Physical activity trajectories and mortality: population based cohort study.

OBJECTIVE: To assess the prospective associations of baseline and long term trajectories of physical activity on mortality from all causes, cardiovascular disease, and cancer. DESIGN: Population based cohort study. SETTING: Adults from the general population in the UK. PARTICIPANTS: 14 599 men and women (aged 40 to 79) from the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort, assessed at baseline (1993 to 1997) up to 2004 for lifestyle and other risk factors; then followed to 2016 for mortality (median of 12.5 years of follow-up, after the last exposure assessment). MAIN EXPOSURE: Physical activity energy expenditure (PAEE) derived from questionnaires, calibrated against combined movement and heart rate monitoring. MAIN OUTCOME MEASURES: Mortality from all causes, cardiovascular disease, and cancer. Multivariable proportional hazards regression models were adjusted for age, sex, sociodemographics, and changes in medical history, overall diet quality, body mass index, blood pressure, triglycerides, and cholesterol levels. RESULTS: During 171 277 person years of follow-up, 3148 deaths occurred. Long term increases in PAEE were inversely associated with mortality, independent of baseline PAEE. For each 1 kJ/kg/day per year increase in PAEE (equivalent to a trajectory of being inactive at baseline and gradually, over five years, meeting the World Health Organization minimum physical activity guidelines of 150 minutes/week of moderate-intensity physical activity), hazard ratios were: 0.76 (95% confidence interval 0.71 to 0.82) for all cause mortality, 0.71 (0.62 to 0.82) for cardiovascular disease mortality, and 0.89 (0.79 to 0.99) for cancer mortality, adjusted for baseline PAEE, and established risk factors. Similar results were observed when analyses were stratified by medical history of cardiovascular disease and cancer. Joint analyses with baseline and trajectories of physical activity show that, compared with consistently inactive individuals, those with increasing physical activity trajectories over time experienced lower risks of mortality from all causes, with hazard ratios of 0.76 (0.65 to 0.88), 0.62 (0.53 to 0.72), and 0.58 (0.43 to 0.78) at low, medium, and high baseline physical activity, respectively. At the population level, meeting and maintaining at least the minimum physical activity recommendations would potentially prevent 46% of deaths associated with physical inactivity. CONCLUSIONS: Middle aged and older adults, including those with cardiovascular disease and cancer, can gain substantial longevity benefits by becoming more physically active, irrespective of past physical activity levels and established risk factors. Considerable population health impacts can be attained with consistent engagement in physical activity during mid to late life.The EPIC-Norfolk study is supported by programme grants from the Medical Research CouncilandCancer Research UKwith additional support from the Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and the Wellcome Trust. Alexander Mok was supported by the National Science Scholarship from Singapore, A*STAR (Agency for Science, Technology and Research).The work of Nick Wareham and Soren Brage was funded by the Medical Research Council UK [MC_UU_12015/1 and MC_UU_12015/3].The funders had no role in the study design; the collection, analysis, and interpretation of data; the writing of the manuscript; or the decision to submit the article for publication

Evidence of Neurotoxicity of Ecstasy: Sustained Effects on Electroencephalographic Activity in Polydrug Users

According to previous EEG reports of indicative disturbances in Alpha and Beta activities, a systematic search for distinct EEG abnormalities in a broader population of Ecstasy users may especially corroborate the presumed specific neurotoxicity of Ecstasy in humans.105 poly-drug consumers with former Ecstasy use and 41 persons with comparable drug history without Ecstasy use, and 11 drug naives were investigated for EEG features. Conventional EEG derivations of 19 electrodes according to the 10-20-system were conducted. Besides standard EEG bands, quantitative EEG analyses of 1-Hz-subdivided power ranges of Alpha, Theta and Beta bands have been considered.Ecstasy users with medium and high cumulative Ecstasy doses revealed an increase in Theta and lower Alpha activities, significant increases in Beta activities, and a reduction of background activity. Ecstasy users with low cumulative Ecstasy doses showed a significant Alpha activity at 11 Hz. Interestingly, the spectral power of low frequencies in medium and high Ecstasy users was already significantly increased in the early phase of EEG recording. Statistical analyses suggested the main effect of Ecstasy to EEG results.Our data from a major sample of Ecstasy users support previous data revealing alterations of EEG frequency spectrum due rather to neurotoxic effects of Ecstasy on serotonergic systems in more detail. Accordingly, our data may be in line with the observation of attentional and memory impairments in Ecstasy users with moderate to high misuse. Despite the methodological problem of polydrug use also in our approach, our EEG results may be indicative of the neuropathophysiological background of the reported memory and attentional deficits in Ecstasy abusers. Overall, our findings may suggest the usefulness of EEG in diagnostic approaches in assessing neurotoxic sequela of this common drug abuse

Probing Evidence of Cerebral White Matter Microstructural Disruptions in Ischemic Heart Disease Before and Following Cardiac Rehabilitation: A Diffusion Tensor MR Imaging Study.

