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1.
Vitamin D and human health: evidence from Mendelian randomization studies.
Fang, A, Zhao, Y, Yang, P, Zhang, X, Giovannucci, EL
European journal of epidemiology. 2024
Abstract
We summarized the current evidence on vitamin D and major health outcomes from Mendelian randomization (MR) studies. PubMed and Embase were searched for original MR studies on vitamin D in relation to any health outcome from inception to September 1, 2022. Nonlinear MR findings were excluded due to concerns about the validity of the statistical methods used. A meta-analysis was preformed to synthesize study-specific estimates after excluding overlapping samples, where applicable. The methodological quality of the included studies was evaluated according to the STROBE-MR checklist. A total of 133 MR publications were eligible for inclusion in the analyses. The causal association between vitamin D status and 275 individual outcomes was examined. Linear MR analyses showed genetically high 25-hydroxyvitamin D (25(OH)D) concentrations were associated with reduced risk of multiple sclerosis incidence and relapse, non-infectious uveitis and scleritis, psoriasis, femur fracture, leg fracture, amyotrophic lateral sclerosis, anorexia nervosa, delirium, heart failure, ovarian cancer, non-alcoholic fatty liver disease, dyslipidemia, and bacterial pneumonia, but increased risk of Behçet's disease, Graves' disease, kidney stone disease, fracture of radium/ulna, basal cell carcinoma, and overall cataracts. Stratified analyses showed that the inverse association between genetically predisposed 25(OH)D concentrations and multiple sclerosis risk was significant and consistent regardless of the genetic instruments GIs selected. However, the associations with most of the other outcomes were only pronounced when using genetic variants not limited to those in the vitamin D pathway as GIs. The methodological quality of the included MR studies was substantially heterogeneous. Current evidence from linear MR studies strongly supports a causal role of vitamin D in the development of multiple sclerosis. Suggestive support for a number of other health conditions could help prioritize conditions where vitamin D may be beneficial or harmful.
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Artificially Sweetened Beverages and Health Outcomes: An Umbrella Review.
Diaz, C, Rezende, LFM, Sabag, A, Lee, DH, Ferrari, G, Giovannucci, EL, Rey-Lopez, JP
Advances in nutrition (Bethesda, Md.). 2023;(4):710-717
Abstract
The consumption of artificially sweetened beverages (ASBs) is increasing in some countries. However, some meta-analyses have found that habitual consumers of ASBs (compared with low or no consumption) had an increased risk on some health outcomes. We performed an umbrella review of meta-analyses to grade the credibility of the evidence of claimed observational associations between ASBs and health outcomes. Data were searched in Web of Science, Embase, and PubMed for systematic reviews published up to 25 May 2022, examining association between ASBs and any health outcomes. Certainty of the evidence for each health outcome was obtained based on statistical results of tests used in umbrella reviews. The AMSTAR-2 tool (16 items) was used to identify high-quality systematic reviews. Answers of each item were rated as yes, no, or partial yes (for a partial adherence to the standard). We included data from 11 meta-analyses with unique population, exposure, comparison group, outcome obtained from 7 systematic reviews (51 cohort studies and 4 case-control studies). ASBs were associated with higher risk of obesity, type 2 diabetes, all-cause mortality, hypertension, and cardiovascular disease incidence (supported by highly suggestive evidence). Evidence for other outcomes (colorectal cancer, pancreatic cancer, gastrointestinal cancer, cancer mortality, cardiovascular mortality, chronic kidney disease, coronary artery disease, and stroke) was weak. Results of the quality assessment of systematic reviews using AMSTAR-2 showed some notable deficiencies: unclear sources of funding of eligible studies and lack of predefined study protocols to guide authors. The consumption of ASBs was associated with a higher risk of obesity, type 2 diabetes, all-cause mortality, hypertension, and cardiovascular disease incidence. However, further cohort studies and clinical trials in humans are still needed to understand the impact of ASBs on health outcomes.
