Vitamin D supplementation and total cancer incidence and mortality by daily vs. infrequent large-bolus dosing strategies: a meta-analysis of randomised controlled trials.

BACKGROUND: Efficacy of vitamin D supplementation may vary by dosing strategies and adiposity. To address such heterogeneity, we performed a meta-analysis of randomised controlled trials of vitamin D supplementation and total cancer outcomes. METHODS: PubMed and Embase were searched through January 2022. Summary relative risk (SRR) and 95% confidence interval (CI) were estimated using the DerSimonian-Laird random-effects model. RESULTS: For total cancer incidence (12 trials), the SRR for vitamin D supplementation vs. control group was 0.99 (95% CI, 0.94-1.03; P = 0.54; I2 = 0%). No significant association was observed regardless of whether the supplement was given daily or infrequently in a large-bolus. Yet, among trials testing daily supplementation, a significant inverse association was observed among normal-weight individuals (SRR, 0.76; 95% CI, 0.64-0.90; P = 0.001, I2 = 0%), but not among overweight or obese individuals (Pheterogeneity = 0.02). For total cancer mortality (six trials), the SRR was 0.92 (95% CI, 0.82-1.03; P = 0.17; I2 = 33%). A significant inverse association emerged (SRR, 0.87; 95% CI, 0.78-0.96; P = 0.007; I2 = 0%) among studies testing daily supplementations but not among studies that testing infrequent large-bolus supplementations (Pheterogeneity = 0.09). CONCLUSIONS: For vitamin D supplementation, daily dosing, but not infrequent large-bolus dosing, reduced total cancer mortality. For total cancer incidence, bolus dosing did not reduce the risk and the benefits of daily dosing were limited to normal-weight individuals.

Vitamin D, respiratory infections, and chronic disease: Review of meta-analyses and randomized clinical trials.

BACKGROUND: Observational studies have suggested associations of vitamin D deficiency (VDD) with respiratory tract infections, impaired bone health, and myriad chronic diseases. OBJECTIVE: To assess potential causal relationships between vitamin D supplementation and a reduced risk of these conditions, a review of the evidence across available meta-analyses of randomized control trials (RCTs) and RCTs was performed. METHOD: PubMed, Embase, Cochrane Library, and Web of Science were searched from their inception to March 2021. We included only RCTs and meta-analyses of RCTs focusing on the association between vitamin D and respiratory disease, bone health, cardiovascular disease (CVD), diabetes mellitus, and cancer. RESULTS: A total of 107 RCTs and 62 meta-analysis of RCTs were included. Although most RCTs did not support benefits of vitamin D supplementation, suggestive evidence for benefit was found in populations at greater risk of VDD and for acute respiratory infections, fractures in institutionalized older adults, type 2 diabetes among patients with prediabetes, and cancer mortality. In contrast, no compelling evidence for benefit was found for other respiratory conditions, fractures in community-dwelling adults, falls, cancer incidence, or CVD. CONCLUSIONS: Current evidence from RCTs and meta-analyses of RCTs is inconsistent regarding the effects of vitamin D supplementation on respiratory infections and chronic diseases. Individuals most likely to benefit are those with baseline VDD or with selected high-risk conditions. Public health initiatives are needed to eliminate VDD globally, and future research will be enhanced by a 'precision prevention' approach to identify those most likely to benefit from vitamin D supplementation.

Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials.

BACKGROUND: Previous meta-analyses of randomized controlled trials (RCTs) of vitamin D supplementation and total cancer incidence and mortality found inconsistent results, and most included trials administered generally low doses of vitamin D (≤1100 IU/day). We updated the meta-analysis by incorporating recent RCTs that have tested higher doses of vitamin D supplements. MATERIALS AND METHODS: PubMed and Embase were searched from the inception to November 2018. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random-effects model. RESULTS: For total cancer incidence, 10 trials were included [6537 cases; 3-10 years of follow-up; 54-135 nmol/l of attained levels of circulating 25(OH) vitamin D [25(OH)D] in the intervention group]. The summary RR was 0.98 (95% CI, 0.93-1.03; P = 0.42; I2 = 0%). The results remained null across subgroups tested, including even when attained 25(OH)D levels exceeded 100 nmol/l (RR, 0.95; 95% CI, 0.83-1.09; P = 0.48; I2 = 26%). For total cancer mortality, five trials were included [1591 deaths; 3-10 years of follow-up; 54-135 nmol/l of attained levels of circulating 25(OH)D in the intervention group]. The summary RR was 0.87 (95% CI, 0.79-0.96; P = 0.005; I2 = 0%), which was largely attributable to interventions with daily dosing (as opposed to infrequent bolus dosing). No statistically significant heterogeneity was observed by attained levels of circulating 25(OH)D (Pheterogeneity = 0.83), with RR being 0.88 (95% CI, 0.78-0.98; P = 0.02; I2 = 0%) for ≤100 nmol/l and 0.85 (95% CI, 0.70-1.03; P = 0.11; I2 = 0%) for >100 nmol/l. CONCLUSIONS: In an updated meta-analysis of RCTs, vitamin D supplementation significantly reduced total cancer mortality but did not reduce total cancer incidence.

VITamin D and OmegA-3 TriaL (VITAL) bone health ancillary study: clinical factors associated with trabecular bone score in women and men.

We investigated the association of clinical variables with TBS at baseline in the bone health sub-cohort of the VITamin D and OmegA-3 TriaL (VITAL). Lower TBS was associated with female sex, aging, BMI ≥ 25 kg/m2, SSRI use, high alcohol intake, and presence of diabetes; there was a trend towards significance between lower TBS and history of fragility fractures. INTRODUCTION: We investigated whether TBS differs by sex, race, body mass index (BMI), and other clinical variables. METHODS: The VITamin D and OmegA-3 TriaL (VITAL) is determining effects of vitamin D3 and/or omega-3 fatty acid (FA) supplements in reducing risks of cancer and cardiovascular disease. In the VITAL: Effects on Bone Structure/Architecture ancillary study, effects of these interventions on bone will be investigated. Here, we examine the associations of clinical risk factors with TBS assessments at baseline in the bone health sub-cohort, comprised of 672 participants (369 men and 303 women), mean (± SD) age 63.5 ± 6.0 years; BMI ≤ 37 kg/m2, no bisphosphonates within 2 years or other bone active medications within 1 year. RESULTS: TBS was greater in men than women (1.311 vs. 1.278, P < 0.001) and lower with elevated BMIs (P < 0.001), higher age (P = 0.004), diabetes (P = 0.008), SSRI use (P = 0.044), and high alcohol intake (P = 0.009). There was a trend for history of fragility fractures (P = 0.072), and lower TBS. TBS did not vary when analyzed by race, smoking, history of falls, and multivitamin or caffeine use. CONCLUSIONS: Lower TBS was associated with female sex, aging, BMI ≥ 25 kg/m2, SSRI use, alcohol use, and presence of diabetes; there was a trend between lower TBS and history of fragility fractures. TBS may be useful clinically to assess structural changes that may be associated with fractures among patients who are overweight or obese, those on SSRIs, or with diabetes. Ongoing follow-up studies will clarify the effects of supplemental vitamin D3 and/or FA's on TBS and other bone health measures. TRIAL REGISTRATION: NCT01747447.

Consumption of soy foods and isoflavones and risk of type 2 diabetes: a pooled analysis of three US cohorts.

BACKGROUND/OBJECTIVES: Evidence regarding the consumption of soy foods and isoflavones in relation to risk of type 2 diabetes (T2D) is scarce. Our study was to evaluate the association between soy food and isoflavone consumption and risk of T2D in US men and women. SUBJECTS/METHODS: We followed 63 115 women in the Nurses' Health Study (1998-2012), 79 061 women in the Nurses' Health Study II (1999-2013) and 21 281 men in the Health Professionals Follow-Up Study (2002-2010). Diet was assessed by a validated food-frequency questionnaire and was updated every 4 years. Self-reports of incident T2D were confirmed by a validated supplementary questionnaire. RESULTS: During 1 966 321 person-years of follow-up, 9185 incident T2D cases were documented. After multivariate adjustment for covariates, consumption of soy foods (tofu and soy milk) was not associated with a lower T2D risk. Compared with non-consumers of soy foods, the hazard ratio (HR) was 1.00 (95% confidence interval (CI): 0.93, 1.07) for <1 serving/week and 0.93 (95% CI: 0.83, 1.03) for ⩾1 serving/week of soy foods (P for trend=0.14). In contrast, intake of total isoflavones was inversely associated with T2D risk. Comparing extreme quintiles of isoflavones, the HR was 0.89 (95% CI: 0.83, 0.96; P for trend=0.009). Inverse associations were also found for consumption of major individual isoflavones, including daidzein and genistein, with risk of T2D. CONCLUSIONS: Intake of isoflavones was associated with a modestly lower T2D risk in US men and women who typically consumed low-to-moderate amounts of soy foods. These findings warrant replications in other populations with similar soy intake levels.