BACKGROUND: Ischemic heart disease (IHD) is linked to brain white matter (WM) breakdown but how age or disease effects WM integrity, and whether it is reversible using cardiac rehabilitation (CR), remains unclear. PURPOSE: To assess the effects of brain aging, cardiovascular disease, and CR on WM microstructure in brains of IHD patients following a cardiac event. STUDY TYPE: Retrospective. POPULATION: Thirty-five IHD patients (9 females; mean age = 59 ± 8 years), 21 age-matched healthy controls (10 females; mean age = 59 ± 8 years), and 25 younger controls (14 females; mean age = 26 ± 4 years). FIELD STRENGTH/SEQUENCE: 3 T diffusion-weighted imaging with single-shot echo planar imaging acquired at 3 months and 9 months post-cardiac event. ASSESSMENT: Tract-based spatial statistics (TBSS) and tractometry were used to compare fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in cerebral WM between: 1) older and younger controls to distinguish age-related from disease-related WM changes; 2) IHD patients at baseline (pre-CR) and age-matched controls to investigate if cardiovascular disease exacerbates age-related WM changes; and 3) IHD patients pre-CR and post-CR to investigate the neuroplastic effect of CR on WM microstructure. STATISTICAL TESTS: Two-sample unpaired t-test (age: older vs. younger controls; IHD: IHD pre-CR vs. age-matched controls). One-sample paired t-test (CR: IHD pre- vs. post-CR). Statistical threshold: P \u3c 0.05 (FWE-corrected). RESULTS: TBSS and tractometry revealed widespread WM changes in older controls compared to younger controls while WM clusters of decreased FA in the fornix and increased MD in body of corpus callosum were observed in IHD patients pre-CR compared to age-matched controls. Robust WM improvements (increased FA, increased AD) were observed in IHD patients post-CR. DATA CONCLUSION: In IHD, both brain aging and cardiovascular disease may contribute to WM disruptions. IHD-related WM disruptions may be favorably modified by CR. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2

Vitamin B12 Deficiency and Hyperhomocysteinemia in Outpatients with Stroke or Transient Ischemic Attack: a cohort study at an academic medical centre

Objective We sought to assess the current magnitude of the opportunity for secondary stroke prevention with B vitamins. Design A cohort study. Setting The Urgent TIA (Transient Ischaemic Attack) Clinic at an academic medical centre. Main outcome measures We assessed the prevalence of biochemical vitamin B 12 deficiency (B 12 Def, serum B 12 \u3c156 pmol/L), hyperhomocysteinaemia (HHcy; plasma total homocysteine [tHcy] \u3e14 μmol/L) and metabolic B 12 deficiency (MetB 12 Def, serum B 12 \u3c258 pmol/L and HHcy) between 2002 and 2017, by age group and by stroke subtype. Results Data were available in 4055 patients. B 12 Def was present in 8.2% of patients overall; it declined from 10.9% of patients referred before 2009 to 5.4% thereafter (p=0.0001). MetB 12 Def was present in 10.6% of patients, and HHcy was present in 19.1% of patients. Among the patients aged ≥80 years, MetB 12 Def was present in 18.1% and HHcy in 35%. Among the 3410 patients whose stroke subtype was determined, HHcy was present in 18.4% of patients: 23.3% of large artery atherosclerosis, 18.1% of cardioembolic, 16.3% of small vessel disease, 10.8% of other unusual aetiologies and 13.6% of undetermined subtypes (p=0.0001). Conclusions Despite a decline in our referral area since 2009, B 12 Def, MetB 12 Def and HHcy remain common in patients with stroke/TIA. Because these conditions are easily treated and have serious consequences, all patients with stroke/TIA should have their serum B 12 and tHcy measured

Clinical outcome after first and recurrent hemorrhage in patients with untreated brain arteriovenous malformation

