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Effects of vitamin D, omega-3 and a simple strength exercise programme in cardiovascular disease prevention: The DO-HEALTH randomized controlled trial.
Gaengler, S, Sadlon, A, De Godoi Rezende Costa Molino, C, Willett, WC, Manson, JE, Vellas, B, Steinhagen-Thiessen, E, Von Eckardstein, A, Ruschitzka, F, Rizzoli, R, et al
The journal of nutrition, health & aging. 2024;(2):100037
Abstract
BACKGROUND The effects of non-pharmaceutical interventions in the prevention of cardiovascular diseases (CVD) in older adults remains unclear. Therefore, the aim was to investigate the effect of 2000 IU/day of vitamin D3, omega-3 fatty acids (1 g/day), and a simple home strength exercise program (SHEP) (3×/week) on lipid and CVD biomarkers plasma changes over 3 years, incident hypertension and major cardiovascular events (MACE). METHODS The risk of MACE (coronary heart event or intervention, heart failure, stroke) was an exploratory endpoint of DO-HEALTH, incident hypertension and change in biomarkers were secondary endpoints. DO-HEALTH is a completed multicentre, randomised, placebo-controlled, 2 × 2 × 2 factorial design trial enrolling 2157 Europeans aged ≥70 years. RESULTS Participants' median age was 74 [72, 77] years, 61.7% were women, 82.5% were at least moderately physically active, and 40.7% had 25(OH)D < 20 ng/mL at baseline. Compared to their controls, omega-3 increased HDL-cholesterol (difference in change over 3 years: 0.08 mmol/L, 95% CI 0.05-0.10), decreased triglycerides (-0.08 mmol/L, (95%CI -0.12 to -0.03), but increased total- (0.15 mmol/L, 95%CI 0.09; 0.2), LDL- (0.11 mmol/L, 0.06; 0.16), and non-HDL-cholesterol (0.07 mmol/L, 95%CI 0.02; 0.12). However, neither omega-3 (adjustedHR 1.00, 95%CI 0.64-1.56), nor vitamin D3 (aHR 1.37, 95%CI 0.88-2.14), nor SHEP (aHR 1.18, 95%CI 0.76-1.84) reduced risk of MACE or incident hypertension compared to control. CONCLUSION Among generally healthy, active, and largely vitamin D replete, older adults, treatment with omega-3, vitamin D3, and/or SHEP had no benefit on MACE prevention. Only omega-3 supplementation changed lipid biomarkers, but with mixed effects. TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER NCT01745263.
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Sugar-sweetened beverage consumption and weight gain in children and adults: a systematic review and meta-analysis of prospective cohort studies and randomized controlled trials.
Nguyen, M, Jarvis, SE, Tinajero, MG, Yu, J, Chiavaroli, L, Mejia, SB, Khan, TA, Tobias, DK, Willett, WC, Hu, FB, et al
The American journal of clinical nutrition. 2023;(1):160-174
Abstract
BACKGROUND Sugar-sweetened beverages (SSBs) have been implicated in fueling the obesity epidemic. OBJECTIVES This study aimed to update a synthesis of the evidence on SSBs and weight gain in children and adults. METHODS MEDLINE, Embase, and Cochrane databases were searched through September 8, 2022, for prospective cohort studies and randomized controlled trials (RCTs) that evaluated intake of SSBs in relation to BMI and body weight in children and adults, respectively. Eligible interventions were compared against a noncaloric control. Study-level estimates were pooled using random-effects meta-analysis and presented as β-coefficients with 95% CIs for cohorts and weighted mean differences (MDs) with 95% CIs for RCTs. RESULTS We identified 85 articles including 48 in children (40 cohorts, n = 91,713; 8 RCTs, n = 2783) and 37 in adults (21 cohorts, n = 448,661; 16 RCTs, n = 1343). Among cohort studies, each serving/day increase in SSB intake was associated with a 0.07-kg/m2 (95% CI: 0.04 kg/m2, 0.10 kg/m2) higher BMI in children and a 0.42-kg (95% CI: 0.26 kg, 0.58 kg) higher body weight in adults. RCTs in children indicated less BMI gain with SSB reduction interventions compared with control (MD: -0.21 kg/m2; 95% CI: -0.40 kg/m2, -0.01 kg/m2). In adults, randomization to addition of SSBs to the diet led to greater body weight gain (MD: 0.83 kg; 95% CI: 0.47 kg, 1.19 kg), and subtraction of SSBs led to weight loss (MD: -0.49 kg; 95% CI: -0.66 kg, -0.32 kg) compared with the control groups. A positive linear dose-response association between SSB consumption and weight gain was found in all outcomes assessed. CONCLUSIONS Our updated systematic review and meta-analysis expands on prior evidence to confirm that SSB consumption promotes higher BMI and body weight in both children and adults, underscoring the importance of dietary guidance and public policy strategies to limit intake. This meta-analysis was registered at the International Prospective Register of Systematic Reviews as CRD42020209915.
