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1.
Sci Rep ; 10(1): 16534, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024201

RESUMO

Obesity is a risk factor for > 13 cancer sites, although it is unknown whether there is a common mechanism across sites. Evidence suggests a role for impaired branched-chain amino acid (BCAAs; isoleucine, leucine, valine) metabolism in obesity, insulin resistance, and immunity; thus, we hypothesized circulating BCAAs may be associated with incident obesity-related cancers. We analyzed participants in the prospective Women's Health Study without a history of cancer at baseline blood collection (N = 26,711, mean age = 54.6 years [SD = 7.1]). BCAAs were quantified via NMR spectroscopy, log-transformed, and standardized. We used Cox proportional regression models adjusted for age, race, smoking, diet, alcohol, physical activity, menopausal hormone use, Body Mass Index (BMI), diabetes, and other risk factors. The endpoint was a composite of obesity-related cancers, defined per the International Agency for Research on Cancer 2016 report, over a median 24 years follow-up. Baseline BMI ≥ 30 kg/m2 compared with BMI 18.5-25.0 kg/m2 was associated with 23% greater risk of obesity-related cancers (n = 2751 events; multivariable HR 1.23, 95% CI 1.11-1.37). However, BCAAs were not associated with obesity-related cancers (multivariable HR per SD = 1.01 [0.97-1.05]). Results for individual BCAA metabolites suggested a modest association for leucine with obesity-related cancers (1.04 [1.00-1.08]), and no association for isoleucine or valine (0.99 [0.95-1.03] and 1.00 [0.96-1.04], respectively). Exploratory analyses of BCAAs with individual sites included positive associations between leucine and postmenopausal breast cancer, and isoleucine with pancreatic cancer. Total circulating BCAAs were unrelated to obesity-related cancer incidence although an association was observed for leucine with incident obesity-related cancer.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32967863

RESUMO

BACKGROUND: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. METHODS: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. RESULTS: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. CONCLUSIONS: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. IMPACT: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

3.
JAMA ; 324(5): 471-480, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32749491

RESUMO

Importance: Low levels of 25-hydroxyvitamin D have been associated with higher risk for depression later in life, but there have been few long-term, high-dose large-scale trials. Objective: To test the effects of vitamin D3 supplementation on late-life depression risk and mood scores. Design, Setting, and Participants: There were 18 353 men and women aged 50 years or older in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among 25 871 adults in the US. There were 16 657 at risk for incident depression (ie, no depression history) and 1696 at risk for recurrent depression (ie, depression history but no treatment for depression within the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017, and this was the final date of follow-up. Intervention: Randomized assignment in a 2 × 2 factorial design to vitamin D3 (2000 IU/d of cholecalciferol) and fish oil or placebo; 9181 were randomized to vitamin D3 and 9172 were randomized to matching placebo. Main Outcomes and Measures: The primary outcomes were the risk of depression or clinically relevant depressive symptoms (total of incident and recurrent cases) and the mean difference in mood scores (8-item Patient Health Questionnaire depression scale [PHQ-8]; score range, 0 points [least symptoms] to 24 points [most symptoms]; the minimal clinically important difference for change in scores was 0.5 points). Results: Among the 18 353 randomized participants (mean age, 67.5 [SD, 7.1] years; 49.2% women), the median treatment duration was 5.3 years and 90.5% completed the trial (93.5% among those alive at the end of the trial). Risk of depression or clinically relevant depressive symptoms was not significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/1000 person-years) (hazard ratio, 0.97 [95% CI, 0.87 to 1.09]; P = .62); there were no significant differences between groups in depression incidence or recurrence. No significant differences were observed between treatment groups for change in mood scores over time; mean change in PHQ-8 score was not significantly different from zero (mean difference for change in mood scores, 0.01 points [95% CI, -0.04 to 0.05 points]). Conclusions and Relevance: Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with vitamin D3 compared with placebo did not result in a statistically significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms or for change in mood scores over a median follow-up of 5.3 years. These findings do not support the use of vitamin D3 in adults to prevent depression. Trial Registration: ClinicalTrials.gov Identifiers: NCT01169259 and NCT01696435.


