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1.  Association between Family Risk of Stroke and Myocardial Infarction with Prevalent Risk Factors and Coexisting Diseases 
Background
Familial transmission of stroke and myocardial infarction (MI) is partially mediated by transmission of cerebrovascular and cardiovascular risk factors. We examined relationships between family risk of stroke and MI with risk factors for these phenotypes.
Methods
Cross-sectional association between the stratified log-rank family score (SLFS) for stroke and MI with prevalent risk factors was assessed in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.
Results
Individuals in the 4th quartile of SLFS scores for stroke were more likely to have prevalent risk factors including hypertension (OR: 1.43; 95% CI: [1.30, 1.58]), left ventricular hypertrophy (OR 1.42; 95% CI: [1.16, 1.42]), diabetes (OR: 1.26; 95% CI: [1.12, 1.43]) and atrial fibrillation (OR 1.23; 95% CI: [1.03, 1.45]) compared to individuals in the 1st quartile. Likewise, individuals in the 4th quartile of SLFS scores for MI were more likely to have prevalent risk factors including hypertension (OR 1.57; 95% CI: [1.27, 1.94]) and diabetes (OR 1.29; 95% CI: [1.12, 1.43]) than the 1st quartile. In contrast to stroke, the family risk score for MI was associated with dyslipidemia (OR 1.38; 95% CI: [1.23, 1.55]) and overweight/obesity (OR 1.22; 95% CI: [1.10, 1.37]).
Conclusions
Family risk of stroke and MI are strongly associated with the majority of risk factors associated with each disease. Family history and genetic studies separating nonspecific contributions of intermediate phenotypes from specific contributions to the disease phenotype may lead to more thorough understanding of transmission for these complex disorders.
doi:10.1161/STROKEAHA.111.645044
PMCID: PMC3805250  PMID: 22328552
stroke; myocardial infarction; cohort studies; family risk; REGARDS
2.  Impact of Different Operational Definitions on Mild Cognitive Impairment Rate and MMSE and MoCA Performance in Transient Ischaemic Attack and Stroke 
Background
Mild cognitive impairment (MCI) is at least as prevalent as dementia after transient ischaemic attack (TIA)/stroke and is increasingly recognised as an important outcome in observational studies and randomised trials. However, there is no consensus on how impairment should be defined, and numerous different criteria exist. Previous studies have shown that different criteria for cognitive impairment impact on prevalence rates in epidemiological studies. However, there are few data on how operational differences within established criteria (e.g. Petersen-MCI) affect measured impairment rates and the performance of short cognitive tests such as the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), particularly in cerebrovascular disease. We therefore evaluated the effect of different operational definitions on measured rates of Petersen-MCI and on reliability of short cognitive tests in patients with TIA and stroke.
Methods
Consecutive patients underwent the MMSE, MoCA and neuropsychological battery ≥1 year after TIA or stroke in a population-based study. MCI was defined using the Petersen method and subclassified as single or multiple domain, both with (original) and without (modified) subjective memory impairment. Different cut-offs (>1, >1.5 and >2 standard deviations, SD) on a given test relative to published norms were compared together with use of single versus multiple tests to define domain impairment.
Results
91 non-demented subjects completed neuropsychological testing (mean age ± SD 69.7 ± 11.6 years, 54 male, 49 stroke) at a mean of 3.1 ± 1.9 years after the index event. Rates of cognitive impairment ranged from 14/91 (15%) for MCI-original at >2 SD cut-off to 61/91 (67%) MCI-modified at >1 SD cut-off, and the proportion of MCI that was multiple domain varied, e.g. 24/46 (52%) versus only 5/27 (20%) at 1 versus 2 SD cut-off for MCI-modified. Requirement for subjective memory complaint approximately halved estimates [e.g. 17 (19%) vs. 39 (43%) for MCI at 1.5 SD cut-off, single test definition], whereas use of multiple tests versus a single test to define a cognitive domain had less impact. In general, diagnostic accuracy was higher, and optimal cut-offs lower, on MMSE and MoCA for multiple-domain versus single-domain MCI, but the MoCA appeared superior for detecting MCI-modified, whereas the MMSE performed well in detecting MCI-original.
