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Cerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g., blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g., the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipeline's generalisability across datasets. Our method provided subject-level detection accuracy > 80% on all the datasets (within-dataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities. [ABSTRACT FROM AUTHOR]

Ischaemic heart disease and stroke are the leading causes of death worldwide at 119 per 100,000 and 85 per 100,000 population. For the USA, heart disease is leading cause of death at 165 per 100,000 population. In developed countries, strokes and acute myocardial infarction in the general population have fallen from smoking reduction, lifestyle modifications and therapeutic interventions including statins. In a population-based stroke study in the UK involving primary care practices, of in-hospital strokes 90% were ischaemic, and 37% occurred within 1 week of an operation. Approximately 50% of the patients were not on a statin. In the UK, there is a national screening initiative for the prevention of atherosclerotic cardiovascular disease (ASCVD) offered to people aged 40-74 yr old. The QRISK3 tool calculates the risk of developing heart disease or stroke over 10 yr, from which recommendations are made on interventions for the prevention of ASCVD up to age 84 yr, with similar screening and assessment tools in Europe and the US. If the QRISK3 score tool for calculating cardiovascular risk is considered sufficiently robust for population screening in primary care, should anaesthetists not use the same screening for secondary care? We present a case for statin use over the perioperative period, to reduce early vascular adverse events based on statins' early pleiotropic actions, using the primary care QRISK tool for screening of ASCVD risk. [ABSTRACT FROM AUTHOR]

Background: recognition of prevalent delirium and prediction of incident delirium may be difficult at first assessment. We therefore aimed to validate a pragmatic delirium susceptibility (for any, prevalent and incident delirium) score for use in front-line clinical practice in a consecutive cohort of older acute medicine patients. Methods: consecutive patients aged ≥65 years over two 8-week periods (2010-12) were screened prospectively for delirium using the Confusion Assessment Method (CAM), and delirium was diagnosed using the DSM IV criteria. The delirium susceptibility score was the sum of weighted risk factors derived using pooled data from UK-NICE guidelines: age >80 = 2, cognitive impairment (cognitive score below cut-off/dementia) = 2, severe illness (systemic inflammatory response syndrome) = 1, infection = 1, visual impairment = 1. Score reliability was determined by the area under the receiver operating curve (AUC). Results: among 308 consecutive patients aged ≥65 years (mean age/SD = 81/8 years, 164 (54%) female), AUC was 0.78 (95% CI 0.71-0.84) for any delirium; 0.71 (0.64-0.79), for prevalent delirium; 0.81 (0.70-0.92), for incident delirium; odds ratios (ORs) for risk score 5-7 versus <2 were 17.9 (5.4-60.0), P < 0.0001 for any delirium, 8.1 (2.2-29.7), P = 0.002 for prevalent delirium, and 25.0 (3.0-208.9) P = 0.003 for incident delirium, with corresponding relative risks of 5.4, 4.7 and 13. Higher risk scores were associated with frailty markers, increased care needs and poor outcomes. Conclusions: the externally derived delirium susceptibility score reliably identified prevalent and incident delirium using clinical data routinely available at initial patient assessment and might therefore aid recognition of vulnerability in acute medical admissions early in the acute care pathway. [ABSTRACT FROM AUTHOR]

The Carotid Disease and Cardiac Surgery Consensus Meeting was convened as a multidisciplinary gathering to consider the management of patients undergoing cardiac surgery who are found to have asymptomatic carotid artery disease. There are no randomized trials concerning whether carotid interventions are of value in this situation and the natural history is unclear. Bilateral carotid artery disease (≥70% stenosis) should be regarded clinically relevant when considering hemodynamic and short-term surgical stroke risk. However, this may be because the presence of significant carotid disease is also a marker for aortic arch and intracerebral disease. A natural history study is urgently needed to determine the incidence, predictive factors, and natural history of asymptomatic carotid disease in patients undergoing contemporary cardiac surgical interventions to inform the design of any future randomized trial. [ABSTRACT FROM PUBLISHER]

The article discusses a study on the effect of daily aspirin on long-term risk of death due to colorectal cancer and other cancers in Great Britain. The study used individual patient data from all randomised trials of daily aspirin versus no aspirin with mean duration of scheduled trial treatment of 4 years or longer. It was shown that allocation to aspirin reduced death due to cancer in eight eligible trials conducted. It was also concluded that benefit increased with duration of treatment and was consistent across the different study populations.