Assuntos
Afeto/efeitos dos fármacos , Colecalciferol/uso terapêutico , Depressão/tratamento farmacológico , Transtorno Depressivo/prevenção & controle , Vitaminas/uso terapêutico , Idoso , Colecalciferol/farmacologia , Depressão/prevenção & controle , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva , Inquéritos e Questionários , Vitaminas/farmacologia
4.
Cancer Res ; 80(18): 4004-4013, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32641412

RESUMO

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10-6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.

5.
Arthritis Rheumatol ; 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32583982

RESUMO

OBJECTIVE: Knee pain from osteoarthritis is frequent in the adult population. Prior trials have had conflicting results concerning the therapeutic effects of vitamin D on knee pain, and few trials have investigated marine Omega-3 fatty acids (n-3 FA). METHODS: In the double-blind, placebo-controlled Vitamin D and Omega-3 Trial (VITAL), 25,871 US adults were randomized in a 2-by-2 factorial design to receive vitamin D or n-3 FA. We identified a subgroup with chronic knee pain prior to randomization and assessed knee pain at baseline and annually during follow-up using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (graded on a 0-100 scale, where 100 indicates worst symptoms). Repeated measures modeling was used to test the effect of randomized treatment on WOMAC pain scores over follow-up after adjustment for age and sex. Analyses were repeated for WOMAC function and stiffness. RESULTS: This study included 1,398 participants who returned at least one knee pain questionnaire. The mean age was 67.7 years, 66% were women, and the mean ± SD WOMAC pain score was 37 ± 19. The mean ± SD follow-up time was 5.3 ± 0.7 years. WOMAC pain did not differ between the active vitamin D group and the vitamin D placebo group or between the active n-3 FA group and the n-3 FA placebo group at any time point during follow-up. Linear time-by-treatment interactions were not significant for either treatment (vitamin D, P = 0.41; n-3 FA, P = 0.77). Vitamin D and n-3 FA supplementation did not significantly affect WOMAC function or stiffness scores over time. CONCLUSION: Our findings indicate that vitamin D and n-3 FA supplementation for a mean of 5.3 years does not reduce knee pain or improve function or stiffness in a large sample of US adults with chronic knee pain.

6.
JAMA ; 323(22): 2281-2289, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32515815

RESUMO

Importance: Migraine with aura is known to increase the risk of cardiovascular disease (CVD). The absolute contribution of migraine with aura to CVD incidence in relation to other CVD risk factors remains unclear. Objective: To estimate the CVD incidence rate for women with migraine with aura relative to women with other major vascular risk factors. Design, Setting, and Participants: Female health professionals in the US (the Women's Health Study cohort) with lipid measurements and no CVD at baseline (1992-1995) were followed up through December 31, 2018. Exposures: Self-reported migraine with aura compared with migraine without aura or no migraine at baseline. Main Outcomes and Measures: The primary outcome was major CVD (first myocardial infarction, stroke, or CVD death). Generalized modeling procedures were used to calculate multivariable-adjusted incidence rates for major CVD events by risk factor status that included all women in the cohort. Results: The study population included 27 858 women (mean [SD] age at baseline, 54.7 [7.1] years), among whom 1435 (5.2%) had migraine with aura and 26 423 (94.8%) did not (2177 [7.8%] had migraine without aura and 24 246 [87.0%] had no migraine in the year prior to baseline). During a mean follow-up of 22.6 years (629 353 person-years), 1666 major CVD events occurred. The adjusted incidence rate of major CVD per 1000 person-years was 3.36 (95% CI, 2.72-3.99) for women with migraine with aura vs 2.11 (95% CI, 1.98-2.24) for women with migraine without aura or no migraine (P < .001). The incidence rate for women with migraine with aura was significantly higher than the adjusted incidence rate among women with obesity (2.29 [95% CI, 2.02-2.56]), high triglycerides (2.67 [95% CI, 2.38-2.95]), or low high-density lipoprotein cholesterol (2.63 [95% CI, 2.33-2.94]), but was not significantly different from the rates among those with elevated systolic blood pressure (3.78 [95% CI, 2.76-4.81]), high total cholesterol (2.85 [95% CI, 2.38-3.32]), or family history of myocardial infarction (2.71 [95% CI, 2.38-3.05]). Incidence rates among women with diabetes (5.76 [95% CI, 4.68-6.84]) or who currently smoked (4.29 [95% CI, 3.79-4.79]) were significantly higher than those with migraine with aura. The incremental increase in the incidence rate for migraine with aura ranged from 1.01 additional cases per 1000 person-years when added to obesity to 2.57 additional cases per 1000 person-years when added to diabetes. Conclusions and Relevance: In this study of female health professionals aged at least 45 years, women with migraine with aura had a higher adjusted incidence rate of CVD compared with women with migraine without aura or no migraine. The clinical importance of these findings, and whether they are generalizable beyond this study population, require further research.