Conclusion
Even within established criteria for MCI, differences in operational methodology result in 4-fold variation in MCI estimates. Optimal MMSE and MoCA cut-offs are lower, and reliability more similar, when criteria for MCI are more stringent. Our findings have implications for sample size and adjusted relative risk calculations in randomised trials and for comparisons between studies.
doi:10.1159/000355496
PMCID: PMC3902763  PMID: 24217342
Mild cognitive impairment; Montreal Cognitive Assessment; Mini Mental State Examination; Transient ischaemic attack; Stroke; Vascular cognitive impairment

3.  Transient isolated brainstem symptoms preceding posterior circulation stroke: a population-based study 
Lancet Neurology  2013;12(1):65-71.
Summary
Background
Transient isolated brainstem symptoms (eg, isolated vertigo, dysarthria, diplopia) are not consistently classified as transient ischaemic attacks (TIAs) and data for prognosis are limited. If some of these transient neurological attacks (TNAs) are due to vertebrobasilar ischaemia, then they should be common during the days and weeks preceding posterior circulation strokes. We aimed to assess the frequency of TNAs before vertebrobasilar ischaemic stroke.
Methods
We studied all potential ischaemic events during the 90 days preceding an ischaemic stroke in patients ascertained within a prospective, population-based incidence study in Oxfordshire, UK (Oxford Vascular Study; 2002–2010) and compared rates of TNA preceding vertebrobasilar stroke versus carotid stroke. We classified the brainstem symptoms isolated vertigo, vertigo with non-focal symptoms, isolated double vision, transient generalised weakness, and binocular visual disturbance as TNAs in the vertebrobasilar territory; atypical amaurosis fugax and limb-shaking as TNAs in the carotid territory; and isolated slurred speech, migraine variants, transient confusion, and hemisensory tingling symptoms as TNAs in uncertain territory.
Findings
Of the 1141 patients with ischaemic stroke, vascular territory was categorisable in 1034 (91%) cases, with 275 vertebrobasilar strokes and 759 carotid strokes. Isolated brainstem TNAs were more frequent before a vertebrobasilar stroke (45 of 275 events) than before a carotid stroke (10 of 759; OR 14·7, 95% CI 7·3–29·5, p<0·0001), particularly during the preceding 2 days (22 of 252 before a vertebrobasilar stroke vs two of 751 before a carotid stroke, OR 35·8, 8·4–153·5, p<0·0001). Of all 59 TNAs preceding (median 4 days, IQR 1–30) vertebrobasilar stroke, only five (8%) fulfilled the National Institute of Neurological Disorders and Stroke (NINDS) criteria for TIA. The other 54 cases were isolated vertigo (n=23), non-NINDS binocular visual disturbance (n=9), vertigo with other non-focal symptoms (n=10), isolated slurred speech, hemisensory tingling, or diplopia (n=8), and non-focal events (n=4). Only 10 (22%) of the 45 patients with isolated brainstem TNAs sought medical attention before the stroke and a vascular cause was suspected by their physician in only one of these cases.
Interpretation
In patients with definite vertebrobasilar stroke, preceding transient isolated brainstem symptoms are common, but most symptoms do not satisfy traditional definitions of TIA. More studies of the prognosis of transient isolated brainstem symptoms are required.
Funding
Wellcome Trust, UK Medical Research Council, Dunhill Medical Trust, Stroke Association, National Institute for Health Research (NIHR), Thames Valley Primary Care Research Partnership, and the NIHR Biomedical Research Centre, Oxford.
doi:10.1016/S1474-4422(12)70299-5
PMCID: PMC3530272  PMID: 23206553
4.  Leukoaraiosis and Increased Cerebral Susceptibility to Ischemia: Lack of Confounding by Carotid Disease 
Background
Leukoaraiosis is associated with an increased risk of stroke, but the underlying mechanism remains uncertain, as do the associations with other risk factors, such as carotid disease. We aimed to determine the role of carotid disease and of other clinical variables in the development of leukoaraiosis and to define their contributions to the associated increased risk of stroke.
Methods and Results
We prospectively studied a large cohort of consecutive patients with transient ischemic attack (TIA) and minor stroke who attended a TIA clinic between 2002 and 2009. Detailed clinical data were obtained, and patients underwent magnetic resonance brain and vascular imaging. We assessed the severity of leukoaraiosis with use of the ARWMC (Age Related White Matter Changes) score: 671 patients (374 [56%] men; mean [SD] age 71 [11] years) were studied, of whom 415 (62%) had leukoaraiosis. In a multivariate analysis, leukoaraiosis was associated with increasing age (P<0.0001) and hypertension (P=0.01), as well as the presence of acute (P<0.0001) and chronic (P=0.014) infarction on magnetic resonance imaging. In the univariate analysis, a current and past diagnosis of stroke versus TIA also showed a strong association. Carotid disease was not associated with leukoaraiosis, even in the presence of a flow‐limiting (>70%) stenosis or occlusion, and the risk factor profiles for leukoaraiosis and carotid disease differed.