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Ultra-processed foods and health: a comprehensive review.
Zhang, Y, Giovannucci, EL
Critical reviews in food science and nutrition. 2023;(31):10836-10848
Abstract
Dramatically increasing trends in consumption of ultra-processed foods have been reported across the globe. Public concern about the health consequences of ultra-processed foods is high. This manuscript provides a comprehensive review of trends in global consumption of ultra-processed foods, dietary nutrient profile of ultra-processed foods, demographic, socioeconomic, psychological, and behavioral characteristics of ultra-processed food consumers, current evidence from longitudinal studies at the population level on the association between ultra-processed foods consumption and major health outcomes (including all-cause and cause-specific mortality, cardiovascular disease, overweight and obesity, body composition and fat deposition, diabetes, cancer, and gastrointestinal and other diseases), potential mechanisms linking ultra-processed foods with these outcomes (nutrient displacement, factors that influence adiposity, and processing), and challenges and future research directions. The global trends in consumption of ultra-processed foods, the generally unfavorable nutrient profile of ultra-processed foods, the characteristics of ultra-processed food consumers, the accumulating longitudinal studies associating ultra-processed foods with major health outcomes, and the uncertainties and complexities in putative mechanisms all highlight the need for future high-quality epidemiologic and mechanistic investigations on this topic. It is critical to interpret findings in the light of the totality of evidence.
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4.
Cheese consumption and multiple health outcomes: an umbrella review and updated meta-analysis of prospective studies.
Zhang, M, Dong, X, Huang, Z, Li, X, Zhao, Y, Wang, Y, Zhu, H, Fang, A, Giovannucci, EL
Advances in nutrition (Bethesda, Md.). 2023;(5):1170-1186
Abstract
This umbrella review aims to provide a systematic and comprehensive overview of current evidence from prospective studies on the diverse health effects of cheese consumption. We searched PubMed, Embase, and Cochrane Library to identify meta-analyses/pooled analyses of prospective studies examining the association between cheese consumption and major health outcomes from inception to August 31, 2022. We reanalyzed and updated previous meta-analyses and performed de novo meta-analyses with recently published prospective studies, where appropriate. We calculated the summary effect size, 95% prediction confidence intervals, between-study heterogeneity, small-study effects, and excess significance bias for each health outcome. We identified 54 eligible articles of meta-analyses/pooled analyses. After adding newly published original articles, we performed 35 updated meta-analyses and 4 de novo meta-analyses. Together with 8 previous meta-analyses, we finally included 47 unique health outcomes. Cheese consumption was inversely associated with all-cause mortality (highest compared with lowest category: RR = 0.95; 95% CI: 0.92, 0.99), cardiovascular mortality (RR = 0.93; 95% CI: 0.88, 0.99), incident cardiovascular disease (CVD) (RR = 0.92; 95% CI: 0.89, 0.96), coronary heart disease (CHD) (RR = 0.92; 95% CI: 0.86, 0.98), stroke (RR = 0.93; 95% CI: 0.89, 0.98), estrogen receptor-negative (ER-) breast cancer (RR = 0.89; 95% CI: 0.82, 0.97), type 2 diabetes (RR = 0.93; 95% CI: 0.88, 0.98), total fracture (RR = 0.90; 95% CI: 0.86, 0.95), and dementia (RR = 0.81; 95% CI: 0.66, 0.99). Null associations were found for other outcomes. According to the NutriGrade scoring system, moderate quality of evidence was observed for inverse associations of cheese consumption with all-cause and cardiovascular mortality, incident CVD, CHD, and stroke, and for null associations with cancer mortality, incident hypertension, and prostate cancer. Our findings suggest that cheese consumption has neutral to moderate benefits for human health.
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Is early-onset cancer an emerging global epidemic? Current evidence and future implications.
