regression to correct for estimation bias and adjusted for potentially confounding factors.
Results: A 1-SD increase in HAZ was associated with more schooling (0.78 grades) and higher test scores for reading and nonverbal cognitive skills (0.28 and 0.25 SDs, respectively), characteristics of marriage partners (1.39 y older, 1.02 grade more schooling, and 1.01 cm taller) and, for women, a higher age at first birth (0.77 y) and fewer number of pregnancies and children (0.63 and 0.43, respectively). A 1-SD increase in HAZ was associated with increased household per capita expenditure (21%) and a lower probability of living in poverty (10 percentage points). Conversely, being stunted at 2 y was associated with less schooling, a lower test performance, a lower household per capita expenditure, and an increased probability of living in poverty. For women, stunting was associated with a lower age at first birth and higher number of pregnancies and children. There was little relation between either HAZ or stunting and adult health.
Conclusion: Growth failure in early life has profound adverse consequences over the life course on human, social, and economic capital.
PMCID: PMC3798075  PMID: 24004889
8.  Heritability of objectively assessed daily physical activity and sedentary behavior1234 
Background: Twin and family studies that estimated the heritability of daily physical activity have been limited by poor measurement quality and a small sample size.
Objective: We examined the heritability of daily physical activity and sedentary behavior assessed objectively by using combined heart rate and movement sensing in a large twin study.
Design: Physical activity traits were assessed in daily life for a mean (±SD) 6.7 ± 1.1 d in 1654 twins from 420 monozygotic and 352 dizygotic same-sex twin pairs aged 56.3 ± 10.4 y with body mass index (in kg/m2) of 26.1 ± 4.8. We estimated the average daily movement, physical activity energy expenditure, and time spent in moderate-to-vigorous intensity physical activity and sedentary behavior from heart rate and acceleration data. We used structural equation modeling to examine the contribution of additive genetic, shared environmental, and unique environmental factors to between-individual variation in traits.
Results: Additive genetic factors (ie, heritability) explained 47% of the variance in physical activity energy expenditure (95% CI: 23%, 53%) and time spent in moderate-to-vigorous intensity physical activity (95% CI: 29%, 54%), 35% of the variance in acceleration of the trunk (95% CI: 0%, 44%), and 31% of the variance in the time spent in sedentary behavior (95% CI: 9%, 51%). The remaining variance was predominantly explained by unique environmental factors and random error, whereas shared environmental factors played only a marginal role for all traits with a range of 0–15%.
Conclusions: The between-individual variation in daily physical activity and sedentary behavior is mainly a result of environmental influences. Nevertheless, genetic factors explain up to one-half of the variance, suggesting that innate biological processes may be driving some of our daily physical activity.
PMCID: PMC3798083  PMID: 24047914
9.  Dietary intake of young twins: nature or nurture?123 
Background: The early years in life are increasingly recognized as a critical period for the development of diet-related behavioral traits. However, discussions continue on the relative role of genes and the environment in determining dietary intake, particularly in young children for whom detailed dietary information is limited.
Objectives: This study tested the hypothesis that diet in early childhood is primarily determined by the environment rather than by genes. A secondary aim was to characterize the early childhood diet.
Design: A classic twin design used 3-d dietary data collected at age 21 mo from the Gemini cohort. From the full sample of 2402 families with twins, dietary diaries were available for 1216 twin pairs (384 monozygotic and 832 dizygotic pairs) after exclusions. Intakes of macronutrients, food, and beverages were estimated. Twin analyses quantified the contributions of genetic and environmental factors to population variation in intake.
Results: At age 21 mo, children consumed small portions of a wide range of family foods. The shared environment was the predominant determinant, contributing between 66% (95% CI: 52%, 77%; milk-based desserts) and 97% (95% CI: 95%, 98%; juice) of the variation in intake. Genetic factors were estimated to account for between 4% (95% CI: 0%, 10%; savory snacks) and 18% (95% CI: 14%, 23%; bread) of dietary intake variation.
Conclusion: Shared environmental influences are the predominant drivers of dietary intake in very young children, indicating the importance of factors such as the home food environment and parental behaviors.
PMCID: PMC3798084  PMID: 24047917
10.  Biofortified orange maize is as efficacious as a vitamin A supplement in Zambian children even in the presence of high liver reserves of vitamin A: a community-based, randomized placebo-controlled trial123456 
Background: Biofortification is a strategy to relieve vitamin A (VA) deficiency. Biofortified maize contains enhanced provitamin A concentrations and has been bioefficacious in animal and small human studies.
Objective: The study sought to determine changes in total body reserves (TBRs) of vitamin A with consumption of biofortified maize.
Design: A randomized, placebo-controlled biofortified maize efficacy trial was conducted in 140 rural Zambian children. The paired 13C-retinol isotope dilution test, a sensitive biomarker for VA status, was used to measure TBRs before and after a 90-d intervention. Treatments were white maize with placebo oil (VA−), orange maize with placebo (orange), and white maize with VA in oil [400 μg retinol activity equivalents (RAEs) in 214 μL daily] (VA+).
Results: In total, 133 children completed the trial and were analyzed for TBRs (n = 44 or 45/group). Change in TBR residuals were not normally distributed (P < 0.0001); median changes (95% CI) were as follows: VA−, 13 (−19, 44) μmol; orange, 84 (21, 146) μmol; and VA+, 98 (24, 171) μmol. Nonparametric analysis showed no statistical difference between VA+ and orange (P = 0.34); both were higher than VA− (P = 0.0034). Median (95% CI) calculated liver reserves at baseline were 1.04 (0.97, 1.12) μmol/g liver, with 59% >1 μmol/g, the subtoxicity cutoff; none were <0.1 μmol/g, the deficiency cutoff. The calculated bioconversion factor was 10.4 μg β-carotene equivalents/1 μg retinol by using the middle 3 quintiles of change in TBRs from each group. Serum retinol did not change in response to intervention (P = 0.16) but was reduced with elevated C-reactive protein (P = 0.0029) and α-1-acid glycoprotein (P = 0.0023) at baseline.
Conclusions: β-Carotene from maize was efficacious when consumed as a staple food in this population and could avoid the potential for hypervitaminosis A that was observed with the use of preformed VA from supplementation and fortification. Use of more sensitive methods other than serum retinol alone, such as isotope dilution, is required to accurately assess VA status, evaluate interventions, and investigate the interaction of VA status and infection. This trial was registered at as NCT01814891.
PMCID: PMC4232019  PMID: 25411289
13C-retinol dilution; Zambia; biofortified maize; plant carotenoids; retinol
11.  Improving women's diet quality preconceptionally and during gestation: effects on birth weight and prevalence of low birth weight—a randomized controlled efficacy trial in India (Mumbai Maternal Nutrition Project)12345 
Background: Low birth weight (LBW) is an important public health problem in undernourished populations.
Objective: We tested whether improving women's dietary micronutrient quality before conception and throughout pregnancy increases birth weight in a high-risk Indian population.
Design: The study was a nonblinded, individually randomized controlled trial. The intervention was a daily snack made from green leafy vegetables, fruit, and milk (treatment group) or low-micronutrient vegetables (potato and onion) (control group) from ≥90 d before pregnancy until delivery in addition to the usual diet. Treatment snacks contained 0.69 MJ of energy (controls: 0.37 MJ) and 10–23% of WHO Reference Nutrient Intakes of β-carotene, riboflavin, folate, vitamin B-12, calcium, and iron (controls: 0–7%). The primary outcome was birth weight.
Results: Of 6513 women randomly assigned, 2291 women became pregnant, 1962 women delivered live singleton newborns, and 1360 newborns were measured. In an intention-to-treat analysis, there was no overall increase in birth weight in the treatment group (+26 g; 95% CI: −15, 68 g; P = 0.22). There was an interaction (P < 0.001) between the allocation group and maternal prepregnant body mass index (BMI; in kg/m2) [birth-weight effect: −23, +34, and +96 g in lowest (<18.6), middle (18.6–21.8), and highest (>21.8) thirds of BMI, respectively]. In 1094 newborns whose mothers started supplementation ≥90 d before pregnancy (per-protocol analysis), birth weight was higher in the treatment group (+48 g; 95% CI: 1, 96 g; P = 0.046). Again, the effect increased with maternal BMI (−8, +79, and +113 g; P-interaction = 0.001). There were similar results for LBW (intention-to-treat OR: 0.83; 95% CI: 0.66, 1.05; P = 0.10; per-protocol OR = 0.76; 95% CI: 0.59, 0.98; P = 0.03) but no effect on gestational age in either analysis.