Conclusions
The association with more severe ischemic events (stroke versus TIA) and infarction on imaging is consistent with leukoaraiosis being a marker of increased cerebral susceptibility to ischemia. In contrast, the presence, severity of, and risk factors for atheromatous disease showed no association with leukoaraiosis, suggesting that these are two unrelated disease processes.
doi:10.1161/JAHA.113.000261
PMCID: PMC3828783  PMID: 23963757
leukoaraiosis; MRI; stroke
5.  Factors That Can Affect the External Validity of Randomised Controlled Trials 
PLoS Clinical Trials  2006;1(1):e9.
doi:10.1371/journal.pctr.0010009
PMCID: PMC1488890  PMID: 16871331
6.  Aspirin in the Chemoprevention of Colorectal Neoplasia: An Overview 
Considerable evidence supports the effectiveness of aspirin for chemoprevention of colorectal cancer (CRC) in addition to its well-established benefits in the prevention of vascular disease. Epidemiologic studies have consistently observed an inverse association between aspirin use and risk of CRC. A recent pooled analysis of a long-term post-trial follow-up of nearly 14,000 patients from 4 randomized, cardiovascular disease prevention trials showed that daily aspirin treatment for about 5 years was associated with a 34% reduction in 20-year CRC mortality. A separate meta-analysis of nearly 3,000 patients with a history of colorectal adenoma or cancer in 4 randomized adenoma prevention trials demonstrated that aspirin reduced the occurrence of advanced adenomas by 28% and any adenoma by 17%. Aspirin has also been shown to be beneficial in a clinical trial of patients with Lynch syndrome, a hereditary CRC syndrome; in those treated with aspirin for at least 2 years, there was a ≥ 50% reduction in the risk of CRC commencing 5 years after randomization and after aspirin had been discontinued. A few observational studies have shown an increase in survival among patients with CRC who use aspirin. Taken together, these findings strengthen the case for consideration of long-term aspirin use in CRC prevention. Despite these compelling data, there is a lack of consensus about the balance of risks and benefits associated with long-term aspirin use, particularly in low-risk populations. The optimal dose to use for cancer prevention and the precise mechanism underlying aspirin’s anticancer effect require further investigation.
doi:10.1158/1940-6207.CAPR-11-0391
PMCID: PMC3273592  PMID: 22084361
Aspirin; colorectal cancer; colorectal adenoma; Lynch syndrome; adjuvant chemotherapy
7.  Five years of Trials 
Trials  2011;12:248.
This editorial marks the launch of a special collection of articles highlighting 'Five years of Trials' (http://www.trialsjournal.com/series/5years). The journal's achievements on its objectives since 2006 are described and some of the challenges still ahead are outlined - in particular further innovating in the reporting of trials and the publication of negative results. The other articles in this series are examples of where Trials has demonstrated progress on its objectives. These include the publication of raw data, extended versions of previously published trial-related articles, descriptions of 'lessons learned', negative results, and educational articles regarding ethics and reporting bias.
doi:10.1186/1745-6215-12-248
PMCID: PMC3254076  PMID: 22112799
8.  Reporting of observational studies 
BMJ : British Medical Journal  2007;335(7624):783-784.
New recommendations should help researchers, journal editors, and readers
doi:10.1136/bmj.39351.581366.BE
PMCID: PMC2034700  PMID: 17947746
9.  Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal 
Trials  2010;11:85.