Calcium supplement intake and risk of cardiovascular disease in women.

UNLABELLED: Some recent reports suggest that calcium supplement use may increase risk of cardiovascular disease. In a prospective cohort study of 74,245 women in the Nurses' Health Study with 24 years of follow-up, we found no independent associations between supplemental calcium intake and risk of incident coronary heart disease (CHD) and stroke. INTRODUCTION: Some recent reports suggest that calcium supplements may increase cardiovascular disease (CVD) risk. The objective was to examine the independent associations between calcium supplement use and risk of CVD. METHODS: We conducted a prospective cohort study of supplemental calcium use and incident CVD in 74,245 women in the Nurses' Health Study (1984-2008) free of CVD and cancer at baseline. Calcium supplement intake was assessed every 4 years. Outcomes were incident CHD (nonfatal or fatal MI) and stroke (ischemic or hemorrhagic), confirmed by medical record review. RESULTS: During 24 years of follow-up, 4,565 cardiovascular events occurred (2,709 CHD and 1,856 strokes). At baseline, women who took calcium supplements had higher levels of physical activity, smoked less, and had lower trans fat intake compared with those who did not take calcium supplements. After multivariable adjustment for age, body mass index, dietary calcium, vitamin D intake, and other CVD risk factors, the relative risk of CVD for women taking >1,000 mg/day of calcium supplements compared with none was 0.82 (95% confidence interval [CI] 0.74 to 0.92; p for trend <0.001). For women taking >1,000 mg/day of calcium supplements compared with none, the multivariable-adjusted relative risk for CHD was 0.71 (0.61 to 0.83; p for trend < 0.001) and for stroke was 1.03 (0.87 to 1.21; p for trend = 0.61). The relative risks were similar in analyses limited to non-smokers, women without hypertension, and women who had regular physical exams. CONCLUSIONS: Our findings do not support the hypothesis that calcium supplement intake increases CVD risk in women.

Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study.

SUMMARY: The Women's Health Initiative (WHI) double-blind, placebo-controlled clinical trial randomly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D(3) daily or placebo, with average intervention period of 7.0 years. The trial was designed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture, and secondarily, total fracture and colorectal cancer. INTRODUCTION: This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality. METHODS: WHI calcium and vitamin D randomized clinical trial (CT) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation, and these data were contrasted and combined with corresponding data from the WHI prospective observational study (OS). RESULTS: Among women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio [HR] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 (95 % confidence interval (CI), 0.38-1.00). In combined analyses of CT and OS data, the corresponding HR was 0.65 (95 % CI, 0.44-0.98). Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive. CONCLUSION: Though based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women. Other health benefits and risks of supplementation at doses considered, including an elevation in urinary tract stone formation, appear to be modest and approximately balanced.

Pressure-induced local structure distortions in Cu(pyz)F2(H2O)2.

We employed infrared spectroscopy along with complementary lattice dynamics and spin density calculations to investigate pressure-driven local structure distortions in the copper coordination polymer Cu(pyz)F(2)(H(2)O)(2). Here, pyz is pyrazine. Our study reveals rich and fully reversible local lattice distortions that buckle the pyrazine ring, disrupt the bc-plane O-H···F hydrogen-bonding network, and reinforce magnetic property switching. The resiliency of the soft organic ring is a major factor in the stability of this material. Interestingly, the collective character of the lattice vibrations masks direct information on the Cu-N and Cu-O linkages through the series of pressure-induced Jahn-Teller axis switching transitions, although Cu-F bond softening is clearly identified above 3 GPa. These findings illustrate the importance of combined bulk and local probe techniques for microscopic structure determination in complex materials.

Division of labour within flowers: heteranthery, a floral strategy to reconcile contrasting pollen fates.

In many nectarless flowering plants, pollen serves as both the carrier of male gametes and as food for pollinators. This can generate an evolutionary conflict if the use of pollen as food by pollinators reduces the number of gametes available for cross-fertilization. Heteranthery, the production of two or more stamen types by individual flowers reduces this conflict by allowing different stamens to specialize in 'pollinating' and 'feeding' functions. We used experimental studies of Solanum rostratum (Solanaceae) and theoretical models to investigate this 'division of labour' hypothesis. Flight cage experiments with pollinating bumble bees (Bombus impatiens) demonstrated that although feeding anthers are preferentially manipulated by bees, pollinating anthers export more pollen to other flowers. Evolutionary stability analysis of a model of pollination by pollen consumers indicated that heteranthery evolves when bees consume more pollen than should optimally be exchanged for visitation services, particularly when pollinators adjust their visitation according to the amount of pollen collected.

Effects of oral magnesium supplementation on glycaemic control in Type 2 diabetes: a meta-analysis of randomized double-blind controlled trials.

AIMS: The aim of this study was to assess the evidence on the effect of oral magnesium supplementation on glycaemic control in patients with Type 2 diabetes. METHODS: We searched the electronic databases of medline, embase and the Cochrane Controlled Trials Register up to January 2005. We identified nine randomized double-blind controlled trials with a total of 370 patients with Type 2 diabetes and of duration 4-16 weeks. The median dose of oral magnesium supplementation was 15 mmol/day (360 mg/day) in the treatment groups. The primary outcome was glycaemic control, as measured by glycated haemoglobin (HbA(1c)) or fasting blood glucose levels; the secondary outcomes included body mass index, blood pressure (BP) and lipids. Using a random-effects model, we calculated the weighted mean differences (WMD) and 95% confidence interval (CI). RESULTS: After a median duration of 12 weeks, the weighted mean post-intervention fasting glucose was significantly lower in the treatment groups compared with the placebo groups [-0.56 mmol/l (95% CI, -1.10 to -0.01); P for heterogeneity = 0.02]. The difference in post-intervention HbA(1c) between magnesium supplementation groups and control groups was not significant [-0.31% (95% CI, -0.81 to 0.19); P for heterogeneity = 0.10]. Neither systolic nor diastolic BP was significantly changed. Magnesium supplementation increased on high-density lipoprotein (HDL) cholesterol levels [0.08 mmol/l (95% CI, 0.03 to 0.14); P for heterogeneity = 0.36] but had no effect on total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride. CONCLUSIONS: Oral magnesium supplementation for 4-16 weeks may be effective in reducing plasma fasting glucose levels and raising HDL cholesterol in patients with Type 2 diabetes, although the long-term benefits and safety of magnesium treatment on glycaemic control remain to be determined.

Pilot study of preoperative combined modality treatment for locally advanced operable oesophageal carcinoma: toxicities and long-term outcome.

AIMS: Paclitaxel, a radiosensitiser, has significant activity in oesophageal cancer. We aimed to conduct a feasibility study of preoperative chemoradiation using paclitaxel, cisplatin and 5-fluorouracil (5-FU). MATERIALS AND METHODS: Sixteen eligible patients were enrolled. Infusional 5-FU, paclitaxel and cisplatin were given for 6 weeks before and concurrent with radiation. Conformal radiotherapy was delivered in two phases (45 Gy in 25 fractions). RESULTS: A total of 62.5% of the patients experienced Grade 3-4 toxicities, 50% required admission; one patient died during the neo-adjuvant phase. Twelve (75%) patients had oesophagectomy, and two (12.5%) died after surgery. Pathological complete remission (PCR) and minimal residual disease were observed in 25% (95% CI 0.5-49.5%) and 18% (95% CI 0-38%) of patients, respectively, who underwent surgery. The median survival was 39.7 months (95% CI 15, not reached); 1-, 2-, 3-, and 4-year survivals were 75% (95% CI 56.5-99.5), 56.3% (36.5-86.7), 50% (30.6-81.6), and 50% (30.6-81.6), respectively. CONCLUSION: Paclitaxel, cisplatin and 5-FU (TCF)-chemoradiation is an active regimen; the current dose schedule tested is associated with unacceptable toxicity, and cannot be recommended for routine clinical use.

Randomised beta-carotene supplementation and incidence of cancer and cardiovascular disease in women: is the association modified by baseline plasma level?

In a nested case-control study of 513 women with cancer; 130 with cardiovascular disease and equal numbers of controls, we found no effect of randomised beta-carotene on risk of cancer or cardiovascular disease within any quartile of baseline plasma beta-carotene, nor was there a trend across quartiles (P for trend 0.15 and 0.62, respectively).

Types of dietary fat and risk of coronary heart disease: a critical review.

