Long-Term Aspirin Use and Self-Reported Walking Speed in Older Men: The Physicians' Health Study.

BACKGROUND: Mobility limitation is a component of frailty that shares a bidirectional relationship with cardiovascular disease (CVD). Data are limited on the role of established CVD prevention therapies, such as aspirin, for prevention of frailty and mobility limitation. OBJECTIVES: Examine the association between long-term aspirin use and walking speed. DESIGN, SETTING, PARTICIPANTS: Prospective cohort of 14,315 men who participated in the Physicians' Health Study I, a completed randomized controlled trial of aspirin (1982-1988), with extended post-trial follow-up. MEASUREMENTS: Annual questionnaires collected data on aspirin use, lifestyle and other factors. Average annual aspirin use was categorized for each participant: ≤60 days/year and >60 days/year. Mobility was defined according to self-reported walking pace, categorized as: don't walk regularly (reference), easy/casual <2mph, normal ≥2-2.9mph, or brisk/very brisk ≥3mph. Propensity scoring balanced covariates between aspirin categories. Multinomial logistic regression models estimated odds of being in each self-reported walking category. RESULTS: Mean age was 70±8 years; mean aspirin use 11 years. There were 2,056 (14.3%) participants who reported aspirin use ≤60 days/year. Aspirin use >60 days/year was associated with drinking alcohol, smoking, hypertension, heart disease and stroke, while ≤60 days/year was associated with anticoagulation use and bleeding history. In all, 13% reported not walking regularly, 12% walked <2 mph, 44% walked ≥2-2.9 mph, and 31% walked ≥3 mph. After propensity score adjustment, regular aspirin use was associated with a faster walking speed. Odds ratios (95% confidence intervals) were 1.16 (0.97 to 1.39), 1.24 (1.08 to 1.43), and 1.40 (1.21 to 1.63) for <2 mph, ≥2-2.9 mph and ≥3 mph, respectively, compared to not walking regularly (p-trend<0.001). CONCLUSIONS: In this cohort of older men, long-term aspirin use is associated with a greater probability of faster walking speed later in life.

Aspirin has potential benefits for primary prevention of cardiovascular outcomes in diabetes: updated literature-based and individual participant data meta-analyses of randomized controlled trials.

BACKGROUND: The clinical benefit of aspirin for the primary prevention of cardiovascular disease (CVD) in diabetes remains uncertain. To evaluate the efficacy and safety of aspirin for the primary prevention of cardiovascular outcomes and all-cause mortality events in people with diabetes, we conducted an updated meta-analysis of published randomised controlled trials (RCTs) and a pooled analysis of individual participant data (IPD) from three trials. METHODS: Randomised controlled trials of aspirin compared with placebo (or no treatment) in participants with diabetes with no known CVD were identified from MEDLINE, Embase, Cochrane Library, and manual search of bibliographies to January 2019. Relative risks with 95% confidence intervals were used as the summary measures of associations. RESULTS: We included 12 RCTs based on 34,227 participants with a median treatment duration of 5.0 years. Comparing aspirin use with no aspirin, there was a significant reduction in risk of major adverse cardiovascular events (MACE)0.89 (0.83-0.95), with a number needed to treat (NNT)of 95 (95% CI 61 to 208) to prevent one MACE over 5 years average follow-up. Evidence was lacking of heterogeneity and publication bias among contributing trials for MACE. Aspirin use had no effect on other endpoints including all-cause mortality; however, there was a significant reduction in stroke for aspirin dosage ≤ 100 mg/day 0.75 (0.59-0.95). There were no significant effects of aspirin use on major bleeding and other bleeding events, though some of the estimates were imprecise. Pooled IPD from the three trials (2306 participants) showed no significant evidence of an effect of aspirin on any of the outcomes evaluated; however, aspirin reduced the risk of MACE in non-smokers 0.70 (0.51-0.96) with a NNT of 33 (95% CI 20 to 246) to prevent one MACE. CONCLUSIONS: Aspirin has potential benefits in cardiovascular primary prevention in diabetes. The use of low dose aspirin may need to be individualised and based on each individual's baseline CVD and bleeding risk. Systematic review registration PROSPERO: CRD42019122326.

Vitamin B6 catabolism and lung cancer risk: results from the Lung Cancer Cohort Consortium (LC3).

BACKGROUND: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. MATERIALS AND METHODS: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. RESULTS: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23). CONCLUSION: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.

No association between circulating concentrations of vitamin D and risk of lung cancer: an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3).

Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods: The study included 5313 lung cancer cases and 5313 controls. Blood samples for the cases were collected, on average, 5 years before lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in five categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 25(OH)D as both continuous and categorical variables. Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% CI: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion: This study did not support an association between vitamin D concentrations and lung cancer risk.

Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies.

BACKGROUND: Body mass index (BMI), a measure of obesity typically assessed in middle age or later, is known to be positively associated with pancreatic cancer. However, little evidence exists regarding the influence of central adiposity, a high BMI during early adulthood, and weight gain after early adulthood on pancreatic cancer risk. DESIGN: We conducted a pooled analysis of individual-level data from 20 prospective cohort studies in the National Cancer Institute BMI and Mortality Cohort Consortium to examine the association of pancreatic cancer mortality with measures of central adiposity (e.g. waist circumference; n = 647 478; 1947 pancreatic cancer deaths), BMI during early adulthood (ages 18-21 years) and BMI change between early adulthood and cohort enrollment, mostly in middle age or later (n = 1 096 492; 3223 pancreatic cancer deaths). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. RESULTS: Higher waist-to-hip ratio (HR = 1.09, 95% CI 1.02-1.17 per 0.1 increment) and waist circumference (HR = 1.07, 95% CI 1.00-1.14 per 10 cm) were associated with increased risk of pancreatic cancer mortality, even when adjusted for BMI at baseline. BMI during early adulthood was associated with increased pancreatic cancer mortality (HR = 1.18, 95% CI 1.11-1.25 per 5 kg/m(2)), with increased risk observed in both overweight and obese individuals (compared with BMI of 21.0 to <23 kg/m(2), HR = 1.36, 95% CI 1.20-1.55 for BMI 25.0 < 27.5 kg/m(2), HR = 1.48, 95% CI 1.20-1.84 for BMI 27.5 to <30 kg/m(2), HR = 1.43, 95% CI 1.11-1.85 for BMI ≥30 kg/m(2)). BMI gain after early adulthood, adjusted for early adult BMI, was less strongly associated with pancreatic cancer mortality (HR = 1.05, 95% CI 1.01-1.10 per 5 kg/m(2)). CONCLUSIONS: Our results support an association between pancreatic cancer mortality and central obesity, independent of BMI, and also suggest that being overweight or obese during early adulthood may be important in influencing pancreatic cancer mortality risk later in life.

Telomere length and Parkinson's disease in men: a nested case-control study.

BACKGROUND AND PURPOSE: Telomere shortening has been implicated in neurodegenerative disorders. However, available data on the association between telomere length and Parkinson's disease (PD) are inconclusive. METHODS: A nested case-control design was used amongst men participating in the prospective Physicians' Health Study. A large proportion of participants provided blood samples in 1997 and they were followed through 2010. Men with self-reported PD were age-matched to controls in a 1:2 ratio. Quantitative PCR was used to determine the telomere repeat copy number to single gene copy number ratio (TSR) in genomic DNA extracted from peripheral blood leukocytes. TSR was used as a measure for relative telomere length (RTL) in our analyses. Conditional logistic regression was used to determine the risk of PD associated with RTL. RESULTS: Data on RTL were available from 408 cases and 809 controls. Median TSR was shorter in controls than in cases (47.7 vs. 50.2; P = 0.02). The age-adjusted odds ratio (OR) for PD was 0.66 [95% confidence interval (CI) 0.46-0.95; Ptrend over quartiles 0.02] comparing the lowest to the highest quartile. The pattern of association was unchanged when comparing RTL below versus above the median (age-adjusted OR 0.75; 95% CI 0.59-0.96). Associations were similar after additional adjustment for many covariates. CONCLUSION: Contrary to what was expected, in this large nested case-control study amongst men shorter telomeres were associated with reduced PD risk. Future research on the nature of this counterintuitive association is warranted.

Association between modifiable lifestyle factors and residual lifetime risk of diabetes.

BACKGROUND AND AIMS: While clinical trials have reported beneficial effects of diet, exercise, and weight loss on incident diabetes in subjects with obesity or impaired glucose tolerance, little is known about the incremental benefit of not smoking and moderate drinking on diabetes risk. We sought to examine the association between modifiable lifestyle factors and residual lifetime risk of diabetes. METHODS AND RESULTS: Prospective cohorts involving 20,915 men (1982-2008) and 36,594 women (1992-2008). Modifiable lifestyle factors and adiposity were ascertained at baseline in each cohort and incident diabetes was ascertained during follow up. The mean age at baseline was 53.5 y in men and 54.6 y in women. During an average follow up of 22.6 y in men and 13.0 y in women, 2096 men and 2390 women developed diabetes. At age 45 y, the residual lifetime risk of diabetes (95% CI) for men with 0, 1, 2, 3, and 4 + healthy lifestyle factors was 30.5 (27.3-33.7); 21.5 (19.9-23.0); 15.1 (13.9-16.3); 10.3 (9.1-11.5); and 7.3 (5.7-8.9) percent; respectively. Corresponding values for women were 31.4 (28.3-34.5); 24.1 (21.8-26.5); 14.2 (12.7-15.7); 11.6 (9.7-13.5); and 6.4 (4.2-8.6) percent, respectively. CONCLUSIONS: These data show an inverse and graded relation between desirable lifestyle factors and residual lifetime risk of diabetes in men and women. Not smoking and moderate drinking may have additional benefits when added to exercise, weight control, and diet.

Nut consumption and risk of atrial fibrillation in the Physicians' Health Study.

BACKGROUND: Atrial Fibrillation is highly prevalent in clinical practice affecting approximately 2.3 million people in USA and 4.5 million people in European Union. The aim of the study was to examine the association between nut consumption and incident atrial fibrillation. METHODS: Prospective cohort of 21,054 male participants of Physicians' Health Study I. Nut consumption was estimated using food frequency questionnaire and incident atrial fibrillation was ascertained through yearly follow-up questionnaires. Cox regression was used to estimate relative risks of atrial fibrillation. RESULTS: The average age was 54.6 ± 9.5 years (40.7-87.1). During a mean follow up of 20 years (median 24 years), 3,317 cases of atrial fibrillation occurred. The crude incidence rate was 7.6, 7.4, 8.2, 7.9, and 6.8 cases/1000 person-years for people reporting nut consumption of rarely/never, 1-3/month, 1/per week, 2-6/week, and ≥ 7/week, respectively. Multivariable adjusted hazard ratios (95% CI) for incident atrial fibrillation were 1.00 (ref), 1.00 (0.90-1.11), 1.09 (0.97-1.21), 1.07 (0.95-1.21), and 0.91 (0.70-1.17) for nut consumption from the lowest to the highest category of nut consumption (p for trend 0.26). No statistically significant association between nut consumption and atrial fibrillation was found when stratified by body mass index (BMI < 25 vs ≥ 25 kg/m2) or age (< 65 vs. ≥ 65 years). CONCLUSIONS: Our data did not show an association between nut consumption and incident atrial fibrillation among US male physicians.

Effects of cocoa products/dark chocolate on serum lipids: a meta-analysis.

Cocoa products, which are rich sources of flavonoids, have been shown to reduce blood pressure and the risk of cardiovascular disease. Dark chocolate contains saturated fat and is a source of dietary calories; consequently, it is important to determine whether consumption of dark chocolate adversely affects the blood lipid profile. The objective was to examine the effects of dark chocolate/cocoa product consumption on the lipid profile using published trials. A detailed literature search was conducted via MEDLINE (from 1966 to May 2010), CENTRAL and ClinicalTrials.gov for randomized controlled clinical trials assessing the effects of flavanol-rich cocoa products or dark chocolate on lipid profile. The primary effect measure was the difference in means of the final measurements between the intervention and control groups. In all, 10 clinical trials consisting of 320 participants were included in the analysis. Treatment duration ranged from 2 to 12 weeks. Intervention with dark chocolate/cocoa products significantly reduced serum low-density lipoprotein (LDL) and total cholesterol (TC) levels (differences in means (95% CI) were -5.90 mg/dl (-10.47, -1.32 mg/dl) and -6.23 mg/dl (-11.60, -0.85 mg/dl), respectively). No statistically significant effects were observed for high-density lipoprotein (HDL) (difference in means (95% CI): -0.76 mg/dl (-3.02 to 1.51 mg/dl)) and triglyceride (TG) (-5.06 mg/dl (-13.45 to 3.32 mg/dl)). These data are consistent with beneficial effects of dark chocolate/cocoa products on total and LDL cholesterol and no major effects on HDL and TG in short-term intervention trials.

Diet and metabolic syndrome.

Given the higher burden of risk factors for metabolic syndrome (MetS) on morbidity and mortality, it is critical to prevent the development of metabolic syndrome in the first place. While dietary habits have been favorably associated with some of the factors included in the definition of metabolic syndrome, limited and inconsistent data have been reported on the role of nutrition in the development of metabolic syndrome. Currently, there is no consensus as to which dietary patterns would confer the lowest risk of MetS. Identification of dietary patterns, food groups, or nutrients that may lower the incidence of metabolic syndrome could improve prevention strategies as well as prognosis among subjects with existing MetS. This manuscript reviews current evidence on dietary patterns, consumption of fat, whole grains, carbohydrate quality and quantity, and moderate alcohol consumption as they relate to metabolic syndrome.

Nut consumption and risk of type II diabetes in the Physicians' Health Study.

BACKGROUND/OBJECTIVES: While type II diabetes (DM) is a major cause of morbidity in the United States, limited data are available on the association between nut intake and incident DM. We sought to examine the association between nut consumption and the risk of DM. SUBJECTS/METHODS: Prospective cohort of 20 224 male participants of the Physicians' Health Study I. Nut consumption was estimated using a 19-item brief food frequency questionnaire, and incident DM was ascertained through yearly follow-up questionnaires. Cox regression was used to estimate relative risks of DM. RESULTS: The average age of the study participants was 54.4+/-9.4 years (range: 40.7-87.1). During a mean follow-up of 19.2 years, 1828 cases of DM occurred. The crude incidence rates of DM were 4.82, 4.85, 4.92, 4.16, 4.29 and 3.32 cases per 1000 person-years for individuals reporting nut consumption of rarely/never, <1, 1, 2-4, 5-6 and 7+ servings per week, respectively. While nut consumption was associated with a lower risk of DM in a model adjusted for age (P for tend 0.017), such relation was attenuated on additional control for other confounders (multivariable adjusted hazard ratios (95% confidence interval) for DM were 1.0 (reference), 1.06 (0.93-1.20), 1.10 (0.95-1.26), 0.97 (0.82-1.14), 0.99 (0.76-1.30) and 0.87 (0.61-1.24) from the lowest to the highest category of nut consumption, respectively (P for trend 0.99). No statistically significant association between nut consumption and DM was found in either lean or overweight/obese participants. CONCLUSIONS: Our data do not show an association between nut consumption and incident DM in US male physicians.

Parental history of myocardial infarction and risk of heart failure in male physicians.

BACKGROUND: Although heart failure (HF) remains a major public health issue, limited data are available on the utility of parental information on the risk of HF in offspring. MATERIALS AND METHODS: We prospectively examined the association between parental history of myocardial infarction (MI) and incident HF among 20,187 offspring in the Physicians' Health Study I. Parental history and age at MI was assessed by a questionnaire and a Cox regression was used to estimate relative risks of HF. RESULTS: After an average follow-up of 19.6 years, 1036 new HF cases were documented. Overall, while a history of early parental MI (before age 55) was associated with a 32% increased risk of HF in offspring compared with subjects whose parent did not have MI, parental MI at older ages was not associated with HF risk. However, the relation between parental history of MI and HF was stronger and mainly observed for HF with antecedent MI. Compared with subjects without parental history of MI, multivariable adjusted hazard ratios (95% CI) for HF with antecedent MI were 3.44 (2.15-5.51), 2.24 (1.20-4.21), 1.26 (0.63-2.51), and 1.37 (0.92-2.03) for parental MI occurred at the age of < 55, 55-59, 60-64, and 65 + y, respectively. CONCLUSIONS: Our data suggest that parental MI at an early age is a strong and independent predictor of HF with antecedent MI among US male physicians. This information, along with existing tools, may help clinicians identify patients at risk of HF with antecedent MI.

Effects of G/A polymorphism, rs266882, in the androgen response element 1 of the PSA gene on prostate cancer risk, survival and circulating PSA levels.

Prostate-specific antigen (PSA) is a protease produced in the prostate that cleaves insulin-like growth factor binding protein-3 and other proteins. Production is mediated by the androgen receptor (AR) binding to the androgen response elements (ARE) in the promoter region of the PSA gene. Studies of a single nucleotide polymorphism (PSA -158 G/A, rs266882) in ARE1 of the PSA gene have been conflicting for risk of prostate cancer and effect on plasma PSA levels. In this nested case-control analysis of 500 white cases and 676 age- and smoking-matched white controls in the Physicians' Health Study we evaluated the association of rs266882 with risk and survival of prostate cancer and prediagnostic total and free PSA plasma levels, alone or in combination with AR CAG repeats. We used conditional logistic regression, linear regression and Cox regression, and found no significant associations between rs266882 (GG allele vs AA allele) and overall prostate cancer risk (RR=1.21, 95% confidence intervals (CI): 0.88-1.67) or prostate cancer-specific survival (RR=0.94, 95%CI: 0.56-1.58). Similarly, no associations were found among high grade or advanced stage tumours, or by calendar year of diagnosis. There was no significant association between rs266882 and baseline total or free PSA levels or the AR CAG repeats, nor any interaction associated with prostate cancer risk. Meta-analysis of 12 studies of rs266882 and overall prostate cancer risk was null.

Parkinson disease and risk of mortality: a prospective comorbidity-matched cohort study.

OBJECTIVE: To evaluate the association between Parkinson disease (PD) and mortality after adjustment for comorbidities. METHODS: We conducted a matched cohort analysis among 22,071 participants in the Physicians' Health Study. Five hundred sixty incident PD cases were identified by self-report. We used a modified Charlson Comorbidity Index to calculate a comorbidity score. Each PD case was matched by age to a comparator who was alive and had an identical comorbidity score at the time of PD diagnosis of the case. Both cohorts were followed for all-cause mortality. We used proportional hazards models to calculate hazard ratios (HRs) for mortality. RESULTS: A total of 330 participants died over a median follow-up of 5.8 years, 200 (35.7%) in the PD group and 130 (23.2%) in the reference group. After adjustment for smoking and age at PD onset, the HR for mortality was 2.32 (95% CI 1.85-2.92). The mortality risk remained significant with increasing age at onset, even in those aged >or=80 years (HR = 2.10; 95% CI 1.44-3.00). The increased risk was apparent for short PD duration (<2 years) and remained stable with increasing duration. We found no different risk of mortality associated with PD according to smoking status. CONCLUSIONS: In this large prospective cohort of men and after matching on comorbidities, we found that Parkinson disease patients had an increased risk of all-cause mortality. Mortality was increased regardless of disease duration, did not diminish with increasing age at onset, and was not influenced by smoking status.

Randomised aspirin assignment and risk of adult-onset asthma in the Women's Health Study.

BACKGROUND: Randomised data in men show a small but significant reduction in the risk of adult-onset asthma among those given aspirin. The results from an observational study in women suggest that frequent use of aspirin decreases the risk of adult-onset asthma, but randomised data in women are lacking. A study was undertaken to test the effect of 100 mg aspirin or placebo on alternate days on the risk of adult-onset asthma in the Women's Health Study. METHODS: A randomised, double-blind, placebo-controlled clinical trial of aspirin and vitamin E was performed in apparently healthy women with no indication or contraindication to aspirin therapy and no history of asthma at study entry. Female health professionals self-reported an asthma diagnosis on yearly questionnaires. RESULTS: Among 37 270 women with no reported history of asthma prior to randomisation and during 10 years of follow-up, there were 872 new cases diagnosed with asthma in the aspirin group and 963 in the placebo group (hazard ratio 0.90; 95% CI 0.82 to 0.99; p = 0.027). This apparent 10% lower relative risk of incident adult-onset asthma among those assigned to aspirin was significantly modified by body mass index, with no effect in women with a body mass index of >/=30 kg/m2. The effect of aspirin on adult-onset asthma was not significantly modified by age, smoking status, exercise levels, postmenopausal hormone use or randomised vitamin E assignment. CONCLUSIONS: In this large randomised clinical trial of apparently healthy adult women, administration of 100 mg aspirin on alternate days reduced the relative risk of a newly reported diagnosis of asthma.

Body mass index and mortality in men: evaluating the shape of the association.

OBJECTIVE: Controversy regarding the relationship between body mass index (BMI) and mortality continues to exist. Most of the previous studies have not comprehensively accounted for major sources of bias. We examined the association between BMI and all-cause mortality according to pre-existing disease and smoking status in a large prospective cohort. METHODS: Participants were 99 253 male physicians in the Physicians' Health Study enrollment cohort (40-84 years) who provided self-reported information in 1982. We used Cox proportional hazards regression to examine the association between baseline BMI and mortality. RESULTS: A total of 5438 men died (median follow-up, 5.7 years). Although a U-shaped association between BMI and all-cause mortality was seen among all men, we found a linear relationship when accounting for potential sources of bias. In the optimal model excluding men who died within 2 years, and adjusting for age, smoking, alcohol consumption, physical activity, prior disease and interactions between BMI and prior disease, and between BMI and smoking, those with BMI <20.0 kg/m(2) had a relative risk (RR) of death of 0.88 (95% confidence interval (CI), 0.56-1.40), as compared to men with BMI 22.5-24.9 kg/m(2). By contrast, men with BMI 30.0-34.9 kg/m(2) had an RR of 1.45 (95% CI, 1.10-1.91) and those with BMI >or=35.0 kg/m(2) had an RR of 1.62 (95% CI, 1.12-2.35; P for linear trend, <0.001). According to WHO categories, men in the 'overweight' range (BMI 25.0-29.9 kg/m(2)) had an RR of 1.20 (95% CI, 1.05-1.38) as compared to men in the 'normal' range (BMI <25.0 kg/m(2)). CONCLUSIONS: In this large, prospective cohort, we found a consistent linear association between higher BMI and increased risk of mortality after accounting for several potential sources of bias, even among those within the 'overweight' range of BMI. Public health messages should emphasize the preponderance of evidence supporting the adverse health effects associated with higher body weight.

Lipid levels and the risk of ischemic stroke in women.

OBJECTIVE: To evaluate the association between total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol to HDL-C ratio, and non-HDL-C with the risk of ischemic stroke in a large cohort of apparently healthy women. METHODS: Prospective cohort study among 27,937 US women aged > or =45 years participating in the Women's Health Study who provided baseline blood samples. Stroke occurrence was self-reported and confirmed by medical record review. We categorized plasma lipid measurements into quintiles. We used Cox proportional hazards models to evaluate the association between lipids and risk of ischemic stroke. RESULTS: During 11 years of follow-up, 282 ischemic strokes occurred. All lipid levels were strongly associated with increased risk of ischemic stroke in age-adjusted models. The association attenuated particularly for HDL-C after adjustment for potential confounders. For the comparison of the highest to the lowest quintile, the multivariable-adjusted hazard ratios (95% CI; p for trend across mean quintile values) of ischemic stroke were 2.27 (1.43, 3.60; p(trend) < 0.001) for total cholesterol; 1.74 (1.14, 2.66; p(trend) = 0.003) for LDL-C; 0.78 (0.52, 1.17; p(trend) = 0.27) for HDL-C; 1.65 (1.06, 2.58; p(trend) = 0.02) for the total cholesterol to HDL-C ratio; and 2.45 (1.54, 3.91; p(trend) < 0.001) for non-HDL-C. CONCLUSIONS: In this large cohort of apparently healthy women, total cholesterol, low-density lipoprotein cholesterol, the total cholesterol to high-density lipoprotein cholesterol ratio, and non-high-density lipoprotein cholesterol were significantly associated with increased risk of ischemic stroke.