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Racial and ethnic heterogeneity in diets of low-income adult females in the United States: results from National Health and Nutrition Examination Surveys from 2011 to 2018.
Stephenson, BJK, Willett, WC
The American journal of clinical nutrition. 2023;(3):625-634
Abstract
BACKGROUND Poor diet is a major risk factor of cardiovascular and chronic diseases, particularly for low-income female adults. However, the pathways by which race and ethnicity plays a role in this risk factor have not been fully explored. OBJECTIVES This observational study aimed to identify dietary consumption differences by race and ethnicity of US female adults living at or below the 130% poverty income level from 2011 to 2018. METHODS A total of 2917 adult females aged 20 to 80 years from the National Health and Nutrition Examination Survey (2011-2018) living at or below the 130% poverty income level with at least one complete 24-hour dietary recall were classified into 5 self-identified racial and ethnic subgroups (Mexican, other Hispanic, non-Hispanic [NH]-White, NH-Black, and NH-Asian). Dietary consumption patterns were defined by 28 major food groups summarized from the Food Pattern Equivalents Database and derived via a robust profile clustering model, which identifies foods that share consumption patterns across all low-income female adults and foods that differ in consumption patterns based on the racial and ethnic subgroups. RESULTS All food consumption patterns were identified at the local level, defined by racial and ethnic subgroups. Legumes and cured meats were the most differentiating foods identified across all racial and ethnic subgroups. Higher consumption levels of legumes were observed among Mexican-American and other Hispanic females. Higher consumption levels of cured meat were observed among NH-White and Black females. NH-Asian females had the most uniquely characterized patterns with a higher consumption of prudent foods (fruits, vegetables, and whole grains). CONCLUSIONS Differences among the consumption behaviors of low-income female adults were found along racial and ethnic lines. Efforts to improve the nutritional health of low-income female adults should consider racial and ethnic differences in diets to appropriately focus interventions.
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Effects of Vitamin D, Omega-3 Fatty Acids and a Home Exercise Program on Prevention of Pre-Frailty in Older Adults: The DO-HEALTH Randomized Clinical Trial.
