Tobias Kurth

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Abstract: The prevalence of vascular risk factors, cardiovascular disease, and restless legs syndrome increases with age. Prior studies analyzing the associations between vascular risk factors, cardiovascular disease, and restless legs syndrome found controversial results. We therefore aim to evaluate the associations between prevalent vascular risk factors, prevalent cardiovascular disease, and restless legs syndrome.

Abstract: BACKGROUND: Atropine has is currently recommended to facilitate haemodynamic stability during critical care intubation. Our objective was to determine whether atropine use at induction influences ICU mortality. METHODOLOGYPRINCIPAL FINDINGS: A 2-year prospective, observational study of all first non-planned intubations, September 2007-9 in PICU and Intensive Care Transport team of Hôpital Robert Debré, Paris, 4 other PICUs and 5 NICUs in the Paris Region, France. Follow-up was from intubation to ICU discharge. A propensity score was used to adjust for patient specific characteristics influencing atropine prescription. 264/333 (79%) intubations were included. The unadjusted ICU mortality was 7.2% (9/124) for those who received atropine compared to 15.7% (22/140) for those who did not (OR 0.42, 95%CI 0.19-0.95, p = 0.04). One child died during intubation (1/264, 0.4%). Two age sub-groups of neonates (≤28 days) and older children (>28 days, <8 years) were examined. This difference in mortality arose from the higher mortality in children aged over one month when atropine was not used (propensity score adjusted OR 0.22, 95%CI 0.06-0.85, p = 0.028). No effect was seen in neonates (propensity score adjusted OR 1.3, 95%CI 0.31-5.1 p = 0.74). Using the propensity score, atropine maintained the mean heart rate 45.9 bpm above that observed when no atropine was used in neonates (95%CI 34.3-57.5, p<0.001) and 43.5 bpm for older children (95%CI 25.5-61.5 bpm, p<0.001). CONCLUSIONSSIGNIFICANCE: Atropine use during induction was associated with a reduction in ICU mortality in children over one month. This effect is independent of atropine's capacity to attenuate bradycardia during intubation which occurred similarly in neonates and older children. This result needs to be confirmed in a study using randomised methodology.

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Abstract: BACKGROUND: Subdural hematomas are an important bleeding complication of antithrombotic therapies. We sought to characterize the risk of subdural hematoma associated with antiplatelet therapy. METHODS: Trials were gathered from the Cochrane Central Register of Controlled Trials and from recent meta-analyses of trials regarding antiplatelet therapy for the primary prevention of stroke. Randomized trials published since 1980 comparing antiplatelet therapy with placebo or control and reporting subdural hematoma were included in the analysis. For recent large trials that did not report subdural hematomas, unpublished results were sought. Two reviewers independently extracted data on study design and subdural hematomas, with differences resolved by joint review and consensus. RESULTS: Four published trials were identified that compared aspirin with placebo/control involving 6565 participants (mean age 66 years) with 8 total subdural hematomas. Unpublished data from 5 aspirin trials with 90,689 participants reported 18 total subdural hematomas. The incidence of subdural hematomas varied from 0.02 per 1000 patient-years for primary prevention trials of middle-aged health professionals to 1 to 2 per 1000 patient-years for older patients with atrial fibrillation. Pooled data from all 9 trials revealed an odds ratio of 1.6 (95% confidence interval 0.8-3.5; heterogeneity P = .8; I(2) index 0%) for antiplatelet therapy and risk of subdural hematoma. CONCLUSIONS: Based on the limited available data, it is uncertain whether aspirin therapy increases the risk of subdural hematoma: the observed 1.6-fold increased risk was not statistically significant. The incidence of subdural hematoma during aspirin therapy is low but varies widely depending upon the age of the patient population.

Abstract: No abstract available.

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Abstract: PURPOSE: Previous studies have suggested that migraineurs are at decreased risk for developing breast cancer. Further prospective studies are warranted to confirm these results. In addition, studies evaluating migraine characteristics (e.g., migraine subtypes and frequency) are lacking. METHODS: We conducted a prospective cohort study among 39,696 participants in the Women's Health Study who were 45 years and older at study entry. Information on migraine was self-reported with good validation rates. Incident breast cancer cases were confirmed by medical record review. We distinguished the following major endpoints: any breast cancer, a combined endpoint of invasive and in situ cases, in situ breast cancer only, and invasive breast cancer only. Cox proportional hazards models were used to calculate age- and multivariable-adjusted hazard ratios (HRs) and 95 % confidence intervals (95 % CI). RESULTS: A total of 7,318 (18.4 %) women reported any migraine. During a mean follow-up time of 13.6 years, 432 in situ and 1,846 invasive breast cancer cases occurred. Migraine was not associated with breast cancer risk. The multivariable-adjusted HRs (95 % CI) were 1.10 (0.99-1.22) for any breast cancer, 1.06 (0.83-1.35) for in situ breast cancer, and 1.11 (0.99-1.25) for invasive breast cancer. The risk for developing breast cancer differed according to hormone receptor status with a suggestion of increased risks for hormone receptor negative tumors (HR ER-/PR- : 1.28, 95 % CI: 0.96-1.71). We did not observe meaningful differences with regard to histologic subtype or according to migraine aura status or migraine attack frequency. CONCLUSIONS: Results of our study do not support the hypothesis that migraineurs have a decreased risk for breast cancer.

Abstract: Background Previous studies suggest an association between migraine and restless legs syndrome (RLS). Population-based data, however, have been limited to women. The aim of this study is to evaluate the association between migraine and RLS in a male cohort. Methods We conducted a cross-sectional study among 22,926 participants in the Physicians' Health Study. Migraine and RLS information was self-reported. RLS was classified according to four minimal diagnostic criteria. Age- and multivariable-adjusted logistic regression models were calculated. Results Of the 22,926 participants (mean age 67.8), 2816 (12.3%) reported migraine and 1717 (7.5%) RLS. Migraine was associated with an increased multivariable-adjusted odds ratio (OR) (95% confidence interval (CI)) of 1.20 (1.04-1.38) for having RLS. The association remained stable after excluding men with potential mimics of RLS and was not modified by age. Conclusions Results of our study indicate an association between migraine and RLS in men. The magnitude of effect is similar to what has been reported in women.

Abstract: BACKGROUND AND PURPOSE: Several biomarkers have been associated with an increased risk of ischaemic stroke. However, the association between these biomarkers and functional outcome from cerebral ischaemic events is unclear. We aimed to assess the patterns of association between cardiovascular disease biomarkers and functional outcomes after incident ischaemic cerebral events in women. METHODS: Prospective cohort study of 27,728 women enrolled in the Women's Health Study who provided information on blood samples and were free of stroke or transient ischaemic attack (TIA) at baseline. Multinomial logistic regression was used to determine the association between elevated biomarker levels and functional outcomes from ischaemic cerebral events. Possible functional outcomes included TIA and ischaemic stroke with modified Rankin Scale (mRS) score of 0-1, 2-3, or 4-6. RESULTS: After a mean follow-up of 15.1 years, 461 TIAs and 380 ischaemic strokes occurred. Elevated levels of total cholesterol were associated with the highest risk of poor functional outcome (mRS 4-6) after incident cerebral ischaemic events (relative risk = 2.02, 95% CI = 1.18-3.46). We observed significant associations between elevated levels of total cholesterol, Lp(a), C-reactive protein, and triglycerides, and mild or moderate functional outcomes after ischaemic cerebral events. Elevations in all other biomarkers were not significantly associated with functional outcomes. CONCLUSIONS: Whilst total cholesterol level was associated with highest risks of poor functional outcome after stroke, we overall observed an inconsistent pattern of association between biomarkers linked with an increased risk of vascular events and more impaired functional outcomes from stroke.

Abstract: Although aspirin is effective in prevention of stroke, fewer studies have examined the impact of aspirin on stroke morbidity.

Abstract: BACKGROUND: While cross-sectional studies have shown associations between migraine and depression, few studies have been able to evaluate the association between migraine and incident depression. METHODS: A prospective cohort study among 36,016 women without a history of depression enrolled in the Women's Health Study who provided information about migraine and headache at baseline. Women were classified as either having nonmigraine headache, migraine with aura, migraine without aura, past history of migraine or no history of headache. Cox proportional hazards models were used to evaluate the association between migraine and headache status and incident depression. RESULTS: At baseline, 5115 women reported a history of nonmigraine headache, 1805 reported migraine with aura, 2723 reported migraine without aura, and 1896 reported a past history of migraine. During 13.8 mean years of follow-up, 3833 new cases of depression occurred. The adjusted relative risks of incident depression were 1.44 (95% CI: 1.32, 1.56) for nonmigraine headache, 1.53 (95% CI: 1.35, 1.74) for migraine with aura, 1.40 (95% CI: 1.25, 1.56) for migraine without aura, and 1.56 (95% CI: 1.37, 1.77) for past history of migraine compared to no history of headache. CONCLUSIONS: Middle-aged women with migraine or nonmigraine headache are at increased risk of incident depression. Frequent migraine attacks (weekly or daily) were associated with the highest risk for developing depression.

Abstract: Previous studies evaluating the association of cardiovascular disease and vascular risk factors with restless legs syndrome showed inconsistent results, especially for the potential relation between various vascular risk factors and restless legs syndrome. We therefore aimed to analyze the relationships between vascular risk factors, prevalent cardiovascular disease, and restless legs syndrome.

Abstract: OBJECTIVE: To evaluate the association between migraine and cognitive decline among women. DESIGN: Prospective cohort study. SETTING: Women's Health Study, United States. PARTICIPANTS: 6349 women aged 65 or older enrolled in the Women's Health Study who provided information about migraine status at baseline and participated in cognitive testing during follow-up. Participants were classified into four groups: no history of migraine, migraine with aura, migraine without aura, and past history of migraine (reports of migraine history but no migraine in the year prior to baseline). MAIN OUTCOME MEASURES: Cognitive testing was carried out at two year intervals up to three times using the telephone interview for cognitive status, immediate and delayed recall trials of the east Boston memory test, delayed recall trial of the telephone interview for cognitive status 10 word list, and a category fluency test. All tests were combined into a global cognitive score, and tests assessing verbal memory were combined to create a verbal memory score. RESULTS: Of the 6349 women, 853 (13.4%) reported any migraine; of these, 195 (22.9%) reported migraine with aura, 248 (29.1%) migraine without aura, and 410 (48.1%) a past history of migraine. Compared with women with no history of migraine, those who experienced migraine with or without aura or had a past history of migraine did not have significantly different rates of cognitive decline in any of the cognitive scores: values for the rate of change of the global cognitive score between baseline and the last observation ranged from -0.01 (SE 0.04) for past history of migraine to 0.08 (SE 0.04) for migraine with aura when compared with women without any history of migraine. Women who experienced migraine were also not at increased risk of substantial cognitive decline (worst 10% of the distribution of decline). When compared with women without a history of migraine, the relative risks for the global score ranged from 0.77 (95% confidence interval 0.46 to 1.28) for women with migraine without aura to 1.17 (0.84 to 1.63) for women with a past history of migraine. CONCLUSION: In this prospective cohort of women, migraine status was not associated with faster rates of cognitive decline.

Abstract: Objectives To evaluate the association between restless legs syndrome (RLS) and all-cause mortality. Design Four prospective cohort studies. Setting The Dortmund Health Study (DHS) and the Study of Health in Pomerania (SHIP) from Germany. The Women's Health Study (WHS) and the Physicians’ Health Study (PHS) from the USA. Participants In DHS: a random sample (n=1 299) from the population of Dortmund; in SHIP: a sample (n=4 291) from residents living in West Pomerania were drawn by multistage random sampling design; in WHS: female healthcare professionals (n=31 370); in PHS: male physicians (n=22 926) Main outcome measures All-cause mortality. Results The prevalence of RLS ranged between 7.4% and 11.9% at baseline. During follow-up (ranging between 6 and 11 years) RLS was not associated with increased risk of all-cause mortality in any of the four cohorts. The multivariable-adjusted HRs (95% CI) for all-cause mortality ranged from 0.21 (0.03 to 1.53) to 1.07 (0.93 to 1.23) across the four studies. The HRs for all-cause mortality did not differ according to gender. Conclusions In these four independently conducted large prospective cohort studies from Germany and the USA, RLS did not increase the risk of all-cause mortality. These findings do not support the hypothesis that RLS is a risk factor for mortality of any cause.

Abstract: Objective To evaluate the association between use of benzodiazepines and incident dementia. Design Prospective, population based study. Setting PAQUID study, France. Participants 1063 men and women (mean age 78.2 years) who were free of dementia and did not start taking benzodiazepines until at least the third year of follow-up. Main outcome measures Incident dementia, confirmed by a neurologist. Results During a 15 year follow-up, 253 incident cases of dementia were confirmed. New use of benzodiazepines was associated with an increased risk of dementia (multivariable adjusted hazard ratio 1.60, 95% confidence interval 1.08 to 2.38). Sensitivity analysis considering the existence of depressive symptoms showed a similar association (hazard ratio 1.62, 1.08 to 2.43). A secondary analysis pooled cohorts of participants who started benzodiazepines during follow-up and evaluated the association with incident dementia. The pooled hazard ratio across the five cohorts of new benzodiazepine users was 1.46 (1.10 to 1.94). Results of a complementary nested case-control study showed that ever use of benzodiazepines was associated with an approximately 50% increase in the risk of dementia (adjusted odds ratio 1.55, 1.24 to 1.95) compared with never users. The results were similar in past users (odds ratio 1.56, 1.23 to 1.98) and recent users (1.48, 0.83 to 2.63) but reached significance only for past users. Conclusions In this prospective population based study, new use of benzodiazepines was associated with increased risk of dementia. The result was robust in pooled analyses across cohorts of new users of benzodiazepines throughout the study and in a complementary case-control study. Considering the extent to which benzodiazepines are prescribed and the number of potential adverse effects of this drug class in the general population, indiscriminate widespread use should be cautioned against.

Abstract: No abstract available.

Abstract: OBJECTIVES: To evaluate the association between restless legs syndrome (RLS) and incident cardiovascular disease (CVD). DESIGN: Prospective cohort study. SETTING: Women's Health Study (WHS) and Physicians' Health Study (PHS), USA. PARTICIPANTS: 29 756 female health professionals aged ≥45 years and 19 182 male physicians aged ≥40 years at baseline. MAIN OUTCOME MEASURES: Main outcome was incidence of major CVD; secondary outcomes were first incidence of myocardial infarction, stroke, death due to CVD or coronary revascularisation. RESULTS: 3487 (11.7%) women and 1373 (7.2%) men met International Restless Legs Study Group criteria for RLS. In the WHS 450 major CVD events occurred and 1064 major CVD events were confirmed in the PHS. In both cohorts, RLS was not associated with increased risk of major CVD, stroke, myocardial infarction, CVD death or coronary revascularisation. After adjustment for major vascular risk factors, the HRs (95% CI) for major CVD were 1.15 (0.88 to 1.50) in women and 1.01 (0.81 to 1.25) in men. Highest multivariable-adjusted HRs were 1.29 (0.91 to 1.82) for total stroke in women and 1.22 (0.87 to 1.70) for CVD death in men. Excluding participants with comorbidities potentially leading to RLS did not substantially change the effect estimates. CONCLUSIONS: In these large prospective studies of female and male health professionals, RLS was not associated with an increased risk of any incident CVD event. The data do not support the hypothesis that RLS is a marker of increased risk of vascular disease.

Abstract: Purpose To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of the diagnosis of age-related macular degeneration (AMD) in a large-scale randomized trial of male physicians. Design Randomized, double-masked, placebo-controlled trial. Participants We included 14 236 apparently healthy United States male physicians aged ≥50 years who did not report a diagnosis of AMD at baseline. Methods Participants were randomly assigned to receive 400 international units (IU) of vitamin E or placebo on alternate days, and 500 mg of vitamin C or placebo daily. Participants reported new diagnoses of AMD on annual questionnaires and medical record data were collected to confirm the reports. Main Outcome Measures Incident diagnosis of AMD responsible for a reduction in best-corrected visual acuity to ≤20/30. Results After 8 years of treatment and follow-up, a total of 193 incident cases of visually significant AMD were documented. There were 96 cases in the vitamin E group and 97 in the placebo group (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.78–1.37). For vitamin C, there were 97 cases in the active group and 96 in the placebo group (HR, 0.99; 95% CI, 0.75–1.31). Conclusions In a large-scale, randomized trial of United States male physicians, alternate-day use of 400 IU of vitamin E and/or daily use of 500 mg of vitamin C for 8 years had no appreciable beneficial or harmful effect on risk of incident diagnosis of AMD.

Abstract: To determine whether use of intermediate acting neuromuscular blocking agents during general anesthesia increases the incidence of postoperative respiratory complications.

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Abstract: Previous cross-sectional studies evaluating the relationship between diabetes prevalence and migraine status have found conflicting results. We examined the relationship between migraine and incident type 2 diabetes (T2D) in a cohort of adult women.

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Abstract: Zusammenfassung Diese kurze Übersicht soll jungen Autoren helfen wissenschaftliche Publikationen zu schreiben und erfolgreich einzureichen. Dabei werden Empfehlungen gegeben wie die einzelnen Teile einer Publikation strukturiert und formuliert werden sollen. Abschließend wird auf die Sichtweise von Herausgebern und Reviewern eingegangen. Abstract This short review aims to help young authors how to write scientific papers and to submit them to scientific journals. We provide recommendations on the structure of manuscripts. We also discuss the role of editors and referees.

Abstract: Few prospective studies have explored the association between renal function and risk for incident atrial fibrillation (AF) in apparently healthy populations. A total of 24,746 women participating in the Women's Health Study who were free of cardiovascular disease and AF and provided blood samples at baseline were prospectively followed for incident AF from 1993 to 2010. AF events were confirmed by medical chart review. Estimated glomerular filtration rate (eGFR) was calculated from baseline creatinine using the Chronic Kidney Disease Epidemiology (CKD-EPI) equation. Cox models were used to estimate hazard ratios and 95% confidence intervals (CIs) for incident AF across eGFR categories controlling for AF risk factors. During a median of 15.4 years of follow-up, 786 incident AF events occurred. The multivariate-adjusted hazard ratios for incident AF across eGFR categories (<60, 60 to 74.9, 75 to 89, and ≥90 ml/min/1.73 m(2)) were 1.36 (95% CI 1.00 to 1.84), 0.90 (95% CI 0.71 to 1.14), 0.99 (95% CI 0.84 to 1.18) and 1.00, respectively, without evidence of a linear association (P for trend = 0.48). Similarly, there was no significant curvilinear association (quadratic p = 0.10) in multivariate analysis across categories. Compared to women with eGFRs ≥60 ml/min/1.73 m(2), the 1,008 women with eGFRs <60 ml/min/1.73 m(2) had a multivariate-adjusted hazard ratio for AF of 1.39 (95% CI 1.04 to 1.86, p = 0.03). In conclusion, no significant linear or curvilinear relation was observed between incident AF and less severe impairment of renal function in this large prospective cohort of women. However, a significant elevation in AF risk was observed at a threshold eGFR of <60 ml/min/1.73 m(2).