Conclusions: A daily snack providing additional green leafy vegetables, fruit, and milk before conception and throughout pregnancy had no overall effect on birth weight. Per-protocol and subgroup analyses indicated a possible increase in birth weight if the mother was supplemented ≥3 mo before conception and was not underweight. This trial was registered at as ISRCTN62811278.
PMCID: PMC4196482  PMID: 25332324
12.  Serum 25-hydroxyvitamin D, mortality, and incident cardiovascular disease, respiratory disease, cancers, and fractures: a 13-y prospective population study1234 
Background: Vitamin D is associated with many health conditions, but optimal blood concentrations are still uncertain.
Objectives: We examined the prospective relation between serum 25-hydroxyvitamin D [25(OH)D] concentrations [which comprised 25(OH)D3 and 25(OH)D2] and subsequent mortality by the cause and incident diseases in a prospective population study.
Design: Serum vitamin D concentrations were measured in 14,641 men and women aged 42–82 y in 1997–2000 who were living in Norfolk, United Kingdom, and were followed up to 2012. Participants were categorized into 5 groups according to baseline serum concentrations of total 25(OH)D <30, 30 to <50, 50 to <70, 70 to <90, and ≥90 nmol/L.
Results: The mean serum total 25(OH)D was 56.6 nmol/L, which consisted predominantly of 25(OH)D3 (mean: 56.2 nmol/L; 99% of total). The age-, sex-, and month-adjusted HRs (95% CIs) for all-cause mortality (2776 deaths) for men and women by increasing vitamin D category were 1, 0.84 (0.74, 0.94), 0.72 (0.63, 0.81), 0.71 (0.62, 0.82), and 0.66 (0.55, 0.79) (P-trend < 0.0001). When analyzed as a continuous variable and with additional adjustment for body mass index, smoking, social class, education, physical activity, alcohol intake, plasma vitamin C, history of cardiovascular disease, diabetes, or cancer, HRs for a 20-nmol/L increase in 25(OH)D were 0.92 (0.88, 0.96) (P < 0.001) for total mortality, 0.96 (0.93, 0.99) (P = 0.014) (4469 events) for cardiovascular disease, 0.89 (0.85, 0.93) (P < 0.0001) (2132 events) for respiratory disease, 0.89 (0.81, 0.98) (P = 0.012) (563 events) for fractures, and 1.02 (0.99, 1.06) (P = 0.21) (3121 events) for incident total cancers.
Conclusions: Plasma 25(OH)D concentrations predict subsequent lower 13-y total mortality and incident cardiovascular disease, respiratory disease, and fractures but not total incident cancers. For mortality, lowest risks were in subjects with concentrations >90 nmol/L, and there was no evidence of increased mortality at high concentrations, suggesting that a moderate increase in population mean concentrations may have potential health benefit, but <1% of the population had concentrations >120 nmol/L.
PMCID: PMC4196486  PMID: 25332334
13.  Intake of dietary flavonoids and risk of epithelial ovarian cancer1234 
Background: The impact of different dietary flavonoid subclasses on risk of epithelial ovarian cancer is unclear, with limited previous studies that have focused on only a few compounds.
Objective: We prospectively examined associations between habitual flavonoid subclass intake and risk of ovarian cancer.
Design: We followed 171,940 Nurses’ Health Study and Nurses’ Health Study II participants to examine associations between intakes of total flavonoids and their subclasses (flavanones, flavonols, anthocyanins, flavan-3-ols, flavones, and polymeric flavonoids) and risk of ovarian cancer by using Cox proportional hazards models. Intake was calculated from validated food-frequency questionnaires collected every 4 y.
Results: During 16–22 y of follow-up, 723 cases of ovarian cancer were confirmed through medical records. In pooled multivariate-adjusted analyses, total flavonoids were not statistically significantly associated with ovarian cancer risk (HR for the top compared with the bottom quintile: 0.85; 95% CI: 0.66, 1.09; P-trend = 0.17). However, participants in the highest quintiles of flavonol and flavanone intakes had modestly lower risk of ovarian cancer than did participants in the lowest quintile, although the P-trend was not significant [HRs: 0.76 (95% CI: 0.59, 0.98; P-trend = 0.11) and 0.79 (95% CI: 0.63,1.00; P-trend = 0.26), respectively]. The association for flavanone intake was stronger for serous invasive and poorly differentiated tumors (comparable HR: 0.68; 95% CI: 0.50, 0.92; P-heterogeneity = 0.10, P-trend = 0.07) compared with nonserous and less-aggressive tumors. Intakes of other subclasses were not significantly associated with risk. In food-based analyses used to compare subjects who consumed >1 and ≤1 cup black tea/d, the HR was 0.68 (95% CI: 0.51, 0.90; P < 0.01).
Conclusions: Higher intakes of flavonols and flavanones as well as black tea consumption may be associated with lower risk of ovarian cancer. Additional prospective studies are required to confirm these findings.
PMCID: PMC4196485  PMID: 25332332
14.  Zinc deficiency in children with environmental enteropathy—development of new strategies: report from an expert workshop1234 
Zinc deficiency is a major cause of childhood morbidity and mortality. The WHO/UNICEF strategy for zinc supplementation as adjunctive therapy for diarrhea is poorly implemented. A conference of experts in zinc nutrition and gastrointestinal disorders was convened to consider approaches that might complement the current recommendation and what research was needed to develop these approaches. Several key points were identified. The design of novel zinc interventions would be facilitated by a better understanding of how disturbed gut function, such as environmental (or tropical) enteropathy, affects zinc absorption, losses, and homeostasis. Because only 10% of zinc stores are able to be rapidly turned over, and appear to be rapidly depleted by acute intestinal illness, they are probably best maintained by complementary regular supplementation in a primary prevention strategy rather than secondary prevention triggered by acute diarrhea. The assessment of zinc status is challenging and complex without simple, validated measures to facilitate field testing of novel interventions. Zinc bioavailability may be a crucial factor in the success of primary prevention strategies, and a range of options, all still inadequately explored, might be valuable in improving zinc nutrition. Some therapeutic actions of zinc on diarrhea seem attributable to pharmacologic effects, whereas others are related to the reversal of deficiency (ie, nutritional). The distinction between these 2 mechanisms cannot be clarified given the insensitivity of serum zinc to identify subclinical deficiency states. Why zinc seems to be less effective than expected at all ages, and ineffective for secondary prevention of diarrhea in children <12 mo of age, remains unclear. It was concluded that a reframing of the current recommendation is warranted with consideration of how to better optimize and deliver zinc and whether to provide a complementary public health primary prevention zinc strategy. This requires careful consideration of the zinc product to be used as well as strategies for its delivery.
PMCID: PMC4163797  PMID: 25240082
15.  Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis1234 
Background: Concerns have been raised about the concurrent temporal trend between simple sugar intakes, especially of fructose or high-fructose corn syrup (HFCS), and rates of nonalcoholic fatty liver disease (NAFLD) in the United States.
Objective: We examined the effect of different amounts and forms of dietary fructose on the incidence or prevalence of NAFLD and indexes of liver health in humans.
Design: We conducted a systematic review of English-language, human studies of any design in children and adults with low to no alcohol intake and that reported at least one predetermined measure of liver health. The strength of the evidence was evaluated by considering risk of bias, consistency, directness, and precision.
Results: Six observational studies and 21 intervention studies met the inclusion criteria. The overall strength of evidence for observational studies was rated insufficient because of high risk of biases and inconsistent study findings. Of 21 intervention studies, 19 studies were in adults without NAFLD (predominantly healthy, young men) and 1 study each in adults or children with NAFLD. We found a low level of evidence that a hypercaloric fructose diet (supplemented by pure fructose) increases liver fat and aspartate aminotransferase (AST) concentrations in healthy men compared with the consumption of a weight-maintenance diet. In addition, there was a low level of evidence that hypercaloric fructose and glucose diets have similar effects on liver fat and liver enzymes in healthy adults. There was insufficient evidence to draw a conclusion for effects of HFCS or sucrose on NAFLD.
Conclusions: On the basis of indirect comparisons across study findings, the apparent association between indexes of liver health (ie, liver fat, hepatic de novo lipogenesis, alanine aminotransferase, AST, and γ-glutamyl transpeptase) and fructose or sucrose intake appear to be confounded by excessive energy intake. Overall, the available evidence is not sufficiently robust to draw conclusions regarding effects of fructose, HFCS, or sucrose consumption on NAFLD.
PMCID: PMC4135494  PMID: 25099546
16.  High-fat meals rich in EPA plus DHA compared with DHA only have differential effects on postprandial lipemia and plasma 8-isoprostane F2α concentrations relative to a control high–oleic acid meal: a randomized controlled trial1234 
Background: Eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) supplementation has beneficial cardiovascular effects, but postprandial influences of these individual fatty acids are unclear.
Objectives: The primary objective was to determine the vascular effects of EPA + DHA compared with DHA only during postprandial lipemia relative to control high–oleic acid meals; the secondary objective was to characterize the effects of linoleic acid–enriched high-fat meals relative to the control meal.
Design: We conducted a randomized, controlled, double-blind crossover trial of 4 high-fat (75-g) meals containing 1) high–oleic acid sunflower oil (HOS; control), 2) HOS + fish oil (FO; 5 g EPA and DHA), 3) HOS + algal oil (AO; 5 g DHA), and 4) high–linoleic acid sunflower oil (HLS) in 16 healthy men (aged 35–70 y) with higher than optimal fasting triacylglycerol concentrations (mean ± SD triacylglycerol, 1.9 ± 0.5 mmol/L).
Results: Elevations in triacylglycerol concentration relative to baseline were slightly reduced after FO and HLS compared with the HOS control (P < 0.05). The characteristic decrease from baseline in plasma nonesterified fatty acids after a mixed meal was inhibited after AO (Δ 0–3 h, P < 0.05). HLS increased the augmentation index compared with the other test meals (P < 0.05), although the digital volume pulse–reflection index was not significantly different. Plasma 8-isoprostane F2α analysis revealed opposing effects of FO (increased) and AO (reduced) compared with the control (P < 0.05). No differences in nitric oxide metabolites were observed.
Conclusions: These data show differential postprandial 8-isoprostane F2α responses to high-fat meals containing EPA + DHA–rich fish oil compared with DHA-rich AO, but these differences were not associated with consistent effects on postprandial vascular function or lipemia. More detailed analyses of polyunsaturated fatty acid–derived lipid mediators are required to determine possible divergent functional effects of single meals rich in either DHA or EPA. This trial was registered at as NCT01618071.
PMCID: PMC4163792  PMID: 25099540
17.  Prospective associations between sugar-sweetened beverage intakes and cardiometabolic risk factors in adolescents123 
Background: High sugar-sweetened beverage (SSB) consumption is associated with cardiometabolic disturbances in adults, but this relation is relatively unexplored in children and adolescents.
Objective: We tested the hypothesis that higher SSB intakes are associated with increases in cardiometabolic risk factors between 14 and 17 y of age.
Design: Data were provided by 1433 adolescent offspring from the Western Australian Pregnancy Cohort (Raine) Study. At 14 and 17 y of age, SSB intakes were estimated by using a food-frequency questionnaire; body mass index (BMI), waist circumference, blood pressure, fasting serum lipids, glucose, and insulin were measured, and overall cardiometabolic risk was estimated. Prospective associations between cardiovascular disease risk factors and SSB intake were examined with adjustment for age, pubertal stage, physical fitness, socioeconomic status, and major dietary patterns.
Results: The average SSB intake in consumers (89%) was 335 g/d or 1.3 servings/d. Girls who moved into the top tertile of SSB consumption (>1.3 servings/d) between 14 and 17 y of age had increases in BMI (3.8%; 95% CI: 1.8%, 5.7%), increased overweight and obesity risk (OR: 4.8, 95% CI: 2.1, 11.4), and greater overall cardiometabolic risk (OR: 3.2; 95% CI: 1.6, 6.2) (all P-trend ≤ 0.001). Girls and boys who moved into the top tertile of SSB intake showed increases in triglycerides (7.0–8.4%; P-trend ≤ 0.03), and boys showed reductions in HDL cholesterol (−3.1%; 95% CI: −6.2%, 0.1%; P-trend < 0.04) independent of BMI. Some associations were attenuated after adjustment for major dietary patterns.
Conclusion: Increased SSB intake may be an important predictor of cardiometabolic risk in young people, independent of weight status.
PMCID: PMC3712546  PMID: 23719557
18.  Accuracy of prediction equations for serum osmolarity in frail older people with and without diabetes1234 
Background: Serum osmolality is an accurate indicator of hydration status in older adults. Glucose, urea, and electrolyte concentrations are used to calculate serum osmolarity, which is an indirect estimate of serum osmolality, but which serum osmolarity equations best predict serum osmolality in the elderly is unclear.
Objective: We assessed the agreement of measured serum osmolality with calculated serum osmolarity equations in older people.
Design: Serum osmolality was measured by using freezing point depression in a cross-sectional study. Plasma glucose, urea, and electrolytes were analyzed and entered into 38 serum osmolarity-prediction equations. The Bland-Altman method was used to evaluate the agreement and differential bias between measured osmolality and calculated osmolarity. The sensitivity and specificity of the most-promising equations were examined against serum osmolality (reference standard).
Results: A total of 186 people living in UK residential care took part in the Dehydration Recognition In our Elders study (66% women; mean ± SD age: 85.8 ± 7.9 y; with a range of cognitive and physical impairments) and were included in analyses. Forty-six percent of participants had impending or current dehydration (serum osmolality ≥295 mmol/kg). Participants with diabetes (n = 33; 18%) had higher glucose (P < 0.001) and serum osmolality (P < 0.01). Of 38 predictive equations used to calculate osmolarity, 4 equations showed reasonable agreement with measured osmolality. One [calculated osmolarity = 1.86 × (Na+ + K+) + 1.15 × glucose + urea +14; all in mmol/L] was characterized by narrower limits of agreement and the capacity to predict serum osmolality within 2% in >80% of participants, regardless of diabetes or hydration status. The equation's sensitivity (79%) and specificity (89%) for impending dehydration (≥295 mmol/kg) and current dehydration (>300 mmol/kg) (69% and 93%, respectively) were reasonable.
Conclusions: The assessment of a panel of equations for the prediction of serum osmolarity led to identification of one formula with a greater diagnostic performance. This equation may be used to predict hydration status in frail older people (as a first-stage screening) or to estimate hydration status in population studies. This trial was registered at the Research Register for Social Care ( as 122273.
PMCID: PMC4135495  PMID: 25030781
19.  Serum carbon and nitrogen stable isotopes as potential biomarkers of dietary intake and their relation with incident type 2 diabetes: the EPIC-Norfolk study123 
Background: Stable-isotope ratios of carbon (13C/12C, expressed as δ13C) and nitrogen (15N/14N, or δ15N) have been proposed as potential nutritional biomarkers to distinguish between meat, fish, and plant-based foods.
Objective: The objective was to investigate dietary correlates of δ13C and δ15N and examine the association of these biomarkers with incident type 2 diabetes in a prospective study.
Design: Serum δ13C and δ15N (‰) were measured by using isotope ratio mass spectrometry in a case-cohort study (n = 476 diabetes cases; n = 718 subcohort) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)–Norfolk population-based cohort. We examined dietary (food-frequency questionnaire) correlates of δ13C and δ15N in the subcohort. HRs and 95% CIs were estimated by using Prentice-weighted Cox regression.
Results: Mean (±SD) δ13C and δ15N were −22.8 ± 0.4‰ and 10.2 ± 0.4‰, respectively, and δ13C (r = 0.22) and δ15N (r = 0.20) were positively correlated (P < 0.001) with fish protein intake. Animal protein was not correlated with δ13C but was significantly correlated with δ15N (dairy protein: r = 0.11; meat protein: r = 0.09; terrestrial animal protein: r = 0.12, P ≤ 0.013). δ13C was inversely associated with diabetes in adjusted analyses (HR per tertile: 0.74; 95% CI: 0.65, 0.83; P-trend < 0.001], whereas δ15N was positively associated (HR: 1.23; 95% CI: 1.09, 1.38; P-trend = 0.001).
Conclusions: The isotope ratios δ13C and δ15N may both serve as potential biomarkers of fish protein intake, whereas only δ15N may reflect broader animal-source protein intake in a European population. The inverse association of δ13C but a positive association of δ15N with incident diabetes should be interpreted in the light of knowledge of dietary intake and may assist in identifying dietary components that are associated with health risks and benefits.
PMCID: PMC4095667  PMID: 24990425
20.  Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals12345 
Background: Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain.
Objective: The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging.
Design: A meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE)–type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals).
Results: The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean ± SE: −0.054 ± 0.004 and −0.036 ± 0.001/y, respectively). Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: −0.05, 0.06). Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: −0.01; 95% CI: −0.03, 0.02). Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: −0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment.