Gagesch, M, Wieczorek, M, Vellas, B, Kressig, RW, Rizzoli, R, Kanis, J, Willett, WC, Egli, A, Lang, W, Orav, EJ, et al
The Journal of frailty & aging. 2023;(1):71-77
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BACKGROUND The benefits of supplemental vitamin D3, marine omega-3 fatty acids, and a simple home exercise program (SHEP) on frailty prevention in generally healthy community-dwelling older adults are unclear. OBJECTIVE To test the effect of vitamin D3, omega-3s, and a SHEP, alone or in combination on incident pre-frailty and frailty in robust older adults over a follow-up of 36 months. METHODS DO-HEALTH is a multi-center, double-blind, placebo-controlled, 2x2x2 factorial randomized clinical trial among generally healthy European adults aged 70 years or older, who had no major health events in the 5 years prior to enrollment, sufficient mobility and intact cognitive function. As a secondary outcome of the DO-HEALTH trial, among the subset of participants who were robust at baseline, we tested the individual and combined benefits of supplemental 2,000 IU/day of vitamin D3, 1 g/day of marine omega-3s, and a SHEP on the odds of being pre-frail and frail over 3 years of follow-up. RESULTS At baseline, 1,137 out of 2,157 participants were robust (mean age 74.3 years, 56.5% women, mean gait speed 1.18 m/s). Over a median follow-up time of 2.9 years, 696 (61.2%) became pre-frail and 29 (2.6%) frail. Odds ratios for becoming pre-frail were not significantly lower for vitamin D3, or omega 3-s, or SHEP, individually, compared to control (placebo for the supplements and control exercise). However, the three treatments combined showed significantly decreased odds (OR 0.61 [95% CI 0.38-0.98; p=0.04) of becoming pre-frail compared to control. None of the individual treatments or their combination significantly reduced the odds of becoming frail. CONCLUSION Robust, generally healthy and active older adults without major comorbidities, may benefit from a combination of high-dose, supplemental vitamin D3, marine omega-3s, and SHEP with regard to the risk of becoming pre-frail over 3 years.
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Effects of non-nutritive sweeteners on the BMI of children and adolescents: a systematic review and meta-analysis of randomised controlled trials and prospective cohort studies.
Espinosa, A, Mendoza, K, Laviada-Molina, H, Rangel-Méndez, JA, Molina-Segui, F, Sun, Q, Tobias, DK, Willett, WC, Mattei, J
The Lancet. Global health. 2023;:S8
Abstract
BACKGROUND Considering the biological variation across subgroups during periods of growth, the role of non-nutritive sweeteners in weight-related outcomes among children and adolescents is unclear. We did a systematic review and meta-analysis to summarise the evidence on experimental and habitual consumption of non-nutritive sweeteners and prospective changes in BMI in paediatric populations. METHODS We searched eligible (ie, lasting a minimum of 4 weeks) randomised controlled trials of the effect of non-nutritive sweeteners versus non-caloric or caloric comparators on BMI change and prospective cohort studies reporting multivariable-adjusted coefficients for non-nutritive sweetener intake and BMI in children (aged 2-9 years) and adolescents (aged 10-24 years). We generated pooled estimates using random effects meta-analysis and did secondary stratified analyses to explore heterogeneity by study-level and subgroup characteristics. We further evaluated the quality of the included evidence and classified industry-funded studies, or those whose authors were related to the food industry, as having potential conflicts of interest. FINDINGS From 2789 results, we included five randomised controlled trials (n=1498 participants; median follow-up 19·0 weeks [IQR 13·0-37·5]); three [60%] with potential conflicts of interest), and eight prospective cohort studies (n=35 340 participants; median follow-up 2·5 years [IQR 1·7-6·3]; two [25%] with potential conflicts of interest). Random allocation to intake of non-nutritive sweeteners (25-2400 mg/day, from food and beverages) suggested less BMI gain (standardised mean difference -0·42 kg/m2 [95% CI -0·79 to -0·06]; I2=89%) compared with intake of sugar from food and beverages. Stratified estimates were significant only in adolescents, participants with obesity at baseline, consumers of a mixture of non-nutritive sweeteners, longer trials, and trials not found to have potential conflicts of interest. No randomised controlled trials tested beverages containing non-nutritive sweeteners versus water. Prospective cohorts reported a non-significant association between consumption of beverages containing non-nutritive sweeteners and BMI gain (0·05 kg/m2 [95% CI -0·02 to 0·12]; I2=67%; per daily serving of 355 mL), which was accentuated for adolescents, boys, and cohorts with longer follow-ups. Removing studies with potential conflicts of interest attenuated the estimates. Evidence was predominantly classified as of low to moderate quality. INTERPRETATION Intake of non-nutritive sweeteners versus sugar in randomised controlled trials resulted in less BMI gain in adolescents and participants with obesity. Better designed studies should contrast beverages containing non-nutritive sweeteners with water. Long-term prospective analyses with changes in repeated measures might clarify the effect of intake of non-nutritive sweeteners on BMI changes in childhood and adolescence. FUNDING None.