Abstract: Migraine is a common and debilitating neurovascular disorder with a complex envirogenomic aetiology. Numerous studies have demonstrated a preponderance of women affected with migraine and previous pedigree linkage studies in our laboratory have identified susceptibility loci on chromosome Xq24-Xq28. In this study we have used the genetic isolate of Norfolk Island to further analyse the X chromosome for migraine susceptibility loci.An association approach was employed to analyse 14,124 SNPs spanning the entire X chromosome. Genotype data from 288 individuals comprising a large core-pedigree, of which 76 were affected with migraine, were analysed. Although no SNP reached chromosome-wide significance (empirical α = 1 × 10(-5)) ranking by P-value revealed two primary clusters of SNPs in the top 25. A 10 SNP cluster represents a novel migraine susceptibility locus at Xq12 whilst a 11 SNP cluster represents a previously identified migraine susceptibility locus at Xq27. The strongest association at Xq12 was seen for rs599958 (OR = 1.75, P = 8.92 × 10(-4)), whilst at Xq27 the strongest association was for rs6525667 (OR = 1.53, P = 1.65 × 10(-4)). Further analysis of SNPs at these loci was performed in 5,122 migraineurs from the Women's Genome Health Study and provided additional evidence for association at the novel Xq12 locus (P<0.05).Overall, this study provides evidence for a novel migraine susceptibility locus on Xq12. The strongest effect SNP (rs102834, joint P = 1.63 × 10(-5)) is located within the 5'UTR of the HEPH gene, which is involved in iron homeostasis in the brain and may represent a novel pathway for involvement in migraine pathogenesis.

Abstract: Migraine has been linked with an increased risk of stroke and an increased prevalence of clinically silent brain lesions and white-matter hyperintensities. As it is known that stroke and structural brain lesions are associated with an increased risk of cognitive decline, it has been hypothesized that migraine may be a progressive brain disorder and associated with an increased risk of cognitive impairment. Given the prevalence of migraine in the population, especially among women, and the aging of the population, an association between migraine and cognitive impairment would have substantial public health implications. In this review, we will summarize the existing evidence evaluating the association between migraine and cognitive function. Additionally, we will discuss methodological issues in migraine and cognitive function assessment and elaborate on study design strategies to address this important question.

Abstract: BACKGROUND: Migraine has been linked with several measures of socioeconomic status (SES). However, results are inconsistent and data on the association between SES and non-migraine headache, migraine subtypes and migraine frequency are sparse. METHODS: We conducted a cross-sectional study among 36,858 participants in the Women's Health Study. As proxy for SES, we calculated an SES index using annual household income and education. Migraine, migraine aura, and non-migraine headache were self-reported with good validation rates. Multinomial logistic regression models were used to evaluate the association between the SES index and the various headache forms. RESULTS: Of the women participating in the study, 12,140 (32.9%) reported any history of headache, 6801 (18.4%) reported any history of migraine and 5339 (14.5%) reported non-migraine headache. Women with low SES had an increased risk for all headache forms. The multivariable-adjusted odds ratios (ORs; 95% CI) were 1.22 (1.10-1.36) for non-migraine headache, 1.40 (1.28-1.54) for any migraine, 1.44 (1.23-1.69) for migraine with aura, and 1.38 (1.21-1.58) for migraine without aura. Among active migraineurs, low SES was associated with an increased OR for ≥ weekly attack frequency (1.77, 1.26-2.49). CONCLUSIONS: In this large cohort of female health professionals, low SES was associated with an increased prevalence for all headache forms and an increased migraine attack frequency.

Abstract: Migraine and stroke are two common and heterogeneous neurovascular disorders with complex relations. Data show no firm association between stroke and migraine without aura--by far the most common type of migraine--but a doubling of the risk of ischaemic stroke in people who have migraine with aura. Migraine with aura is characterised by a low brain threshold for cortical spreading depression, the biological substrate of the aura, which can be triggered by many factors, including specific diseases that can by themselves increase the risk of ischaemic stroke. Whether the increased risk of ischaemic stroke applies to migraine with aura as a primary headache disorder or is partly due to migraine with aura secondary to other disorders remains to be elucidated.

Abstract: BACKGROUND: Migraine is an independent risk factor for stroke. Mechanisms underlying this association are unclear. Familial hemiplegic migraine (FHM), a migraine subtype that also carries an increased stroke risk, is a useful model for common migraine phenotypes because of shared aura and headache features, trigger factors, and underlying glutamatergic mechanisms. METHODS AND RESULTS: Here, we show that FHM type 1 (FHM1) mutations in Ca(V)2.1 voltage-gated Ca(2+) channels render the brain more vulnerable to ischemic stroke. Compared with wild-type mice, 2 FHM1 mutant mouse strains developed earlier onset of anoxic depolarization and more frequent peri-infarct depolarizations associated with rapid expansion of infarct core on diffusion-weighted magnetic resonance imaging and larger perfusion deficits on laser speckle flowmetry. Cerebral blood flow required for tissue survival was higher in the mutants, leading to infarction with milder ischemia. As a result, mutants developed larger infarcts and worse neurological outcomes after stroke, which were selectively attenuated by a glutamate receptor antagonist. CONCLUSIONS: We propose that enhanced susceptibility to ischemic depolarizations akin to spreading depression predisposes migraineurs to infarction during mild ischemic events, thereby increasing the stroke risk.

Abstract: Some cross-sectional studies have suggested an association between migraine and increased body weight. However, prospective data on the association are lacking.

Abstract: No abstract available.

Abstract: Abstract Objectives To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer’s disease and to estimate the risk of incident cancer among participants with and without Alzheimer’s disease. Design Community based prospective cohort study; nested age and sex matched case-control study. Setting Framingham Heart Study, USA. Participants 1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90). Main outcome measures Hazard ratios and 95% confidence intervals for the risks of Alzheimer’s disease and cancer. Results Over a mean follow-up of 10 years, 221 cases of probable Alzheimer’s disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer’s disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer’s disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer’s disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer’s disease (0.38) and any dementia (0.44). Conclusions Cancer survivors had a lower risk of Alzheimer’s disease than those without cancer, and patients with Alzheimer’s disease had a lower risk of incident cancer. The risk of Alzheimer’s disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson’s disease and suggests an inverse association between cancer and neurodegeneration.

Abstract: Background: Few clinic-based studies report an association between migraine and restless legs syndrome (RLS); however, population-based data are unavailable. Methods: Cohort study among 31,370 women participating in the Women’s Health Study. We had detailed self-reported information on migraine, including aura status, and RLS. RLS was ascertained at the 9-year follow-up. We calculated odds ratios (OR) and 95% confidence intervals (CI) for the association between migraine and RLS. We investigated any indication of migraine until RLS ascertainment as well as migraine with and without aura at baseline, prior migraine before baseline, and new reports of migraine during follow-up. Results: At baseline or during follow-up 6857 (21.9%) women reported any migraine. These women had an increased risk for RLS (multivariable-adjusted OR = 1.22; 95%CI 1.13–1.32). Further analyses indicated a similar association for migraine with aura (multivariable-adjusted OR = 1.27; 95%CI 1.10–1.48) and migraine without aura (multivariable-adjusted OR = 1.24; 95%CI 1.09–1.40) as well as for new reports of migraine during follow-up (multivariable-adjusted OR = 1.30; 95%CI 1.10–1.54). Prior migraine did not appear to be associated with RLS. Conclusions: Our data suggest an association between migraine and RLS at the population level. The association is similar for migraine with and without aura and for new reports of migraine during follow-up.

Abstract: No abstract available.

Abstract: BACKGROUND: α-Methylacyl-CoA racemase (AMACR) is an enzyme that serves as a diagnostic biomarker of prostate cancer in clinical practice. Recent studies suggest that low AMACR expression is associated with biochemical recurrence and the development of fatal disease. METHODS: We conducted a prospective cohort study among 920 men aged 47-84 years, who were diagnosed with prostate cancer in the Physicians' Health Study and the Health Professionals Follow-up Study cohorts, and whose resected tissue specimens were available for immunohistochemical analysis. We used Cox proportional hazards regression to evaluate the association of AMACR expression with lethal prostate cancer over a 20-year follow-up period. RESULTS: In total, 68 men died from prostate cancer, and an additional 18 developed bony metastases during follow-up. We found that lower AMACR intensity was associated with higher prostate-specific antigen levels (P = 0.003) and more advanced clinical stage (P = 0.06) at diagnosis, and a nonsignificant trend for higher risk of lethal outcomes. The hazard ratio (HR) comparing the lowest to the highest quartile of AMACR expression intensity was 1.53 ((95% CI: 0.86-2.73), P-for-trend across quartiles = 0.07); this trend was further attenuated after adjustment for age, Gleason score, stage, and cohort with a HR of 1.24 (95% CI: 0.69-2.22), P-for-trend = 0.23. CONCLUSIONS: Low AMACR expression in primary tumor specimens was not independently associated with the development of metastatic and lethal prostate cancer after treatment over a 20-year follow-up period, after adjustment for important clinical covariates at diagnosis.

Abstract: To provide a reliable assessment of the hypothesized association of fish consumption with stroke risk accumulatively, an updated meta-analysis of published prospective cohort studies was conducted.

Abstract: BACKGROUND: An association between the 677C>T polymorphism (rs1801133) in the methylenetetrahydrofolate reductase gene (MTHFR) and cluster headache is plausible, but has not been investigated. OBJECTIVE: To investigate this association among Caucasians. METHODS: Case-control study among 147 cluster headache patients and 599 population-based age- and gender-matched controls. Cluster headache was diagnosed according to the criteria of the International Headache Society. Genotypes of the MTHFR 677C>T polymorphism were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between cluster headache and genotypes with additive, dominant, and recessive models. We considered a Bonferroni-corrected P value <.004 as significant. RESULTS: Mean age at study entry among patients was 44.9 years (SD 11.4), of whom 76.2% were men. The genotype distribution among controls and patients was in Hardy-Weinberg equilibrium. The genotype and allele distribution did not differ between patients with any cluster headache and controls. We also did not find an association when assuming additive, dominant or recessive genetic models. When we looked at subgroups, the effect estimates suggested an increased risk for chronic cluster headache (dominant model: odds ratio = 2.82; 99.6% confidence interval = 0.72-11.07; P = .03). CONCLUSIONS: Data from our case-control study do not indicate an association between genotypes of the MTHFR 677C>T polymorphism and cluster headache overall. Subgroup analyses suggested that carriers of the MTHFR 677T allele may have an increased risk for chronic cluster headache. This may be regarded as hypothesis-generating and should be further investigated in independent studies.

Abstract: Modification of lifestyle habits is a key preventive strategy for many diseases. The role of lifestyle for the onset of headache in general and for specific headache types, such as migraine and tension-type headache (TTH), has been discussed for many years. Most results, however, were inconsistent and data on the association between lifestyle factors and probable headache forms are completely lacking. We evaluated the cross-sectional association between different lifestyle factors and headache subtypes using data from three different German cohorts. Information was assessed by standardized face-to-face interviews. Lifestyle factors included alcohol consumption, smoking status, physical activity and body mass index. According to the 2004 diagnostic criteria, we distinguished the following headache types: migraine, TTH and their probable forms. Regional variations of lifestyle factors were observed. In the age- and gender-adjusted logistic regression models, none of the lifestyle factors was statistically significant associated with migraine, TTH, and their probable headache forms. In addition, we found no association between headache subtypes and the health index representing the sum of individual lifestyle factors. The lifestyle factors such as alcohol consumption, smoking, physical activity and overweight seem to be unrelated to migraine and TTH prevalence. For a judgement on their role in the onset of new or first attacks of migraine or TTH (incident cases), prospective cohort studies are required.

Abstract: OBJECTIVE: To evaluate the evidence on the association between migraine and mortality. METHODS: Systematic review and meta-analysis of studies investigating the association between any migraine (all forms of migraine collectively) or migraine subtypes (e.g. migraine with aura) and mortality published until March 2011. RESULTS: We identified ten cohort studies. Studies differed regarding the types of mortality investigated and only four presented aura-stratified results, limiting pooled analyses with regard to migraine subtypes and with regard to cause-specific mortality. For any migraine pooled analyses do not suggest an association with all-cause mortality (five studies; pooled relative risk (RR)=0.90, 95% confidence interval (CI) 0.71-1.16), cardiovascular disease mortality (CVD; six studies; pooled RR=1.09, 95% CI 0.89-1.32), or coronary heart disease mortality (CHD; three studies; pooled RR=0.95, 95% CI 0.57-1.60). Heterogeneity among studies is moderate to high. Two studies suggest that migraine with aura increases risk for CVD and CHD mortality. CONCLUSION: This meta-analysis does not suggest that any migraine is associated with increased risk of mortality from all causes, CVD, or CHD. However, there is heterogeneity among studies and suggestion that migraine with aura increases CVD and CHD mortality. Given the high prevalence of migraine in the general population a definitive answer to the question of whether migraine or a subtype alters risk for mortality is of high public health importance and further targeted research implicated.

Abstract: Background Migraine is associated with an increased risk for cardiovascular disease (CVD). Both migraine and CVD are highly heritable. However, the genetic liability for CVD among migraineurs is unclear. Methods We performed a genome-wide association study for incident CVD events during 12 years of follow-up among 5,122 migraineurs participating in the population-based Women's Genome Health Study. Migraine was self-reported and CVD events were confirmed after medical records review. We calculated odds ratios (OR) and 95% confidence intervals (CI) and considered a genome-wide p-value <5×10−8 as significant. Results Among the 5,122 women with migraine 164 incident CVD events occurred during follow-up. No SNP was associated with major CVD, ischemic stroke, myocardial infarction, or CVD death at the genome-wide level; however, five SNPs showed association with p<5×10−6. Among migraineurs with aura rs7698623 in MEPE (OR = 6.37; 95% CI 3.15–12.90; p = 2.7×10−7) and rs4975709 in IRX4 (OR = 5.06; 95% CI 2.66–9.62; p = 7.7×10−7) appeared to be associated with ischemic stroke, rs2143678 located close to MDF1 with major CVD (OR = 3.05; 95% CI 1.98–4.69; p = 4.3×10−7), and the intergenic rs1406961 with CVD death (OR = 12.33; 95% CI 4.62–32.87; p = 5.2×10−7). Further, rs1047964 in BACE1 appeared to be associated with CVD death among women with any migraine (OR = 4.67; 95% CI 2.53–8.62; p = 8.0×10−7). Conclusion Our results provide some suggestion for an association of five SNPs with CVD events among women with migraine; none of the results was genome-wide significant. Four associations appeared among migraineurs with aura, two of those with ischemic stroke. Although our population is among the largest with migraine and incident CVD information, these results must be treated with caution, given the limited number of CVD events among women with migraine and the low minor allele frequencies for three of the SNPs. Our results await independent replication and should be considered hypothesis generating for future research.

Abstract: BACKGROUND: Migraine with aura (MA) has been associated with increased risk of cardiovascular disease (CVD). The role of aspirin on this association remains unclear. METHODS: Post-hoc subgroup analyses of the Women's Health Study, a randomized trial testing 100 mg aspirin on alternate days in primary prevention of CVD among 39,876 women aged ≥ 45. RESULTS: During 10 years, 998 major CVD events were confirmed in 39,757 women with complete migraine information. Aspirin reduced risk of ischaemic stroke (relative risk, RR, 0.76, 95% CI 0.63-0.93) but not other CVD. Migraine or MA did not modify the effect of aspirin on CVD except for myocardial infarction (MI) (p for interaction = 0.01). Women with MA on aspirin had increased risk of MI (RR 3.72, 95% CI 1.39-9.95). Further exploratory analyses indicate that this increased risk is only apparent among women with MA on aspirin who ever smoked or had history of hypertension (p for interaction<0.01). CONCLUSIONS: In post-hoc subgroup analyses, aspirin had similar protective effects on ischaemic stroke for women with or without migraine. By contrast, our data suggest that women with MA on aspirin had increased risk of MI. The small number of outcome events in subgroups, the exploratory nature of our analyses, and lack of plausible mechanisms raise the possibility of a chance finding, which must caution the interpretation.

Abstract: Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.

Abstract: BACKGROUND: Previous studies on migraine and cognition have shown mixed results. However, many could not assess the relationship between migraine and change in cognitive function or only used a limited number of cognitive tests. METHODS: Prospective cohort study among 1170 participants of the Epidemiology of Vascular Ageing Study who provided information about migraine status and completed cognitive testing. Participants were classified as having no severe headache, non-migraine headache and migraine. Cognitive functioning was measured at up to four time points using nine different cognitive functioning tests. Linear mixed effects models were used to evaluate the relationship between migraine status and change in cognitive function. RESULTS: Of the 1170 participants, 938 had no severe headache, 167 had migraine, and 65 had non-migraine headache. After adjusting for age, gender, education and smoking status, people with migraine or non-migraine headache did not experience a greater rate of cognitive decline than those without headache or migraine in any domain (for the Mini Mental State Examination (MMSE), p-values were 0.68 for the non-migraine headache and time interaction and 0.85 for the migraine and time interaction) during 4-5 years of follow-up. For the Wechsler Adult Intelligence Scale-Revised, those with migraine declined less over time (p-value=0.02). CONCLUSION: Migraine was not associated with faster cognitive decline over time.

Abstract: Background The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514million people. Aims To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country. Methods The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27+Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010. Results The total cost of disorders of the brain was estimated at €798billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients' production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between €285 for headache and €30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was €1550 on average but varied by country. The cost (in billion €PPP 2010) of the disorders of the brain included in this study was as follows: addiction: €65.7; anxiety disorders: €74.4; brain tumor: €5.2; child/adolescent disorders: €21.3; dementia: €105.2; eating disorders: €0.8; epilepsy: €13.8; headache: €43.5; mental retardation: €43.3; mood disorders: €113.4; multiple sclerosis: €14.6; neuromuscular disorders: €7.7; Parkinson's disease: €13.9; personality disorders: €27.3; psychotic disorders: €93.9; sleep disorders: €35.4; somatoform disorder: €21.2; stroke: €64.1; traumatic brain injury: €33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted €477billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US. Discussion This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges. Recommendations Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.

Abstract: BACKGROUND: Data on the association between TNFα and TNFβ gene polymorphisms and migraine are conflicting. METHODS: We performed a systematic review and meta-analysis of studies published until January 2011. We used data from published papers and as provided after contact with the authors. We calculated study specific odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models as well as pooled effect estimates. RESULTS: Among the ten studies identified, the best evidence is available for the TNFα -308G>A and TNFβ 252A > G polymorphisms indicating no overall association with migraine. Subgroup analyses suggested that the A allele of the TNFα -308G > A variant more than doubles the risk for migraine among populations with a heterogeneous ethnic background, which was driven by associations for migraine without aura (additive model: pooled OR = 2.87, 95% CI 1.86-4.43). Further, the risk for migraine with aura was increased among Asian populations (additive model: pooled OR = 1.71, 95% CI 1.07-2.71). Both observed effects were stronger among females than males. CONCLUSIONS: Our results indicate no overall association between TNFα and TNFβ gene variants and migraine. However, associations differed among specific populations. Our findings need to be treated with caution and further targeted research is warranted to evaluate population-specific effects including population stratification.

Abstract: Abstract PURPOSE: We examined patient reported outcomes among patients with prostate cancer treated with watchful waiting in a nationwide cohort. MATERIALS AND METHODS: We collected treatment information and patient reported outcomes from 1,230 patients with prostate cancer diagnosed with T1-T2 prostate cancer in the Physicians' Health Study, of whom 125 were initially treated with watchful waiting. Cox proportional hazards regression was used to identify predictors of treatment initiation among patients on watchful waiting. Logistic regression was used to calculate the OR and 95% CI to assess disease targeted quality of life by initial treatment or watchful waiting. RESULTS: At a mean 7.3-year followup 41% of patients on watchful waiting remained free of treatment while 34% had received radiotherapy or brachytherapy, 16% had received primary hormonal therapy and 10% had undergone prostatectomy. Younger age, higher clinical stage, higher Gleason score and higher prostate specific antigen at diagnosis predicted progression to treatment. Watchful waiting compared to immediate treatment was associated with less urinary incontinence (3.5% vs 10%) and impotence (68% vs 78%) but more common obstructive urinary symptoms (22% vs 13%) on univariate analysis (each p <0.05). Incontinence and impotence differences remained significant after adjusting for age, comorbidity and time after cancer diagnosis. Quality of life outcomes in men who underwent delayed treatment after initially waiting were not worse than in men who underwent immediate treatment. CONCLUSIONS: Findings suggest quality of life benefits after watchful waiting in select patients with early stage prostate cancer compared to men treated immediately after diagnosis. Younger age and greater cancer severity at diagnosis predicted progression to treatment.

Abstract: Background and Purpose—In studies enrolling patients with stroke, higher levels of prestroke physical activity are associated with better functional outcomes. However, prospective studies evaluating this association are sparse. Using a cohort of initially healthy men, we aimed to prospectively assess the association between physical activity and functional outcomes from cerebral vascular events. Methods—We conducted a prospective cohort study among 21 794 men enrolled in the Physician's Health Study who provided information on physical activity at baseline and who did not have a history of stroke or transient ischemic attack (TIA). Baseline levels of physical activity were categorized as: vigorous exercise <1, 1, 2 to 4, and ≥5 times/week. Possible functional outcomes included TIA and stroke with modified Rankin Scale score of 0 to 1, 2 to 3, or 5 to 6. Multinomial logistic regression was used to determine the association between physical activity and functional outcomes from cerebral vascular events. Results—After a mean of 20.2 years of follow-up, 761 TIAs, 1146 ischemic strokes, 221 hemorrhagic strokes, and 11 strokes of unknown type occurred. Compared with men who did not experience a stroke or TIA and who exercise vigorously <1 time/week, men who exercise vigorously ≥5 times/week had adjusted relative risk (95% CIs) of 0.67 (0.53–0.86) for TIA, 0.84 (0.61–1.14) for stroke with modified Rankin Scale score 0 to 1, 0.85 (0.67–1.08) for modified Rankin Scale score 2 to 3, and 1.12 (0.78–1.60) for modified Rankin Scale score 5 to 6 after total stroke. Other levels of physical activity did not have a significant impact on the risk of our outcomes. Conclusions—Physical activity before TIA or stroke does not appear to influence functional outcomes after cerebral vascular events.

Abstract: BACKGROUND: Migraine with aura has been associated with increased prevalence of cardiovascular risk factors, including elevated levels of some vascular biomarkers. However, little research has been done on this association among the elderly. We examined the associations of lipid levels with headache and migraine in a cohort of elderly individuals. METHODS: Cross-sectional study among 1155 participants enrolled in the Epidemiology of Vascular Ageing Study with available information on headache and blood biomarkers. We used multinomial logistic regression to evaluate the association between biomarker tertiles and headache categories. RESULTS: 925 people had no severe headache, 64 people had non-migraine headache and 166 people had migraine, of whom 23 had aura. Compared with participants without headache, we observed strong associations between increasing tertiles of total cholesterol and migraine with aura. The odds ratio (95% confidence interval) was 4.67 (0.99-21.97) for the 2nd tertile and 5.97 (1.29-27.61) for the 3rd tertile. We also found strong associations between triglycerides and migraine with aura (odds ratio for 3rd tertile: 4.42 (1.32-14.77)). We did not see significant associations between increased biomarker levels and any other headache group. CONCLUSIONS: Elevated levels of total cholesterol and triglycerides are associated with migraine with aura but not other headache forms in the elderly.

Abstract: BACKGROUND: Smoking has a well-documented detrimental effect on risk for myocardial infarction and stroke, but less information is available regarding peripheral artery disease (PAD), particularly among women. OBJECTIVE: To prospectively assess the association of current smoking status, cumulative smoking exposure, and smoking cessation with incident symptomatic PAD in women. DESIGN: Prospective cohort study. SETTING: U.S. female health care professionals in the Women's Health Study. PARTICIPANTS: 39,825 women with no cardiovascular disease who were prospectively followed for a median of 12.7 years. MEASUREMENTS: Incidence of symptomatic PAD. Cox proportional hazards models were used to compare PAD risk across smoking categories. RESULTS: 178 confirmed PAD events occurred. Across the 4 smoking categories (never, former, <15 cigarettes/d, and ≥15 cigarettes/d), age-adjusted incidence rates were 0.12, 0.34, 0.95, and 1.63 per 1000 person-years of follow-up, respectively. Multivariate adjustment had little effect on this relationship (adjusted hazard ratios [HRs], 3.14 [95% CI, 2.01 to 4.90], 8.93 [CI, 5.02 to 15.89], and 16.95 [CI, 10.77 to 26.67], respectively, vs. women who never smoked). Additional adjustment for high-sensitivity C-reactive protein and soluble intercellular adhesion molecule-1 levels among women with available blood samples (28,314 participants, 117 events) attenuated risk estimates (HR, 5.58 [CI, 2.61 to 11.93] for smoking <15 cigarettes/d and 9.52 [CI, 5.17 to 17.53] for smoking ≥15 cigarettes/d). Lifetime exposure showed a strong dose-response relationship; fully adjusted HRs for smoking abstinence of fewer than 10, 10 to 29, and 30 or more pack-years were 2.52 (CI, 1.49 to 4.25), 6.75 (CI, 4.33 to 10.52), and 11.09 (CI, 6.94 to 17.72), respectively. Compared with current smokers, the adjusted HRs for fewer than 10 years, 10 to 20 years, more than 20 years, or lifelong abstinence were 0.39 (CI, 0.24 to 0.66), 0.28 (CI, 0.17 to 0.46), 0.16 (CI, 0.10 to 0.26), and 0.08 (CI, 0.05 to 0.12), respectively. LIMITATION: The use of symptomatic PAD as the a priori primary end point excludes asymptomatic disease. CONCLUSION: Among initially healthy women, smoking is a potent risk factor for symptomatic PAD and was associated with subclinical inflammation. Smoking cessation substantially reduces risk for PAD, but an increased occurrence of PAD persists even among former smokers who maintain abstinence.

Abstract: This manuscript discusses sex-related differences in headache prevalence, the symptoms and natural history of migraine, associated disability, and co-morbid disorders. The role of sex hormones is discussed with reference to the effects of hormonal events across the reproductive years and the specific effects of the menstrual cycle on migraine. Differences between the sexes were identified across all parameters reviewed. Future research should ensure that data are analyzed separately for men and women to ensure that differences between the sexes are identified.

Abstract: Limited data are available on the prevention of intracerebral hemorrhage (ICH) recurrence, which is substantial, especially in the case of lobar ICH related to cerebral amyloid angiopathy. In view of the relative paucity of prospectively generated data, current strategies for the secondary prevention of ICH involve the extrapolation of data on primary prevention of ICH to its secondary prevention and the avoidance of certain agents that have been shown in clinical series to be associated with increased risk of ICH recurrence. This review analyzes ways to approach the secondary prevention of ICH in the setting of a paucity of adequate prospectively generated data on the subject.

Abstract: OBJECTIVE: To evaluate the association of overall and specific headaches with volume of white matter hyperintensities, brain infarcts, and cognition. DESIGN: Population based, cross sectional study. SETTING: Epidemiology of Vascular Ageing study, Nantes, France. PARTICIPANTS: 780 participants (mean age 69, 58.5% women) with detailed headache assessment. MAIN OUTCOME MEASURES: Brain scans were evaluated for volume of white matter hyperintensities (by fully automated imaging processing) and for classification of infarcts (by visual reading with a standardised assessment grid). Cognitive function was assessed by a battery of tests including the mini-mental state examination. RESULTS: 163 (20.9%) participants reported a history of severe headache and 116 had migraine, of whom 17 (14.7%) reported aura symptoms. An association was found between any history of severe headache and increasing volume of white matter hyperintensities. The adjusted odds ratio of being in the highest third for total volume of white matter hyperintensities was 2.0 (95% confidence interval 1.3 to 3.1, P for trend 0.002) for participants with any history of severe headache when compared with participants without severe headache being in the lowest third. The association pattern was similar for all headache types. Migraine with aura was the only headache type strongly associated with volume of deep white matter hyperintensities (highest third odds ratio 12.4, 1.6 to 99.4, P for trend 0.005) and with brain infarcts (3.4, 1.2 to 9.3). The location of infarcts was predominantly outside the cerebellum and brain stem. Evidence was lacking for cognitive impairment for any headache type with or without brain lesions. CONCLUSIONS: In this population based study, any history of severe headache was associated with an increased volume of white matter hyperintensities. Migraine with aura was the only headache type associated with brain infarcts. Evidence that headache of any type by itself or in combination with brain lesions was associated with cognitive impairment was lacking.

Abstract:

Abstract: BACKGROUND: The oxidant/antioxidant balance in lung tissue is hypothesised to contribute to the risk of chronic obstructive pulmonary disease (COPD). Observational studies consistently report higher antioxidant status associated with lower COPD risk, but few randomised studies have been reported. METHODS: A post hoc analysis of 38,597 women without chronic lung disease at baseline was conducted in the Women's Health Study (WHS) to test the effect of vitamin E on the risk of incident chronic lung disease. The WHS is a randomised double-blind placebo-controlled factorial trial of vitamin E (600 IU every other day) and aspirin (100 mg every other day) in female health professionals aged≥45 years. Using Cox proportional hazards models, the effect of randomised vitamin E assignment on self-reported physician-diagnosed chronic lung disease was evaluated. RESULTS: During 10 years of follow-up (376,710 person-years), 760 first occurrences of chronic lung disease were reported in the vitamin E arm compared with 846 in the placebo arm (HR 0.90; 95% CI 0.81 to 0.99; p=0.029). This 10% reduction in the risk of incident chronic lung disease was not modified by cigarette smoking, age, randomised aspirin assignment, multivitamin use or dietary vitamin E intake (minimum p for interaction=0.19). Current cigarette smoking was a strong predictor of chronic lung disease risk (HR 4.17; 95% CI 3.70 to 4.70; vs. never smokers). CONCLUSIONS: In this large randomised trial, assignment to 600 IU vitamin E led to a 10% reduction in the risk of chronic lung disease in women.

Abstract: Abstract OBJECTIVE: To evaluate the relation between Parkinson's disease and prior use of non-steroidal anti-inflammatory drugs (NSAIDs) in a large cohort of men. DESIGN: Case-control analysis nested in the Physicians' Health Study. PARTICIPANTS: 22,007 male physicians aged 40-84 years without indications for or contraindications to regular NSAID use and free of Parkinson's disease at baseline. Cases and controls were matched by age alone or by age and scores for confounders (comorbidity and indicators of NSAID use). Up to five controls were matched to each of 616 cases by age and 565 cases by age and confounder scores. SETTING: United States. MAIN OUTCOME MEASURES: Odds of having been exposed to prior non-aspirin NSAID or aspirin use by participants with Parkinson's disease and by their controls in each case-control set. RESULTS: Participants who had ever used non-aspirin NSAIDs had an increased risk of Parkinson's disease (odds ratio 1.28 (95% CI 1.05 to 1.56) in the age matched group but not in the group also matched on confounder scores (odds ratio 1.17 (0.94 to 1.46)). There was an increased risk of Parkinson's disease in men who had 1-2 years of regular non-aspirin NSAID use (odds ratio 1.35 (1.07 to 1.70)), a finding that remained significant after matching for confounder scores as well (odds ratio 1.35 (1.05 to 1.75)). In contrast, the significant association of use of non-aspirin NSAIDs for ≥ 5 years (odds ratio 1.48 (1.05 to 2.09)) in the age matched group was entirely attenuated in the group also matched on confounder scores (1.03 (0.70 to 1.53)). There was also a suggestion that men who regularly used aspirin had an increased risk of Parkinson's disease. Positive associations between non-aspirin NSAID or aspirin and risk of Parkinson's disease tended to disappear when analyses were limited to drug use ≥ 5 years before the disease diagnosis. CONCLUSIONS: This case-control study did not find evidence that NSAID use reduces Parkinson's disease risk. The positive associations observed between NSAID use and Parkinson's disease might have been due to confounding by indication as the use was clustered in the few years before disease diagnosis.

Abstract: AIMS: Migraine has a wide clinical spectrum. Our aim was to group information on migraine characteristics into meaningful components and to identify key components of the migraine phenotype. METHODS: We performed two principal component analyses, one among participants in the Women's Health Study enrollment cohort and one in a sub-cohort with additional migraine-specific information. RESULTS: Among the 9427 women with migraine attack-related information at enrollment, the three most important components pertained to central nervous system (CNS) sensitization, attack frequency/pain location and aura/visual phenomena. In the subgroup of 1675 women with more detailed information, food triggers and unspecific symptoms constituted two principal components that explain more of the variance of the migraine phenotype than the three attack-related components. CONCLUSIONS: Our results indicate that information on migraine-associated features, symptoms and triggers is highly correlated, allowing the extraction of principal components. Migraine attack-related symptoms are best summarized by symptoms related to CNS sensitization, attack frequency/pain location and aura/visual phenomena. Taking a more general view, unspecific symptoms and food triggers appear to carry stronger importance in characterizing the migraine phenotype. These components are useful for future research on the pathophysiology and genetics of migraine and may have implications for diagnosing and treating patients.

Abstract:

Abstract: OBJECTIVE: We evaluated the current evidence on the association between migraine, including aura status, and cervical artery dissection. METHODS: We performed a systematic review and meta-analysis of studies investigating the association between migraine or migraine subtypes (e.g. migraine with aura) and cervical artery dissection published through October 2010. RESULTS: We identified five case-control studies investigating the association between migraine and cervical artery dissection. In pooled analysis, migraine doubled the risk of cervical artery dissection (pooled odds ratio [OR]=2.06, 95% confidence interval [CI] 1.33-3.19). All studies allowed evaluation of migraine aura status. While the effect estimate for migraine without aura (pooled OR=1.94, 95% CI 1.21-3.10) was similar to overall migraine, the association was weaker for migraine with aura (pooled OR= 1.50, 95% CI 0.76-2.96). However, there is no evidence that aura status significantly modifies the association between migraine and cervical artery dissection (meta-regression on aura status p= .58). The risk does not appear to differ between women and men; however, only few studies presented gender-specific data. Heterogeneity among studies was low to moderate. CONCLUSION: In this meta-analysis migraine is associated with a two-fold increased risk of cervical artery dissection. This risk does not appear to significantly differ by migraine aura status or gender.

Abstract: Adipose tissue is a dynamic neuroendocrine organ that is involved in multiple physiological and pathological processes, and when excessive, results in obesity. Clinical and population-based data suggest that migraine and chronic daily headache are associated with obesity, as estimated by anthropometric indices. In addition, translational and basic science research shows multiple areas of overlap between migraine pathophysiology and the central and peripheral pathways regulating feeding. Specifically, neurotransmittors such as serotonin, peptides such as orexin, and adipocytokines such as adiponectin and leptin have been suggested to have roles in both feeding and migraine. In this article, we first review the definition and ascertainment of obesity. This is followed by a review of the clinical and population-based studies evaluating the associations between obesity and chronic daily headache and migraine. We then discuss the central and peripheral pathways involved in the regulation of feeding, where it overlaps with migraine pathophysiology, and where future research may be headed in light of these data.

Abstract: Data on the association of the MTHFR 677C→T and ACE D/I polymorphisms with migraine severity, measured by attack frequency, are scarce. We performed an association study among 24 961 women participating in the Women's Health Study. Migraine, aura status and attack frequency were self-reported. Multinomial logistic regression was used to investigate the genotype-migraine association. Among the 3186 migraineurs with complete genotype and attack frequency data, 1270 reported migraine with aura (MA) (attack frequency 76 ≥ weekly; 219 monthly; 123 every other month; 852 fewer than six times/year) and 1916 migraine without aura (MoA) (attack frequency: 85 ≥ weekly; 414 monthly; 208 every other month; 1209 fewer than six times/year). The MTHFR 677TT genotype was associated with a reduced risk for MA, which only appeared for attacks fewer than six times/year (age-adjusted odds ratio 0.78; 95% confidence interval 0.61, 0.99). We did not find a specific pattern of association of the ACE D/I polymorphism with attack frequency for MA or MoA.

Abstract: OBJECTIVES: Although the relationship between migraine and cardiovascular disease (CVD) has been studied, several questions remain unanswered. Herein we contrast the rate of diagnosed CVD as well as of risk factors for CVD in individuals with migraine with and without aura (MA and MO) and in controls. METHODS: In this case-control study, migraineurs (n = 6,102) and controls (n = 5,243) were representative of the adult US population. Headache diagnosis was formally assigned using a validated mailed questionnaire which also obtained details on treatment, comorbidities, and other variables. CVD events were obtained based on self-reported medical diagnosis. Risk factors for CVD and modified Framingham scores were computed. RESULTS: In unadjusted analyses, migraine overall and MA were associated with myocardial infarction, stroke, and claudication, and MO was associated with myocardial infarction and claudication. Migraineurs were more likely than controls to have a medical diagnosis of diabetes (12.6% vs 9.4%, odds ratio [OR] 1.4, 95% confidence interval [CI] 1.2-1.6), hypertension (33.1% vs 27.5%, OR 1.4, 95% CI 1.3-1.6), and high cholesterol (32.7% vs 25.6%, OR 1.4, 95% CI 1.3-1.5). Risk was highest in MA, but remained elevated in MO. Framingham scores were significantly higher in MO and MA than in controls. After adjustments (gender, age, disability, treatment, CVD risk factors), migraine remained significantly associated with myocardial infarction (OR 2.2, 95% CI 1.7-2.8), stroke (OR 1.5, 95% CI 1.2-2.1), and claudication (OR 2.69, 95% CI 1.98-3.23). CONCLUSION: Both migraine with and without aura are associated with cardiovascular disease (CVD) and with risk factors for CVD. However, since our sample size is large, the clinical relevance of the differences is yet to be established.