Objective To assess the influence of general practice opening hours on health care seeking behaviour after transient ischaemic attack (TIA) and minor stroke and feasibility of clinical assessment within 24 hours of symptom onset. Design Population based prospective incidence study (Oxford vascular study). Setting Nine general practices in Oxfordshire. Participants 91 000 patients followed from 1 April 2002 to 31 March 2006. Main outcome measures Events that occurred overnight and at weekends (out of hours) and events that occurred during surgery hours. Results Among 359 patients with TIA and 434 with minor stroke, the median (interquartile range) time to call a general practitioner after an event during surgery hours was 4.0 (1.0- 45.5) hours, and 68% of patients with events during surgery hours called within 24 hours of onset of symptoms. Median (interquartile range) time to call a general practitioner after events out of hours was 24.8 (9.0-54.5) hours for patients who waited to contact their registered practice compared with 1.0 (0.3-2.6) hour in those who used an emergency general practitioner service (P<0.001). In patients with events out of hours who waited to see their own general practitioner, seeking attention within 24 hours was considerably less likely for events at weekends than weekdays (odds ratio 0.10, 95% confidence interval 0.05 to 0.21): 70% with events Monday to Friday, 33% on Sundays, and none on Saturdays. Thirteen patients who had events out of hours and did not seek emergency care had a recurrent stroke before they sought medical attention. A primary care centre open 8 am-8 pm seven days a week would have offered cover to 73 patients who waited until surgery hours to call their general practitioner, reducing median delay from 50.1 hours to 4.0 hours in that group and increasing those calling within 24 hours from 34% to 68%. Conclusions General practitioners' opening hours influence patients' healthcare seeking behaviour after TIA and minor stroke. Current opening hours can increase delay in assessment. Improved access to primary care and public education about the need for emergency care are required if the relevant targets in the national stroke strategy are to be met. [ABSTRACT FROM AUTHOR]

Objectives to measure the number of all transient ischaemic attack (TIAs) and minor strokes managed as outpatients, and hence, the need for 'TIA clinics' in comparison to current estimates of 20,000 TIAs annually in England, based on previous rates of incident-definite events. Subjects all individuals with confirmed or suspected TIA or stroke between 2002 and 2005 in a population-based study of 91,105 individuals in Oxfordshire, UK. Outcome Measures numbers, rates, and risks of recurrent stroke for incident-definite TIA, any probable or definite TIA, stroke, and all referrals of suspected TIA and stroke, stratified according to inpatient versus outpatient management. Results of 1,174 confirmed or suspected events ascertained, 729 (62.1%) were managed as outpatients and 445 (37.9%) as inpatients. Among 757 probable or definite events, 432 (57%) were managed as outpatients. Incident-definite TIAs accounted for only 18% of all referrals to outpatient services. Annual rates per 1,000 population were 2.98 (2.77-3.2) for all referrals to outpatient services and 1.88 (1.71-2.06) for inpatient admissions. Of 73 recurrent strokes within 90 days of initial TIA or stroke, 48 (65.8%) occurred in the outpatient population. Applying these rates to the population of England yields approximately 150,000 new referrals annually to TIA clinics with about 10,000 early recurrent strokes. Conclusion more patients with TIA or stroke are managed as outpatients than inpatients in the UK, and this group has the majority of possibly preventable early recurrent strokes. Current projections of need for TIA clinics in England substantially underestimate the overall requirement for outpatient services. [ABSTRACT FROM AUTHOR]

The article considers the proposed Single Fund to be set up by the United Kingdom Medical Research Council and the National Health Service Research & Development program to administer government-funded medical research. The article calls for the fund to not neglect the practice-oriented clinical research in favor of the more glamorous laboratory-based research. Laboratory developments that are lauded as break-throughs often have little practical application, while clinical research has the benefit or originating in a practical setting.

Objectives To determine if risk of multiple sclerosis (MS) is associated with month of birth in countries in the northern hemisphere and if factors related to month of birth interact with genetic risk. Design Population based study with population and family based controls and a retrospective cohort identified from death certificates. A post hoc pooled analysis was carried out for large northern datasets including Sweden and Denmark. Setting 19 MS clinics in major cities across Canada (Canadian collaborative project on the genetic susceptibility to multiple sclerosis); incident cases of MS from a population based study in the Lothian and Border regions of Scotland; and death records from the UK Registrar General. Populations 17 874 Canadian patients and 11 502 British patients with multiple sclerosis. Main outcome measure Diagnosis of multiple sclerosis. Results In Canada (n = 17 874) significantly fewer patients with MS were born in November compared with controls from the population census and unaffected siblings. These observations were confirmed in a dataset of British patients (n = 11 502), in which there was also an increase in the number of births in May. A pooled analysis of datasets from Canada, Great Britain, Denmark, and Sweden (n = 42 045) showed that significantly fewer (8.5%) people with MS were born in November and significantly more (9.1%) were born in May. For recent incident data, the effect of month of birth was most evident in Scotland, where MS prevalence is the highest. Conclusions Month of birth and risk of MS are associated, more so in familial cases, implying interactions between genes and environment that are related to climate. Such interactions may act during gestation or shortly after birth in individuals born in the northern countries studied. [ABSTRACT FROM AUTHOR]

The author reflects on the clinical research in Great Britain and its impact to neurologist. He cites the issue on the journal "Practical Neurology" regarding the importance of high quality clinical research on transient epileptic amnesia and cerebral vasoconstriction syndrome. He also mentions several issues on Great Britain's clinical research which affect neurologists including the poor research funding and the decrease of the number of academic clinicians in Great Britain.

Objectives To assess timeliness of carotid endarterectomy services in the United Kingdom. Design Observational study with follow-up to March 2008. Setting UK hospitals performing carotid endarterectomy. Participants UK surgeons undertaking carotid endarterectomy from December 2005 to December 2007. Main outcome measures Provision and speed of delivery of appropriate assessments of patients; carotid endarterectomy and operative mortality; 30 day postoperative mortality. Results 240 (61% of those eligible) consultant surgeons took part from 102 (76%) hospitals and trusts. Of 9913 carotid endarterectomies recorded on hospital episode statistics, 5513 (56%) were included. Of the patients who underwent endarterectomy, 83% had a history of transient ischaemic attack or stroke. Of these recently symptomatic patients, 20% had their operation within two weeks of onset of symptoms, and 30% waited more than 12 weeks. Operative mortality was 0.5% during the inpatient stay and 1.0% (95% confidence interval 0.7% to 1.3%) by 30 days. Conclusion Only 20% of symptomatic patients had surgery within the two week target time set by the National Institute for Health and Clinical Excellence (NICE). Although operative mortality rates are comparable with those in other countries, some patients might experience disabling or fatal stroke while waiting for surgery and hence not be included inoperative statistics. Major improvements in services are necessary to enable early surgery in appropriate patients in order to prevent strokes. [ABSTRACT FROM AUTHOR]

Focuses on the poor outcomes of audits of medical and surgical interventions in Great Britain. Requirements of assessments of clinical performance; Statistics involving audits across Great Britain; Complications in small centers; Use of randomised controlled trials.

Compares the use of Azathioprine and other forms of drug treatment for multiple sclerosis (MS). Evidence that Azathioprine decreases relapse rate of MS; Costs of treatments.

Background: There are few published data on the incidence and long-term outcomes of critical limb ischemia, acute limb ischemia, or acute visceral ischemia with which to inform health service planning, to monitor prevention, and to enable risk prediction.Methods and Results: In a prospective population-based study (Oxfordshire, UK; 2002-2012), we determined the incidence and outcome of all acute peripheral arterial events in a population of 92,728. Risk factors were assessed by comparison with the underlying population. A total of 510 acute events occurred in 386 patients requiring 803 interventions. Two hundred twenty-one patients (59.3%) were ≥75 years of age, and 98 (26.3%) were ≥85 years old. Two hundred thirty patients (62.3%) were independent before the event, but 270 (73.4%) were dead or dependent at the 6-month follow-up, and 328 (88.9%) were dead or dependent at 5 years. The 30-day survival was lowest for patients with acute visceral ischemia (28.2%) compared with acute limb ischemia (75.3%) and critical limb ischemia (92.6%; P<0.001). Risk factors (all P<0.001) were hypertension (age- and sex-adjusted risk ratio, 2.75; 95% confidence interval, 1.95-3.90), smoking (adjusted risk ratio, 2.14; 95% confidence interval, 1.37-3.34), and diabetes mellitus (adjusted risk ratio, 3.01; 95% confidence interval, 1.69-5.35), particularly for critical limb ischemia (adjusted risk ratio, 5.96; 95% confidence interval, 3.15-11.26). Two hundred eighty-eight patients (77.2%) had known previous cardiovascular disease, and 361 (96.8%) had vascular risk factors, but only 203 (54.4%) were on an antiplatelet and only 166 (44.5%) were on a statin. Although 260 patients (69.7%) were taking antihypertensives, 42.9% of all blood pressures recorded during the 5 years before the event were >140/90 mm Hg. Of 88 patients (23.6%) with incident cardioembolic events, 62 had known atrial fibrillation (diagnosed before the event), of whom only 14.5% were anticoagulated despite 82.3% having a CHA2DS2VASC score ≥2 without contraindications.Conclusions: The clinical burden of peripheral arterial events is substantial. Although the vast majority of patients have known vascular disease in other territories and multiple treatable risk factors, premorbid control is poor. [ABSTRACT FROM AUTHOR]

Summary Background A third of transient ischaemic attacks (TIAs) and ischaemic strokes are of undetermined cause (ie, cryptogenic), potentially undermining secondary prevention. If these events are due to occult atheroma, the risk-factor profile and coronary prognosis should resemble that of overt large artery events. If they have a cardioembolic cause, the risk of future cardioembolic events should be increased. We aimed to assess the burden, outcome, risk factors, and long-term prognosis of cryptogenic TIA and stroke. Methods In a population-based study in Oxfordshire, UK, among patients with a first TIA or ischaemic stroke from April 1, 2002, to March 31, 2014, we compared cryptogenic events versus other causative subtypes according to the TOAST classification. We compared markers of atherosclerosis (ie, risk factors, coronary and peripheral arterial disease, asymptomatic carotid stenosis, and 10-year risk of acute coronary events) and of cardioembolism (ie, risk of cardioembolic stroke, systemic emboli, and new atrial fibrillation [AF] during follow-up, and minor-risk echocardiographic abnormalities and subclinical paroxysmal AF at baseline in patients with index events between 2010 and 2014). Findings Among 2555 patients, 812 (32%) had cryptogenic events (incidence of cryptogenic stroke 0·36 per 1000 population per year, 95% CI 0·23–0·49). Death or dependency at 6 months was similar after cryptogenic stroke compared with non-cardioembolic stroke (23% vs 27% for large artery and small vessel subtypes combined; p=0·26) as was the 10-year risk of recurrence (32% vs 27%; p=0·91). However, the cryptogenic group had fewer atherosclerotic risk factors than the large artery disease (p<0·0001), small vessel disease (p=0·001), and cardioembolic (p=0·008) groups. Compared with patients with large artery events, those with cryptogenic events had less hypertension (adjusted odds ratio [OR] 0·41, 95% CI 0·30–0·56; p<0·0001), diabetes (0·62, 0·43–0·90; p=0·01), peripheral vascular disease (0·27, 0·17–0·45; p<0·0001), hypercholesterolaemia (0·53, 0·40–0·70; p<0·0001), and history of smoking (0·68, 0·51–0·92; p=0·01), and compared with small vessel and cardioembolic subtypes, they had no excess risk of asymptomatic carotid disease (adjusted OR 0·64, 95% CI 0·37–1·11; p=0·11) or acute coronary events (adjusted hazard ratio [HR] 0·76, 95% CI 0·49–1·18; p=0·22) during follow-up. Compared with large artery and small vessel subtypes combined, patients with cryptogenic events also had no excess of minor-risk echocardiographic abnormalities (cryptogenic 37% vs 45%; p=0·18) or paroxysmal AF (6% vs 10%; p=0·17) at baseline or of new AF (adjusted HR 1·23, 0·78–1·95; p=0·37) or presumed cardioembolic events (1·16, 0·62–2·17; p=0·64) during follow-up. Interpretation The clinical burden of cryptogenic TIA and stroke is substantial. Although stroke recurrence rates are comparable with other subtypes, cryptogenic events have the fewest atherosclerotic markers and no excess of cardioembolic markers. Funding Wellcome Trust, Wolfson Foundation, UK Stroke Association, British Heart Foundation, Dunhill Medical Trust, National Institute for Health Research, Medical Research Council, and the NIHR Oxford Biomedical Research Centre. [ABSTRACT FROM AUTHOR]

Summary: Background: It is often assumed that blood pressure increases acutely after major stroke, resulting in so-called post-stroke hypertension. In view of evidence that the risks and benefits of blood pressure-lowering treatment in acute stroke might differ between patients with major ischaemic stroke and those with primary intracerebral haemorrhage, we compared acute-phase and premorbid blood pressure levels in these two disorders. Methods: In a population-based study in Oxfordshire, UK, we recruited all patients presenting with stroke between April 1, 2002, and March 31, 2012. We compared all acute-phase post-event blood pressure readings with premorbid readings from 10-year primary care records in all patients with acute major ischaemic stroke (National Institutes of Health Stroke Scale >3) versus those with acute intracerebral haemorrhage. Findings: Of 653 consecutive eligible patients, premorbid and acute-phase blood pressure readings were available for 636 (97%) individuals. Premorbid blood pressure (total readings 13 244) had been measured on a median of 17 separate occasions per patient (IQR 8–31). In patients with ischaemic stroke, the first acute-phase systolic blood pressure was much lower than after intracerebral haemorrhage (158·5 mm Hg [SD 30·1] vs 189·8 mm Hg [38·5], p<0·0001; for patients not on antihypertensive treatment 159·2 mm Hg [27·8] vs 193·4 mm Hg [37·4], p<0·0001), was little higher than premorbid levels (increase of 10·6 mm Hg vs 10-year mean premorbid level), and decreased only slightly during the first 24 h (mean decrease from <90 min to 24 h 13·6 mm Hg). By contrast with findings in ischaemic stroke, the mean first systolic blood pressure after intracerebral haemorrhage was substantially higher than premorbid levels (mean increase of 40·7 mm Hg, p<0·0001) and fell substantially in the first 24 h (mean decrease of 41·1 mm Hg; p=0·0007 for difference from decrease in ischaemic stroke). Mean systolic blood pressure also increased steeply in the days and weeks before intracerebral haemorrhage (regression p<0·0001) but not before ischaemic stroke. Consequently, the first acute-phase blood pressure reading after primary intracerebral haemorrhage was more likely than after ischaemic stroke to be the highest ever recorded (OR 3·4, 95% CI 2·3–5·2, p<0·0001). In patients with intracerebral haemorrhage seen within 90 min, the highest systolic blood pressure within 3 h of onset was 50 mm Hg higher, on average, than the maximum premorbid level whereas that after ischaemic stroke was 5·2 mm Hg lower (p<0·0001). Interpretation: Our findings suggest that systolic blood pressure is substantially raised compared with usual premorbid levels after intracerebral haemorrhage, whereas acute-phase systolic blood pressure after major ischaemic stroke is much closer to the accustomed long-term premorbid level, providing a potential explanation for why the risks and benefits of lowering blood pressure acutely after stroke might be expected to differ. Funding: Wellcome Trust, Wolfson Foundation, UK Medical Research Council, Stroke Association, British Heart Foundation, National Institute for Health Research. [Copyright &y& Elsevier]

Abstract: Objectives: High hospitalization rates, prolonged length of stay, and increased risks of subsequent events mean a steep increase in health care usage after stroke. No study, however, has examined to what extent increased costs after transient ischemic attack (TIA) or stroke are due to hospitalizations for the initial event, recurrent events, and/or nonvascular hospitalizations, and how costs compare with the year prior to the event. Methods: We studied patients in a population-based cohort study (Oxford Vascular Study) in the United Kingdom from 2003 to 2007. Hospitalization and cost details were obtained from patients’ individualized Hospital Episode Statistics records. Results: A total of 295 incident TIA and 439 incident stroke patients were included. For patients with stroke, average costs increased from £1437 in the year pre-event to £6629 in the year post-event (P<0.0001). Sixty-four percent (£4224) of poststroke costs were due to hospitalizations linked to the index stroke, more than 30% of which were given nonvascular primary diagnoses on Hospital Episode Statistics, and £653 (10%) were due to hospitalizations linked to subsequent vascular events. For patients with TIA, costs increased from £876 1 year before the event to £2410 in the year post-event (P<0.0001). Patients with TIA incurred nonsignificantly higher costs due to hospitalizations linked to subsequent vascular events (£774) than for hospitalizations linked to the index TIA (£720). Conclusions: Hospital costs increased after TIA or stroke, primarily because of increased initial cerebrovascular hospitalizations. The finding that costs due to nonvascular diagnoses also increased after TIA or stroke appears, in part, to be explained by the miscoding of TIA/stroke-related hospitalizations in electronic information systems. [Copyright &y& Elsevier]

Background: Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension., Methods: The TIME study is a prospective, pragmatic, decentralised, parallel-group study in the UK, that recruited adults (aged ≥18 years) with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned (1:1), without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning (0600-1000 h) or in the evening (2000-0000 h). Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke. Endpoints were identified by participant report or record linkage to National Health Service datasets and were adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention-to-treat population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641), and is now complete., Findings: Between Dec 17, 2011, and June 5, 2018, 24 610 individuals were screened and 21 104 were randomly assigned to evening (n=10 503) or morning (n=10 601) dosing groups. Mean age at study entry was 65·1 years (SD 9·3); 12 136 (57·5%) participants were men; 8968 (42·5%) were women; 19 101 (90·5%) were White; 98 (0·5%) were Black, African, Caribbean, or Black British (ethnicity was not reported by 1637 [7·8%] participants); and 2725 (13·0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5·2 years (IQR 4·9-5·7), and 529 (5·0%) of 10 503 participants assigned to evening treatment and 318 (3·0%) of 10 601 assigned to morning treatment had withdrawn from all follow-up. A primary endpoint event occurred in 362 (3·4%) participants assigned to evening treatment (0·69 events [95% CI 0·62-0·76] per 100 patient-years) and 390 (3·7%) assigned to morning treatment (0·72 events [95% CI 0·65-0·79] per 100 patient-years; unadjusted hazard ratio 0·95 [95% CI 0·83-1·10]; p=0·53). No safety concerns were identified., Interpretation: Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects., Funding: British Heart Foundation., Competing Interests: Declaration of interests ISM reports research grants from Menarini, EMA, Sanofi, HDR UK, National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA), and Innovative Medicines Initiative outside of the submitted work; institutional consultancy income from AstraZeneca outside of the submitted work; and personal income from AstraZeneca and Amgen outside of the submitted work. TMM reports grants from Menarini/Ipsen/Teijin, NIHR HTA, and MSD outside of the submitted work; personal income for consultancy from Novartis and AstraZeneca outside of the submitted work; and is a trustee of the Scottish Heart Arterial Risk Prevention (SHARP) Society. NRP reports receiving financial support from several pharmaceutical companies that manufacture blood pressure lowering agents for consulting (Servier and Aktiia), research projects and staffing (Servier and Pfizer), and for arranging and speaking at educational meetings (Servier, Sanofi, Eva Pharma, Pfizer, Emcure India, and Dr Reddy's Laboratories); he holds no stocks or shares in any of these companies. BW is supported by the NIHR University College London Hospitals Biomedical Research Centre; reports research grants from Omron, MRC, and NIHR; and reports honoraria from Daiichi Sankyo, Omron, Servier, Pfizer, Novartis, and Menarini outside of the submitted work. MJB is supported by the NIHR Barts Health Biomedical Research Centre and reports research grants from the British Heart Foundation, MRC, and NIHR. PMR declares consultancy income from Abbot and Bayer, and honoraria from Sanofi; he is also a member of the AXIOMATIC trial Data Monitoring Committee. CCL reports membership of a data safety monitoring board or steering committee for Novo Nordisk. AR reports an unpaid membership of an NIHR steering committee. AM reports a British Heart Foundation grant to his university to support salary costs. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Diagnosis of transient ischaemic attacks (TIAs) can be difficult. There is consensus on classic symptoms (eg, motor weakness, dysphasia, hemianopia, monocular visual loss) but no consensus on several monosymptomatic events with sudden-onset, non-progressive, focal negative symptoms (eg, isolated diplopia, dysarthria, vertigo, ataxia, sensory loss, and bilateral visual disturbance), with much variation in investigation and treatment., Methods: We prospectively ascertained and investigated all strokes and sudden onset transient neurological symptoms in a population of 92 728 people (no age restrictions) from Oxfordshire, UK, who sought medical attention at nine primary care practices or at the John Radcliffe Hospital, Oxford, UK (Oxford Vascular Study). Patients classified at baseline with minor ischaemic stroke (National Institutes of Health Stroke Score <5), classic TIA, or non-consensus TIA were treated according to secondary prevention guidelines. Risks of stroke (7-day, 90-day, and 10-year risks) and risks of all major vascular events (from the time of first event, and from the time of seeking medical attention) were established by face-to-face follow-up visits and were compared with the risk expected from age and sex-specific stroke incidence in the underlying study population., Findings: Between April 1, 2002, and March 31, 2018, 2878 patients were identified with minor ischaemic stroke (n=1287), classic TIA (n=1021), or non-consensus TIA (n=570). Follow-up was to Oct 1, 2018 (median 5·2 [IQR 2·6-9·2] years). 577 first recurrent strokes after the index event occurred during 17 009 person-years of follow-up. 90-day stroke risk from time of the index event after a non-consensus TIA was similar to that after classic TIA (10·6% [95% CI 7·8-12·9] vs 11·6% [95% CI 9·6-13·6]; hazard ratio 0·87, 95% CI 0·64-1·19; p=0·43), and higher than after amaurosis fugax (4·3% [95% CI 0·6-8·0]; p=0·042). However, patients with non-consensus TIA were less likely to seek medical attention on the day of the event than were those with classic TIA (336 of 570 [59%] vs 768 of 1021 [75%]; odds ratio [OR] 0·47, 95% CI 0·38-0·59; p<0·0001) and were more likely to have recurrent strokes before seeking attention (45 of 570 [8%] vs 47 of 1021 [5%]; OR 1·77, 95% CI 1·16-2·71; p=0·007). After excluding such recurrent strokes, 7-day stroke risk after seeking attention for non-consensus TIA (2·9% [95% CI 1·5-4·3]) was still considerably higher than the expected background risk (relative risk [RR] 203, 95% CI 113-334), particularly if the patient sought attention on the day of the index event (5·0% [2·1-7·9]; RR 300, 137-569). 10-year risk of all major vascular events was similar for non-consensus and classic TIAs (27·1% [95% CI 22·8-31·4] vs 30·9% [27·2-33·7]; p=0·12). Baseline prevalence of atrial fibrillation, patent foramen ovale, and arterial stenoses were also similar for non-consensus TIA and classic TIA, although stenoses in the posterior circulation were more frequent with non-consensus TIA (OR 2·21, 95% CI 1·59-3·08; p<0·0001)., Interpretation: Patients with non-consensus TIA are at high early and long-term risk of stroke and have cardiovascular pathological findings on investigation similar to those of classic TIA. Designation of non-consensus TIAs as definite cerebrovascular events will increase overall TIA diagnoses by about 50%., Funding: Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, Wolfson Foundation, Masonic Charitable Foundation, and British Heart Foundation., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Symptomatic vertebral artery (VA) stenosis has been associated with a markedly increased early risk of recurrent stroke. VA stenosis can be treated with stenting; however, there are few data from randomised controlled trials evaluating the efficacy of this treatment, and recent studies in intracranial stenosis have suggested that stenting may be associated with increased risk., Objective: The Vertebral artery Ischaemia Stenting Trial (VIST) was established to compare the risks and benefits of vertebral angioplasty and stenting with best medical treatment (BMT) alone for recently symptomatic VA stenosis., Design: VIST was a prospective, randomised, open, parallel, blinded end-point clinical trial., Setting: The trial was performed in 14 hospitals in the UK., Participants: Recruitment began on 23 October 2008 and follow-up ended on 1 March 2016, by which time every patient had been followed up for at least 1 year. Participants had to have symptomatic vertebral stenosis of at least 50% resulting from presumed atheromatous disease. Both patients and clinicians were aware of treatment allocation; however, an independent adjudication committee, masked to treatment allocation, assessed all primary and secondary end points., Interventions: Participants were randomly assigned (1 : 1) to either vertebral angioplasty/stenting plus BMT ( n  = 91) or BMT alone ( n  = 88). A total of 182 patients were initially enrolled; however, three patients (two who withdrew after randomisation and one who did not attend after the initial randomisation visit) did not contribute any follow-up data and were excluded. None of these three patients had outcome events., Main Outcomes and Measures: The primary end point was the occurrence of fatal or non-fatal stroke in any arterial territory during follow-up., Results: The median follow-up was 3.5 (interquartile range 2.1-4.7) years. Of the 61 patients who were stented, 48 (78.7%) had extracranial stenosis and 13 (21.3%) had intracranial stenosis. No perioperative complications occurred with extracranial stenting; two strokes occurred during intracranial stenting. The primary end point occurred in five patients (including one fatal stroke) in the stent group and in 12 patients (including two fatal strokes) in the medical group (giving a hazard ratio of 0.40, 95% confidence interval 0.14 to 1.13; p  = 0.08), with an absolute risk reduction of 25 strokes per 1000 person-years., Limitations: The study was underpowered because it failed to reach target recruitment. The high rate of non-confirmation of stenosis in the stented group of the trial was a second limitation., Conclusions: The trial found no difference in risk of the primary end point between the two groups., Future: Post hoc analysis suggested that stenting could be associated with a reduced recurrent stroke risk in symptomatic VA and further studies are now required to confirm these findings, particularly in extracranial VA stenosis where complication rates with stenting were confirmed to be very low., Trial Registration: Current Controlled Trials ISRCTN95212240., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 41. See the NIHR Journals Library website for further project information. In addition, funding for the pilot phase was provided by the Stroke Association., Competing Interests: Hugh S Markus is supported by a National Institute for Health Research (NIHR) Senior Investigator award and his work is supported by the Cambridge University Hospitals Trust NIHR Comprehensive Biomedical Research Centre. He reports personal fees from AstraZeneca plc (Cambridge, UK) for teaching outside the submitted work. Peter M Rothwell is supported by Wellcome Trust and NIHR Senior Investigator awards and his work is supported by the NIHR Biomedical Research Centre, Oxford, UK. He reports personal fees from Bayer AG (Leverkusen, Germany) outside the submitted work.

Background Administrative hospital diagnostic coding data are increasingly used in "big data" research and to assess complication rates after surgery or acute medical conditions. Acute stroke is a common complication of several procedures/conditions, such as carotid interventions, but data are lacking on the sensitivity of administrative coding in identifying acute stroke during inpatient stay. Methods and Results Using all acute strokes ascertained in a population-based cohort (2002-2017) as the reference, we determined the sensitivity of hospital administrative diagnostic codes ( International Classification of Diseases, Tenth Revision; ICD-10) for identifying acute strokes that occurred during hospital admission for other reasons, stratified by coding strategies, study periods, and stroke severity (National Institutes of Health Stroke Scoretrend =0.54). Sensitivity was lower during admissions for surgery/procedures than for other acute medical admissions (n/% 17/23.3% versus 49/39.2%; P=0.02). Sensitivity improved to 60.6% (53.6-67.2) for all and 61.6% (50.0-72.1) for surgery/procedures if other diagnostic positions were used, and to 65.2% (58.2-71.5) and 68.5% (56.9-78.1) respectively if combined with use of all possible nonspecific stroke-related codes (ie, adding ICD-10=I62 and I65-I68). Conclusions Low sensitivity of administrative coding in identifying acute strokes that occurred during admission does not support its use alone for audit of complication rates of procedures or hospitalization for other reasons.

Background: Risk of dementia after stroke is a major concern for patients and carers. Reliable data for risk of dementia, particularly after transient ischaemic attack or minor stroke, are scarce. We studied the risks of, and risk factors for, dementia before and after transient ischaemic attack and stroke., Methods: The Oxford Vascular Study is a prospective incidence study of all vascular events in a population of 92 728 people residing in Oxfordshire, UK. Patients with transient ischaemic attack or stroke occurring between April 1, 2002, and March 31, 2012, were ascertained with multiple methods, including assessment in a dedicated daily emergency clinic and daily review of all hospital admissions. Pre-event and post-event (incident) dementia were diagnosed at initial assessment and during 5-years' follow-up on the basis of cognitive testing supplemented by data obtained from hand searches of all hospital and primary care records. We assessed the association between post-event dementia and stroke severity (as measured with the US National Institutes of Health Stroke Scale [NIHSS] score), location (ie, dysphasia), previous events, markers of susceptibility or reserve (age, low education, pre-morbid dependency, leucoaraiosis), baseline cognition, and vascular risk factors with Cox regression models adjusted for age, sex, and education. We compared incidence and prevalence of dementia in our population with published UK population age-matched and sex-matched rates., Findings: Among 2305 patients (mean age 74·4 years [SD 13·0]), 688 (30%) had transient ischaemic attacks and 1617 (70%) had strokes. Pre-event dementia was diagnosed in 225 patients; prevalence was highest in severe stroke (ie, NIHSS >10) and lowest in transient ischaemic attack. Of 2080 patients without pre-event dementia, 1982 (95%) were followed up to the end of study or death. Post-event dementia occurred in 432 of 2080 patients during 5 years of follow-up. The incidence of post-event dementia at 1 year was 34·4% (95% CI 29·7-41·5) in patients with severe stroke (NIHSS score >10), 8·2% (6·2-10·2) in those with minor stroke (NIHSS score <3), and 5·2% (3·4-7·0) in those with transient ischaemic attack. Compared with the UK age-matched and sex-matched population, the 1-year standardised morbidity ratio for the incidence of dementia was 47·3 (95% CI 35·9-61·2), 5·8 (4·4-7·5), and 3·5 (2·5-4·8), respectively. Consequently, prevalence of dementia in 1-year survivors was brought forward by approximately 25 years in those who had severe strokes, 4 years in those who had minor strokes, and 2 years in those who had transient ischaemic attacks. 5-year risk of dementia was associated with age, event severity, previous stroke, dysphasia, baseline cognition, low education, pre-morbid dependency, leucoaraiosis, and diabetes (p<0·0001 for all comparisons, except for previous stroke [p=0·006])., Interpretation: The incidence of dementia in patients who have had a transient ischaemic attack or stroke varies substantially depending on clinical characteristics including lesion burden and susceptibility factors. Incidence of dementia is nearly 50 times higher in the year after a major stroke compared with that in the general population, but excess risk is substantially lower after transient ischaemic attack and minor stroke., Funding: Wellcome Trust, Wolfson Foundation, British Heart Foundation, National Institute for Health Research, and the National Institute for Health Research Oxford Biomedical Research Centre., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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 < .001). One hundred eighty-eight patients had a stroke within 90 days of their initial TIA or stroke, of whom 93 (49.5%) followed unheeded TIAs for which no medical attention was sought, similar before and after the FAST campaign (43 of 538 [8.0%] before vs 50 of 615 [8.1%] after, 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.

Objective: In patients with TIA and ischemic stroke, we validated the total small vessel disease (SVD) score by determining its prognostic value for recurrent stroke., Methods: Two independent prospective studies were conducted, one comprising predominantly Caucasian patients with TIA/ischemic stroke (Oxford Vascular Study [OXVASC]) and one predominantly Chinese patients with ischemic stroke (University of Hong Kong [HKU]). Cerebral MRI was performed and assessed for lacunes, microbleeds, white matter hyperintensities (WMH), and perivascular spaces (PVS). Predictive value of total SVD score for risk of recurrent stroke was determined and potential refinements considered., Results: In 2,002 patients with TIA/ischemic stroke (OXVASC n = 1,028, HKU n = 974, 6,924 patient-years follow-up), a higher score was associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio [HR] per unit increase: 1.32, 1.16-1.51, p < 0.0001; c statistic 0.61, 0.56-0.65, p < 0.0001) and intracerebral hemorrhage (ICH) (HR 1.54, 1.11-2.13, p = 0.009; c statistic 0.65, 0.54-0.76, p = 0.006). A higher score predicted recurrent stroke in SVD and non-SVD TIA/ischemic stroke subtypes ( c statistic 0.67, 0.59-0.74, p < 0.0001 and 0.60, 0.55-0.65, p < 0.0001). Including burden of microbleeds and WMH and adjusting the cutoff of basal ganglia PVS potentially improved predictive power for ICH ( c statistic 0.71, 0.60-0.81, p het = 0.45), but not for recurrent ischemic stroke ( c statistic 0.60, 0.56-0.65, p het = 0.76) on internal validation., Conclusions: The total SVD score has predictive value for recurrent stroke after TIA/ischemic stroke. Prediction of recurrence in patients with nonlacunar events highlights the potential role of SVD in wider stroke etiology., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Purpose: Development of interventions to manage patients with stroke after discharge from the hospital requires estimates of need. This study estimates the prevalence of self-reported need in community-dwelling stroke survivors across the United Kingdom., Methods: We conducted a survey of stroke survivors 1 to 5 years poststroke recruited through Medical Research Council General Practice Research Framework general practices and 2 population-based stroke registers. Levels and type of need were calculated with comparisons among sociodemographic groups, disability level, and cognitive status using the χ2 test or Fisher exact test, as appropriate., Results: From 1251 participants, response rates were 60% (national sample) and 78% (population registers sample) with few differences in levels of reported need between the 2 samples. Over half (51%) reported no unmet needs; among the remainder, the median number of unmet needs was 3 (range, 1 to 13). Proportions reporting unmet clinical needs ranged from 15% to 59%; 54% reported an unmet need for stroke information; 52% reported reduction in or loss of work activities, significantly more from black ethnic groups (P=0.006); 18% reported a loss in income and 31% an increase in expenses with differences by age, ethnic group, and deprivation score. In multivariable analysis, ethnicity (P=0.032) and disability (P=0.014) were associated with total number of unmet needs., Conclusions: Multiple long-term clinical and social needs remain unmet long after incident stroke. Higher levels of unmet need were reported by people with disabilities, from ethnic minority groups, and from those living in the most deprived areas. Development and testing of novel methods to meet unmet needs are required.

Background: Mapping disease-specific instruments into generic health outcomes or utility values is an expanding field of interest in health economics. This article constructs an algorithm to translate the modified Rankin scale (mRS) into EQ-5D utility values., Methods: mRS and EQ-5D information was derived from stroke or transient ischemic attack (TIA) patients identified as part of the Oxford Vascular study (OXVASC). Ordinary least squares (OLS) regression was used to predict UK EQ-5D tariffs from mRS scores. An alternative method, using multinomial logistic regression with a Monte Carlo simulation approach (MLogit) to predict responses to each EQ-5D question, was also explored. The performance of the models was compared according to the magnitude of their predicted-to-actual mean EQ-5D tariff difference, their mean absolute and mean squared errors (MAE and MSE), and associated 95% confidence intervals (CIs). Out-of-sample validation was carried out in a subset of coronary disease and peripheral vascular disease (PVD) patients also identified as part of OXVASC but not used in the original estimation., Results: The OLS and MLogit yielded similar MAE and MSE in the internal and external validation data sets. Both approaches also underestimated the uncertainty around the actual mean EQ-5D tariff producing tighter 95% CIs in both data sets., Conclusions: The choice of algorithm will be dependent on the study aim. Individuals outside the United Kingdom may find it more useful to use the multinomial results, which can be used with different country-specific tariff valuations. However, these algorithms should not replace prospective collection of utility data.