Mounting evidence suggests that there is frequently considerable variation in the risk of the outcome of interest in clinical trial populations. These differences in risk will often cause clinically important heterogeneity in treatment effects (HTE) across the trial population, such that the balance between treatment risks and benefits may differ substantially between large identifiable patient subgroups; the "average" benefit observed in the summary result may even be non-representative of the treatment effect for a typical patient in the trial. Conventional subgroup analyses, which examine whether specific patient characteristics modify the effects of treatment, are usually unable to detect even large variations in treatment benefit (and harm) across risk groups because they do not account for the fact that patients have multiple characteristics simultaneously that affect the likelihood of treatment benefit. Based upon recent evidence on optimal statistical approaches to assessing HTE, we propose a framework that prioritizes the analysis and reporting of multivariate risk-based HTE and suggests that other subgroup analyses should be explicitly labeled either as primary subgroup analyses (well-motivated by prior evidence and intended to produce clinically actionable results) or secondary (exploratory) subgroup analyses (performed to inform future research). A standardized and transparent approach to HTE assessment and reporting could substantially improve clinical trial utility and interpretability.
doi:10.1186/1745-6215-11-85
PMCID: PMC2928211  PMID: 20704705
10.  Transient ischaemic attacks: time to wake up 
Heart  2007;93(8):893-894.
“The risk of stroke in the week after a transient ischaemic attack or minor stroke is high and relatively predictable. Emergency investigation and treatment are justified.”
doi:10.1136/hrt.2007.121111
PMCID: PMC1994402  PMID: 17639101
transient ischaemic attacks
11.  Mitochondrial DNA haplogroups and risk of transient ischaemic attack and ischaemic stroke: a genetic association study 
Lancet Neurology  2010;9(5):498-503.
Summary
Background
Genetic factors have a role in the pathogenesis of ischaemic stroke, but the main genes involved have yet to be defined. Mitochondrial mechanisms have been implicated in the pathophysiology of acute stroke, but the role of mitochondrial DNA (mtDNA) has not been comprehensively studied. We investigated whether there is an association between mtDNA haplotypes and incidence of stroke.
Methods
The major European mtDNA haplogroups were identified in two independent subpopulations (n=950) from a study of occurrence of transient ischaemic attack (TIA) and ischaemic stroke and were compared with those of patients with acute coronary syndromes from the same populations (n=340) and with those of independent population controls (n=2939).
Findings
The presence of mtDNA sub-haplogroup K was significantly less frequent in patients with TIA or stroke than in controls in both subpopulations separately and in a pooled analysis (odds ratio 0·54, 95% CI 0·39–0·75, p<0·00001). This association remained highly significant after adjustment for multiple haplogroup comparisons. The association was significant for patients with TIA and stroke separately and was independent of known risk factors, but was not found for patients with acute coronary events. The mtDNA sub-haplogroup K was present in 8·7% of the total UK population controls and therefore confers a 4·0% (95% CI 2·2–5·7) reduction in population attributable risk of TIA and stroke.
Interpretation
Genetic variation of mtDNA sub-haplogroup K is an independent determinant of risk of cerebral, but not coronary, ischaemic vascular events. These findings implicate mitochondrial mechanisms in the aetiology of ischaemic stroke and provide a new means for the identification of individuals with a high susceptibility of developing ischaemic stroke.
Funding
Medical Research Council UK, National Institute of Health Research (NIHR), the Stroke Association, the Dunhill Medical Trust, the NIHR-funded Oxford Biomedical Research Centre, the NIHR-funded Newcastle Biomedical Research Centre in Ageing, and the Wellcome Trust.
doi:10.1016/S1474-4422(10)70083-1
PMCID: PMC2855429  PMID: 20362514
12.  Waiting times for carotid endarterectomy in UK: observational study 
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 in operative statistics. Major improvements in services are necessary to enable early surgery in appropriate patients in order to prevent strokes.
doi:10.1136/bmj.b1847
PMCID: PMC2691453  PMID: 19502220
13.  Influence of general practice opening hours on delay in seeking medical attention after transient ischaemic attack (TIA) and minor stroke: prospective population based study 
Objective To assess the influence of general practice opening hours on healthcare 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.
doi:10.1136/bmj.a1569
PMCID: PMC2548294  PMID: 18801867
14.  Vessel Wall Contrast Enhancement: A Diagnostic Sign of Cerebral Vasculitis 
Purpose
Inflammatory stenoses of cerebral arteries cause stroke in patients with florid vasculitis. However, diagnosis is often difficult even with digital subtraction angiography (DSA) and biopsy. The purpose of this study was to establish the value of contrast-enhanced MRI, proven to be sensitive to extradural arteritis, for the identification of intracranial vessel wall inflammation.