Abstract: BACKGROUND: Adipocytokines may mediate the association between adiposity and lethal prostate cancer outcomes. METHODS: In the Physicians' Health Study, we prospectively examined the association of prediagnostic plasma concentrations of adiponectin and leptin with risk of developing incident prostate cancer (654 cases diagnosed 1982-2000 and 644 age-matched controls) and, among cases, risk of dying from prostate cancer by 2007. RESULTS: Adiponectin concentrations were not associated with risk of overall prostate cancer. However, men with higher adiponectin concentrations had lower risk of developing high-grade or lethal cancer (metastatic or fatal disease). The relative risk (95% CI) comparing the highest quintile to the lowest (Q5 vs Q1) was 0.25 (95% CI 0.07-0.87; P(trend) = 0.02) for lethal cancer. Among all the cases, higher adiponectin concentrations predicted lower prostate cancer-specific mortality [hazard ratio (HR)(Q5 vs Q1)= 0.39; 95% CI 0.17-0.85; P(trend) = 0.02], independent of body mass index (BMI), plasma C-peptide (a marker of insulin secretion), leptin, clinical stage, and tumor grade. This inverse association was apparent mainly among men with a BMI >or=25 kg/m(2) (HR(Q5 vs Q1)= 0.10; 95% CI 0.01-0.78; P(trend) = 0.02), but not among men of normal weight (P(trend) = 0.51). Although the correlation of leptin concentrations with BMI (r = 0.58, P < 0.001) was stronger than that of adiponectin (r = -0.17, P < 0.001), leptin was unrelated to prostate cancer risk or mortality. CONCLUSIONS: Higher prediagnostic adiponectin (but not leptin) concentrations predispose men to a lower risk of developing high-grade prostate cancer and a lower risk of subsequently dying from the cancer, suggesting a mechanistic link between obesity and poor prostate cancer outcome.

Abstract: BACKGROUND: Data on the association between the MTHFR 677C>T and ACE D/I polymorphisms and migraine including aura status are conflicting. OBJECTIVE: The objective of this study is to perform a systematic review and meta-analysis on this topic. METHODS: We searched for studies published until March 2009 using electronic databases (MEDLINE, EMBASE, Science Citation Index) and reference lists of studies and reviews on the topic. Assessment for eligibility of studies and extraction of data was performed by 2 independent investigators. For each study we calculated the odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. RESULTS: Thirteen studies investigated the association between the MTHFR 677C>T polymorphism and migraine. The TT genotype was associated with an increased risk for any migraine, which only appeared for migraine with aura (pooled OR = 1.48, 95% CI 1.02-2.13), but not for migraine without aura. Nine studies investigated the association of the ACE D/I polymorphism with migraine. The II genotype was associated with a reduced risk for migraine with aura (pooled OR = 0.71, 95% CI 0.55-0.93) and migraine without aura (pooled OR = 0.84, 95% CI 0.70-0.99). Results for both variants were driven by studies in non-Caucasian populations. Results among Caucasians did not suggest an association. Extractable data did not allow investigation of gene-gene interactions. CONCLUSIONS: The MTHFR 677TT genotype is associated with an increased risk for migraine with aura, while the ACE II genotype is protective against both migraine with and without aura. Results for both variants appeared only among non-Caucasian populations. There was no association among Caucasians.

Abstract: The role of selenium in prostate cancer (PCa) risk remains controversial, but many epidemiologic studies suggest an inverse association with more aggressive disease. A recently discovered selenoprotein, SEP15, which is highly expressed in the prostate, may play a role either independently or by modifying the effects of selenium. We genotyped four common single-nucleotide polymorphisms capturing common variation (frequency >5%; R(2) > 0.8) within SEP15, as well as rs5859 in the 3' untranslated region, previously reported to reduce the efficiency of selenium incorporation into SEP15. We examined the association of these single-nucleotide polymorphisms with PCa risk and PCa-specific mortality, as well as their interactions with plasma selenium levels, in the Physicians' Health Study. In this nested case-control study (1,286 cases and 1,267 controls), SEP15 polymorphisms were not significantly associated with PCa risk. However, among the cases, three variants were significantly associated with PCa-specific mortality [rs479341 hazard ratio (HR), 1.94; 95% confidence interval (95% CI), 1.15-3.25; rs1407131 HR, 2.85; 95% CI, 1.45-5.59; rs561104 HR, 1.54; 95% CI, 1.12-2.11] with a recessive model. Additionally, rs561104 significantly modified the association of plasma selenium with PCa survival (P(interaction) = 0.02); an inverse relationship of high levels of selenium with PCa mortality was apparent only among those without the increased risk genotype. This study provides evidence that SEP15 genetic variation may influence PCa mortality. Additionally, the association of selenium with PCa mortality was modified by a variant, suggesting the possibility that some men with PCa may benefit more from selenium than others, depending on their genotype.

Abstract: BACKGROUND &#38; AIMS: While nut consumption has been shown to lower the risk of hypertension and coronary disease, it is not known whether nut consumption is associated with the risk of stroke. We sought to examine whether nut consumption is associated with total and subtypes of stroke. METHODS: Prospective cohort of 21,078 participants from the Physicians' Health Study (1982-2008) who were free of stroke at baseline. Nut consumption was assessed using a simple 19-item food questionnaire and stroke cases were confirmed after reviewing medical records. We used Cox's proportional hazards regression to estimate relative risks of total, ischemic, and hemorrhagic stroke according to consumption of any nuts. RESULTS: During a mean follow up of 21.1 years, 1424 incident cases of stroke occurred (219 hemorrhagic, 1189 ischemic, and 16 of undetermined cause). There was no statistically significant association between nut consumption and total or ischemic stroke. In contrast, there was a suggestive non-linear relation between nut intake and hemorrhagic stroke: compared to subjects who did not consume nuts, multivariable-adjusted hazard ratios (95% CI) for hemorrhagic stroke for subjects consuming nuts <1, 1, 2-4, 5-6, and ≥7 times/week were 1.13 (0.78-1.62), 1.05 (0.70-1.58), 0.49 (0.27-0.89), 1.50 (0.79-2.84), and 1.84 (0.95-3.57), respectively (p for quadratic trend 0.12). CONCLUSIONS: Our data showed no association between nuts and ischemic stroke and suggested a J-shaped relation between nut consumption and hemorrhagic stroke. Replication of our findings in the general population is warranted.

Abstract: Migraine is a common, chronic-intermittent primary headache disorder affecting mostly women. The migraine pathophysiology involves both the neuronal and vascular systems, and in some patients, transient neurologic symptoms occur, which are known as migraine aura. A large body of literature supports an association between migraine and ischemic stroke, which is apparent mostly in young women with migraine with aura. Further increased risks have been observed particularly in smokers and women who use oral contraceptives. The vast majority of individual studies, as well as a recent meta-analysis, did not find an association between migraine without aura and ischemic stroke. Although there are several hypotheses about potential biological mechanisms linking migraine with aura to ischemic stroke, the precise causes remain unclear. Because the absolute risk of stroke is considerably low in patients with migraine, the vast majority of migraine patients will not experience a stroke event because of the migraine.

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Abstract: Early identification of individuals at risk of dementia will become crucial when effective preventative strategies for this condition are developed. Various dementia prediction models have been proposed, including clinic-based criteria for mild cognitive impairment, and more-broadly constructed algorithms, which synthesize information from known dementia risk factors, such as poor cognition and health. Knowledge of the predictive accuracy of such models will be important if they are to be used in daily clinical practice or to screen the entire older population (individuals aged >or=65 years). This article presents an overview of recent progress in the development of dementia prediction models for use in population screening. In total, 25 articles relating to dementia risk screening met our inclusion criteria for review. Our evaluation of the predictive accuracy of each model shows that most are poor at discriminating at-risk individuals from not-at-risk cases. The best models incorporate diverse sources of information across multiple risk factors. Typically, poor accuracy is associated with single-factor models, long follow-up intervals and the outcome measure of all-cause dementia. A parsimonious and cost-effective consensus model needs to be developed that accurately identifies individuals with a high risk of future dementia.

Abstract: BACKGROUND AND PURPOSE: Physical activity has generally been inversely related to the risk of developing stroke, but details regarding the amount and kinds of activity required are unclear as are associations for specific stroke subtypes. METHODS: Eligible subjects were 39 315 healthy US women, > or =45 years of age, from the Women's Health Study. Women reported physical activity at baseline (1992 to 1995) and at 36, 72, 96, 125, and 149 months' follow-up. During an average follow-up of 11.9 years, 579 women developed incident stroke (473 ischemic, 102 hemorrhagic, and 4 of unknown type). Proportional hazards models related physical activity, updated over time, to the risk of incident stroke. RESULTS: The multivariable relative risks associated with <200, 200 to 599, 600 to 1499, and > or =1500 kcal/week of leisure-time physical activity were 1.00 (referent), 1.11 (95% CI, 0.87 to 1.41), 0.86 (95% CI, 0.67 to 1.10), and 0.83 (95% CI, 0.63 to 1.08), respectively (P trend=0.06). Similar results were observed for ischemic stroke, whereas no associations were observed for hemorrhagic stroke. Vigorous physical activity was not related to stroke risk (P trend=0.50); however, walking time and walking pace were inversely related, either significantly or with borderline significance, to total, ischemic, and hemorrhagic stroke risks (P trend between 0.002 and 0.07). CONCLUSIONS: This study shows a tendency for leisure-time physical activity to be associated with lower stroke risk in women. In particular, walking was generally associated with lower risks of total, ischemic, and hemorrhagic stroke.

Abstract: BACKGROUND: Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline among healthy, community-dwelling older men without diabetes. METHODS: Fasting plasma insulin and C-peptide (insulin secretion) levels were measured in 1,353 nondiabetic men, aged 60-92 years (mean = 71.3 years), in the Physicians' Health Study II, who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range = 1.5-4.0 years) using telephone-based tests (general cognition, verbal memory and category fluency). Primary outcomes were the Telephone Interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging 4 verbal tests). Multivariable linear regression models were used to estimate the relations of insulin and C-peptide to cognitive decline. RESULTS: Higher fasting insulin was associated with a greater decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency, e.g. the multivariable-adjusted mean difference (95% CI) in decline for men with the highest versus lowest insulin levels was -0.62 (-1.15, -0.09) points on the TICS (p for trend = 0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was a greater decline across all tests with increasing C-peptide, but the findings were statistically significant only for the global score (p for trend = 0.03). CONCLUSIONS: Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes.

Abstract: BACKGROUND: Many studies support an association between migraine and cardiovascular disease (CVD). This association appears particularly in migraine with aura and is also modified by additional factors. OBJECTIVE: We sought to investigate whether the association between migraine and CVD in addition to aura status is affected by certain migraine features. METHODS: Cohort study among 27,840 women, participating in the Women's Health Study. We had detailed self-reported information on migraine and migraine features among women with active migraine (migraine during the year prior to baseline). Incident CVD events were confirmed after medical record review. We used Cox proportional hazards models to evaluate the association between migraine and incident CVD. The results have been presented in part before. We ran additional analyses according to migraine features. RESULTS: At baseline, 5125 (18.4%) women reported history of migraine; 39.7% of the 3610 women with active migraine indicated aura. During a mean of 11.9 years of follow-up, 708 CVD events occurred. Migraine with aura doubled the risk for CVD, ischemic stroke, and myocardial infarction. With regard to ischemic stroke, this association seemed stronger in the absence than in the presence of migraine features. This was most pronounced in the absence (hazard ratio = 3.27; 95% CI = 1.93-5.51; P < .0001) than in the presence of nausea/vomiting (hazard ratio = 0.91; 95% CI = 0.43-1.93; P = .80). In contrast, the association with myocardial infarction did not reveal a certain pattern. CONCLUSIONS: These data suggest that the association between migraine with aura and ischemic stroke may differ by absence or presence of migraine features.

Abstract: BACKGROUND: Environmental exposure to polychlorinated biphenyls (PCBs) and p,p'-dichlorodiphenyldichloroethylene (p, p'-DDE) has been associated with the risk of non-Hodgkin lymphoma. METHODS: We conducted a case-control study nested within the Physicians' Health Study, a prospective cohort established in 1982. We measured concentrations of PCBs and p,p'-DDE in baseline blood samples from 205 men later diagnosed with non-Hodgkin lymphoma and 409 age- and race-matched controls. Lipid-adjusted organochlorine concentrations were categorized into quintiles based on the distribution among controls. We used conditional logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for each quintile relative to the lowest quintile. We also evaluated these associations for major histologic subtypes of non-Hodgkin lymphoma. RESULTS: The risk of non-Hodgkin lymphoma was positively associated with the sum of 51 PCB congeners assayed (SigmaPCB); the group of immunotoxic congeners; the individual congeners 118, 138, 153, and 180; and the sum of these 4 congeners. The simple OR for the highest quintile of lipid-adjusted SigmaPCB versus the lowest was 1.9 (95% CI = 1.1-3.2; test for trend, P = 0.001), with similar trends for individual congeners and groups defined as above. Adjustment for height, body mass index, alcohol intake, smoking, and fish intake did not substantially change the effect estimates. No association was observed for p,p'-DDE. There was no evidence of statistical heterogeneity in effects by histologic subtype of lymphoma; however, this analysis was underpowered. CONCLUSIONS: These results support the hypothesis of a positive association between PCB exposure and development of NHL in men.

Abstract: BACKGROUND: The acid-labile subunit (ALS) acts in the insulin-like growth (IGF) system by binding circulating IGF-I in a ternary complex with binding protein (IGFBP)-3 to prevent IGF-I from crossing the endothelial barrier. Given the role of the IGF system in prostate cancer, ALS may influence carcinogenesis by modulating IGF-I levels or bioavailability. METHODS: We undertook a prospective study nested in the Physicians' Health Study to examine ALS, free IGF-I, and prostate cancer. We assayed circulating levels of ALS and IGF components among 545 incident cases and 545 matched controls. We calculated relative risks (RR) and 95% confidence intervals (95% CI) adjusted for life-style factors, total IGF-I, and IGFBP3. RESULTS: ALS was positively correlated with total IGF-I (r = 0.58), IGFBP3 (r = 0.68), and free IGF-I (r = 0.36). Comparing highest versus lowest quartiles, we found no association between free IGF-I and prostate cancer risk (RR, 0.9; 95% CI, 0.6-1.3). In contrast, ALS was positively associated with risk among men in the 2nd (RR, 1.5; 94% CI, 1.0-2.3), 3rd (RR, 1.6; 94% CI, 1.1-2.5), and 4th quartiles (RR, 1.4; 94% CI, 0.9-2.1) compared with lowest quartile. The association was stronger for advanced stage tumors (RR, 2.0; 94% CI, 0.8-4.6). There was a suggestion of an interaction between ALS and total IGF-I, whereby high circulating IGF-I was associated with an increased risk of advanced prostate cancer among men with low but not higher ALS levels. DISCUSSION: Plasma ALS is positively associated with prostate cancer risk, and may interact biologically with IGF-I to affect carcinogenesis. These data provide further support for the role of the IGF axis in prostate cancer.

Abstract: BACKGROUND AND PURPOSE: Light-to-moderate alcohol consumption has been associated with reduced risk of total and ischemic stroke. However, data on the relationship between alcohol consumption and functional outcomes from stroke are sparse. METHODS: Prospective cohort study among 21 860 men enrolled in the Physicians' Health Study who provided information on alcohol consumption at baseline and had no prior history of stroke or transient ischemic attack (TIA). Alcohol consumption was divided into 5 categories: <1 drink/wk, 1 drink/wk, 2 to 4 drinks/wk, 5 to 6 drinks/wk, and >/=1 drink/d. Possible functional outcomes included TIA, modified Rankin Scale (mRS)=0 to 1, mRS=2 to 3, and mRS=4 to 6. We used multinomial logistic regression to evaluate the relationship between levels of alcohol consumption and functional outcomes from stroke. RESULTS: During a mean of 21.6 years of follow-up, 766 TIAs and 1393 strokes (1157 ischemic, 222 hemorrhagic, and 14 unknown type) occurred. Men who consumed 1 drink/wk had lowest associated odds for any outcome. Compared with men who did not experience a TIA or stroke and who consumed <1 drink/wk, men who consumed 1 drink/wk had odds ratio (95% CI) for total stroke of 0.85 (0.60 to 1.21) for mRS=0 to 1, 0.84 (0.64 to 1.10) for mRS=2 to 3, and 0.60 (0.37 to 0.97) for mRS=4 to 6. The odds ratio for TIA was 0.95 (0.73 to 1.23). The pattern of association did not substantially differ for ischemic and hemorrhagic stroke. Higher alcohol consumption showed no association with functional outcome after stroke. CONCLUSIONS: Our data do not show strong associations between alcohol consumption and functional outcome after stroke. Modest beneficial associations exist with low alcohol consumption.

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Abstract: Variation in genes contributing to the host immune response may mediate the relationship between inflammation and prostate carcinogenesis. RNASEL at chromosome 1q25 encodes ribonuclease L, part of the interferon-mediated immune response to viral infection. We therefore investigated the association between variation in RNASEL and prostate cancer risk and progression in a study of 1286 cases and 1264 controls nested within the prospective Physicians' Health Study. Eleven single-nucleotide polymorphisms (SNPs) were selected using the web-based 'Tagger' in the HapMap CEPH panel (Utah residents of Northern and Western European Ancestry). Unconditional logistic regression models assessed the relationship between each SNP and incident advanced stage (T(3)/T(4), T(0)-T(4)/M(1) and lethal disease) and high Gleason grade (>/=7) prostate cancer. Further analyses were stratified by calendar year of diagnosis. Cox proportional hazards models examined the relationship between genotype and prostate cancer-specific survival. We also explored associations between genotype and serum inflammatory biomarkers interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-alpha receptor 2 using linear regression. Individuals homozygous for the variant allele of rs12757998 had an increased risk of prostate cancer [AA versus GG; odds ratio (OR): 1.63, 95% confidence interval (CI): 1.18-2.25), and more specifically, high-grade tumors (OR: 1.90, 95% CI: 1.25-2.89). The same genotype was associated with increased CRP (P = 0.02) and IL-6 (P = 0.05) levels. Missense mutations R462Q and D541E were associated with an increased risk of advanced stage disease only in the pre-prostate-specific antigen era. There were no significant associations with survival. The results of this study support a link between RNASEL and prostate cancer and suggest that the association may be mediated through inflammation. These novel findings warrant replication in future studies.