Ugai, T, Sasamoto, N, Lee, HY, Ando, M, Song, M, Tamimi, RM, Kawachi, I, Campbell, PT, Giovannucci, EL, Weiderpass, E, et al
Nature reviews. Clinical oncology. 2022;(10):656-673
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Abstract
Over the past several decades, the incidence of early-onset cancers, often defined as cancers diagnosed in adults <50 years of age, in the breast, colorectum, endometrium, oesophagus, extrahepatic bile duct, gallbladder, head and neck, kidney, liver, bone marrow, pancreas, prostate, stomach and thyroid has increased in multiple countries. Increased use of screening programmes has contributed to this phenomenon to a certain extent, although a genuine increase in the incidence of early-onset forms of several cancer types also seems to have emerged. Evidence suggests an aetiological role of risk factor exposures in early life and young adulthood. Since the mid-20th century, substantial multigenerational changes in the exposome have occurred (including changes in diet, lifestyle, obesity, environment and the microbiome, all of which might interact with genomic and/or genetic susceptibilities). However, the effects of individual exposures remain largely unknown. To study early-life exposures and their implications for multiple cancer types will require prospective cohort studies with dedicated biobanking and data collection technologies. Raising awareness among both the public and health-care professionals will also be critical. In this Review, we describe changes in the incidence of early-onset cancers globally and suggest measures that are likely to reduce the burden of cancers and other chronic non-communicable diseases.
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Post-Diagnosis Vitamin D Supplement Use and Survival among Cancer Patients: A Meta-Analysis.
Chen, QY, Kim, S, Lee, B, Jeong, G, Lee, DH, Keum, N, Manson, JE, Giovannucci, EL
Nutrients. 2022;(16)
Abstract
Vitamin D administered pre-diagnostically has been shown to reduce mortality. Emerging evidence suggests a role of post-diagnosis vitamin D supplement intake for survival among cancer patients. Thus, we conducted a meta-analysis to evaluate the relationship. PubMed and Embase were searched for relevant observational cohort studies and randomized trials published through April 2022. Summary relative risk (SRR) and 95% confidence interval (CI) were estimated using the DerSimonian-Laird random-effects model. The SRR for post-diagnosis vitamin D supplement use vs. non-use, pooling cohort studies and randomized trials, was 0.87 (95% CI, 0.78-0.98; p = 0.02; I2 = 0%) for overall survival, 0.81 (95% CI, 0.62-1.06; p = 0.12; I2 = 51%) for progression-free survival, 0.86 (95% CI, 0.72-1.03; p = 0.10; I2 = 0%) for cancer-specific survival, and 0.86 (95% CI, 0.64-1.14; p = 0.29; I2 = 0%) for relapse. Albeit not significantly heterogeneous by variables tested, a significant inverse association was limited to cohort studies and supplement use during cancer treatment for overall survival, and to studies with ≤3 years of follow-up for progression-free survival. Post-diagnosis vitamin D supplement use was associated with improved overall survival, but not progression-free or cancer-specific survival or relapse. Our findings require confirmation, as randomized trial evidence was insufficient to establish cause-and-effect relationships.
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The timing of adiposity and changes in the life course on the risk of cancer.