During the past several decades, reduction in fat intake has been the main focus of national dietary recommendations to decrease risk of coronary heart disease (CHD). Several lines of evidence. however, have indicated that types of fat have a more important role in determining risk of CHD than total amount of fat in the diet. Metabolic studies have long established that the type of fat, but not total amount of fat, predicts serum cholesterol levels. In addition, results from epidemiologic studies and controlled clinical trials have indicated that replacing saturated fat with unsaturated fat is more effective in lowering risk of CHD than simply reducing total fat consumption. Moreover, prospective cohort studies and secondary prevention trials have provided strong evidence that an increasing intake of n-3 fatty acids from fish or plant sources substantially lowers risk of cardiovascular mortality. In this article, we review evidence from epidemiologic studies and dietary intervention trials addressing the relationship between dietary fat intake and risk of CHD, with a particular emphasis on different major types of fat, n-3 fatty acids and the optimal balance between n-3 and n-6 fatty acids. We also discuss the implications of the available evidence in the context of current dietary recommendations.

Intake of fish and omega-3 fatty acids and risk of stroke in women.

CONTEXT: Some prospective studies have shown an inverse association between fish intake and risk of stroke, but none has examined the relationship of fish and omega-3 polyunsaturated fatty acid intake with risk of specific stroke subtypes. OBJECTIVE: To examine the association between fish and omega-3 polyunsaturated fatty acid intake and risk of stroke subtypes in women. DESIGN, SETTING, AND SUBJECTS: Prospective cohort study of women in the Nurses' Health Study cohort, aged 34 to 59 years in 1980, who were free from prior diagnosed cardiovascular disease, cancer, and history of diabetes and hypercholesterolemia and who completed a food frequency questionnaire including consumption of fish and other frequently eaten foods. The 79 839 women who met our eligibility criteria were followed up for 14 years. MAIN OUTCOME MEASURE: Relative risk of stroke in 1980-1994 compared by category of fish intake and quintile of omega-3 polyunsaturated fatty acid intake. RESULTS: After 1 086 261 person-years of follow-up, 574 incident strokes were documented, including 119 subarachnoid hemorrhages, 62 intraparenchymal hemorrhages, 303 ischemic strokes (264 thrombotic and 39 embolic infarctions), and 90 strokes of undetermined type. Among thrombotic infarctions, 90 large-artery occlusive infarctions and 142 lacunar infarctions were identified. Compared with women who ate fish less than once per month, those with higher intake of fish had a lower risk of total stroke: the multivariate relative risks (RRs), adjusted for age, smoking, and other cardiovascular risk factors, were 0.93 (95% confidence interval [CI], 0.65-1.34) for fish consumption 1 to 3 times per month, 0.78 (95% CI, 0.55-1.12) for once per week, 0.73 (95% CI, 0.47-1.14) for 2 to 4 times per week, and 0.48 (95% CI, 0.21-1.06) for 5 or more times per week (P for trend =.06). Among stroke subtypes, a significantly reduced risk of thrombotic infarction was found among women who ate fish 2 or more times per week (multivariate RR, 0.49; 95% CI, 0.26-0.93). Women in the highest quintile of intake of long-chain omega-3 polyunsaturated fatty acids had reduced risk of total stroke and thrombotic infarction, with multivariate RRs of 0.72 (95% CI, 0.53-0.99) and 0.67 (95% CI, 0.42-1.07), respectively. When stratified by aspirin use, fish and omega-3 polyunsaturated fatty acid intakes were inversely associated with risk of thrombotic infarction, primarily among women who did not regularly take aspirin. There was no association between fish or omega-3 polyunsaturated fatty acid intake and risk of hemorrhagic stroke. CONCLUSIONS: Our data indicate that higher consumption of fish and omega-3 polyunsaturated fatty acids is associated with a reduced risk of thrombotic infarction, primarily among women who do not take aspirin regularly, but is not related to risk of hemorrhagic stroke.

Physical activity and risk for cardiovascular events in diabetic women.