Abstract: Data on the association between the SLC6A4 STin2 VNTR polymorphism and migraine are conflicting. To perform pooled and meta-analyses, we searched for studies published until September 2009 using electronic databases (MEDLINE, EMBASE, Science Citation Index) and reference lists of studies. Assessment for eligibility and extraction of data was performed by two independent investigators. We extracted allele and genotype frequencies for each study. We then calculated study-specific and pooled odds ratios (OR) and 95% confidence intervals (CI) assuming allele and genotype models. We also calculated pooled ORs and 95% CIs based on study-specific effect estimates for the allele model. We included five studies investigating the association between the STin2 VNTR polymorphism and migraine. Results from the allele model suggested a protective effect against migraine for the STin2.9 and STin2.10 alleles compared to the STin2.12 allele among populations of European descent, which however was not significant. Results from the genotype model indicated a significant approximately 25% reduced risk for migraine among carriers of the 10/12 genotype compared with carriers of the 12/12 genotype among all study populations (OR = 0.76, 95% CI 0.60-0.97) for any migraine, which was more pronounced among populations of European descent (OR = 0.68, 95% CI 0.53-0.87). Results for migraine with and without aura were of similar magnitude, but were not statistically significant. Our results suggest a protective effect of non-STin2.12 alleles compared to STin2.12 alleles, respectively, 10/12 and 10/10 genotypes compared to the 12/12 genotype against migraine among populations of European descent. Associations in non-European populations may differ.

Abstract: BACKGROUND: A pressing clinical issue in prostate cancer is to distinguish which men will have an indolent or aggressive course of disease. Clinical variables such as Gleason grade and stage are useful predictors of lethal cancer; however, the low predictive values of the common Gleason scores, changes in grading over time, and earlier diagnosis of patients due to screening limits their clinical utility. Identifying genetic variants associated with lethal prostate cancer could inform clinical decision making. METHODS: We conducted a genome-wide association study, comparing lethal prostate cancer cases to cases surviving at least 10 years beyond their initial diagnosis. Genotyping was done with the Affymetrix 5.0 chip [∼500,000 single nucleotide polymorphisms (SNP) and 1,483 copy number variants (CNV)] on DNA from participants in the Physicians' Health Study and Health Professionals Follow-up Study (196 lethal cases, 368 long-term survivors). After excluding SNPs and individuals based on quality control criteria, logistic regression assuming an additive model was done using the PLINK software. RESULTS: No SNP reached genome-wide significance (P ≤ 1 × 10(-7)); however, three independent SNPs had P < 1 × 10(-5). One top-ranked SNP replicated (P = 0.05) in an independent follow-up study. Although no CNV had genome-wide significance, 14 CNVs showed nominal association with prostate cancer mortality (P < 0.05). CONCLUSIONS: No variants were significantly associated at a genome-wide level with prostate cancer mortality. Common genetic determinants of lethal prostate cancer are likely to have odds ratios <2.0. IMPACT: Genetic markers identified could provide biological insight to improve therapy for men with potentially fatal cancer. Larger studies are necessary to detect the genetic causes of prostate cancer mortality.

Abstract: BACKGROUND: Data on the association between sex hormone receptor polymorphisms and migraine are conflicting. METHODS: We performed a systematic review and meta-analysis on this topic searching for studies published until August 2009. For each study, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. RESULTS AND CONCLUSION: Among the seven genes targeted, four variants were investigated in multiple studies. Effect estimates from an additive model suggest that the ESR-1 594 G>A (pooled OR 1.37; 95% CI 1.02-1.83) and ESR-1 325 C>G (pooled OR 1.16; 95% CI 1.03-1.32) variants are associated with any migraine. This pattern does not differ between migraine with and without aura. In contrast, the ESR-1 Pvu II C>T and PGR PROGINS insert polymorphism do not appear to be associated with migraine. Results were driven by studies among Caucasians and may differ in other ethnic groups.

Abstract: OBJECTIVE: To evaluate the effect of vitamin E supplementation on incident total, ischaemic, and haemorrhagic stroke. DESIGN: Systematic review and meta-analysis of randomised, placebo controlled trials published until January 2010. DATA SOURCES: Electronic databases (Medline, Embase, Cochrane Central Register of Controlled Trials) and reference lists of trial reports. Selection criteria Randomised, placebo controlled trials with ≥1 year of follow-up investigating the effect of vitamin E on stroke. Review methods and data extraction Two investigators independently assessed eligibility of identified trials. Disagreements were resolved by consensus. Two different investigators independently extracted data. Risk ratios (and 95% confidence intervals) were calculated for each trial based on the number of cases and non-cases randomised to vitamin E or placebo. Pooled effect estimates were then calculated. RESULTS: Nine trials investigating the effect of vitamin E on incident stroke were included, totalling 118 765 participants (59 357 randomised to vitamin E and 59 408 to placebo). Among those, seven trials reported data for total stroke and five trials each for haemorrhagic and ischaemic stroke. Vitamin E had no effect on the risk for total stroke (pooled relative risk 0.98 (95% confidence interval 0.91 to 1.05), P=0.53). In contrast, the risk for haemorrhagic stroke was increased (pooled relative risk 1.22 (1.00 to 1.48), P=0.045), while the risk of ischaemic stroke was reduced (pooled relative risk 0.90 (0.82 to 0.99), P=0.02). There was little evidence for heterogeneity among studies. Meta-regression did not identify blinding strategy, vitamin E dose, or morbidity status of participants as sources of heterogeneity. In terms of absolute risk, this translates into one additional haemorrhagic stroke for every 1250 individuals taking vitamin E, in contrast to one ischaemic stroke prevented per 476 individuals taking vitamin E. CONCLUSION: In this meta-analysis, vitamin E increased the risk for haemorrhagic stroke by 22% and reduced the risk of ischaemic stroke by 10%. This differential risk pattern is obscured when looking at total stroke. Given the relatively small risk reduction of ischaemic stroke and the generally more severe outcome of haemorrhagic stroke, indiscriminate widespread use of vitamin E should be cautioned against.

Abstract: OBJECTIVE: To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of age-related cataract in a large cohort of men. METHODS: In a randomized, double-masked, placebo-controlled trial, 11,545 apparently healthy US male physicians 50 years or older without a diagnosis of cataract at baseline were randomly assigned to receive 400 IU of vitamin E or placebo on alternate days and 500 mg of vitamin C or placebo daily. MAIN OUTCOME MEASURE: Incident cataract responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-report confirmed by medical record review. APPLICATION TO CLINICAL PRACTICE: Long-term use of vitamin E and C supplements has no appreciable effect on cataract. RESULTS: After 8 years of treatment and follow-up, 1174 incident cataracts were confirmed. There were 579 cataracts in the vitamin E-treated group and 595 in the vitamin E placebo group (hazard ratio, 0.99; 95% confidence interval, 0.88-1.11). For vitamin C, there were 593 cataracts in the treated group and 581 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14). CONCLUSION: Long-term alternate-day use of 400 IU of vitamin E and daily use of 500 mg of vitamin C had no notable beneficial or harmful effect on the risk of cataract. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00270647.

Abstract: BACKGROUND: Studies have linked migraine with aura to an increased risk of ischemic stroke, particularly among women. Data on the relationship of migraine and functional outcome from ischemic cerebral events are sparse. METHODS AND RESULTS: This was a prospective cohort study among 27 852 women enrolled in the Women's Health Study for whom we had information on migraine and measured cholesterol values and who had no prior stroke or transient ischemic attack (TIA) at baseline. Migraine was classified into no history of migraine, active migraine with aura, active migraine without aura, and past history of migraine. Possible functional outcomes were no stroke or TIA, TIA, and stroke with modified Rankin Scale (mRS) score 0 to 1, mRS 2 to 3, and mRS 4 to 6. We used multinomial logistic regression to evaluate the relationship of migraine with functional outcomes after ischemic stroke. During a mean of 13.5 years of follow-up, 398 TIAs and 345 ischemic strokes occurred. Compared with women without history of migraine and who did not experience a TIA or stroke, women who reported migraine with aura had adjusted relative risk (95% confidence interval) of 1.56 (1.03 to 2.36) for TIA, 2.33 (1.37 to 3.97) for stroke with mRS 0 to 1, 0.82 (0.30 to 2.24) for mRS 2 to 3, and 1.18 (0.28 to 4.97) for mRS 4 to 6. The risk of any outcome was not significantly elevated for women who experienced migraine without aura or who had a past history of migraine. CONCLUSIONS: Results of this large prospective cohort suggest that women with migraine with aura are at increased risk of experiencing TIA or ischemic stroke with good functional outcome

Abstract: BACKGROUND AND METHODS: Data on the association between the SLC6A4 5-HTTLPR polymorphism and migraine are conflicting. We performed a systematic review and meta-analysis among studies published up to September 2009. For each study with genotype information, we calculated odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. RESULTS: Among the ten studies identified there was no overall association between the polymorphism and any migraine for Europeans or Asians. However, European women carrying the S allele had an increased risk for any migraine (dominant model: pooled OR=2.02; 95% CI 1.24-3.28). Results among Europeans further suggested an increased risk for migraine with aura among carriers of the S/S genotype (recessive model: pooled OR=1.41; 95% CI 0.83-2.40). CONCLUSIONS: While our results indicate no overall association between the SLC6A4 5-HTTLPR polymorphism and migraine among Europeans and Asians, gender and migraine aura status may have modifying roles among Europeans.

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Abstract: The authors performed a matched case-control study (1982-2007) nested in a prospective cohort of 22,071 US men to determine the prevalence of chronic diseases of aging in those with newly diagnosed cancer. They matched one control by age to each of 5,622 men who developed cancer over the 25 years of follow-up, as of the date of cancer diagnosis. A modified Charlson score was calculated that reflected comorbidities prior to the matching date, and the authors used conditional logistic regression to determine the odds ratios of various diseases. No substantial differences were found between the scores of cases and controls overall, by cancer subtype, or by age at diagnosis. Overall, men who developed cancer were less likely to have had hypercholesterolemia (odds ratio (OR) = 0.79, 95% confidence interval (CI): 0.72, 0.87) or coronary artery disease (OR = 0.85, 95% CI: 0.77, 0.96). Compared with controls, men with cancers for which there is routine screening had fewer diseases, whereas those with smoking-related cancers had more. Prostate cancer was inversely associated with both coronary artery disease (OR = 0.72, 95% CI: 0.62, 0.84) and diabetes (OR = 0.72, 95% CI: 0.58, 0.89). Overall, men who developed cancer had no more comorbidity or frequent history of chronic disease than their age-matched controls.

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Abstract: OBJECTIVES: To examine the association between migraine and migraine aura status with risk of haemorrhagic stroke. DESIGN: Prospective cohort study. SETTING: Women's Health Study, United States. PARTICIPANTS: 27,860 women aged >or=45 who were free from stroke or other major disease at baseline and had provided information on self reported migraine, aura status, and lipid values. MAIN OUTCOME MEASURES: Time to first haemorrhagic stroke and subtypes of haemorrhagic stroke. RESULTS: At baseline, 5130 (18%) women reported any history of migraine; of the 3612 with active migraine (migraine in the previous year), 1435 (40%) described having aura. During a mean of 13.6 years of follow-up, 85 haemorrhagic strokes were confirmed after review of medical records. Compared with women without a history of migraine, there was no increased risk of haemorrhagic stroke in those who reported any history of migraine (adjusted hazard ratio 0.98, 95% confidence interval 0.56 to 1.71, P=0.93). In contrast, risk was increased in women with active migraine with aura (2.25, 1.11 to 4.54, P=0.024). The age adjusted increased risk was stronger for intracerebral haemorrhage (2.78, 1.09 to 7.07, P=0.032) and for fatal events (3.56, 1.23 to 10.31, P=0.02). Four additional haemorrhagic stroke events were attributable to migraine with aura per 10 000 women per year. Women who reported active migraine without aura had no increased risk for haemorrhagic stroke. CONCLUSION: Migraine with aura might, in addition to ischaemic events, also be a risk factor for haemorrhagic stroke. The relatively low number of events and attributable risk should caution against definitive conclusions and call for further confirmation of these observations.

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Abstract: PURPOSE: To determine our institutional adherence to the Brain Trauma Foundation guidelines with respect to intracranial pressure (ICP) monitoring, and examine the relationship between external ventricular drain (EVD) use and mortality. MATERIALS &#38; METHODS: Retrospective cohort study of 171 patients with severe traumatic brain injury (TBI). Propensity score adjusted logistic regression was used to model the association between EVD use and mortality. RESULTS: EVDs were inserted in 98 of 171 patients. Of the 73 patients without an EVD, 63 (86%) would have qualified for ICP monitoring under the current guidelines. EVDs were in situ for a median of 8 days (SD 6). In adjusted analyses, EVD use was associated with hospital mortality (OR 2.8, 95% CI: 1.1 - 7.1, p = 0.04) and 28-day mortality (OR 2.1, 95% CI: 0.80 - 5.6, p = 0.13). We observed significant modification of the association between EVD and 28-day mortality by GCS within 12 hours (p-interaction = 0.04), indicating strong association only among those patients with GCS score of at least 6 (OR 5.0, 95% CI: 1.5 - 16.7, p < 0.01). CONCLUSIONS: The association of EVD with 28-day mortality was only apparent among patients with GCS score of > or = 6. Further research is warranted to further refine which patients may benefit from ICP monitoring.

Abstract: OBJECTIVE: To estimate the incidence rate (IR) of progressive multifocal leukoencephalopathy (PML) in patients without HIV. METHODS: Within a large US health insurer database between January 2000 and June 2008, we conducted a retrospective observational study. We identified people with autoimmune diseases, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), or history of bone marrow or solid organ transplantation, and a general population cohort. We developed a PML case-finding algorithm and validated PML diagnoses in medical charts. RESULTS: There were 138,469 patients with autoimmune diseases, 25,706 with NHL or CLL, and 8,778 with transplants. Among 699 people who met screening criteria for potential PML, 89 had a claim diagnosis of PML (International Classification of Diseases-9 046.3). Medical records were sought for 24 patients without HIV, and 6 had confirmed PML upon review of medical records. The PML IR was 2.4 (95% confidence interval [CI] 0.06-13.18) in the systemic lupus erythematosus cohort and 10.8 (95% CI 0.27-60.39) in the autoimmune vasculitis cohort per 100,000 person-years. In the NHL and CLL cohorts, the IR was 8.3 (95% CI 1.71-24.24) and 11.1 (0.28-61.74) per 100,000 person-years. The IR among patients with bone marrow transplantation was 35.4 per 100,000 person-years (95% CI 0.90-197.29). There were no cases of PML among patients with rheumatoid arthritis (95% CI 0.0-2.24), multiple sclerosis (95% CI 0.0-5.24), Sjögren disease (95% CI 0.0-21.84), or solid organ transplantation (95% CI 0.0-26.81). CONCLUSIONS: In this large population-based investigation of PML with thorough case finding and a known source population, the IR of medical record-confirmed PML was rare in non-HIV patient cohorts.

Abstract: PURPOSE: To evaluate health care resource utilization (HRU) in active epilepsy. METHODS: Thomson-Reuters insurance databases included 14 million persons in 2005-2007. We extracted information for individuals with insurance claims suggestive of epilepsy. Using iterative expert classification, we sorted patients by type of epilepsy. For each type we calculated prevalence and HRU. A distance analysis identified closely similar types, and a principal components analysis revealed dimensions of variation in HRU. RESULTS: The prevalence of active epilepsy was 3.4 per 1,000. Most common diagnoses among 46,847 patients were generalized convulsive epilepsy (33.3%) and complex partial seizures (24.8%). Patients averaged 10 physician visits per year, 24 diagnostic tests/procedures per year, >30 drug dispensings per year, and <1 emergency room (ER) visit per year, the minority of each of these being related to epilepsy. Female patients generally had more HRU, and HRU increased with age. Patients were hospitalized most frequently for disorders other than epilepsy. HRU was similar for most epilepsy types, excepting grand mal status, epilepsia partialis continua, and infantile spasms. The first principal components of HRU variation was nonepilepsy HRU, followed by components of epilepsy-related medications, other epilepsy/emergency care, and epilepsy visits/diagnostic procedures. DISCUSSION: The prevalence of active epilepsy in the United States is substantially less than the prevalence of any history of recurrent seizure. Nonepilepsy-related HRU dominated HRU in epilepsy patients and was the principal source of variation. There is a core set of epilepsy diagnoses, the HRU patterns of which are indistinguishable, whereas patients with grand mal status, epilepsia partialis continua, and infantile spasms all have distinct patterns. To provide more specific insights into the economic impact of the condition, studies of HRU in epilepsy should make a distinction about epilepsy-related and unrelated care.

Abstract: BACKGROUND: Few studies have assessed the relationship between triglycerides and the risk of hemorrhagic stroke, which contrasts the considerable number of studies about triglycerides and ischemic vascular events. We analyzed the association pattern between triglycerides and incident intracerebral hemorrhage as compared with coronary events and ischemic stroke, in a large cohort of elderly. METHODS: Population-based, prospective cohort study among 8393 men and women participating in the Three-City Study, aged > or = 65 years at baseline. Fasting blood lipids, including triglycerides, were measured at baseline. Fatal and non-fatal strokes and coronary events were adjudicated and validated by scientific committees. Cox proportional hazards models were used to adjust for potential confounders. RESULTS: During a mean follow-up of 5.0 years, 36 hemorrhagic strokes, 143 ischemic strokes, and 393 coronary events occurred. An increased level of triglycerides was associated with an increased risk of ischemic vascular events. Conversely, a low level of triglycerides (< or = 0.94 mmol/L) was associated with an increased risk of hemorrhagic stroke (adjusted hazard ratio 2.35; 95% confidence interval 1.18-4.70). The relationship with hemorrhagic stroke was mainly apparent in men, in individuals with high blood pressure, and in those with low levels of cholesterol. CONCLUSIONS: In this large cohort of elderly men and women, low triglycerides levels were associated with an increased risk of hemorrhagic stroke and a decreased risk of ischemic vascular events. The association between triglycerides and hemorrhagic stroke was particularly strong in men, in subjects with high blood pressure and in those with low cholesterol levels.