Assuntos
Doenças Cardiovasculares/etiologia , Enxaqueca com Aura/complicações , Enxaqueca sem Aura/complicações , Doenças Cardiovasculares/epidemiologia , Complicações do Diabetes , Feminino , Seguimentos , Humanos , Hiperlipidemias/complicações , Incidência , Pessoa de Meia-Idade , Modelos Cardiovasculares , Obesidade/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Fumar/efeitos adversos , Saúde da Mulher
7.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1784-1791, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32546605

RESUMO

BACKGROUND: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. METHODS: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. RESULTS: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10-6) was observed in the meta-analysis (P GxE = 1.2 ×10-6, P Joint = 4.2 ×10-7). CONCLUSIONS: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. IMPACT: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

8.
J Clin Endocrinol Metab ; 105(9)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32492153

RESUMO

CONTEXT: It is unclear whether vitamin D supplementation reduces risk of falls, and results from randomized controlled trials (RCTs) are conflicting. OBJECTIVE: The objective of this work is to determine whether 2000 IU/day of supplemental vitamin D3 decreases fall risk. DESIGN: VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT including 25 871 adults, randomly assigned November 2011 to March 2014 and treated for 5.3 years (median). SETTING: This is a nationwide study. PARTICIPANTS: Men 50 years or older and women 55 years or older (mean age, 67.1 years) without cancer or cardiovascular disease at baseline participated in this study. INTERVENTIONS: Interventions included vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (1 g/day) or respective placebos in a 2 × 2 factorial design. MAIN OUTCOME MEASURES: Main outcome measures include 2 or more falls and falls resulting in a doctor or hospital visit. RESULTS: Baseline serum total 25-hydroxyvitamin D (25[OH]D) level was 77 nmol/L; characteristics were well-balanced between groups. Numbers of participants with 2 or more falls were similar between active and placebo groups (9.8% vs 9.4%). Over 5 years, there were no differences in the proportion having 2 or more falls (odds ratio [OR] = 0.97; 95% CI, 0.90-1.05, P = .50), falls resulting in a doctor visit (OR = 1.03; 95% CI, 0.94-1.13, P = .46), or resulting in a hospital visit (OR = 1.04; 95% CI, 0.90-1.19, P = .61) between groups. Results did not differ between those with baseline 25(OH)D less than 50 vs 50 nmol/L or greater or other cut points. CONCLUSION: Daily supplemental vitamin D3 vs placebo did not decrease fall risk in generally healthy adults not selected for vitamin D insufficiency. This large RCT does not indicate that supplemental vitamin D should be used for primary prevention of falls in the US population.

9.
Br J Cancer ; 123(2): 316-324, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32376888

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -ß, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC. METHODS: We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases). RESULTS: Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors. CONCLUSIONS: This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

10.
J Am Coll Cardiol ; 75(17): 2122-2135, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32354380

RESUMO

BACKGROUND: Elevated triglyceride-rich lipoprotein (TRL) and small-dense low-density lipoprotein (sdLDL) particles are hallmarks of atherogenic dyslipidemia, and their cholesterol content is hypothesized to drive atherosclerotic risk. Prospective epidemiological data pertaining to cholesterol content of TRLs and sdLDL in primary prevention populations are mostly limited to coronary heart disease. OBJECTIVES: The purpose of this study was to prospectively evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD) outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD). METHODS: In a prospective case-cohort study within the Women's Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). Models were adjusted for traditional risk factors, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. RESULTS: The risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with MI and PAD (MI hazard ratio [HR]Q4: 3.05 [95% confidence interval (CI): 1.46 to 6.39]; ptrend = 0.002; PAD HRQ4: 2.58 [95% CI: 1.18 to 5.63]; ptrend = 0.019), whereas sdLDL-C was significantly associated with MI alone (HRQ4: 3.71 [95% CI: 1.59 to 8.63]; ptrend < 0.001). Both markers weakly associated with IS. Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B <100 mg/dl). CONCLUSIONS: TRL-C strongly associates with future MI and PAD events, whereas sdLDL-C strongly associates with MI alone. These findings signal that the cholesterol content of TRLs and sdLDL influence atherogenesis independently of low-density lipoprotein cholesterol, and high sensitivity C-reactive protein, with potentially different potency across vascular beds. (Women's Health Study; NCT00000479).

11.
J Hepatol ; 73(4): 863-872, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32437829

RESUMO

BACKGROUND & AIMS: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear. METHODS: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study. RESULTS: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only. CONCLUSION: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography. LAY SUMMARY: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.

12.
J Headache Pain ; 21(1): 27, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32183686

RESUMO

BACKGROUND: Migraine carries a high global burden, disproportionately affects women, and has been implicated as a risk factor for cardiovascular disease. Migraine with aura has been consistently associated with increased risk of cardiovascular mortality. However, published evidence on relationships between migraine or non-migraine headache and all-cause mortality is inconclusive. Therefore, we aimed to estimate the effect of non-migraine headache and migraine as well as migraine subtypes on all-cause and cause-specific mortality in women. METHODS: In total, 27,844 Women's Health Study participants, aged 45 years or older at baseline, were followed up for a median of 22.7 years. We included participants who provided information on migraine (past history, migraine without aura, or migraine with aura) or headache status and a blood sample at study start. An endpoints committee of physicians evaluated reports of incident deaths and used medical records to confirm deaths due to cardiovascular, cancer, or female-specific cancer causes. We used multivariable Cox proportional hazards models to estimate the effect of migraine or headache status on both all-cause and cause-specific mortality. RESULTS: Compared to individuals without any headache, no differences in all-cause mortality for individuals suffering from non-migraine headache or any migraine were observed after adjustment for confounding (HR = 1.01, 95%CI, 0.93-1.10 and HR = 0.96, 95% CI: 0.89-1.04). No differences were observed for the migraine subtypes and all-cause death. Women having the migraine with aura subtype had  a higher mortality due to cardiovascular disease (adjusted HR = 1.64, 95%CI: 1.06-2.54). As an explanation for the lack of overall association with all-cause mortality, we observed slightly protective signals for any cancer and female-specific cancers in this group. CONCLUSIONS: In this large prospective study of women, we found no association between non-migraine headache or migraine and all-cause mortality. Women suffering from migraine with aura had an increased risk of cardiovascular death. Future studies should investigate the reasons for the increased risk of cardiovascular mortality and evaluate whether changes in migraine patterns across the life course have differential effects on mortality.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Cefaleia/epidemiologia , Cefaleia/mortalidade , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/mortalidade , Idoso , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
13.
J Clin Lipidol ; 14(2): 241-251, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32205068

RESUMO

BACKGROUND: Elevated postprandial triglycerides reflect a proatherogenic milieu, but underlying mechanisms are unclear. OBJECTIVE: We examined differences between fasting and nonfasting profiles of directly measured lipoprotein size and subfractions to assess if postprandial triglycerides reflected increases in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and remnants, or small dense lipid depleted LDL (sdLDL) particles. METHODS: We conducted a cross-sectional analysis of 15,397 participants (10,135 fasting; 5262 nonfasting [<8 hours since last meal]) from the VITamin D and OmegA-3 TriaL. Baseline cholesterol subfractions were measured by the vertical auto profile method and particle subfractions by ion mobility. We performed multivariable linear regression adjusting for cardiovascular and lipoprotein-modifying risk factors. RESULTS: Mean age (SD) was 68.0 years (±7.0), with 50.9% women. Adjusted mean triglyceride concentrations were higher nonfasting by 17.8 ± 1.3%, with higher nonfasting levels of directly measured VLDL cholesterol (by 3.5 ± 0.6%) and total VLDL particles (by 2.0 ± 0.7%), specifically large VLDL (by 12.3 ± 1.3%) and medium VLDL particles (by 5.3 ± 0.8%), all P < .001. By contrast, lower concentrations of low density lipoprotein (LDL) and IDL cholesterol and particles were noted for nonfasting participants. sdLDL cholesterol levels and particle concentrations showed no statistically significant difference by fasting status (-1.3 ± 2.1% and 0.07 ± 0.6%, respectively, P > .05). CONCLUSIONS: Directly measured particle and cholesterol concentrations of VLDL, not sdLDL, were higher nonfasting and may partly contribute to the proatherogenicity of postprandial hypertriglyceridemia. These differences, although statistically significant, were small and may not fully explain the increased risk of postprandial hypertriglyceridemia.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32062040