BACKGROUND: Increased physical activity has been associated with reduced risk for cardiovascular disease in the general population, but data are limited on its role among persons with type 2 diabetes mellitus. OBJECTIVE: To determine whether physical activity decreases risk for cardiovascular disease among diabetic women. DESIGN: Prospective cohort study. SETTING: The Nurses' Health Study. PATIENTS: 5125 female nurses with diabetes. MEASUREMENTS: Physical activity was first assessed in 1980 and was updated in 1982, 1986, 1988, and 1992 through validated questionnaires. Average hours of moderate or vigorous exercise and a metabolic equivalent of task (MET) score were computed. RESULTS: During 14 years of follow-up (31 432 person-years), 323 new cases of cardiovascular disease were documented (225 cases of coronary heart disease and 98 cases of stroke). The age-adjusted relative risks according to average hours of moderate or vigorous activity per week (<1, 1 to 1.9, 2 to 3.9, 4 to 6.9, >/=7) were 1.0, 0.93 (95% CI, 0.69 to 1.26), 0.82 (CI, 0.61 to 1.10), 0.54 (CI, 0.39 to 0.76), and 0.52 (CI, 0.25 to 1.09) (P < 0.001 for trend). These figures did not change materially after adjustment for smoking, body mass index, and other cardiovascular risk factors (1.0, 1.02, 0.87, 0.61, and 0.55, respectively; P = 0.001 for trend). In separate analyses, levels of physical activity were inversely associated with coronary heart disease and ischemic stroke. Among women who did not exercise vigorously, the multivariate relative risks for cardiovascular disease across quartiles of MET score for walking were 1.0, 0.85, 0.63, and 0.56 (P = 0.03 for trend). Faster usual walking pace was independently associated with lower risk. CONCLUSION: Among diabetic women, increased physical activity, including regular walking, is associated with substantially reduced risk for cardiovascular events.

Prospective study of fat and protein intake and risk of intraparenchymal hemorrhage in women.

BACKGROUND: -Dietary animal fat and protein have been inversely associated with a risk of intraparenchymal hemorrhage in ecological studies. METHODS AND RESULTS: In 1980, 85 764 women in the Nurses' Health Study cohort, who were 34 to 59 years old and free of diagnosed cardiovascular disease and cancer, completed dietary questionnaires. From these questionnaires, we calculated fat and protein intake. By 1994, after 1.16 million person-years of follow-up, 690 incident strokes, including 74 intraparenchymal hemorrhages, had been documented. Multivariate-adjusted risk of intraparenchymal hemorrhage was higher among women in the lowest quintile of energy-adjusted saturated fat intake than at all higher levels of intake (relative risk [RR], 2.36; 95% CI, 1.10 to 5.09; P:=0.03). For trans unsaturated fat, the corresponding RR was 2.50 (95% CI, 1.35 to 4.65; P:=0.004). Animal protein intake was inversely associated with risk (RR in the highest versus lowest quintiles, 0.32; 95% CI, 0.10 to 1.00; P:=0.04). The excess risk associated with low saturated fat intake was observed primarily among women with a history of hypertension (RR, 3.66; 95% CI, 1.09 to 12.3; P=0.04), but such an interaction was not seen for trans unsaturated fat or animal protein. These nutrients were not related to risk of other stroke subtypes. Dietary cholesterol and monounsaturated and polyunsaturated fat were not related to risk of any stroke subtype. CONCLUSIONS: Low intake of saturated fat and animal protein was associated with an increased risk of intraparenchymal hemorrhage, which may help to explain the high rate of this stroke subtype in Asian countries. The increased risk with low intake of saturated fat and trans unsaturated fat is compatible with the reported association between low serum total cholesterol and risk.

Fruit and vegetable intake and risk of cardiovascular disease: the Women's Health Study.

BACKGROUND: Prospective data relating fruit and vegetable intake to cardiovascular disease (CVD) risk are sparse, particularly for women. OBJECTIVE: In a large, prospective cohort of women, we examined the hypothesis that higher fruit and vegetable intake reduces CVD risk. DESIGN: In 1993 we assessed fruit and vegetable intake among 39876 female health professionals with no previous history of CVD or cancer by use of a detailed food-frequency questionnaire. We subsequently followed these women for an average of 5 y for incidence of nonfatal myocardial infarction (MI), stroke, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, or death due to CVD. RESULTS: During 195647 person-years of follow-up, we documented 418 incident cases of CVD including 126 MIs. After adjustment for age, randomized treatment status, and smoking, we observed a significant inverse association between fruit and vegetable intake and CVD risk. For increasing quintiles of total fruit and vegetable intake (median servings/d: 2. 6, 4.1, 5.5, 7.1, and 10.2), the corresponding relative risks (RRs) were 1.0 (reference), 0.78, 0.72, 0.68, and 0.68 (95% CI comparing the 2 extreme quintiles: 0.51, 0.92; P: for trend = 0.01). An inverse, though not statistically significant, trend remained after additional adjustment for other known CVD risk factors, with RRs of 1.0, 0.75, 0.83, 0.80, and 0.85 (95% CI for extreme quintiles: 0.61, 1.17). After excluding participants with a self-reported history of diabetes, hypertension, or high cholesterol at baseline, the multivariate-adjusted RR was 0.45 when extreme quintiles were compared (95% CI: 0.22, 0.91; P: for trend = 0.09). Higher fruit and vegetable intake was also associated with a lower risk of MI, with an adjusted RR of 0.62 for extreme quintiles (95% CI: 0.37, 1.04; P: for trend = 0.07). CONCLUSION: These data suggest that higher intake of fruit and vegetables may be protective against CVD and support current dietary guidelines to increase fruit and vegetable intake.