Abstract: Population-based studies have established an association between migraine and cardiovascular disease (CVD). We sought to investigate whether genetic variants implicated in CVD are associated with migraine. We performed an association study among 25,713 women participating in the Women's Health Study, with information on 77 previously characterized polymorphisms. Migraine and migraine aura status were self-reported. We used logistic regression to investigate the genotype-migraine association. At baseline, 4705 (18.3%) women reported history of migraine; 39.6% of the 3306 women with active migraine indicated aura. Regarding any history of migraine, the multivariable-adjusted odds ratios (95% confidence intervals) for TNF rs673 were 0.52 (0.30 to 0.89), for TGFB1 rs1800469 0.93 (0.89 to 0.98), and for CCR2 rs1799864 1.12 (1.03 to 1.21). Among active migraine with aura, the odds ratios (95% confidence intervals) were 1.35 (1.0 to 1.81) for TNF rs1800750, 1.13 (1.02 to 1.26) for TNF rs1800629, and 1.22 (1.07 to 1.40) for CCR2 rs1799864; among active migraine without aura, 0.9 (0.84 to 0.97) for TGFB1 rs1800469, 1.13 (1.01 to 1.27) for NOS3 rs3918226, and 1.12 (1.02 to 1.24) for IL9 rs2069885. After correction for multiple testing using the false discovery rate, none of the results remained significant. Our data suggest an association of polymorphisms implicated in inflammatory pathways and migraine in women. TNF, CCR2, TGFB1, NOS3, and IL9 warrant further investigation. PERSPECTIVE: This article presents results from an association study of 77 polymorphisms, implicated in CVD, and migraine. Variants in TNF, CCR2, TGFB1, NOS3, and IL9 were found to be associated with migraine but did not remain significant after adjustment for multiple testing. Variations in these genes warrant further investigation.

Abstract: BACKGROUND: Migraine has been associated with risk of cardiovascular disease (CVD). Data on the association between migraine frequency and CVD are sparse. METHODS: Prospective cohort study of 27,798 US women aged >or=45 years, who were free of CVD, and for whom we had information on lipids and migraine frequency. We categorized migraine frequency as < monthly, monthly, and >or= weekly. Incident CVD was confirmed after medical record review. RESULTS: Of the 3,568 women with active migraine at baseline, 75.3% reported a migraine frequency of < monthly, 19.7% monthly, and 5.0% >or= weekly. During 11.9 years of follow-up, 706 CVD events occurred. Compared with women without migraine, the multivariable-adjusted hazard ratios (HRs) (95% confidence intervals) among active migraineurs for CVD were 1.55 (1.22-1.97), 0.65 (0.31-1.38), and 1.93 (0.86-4.33) for an attack frequency of < monthly, monthly, and >or= weekly, respectively. The association between migraine frequency and CVD was only apparent among migraineurs with aura. Among those, the multivariable-adjusted HRs for women with a migraine frequency < monthly ranged from 1.81 (1.30-2.50) for coronary revascularizations to 2.43 (1.58-3.74) for myocardial infarction. For women with active migraine with aura and migraine frequencies of >or= weekly, we only found significant increased risk of ischemic stroke (HR = 4.25 [1.36-13.29]). CONCLUSIONS: In our data, the association between migraine and cardiovascular disease varies by migraine frequency. Significant associations were only found among women with migraine with aura. Ischemic stroke was the only outcome associated with a high-attack frequency while a low-attack frequency was associated with any vascular event. Low number of outcome events should caution the interpretation.

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Abstract: OBJECTIVE: To evaluate the association of kidney function with cardiovascular disease and mortality among apparently healthy women. DESIGN: Prospective cohort study. SETTING: Women's Health Study, United States. PARTICIPANTS: 27 939 female health professionals aged >or=45 who were free of cardiovascular disease and other major disease and who provided a blood sample at study entry. MAIN OUTCOME MEASURES: Time to cardiovascular disease (non-fatal stroke, non-fatal myocardial infarction, coronary revascularisation procedures, or death from cardiovascular cause), specific cardiovascular disease events, and all-cause mortality. End points were confirmed after review of medical records and death certificates. RESULTS: Glomerular filtration rate (GFR) was estimated with the abbreviated Modification of Diet in Renal Disease Study equation. At baseline, 1315 (4.7%) women had GFR <60 ml/min/1.73 m(2). During 12 years of follow-up, 1199 incident cardiovascular disease events and 856 deaths (179 from cardiovascular disease) occurred. Compared with women with GFR >or=90 ml/min/1.73 m(2), the multivariable adjusted hazard ratios for any first cardiovascular disease were 0.95 (95% CI 0.83 to 1.08), 0.84 (0.70 to 1.00), and 1.00 (0.79 to 1.27) among women with GFR of 75-89.9, 60-74.9, and <60 ml/min/1.73 m(2), respectively; the equivalent hazard ratios for all cause mortality were 0.93 (0.79 to 1.09), 1.03 (0.85 to 1.26), and 1.09 (0.83 to 1.45). Similar null findings were observed for myocardial infarction, stroke, coronary revascularisation, and non-cardiovascular death. However, an increased risk of death from cardiovascular disease was found among women with GFR <60 ml/min/1.73 m(2) (hazard ratio 1.68 (1.02 to 2.79)). CONCLUSIONS: In this large cohort of women, a glomerular filtration rate <60 ml/min/1.73 m(2) was associated with increased risk of cardiovascular disease death but not other cardiovascular disease events or non-cardiovascular disease mortality. We observed no increase in risk of any of the outcomes among women with less severe impairment of kidney function.

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Abstract: We evaluated the association of body mass index (BMI) with migraine and migraine specifics in a cross-sectional study of 63 467 women aged > or = 45 years, of whom 12,613 (19.9%) reported any history of migraine and 9195 had active migraine. Compared with women without migraine and a BMI < 23 kg/m(2), women with a BMI > or = 35 kg/m(2) had adjusted odds ratios (ORs) (95% confidence intervals) of 1.03 (0.95, 1.12) for any history of migraine. Findings were similar for active migraineurs. Women with a BMI of > or = 35 kg/m(2) had increased risk for low and high migraine frequency, with the highest estimate for women who reported daily migraine. Compared with women with the lowest associated risk (migraine frequency < 6 times/year; BMI between 27.0 and 29.9 kg/m(2)), women with a BMI > or = 35 kg/m(2) had an OR of daily migraine of 3.11 (1.12, 8.67). Among the women with active migraine, a BMI > or = 35 kg/m(2) was associated with increased risk of phonophobia and photophobia and decreased risk of a unilateral pain characteristic and migraine aura. Our data confirm previous findings that the association between BMI with migraine is limited to migraine frequency and specific migraine features.

Abstract: Migraine is a common headache disorder that is increasingly being evaluated in population-based studies. The American Migraine Study II and the Women's Health Study (WHS) have successfully used 'modified' International Classification of Headache Disorders, 1st edition (ICHD-I) criteria to classify patients. Investigating agreement of self-reported migraine in large epidemiological studies with the criteria of the revised version [International Classification of Headache Disorders, 2nd edition (ICHD-II)] is sparse. We have investigated 1675 women with self-reported migraine participating in the WHS, who provided additional information on a detailed migraine questionnaire that allowed us to apply all ICHD-II criteria. In this sub-cohort, we confirmed self-reported migraine in > 87% of women when applying the ICHD-II criteria for migraine (71.5%) and probable migraine without aura (16.2%). In conclusion, there is excellent agreement between self-reported migraine and ICHD-II-based migraine classification in the WHS. In addition, questionnaire-based migraine assessment according to full ICHD-II criteria in large population-based studies is feasible.

Abstract: OBJECTIVE: To evaluate the association between migraine and cardiovascular disease, including stroke, myocardial infarction, and death due to cardiovascular disease. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic databases (PubMed, Embase, Cochrane Library) and reference lists of included studies and reviews published until January 2009. Selection criteria Case-control and cohort studies investigating the association between any migraine or specific migraine subtypes and cardiovascular disease. Review methods Two investigators independently assessed eligibility of identified studies in a two step approach. Disagreements were resolved by consensus. Studies were grouped according to a priori categories on migraine and cardiovascular disease. DATA EXTRACTION: Two investigators extracted data. Pooled relative risks and 95% confidence intervals were calculated. RESULTS: Studies were heterogeneous for participant characteristics and definition of cardiovascular disease. Nine studies investigated the association between any migraine and ischaemic stroke (pooled relative risk 1.73, 95% confidence interval 1.31 to 2.29). Additional analyses indicated a significantly higher risk among people who had migraine with aura (2.16, 1.53 to 3.03) compared with people who had migraine without aura (1.23, 0.90 to 1.69; meta-regression for aura status P=0.02). Furthermore, results suggested a greater risk among women (2.08, 1.13 to 3.84) compared with men (1.37, 0.89 to 2.11). Age less than 45 years, smoking, and oral contraceptive use further increased the risk. Eight studies investigated the association between migraine and myocardial infarction (1.12, 0.95 to 1.32) and five between migraine and death due to cardiovascular disease (1.03, 0.79 to 1.34). Only one study investigated the association between women who had migraine with aura and myocardial infarction and death due to cardiovascular disease, showing a twofold increased risk. CONCLUSION: Migraine is associated with a twofold increased risk of ischaemic stroke, which is only apparent among people who have migraine with aura. Our results also suggest a higher risk among women and risk was further magnified for people with migraine who were aged less than 45, smokers, and women who used oral contraceptives. We did not find an overall association between any migraine and myocardial infarction or death due to cardiovascular disease. Too few studies are available to reliably evaluate the impact of modifying factors, such as migraine aura, on these associations.

Abstract: Migraine, especially migraine with aura (MA), is an established risk factor for ischemic lesions of the brain. Recent evidence has also linked migraine to a broader range of ischemic vascular disorders including angina, myocardial infarction, coronary revascularization, claudication, and cardiovascular mortality. The mechanisms which link migraine to ischemic vascular disease remain uncertain and are likely to be complex. Cortical spreading depression, the presumed substrate of aura, may directly predispose to brain lesions and that would explain why MA is consistently demonstrated as a risk factor for cerebral ischemia, while for migraine without aura (MO), the evidence is less consistent. Additionally, individuals with migraine have a higher prevalence of risk factors known to be associated with cardiovascular disease (CVD), including hypertension, diabetes, and hyperlipidemia. The increased prevalence of CVD risk factors is also higher for MA than for MO. Since the evidence linking migraine and CVD is getting robust, neurologists should be aware of this association. Individuals with MO seem to be at little increased risk of CVD. MA is associated with an increased risk of ischemic stroke and likely also for other ischemic CVD events. Accordingly, heightened vigilance is recommended for modifiable cardiovascular risk factors in migraineurs, especially with MA. Ultimately, it will be important to determine whether MA is a modifiable risk factor for CVD and if preventive medications for migraine or antiplatelet therapy might reduce the risk of CVD in patients with MA.

Abstract: BACKGROUND: Interrelationships among the ACE deletion/insertion (D/I) polymorphism (rs1799752), migraine, and cardiovascular disease (CVD) are biologically plausible but remain controversial. METHODS: Association study among 25,000 white US women, participating in the Women's Health Study, with information on the ACE D/I polymorphism. Migraine and migraine aura status were self-reported. Incident CVD events were confirmed after medical record review. We used logistic regression to investigate the genotype-migraine association and proportional hazards models to evaluate the interrelationship among genotype, migraine, and incident CVD. RESULTS: At baseline, 4,577 (18.3%) women reported history of migraine; 39.5% of the 3,226 women with active migraine indicated aura. During 11.9 years of follow-up, 625 CVD events occurred. We did not find an association of the ACE D/I polymorphism with migraine or migraine aura status. There was a lack of association between the ACE D/I polymorphism and incident major CVD, ischemic stroke, and myocardial infarction. Migraine with aura doubled the risk for CVD, but only for carriers of the DD (multivariable-adjusted relative risk [RR] = 2.10; 95% CI = 1.22-3.59; p = 0.007) and DI genotype (multivariable-adjusted RR = 2.31; 95% CI = 1.52-3.51; p < 0.0001). The risk was not significant among carriers of the II genotype, a pattern we observed for myocardial infarction and ischemic stroke. CONCLUSIONS: Data from this large cohort of women do not suggest an association of the ACE deletion/insertion (D/I) polymorphism with migraine, migraine aura status, or cardiovascular disease (CVD). The increased risk for CVD among migraineurs with aura was only apparent for carriers of the DD/DI genotype. Due to limited number of outcome events, however, future studies are warranted to further investigate this association.

Abstract: BACKGROUND AND PURPOSE: White matter lesions (WMLs) have been shown to be associated with the risk of stroke in previous studies but little is known about the prediction of other vascular events. We evaluated the risk of stroke and other vascular events according to WML volume in a large population-based sample. We also studied WML volume by type (deep or periventricular) in relation to these events. METHODS: The 3-City Study is a population-based prospective cohort of people aged >or=65 years followed up for, on average, 4.9 years. Among them, 1643 participants free of prevalent vascular events had quantitative measurements of WML volume at baseline using a fully automatic method. The risks of incident major vascular events according to WML volume were evaluated using Cox proportional hazards models. RESULTS: The risk of incident stroke significantly increased with increasing baseline WML volume and was multiplied by 5 for those in the highest quartile of WML volume. Nonstroke vascular events' incidence was not associated with WML volumes, whatever their type. CONCLUSIONS: WMLs are an independent predictor of stroke in the elderly. This association is specific because WMLs are not associated with the risk of other vascular events.

Abstract: BACKGROUND: A recent nested case-control study found that the presence of antibodies against Trichomonas vaginalis, a common nonviral sexually transmitted infection, was positively associated with subsequent incidence of prostate cancer. We confirmed these findings in an independent population and related serostatus for antibodies against T vaginalis to prostate cancer incidence and mortality. METHODS: We conducted a case-control study nested within the Physicians' Health Study that included 673 case subjects with prostate cancer and 673 individually matched control subjects who had available plasma samples. Plasma from blood samples collected at baseline was assayed for antibodies against T vaginalis with an enzyme-linked immunosorbent assay. We used conditional logistic regression to estimate the odds ratios (ORs) of incident prostate cancer, extraprostatic prostate cancer, and cancer that would ultimately progress to bony metastases or prostate cancer-specific death. RESULTS: Although not statistically significant, the magnitude of the association between T vaginalis-seropositive status and overall prostate cancer risk (OR = 1.23, 95% confidence interval [CI] = 0.94 to 1.61) was similar to that reported previously. Furthermore, a seropositive status was associated with statistically significantly increased risks of extraprostatic prostate cancer (OR = 2.17, 95% CI = 1.08 to 4.37) and of cancer that would ultimately progress to bony metastases or prostate cancer-specific death (OR = 2.69, 95% CI = 1.37 to 5.28). CONCLUSIONS: This large prospective case-control study obtained further support for an association between a seropositive status for antibodies against T vaginalis and the risk of prostate cancer, with statistically significant associations identified for the risk of extraprostatic prostate cancer and for clinically relevant, potentially lethal prostate cancer.

Abstract: Migraine has been established as a risk factor for ische-mic stroke. Further evidence suggests that migraine is also associated with other ischemic vascular events, including myocardial infarction and cardiovascular death. However, these associations appear to be limited to the subgroup of patients with migraine with aura (MA). Moreover, there is increasing evidence that among patients with MA, additional subgroups exist that carry particular increased risk. The association with ischemic stroke is, for example, particularly strong for younger women with MA who smoke and/or use oral contraceptives. Results from recent studies support an even more complex interrelationship characterized by additional modifying effects of other factors on the association between MA and ischemic vascular events. These include vascular risk factors, migraine attack frequency, and genetic variants. In addition, there appear to be differential effects with regard to ischemic stroke and myocardial infarction. These new findings await confirmation in independent patient populations and are currently not sufficient to argue for a change in diagnostic testing or treatment.

Abstract: PURPOSE Gleason grading is an important predictor of prostate cancer (PCa) outcomes. Studies using surrogate PCa end points suggest outcomes for Gleason score (GS) 7 cancers vary according to the predominance of pattern 4. These studies have influenced clinical practice, but it is unclear if rates of PCa mortality differ for 3 + 4 and 4 + 3 tumors. Using PCa mortality as the primary end point, we compared outcomes in Gleason 3 + 4 and 4 + 3 cancers, and the predictive ability of GS from a standardized review versus original scoring. PATIENTS AND METHODS Three study pathologists conducted a blinded standardized review of 693 prostatectomy and 119 biopsy specimens to assign primary and secondary Gleason patterns. Tumor specimens were from PCa patients diagnosed between 1984 and 2004 from the Physicians' Health Study and Health Professionals Follow-Up Study. Lethal PCa (n = 53) was defined as development of bony metastases or PCa death. Hazard ratios (HR) were estimated according to original GS and standardized GS. We compared the discrimination of standardized and original grading with C-statistics from models of 10-year survival. Results For prostatectomy specimens, 4 + 3 cancers were associated with a three-fold increase in lethal PCa compared with 3 + 4 cancers (95% CI, 1.1 to 8.6). The discrimination of models of standardized scores from prostatectomy (C-statistic, 0.86) and biopsy (C-statistic, 0.85) were improved compared to models of original scores (prostatectomy C-statistic, 0.82; biopsy C-statistic, 0.72). CONCLUSION Ignoring the predominance of Gleason pattern 4 in GS 7 cancers may conceal important prognostic information. A standardized review of GS can improve prediction of PCa survival.

Abstract: CONTEXT: Many individuals take vitamins in the hopes of preventing chronic diseases such as cancer, and vitamins E and C are among the most common individual supplements. A large-scale randomized trial suggested that vitamin E may reduce risk of prostate cancer; however, few trials have been powered to address this relationship. No previous trial in men at usual risk has examined vitamin C alone in the prevention of cancer. OBJECTIVE: To evaluate whether long-term vitamin E or C supplementation decreases risk of prostate and total cancer events among men. DESIGN, SETTING, AND PARTICIPANTS: The Physicians' Health Study II is a randomized, double-blind, placebo-controlled factorial trial of vitamins E and C that began in 1997 and continued until its scheduled completion on August 31, 2007. A total of 14,641 male physicians in the United States initially aged 50 years or older, including 1307 men with a history of prior cancer at randomization, were enrolled. INTERVENTION: Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily. MAIN OUTCOME MEASURES: Prostate and total cancer. RESULTS: During a mean follow-up of 8.0 years, there were 1008 confirmed incident cases of prostate cancer and 1943 total cancers. Compared with placebo, vitamin E had no effect on the incidence of prostate cancer (active and placebo vitamin E groups, 9.1 and 9.5 events per 1000 person-years; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.85-1.09; P = .58) or total cancer (active and placebo vitamin E groups, 17.8 and 17.3 cases per 1000 person-years; HR, 1.04; 95% CI, 0.95-1.13; P = .41). There was also no significant effect of vitamin C on total cancer (active and placebo vitamin C groups, 17.6 and 17.5 events per 1000 person-years; HR, 1.01; 95% CI, 0.92-1.10; P = .86) or prostate cancer (active and placebo vitamin C groups, 9.4 and 9.2 cases per 1000 person-years; HR, 1.02; 95% CI, 0.90-1.15; P = .80). Neither vitamin E nor vitamin C had a significant effect on colorectal, lung, or other site-specific cancers. Adjustment for adherence and exclusion of the first 4 or 6 years of follow-up did not alter the results. Stratification by various cancer risk factors demonstrated no significant modification of the effect of vitamin E on prostate cancer risk or either agent on total cancer risk. CONCLUSIONS: In this large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer. These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00270647.

