Vitamin intervention for stroke prevention trial: An efficacy analysis

Background and Purpose - The Vitamin Intervention for Stroke Prevention trial (VISP) intention-to-treat analysis did not show efficacy of combined vitamin therapy for recurrent vascular events in patients with nondisabling stroke. Reasons for lack of efficacy may have included folate fortification of grain products, inclusion of the recommended daily intake for B12 in the low-dose arm, treatment with parenteral B12 in patients with low B12 levels in both study arms, a dose of B12 too low for patients with malabsorption, supplementation with nonstudy vitamins, and failure of patients with significant renal impairment to respond to vitamin therapy. We conducted an efficacy analysis limited to patients most likely to benefit from the treatment, based on hypotheses arising from evidence developed since VISP was initiated. The criteria for this subgroup were defined before any data analysis. Methods - For this analysis, we excluded patients with low and very high B12 levels at baseline (\u3c250 and \u3e637 pmol/L, representing the 25th and 95th percentiles), to exclude those likely to have B12 malabsorption or to be taking B12 supplements outside the study and patients with significant renal impairment (glomerular filtration rate \u3c46.18; the 10th percentile). Results - This subgroup represents 2155 patients (37% female), with a mean age of 66±10.7 years. For the combined end point of ischemic stroke, coronary disease, or death, there was a 21% reduction in the risk of events in the high-dose group compared with the low-dose group (unadjusted P=0.049; adjusted for age, sex, blood pressure, smoking, and B12 level P=0.056). In Kaplan-Meier survival analysis comparing 4 groups, patients with a baseline B12 level at the median or higher randomized to high-dose vitamin had the best overall outcome, and those with B12 less than the median assigned to low-dose vitamin had the worst (P=0.02 for combined stroke, death, and coronary events; P=0.03 for stroke and coronary events). Conclusions - In the era of folate fortification, B12 plays a key role in vitamin therapy for total homocysteine. Higher doses of B12, and other treatments to lower total homocysteine may be needed for some patients. © 2005 American Heart Association, Inc

Cutaneous nevi and internal cancer risk: Results from two large prospective cohorts of US women

Elevated cutaneous nevus number has been linked to longer telomeres. Recently, a large systematic Mendelian randomization study identified a significant positive association between telomere length and risk of cancer. Here, we hypothesized that higher nevus count, as a phenotypic marker of longer telomere, may be associated with increased risk of internal cancer, and prospectively examined the association between nevus count and total as well as site‐specific cancer risk among participants in the Nurses’ Health Study (NHS, 1986–2012) and the Nurses’ Health Study 2 (NHS2, 1989–2013) using Cox proportional hazards models. During 3,900,264 person‐years of follow‐up, we documented a total of 23,004 internal cancer cases (15,484 in the NHS and 7,520 in the NHS2). Compared to participants who had no nevi, the multivariate hazard ratios of total cancer (excluding skin cancer) were 1.06 (95% confidence interval [CI], 1.03–1.09) for women with 1–5 nevi, 1.08 (95% CI, 1.03–1.15) for those who had 6–14 nevi and 1.19 (95% CI, 1.05–1.35) for those with 15 or more nevi (p trend <0.0001). Moreover, because nevus count has been associated with risk of breast cancer previously, we conducted a secondary analysis by excluding breast cancer from the outcomes of interest. The results were very similar to those of our primary analysis. For individual cancer, most of the associations with nevus count were positive but not statistically significant. In conclusion, we identified the number of cutaneous nevi as a phenotypic marker associated with internal cancer risk, which may be explained by telomere biology

A prospective study of plasma fish oil levels and incidence of myocardial infarction in U.S. male physicians

AbstractObjectives. This study evaluated whether increased intake of fish oils (eicosapentaenoic and docosahexaenoic acids) might reduce the risk of coronary heart disease.Background.Observational and clinical studies have suggested that increased intake of fish oils, as reflected in plasma levels of fish oils, may reduce the risk of myocardial infarction.Methods.A nested case-control study was conducted among the 14,916 participants in the Physicians' Health Study with a sample of plasma before randomization. Each participant with myocardial infarction occurring during the first 5 years of follow-up was matched by smoking status and age with a randomly chosen control participant who had not developed coronary heart disease.Results.Mean levels of fish oils (with 95% confidence interval [CI] for paired differences and p values) in case and control participants, expressed as present of total fatty acids, were, for eicosapentaenoic acid, 0.26 versus 0.25 (95% CI - 0.03 to 0.05, p = 0.70) in cholesterol esters and 0.56 versus 0.54 (95% CI -0.04 to 0.09, p = 0.44) in phospholipids, and for docosahexaenoic acid, 0.23 versus 0.24 (95% CI -0.07 to 0.04, p = 0.64) in cholesterol esters and 2.22 versus 2.14 (95% CI -0.10 to 0.27, p = 0.36) in phospholipids. Results adjusted for major cardiovascular risk factors showed a very similar lack of association between fish oil levels and the incidence of myocardial infarction.Conclusions.These results indicate no beneficial effect of increased fish oil consumption on the incidence of a first myocardial infarction. However, the effect of very high levels of fish oils could not be evaluated