Fang, Z, Giovannucci, EL
Cancer metastasis reviews. 2022;(3):471-489
Abstract
Excess body weight has been established as a risk factor for at least twelve cancer sites, though questions remain as to the timing of associations for adiposity and cancer risk throughout the life course. We conducted a narrative review summarizing existing evidence to provide insights into the complex timing relationship between adiposity and risk of seven common obesity-related cancers. We considered five types of studies, including traditional epidemiologic studies examining adiposity at different time points, studies examining weight gain in specific life phases, studies examining weight loss over a period including from bariatric surgery, life course trajectory analysis, and Mendelian randomization studies. The results showed that lifetime excess body weight is associated with increased risk of cancers of endometrium, colorectum, liver, kidney, and pancreas. Early life obesity is one of the strongest risk factors for pancreatic cancer but less directly important than adult obesity for endometrial and kidney cancer. Interestingly, heavy weight during childhood, adolescence, and early adulthood is protective against pre- and postmenopausal breast cancer and possibly advanced prostate cancer. It is apparent that preventing weight gain later in adulthood would likely reduce risk of many cancers, including postmenopausal breast cancer, endometrial cancer, colorectal cancer (especially in men), liver cancer, kidney cancer, and probably advanced prostate cancer. Furthermore, weight loss even late in life may confer benefits for cancers of breast, endometrium, colorectum, and liver among patients with obesity, as mostly demonstrated by studies of bariatric surgery. Overall, maintaining a healthy weight throughout the life course will help prevent a large number of cancers.
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Role of Diet in Colorectal Cancer Incidence: Umbrella Review of Meta-analyses of Prospective Observational Studies.
Veettil, SK, Wong, TY, Loo, YS, Playdon, MC, Lai, NM, Giovannucci, EL, Chaiyakunapruk, N
JAMA network open. 2021;(2):e2037341
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Abstract
IMPORTANCE Several meta-analyses have summarized evidence for the association between dietary factors and the incidence of colorectal cancer (CRC). However, to date, there has been little synthesis of the strength, precision, and quality of this evidence in aggregate. OBJECTIVE To grade the evidence from published meta-analyses of prospective observational studies that assessed the association of dietary patterns, specific foods, food groups, beverages (including alcohol), macronutrients, and micronutrients with the incidence of CRC. DATA SOURCES MEDLINE, Embase, and the Cochrane Library were searched from database inception to September 2019. EVIDENCE REVIEW Only meta-analyses of prospective observational studies with a cohort study design were eligible. Evidence of association was graded according to established criteria as follows: convincing, highly suggestive, suggestive, weak, or not significant. RESULTS From 9954 publications, 222 full-text articles (2.2%) were evaluated for eligibility, and 45 meta-analyses (20.3%) that described 109 associations between dietary factors and CRC incidence were selected. Overall, 35 of the 109 associations (32.1%) were nominally statistically significant using random-effects meta-analysis models; 17 associations (15.6%) demonstrated large heterogeneity between studies (I2 > 50%), whereas small-study effects were found for 11 associations (10.1%). Excess significance bias was not detected for any association between diet and CRC. The primary analysis identified 5 (4.6%) convincing, 2 (1.8%) highly suggestive, 10 (9.2%) suggestive, and 18 (16.5%) weak associations between diet and CRC, while there was no evidence for 74 (67.9%) associations. There was convincing evidence of an association of intake of red meat (high vs low) and alcohol (≥4 drinks/d vs 0 or occasional drinks) with the incidence of CRC and an inverse association of higher vs lower intakes of dietary fiber, calcium, and yogurt with CRC risk. The evidence for convincing associations remained robust following sensitivity analyses. CONCLUSIONS AND RELEVANCE This umbrella review found convincing evidence of an association between lower CRC risk and higher intakes of dietary fiber, dietary calcium, and yogurt and lower intakes of alcohol and red meat. More research is needed on specific foods for which evidence remains suggestive, including other dairy products, whole grains, processed meat, and specific dietary patterns.
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Muscle-strengthening activities and risk of cardiovascular disease, type 2 diabetes, cancer and mortality: A review of prospective cohort studies.