Effects of beta-carotene supplementation on cancer incidence by baseline characteristics in the Physicians' Health Study (United States).

OBJECTIVES: The Physicians' Health Study (PHS) was a randomized trial of beta-carotene (50 mg, alternate days) and aspirin in primary prevention of cancer and cardiovascular disease among 22,071 US male physicians. This report updates results for beta-carotene and examines effect modification by baseline characteristics. METHODS: Beta-carotene's effect on cancer over nearly 13 years was examined overall and within subgroups defined by baseline characteristics using proportional-hazards models. RESULTS: 2667 incident cancers were confirmed, with 1117 prostate, 267 colon, and 178 lung cancers. There were no significant differences with supplementation in total (relative risk (RR) = 1.0, 95% confidence interval (CI) = 0.9-1.0); prostate (RR = 1.0, 95% CI = 0.9-1.1); colon (RR = 0.9, 95% CI = 0.7-1.2); or lung (RR = 0.9, 95% CI = 0.7-1.2) cancer, and no differences over time. In subgroup analyses, total cancer was modestly reduced with supplementation among those aged 70+ years (RR = 0.8, 95% CI = 0.7-1.0), daily drinkers of alcohol (RR = 0.9, 95% CI = 0.8-1.0), and those in the highest BMI quartile (RR = 0.9, 95% CI = 0.7-1.0). Prostate cancer was reduced with supplementation among those in the highest BMI quartile (RR = 0.8, 95% CI = 0.6-1.0), and colon cancer was reduced among daily drinkers of alcohol (RR = 0.5, 95% CI = 0.3-0.8). CONCLUSIONS: The PHS found no overall effect of beta-carotene on total cancer, or the three most common site-specific cancers. The possibility of risk reduction within specific subgroups remains.

Self-selected posttrial aspirin use and subsequent cardiovascular disease and mortality in the physicians' health study.

BACKGROUND: The randomized aspirin component of the Physicians' Health Study (PHS) was terminated early, after 5 years, primarily because of the emergence of a statistically extreme (P<.00001) 44% reduction of first myocardial infarction (MI) among those assigned to aspirin. As a result, there were insufficient numbers of strokes or cardiovascular disease (CVD)-related deaths to evaluate these end points definitively. METHODS: Data on self-selected aspirin use were collected until the beta carotene component ended as scheduled after 12 years. Posttrial use of aspirin was assessed at the 7-year follow-up among 18 496 participants with no previous reported CVD. Randomized and posttrial observational results in the PHS were compared, and differences between those self-selecting aspirin and those not were examined. RESULTS: At 7 years, 59.5% of participants without CVD reported self-selected aspirin use for at least 180 d/y, and 20.8% for 0 to 13 d/y. Use was significantly associated with family history of MI, hypertension, elevated cholesterol levels, body mass index, alcohol consumption, exercise, and use of vitamin E supplements. In multivariate analyses, self-selected aspirin use for at least 180 vs 0 to 13 d/y was associated with lower risk for subsequent MI (relative risk [RR], 0.72; 95% confidence interval [CI], 0.55-0.95), no relation with stroke (RR, 1.02; 95% CI, 0.74-1.39), and significant reductions in CVD-related (RR, 0.65; CI, 0.47-0.89) and total mortality (RR, 0.64; CI, 0.54-0.77). CONCLUSION: These associations between self-selected aspirin use and CVD risk factors increase the likelihood of residual confounding and emphasize the need for large-scale randomized trials, such as the ongoing Women's Health Study, to detect reliably the most plausible small to moderate effects of aspirin in the primary prevention of stroke and CVD-related death.