Intakes of fruits, vegetables and carbohydrate and the risk of CVD

BACKGROUND: Low-carbohydrate diets could lead to reduced fruit and vegetable intake, which may be protective against CVD. The role of carbohydrate intake in modifying the association between fruits and vegetables and CVD has not been evaluated. OBJECTIVE: To evaluate whether carbohydrate intake affects the association between fruits and vegetables and CVD. DESIGN: We included participants from two large prospective studies, the Nurses' Health Study (NHS) and the Health Professionals' Follow-Up Study (HPFS). We followed 70870 eligible NHS females for 16 years and 38918 eligible HPFS males for 14 years. Diet was assessed from an FFQ updated every 4 years. Our primary outcome was ischaemic CVD (fatal and non-fatal myocardial infarction and ischaemic stroke). We used Cox proportional hazards models to evaluate the relationship between fruits and vegetables and ischaemic CVD within groups with low, moderate or high carbohydrate intake. RESULTS: Fruit intake was strongly related with carbohydrate intake, but vegetables showed a very small correlation. Vegetable intake showed stronger associations with ischaemic CVD among the low carbohydrate group (multivariate risk ratio (RR) = 0.82 for an increment of 3 servings/d; 95% CI 0.68, 0.99); green leafy vegetables and carotene-rich fruits and vegetables followed a similar pattern. Total fruit intake was associated with a lower risk of ischaemic CVD only among participants with moderate carbohydrate intake (RR = 0.81 comparing extreme quintiles; 95% CI 0.70, 0.94). CONCLUSIONS: Total vegetables, green leafy vegetables and carotene-rich fruits and vegetables showed stronger associations with ischaemic CVD among the low carbohydrate group. No consistent trends were observed for fruit intake

Change in alcohol intake in relation to weight change in a cohort of United States men with 24 years of follow-up

Objective: We sought to prospectively investigate potential effects of alcohol by subtype on reported long-term weight change. Methods: We examined change in alcohol intake (total, wine, light beer, regular beer, liquor) and simultaneous change in reported body weight within four-year periods from 1986 to 2010 from U.S. men in the Health Professionals Follow-Up Study. We adjusted for age, change in lifestyle and dietary covariates and cardiovascular risk factors. Results: We observed 44,603 four-year periods from 14,971 men. Total alcohol, total beer, regular beer, and liquor, modeled as the increase in weight per increase in drink/day, were each directly associated with moderate weight gain over four-year periods, in pounds: total alcohol: 0.23 (0.10–0.35); total beer: 0.29 (0.08–0.51); regular beer: 0.61 (0.22–1.00); liquor: 0.28 (0.09–0.48). Results for wine and light beer were wine: 0.16 (−0.04–0.36); light beer: −0.38 (−1.07–0.08). Results were strongest for men <55 years old. Conclusions: Increased alcohol consumption was associated with minor reported weight gain at levels unlikely to be clinically meaningful. Beverage specific differences are not substantial enough to make dietary recommendations for weight loss or maintenance by beverage type. The greatest risk of weight gain was among men that increased consumption to levels well above moderation

Light to moderate intake of alcohol, drinking patterns, and risk of cancer: results from two prospective US cohort studies