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Prevalence of healthy aging among community dwelling adults age 70 and older from five European countries.
Schietzel, S, Chocano-Bedoya, PO, Sadlon, A, Gagesch, M, Willett, WC, Orav, EJ, Kressig, RW, Vellas, B, Rizzoli, R, da Silva, JAP, et al
BMC geriatrics. 2022;(1):174
Abstract
BACKGROUND To compare the prevalence of healthy aging among adults age 70 and older from 5 European countries recruited for the DO-HEALTH clinical trial. Participants were selected for absence of prior major health events. METHODS Cross-sectional analysis of DO-HEALTH baseline data. All 2,157 participants (mean age 74.9, SD 4.4; 61.7% women) were included and 2,123 had data for all domains of the healthy aging status (HA) definition. HA was assessed based on the Nurses` Health Study (NHS) definition requiring four domains: no major chronic diseases, no disabilities, no cognitive impairment (Montreal Cognitive Assessment, MoCA ≥25), no mental health limitation (GDS-5 <2, and no diagnosis of depression). Association between HA and age, BMI, gender, and physical function (sit-to-stand, gait speed, grip strength) was assessed by multivariate logistic regression analyses adjusting for center. RESULTS Overall, 41.8% of DO-HEALTH participants were healthy agers with significant variability by country: Austria (Innsbruck) 58.3%, Switzerland (Zurich, Basel, Geneva) 51.2%, Germany (Berlin) 37.6%, France (Toulouse) 36.7% and Portugal (Coimbra) 8.8% (p <0.0001). Differences in prevalence by country persisted after adjustment for age. In the multivariate model, younger age (OR = 0.95, 95% CI 0.93 to 0.98), female gender (OR = 1.36, 95% CI 1.03 to 1.81), lower BMI (OR = 0.94, 95% CI 0.91 to 0.96), faster gait speed (OR = 4.70, 95% CI 2.68 to 8.25) and faster performance in sit-to-stand test (OR = 0.90, 95% CI 0.87 to 0.93) were independently and significantly associated with HA. CONCLUSIONS Despite the same inclusion and exclusion criteria preselecting relatively healthy adults age 70 years and older, HA prevalence in DO-HEALTH varied significantly between countries and was highest in participants from Austria and Switzerland, lowest in participants from Portugal. Independent of country, younger age, female gender, lower BMI and better physical function were associated with HA. TRIAL REGISTRATION DO-HEALTH was registered under the protocol NCT01745263 at the International Trials Registry ( clinicaltrials.gov ), and under the protocol number 2012-001249-41 at the Registration at the European Community Clinical Trial System (EudraCT).
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Effects of vitamin D, omega-3 fatty acids, and a simple home strength exercise program on fall prevention: the DO-HEALTH randomized clinical trial.