Giovannucci, EL, Rezende, LFM, Lee, DH
Journal of internal medicine. 2021;(4):789-805
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Abstract
The benefits of aerobic moderate-to-vigorous physical activity (MVPA) on major non-communicable diseases (NCDs) are well established. However, much less is known whether muscle-strengthening activities (i.e., resistance/weight/strength training) confer similar benefits. Herein, we conducted a narrative literature review and summarized the existing evidence from large prospective cohort studies on muscle strengthening activities and risk of major chronic diseases and mortality in adults generally free of major NCDs at baseline. Current epidemiologic evidence suggests that engagement in muscle-strengthening activities over 1-2 sessions (or approximately 60-150 min) per week was associated with reduced risk of cardiovascular disease (seven studies; approximately 20%-25% reduction), type 2 diabetes (four studies; approximately 30% reduction), cancer mortality (four studies; approximately 15%-20% reduction) as well as all-cause mortality (six studies; approximately 20%-25% reduction). For diabetes, the risk appears to lower further with even higher levels of muscle-strengthening activities, but some studies for cardiovascular and all-cause mortality suggest a reversal whereby higher levels (≥2.5 h/week) have less benefit, or are even harmful, relative to lower levels of activity. The likely mechanisms contributing to a benefit include improvement in body composition, lipid profile, insulin resistance and inflammation. The evidence supports engaging in 1-2 sessions (up to 2.5 h) per week, preferably performed complementary to the recommended levels of aerobic MVPA. Although data are limited, caution is suggested for training exceeding 2.5 h per week. Further studies are required to better understand the influence of frequency, duration and intensity of muscle-strengthening activities on major NCDs and mortality in diverse populations.
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Intermittent Fasting and Obesity-Related Health Outcomes: An Umbrella Review of Meta-analyses of Randomized Clinical Trials.
Patikorn, C, Roubal, K, Veettil, SK, Chandran, V, Pham, T, Lee, YY, Giovannucci, EL, Varady, KA, Chaiyakunapruk, N
JAMA network open. 2021;(12):e2139558
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Abstract
IMPORTANCE Several meta-analyses of randomized clinical trials (RCTs) have demonstrated the many health benefits of intermittent fasting (IF). However, there has been little synthesis of the strength and quality of this evidence in aggregate to date. OBJECTIVE To grade the evidence from published meta-analyses of RCTs that assessed the associations of IF (zero-calorie alternate-day fasting, modified alternate-day fasting, the 5:2 diet, and time-restricted eating) with obesity-related health outcomes. EVIDENCE REVIEW PubMed, Embase, and Cochrane database of systematic reviews were searched from database inception to January 12, 2021. Data analysis was conducted from April 2021 through July 2021. Meta-analyses of RCTs investigating effects of IF in adults were included. The effect sizes of IF were recalculated using a random-effects model. We assessed the quality of evidence per association by applying the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluations) as high, moderate, low, and very low. FINDINGS A total of 11 meta-analyses comprising 130 RCTs (median [IQR] sample size, 38 [24-69] participants; median [IQR] follow-up period, 3 [2-5] months) were included describing 104 unique associations of different types of IF with obesity-related health outcomes (median [IQR] studies per association, 4 [3-5]). There were 28 statistically significant associations (27%) that demonstrated the beneficial outcomes for body mass index, body weight, fat mass, low-density lipoprotein cholesterol, total cholesterol, triglycerides, fasting plasma glucose, fasting insulin, homeostatic model assessment of insulin resistance, and blood pressure. IF was found to be associated with reduced fat-free mass. One significant association (1%) supported by high-quality evidence was modified alternate-day fasting for 1 to 2 months, which was associated with moderate reduction in body mass index in healthy adults and adults with overweight, obesity, or nonalcoholic fatty liver disease compared with regular diet. Six associations (6%) were supported by moderate quality evidence. The remaining associations found to be significant were supported by very low (75 associations [72%]) to low (22 associations [21%]) quality evidence. CONCLUSIONS AND RELEVANCE In this umbrella review, we found beneficial associations of IF with anthropometric and cardiometabolic outcomes supported by moderate to high quality of evidence, which supports the role of IF, especially modified alternate-day fasting, as a weight loss approach for adults with overweight or obesity. More clinical trials with long-term follow-up are needed to investigate the effects of IF on clinical outcomes such as cardiovascular events and mortality.