Objectives: To quantify risk of overall cancer across all levels of alcohol consumption among women and men separately, with a focus on light to moderate drinking and never smokers; and assess the influence of drinking patterns on overall cancer risk. Design: Two prospective cohort studies. Setting: Health professionals in the United States. Participants: 88 084 women and 47 881 men participating in the Nurses’ Health Study (from 1980) and Health Professionals Follow-up Study (from 1986), followed until 2010. Main outcomes and measures Relative risks of cancer. Results: 19 269 and 7571 (excluding non-advanced prostate cancers) incident cancers were documented among women and men, respectively, over 3 144 853 person years. Compared with non-drinkers, light to moderate drinkers had relative risks of total cancer of 1.02 (95% confidence interval 0.98 to 1.06) and 1.04 (1.00 to 1.09; Ptrend=0.12) for alcohol intake of 0.1-4.9 and 5-14.9 g/day among women, respectively. Corresponding values for men were 1.03 (0.96 to 1.11), 1.05 (0.97 to 1.12), and 1.06 (0.98 to 1.15; Ptrend=0.31) for alcohol intake of 0.1-4.9, 5-14.9, and 15-29.9 g/day, respectively. Associations for light to moderate drinking and total cancer were similar among ever or never smokers, although alcohol consumption above moderate levels (in particular ≥30 g/day) was more strongly associated with risk of total cancer among ever smokers than never smokers. For a priori defined alcohol related cancers in men, risk was not appreciably increased for light and moderate drinkers who never smoked (Ptrend=0.18). However, for women, even an alcohol consumption of 5-14.9 g/day was associated with increased risk of alcohol related cancer (relative risk 1.13 (95% confidence interval 1.06 to 1.20)), driven by breast cancer. More frequent and heavy episodic drinking was not further associated with risk of total cancer after adjusting for total alcohol intake. Conclusion: Light to moderate drinking is associated with minimally increased risk of overall cancer. For men who have never smoked, risk of alcohol related cancers is not appreciably increased for light and moderate drinking (up to two drinks per day). However, for women who have never smoked, risk of alcohol related cancers (mainly breast cancer) increases even within the range of up to one alcoholic drink a day

The Effect of Weight-Loss Interventions on Cervical and Chin Subcutaneous Fat Depots; the CENTRAL Randomized Controlled Trial

Accumulation of cervical and chin subcutaneous adipose tissues (SAT) represent known phenotypes of obesity. We aimed to evaluate the sensitivity of these fat storages to long-term weight-loss directed lifestyle-intervention and to assess their relations to bodily-adiposity, insulin-resistance, and cardiometabolic risk; We randomly assigned 278 participants with abdominal-obesity/dyslipidemia to low-fat or Mediterranean/low-carbohydrate diets +/− physical-activity. All participants underwent an 18 month whole-body magnetic resonance imaging follow-up, from which we assessed cervical and chin SAT-areas; Participants (age = 48 years; 90% men; body-mass-index = 30.9 kg/m2) had an 18-month adherence-rate of 86%. Cervical-SAT and chin-SAT decreased after 6-months (−13.1% and −5.3%, respectively, p < 0.001). After 18-months only cervical-SAT remained decreased compared to baseline (−5%, p < 0.001). Cervical and chin-SAT 18-month changes were associated with changes in weight (r = 0.70, r = 0.66 respectively; <0.001 for both) and visceral-adipose-tissue (VAT; r = 0.35, r = 0.42 respectively; <0.001 for both). After adjustment to VAT, waist-circumference, or weight-changes, chin-SAT 18-month reduction was associated with favorable changes in fasting-glucose (β = 0.10; p = 0.05), HbA1c (β = 0.12; p = 0.03), and homeostasis-model-assessment-of-insulin-resistance (β = 0.12; p = 0.03). Cervical-SAT 18-month reduction was associated with decreased triglycerides (β = 0.16; p = 0.02) and leptin (β = 0.19; p = 0.01) independent of VAT; Cervical and chin-SATs are dynamic fat depots that correspond with weight-loss and are associated with changes in cardiometabolic profile. In long-term, chin-SAT displays a larger rebound compared with cervical-SAT. Chin-SAT accumulation is associated with in insulin-resistance, independent of central obesity. (ClinicalTrials identifier NCT01530724

Light-to-moderate alcohol consumption and mortality in the physicians’ health study enrollment cohort