Bischoff-Ferrari, HA, Freystätter, G, Vellas, B, Dawson-Hughes, B, Kressig, RW, Kanis, JA, Willett, WC, Manson, JE, Rizzoli, R, Theiler, R, et al
The American journal of clinical nutrition. 2022;(5):1311-1321
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BACKGROUND The roles of vitamin D, omega-3 fatty acids, and home exercise on fall prevention among generally healthy and active older adults are unclear. OBJECTIVES We tested the effects of daily supplemental vitamin D, daily supplemental marine omega-3s fatty acids, and a simple home exercise program (SHEP), alone or in combination, on the incidences of total and injurious falls among generally healthy older adults. METHODS We performed a 2 × 2 × 2 factorial-design randomized controlled trial among 2157 community-dwelling adults aged 70 years and older, who had no major health events in the 5 years prior to enrolment, recruited from Switzerland, Germany, Austria, France, and Portugal between December 2012 and November 2014. Participants were randomly assigned to supplementation with 2000 international units/day of vitamin D3 and/or 1 g/day of marine omega-3s, and/or a SHEP compared with placebo and/or control exercise over 3 years. The primary endpoint for the present fall analysis was the incidence rate of total falls. Falls were recorded prospectively throughout the trial. Since there were no interactions between treatments, the main effects are reported based on a modified intent-to-treat analysis. RESULTS Of 2157 randomized participants, 1900 (88%) completed the study. The mean age was 74.9 years, 61.7% were women, 40.7% had a serum 25-hydroxyvitamin D concentration < 20 ng/ml, and 83% were at least moderately physically active. In total, 3333 falls were recorded over a median follow-up of 2.99 years. Overall, vitamin D and the SHEP had no benefit on total falls, whilst supplementation with omega-3s compared to no omega-3 supplementation reduced total falls by 10% (incidence rate ratio = 0.90; 95% CI, 0.81-1.00; P = 0.04). CONCLUSIONS Among generally healthy, active, and vitamin D-replete older adults, omega-3 supplementation may have a modest benefit on the incidence of total falls, whilst a daily high dose of vitamin D or a SHEP had no benefit.
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Combined Vitamin D, Omega-3 Fatty Acids, and a Simple Home Exercise Program May Reduce Cancer Risk Among Active Adults Aged 70 and Older: A Randomized Clinical Trial.
Bischoff-Ferrari, HA, Willett, WC, Manson, JE, Dawson-Hughes, B, Manz, MG, Theiler, R, Braendle, K, Vellas, B, Rizzoli, R, Kressig, RW, et al
Frontiers in aging. 2022;:852643
Abstract
Objective: The aim of this study was to test the individual and combined benefit of vitamin D, omega-3, and a simple home strength exercise program on the risk of any invasive cancer. Design: The DO-HEALTH trial is a three-year, multicenter, 2 × 2 × 2 factorial design double-blind, randomized-controlled trial to test the individual and combined benefit of three public health interventions. Setting: The trial was conducted between December 2012 and December 2017 in five European countries. Participants: Generally healthy community-dwelling adults ≥70 years were recruited. Interventions: Supplemental 2000 IU/day of vitamin D3, and/or 1 g/day of marine omega-3s, and/or a simple home strength exercise (SHEP) programme compared to placebo and control exercise. Main outcome: In this pre-defined exploratory analysis, time-to-development of any verified invasive cancer was the primary outcome in an adjusted, intent-to-treat analysis. Results: In total, 2,157 participants (mean age 74.9 years; 61.7% women; 40.7% with 25-OH vitamin D below 20 /ml, 83% at least moderately physically active) were randomized. Over a median follow-up of 2.99 years, 81 invasive cancer cases were diagnosed and verified. For the three individual treatments, the adjusted hazard ratios (HRs, 95% CI, cases intervention versus control) were 0.76 (0.49-1.18; 36 vs. 45) for vitamin D3, 0.70 (0.44-1.09, 32 vs. 49) for omega-3s, and 0.74 (0.48-1.15, 35 vs. 46) for SHEP. For combinations of two treatments, adjusted HRs were 0.53 (0.28-1.00; 15 vs. 28 cases) for omega-3s plus vitamin D3; 0.56 (0.30-1.04; 11 vs. 21) for vitamin D3 plus SHEP; and 0.52 (0.28-0.97; 12 vs. 26 cases) for omega-3s plus SHEP. For all three treatments combined, the adjusted HR was 0.39 (0.18-0.85; 4 vs. 12 cases). Conclusion: Supplementation with daily high-dose vitamin D3 plus omega-3s, combined with SHEP, showed cumulative reduction in the cancer risk in generally healthy and active and largely vitamin D-replete adults ≥70 years. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT01745263.