Background and Purpose: The morbidity from spontaneous hemorrhage of untreated brain arteriovenous malformations(AVM) is not well described.Methods: The 241 consecutive AVM patients (mean age 3716 years, 52% women) from the prospective ColumbiaAVM Databank initially presenting with hemorrhage were evaluated using the Rankin Scale (RS) and the NationalInstitute of Health Stroke Scale (NIHSS). From the 241 AVM patients, 29 (12%) had subsequent intracranialhemorrhage during follow-up. For further comparisons, 84 non-AVM patients with intracerebral hemorrhage from theNorthern Manhattan Study (NOMAS) served as a control group.Results: In 241 AVM patients presenting with hemorrhage the median RS was 2 and the median NIHSS was 1 (49% RS0 to 1, 61% NIHSS 2). The median time between hemorrhage and clinical evaluation was 11 days (mean 219 days).Recurrent AVM hemorrhage during follow-up resulted in no significant increase in morbidity (median RS 2, P0.004;median NIHSS 3, P0.322; time between hemorrhage and study evaluation: median 55 days, mean 657 days). AmongAVM-hemorrhage subtypes, parenchymatous AVM hemorrhage was associated with higher stroke morbidity (oddsratio, 2.9; 95% CI, 1.5 to 5.8 for NIHSS 2) than nonparenchymatous hemorrhages. Parenchymatous AVM hemorrhagehad a significantly better outcome (median NIHSS 1) than non-AVM related hemorrhage (median NIHSS 12;P0.0001).Conclusions: Hemorrhage, either at initial presentation or during follow-up of untreated AVM patients appears to carr

Associations with photoreceptor thickness measures in the UK Biobank.

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness

Investigation of associations between retinal microvascular parameters and albuminuria in UK Biobank: a cross-sectional case-control study.

BACKGROUND: Associations between microvascular variation and chronic kidney disease (CKD) have been reported previously. Non-invasive retinal fundus imaging enables evaluation of the microvascular network and may offer insight to systemic risk associated with CKD. METHODS: Retinal microvascular parameters (fractal dimension [FD] - a measure of the complexity of the vascular network, tortuosity, and retinal arteriolar and venular calibre) were quantified from macula-centred fundus images using the Vessel Assessment and Measurement Platform for Images of the REtina (VAMPIRE) version 3.1 (VAMPIRE group, Universities of Dundee and Edinburgh, Scotland) and assessed for associations with renal damage in a case-control study nested within the multi-centre UK Biobank cohort study. Participants were designated cases or controls based on urinary albumin to creatinine ratio (ACR) thresholds. Participants with ACR ≥ 3 mg/mmol (ACR stages A2-A3) were characterised as cases, and those with an ACR < 3 mg/mmol (ACR stage A1) were categorised as controls. Participants were matched on age, sex and ethnic background. RESULTS: Lower FD (less extensive microvascular branching) was associated with a small increase in odds of albuminuria independent of blood pressure, diabetes and other potential confounding variables (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.03-1.34 for arterioles and OR 1.24, CI 1.05-1.47 for venules). Measures of tortuosity or retinal arteriolar and venular calibre were not significantly associated with ACR. CONCLUSIONS: This study supports previously reported associations between retinal microvascular FD and other metabolic disturbances affecting the systemic vasculature. The association between retinal microvascular FD and albuminuria, independent of diabetes and blood pressure, may represent a useful indicator of systemic vascular damage associated with albuminuria

Randomized controlled trial of Vitamin D supplementation in older people to optimize bone health

Background: Vitamin D insufficiency is common in older people and may lead to increased bone resorption, bone loss, and increased falls and fractures. However, clinical trials assessing the effect of vitamin D supplementation on bone mineral density (BMD) have yielded conflicting results. Objectives This study examined the effect of vitamin D supplementation on BMD at the hip, using dual-energy X-ray absorptiometry. Methods: A total of 379 adults aged ≥70 y (48% women; mean age: 75 y) from the northeast of England were randomly allocated to 1 of 3 doses of vitamin D 3 [12,000 international units (IU), 24,000 IU, or 48,000 IU] given once a month. The primary outcome was change in BMD (δBMD) at the hip. Secondary endpoints comprised the dose effects on femoral neck BMD, falls, circulating calciotropic hormones, bone turnover markers, and adverse events. Results: The mean ± SD baseline plasma 25-hydroxyvitamin D [25(OH)D] concentration was 40.0 ± 20.1 nmol/L, which increased after 12 mo to a mean 25(OH)D of 55.9, 64.6, or 79.0 nmol/L for participants receiving a monthly dose of 12,000, 24,000, or 48,000 IU, respectively (P < 0.01 for difference). There was no between-group difference in δBMD. However, parathyroid hormone concentrations decreased in all 3 groups, with a significantly greater decrease in the 48,000-IU group compared with the 12,000-IU group (P < 0.01). There were no differences in any adverse events between groups, with 3 cases of hypercalcemia, none of nephrolithiasis, and 249 falls observed. Conclusions: There was no difference in change in BMD over 12 mo between the 3 doses of vitamin D, suggesting no effect of the intervention or a similar attenuation of the anticipated decrease in BMD over 12 mo. The treatment was safe and effective in increasing plasma 25(OH)D concentrations, with no dose-related adverse events. This trial was registered at the EU Clinical Trials Register (EudraCT 2011-004890-10) and the ISRCTN Registry (ISRCTN35648481)

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition