Showing papers by "Peter M. Rothwell published in 2018"

Analysis of shared heritability in common disorders of the brain

Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Abstract: Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.

Five-Year Risk of Stroke after TIA or Minor Ischemic Stroke.

Abstract: Background After a transient ischemic attack (TIA) or minor stroke, the long-term risk of stroke and other vascular events is not well known. In this follow-up to a report on 1-year outcomes from a registry of TIA clinics in 21 countries that enrolled 4789 patients with a TIA or minor ischemic stroke from 2009 through 2011, we examined the 5-year risk of stroke and vascular events. Methods We evaluated patients who had had a TIA or minor stroke within 7 days before enrollment in the registry. Among 61 sites that participated in the 1-year outcome study, we selected 42 sites that had follow-up data on more than 50% of their enrolled patients at 5 years. The primary outcome was a composite of stroke, acute coronary syndrome, or death from cardiovascular causes (whichever occurred first), with an emphasis on events that occurred in the second through fifth years. In calculating the cumulative incidence of the primary outcome and secondary outcomes (except death from any cause), we treated death as a competing risk. Results A total of 3847 patients were included in the 5-year follow-up study; the median percentage of patients with 5-year follow-up data per center was 92.3% (interquartile range, 83.4 to 97.8). The composite primary outcome occurred in 469 patients (estimated cumulative rate, 12.9%; 95% confidence interval [CI], 11.8 to 14.1), with 235 events (50.1%) occurring in the second through fifth years. At 5 years, strokes had occurred in 345 patients (estimated cumulative rate, 9.5%; 95% CI, 8.5 to 10.5), with 149 of these patients (43.2%) having had a stroke during the second through fifth years. Rates of death from any cause, death from cardiovascular causes, intracranial hemorrhage, and major bleeding were 10.6%, 2.7%, 1.1%, and 1.5%, respectively, at 5 years. In multivariable analyses, ipsilateral large-artery atherosclerosis, cardioembolism, and a baseline ABCD2 score for the risk of stroke (range, 0 to 7, with higher scores indicating greater risk) of 4 or more were each associated with an increased risk of subsequent stroke. Conclusions In a follow-up to a 1-year study involving patients who had a TIA or minor stroke, the rate of cardiovascular events including stroke in a selected cohort was 6.4% in the first year and 6.4% in the second through fifth years. (Funded by AstraZeneca and others.).

Blood pressure variability and risk of cardiovascular events and death in patients with hypertension and different baseline risks

Abstract: Aims Blood pressure variability is associated with increased risk of cardiovascular events, particularly in high-risk patients. We assessed if variability was associated with increased risk of cardiovascular events and death in hypertensive patients at different risk levels. Methods and results The Valsartan Antihypertensive Long-term Use Evaluation trial was a randomized controlled trial of valsartan vs. amlodipine in patients with hypertension and different risks of cardiovascular events, followed for a mean of 4.2 years. We calculated standard deviation (SD) of mean systolic blood pressure from visits from 6 months onward in patients with ≥3 visits and no events during the first 6 months. We compared the risk of cardiovascular events in the highest and lowest quintile of visit-to-visit blood pressure variability, using Cox regression. For analysis of death, variability was analysed as a continuous variable. Of 13 803 patients included, 1557 (11.3%) had a cardiovascular event and 1089 (7.9%) died. Patients in the highest quintile of SD had an increased risk of cardiovascular events [hazard ratio (HR) 2.1, 95% confidence interval (95% CI) 1.7-2.4; P < 0.0001], and a 5 mmHg increase in SD of systolic blood pressure was associated with a 10% increase in the risk of death (HR 1.10, 95% CI 1.04-1.17; P = 0.002). Associations were stronger among younger patients and patients with lower systolic blood pressure, and similar between patients with different baseline risks, except for higher risk of death among patients with established cardiovascular disease. Conclusion Higher visit-to-visit systolic blood pressure variability is associated with increased risk of cardiovascular events in patients with hypertension, irrespective of baseline risk of cardiovascular events. Associations were stronger in younger patients and in those with lower mean systolic blood pressure.

Long-Term Risk of Myocardial Infarction Compared to Recurrent Stroke After Transient Ischemic Attack and Ischemic Stroke: Systematic Review and Meta-Analysis.

Abstract: BackgroundUncertainties remain about the current risk of myocardial infarction (MI) after ischemic stroke or transient ischemic attack. Methods and ResultsWe undertook a systematic review to estima...

Prognostic Significance of Blood Pressure Variability on Beat-to-Beat Monitoring After Transient Ischemic Attack and Stroke.

Abstract: Background and Purpose—Visit-to-visit and day-to-day blood pressure (BP) variability (BPV) predict an increased risk of cardiovascular events but only reflect 1 form of BPV. Beat-to-beat BPV can be...

Prevalence of patent foramen ovale in cryptogenic transient ischaemic attack and non-disabling stroke at older ages: a population-based study, systematic review, and meta-analysis.

Abstract: Summary Background Percutaneous closure of patent foramen ovale (PFO) has been shown to be superior to medical treatment alone for prevention of recurrent stroke after cryptogenic transient ischaemic attack or non-disabling stroke in patients aged 60 years or younger. The justification for trials in older patients with transient ischaemic attack or stroke depends on whether PFO is shown to be associated with cryptogenic events at older ages, for which existing evidence is conflicting, and on the population burden of PFO-associated events. Therefore, we did a population-based screening study using contrast-enhanced transcranial Doppler (bubble-TCD) to detect probable PFO as indicated by a right-to-left shunt (RLS); we also did a systematic review and meta-analysis to compare our results with previous studies. Methods In this population-based study, nested in the Oxford Vascular Study (OXVASC), we established the prevalence of any RLS, and of large RLS (>20 microbubbles), in consecutive patients attending a rapid-access transient ischaemic attack and stroke clinic, or at 1-month follow-up after stroke unit admission, with transient ischaemic attack or non-disabling ischaemic stroke, comparing cryptogenic events with those of known cause (according to Trial of Org 10172 in Acute Stroke Treatment [TOAST] criteria). We stratified participants by age, and extrapolated data to the UK population. We also did a systematic review of published studies of PFO prevalence (using transthoracic or transoesophageal echocardiography or bubble-TCD) according to stroke subtype, which included older patients and reported age-specific results, and determined by meta-analysis (including the OXVASC data) the pooled odds ratio (95% CI) of finding PFO of any size in cryptogenic events compared with events of known cause, stratified by screening modality (transthoracic or transoesophageal echocardiography or bubble-TCD). The study protocol is registered with PROSPERO, number CRD42018087074. Findings Among 572 consecutive patients with transient ischaemic attack or non-disabling stroke between Sept 1, 2014, and Oct 9, 2017 (439 [77%] patients aged >60 years, mean age 70·0 years [SD 13·7]), bubble-TCD was feasible in 523 patients (91%) of whom 397 were aged older than 60 years. Compared with those with transient ischaemic attack or stroke of known cause, patients with cryptogenic events had a higher prevalence of RLS overall (odds ratio [OR] 1·93, 95% CI 1·32–2·82; p=0·001), and in those aged older than 60 years (2·06, 1·32–3·23; p=0·001). When we pooled the OXVASC data with that from two previous smaller studies of bubble-TCD in patients aged 50 years or older, we found an association between RLS and cryptogenic events (OR 2·35, 95% CI 1·42–3·90; p=0·0009; p heterogeneity =0·15), which was consistent with the equivalent estimate from transoesophageal echocardiography studies (2·20, 1·15–4·22; p=0·02; p heterogeneity =0·02). No data on large RLS in patients with TOAST-defined cryptogenic events compared with other events were available from previous studies, but we found no evidence that the association was diminished in such cases. Of 41 patients with large RLS and cryptogenic transient ischaemic attack or non-disabling stroke in our study, 25 (61%) were aged older than 60 years, which extrapolates to 5951 patients per year in the UK (data from mid-2016). Interpretation Bubble-TCD was feasible in most older patients with transient ischaemic attack or non-disabling stroke, the association of RLS with cryptogenic events remained at older ages, and the population burden of PFO-associated events is substantial. Randomised trials of PFO closure at older ages are required and should be feasible. Funding National Institute for Health Research, Oxford Biomedical Research Centre, Wellcome Trust, and Wolfson Foundation.

Ordinal vs dichotomous analyses of modified Rankin Scale, 5-year outcome, and cost of stroke.

Abstract: Objective To compare how 3 common representations (ordinal vs dichotomized as 0–1/2–6 or 0–2/3–6) of the modified Rankin Scale (mRS)—a commonly used trial outcome measure—relate to long-term outcomes, and quantify trial ineligibility rates based on premorbid mRS. Methods In consecutive patients with ischemic stroke in a population-based, prospective, cohort study (Oxford Vascular Study; 2002–2014), we related 3-month mRS to 1-year and 5-year disability and death (logistic regressions), and health/social care costs (generalized linear model), adjusted for age/sex, and compared goodness-of-fit values (C statistic, mean absolute error). We also calculated the proportion of patients in whom premorbid mRS score >1 or >2 would result in exclusion from trials using dichotomous analysis. Results Among 1,607 patients, the ordinal mRS was more strongly related to 5-year mortality than both the 0–1/2–6 and 0–2/3–6 dichotomies (all p 2 and 434 (30.5%) had mRS score >1; both proportions increased with female sex, socioeconomic deprivation, and age (all p Conclusion The ordinal form of the 3-month mRS relates better to long-term outcomes and costs in survivors of ischemic stroke than either dichotomy. This finding favors using ordinal approaches in trials analyzing the mRS. Exclusion of patients with higher premorbid disability by use of dichotomous primary outcomes will also result in unrepresentative samples.

Long-Term Consequences of Worsened Poststroke Status in Patients With Premorbid Disability.

Abstract: Background and Purpose— Patients with premorbid disability, generally defined as modified Rankin Scale (mRS) score ≥2, are often excluded from trials of acute stroke therapies. However, increased d...

Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack

Abstract: Background and Purpose— A variant in the histone deacetylase 9 ( HDAC9 ) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate. Methods— Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression. Results— A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P =0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3–0.7; P =0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29–0.77; P =0.003). Conclusions— These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke.

Factors contributing to sex differences in functional outcomes and participation after stroke.

Abstract: Objective To examine factors contributing to the sex differences in functional outcomes and participation restriction after stroke. Methods Individual participant data on long-term functional outcome or participation restriction (i.e., handicap) were obtained from 11 stroke incidence studies (1993–2014). Multivariable log-binomial regression was used to estimate the female:male relative risk (RR) of poor functional outcome (modified Rankin Scale score >2 or Barthel Index score Results In unadjusted analyses, women experienced worse functional outcomes after stroke than men (1 year: pooled RR unadjusted 1.32, 95% confidence interval [CI] 1.18–1.48; 5 years: RR unadjusted 1.31, 95% CI 1.16–1.47). However, this difference was greatly attenuated after adjustment for age, prestroke dependency, and stroke severity (1 year: RR adjusted 1.08, 95% CI 0.97–1.20; 5 years: RR adjusted 1.05, 95% CI 0.94–1.18). Women also had greater participation restriction than men (pooled MD unadjusted −5.55, 95% CI −8.47 to −2.63), but this difference was again attenuated after adjustment for the aforementioned factors (MD adjusted −2.48, 95% CI −4.99 to 0.03). Conclusions Worse outcomes after stroke among women were explained mostly by age, stroke severity, and prestroke dependency, suggesting these potential targets to improve the outcomes after stroke in women.

Early time course of major bleeding on antiplatelet therapy after TIA or ischemic stroke.

Abstract: Objective: To study the early time course of major bleeding and its subtypes in patients with cerebral ischemia on dual and single antiplatelet therapy. Methods: We performed a post hoc analysis on individual patient data from 6 randomized clinical trials (Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events [CAPRIE], Second European Stroke Prevention Study [ESPS-2], Management of Atherothrombosis With Clopidogrel in High Risk Patients [MATCH], Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA], European/Australasian Stroke Prevention in Reversible Ischaemia Trial [ESPRIT], and Prevention Regimen for Effectively Avoiding Second Strokes [PRoFESS]) including 45,195 patients with a TIA or noncardioembolic ischemic stroke. We studied incidence rates of bleeding per antiplatelet regimen stratified by time from randomization (≤30, 31–90, 91–180, 181–365, >365 days). We calculated incidence rates per trial and pooled estimates with random-effects meta-analysis. We performed Poisson regression to assess differences between time periods with adjustment for age and sex. Results: The incidence of major bleeding on aspirin plus clopidogrel and aspirin plus -dipyridamole was highest in the first 30 days, 5.8 and 4.9 per 100 person-years, respectively, and was significantly higher than at 31 to 90 days (rate ratio 1.98, 95% confidence interval 1.16–3.40 for aspirin plus clopidogrel; rate ratio 1.94, 95% confidence interval 1.24–3.03 for aspirin plus dipyridamole). Incidence rates on aspirin and clopidogrel monotherapy were 2.8 and 2.5 per 100 person-years, respectively, in the first 30 days, with no significant change over time. The time course was similar for gastrointestinal bleeds. There was no early excess of intracranial hemorrhage in patients on either dual or single antiplatelet therapy. Conclusion: Dual antiplatelet therapy is associated with high early risks of major and gastrointestinal bleeding that decline after the first month in trial cohorts.

Age-Specific Associations of Renal Impairment With Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease in Transient Ischemic Attack and Stroke

Abstract: Background and Purpose— It has been hypothesized that cerebral small vessel disease (SVD) and chronic renal impairment may be part of a multisystem small-vessel disorder, but their association may simply be as a result of shared risk factors (eg, hypertension) rather than to a systemic susceptibility to premature SVD. However, most previous studies were hospital based, most had inadequate adjustment for hypertension, many were confined to patients with lacunar stroke, and none stratified by age. Methods— In a population-based study of transient ischemic attack and ischemic stroke (OXVASC [Oxford Vascular Study]), we evaluated the magnetic resonance imaging markers of cerebral SVD, including lacunes, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular space. We studied the age-specific associations of renal impairment (estimated glomerular filtration rate 2 ) and total SVD burden (total SVD score) adjusting for age, sex, vascular risk factors, and premorbid blood pressure (mean blood pressure during 15 years preevent). Results— Of 1080 consecutive patients, 1028 (95.2%) had complete magnetic resonance imaging protocol and creatinine measured at baseline. Renal impairment was associated with total SVD score (odds ratio [OR], 2.16; 95% confidence interval [CI], 1.69–2.75; P P =0.002; 60–79 years: OR, 1.01; 95% CI, 0.72–1.41; P =0.963; ≥80 years: OR, 0.95; 95% CI, 0.59–1.54; P =0.832). The overall association of renal impairment and total SVD score was also attenuated after adjustment for age, sex, history of hypertension, diabetes mellitus, and premorbid average systolic blood pressure (adjusted OR, 0.76; 95% CI, 0.56–1.02; P =0.067), but the independent association of renal impairment and total SVD score at age P =0.018). Associations of renal impairment and SVD were consistent for each SVD marker at age P =0.013) and moderate–severe periventricular white matter hyperintensities (OR, 6.28; 95% CI, 1.54–25.63; P =0.010). Conclusions— The association of renal impairment and cerebral SVD was attenuated with adjustment for shared risk factors at older ages, but remained at younger ages, consistent with a shared susceptibility to premature disease.

Medical Attention Seeking After Transient Ischemic Attack and Minor Stroke Before and After the UK Face, Arm, Speech, Time (FAST) Public Education Campaign: Results From the Oxford Vascular Study.

Abstract: Importance Risk of major stroke is high during the hours and days after transient ischemic attack (TIA) and minor stroke but is substantially reduced by urgent medical treatment. Public education campaigns have improved the response after major stroke, but their association with behavior after TIA and minor stroke is uncertain. The number of potentially preventable early recurrent strokes in patients who delay or fail to seek medical attention is unknown. Objective To investigate the association of public education with delays and failure in seeking medical attention after TIA and minor stroke. Design, Setting, and Participants Prospective population-based study of all patients with TIA or stroke who sought medical attention between April 1, 2002, and March 31, 2014, registered at 9 general practices in Oxfordshire, United Kingdom. Data analysis took place from July 1, 2013, to March 2, 2015. Exposures Face, Arm, Speech, Time (FAST) public education campaign in the United Kingdom. Main Outcomes and Measures Number of early recurrent strokes in patients who delayed or failed to seek medical attention, as well as the odds of seeking urgent attention after TIA and minor stroke before vs after initiation of the public education campaign. Results Among 2243 consecutive patients with first TIA or stroke (mean [SD] age, 73.6 [13.4] years; 1126 [50.2%] female; 96.3% of white race/ethnicity), 1656 (73.8%) had a minor stroke or TIA. After the FAST campaign, patients with major stroke more often sought medical attention within 3 hours (odds ratio [OR], 2.56; 95% CI, 1.11-5.90; P = .03). For TIA and minor stroke, there was no improvement in use of emergency medical services (OR, 0.79; 95% CI, 0.50-1.23; P for interaction = .03 vs major stroke) or time to first seeking medical attention within 24 hours (OR, 0.75; 95% CI, 0.48-1.19; P for interaction = .006 vs major stroke). Patient perception of symptoms after TIA and minor stroke was associated with more urgent behavior, but correct perception declined after the FAST campaign (from 37.3% [289 of 774] to 27.6% [178 of 645]; OR, 0.64; 95% CI, 0.51-0.80; P P = .93). Conclusions and Relevance This study suggests that in contrast to major stroke, extensive FAST-based public education has not improved the response to TIA and minor stroke in the United Kingdom, emphasizing the need for campaigns that are tailored to transient and less severe symptoms.

Antiplatelet Treatment After Transient Ischemic Attack and Ischemic Stroke in Patients With Cerebral Microbleeds in 2 Large Cohorts and an Updated Systematic Review

Abstract: Background and Purpose— In patients with transient ischemic attack/ischemic stroke, microbleed burden predicts intracerebral hemorrhage (ICH), and ischemic stroke, but implications for antiplatelet treatment are uncertain. Previous cohort studies have had insufficient follow-up to assess the time course of risks, have not stratified risks by antithrombotic use, and have not reported extracranial bleeds or functional outcome of ICH versus ischemic stroke. Methods— In 2 independent prospective cohorts with transient ischemic attack/ischemic stroke (Oxford Vascular Study/mainly white; University of Hong Kong/mainly Chinese), antiplatelet treatment was started routinely irrespective of microbleed burden. Risks, time course and outcome of ICH, extracranial bleeds, and recurrent ischemic events were determined and stratified by microbleed burden (0 versus 1, 2–4, and ≥5), adjusting for age, sex, and vascular risk factors. Results— Microbleeds were more frequent in the Chinese cohort (450 of 1003 versus 165 of 1080; P P trend =0.87), but the 5-year risk of ICH was steeply related ( P trend P trend =0.013), such that risk of ischemic stroke and coronary events exceeded ICH and major extracranial bleeds during the first year, even among patients with ≥5 microbleeds (11.6% versus 3.9%). However, this ratio changed over time, with risk of hemorrhage (11.2%) matching that of ischemic events (12.0%) after 1 year. Moreover, whereas the association between microbleed burden and risk of ischemic stroke was due mainly to nondisabling events ( P trend =0.007), the association with ICH was accounted for ( P trend P =0.035). Conclusions— In white and Chinese patients with ≥5 microbleeds, withholding antiplatelet drugs during the first year after transient ischemic attack/ischemic stroke may be inappropriate. However, the risk of ICH may outweigh any benefit thereafter.

Long-Term Premorbid Blood Pressure and Cerebral Small Vessel Disease Burden on Imaging in Transient Ischemic Attack and Ischemic Stroke.

Abstract: Background and Purpose— Studies of causes of cerebral small vessel disease (SVD) should fully adjust for blood pressure (BP), but most etiological studies use a single BP measurement or history of

Age and sex-specific associations of carotid pulsatility with small vessel disease burden in transient ischemic attack and ischemic stroke.

Abstract: BackgroundAlthough large artery stiffness has been implicated in the pathogenesis of cerebral small vessel disease, whether carotid pulsatility, a convenient surrogate marker of arterial stiffness,...

Automated lesion segmentation with BIANCA: impact of population-level features, classification algorithm and locally adaptive thresholding

Abstract: White matter hyperintensities (WMH) or white matter lesions exhibit high variability in their characteristics both at population- and subject-level, making their detection a challenging task. Population-level factors such as age, vascular risk factors and neurodegenerative diseases affect lesion load and spatial distribution. At the individual level, WMH vary in contrast, amount and distribution in different white matter regions. In this work, we aimed to improve BIANCA, the FSL tool for WMH segmentation, in order to better deal with these sources of variability. We worked on two stages of BIANCA by improving the lesion probability map estimation (classification stage) and making the lesion probability map thresholding stage automated and adaptive to local lesion probabilities. Firstly, in order to take into account the effect of population-level factors, we included population-level lesion probabilities, modelled with respect to a parametric factor (e.g. age), in the classification stage. Secondly, we tested BIANCA performance when using four alternative classifiers commonly used in the literature, with respect to K-nearest neighbour algorithm currently used for lesion probability map estimation in BIANCA. Finally, we propose LOCally Adaptive Threshold Estimation (LOCATE), a supervised method for determining optimal local thresholds to apply to the estimated lesion probability map, as an alternative option to global thresholding (i.e. applying the same threshold to the entire lesion probability map). For these experiments we used data from a neurodegenerative cohort and a vascular cohort. We observed that including population-level parametric lesion probabilities with respect to age and using alternative machine learning techniques provided negligible improvement. However, LOCATE provided a substantial improvement in the lesion segmentation performance when compared to the global thresholding currently used in BIANCA. We further validated LOCATE on a cohort of CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, a genetic form of cerebral small vessel disease characterised by extensive WMH burden, and healthy controls showing that LOCATE adapts well to wide variations in lesion load and spatial distribution.

Late functional improvement after lacunar stroke: a population-based study

Abstract: Background Recovery in function after stroke involves neuroplasticity and adaptation to impairments. Few studies have examined differences in late functional improvement beyond 3 months among stroke subtypes, although interventions for late restorative therapies are often studied in lacunar stroke. Therefore, we compared rates of functional improvement beyond 3 months in patients with lacunar versus non-lacunar strokes. Methods In a prospective, population-based cohort of 3-month ischaemic stroke survivors (Oxford Vascular Study; 2002–2014), we examined changes in functional status (modified Rankin Scale (mRS), Rivermead Mobility Index (RMI), Barthel Index (BI)) in patients with lacunar versus non-lacunar strokes from 3 to 60 months poststroke, stratifying by age. We used logistic regression adjusted for age, sex and baseline disability to compare functional improvement (≥1 mRS grades, ≥1 RMI points and/or ≥2 BI points), particularly from 3 to 12 months. Results Among 1425 3-month survivors, 234 patients with lacunar stroke did not differ from others in 3-month outcome (adjusted OR (aOR) for 3-month mRS >2 adjusted for age/sex/National Institutes of Health Stroke Scale score/prestroke disability: 1.14, 95% CI 0.75 to 1.74, p=0.55), but were more likely to demonstrate further improvement between 3 months and 1 year (aOR (mRS) adjusted for age/sex/3-month mRS: 1.64, 1.17 to 2.31, p=0.004). The results were similar on restricting analyses to patients with 3-month mRS 2–4 and excluding recurrent events (aOR (mRS): 2.28, 1.34 to 3.86, p=0.002), or examining BI and RMI (aOR (RMI) adjusted for age/sex/3-month RMI: 1.78, 1.20 to 2.64, p=0.004). Conclusion Patients with lacunar strokes have significant potential for late functional improvement from 3 to 12 months, which should motivate patients and clinicians to maximise late improvements in routine practice. However, since late recovery is common, intervention studies enrolling patients with lacunar strokes should be randomised and controlled.

Long-Term Prognosis of Patients With Transient Ischemic Attack or Stroke and Symptomatic Vascular Disease in Multiple Arterial Beds

Abstract: Background and Purpose— Cerebrovascular, coronary, and peripheral vascular disease have common underlying arterial pathology and risk factors, but the clinical significance of multiple-territory di...

External validation of risk scores for major bleeding in a population-based cohort of transient ischemic attack and ischemic stroke patients

Abstract: Background and Purpose— The S2TOP-BLEED score may help to identify patients at high risk of bleeding on antiplatelet drugs after a transient ischemic attack or ischemic stroke. The score was derived on trial populations, and its performance in a real-world setting is unknown. We aimed to externally validate the S2TOP-BLEED score for major bleeding in a population-based cohort and to compare its performance with other risk scores for bleeding. Methods— We studied risk of bleeding in 2072 patients with a transient ischemic attack or ischemic stroke on antiplatelet agents in the population-based OXVASC (Oxford Vascular Study) according to 3 scores: S2TOP-BLEED, REACH, and Intracranial-B2LEED3S. Performance was assessed with C statistics and calibration plots. Results— During 8302 patient-years of follow-up, 117 patients had a major bleed. The S2TOP-BLEED score showed a C statistic of 0.69 (95% confidence interval [CI], 0.64–0.73) and accurate calibration for 3-year risk of major bleeding. The S2TOP-BLEED score was much more predictive of fatal bleeding than nonmajor bleeding (C statistics 0.77; 95% CI, 0.69–0.85 and 0.50; 95% CI, 0.44–0.58). The REACH score had a C statistic of 0.63 (95% CI, 0.58–0.69) for major bleeding and the Intracranial-B2LEED3S score a C statistic of 0.60 (95% CI, 0.51–0.70) for intracranial bleeding. The ratio of ischemic events versus bleeds decreased across risk groups of bleeding from 6.6:1 in the low-risk group to 1.8:1 in the high-risk group. Conclusions— The S2TOP-BLEED score shows modest performance in a population-based cohort of patients with a transient ischemic attack or ischemic stroke. Although bleeding risks were associated with risks of ischemic events, risk stratification may still be useful to identify a subgroup of patients at particularly high risk of bleeding, in whom preventive measures are indicated.

Time course of blood pressure control prior to lacunar TIA and stroke: Population-based study

Abstract: Objective To determine the age-specific temporal trends in blood pressure (BP) before acute lacunar vs nonlacunar TIA and stroke. Methods In a population-based study of TIA/ischemic stroke (Oxford Vascular Study), we studied 15-year premorbid BP readings from primary care records in patients with lacunar vs nonlacunar events (Trial of Org 10172 in Acute Stroke Treatment [TOAST]) stratified by age ( Results Of 2,085 patients (1,250 with stroke, 835 with TIA), 309 had lacunar events. In 493 patients p = 0.20), but mean/SD premorbid BP (44,496 BP readings) was higher in patients with lacunar events (15-year records: systolic BP [SBP] 138.5/17.7 vs 133.3/15.0 mm Hg, p = 0.004; diastolic BP [DBP] 84.1/9.6 vs 80.9/8.4 mm Hg, p = 0.001), mainly because of higher mean BP during the 5 years before the event (SBP 142.6/18.8 vs 134.6/16.6 mm Hg, p = 0.0001; DBP 85.2/9.7 vs 80.6/9.0 mm Hg, p p trend = 0.006) toward higher BP leading up to the event ( p = 0.009; DBP 87.9/9.4 vs 80.8/12.8 mm Hg, p = 0.05; mean BP ≤1 year before the event 145.8/22.0 vs 134.7/16.1 mm Hg, p = 0.001; 86.1/10.7 vs 80.4/9.8 mm Hg, p = 0.0001). Maximum BP in the 5 years before the event was also higher in patients with lacunar events (SBP 173.7/26.6 vs 158.6/23.2 mm Hg, p = 0.0001; DBP 102.3/12.9 vs 94.2/11.2 mm Hg, p 160 mm Hg, odd ratio 4.95, 95% confidence interval 1.99–12.31, p = 0.0002). However, no similar differences in BP were observed in patients ≥65 years of age. Conclusion Recent premorbid BP control is strongly temporarily related to acute lacunar events at younger ages, suggesting a direct role of BP in accelerating causal pathology and highlighting the need to control hypertension quickly.

Time course of blood pressure control prior to lacunar TIA and stroke

Abstract: Objective To determine the age-specific temporal trends in blood pressure (BP) before acute lacunar vs nonlacunar TIA and stroke. Methods In a population-based study of TIA/ischemic stroke (Oxford Vascular Study), we studied 15-year premorbid BP readings from primary care records in patients with lacunar vs nonlacunar events (Trial of Org 10172 in Acute Stroke Treatment [TOAST]) stratified by age (<65, ≥65 years). Results Of 2,085 patients (1,250 with stroke, 835 with TIA), 309 had lacunar events. In 493 patients <65 years of age, the prevalence of diagnosed hypertension did not differ between lacunar and nonlacunar events (46 [48.4%] vs 164 [41.2%], p = 0.20), but mean/SD premorbid BP (44,496 BP readings) was higher in patients with lacunar events (15-year records: systolic BP [SBP] 138.5/17.7 vs 133.3/15.0 mm Hg, p = 0.004; diastolic BP [DBP] 84.1/9.6 vs 80.9/8.4 mm Hg, p = 0.001), mainly because of higher mean BP during the 5 years before the event (SBP 142.6/18.8 vs 134.6/16.6 mm Hg, p = 0.0001; DBP 85.2/9.7 vs 80.6/9.0 mm Hg, p < 0.0001), with a rising trend (ptrend = 0.006) toward higher BP leading up to the event (<30-day pre-event SBP: 152.7/16.1 vs 135.3/23.1 mm Hg, p = 0.009; DBP 87.9/9.4 vs 80.8/12.8 mm Hg, p = 0.05; mean BP ≤1 year before the event 145.8/22.0 vs 134.7/16.1 mm Hg, p = 0.001; 86.1/10.7 vs 80.4/9.8 mm Hg, p = 0.0001). Maximum BP in the 5 years before the event was also higher in patients with lacunar events (SBP 173.7/26.6 vs 158.6/23.2 mm Hg, p = 0.0001; DBP 102.3/12.9 vs 94.2/11.2 mm Hg, p < 0.0001), as was persistently elevated BP (≥50% SBP >160 mm Hg, odd ratio 4.95, 95% confidence interval 1.99–12.31, p = 0.0002). However, no similar differences in BP were observed in patients ≥65 years of age. Conclusion Recent premorbid BP control is strongly temporarily related to acute lacunar events at younger ages, suggesting a direct role of BP in accelerating causal pathology and highlighting the need to control hypertension quickly.

Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

Abstract: Background and purpose Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin-protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multistage design of discovery and replication. Methods Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15-49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2-0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onsetage< 60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case-control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base. Results Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additivemodel adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. Conclusion PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.

Aspirin: 120 years of innovation. A report from the 2017 Scientific Conference of the International Aspirin Foundation, 14 September 2017, Charité, Berlin.

Abstract: Acetylsalicylic acid was first synthesised by Dr FeIix Hoffman on 10th August 1897 and Aspirin was born. It quickly became the best-known pain killer in the world and in the 120 years since this event, aspirin has continued to attract interest, innovation and excitement. Set within the walls of the preserved ruins of Rudolf Virchow's lecture hall at Charite, within Berlin's Museum of Medical History, the International Aspirin Foundation's 28th Scientific Conference served to facilitate international, multi-disease, multidisciplinary discussion about the current understanding of aspirin's mechanisms of action and its utility in modern medicine as well as ideas for future research into its multifaceted applications to enhance global health. In addition to the delegates in Berlin, 300 medical doctors at the 19th Annual Scientific Congress of the Chinese Society of Cardiology were able to join the cardiology sessions from Taiyuan, Shangxi province via a live streaming link to and from China. This led to useful discussion and allowed a truly international perspective to the meeting.

Douglas G Altman: statistician, researcher, and driving force behind global initiatives to improve the reliability of health research

Abstract: With the passing of Doug Altman, professor of statistics in medicine at the University of Oxford, the health research community has lost one of its most distinguished members and constructive critics. From the 1970s he conducted original research in fields ranging from neonatal growth to cancer, provided statistical expertise to countless clinical trials and journals, and served as The BMJ ’s chief statistical adviser for more than 20 years. He was also an indefatigable critic of shoddy research practices and did more than anyone else to eliminate them. He sought to drive up standards by every means at his disposal, from lucid lectures and educational papers to global initiatives and research guidelines. Doug consequently became one of the most highly cited researchers in any scientific discipline, with more than 360 000 Google Scholar citations and an h-index of 208, but more importantly, his work helped prevent the unnecessary deaths and suffering of countless patients. Anyone who knew Doug can imagine him looking down at this point, wishing the encomium would cease. Modest about his abilities and achievements (“All that citation index stuff is complete bollocks, of course”), quick to credit others, and always approachable, he was not typical of the academic establishment. Indeed, he had little time for the establishment, regarding it as complicit in the persistence of poor research. Born in London into a middle class family of Jewish descent in 1948, Doug had a largely solitary childhood. …