AbstractOBJECTIVESThis study examined the relationship between light-to-moderate alcohol consumption and cause-specific mortality.BACKGROUNDPrevious studies suggest a J-shaped relation between alcohol and total mortality in men. A decrease in cardiovascular disease (CVD) mortality without a significant increase in other causes of mortality may explain the overall risk reduction at light-to-moderate levels.METHODSWe conducted a prospective cohort study of 89,299 U.S. men from the Physicians’ Health Study enrollment cohort who were 40 to 84 years old in 1982 and free of known myocardial infarction, stroke, cancer or liver disease at baseline. Usual alcohol consumption was estimated by a limited food frequency questionnaire.RESULTSThere were 3,216 deaths over 5.5 years of follow-up. We observed a U-shaped relationship between alcohol consumption and total mortality. Compared with rarely/never drinkers, consumers of 1, 2 to 4 and 5 to 6 drinks per week and 1 drink per day had significant reductions in risk of death (multivariate relative risks [RRs] of 0.74, 0.77, 0.78 and 0.82, respectively) with no overall benefit or harm detected at the ≥2 drinks per day level (RR = 0.95; 95% confidence interval (CI), 0.79 to 1.14). The relationship with CVD mortality was inverse or L-shaped with apparent risk reductions even in the highest category of ≥2 drinks per day (RR = 0.76; 95% CI, 0.57 to 1.01). We found no clear harm or benefit for total or common site-specific cancers. For remaining other cancers, there was a nonsignificant 28% increased risk for those consuming ≥2 drinks per day.CONCLUSIONSThese data support a U-shaped relation between alcohol and total mortality among light-to-moderate drinking men. The U-shaped curve may reflect an inverse association for CVD mortality, no association for common site-specific cancers and a possible positive association for less common cancers

Prediagnostic use of hormone therapy and mortality after breast cancer.

BACKGROUND: A few studies have observed reduced breast cancer mortality in women who used hormone therapy before diagnosis. Due to the high prevalence of past and current hormone use, it is important to investigate whether these preparations are related to breast cancer mortality. METHODS: To evaluate the influence of prediagnostic use of hormone therapy on breast cancer mortality, a prospective cohort of 12,269 women ages 50 years or more diagnosed with incident invasive breast cancer and residents of Wisconsin, Massachusetts, or New Hampshire were enrolled in three phases beginning in 1988. They were followed for death until December 31, 2005, using the National Death Index. Cumulative mortality and multivariable adjusted hazard rate ratios for breast cancer and other mortality causes were calculated for women according to any hormone therapy use, and for exclusive use of estrogen or estrogen-progestin (EP). RESULTS: During an average 10.3 years of follow-up, 1,690 deaths from breast cancer were documented. Cumulative mortality from breast cancer was lower among hormone therapy users, specifically current users at the time of diagnosis, and EP users, compared with nonusers. Adjusted survival varied by type and duration of hormone therapy before diagnosis. A reduced risk of death from breast cancer was associated with EP preparations (hazard rate ratio, 0.73; 0.59-0.91) and with > or =5 years of EP use (0.60; 0.43-0.84). No association was observed for women who were former or current users of E-alone preparations. CONCLUSIONS: Although use of combined EP preparations increases breast cancer risk, in this study, use of these hormones before diagnosis was associated with reduced risk of death after a breast cancer diagnosis. The better survival among users, particularly of EP, persisted after adjustment of screening, stage, and measured confounders

Prediagnostic Plasma Vitamin D Metabolites and Mortality among Patients with Prostate Cancer

Laboratory evidence suggests that vitamin D might influence prostate cancer prognosis.We examined the associations between prediagnostic plasma levels of 25(OH)vitamin D [25(OH)D] and 1,25(OH)(2) vitamin D [1,25(OH)(2)D] and mortality among 1822 participants of the Health Professionals Follow-up Study and Physicians' Health Study who were diagnosed with prostate cancer. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of total mortality (n = 595) and lethal prostate cancer (death from prostate cancer or development of bone metastases; n = 202). In models adjusted for age at diagnosis, BMI, physical activity, and smoking, we observed a HR of 1.22 (95% CI: 0.97, 1.54) for total mortality, comparing men in the lowest to the highest quartile of 25(OH)D. There was no association between 1,25(OH)(2)D and total mortality. Men with the lowest 25(OH)D quartile were more likely to die of their cancer (HR: 1.59; 95% CI: 1.06, 2.39) compared to those in the highest quartile (P(trend) = 0.006). This association was largely explained by the association between low 25(OH)D levels and advanced cancer stage and higher Gleason score, suggesting that these variables may mediate the influence of 25(OH)D on prognosis. The association also tended to be stronger among patients with samples collected within five years of cancer diagnosis. 1,25(OH)(2)D levels were not associated with lethal prostate cancer.Although potential bias of less advanced disease due to more screening activity among men with high 25(OH)D levels cannot be ruled out, higher prediagnostic plasma 25(OH)D might be associated with improved prostate cancer prognosis