Conclusion: Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.
PMCID: PMC4095663  PMID: 24965307
21.  Folic acid handling by the human gut: implications for food fortification and supplementation123 
Background: Current thinking, which is based mainly on rodent studies, is that physiologic doses of folic acid (pterylmonoglutamic acid), such as dietary vitamin folates, are biotransformed in the intestinal mucosa and transferred to the portal vein as the natural circulating plasma folate, 5-methyltetrahydrofolic acid (5-MTHF) before entering the liver and the wider systemic blood supply.
Objective: We tested the assumption that, in humans, folic acid is biotransformed (reduced and methylated) to 5-MTHF in the intestinal mucosa.
Design: We conducted a crossover study in which we sampled portal and peripheral veins for labeled folate concentrations after oral ingestion with physiologic doses of stable-isotope–labeled folic acid or the reduced folate 5-formyltetrahydrofolic acid (5-FormylTHF) in 6 subjects with a transjugular intrahepatic porto systemic shunt (TIPSS) in situ. The TIPSS allowed blood samples to be taken from the portal vein.
Results: Fifteen minutes after a dose of folic acid, 80 ± 12% of labeled folate in the hepatic portal vein was unmodified folic acid. In contrast, after a dose of labeled 5-FormylTHF, only 4 ± 18% of labeled folate in the portal vein was unmodified 5-FormylTHF, and the rest had been converted to 5-MTHF after 15 min (postdose).
Conclusions: The human gut appears to have a very efficient capacity to convert reduced dietary folates to 5-MTHF but limited ability to reduce folic acid. Therefore, large amounts of unmodified folic acid in the portal vein are probably attributable to an extremely limited mucosal cell dihydrofolate reductase (DHFR) capacity that is necessary to produce tetrahydrofolic acid before sequential methylation to 5-MTHF. This process would suggest that humans are reliant on the liver for folic acid reduction even though it has a low and highly variable DHFR activity. Therefore, chronic liver exposure to folic acid in humans may induce saturation, which would possibly explain reports of systemic circulation of unmetabolized folic acid. This trial was registered at as NCT02135393.
PMCID: PMC4095662  PMID: 24944062
22.  Low-calorie sweeteners and body weight and composition: a meta-analysis of randomized controlled trials and prospective cohort studies123 
Background: Replacement of caloric sweeteners with lower- or no-calorie alternatives may facilitate weight loss or weight maintenance by helping to reduce energy intake; however, past research examining low-calorie sweeteners (LCSs) and body weight has produced mixed results.
Objective: The objective was to systematically review and quantitatively evaluate randomized controlled trials (RCTs) and prospective cohort studies, separately, that examined the relation between LCSs and body weight and composition.
Design: A systematic literature search identified 15 RCTs and 9 prospective cohort studies that examined LCSs from foods or beverages or LCSs consumed as tabletop sweeteners. Meta-analyses generated weighted mean differences in body weight and composition values between the LCS and control groups among RCTs and weighted mean correlations for LCS intake and these parameters among prospective cohort studies.
Results: In RCTs, LCSs modestly but significantly reduced all outcomes examined, including body weight (−0.80 kg; 95% CI: −1.17, −0.43), body mass index [BMI (in kg/m2): −0.24; 95% CI: −0.41, −0.07], fat mass (−1.10 kg; 95% CI: −1.77, −0.44), and waist circumference (−0.83 cm; 95% CI: −1.29, −0.37). Among prospective cohort studies, LCS intake was not associated with body weight or fat mass, but was significantly associated with slightly higher BMI (0.03; 95% CI: 0.01, 0.06).
Conclusions: The current meta-analysis provides a rigorous evaluation of the scientific evidence on LCSs and body weight and composition. Findings from observational studies showed no association between LCS intake and body weight or fat mass and a small positive association with BMI; however, data from RCTs, which provide the highest quality of evidence for examining the potentially causal effects of LCS intake, indicate that substituting LCS options for their regular-calorie versions results in a modest weight loss and may be a useful dietary tool to improve compliance with weight loss or weight maintenance plans.
PMCID: PMC4135487  PMID: 24944060
23.  The causal role of breakfast in energy balance and health: a randomized controlled trial in lean adults1234 
Background: Popular beliefs that breakfast is the most important meal of the day are grounded in cross-sectional observations that link breakfast to health, the causal nature of which remains to be explored under real-life conditions.