RESUMO

BACKGROUND & AIMS: The effects of vitamin D on risk of colorectal cancer precursors are not clear. We examined the influence of vitamin D supplementation on risk of colorectal adenomas and serrated polyps in a prespecified ancillary study of a large-scale prevention trial (the vitamin D and omegA-3 trial, VITAL) of individuals who were free of cancer and cardiovascular disease at enrollment. METHODS: In VITAL trial, 25,871 adults with no history of cancer or cardiovascular disease (12,786 men 50 years or older and 13,085 women 55 years or older) were randomly assigned to groups given daily dietary supplements (2000 IU vitamin D3 and 1 g marine n-3 fatty acid) or placebo. Patients were assigned to groups from November 2011 through March 2014 and the study ended on December 31, 2017. We confirmed conventional adenomas and serrated polyps by reviewing histopathology reports from participants who had reported a diagnosis of polyps and were asked by their doctors to return for a repeat colonoscopy or sigmoidoscopy in 5 years or less. We calculated the odds ratios (ORs) and 95% CIs by logistic regression, after adjusting for age, sex, n-3 treatment assignment, and history of endoscopy at time of randomization. RESULTS: During a median follow-up of 5.3 years, we documented 308 cases of conventional adenomas in 12,927 participants in the vitamin D group and 287 cases in 12,944 participants in the placebo group (OR for the association of vitamin D supplementation with adenoma, 1.08; 95% CI, 0.92-1.27). There were 172 cases of serrated polyps in the vitamin D group and 169 cases in the placebo group (OR for the association of vitamin D supplementation with serrated polyp, 1.02; 95% CI, 0.82-1.26). Supplementation was not associated with polyp size, location, multiplicity, or histologic features. We found evidence for an interaction between vitamin D supplementation and serum level of 25-hydroxyvitamin D, measured in 15,787 participants. Among individuals with serum levels of 25-hydroxyvitamin D below 30 ng/mL, the OR associated with supplementation for conventional adenoma was 0.82 (95% CI, 0.60-1.13), whereas among individuals with serum levels of 25-hydroxyvitamin D above 30 ng/mL, the OR for conventional adenoma was 1.20 (95% CI, 0.92-1.55) (P for interaction = .07). There was a significant interaction between vitamin D supplementation and serum level of 25-hydroxyvitamin D in their association with advanced adenoma (P for interaction = .04). CONCLUSIONS: Based on an ancillary study of data from the VITAL trial, daily vitamin D supplementation (2000 IU) was not associated with risk of colorectal cancer precursors in average-risk adults not selected for vitamin D insufficiency. A potential benefit for individuals with low baseline level of vitamin D requires further investigation. ClinicalTrials.gov number: NCT01169259.

15.
J Stroke Cerebrovasc Dis ; 29(5): 104704, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32093989

RESUMO

BACKGROUND: Few prospective cohort studies collect detailed information on stroke characteristics among individuals who experience ischemic stroke, including white matter hyperintensity volume, and thus cannot explore how prospectively collected biomarkers prior to the stroke influence white matter hyperintensity volume. We explored the association between a large panel of prospectively collected lipid and inflammatory biomarkers and white matter hyperintensity volume among participants in the Women's Health Study with incident ischemic stroke. METHODS: Among Women's Health Study participants with first ischemic stroke who had baseline serum biomarkers and available magnetic resonance imaging, we measured white matter hyperintensity volume using a validated semi-automated method. Linear regression was used to explore the associations between biomarkers and log-transformed white matter hyperintensity volume. RESULTS: After multivariate adjustment, a 1% increment in HbA1c% was associated with an increase in white matter hyperintensity volume (P value = .05). Evidence of a nonlinear association between high density lipoprotein cholesterol levels and ApoA1 levels with white matter hyperintensity volume was noted (P values for nonlinearity = .01 and .001, respectively). No other biomarkers were significantly associated with white matter hyperintensity volume. CONCLUSIONS: Chronic hyperglycemia as evidenced by HbA1c levels measured years prior to stroke is associated with white matter hyperintensity volume at the time of stroke. Additional research is needed to explain why low levels of high density lipoprotein cholesterol levels and ApoA1 may be associated with similar white matter hyperintensity volume as high levels.