Abstract: Protein expression of p63 is used to differentiate prostate cancer from benign mimickers. Recent studies suggest that it may also distinguish aggressive prostate cancer with down-regulated expression occurring in men with more advanced disease. We conducted a prospective study among 298 men ages 51 to 84 years who were diagnosed with prostate cancer in the Physicians' Health Study in 1983 to 2004 and whose tissue was available for immunohistochemical staining. We used Cox proportional hazards regression to evaluate the association of p63 protein expression with fatal prostate cancer. We correlated p63 expression with tumor cell proliferation (Ki-67) and apoptosis (TUNEL staining). The predominant location of tumor p63 staining occurred in the cytoplasm, an uncommon departure from the strong nuclear staining usually observed in nonneoplastic basal cells. Increasing expression of cytoplasmic p63 (tertiles) was associated with prostate cancer mortality (n = 19 deaths); the hazard ratios (95% confidence intervals) were 1.0 (reference), 4.0 (0.9-18.9), and 5.9 (1.3-27.5; P(trend) = 0.03). The positive trend remained significant (P = 0.047) after multivariable adjustment for age, year of diagnosis, and Gleason score. Higher tertiles of cytoplasmic p63 were also associated with reduced levels of apoptosis (P(trend) = 0.0408) and increased cellular proliferation (P(trend) = 0.0026). We found aberrant expression of p63 in the cytoplasm to be associated with increased prostate cancer-specific mortality up to 20 years after diagnosis. The mislocalized expression was associated with reduced apoptosis and higher proliferative activity and may suggest an oncogenic role in prostate cancer progression and survival.

Abstract: Although randomized controlled trials (RCTs) are the gold standard for assessing efficacy of a drug intervention, because they are conducted in a highly selected group of patients, they do not necessarily reflect normal customary or optimized patient care. Accordingly, information from RCTs must be supplemented by outcomes research and by nonexperimental or quasi-experimental study designs. Herein, we discuss information that supplements the rigorous but sometimes rigid nature of RCTs in an effort to better understand the clinical utility of drug treatment for migraine with patient-centered outcomes in mind. We start by discussing several lessons we learned from RCTs on comparative triptan studies, followed by presenting data on outcomes studies for rizatriptan. We then briefly discuss migraine treatment behavior issues, including early treatment and adherence to treatment.

Abstract: OBJECTIVE: To estimate the incidence and lifetime risk (LTR) of Parkinson disease (PD) in a large cohort of men. BACKGROUND: Age is the strongest risk factor for PD, but whether its incidence continues to increase after age 80 years remains unclear. METHODS: Prospective cohort of 21,970 US male physicians aged 40-84 years at baseline who did not report PD before study entry. Participants self-reported PD on yearly follow-up questionnaires, and all deaths were confirmed. We calculated incidence rates and cumulative incidence using a modified Kaplan-Meier analysis. LTR was estimated by adjusting cumulative incidence for competing risks of death. RESULTS: Five hundred sixty-three cases of PD were identified over 23 years of follow-up. The crude incidence rate of PD was 121 cases/100,000 person-years. Age-specific incidence rates increased sharply beginning at age 60 years, peaked in those aged 85-89 years, and declined beginning at age 90 years. Cumulative incidence substantially overestimated the long-term risk of PD, particularly in those aged 80 years and older. Cumulative incidence was 9.9% (95% confidence interval [CI] 8.48%-11.30%) from ages 45 to 100 years, whereas LTR for the same period was 6.7% (95% CI 6.01%-7.43%). The incidence and LTR of PD decreased with increasing exposure to smoking. CONCLUSIONS: Our study provides evidence that the incidence of Parkinson disease (PD) in men increases through age 89 years. Whether the subsequent decline represents a true decrease in risk remains to be established. A history of smoking substantially decreased the incidence and lifetime risk of PD. Incidence studies that do not adjust for competing risks of death may overestimate the true risk of PD in the elderly.

Abstract: OBJECTIVE: To investigate the role of three common polymorphisms in the beta2-adrenoceptor gene in migraine. BACKGROUND: Migraine has been associated with increased risk of cardiovascular disease and asthma in which beta2-adrenoceptors play an important role; beta-adrenoceptor antagonists are used in migraine prevention. However, the role of variants in the beta2-adrenoceptor gene in migraine is unclear. METHODS: Association study among 23,753 white women, participating in the Women's Health Study, for whom we had information on migraine at baseline and genotype status of the polymorphisms rs1042713 (Gly16Arg), rs1042714 (Gln27Glu), rs1800888 (Thr164Ile). Migraine was self-reported and we distinguished between any history of migraine, active migraine with and without aura, and prior migraine (history of migraine but not active migraine) in our analyses. RESULTS: At baseline 4339 women reported any history of migraine. Of these, 3041 had active migraine (1221 migraine with aura, 1820 migraine without aura) and 1298 prior migraine. No migraine was reported by 19,414 women. Genotype- and haplotype-based analyses did not show an association of any of the gene variants tested with any history of migraine. The multivariable-adjusted odds ratios (ORs) (95% confidence intervals) for any history of migraine in the additive model were 1.0 (0.96-1.05) for rs1042713, 1.0 (0.95-1.05) for rs1042714, and 0.84 (0.68-1.05) for rs1800888. In the haplotype analysis the ORs ranged from 0.83 (0.67-1.03) to 1.01 (0.94-1.07) with Gly16-Glu27-Thr164 as the reference. We also did not find associations in the genotype- and haplotype-based analyses within migraine-specific subgroups. CONCLUSIONS: Our results do not support a role of 3 investigated polymorphisms in the beta2-adrenoceptor gene in migraine pathophysiology.

Abstract: Interleukin-6 (IL-6) and C-reactive protein (CRP) are elevated in prostate cancer patients, but the role of prediagnostic levels of these inflammatory mediators on prostate cancer outcomes is unclear. We undertook a large, prospective case-control study to evaluate the relation between prediagnostic levels of IL-6 and CRP and prostate cancer incidence and mortality. We also investigated the role of the IL-6 (-174 G/C) polymorphism in relation to circulating levels of IL-6 and CRP, as well as cancer risk and mortality. We used unconditional logistic regression that adjusted for matching factors to analyze prostate cancer risk. For analyses of prostate cancer mortality, we conducted survival analyses in cases. Because of the strong link between inflammatory markers and body mass index (BMI), we assessed interactions between BMI and plasma levels on prostate cancer outcomes. Neither IL-6 nor CRP plasma levels varied significantly by IL-6 genotype. Genotype was not associated with prostate cancer risk or survival. Though neither IL-6 nor CRP was associated with prostate cancer incidence overall, we observed a statistically significant interaction between IL-6 and BMI on prostate cancer incidence (p(interaction) < 0.01). Increasing IL-6 levels were positively associated with risk in healthy weight men, but inversely associated with risk in overweight men. Further, prediagnostic IL-6 was associated with time to prostate cancer progression/death among healthy weight prostate cancer cases (p(trend) = 0.02). Adjusted hazard ratios were 1.73 (95% CI: 0.86, 3.51) comparing the highest to lowest IL-6 level. Our study suggests that IL-6 may potentially be involved in the development or progression of prostate cancer.

Abstract: Results from studies investigating the association between polymorphisms in the beta2-adrenergic receptor gene (ADRB2) and cardiovascular disease (CVD) are controversial. Using haplotype-based analysis, we have previously shown a protective effect of the Gly16-Gln27-Ile164 haplotype on myocardial infarction in men. We sought to replicate these findings in women and further investigated whether the gene variants exert differential effects on myocardial infarction and ischaemic stroke. We performed a prospective study among 25,224 women, participating in the Women's Health Study and free of CVD at study entry. We had information on polymorphisms Gly16Arg, Gln27Glu, and Thr164Ile in the ADRB2. Incident CVD was self-reported and confirmed after medical record review. We used proportional hazards models to investigate the association between genotypes and haplotypes with any myocardial infarction, any ischaemic stroke, and CVD death. During a mean of 11.8 years of follow-up, 274 myocardial infarctions, 299 ischaemic strokes, and 159 CVD deaths occurred. Among the whole cohort genotype- and haplotype-based analyses did not show an association for any of the gene variants with any of the CVD outcomes. When we focused on Caucasian women, the haplotype-based analysis, however, suggested an inverse association of the haplotype Gly16-Gln27-Thr164 with incident myocardial infarction (multivariable-adjusted hazard ratio 0.75; 95% confidence interval 0.58-0.97; p = 0.03). We did not find associations in the haplotype-based analyses with incident ischaemic stroke or CVD death. Our results suggest that the haplotype Gly16-Gln27-Thr164 is associated with reduced risk of incident myocardial infarction but not ischaemic stroke in Caucasian women and suggest differential pathophysiologies for myocardial infarction and stroke.

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Abstract: PURPOSE: Variants at chromosomal loci 8q24 and 17q are established risk factors for prostate cancer. Many studies have confirmed the findings for risk, but few have examined aggressiveness and other clinical variables in detail. Additionally, Gleason score is typically used as a surrogate for the primary end point of prostate cancer mortality. We investigated whether the 8q24 and 17q risk variants are associated with clinical variables as well as prostate cancer mortality. EXPERIMENTAL DESIGN: In the Physicians' Health Study (1,347 cases and 1,462 controls), the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center; 3,714 cases), and the Fred Hutchinson Cancer Research Center King County Case-Control Studies (1,308 cases and 1,266 controls), we examined eight previously identified 8q24 and 17q risk variants for association with prostate cancer mortality in men of European ancestry. We considered associations with other surrogate markers of prostate cancer aggressiveness, such as Gleason score, pathologic stage, prostate-specific antigen at diagnosis, and age at diagnosis. RESULTS: Six of the eight variants were confirmed as prostate cancer risk factors. Several variants were nominally associated with age at diagnosis; when totaling all alleles for single nucleotide polymorphisms significantly associated with risk, each additional allele decreased age at diagnosis by an average of 6 months in the Physicians' Health Study (P = 0.0005) and 4 months in the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center) cohort (P = 0.0016). However, there were no statistically significant associations with prostate cancer mortality. CONCLUSIONS: Our results suggest that the 8q24 and 17q prostate cancer risk variants may influence age at diagnosis but not disease aggressiveness.

Abstract: BACKGROUND: Epidemiologic data on aspirin use and the risk of diabetes are limited. The Physician's Health Study has accumulated 22 years of follow-up data, including 5 years of randomized data, from 22,071 apparently healthy men. METHODS AND RESULTS: At baseline and in yearly follow-up questionnaires, participants self-reported a history of diabetes, aspirin use, and various lifestyle factors. To evaluate the association between aspirin use and risk of subsequent diabetes, we used a Cox proportional hazards model with time-varying regression coefficients. During the 22 follow-up years, 1719 cases of diabetes were reported. The multivariable-adjusted hazard ratio of developing diabetes was 0.86 (95% confidence interval [CI], 0.77-0.97) for those who self-selected any aspirin. During the 5 years of randomized treatment, 318 cases of diabetes were observed, with a hazard ratio of 0.91 (95% CI, 0.73-1.14) for those randomized to aspirin. CONCLUSION: Our data suggest a small but not significant decrease in the risk of diabetes during 5 years of randomized comparison of 325 mg of aspirin every other day. This trend was continued during 22 years of follow-up, indicating that self-selection of any use of aspirin is associated with a significant, approximately 14% decrease in the risk of diabetes. Decreased risk of type 2 diabetes may be added to the list of the clinical benefits of aspirin.

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Abstract: OBJECTIVES: This study examined associations between anthropometric measures (body mass index, waist circumference, waist-to-hip ratio, waist-to-height ratio [WHtR]) and risk of incident cardiovascular disease (CVD) (including nonfatal myocardial infarction, nonfatal ischemic stroke, and cardiovascular death). BACKGROUND: Controversy exists regarding the optimal approach to measure adiposity, and the utility of body mass index has been questioned. METHODS: Participants included 16,332 men in the Physicians' Health Study (mean age 61 years in 1991) and 32,700 women in the Women's Health Study (mean age 61 years in 1999). We used Cox proportional hazards models to determine relative risks and 95% confidence intervals (CIs) for developing CVD according to self-reported anthropometric indexes. RESULTS: A total of 1,505 CVD cases occurred in men and 414 occurred in women (median follow-up 14.2 and 5.5 years, respectively). Although WHtR demonstrated statistically the strongest associations with CVD and best model fit, CVD risk increased linearly and significantly with higher levels of all indexes. Adjusting for confounders, the relative risk for CVD was 0.58 (95% CI: 0.32 to 1.05) for men with the lowest WHtR (<0.45) and 2.36 (95% CI: 1.61 to 3.47) for the highest WHtR (>/=0.69; vs. WHtR 0.49 to <0.53). Among women, the relative risk was 0.65 (95% CI: 0.33 to 1.31) for those with the lowest WHtR (<0.42) and 2.33 (95% CI: 1.66 to 3.28) for the highest WHtR (>/=0.68; vs. WHtR 0.47 to <0.52). CONCLUSIONS: The WHtR demonstrated statistically the best model fit and strongest associations with CVD. However, compared with body mass index, differences in cardiovascular risk assessment using other indexes were small and likely not clinically consequential. Our findings emphasize that higher levels of adiposity, however measured, confer increased risk of CVD. Comment in Which measures of obesity best predict cardiovascular risk? [J Am Coll Cardiol. 2008] Is body mass index really the best measure of obesity in individuals? [J Am Coll Cardiol. 2009] Problems in measurement of body "fatness".

Abstract: BACKGROUND: Recent findings suggest an association between the renin-angiotensin system and migraine. However, genetic studies are scarce and controversial. OBJECTIVE: To investigate the association between the AGTR1 1166A > C and AGT Met235Thr polymorphisms with migraine and migraine aura status. METHODS: We performed an association study among 25,000 Caucasian US women, participating in the Women's Health Study, with information on the AGTR1 1166A > C and AGT Met235Thr polymorphisms. Migraine and migraine aura status were self-reported. We distinguished between any history of migraine, active migraine with aura, active migraine without aura, and prior migraine (history of migraine, but not in the year prior to baseline). We used logistic regression to investigate the genotype-migraine association. RESULTS: At baseline, 4577 (18.3%) women reported any history of migraine; 39.5% of the 3226 women with active migraine indicated aura. The polymorphisms were not associated with migraine or migraine-specific subgroups. We also did not find a significant interaction between the polymorphisms. CONCLUSIONS: Data from this large cohort of Caucasian women do not suggest an association of polymorphisms in the renin-angiotensin system with migraine or aura status. Future studies should focus on haplotype analyses and additional gene-gene as well as gene-environment interactions.

Abstract: 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.

Abstract: Migraine has been associated with an unfavourable cardiovascular risk profile and with increased risk of cardiovascular disease. In a cross-sectional analysis of 27,626 women aged >or=45 years, we evaluated the association of migraine and migraine aura status with elevated levels of total cholesterol, low- and high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoprotein (Apo) A-1 and B(100), lipoprotein (a), C-reactive protein (CRP), fibrinogen, intercellular adhesion molecule-1, homocysteine and creatinine. A total of 5087 (18.4%) women reported any history of migraine. Compared with women with no migraine history, women who reported any history of migraine had modestly increased adjusted odds ratios (95% confidence interval) of 1.09 (1.01, 1.18) for elevated total cholesterol, 1.14 (1.05, 1.23) for non-HDL-C, 1.09 (1.01, 1.18) for Apo B(100) and 1.13 (1.05, 1.22) for CRP. The increase did not meaningfully differ according to migraine aura status and migraine frequency. In this large cohort of women, only a modest association was found between migraine and adverse levels of certain cardiovascular biomarkers.

Abstract: 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.

Abstract: OBJECTIVE: Insulin receptor substrate-1 (IRS-1) acts as a docking protein between the insulin-like growth factor-1 (IGF-1) receptor and intracellular signaling molecules in the IGF-1 signaling pathway. Accumulating data support a role of IGF-1 in prostate carcinogenesis. We assessed the influence of the most common IRS-1 gene polymorphism (Gly972Arg) on prostate cancer risk, alone and in combination with IGF-1 and other components in the IGF-1 signaling pathway. MATERIALS AND METHODS: In a nested case-control study within the Physicians' Health Study, the IRS-1 polymorphism was assayed from prospectively collected samples from 564 incident prostate cancer cases and 758 controls matched on age and smoking. We calculated relative risks (RR) and 95% confidence intervals (CI) using conditional logistic regression. RESULTS: Among the controls, 0.8% were homozygous (AA) and 12% were heterozygous (GA) for the polymorphic allele. There was no association between carriage of the A allele and total prostate cancer risk (RR = 1.1 95% CI = 0.8-1.5), advanced disease (stage C or D or lethal prostate cancer, RR = 1.3 95% CI = 0.8-2.3), or plasma IGF-1 levels. We explored possible interactions with body mass index and components in the IGF-1 pathway including IGFBP3, PI3k, and PTEN but none of these factors influenced the relation between IRS-1 genotype and prostate cancer risk. CONCLUSIONS: Our data do not support an association between carriage of the variant IRS-1 gene and prostate cancer risk.

Abstract: This review reports important co-morbid conditions of migraine and resulting consequences for the choice of acute and preventive treatments of migraine. Comorbidity in this context means the occurrence of two diseases in an individual beyond chance. The basis of comorbidity can be genetic and/or based on common environmental factors. In some cases, the temporal relationship is unclear and one disease can cause another disease. In order to prove a real comorbidity, large-scale and well-performed epidemiological studies are required.

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Abstract: BACKGROUND: Prospective data on nongenetic determinants of exceptional longevity are limited, and information on long-lived men and their functional status is particularly sparse. We examined modifiable factors associated with a life span of 90 or more years and late-life function in men. METHODS: In this prospective cohort study of 2357 healthy men (mean age, 72 years) within the Physicians' Health Study (1981-2006), biological and lifestyle factors and comorbid conditions were assessed by self-report with baseline and annual questionnaires. Mortality and incidence of major diseases were confirmed by medical record review. Late-life function was assessed 16 years after baseline by the Medical Outcomes Study 36-Item Short-Form Health Survey. RESULTS: A total of 970 men (41%) survived to at least age 90 years. Smoking was associated with increased risk of mortality before age 90 years (hazard ratio [HR]; 2.10; 95% confidence interval [CI], 1.75-2.51), and similar associations were observed with diabetes (HR, 1.86; 95% CI, 1.52-2.26), obesity (HR, 1.44; 95% CI, 1.10-1.90), and hypertension (HR, 1.28; 95% CI, 1.15-1.43). Regular exercise was associated with a nearly 30% lower mortality risk (HR, 0.72; 95% CI, 0.62-0.83). The probability of a 90-year life span at age 70 years was 54% in the absence of smoking, diabetes, obesity, hypertension, or sedentary lifestyle. It ranged from 36% to 22% with 2 adverse factors and was negligible (4%) with 5. Compared with nonsurvivors, men with exceptional longevity had a healthier lifestyle (67% vs 53% had <or=1 adverse factor), had a lower incidence of chronic diseases, and were 3 to 5 years older at disease onset. They had better late-life physical function (mean +/- SD score [maximum 100], 73 +/- 23 vs 62 +/- 30; P < .001) and mental well-being (mean score, 84 +/- 14 vs 81 +/- 17; P = .03). More than 68% (vs 45%) rated their late-life health as excellent or very good, and less than 8% (vs 22%) reported fair or poor health (P < .001 for trend). Regular exercise was associated with significantly better-and smoking and overweight with significantly worse-late-life physical function. Smoking also was associated with a significant decrement in mental function. CONCLUSION: Modifiable healthy behaviors during early elderly years, including smoking abstinence, weight management, blood pressure control, and regular exercise, are associated not only with enhanced life span in men but also with good health and function during older age.

Abstract: BACKGROUND: Chronic kidney disease (CKD) and obesity are important public health concerns. We examined the association between anthropomorphic measures and incident CKD and mortality. STUDY DESIGN: Cohort study. SETTING &#38; PARTICIPANTS: Individual patient data pooled from the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. PREDICTORS: Waist-to-hip ratio (WHR), body mass index (BMI). OUTCOMES &#38; MEASUREMENTS: Incident CKD defined as serum creatinine level increase greater than 0.4 mg/dL with baseline creatinine level of 1.4 mg/dL or less in men and 1.2 mg/dL or less in women and final creatinine level greater than these levels, and, in separate analyses, estimated glomerular filtration rate (eGFR) decrease of 15 mL/min/1.73 m(2) or greater with baseline eGFR of 60 mL/min/1.73 m(2) or greater and final eGFR less than 60 mL/min/1.73 m(2). Multivariable logistic regression to determine the association between WHR, BMI, and outcomes. Cox models to evaluate a secondary composite outcome of all-cause mortality and incident CKD. RESULTS: Of 13,324 individuals, mean WHR was 0.96 in men and 0.89 in women and mean BMI was 27.2 kg/m(2) in both men and women. During 9.3 years, 300 patients (2.3%) in creatinine-based models and 710 patients (5.5%) in eGFR-based models developed CKD. In creatinine-based models, each SD increase in WHR was associated with increased risk of incident CKD (odds ratio, 1.22; 95% confidence interval [CI], 1.05 to 1.43) and the composite outcome (hazard ratio, 1.12; 95% CI, 1.06 to 1.18), whereas each SD increase in BMI was not associated with CKD (odds ratio, 1.05; 95% CI, 0.93 to 1.20) and appeared protective for the composite outcome (hazard ratio, 0.94; 95% CI, 0.90 to 0.99). Results of eGFR-based models were similar. LIMITATIONS: Single measures of creatinine, no albuminuria data. CONCLUSIONS: WHR, but not BMI, is associated with incident CKD and mortality. Assessment of CKD risk should use WHR rather than BMI as an anthropomorphic measure of obesity.

Abstract: OBJECTIVE: To evaluate the association between type 2 diabetes and newly reported Parkinson's disease. RESEARCH DESIGN AND METHODS: Our study included 21,841 participants in the Physicians' Health Study, a cohort of U.S. male physicians. Diabetes and Parkinson's disease were self-reported via questionnaire. We used time-varying Cox regression to calculate adjusted relative risk (RR) for Parkinson's disease. RESULTS: Over 23 years, 556 individuals with Parkinson's disease were identified. Subjects with diabetes had an increased Parkinson's disease risk (multivariable-adjusted RR 1.34 [95% CI 1.01-1.77]). The association remained significant after exclusion of those with known vascular disease. The diagnosis of diabetes was clustered around the diagnosis of Parkinson's disease and was more apparent among men with short diabetes duration and those without complications from diabetes. CONCLUSIONS: Results of this large prospective study in men do not suggest that diabetes is a preceding risk factor for Parkinson's disease. Whether the positive association may be explained by ascertainment bias or a common underlying biological mechanism remains to be established.

Abstract: BACKGROUND: Previous studies suggest a positive association between markers of trans-fatty acid intake and prostate cancer. We therefore prospectively evaluated the association between blood trans-fatty acid levels and risk of prostate cancer. METHODS: We conducted a nested case-control study among 14,916 apparently healthy men who provided blood samples in 1982. Blood fatty acid levels were determined for 476 men diagnosed with prostate cancer during a 13-year follow-up and their matched controls. Controls were individually matched to cases according to age and smoking status at baseline. Conditional logistic regression was used to estimate the relative risk and 95% confidence interval of total, nonaggressive (stage A/B and low grade), and aggressive (stage C/D, high grade, subsequent distant metastasis or death) prostate cancer associated with blood levels of specific trans-fatty acids. RESULTS: Blood levels of all the trans-fatty acids examined were unrelated to total prostate cancer risk. When results were divided according to tumor aggressiveness, blood levels of 18:1n-9t, all the 18:2t examined, and total trans-fatty acids were positively associated to nonaggressive tumors. The relative risks (95% confidence intervals; P trend) comparing top with bottom quintile trans-fatty acid levels were 2.16 (1.12-4.17; 0.11) for 18:1n-9t, 1.97 (1.03-3.75; 0.01) for total 18:2t, and 2.21 (1.14-4.29; 0.06) for total trans-fatty acids. None of the trans fats examined was associated with aggressive prostate tumors. CONCLUSION: Blood levels of trans isomers of oleic and linoleic acids are associated with an increased risk of nonaggressive prostate tumors. As this type of tumors represents a large proportion of prostate cancer detected using prostate-specific antigen screening, these findings may have implications for the prevention of prostate cancer.

Abstract: BACKGROUND: Chronic kidney disease is a risk factor for heart failure (HF). Although cystatin C can detect early kidney dysfunction, limited data are available on the association between cystatin C and HF. METHODS: In a prospective nested case-control study design, we examined whether cystatin C is associated with an increased risk of HF in the PHS and whether such an association is stronger in hypertensive subjects. We selected 220 cases of incident HF and 220 controls, matched on age, year of birth, and time of blood collection. Plasma cystatin C was measured using an immunonephelometry method. We used conditional logistic regression to estimate relative risks (RRs). RESULTS: Compared with the lowest tertile, the multivariable adjusted RR (95% CI) for HF was 1.15 (0.69-1.89) and 1.78 (1.01-3.13) for the second and third tertiles of cystatin C, respectively. Additional adjustment for systolic blood pressure and history of hypertension attenuated this association (RR = 1.0, 1.23 [0.73-2.09], and 1.61 [0.90-2.88] from the lowest to the highest tertile, respectively). Furthermore, we observed a 4-fold increased risk of HF in the second and third tertiles of cystatin C among hypertensive individuals and no meaningful effects of cystatin C on HF among nonhypertensive subjects. CONCLUSIONS: Our data demonstrated that higher levels of cystatin C are associated with an increased risk of HF and that such association may be limited to hypertensive individuals. Additional studies are warranted to further examine the relationship between hypertension and cystatin C on the risk of HF.

Abstract: The risks of cognitive impairment among hospitalized patients over age 85 are not adequately understood. We used electronically recorded ICD-9 codes of inpatients over 85 years old to identify patients age > or =85 who showed signs of cognitive impairment during hospitalization at our institution. We randomly selected patient records showing cognitive impairment and patient control records matched for age and admission date but without cognitive impairment and obtained mortality information up to 18 months after discharge. Records were further examined to characterize hospital stay including reason for admission. After adjustment for comorbidities and potential confounders, patients over age 85 with ICD-9-defined cognitive impairment had increased risk of death within the hospital (hazard ratio (HR)=3.99; 95% confidence interval (CI) 0.42-37.90; p=0.229), in the first year after hospitalization (HR=2.35; 95% CI 1.15-4.78; p=0.019), and cumulatively (HR=2.46; 95% CI 1.26-4.82; p=0.009). In this matched cohort of hospitalized patients > or =85 years old, cognitive impairment was associated with an increased mortality rate. Because of this additional risk of death, hospitalized geriatric patients who are cognitively impaired may merit closer monitoring.

Abstract: BACKGROUND: High blood pressure (BP) has been associated with a decrease in kidney function. However, it remains unclear which BP measure best predicts impaired kidney function. METHODS: We compared systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP) and mean arterial pressure (MAP) in predicting risk of chronic kidney disease (CKD). We prospectively followed 8093 male participants in the Physicians' Health Study, without a known history of kidney disease at baseline, who provided BP values on the baseline and 24-month questionnaires, and for whom we had creatinine measures after 14 years of follow-up. Reported BP was averaged from both questionnaires. The main outcome was CKD, defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2). We used multivariable-adjusted logistic regression to evaluate the association between BP measures and CKD and compared models using the likelihood ratio test. RESULTS: After 14 years of follow-up, 1039 men (12.8%) had CKD. An increase of 10 mmHg had corresponding multivariable-adjusted odds ratios (95% confidence intervals) of 1.11 (1.03-1.19) for SBP, 1.11 (1.00-1.23) for MAP, 1.14 (1.05-1.25) for PP and 1.05 (0.93-1.17) for DBP. SBP and PP were the strongest predictors of chronic kidney function, with equal predictive abilities. Combining BP measures did not add significantly to the prediction. CONCLUSIONS: Increases in SBP, PP and MAP were significantly associated with CKD. SBP may be the most clinically useful predictor of CKD, since no further calculations are required.

Abstract: OBJECTIVE: Assess the risk of complications during endotracheal intubation (ETI) and their association with the skill level of the intubating physician. DESIGN: Prospective cohort study of 136 patients intubated by the intensive care team during a 5-month period. Standardized data forms were used to collect detailed information on the intubating physicians, supervisors, techniques, medications and complications. SETTING: Canadian academic intensive care unit. MEASUREMENTS AND RESULTS: All intubations were successful and there were no deaths during intubation. Non-experts were supervised in 92% of procedures. Expert operators were successful within two attempts in 94%, compared to only 82% of non-experts (P = 0.03), with 13.2% of all intubations requiring > or =3 attempts. Furthermore, 10.3% of intubations required 10 or more minutes. Difficult intubation (3 or more attempts by an expert) occurred in 6.6%. Overall risk of complications was 39%, including: severe hypoxemia (19.1%), severe hypotension (9.6%), esophageal intubation (7.4%) and frank aspiration (5.9%). ICU and hospital mortality were 15.4 and 29.4%, respectively. Compared with non-expert intubating physicians, propensity score-adjusted odds ratios (95% confidence interval) for expert physicians were 0.92 (95% CI: 0.28, 3.05, P = 0.89) for any complication, 0.45 (95% CI: 0.09, 2.20, P = 0.32) for ICU mortality and 0.47 (95% CI: 0.13, 1.70, P = 0.25) for hospital mortality. Two or more attempts at ETI was independently associated with an increased risk of severe complications (OR 3.31, 95% CI: 1.30, 8.40, P = 0.01). CONCLUSIONS: These prospective data show a high risk of serious complications, and difficult intubations, that are associated with ETI of the critically ill.

Abstract: BACKGROUND: To evaluate the risk/benefit profiles of gefitinib in comparison with platinum-based doublets chemotherapy as a first-line treatment for chemonaïve patients with advanced non-small-cell lung cancer in East Asia. METHODS: We searched MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov to identify randomized and non-randomized phase II or III clinical trials of gefitinib or chemotherapy treatment in East Asian patients published before 4/30/2007. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. Treatment arms with gefitinib 250mg/day and platinum-based doublets chemotherapy irrespective of dosage and schedule were combined to calculate the pooled estimates for efficacy and safety outcomes of interest. RESULTS: We identified 7 gefitinib and 41 platinum-based doublets chemotherapy trials with nearly 3000 enrolled patients for planned comparison. The pooled response rate (95% confidence interval) to gefitinib for unselected chemonaïve population was 31% (23-38%), not substantially different from 34% (31-38%) reported by platinum-based doublets chemotherapy trials. Patients with certain characteristics were more likely to benefit from gefitinib treatment, with pooled response rates as high as 75% (60-90%) for patients with epidermal growth factor receptor (EGFR) exon 18-21 mutations; 56% (38-74%) for never smokers; 55% (41-69%) for female; and 43% (30-57%) for adenocarcinoma or bronchioalveolar carcinoma. Severe hematological adverse events related to gefitinib treatment were not observed in any of the included trials. However, the risks of severe liver and lung injury related to gefitinib treatment were both approximately 6%, significantly higher than 1% and 0.2% reported by platinum-based doublets chemotherapy trials. CONCLUSION: Our data suggest that one third of chemonaïve NSCLC patients in East Asia would respond to oral gefitinib monotherapy while 6% would develop severe liver and lung injury. Although patients with EGFR gene mutations, female gender, non-smokers, or adenocarcinoma were more likely to respond to gefitinib, further study with valid comparison groups are needed to identify the optimal treatment strategy in these subpopulations.

Abstract: CONTEXT: Basic research and observational studies suggest vitamin E or vitamin C may reduce the risk of cardiovascular disease. However, few long-term trials have evaluated men at initially low risk of cardiovascular disease, and no previous trial in men has examined vitamin C alone in the prevention of cardiovascular disease. OBJECTIVE: To evaluate whether long-term vitamin E or vitamin C supplementation decreases the risk of major cardiovascular events among men. DESIGN, SETTING, AND PARTICIPANTS: The Physicians' Health Study II was a randomized, double-blind, placebo-controlled factorial trial of vitamin E and vitamin C that began in 1997 and continued until its scheduled completion on August 31, 2007. There were 14,641 US male physicians enrolled, who were initially aged 50 years or older, including 754 men (5.1%) with prevalent cardiovascular disease at randomization. INTERVENTION: Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily. MAIN OUTCOME MEASURES: A composite end point of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular disease death). RESULTS: During a mean follow-up of 8 years, there were 1245 confirmed major cardiovascular events. Compared with placebo, vitamin E had no effect on the incidence of major cardiovascular events (both active and placebo vitamin E groups, 10.9 events per 1000 person-years; hazard ratio [HR], 1.01 [95% confidence interval {CI}, 0.90-1.13]; P = .86), as well as total myocardial infarction (HR, 0.90 [95% CI, 0.75-1.07]; P = .22), total stroke (HR, 1.07 [95% CI, 0.89-1.29]; P = .45), and cardiovascular mortality (HR, 1.07 [95% CI, 0.90-1.28]; P = .43). There also was no significant effect of vitamin C on major cardiovascular events (active and placebo vitamin E groups, 10.8 and 10.9 events per 1000 person-years, respectively; HR, 0.99 [95% CI, 0.89-1.11]; P = .91), as well as total myocardial infarction (HR, 1.04 [95% CI, 0.87-1.24]; P = .65), total stroke (HR, 0.89 [95% CI, 0.74-1.07]; P = .21), and cardiovascular mortality (HR, 1.02 [95% CI, 0.85-1.21]; P = .86). Neither vitamin E (HR, 1.07 [95% CI, 0.97-1.18]; P = .15) nor vitamin C (HR, 1.07 [95% CI, 0.97-1.18]; P = .16) had a significant effect on total mortality but vitamin E was associated with an increased risk of hemorrhagic stroke (HR, 1.74 [95% CI, 1.04-2.91]; P = .04). CONCLUSIONS: In this large, long-term trial of male physicians, neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events. These data provide no support for the use of these supplements for the prevention of cardiovascular disease in middle-aged and older men. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00270647.

Abstract: BACKGROUND: Interrelationships among the MTHFR 677C>T polymorphism (rs1801133), migraine, and cardiovascular disease (CVD) are plausible but remain controversial. METHODS: Association study among 25,001 white US women, participating in the Women's Health Study, with information on MTHFR 677C>T polymorphism. Migraine and migraine aura status were self-reported. Incident CVD events were confirmed after medical record review. We used logistic regression to investigate the genotype-migraine association and proportional hazards models to evaluate the interrelationships of genotype and migraine on incident CVD. RESULTS: At baseline, 4,577 (18.3%) women reported history of migraine; 39.5% of the 3,226 women with active migraine indicated aura. During a mean of 11.9 years of follow-up, 625 CVD events occurred. Carriers of the TT genotype were less likely to have migraine with aura. The multivariable-adjusted relative risk (RR) in the recessive model was 0.79 (95% CI = 0.65-0.96; p = 0.02). The TT genotype did not increase the risk for CVD. In contrast, migraine with aura doubled the risk for CVD (multivariable-adjusted RR = 2.06; 95% CI = 1.53-2.78; p < 0.0001). Coexistence of migraine with aura and the TT genotype selectively raised this risk (RR = 3.66; 95% CI = 1.69-7.90; p = 0.001). This pattern was driven by a fourfold increased risk for ischemic stroke (multivariable-adjusted RR = 4.19; 95% CI = 1.38-12.74; p = 0.01) and was not apparent for myocardial infarction. CONCLUSIONS: Data from this large cohort of women suggest a modest protective effect of the MTHFR 677TT genotype on migraine with aura. The increased risk for cardiovascular disease among migraineurs with aura was magnified for TT genotype carriers, which was driven by a substantially increased risk of ischemic stroke.

Abstract: OBJECTIVE: To investigate the influence of increasing age on the incidence and remaining lifetime risk of cardiovascular disease and cancer in a cohort of older men. DESIGN: Prospective cohort study. SETTING: United States. PARTICIPANTS: 22,048 male doctors aged 40-84 who were free of major disease in 1982. MAIN OUTCOME MEASURES: Incidence and remaining lifetime risk of major cardiovascular disease (myocardial infarction, stroke, and death from cardiovascular disease) and cancer. RESULTS: 3252 major cardiovascular events and 5400 incident cancers were confirmed over 23 years of follow-up. The incidence of major cardiovascular disease continued to increase to age 100. Beginning at age 80, however, major cardiovascular disease was more likely to be diagnosed at death. The incidence of cancer peaked in those aged 80-89 and then declined. Cancers detected by screening accounted for most of the decline, whereas most cancers for which there was no screening continued to increase to age 100. Unadjusted cumulative incidence overestimated the risk of cardiovascular disease by 16% and cancer by 8.5%. The remaining lifetime risk of cancer at age 40 was 45.1% (95% confidence interval 43.8% to 46.3%) and at age 90 was 9.6% (7.2% to 11.9%). The remaining lifetime risk of major cardiovascular disease at age 40 was 34.8% (33.1% to 36.5%) and at age 90 was 16.7% (12.9% to 20.6%). CONCLUSIONS: In this prospective cohort of men, the incidence of new cardiovascular disease continued to increase after age 80 but was most often diagnosed at death. The decrease in incidence of cancer late in life seemed largely due to a decline in cancers usually detected by screening. These findings suggest that people aged 80 and older have a substantial amount of undiagnosed disease. The remaining lifetime risk of both diseases approached a plateau in the 10th decade. This may be due to decreased detection of disease and reporting of symptoms and increased resistance to disease in those who survive to old age. Accurate estimates of disease risk in an aging population require adjustment for competing risks of mortality.