Objective: The aim was to conduct a randomized controlled trial examining causal links between breakfast habits and all components of energy balance in free-living humans.
Design: The Bath Breakfast Project is a randomized controlled trial with repeated-measures at baseline and follow-up in a cohort in southwest England aged 21–60 y with dual-energy X-ray absorptiometry–derived fat mass indexes ≤11 kg/m2 in women (n = 21) and ≤7.5 kg/m2 in men (n = 12). Components of energy balance (resting metabolic rate, physical activity thermogenesis, energy intake) and 24-h glycemic responses were measured under free-living conditions with random allocation to daily breakfast (≥700 kcal before 1100) or extended fasting (0 kcal until 1200) for 6 wk, with baseline and follow-up measures of health markers (eg, hematology/biopsies).
Results: Contrary to popular belief, there was no metabolic adaptation to breakfast (eg, resting metabolic rate stable within 11 kcal/d), with limited subsequent suppression of appetite (energy intake remained 539 kcal/d greater than after fasting; 95% CI: 157, 920 kcal/d). Rather, physical activity thermogenesis was markedly higher with breakfast than with fasting (442 kcal/d; 95% CI: 34, 851 kcal/d). Body mass and adiposity did not differ between treatments at baseline or follow-up and neither did adipose tissue glucose uptake or systemic indexes of cardiovascular health. Continuously measured glycemia was more variable during the afternoon and evening with fasting than with breakfast by the final week of the intervention (CV: 3.9%; 95% CI: 0.1%, 7.8%).
Conclusions: Daily breakfast is causally linked to higher physical activity thermogenesis in lean adults, with greater overall dietary energy intake but no change in resting metabolism. Cardiovascular health indexes were unaffected by either of the treatments, but breakfast maintained more stable afternoon and evening glycemia than did fasting. This trial was registered at as ISRCTN31521726.
PMCID: PMC4095658  PMID: 24898233
24.  Cancer in British vegetarians: updated analyses of 4998 incident cancers in a cohort of 32,491 meat eaters, 8612 fish eaters, 18,298 vegetarians, and 2246 vegans1234 
Background: Vegetarian diets might affect the risk of cancer.
Objective: The objective was to describe cancer incidence in vegetarians and nonvegetarians in a large sample in the United Kingdom.
Design: This was a pooled analysis of 2 prospective studies including 61,647 British men and women comprising 32,491 meat eaters, 8612 fish eaters, and 20,544 vegetarians (including 2246 vegans). Cancer incidence was followed through nationwide cancer registries. Cancer risk by vegetarian status was estimated by using multivariate Cox proportional hazards models.
Results: After an average follow-up of 14.9 y, there were 4998 incident cancers: 3275 in meat eaters (10.1%), 520 in fish eaters (6.0%), and 1203 in vegetarians (5.9%). There was significant heterogeneity between dietary groups in risks of the following cancers: stomach cancer [RRs (95% CIs) compared with meat eaters: 0.62 (0.27, 1.43) in fish eaters and 0.37 (0.19, 0.69) in vegetarians; P-heterogeneity = 0.006], colorectal cancer [RRs (95% CIs): 0.66 (0.48, 0.92) in fish eaters and 1.03 (0.84, 1.26) in vegetarians; P-heterogeneity = 0.033], cancers of the lymphatic and hematopoietic tissue [RRs (95% CIs): 0.96 (0.70, 1.32) in fish eaters and 0.64 (0.49, 0.84) in vegetarians; P-heterogeneity = 0.005], multiple myeloma [RRs (95% CIs): 0.77 (0.34, 1.76) in fish eaters and 0.23 (0.09, 0.59) in vegetarians; P-heterogeneity = 0.010], and all sites combined [RRs (95% CIs): 0.88 (0.80, 0.97) in fish eaters and 0.88 (0.82, 0.95) in vegetarians; P-heterogeneity = 0.0007].
Conclusion: In this British population, the risk of some cancers is lower in fish eaters and vegetarians than in meat eaters.
PMCID: PMC4144109  PMID: 24898235
25.  Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake1234 
Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.
Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10−6 were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.
Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10−8) and lower fat (β ± SE: −0.21 ± 0.04%; P = 1.57 × 10−9) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)–increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10−10), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10−7).
Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
PMCID: PMC3652928  PMID: 23636237

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