Assuntos
Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico por imagem , Hemoglobina A Glicada/análise , Hiperglicemia/sangue , Imagem por Ressonância Magnética , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína A-I/sangue , Biomarcadores/sangue , Isquemia Encefálica/epidemiologia , HDL-Colesterol/sangue , Feminino , Humanos , Hiperglicemia/diagnóstico , Hiperglicemia/epidemiologia , Incidência , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia
16.
Cancer Res ; 80(5): 1210-1218, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31932455

RESUMO

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. SIGNIFICANCE: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.


Assuntos
Neoplasias Ovarianas/epidemiologia , Ovário/imunologia , Ovulação/imunologia , Idoso , Anticoncepcionais/administração & dosagem , Tubas Uterinas/imunologia , Tubas Uterinas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/prevenção & controle , Ovário/patologia , Ovulação/efeitos dos fármacos , Modelos de Riscos Proporcionais , Estudos Prospectivos , História Reprodutiva , Medição de Risco , Fatores de Risco
17.
J Bone Miner Res ; 35(5): 883-893, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31923341

RESUMO

Although supplemental vitamin D is used to promote bone health in the general population, data from randomized controlled trials (RCTs) have been inconsistent. We determined whether daily, vitamin D3 supplementation improves bone mineral density (BMD) and/or structure. VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT of supplemental vitamin D3 (2000 IU/d) and/or omega-3 fatty acids (1 g/d) in 25,871 adults nationwide. This ancillary study included a subcohort of 771 participants (men ≥50 and women ≥55 years; not taking bone active medications) evaluated at baseline and at 2-year follow-up (89% retention). Total 25(OH)D levels were measured by liquid chromatography tandem mass spectrometry (Quest Diagnostics, San Juan Capistrano, CA, USA). Free 25(OH)D (FVD) levels were measured using the ELISA assay by Future Diagnostics Solutions BV (Wijchen, Netherlands). Primary endpoints were 2-year changes in areal (a) BMD at the spine, hip, and whole body determined by dual-energy X-ray absorptiometry (DXA). Secondary endpoints were 2-year changes in volumetric (v) BMD and cortical thickness at the radius and tibia assessed by peripheral quantitative computed tomography. Supplemental vitamin D3 versus placebo had no effect on 2-year changes in aBMD at the spine (0.33% versus 0.17%; p = 0.55), femoral neck (-0.27% versus -0.68%; p = 0.16), total hip (-0.76% versus -0.95%; p = 0.23), or whole body (-0.22% versus -0.15%; p = 0.60), or on measures of bone structure. Effects did not vary by sex, race/ethnicity, body mass index, or 25(OH)D levels. Among participants with baseline FVD levels below the median (<14.2 pmol/L), there was a slight increase in spine aBMD (0.75% versus 0%; p = 0.043) and attenuation in loss of total hip aBMD (-0.42% versus -0.98%; p = 0.044) with vitamin D3 . Whether baseline FVD levels help to identify those more likely to benefit from supplementation warrants further study. Supplemental vitamin D3 versus placebo for 2 years in general healthy adults not selected for vitamin D insufficiency did not improve BMD or structure. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