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Competing paradigms of obesity pathogenesis: energy balance versus carbohydrate-insulin models.
Ludwig, DS, Apovian, CM, Aronne, LJ, Astrup, A, Cantley, LC, Ebbeling, CB, Heymsfield, SB, Johnson, JD, King, JC, Krauss, RM, et al
European journal of clinical nutrition. 2022;(9):1209-1221
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The obesity pandemic continues unabated despite a persistent public health campaign to decrease energy intake ("eat less") and increase energy expenditure ("move more"). One explanation for this failure is that the current approach, based on the notion of energy balance, has not been adequately embraced by the public. Another possibility is that this approach rests on an erroneous paradigm. A new formulation of the energy balance model (EBM), like prior versions, considers overeating (energy intake > expenditure) the primary cause of obesity, incorporating an emphasis on "complex endocrine, metabolic, and nervous system signals" that control food intake below conscious level. This model attributes rising obesity prevalence to inexpensive, convenient, energy-dense, "ultra-processed" foods high in fat and sugar. An alternative view, the carbohydrate-insulin model (CIM), proposes that hormonal responses to highly processed carbohydrates shift energy partitioning toward deposition in adipose tissue, leaving fewer calories available for the body's metabolic needs. Thus, increasing adiposity causes overeating to compensate for the sequestered calories. Here, we highlight robust contrasts in how the EBM and CIM view obesity pathophysiology and consider deficiencies in the EBM that impede paradigm testing and refinement. Rectifying these deficiencies should assume priority, as a constructive paradigm clash is needed to resolve long-standing scientific controversies and inform the design of new models to guide prevention and treatment. Nevertheless, public health action need not await resolution of this debate, as both models target processed carbohydrates as major drivers of obesity.
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Egg Consumption and Risk of All-Cause and Cause-Specific Mortality: A Systematic Review and Dose-Response Meta-analysis of Prospective Studies.
Mousavi, SM, Zargarzadeh, N, Rigi, S, Persad, E, Pizarro, AB, Hasani-Ranjbar, S, Larijani, B, Willett, WC, Esmaillzadeh, A
Advances in nutrition (Bethesda, Md.). 2022;(5):1762-1773
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The association between egg consumption and mortality is extremely debatable. This study aimed to investigate the potential dose-response association of egg consumption with risk of mortality from all causes and cause-specific in the general population. The primary comprehensive literature search was conducted in PubMed/Medline, Scopus, ISI Web of Science, and Embase up to March 2021, as well as reference lists of relevant original papers and key journals. We calculated summary RRs and their 95% CIs for the highest and lowest categories, as well as the linear trend estimation of egg intake, using the random-effects model. Thirty-three (32 publications) cohort studies were included. These studies enrolled 2,216,720 participants and recorded 232,408 deaths from all causes. Comparing highest versus lowest egg intake categories was not associated with the risk of mortality from all causes (RR: 1.02; 95% CI: 0.94, 1.11; n = 25), cardiovascular disease (CVD) (RR: 1.04; 95% CI: 0.87, 1.23, n = 11), coronary heart disease (CHD) (RR: 0.98; 95% CI: 0.84, 1.16; n = 10), stroke (RR: 0.81; 95% CI: 0.64, 1.02; n = 9), and respiratory disease (RR: 0.96; 95% CI: 0.53, 1.71; n = 3); however, it was associated with a higher risk of cancer mortality (RR: 1.20; 95% CI: 1.04, 1.39; n = 13). In the linear dose-response analysis, an additional intake of 1 egg per week was associated with a 2% and 4% increased risk of all-cause and cancer mortality, respectively, and a 4% decreased risk of stroke mortality. The certainty of the evidence was rated as low to moderate. Higher egg consumption was not associated with an increased risk of mortality from all causes, CVD, CHD, stroke, or respiratory disease, whereas an elevated risk was observed for cancer mortality. These findings suggest that eggs be consumed in low to moderate amounts (≤1 egg/d) as part of a healthy diet.