Blood pressure measures and risk of total, ischemic, and hemorrhagic stroke in men.

OBJECTIVE: To evaluate which blood pressure measure is the best predictor of risk of total, ischemic, and hemorrhagic stroke. METHODS: The authors used a prospective cohort study among 11,466 men followed for incident stroke during a median of 19.4 years in the Physicians' Health Study. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were self-reported. They calculated relative risks (RRs) and 95% CIs for total, ischemic, and hemorrhagic stroke using Cox proportional hazards models. Model fit was compared using the chi(2) test statistic from likelihood ratio tests. RESULTS: During follow-up, 508 strokes occurred (411 ischemic, 89 hemorrhagic, and eight of unknown etiology). For each 10-mm Hg increase in SBP, the multivariable RRs were 1.31 (95% CI: 1.20 to 1.42) for total stroke, 1.28 (95% CI: 1.16 to 1.40) for ischemic stroke, and 1.38 (95% CI: 1.13 to 1.68) for hemorrhagic stroke. Although DBP, pulse pressure, and mean arterial pressure were all significant predictors of stroke risk, none was a significantly better predictor than SBP alone. Adding DBP did not significantly improve the model fit of SBP alone for any stroke type. CONCLUSION: In this large cohort of initially healthy men, systolic blood pressure was a consistent and significant predictor of total, ischemic, and hemorrhagic stroke. Systolic blood pressure alone was the only measure necessary to predict risk of total stroke or its major subtypes.

Polymorphisms of prostaglandin-endoperoxide synthase 2 gene, and prostaglandin-E receptor 2 gene, C-reactive protein concentrations and risk of atherothrombosis: a nested case-control approach.

OBJECTIVE: Recent data have shown an association between polymorphisms of prostaglandin-endoperoxide synthase-2 gene (PTGS2; alias COX-2), and prostaglandin-E receptor-2 gene (PTGER2) and risk of atherothrombotic disorders. METHODS: We evaluated two PTGS2 (rs20417, rs689470), and three PTGER2 (rs708494/uS5, rs708495/uS7, and chr14: 50 764 013/uS10) gene polymorphisms among 600 Caucasian male participants of the Physicians' Health Study with incident myocardial infarction (MI) or ischemic stroke and 600 age- and smoking-matched controls who remained free of all reported cardiovascular disease. RESULTS: Genotype distributions were in Hardy-Weinberg equilibrium in the control groups. Genotype and allele distribution were similar between cases and controls. The polymorphisms tested were in linkage disequilibrium. Results from the adjusted haplotype-based conditional logistic regression analysis showed a modest association of the PTGER2 2-1-1 haplotype with reduced risk of MI (odds ratio = 0.50, 95% CI; CI = 0.26-0.97, P = 0.04), and the 2-2-1 haplotype with reduced risk of ischemic stroke (odds ratio = 0.68, 95% CI = 0.47-0.99, P = 0.048). In contrast to prior data, we found no evidence for an association of the PTGS2 polymorphisms/haplotypes tested with risk of incident MI nor with ischemic stroke. However, we found suggestive evidence for an association of specific PTGER2 haplotypes with reduced risk of these outcomes. CONCLUSION: Although these prospective data implicate the potential involvement of prostaglandin-E receptor-2 gene variation in atherothrombosis, external validation of our findings is needed.

Homocysteine and risk of developing hypertension in men.

In cross-sectional studies, elevated homocysteine levels are associated with higher blood pressure, but it remains unclear whether plasma homocysteine is a risk factor for hypertension. In a prospective nested case-control study, participants who developed hypertension (n=396) had significantly higher levels of baseline plasma homocysteine (12.6 mol/l) than matched controls (11.8 mol/l, P=0.03); compared to those in the lowest quintile, those in the highest quintile had a crude relative risk (RR) of 1.56 (95% confidence interval (CI), 0.98-2.48; P for trend=0.10) and a multivariable RR of 1.63 (95% CI, 0.97-2.74; P for trend=0.13). Higher plasma homocysteine levels at baseline were associated with an increased but non-significant risk of incident hypertension that was minimally affected by multivariable adjustment.