18.
Circ Res ; 126(1): 112-128, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31895658

RESUMO

Whether marine omega-3 fatty acid (n-3 FA) or vitamin D supplementation can prevent cardiovascular disease (CVD) in general populations at usual risk for this outcome is unknown. A major goal of VITAL (Vitamin D and Omega-3 Trial) was to fill this knowledge gap. In this article, we review the results of VITAL, discuss relevant mechanistic studies regarding n-3 FAs, vitamin D, and vascular disease, and summarize recent meta-analyses of the randomized trial evidence on these agents. VITAL was a nationwide, randomized, placebo-controlled, 2×2 factorial trial of marine n-3 FAs (1 g/d) and vitamin D3 (2000 IU/d) in the primary prevention of CVD and cancer among 25 871 US men aged ≥50 and women aged ≥55 years, including 5106 blacks. Median treatment duration was 5.3 years. Supplemental n-3 FAs did not significantly reduce the primary cardiovascular end point of major CVD events (composite of myocardial infarction, stroke, and CVD mortality; hazard ratio [HR], 0.92 [95% CI, 0.80-1.06]) but were associated with significant reductions in total myocardial infarction (HR, 0.72 [95% CI, 0.59-0.90]), percutaneous coronary intervention (HR, 0.78 [95% CI, 0.63-0.95]), and fatal myocardial infarction (HR, 0.50 [95% CI, 0.26-0.97]) but not stroke or other cardiovascular end points. For major CVD events, a treatment benefit was seen in those with dietary fish intake below the cohort median of 1.5 servings/wk (HR, 0.81 [95% CI, 0.67-0.98]) but not in those above (P interaction=0.045). For myocardial infarction, the greatest risk reductions were in blacks (HR, 0.23 [95% CI, 0.11-0.47]; P interaction by race, 0.001). Vitamin D supplementation did not reduce major CVD events (HR, 0.97 [95% CI, 0.85-1.12]) or other cardiovascular end points. Updated meta-analyses that include VITAL and other recent trials document coronary risk reduction from supplemental marine n-3 FAs but no clear CVD risk reduction from supplemental vitamin D. Additional research is needed to determine which individuals may be most likely to derive net benefit from supplementation. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01169259.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Ácidos Graxos Ômega-3/uso terapêutico , Óleos de Peixe/uso terapêutico , Vitamina D/uso terapêutico , Adulto , Afro-Americanos/estatística & dados numéricos , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etnologia , Suplementos Nutricionais , Método Duplo-Cego , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Óleos de Peixe/administração & dosagem , Seguimentos , Hispano-Americanos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Revascularização Miocárdica/estatística & dados numéricos , Neoplasias/epidemiologia , Neoplasias/prevenção & controle , Obesidade/epidemiologia , Prevenção Primária , Utilização de Procedimentos e Técnicas/estatística & dados numéricos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Estados Unidos/epidemiologia , Vitamina D/administração & dosagem
19.
Int J Cancer ; 146(9): 2394-2405, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276202

RESUMO

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

20.
J Steroid Biochem Mol Biol ; 198: 105522, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31733345

RESUMO

Whether supplemental vitamin D reduces risk of cancer or cardiovascular disease (CVD) is relatively unexplored in randomized trial settings. The VITamin D and OmegA-3 TriaL (VITAL) was a nationwide, randomized, placebo-controlled, 2 × 2 factorial trial of daily vitamin D3 (2000 IU) and marine omega-3 fatty acids (1 g) in the primary prevention of cancer and CVD among 25,871 U.S. men aged ≥50 and women aged ≥55, including 5106 African Americans. Median treatment duration was 5.3 years. Vitamin D did not significantly reduce the primary endpoint of total invasive cancer incidence (hazard ratio [HR] = 0.96 [95% confidence interval 0.88-1.06]) but showed a promising signal for reduction in total cancer mortality (HR = 0.83 [0.67-1.02]), especially in analyses that accounted for latency by excluding the first year (HR = 0.79 [0.63-0.99]) or first 2 years (HR = 0.75 [0.59-0.96]) of follow-up. Vitamin D did not significantly reduce the co-primary endpoint of major CVD events (HR = 0.97 [0.85-1.12]), other cardiovascular endpoints, or all-cause mortality (HR = 0.99 [0.87-1.12]). Updated meta-analyses that include VITAL and other recent vitamin D trials indicate a significant reduction in cancer mortality but not in cancer incidence or CVD endpoints. Additional research is needed to determine which individuals may be most likely to derive a net benefit from vitamin D supplementation. (VITAL clinicaltrials.gov identifier: NCT01169259).

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