Patients and Methods
Twenty-seven patients with a diagnosis of cerebral vasculitis affecting large brain vessels were retrieved from the files: 8 children (2–10 years, 7 female, 1 male) and 19 adults (16–76 years, 10 female, 9 male). Diagnosis was based on histological or serological proof of vasculitis or on clinical and imaging criteria. All MRI examinations included diffusion-weighted imaging, time-of-flight magnetic resonance angiography (TOF-MRA) and contrast-enhanced scans. MRI scans were assessed for the presence of ischemic brain lesions, arterial stenoses, vessel wall thickening and contrast uptake.
Results
Ischemic changes of the brain tissue were seen in 24/27 patients and restricted diffusion suggestive of recent ischemia in 17/27; 25/27 patients had uni- or multifocal stenoses of intracranial arteries on TOF-MRA and 5/6 had stenoses on DSA. Vessel wall thickening was identified in 25/27, wall enhancement in 23/27 patients.
Conclusion
Wall thickening and intramural contrast uptake are frequent findings in patients with active cerebral vasculitis affecting large brain arteries. Further prospective studies are required to determine the specificity of this finding.
doi:10.1159/000135649
PMCID: PMC2813800  PMID: 18511868
Cerebral vasculitis; Vessel wall contrast enhancement; Stenosis
15.  GALA: an international multicentre randomised trial comparing general anaesthesia versus local anaesthesia for carotid surgery 
Trials  2008;9:28.
Background
Patients who have severe narrowing at or near the origin of the internal carotid artery as a result of atherosclerosis have a high risk of ischaemic stroke ipsilateral to the arterial lesion. Previous trials have shown that carotid endarterectomy improves long-term outcomes, particularly when performed soon after a prior transient ischaemic attack or mild ischaemic stroke. However, complications may occur during or soon after surgery, the most serious of which is stroke, which can be fatal. It has been suggested that performing the operation under local anaesthesia, rather than general anaesthesia, may be safer. Therefore, a prospective, randomised trial of local versus general anaesthesia for carotid endarterectomy was proposed to determine whether type of anaesthesia influences peri-operative morbidity and mortality, quality of life and longer term outcome in terms of stroke-free survival.
Methods/design
A two-arm, parallel group, multicentre randomised controlled trial with a recruitment target of 5000 patients. For entry into the study, in the opinion of the responsible clinician, the patient requiring an endarterectomy must be suitable for either local or general anaesthesia, and have no clear indication for either type. All patients with symptomatic or asymptomatic internal carotid stenosis for whom open surgery is advised are eligible. There is no upper age limit. Exclusion criteria are: no informed consent; definite preference for local or general anaesthetic by the clinician or patient; patient unlikely to be able to co-operate with awake testing during local anaesthesia; patient requiring simultaneous bilateral carotid endarterectomy; carotid endarterectomy combined with another operation such as coronary bypass surgery; and, the patient has been randomised into the trial previously. Patients are randomised to local or general anaesthesia by the central trial office. The primary outcome is the proportion of patients alive, stroke free (including retinal infarction) and without myocardial infarction 30 days post-surgery. Secondary outcomes include the proportion of patients alive and stroke free at one year; health related quality of life at 30 days; surgical adverse events, re-operation and re-admission rates; the relative cost of the two methods of anaesthesia; length of stay and intensive and high dependency bed occupancy.
Trial registration
Current Controlled Trials ISRCTN00525237
doi:10.1186/1745-6215-9-28
PMCID: PMC2413207  PMID: 18495004
16.  Underinvestigation and undertreatment of carotid disease in elderly patients with transient ischaemic attack and stroke: comparative population based study 
BMJ : British Medical Journal  2006;333(7567):525-527.
Objective To identify any underinvestigation of older patients with transient ischaemic attack (TIA) and stroke.
Design Comparative population based studies.
Setting Routine clinical practice in all secondary care services in Oxfordshire and a nested population based study of incidence of transient ischaemic attack and stroke (the Oxford vascular study—OXVASC).
Participants/population All patients undergoing carotid imaging for ischaemic retinal or cerebral transient ischaemic attack or stroke from 1 April 2002 to 31 March 2005 in the Oxford vascular study (n = 91 105) and from 1 April 2002 to 31 March 2003 in routine clinical practice (n = 589 899).
Main outcome measures Age specific rates of carotid imaging, diagnosed ≥ 50% symptomatic carotid stenosis, and subsequent endarterectomy, in patients with recent transient ischaemic attack or stroke.
Results Of patients with recent carotid territory transient ischaemic attack or ischaemic stroke, 575 in routine clinical practice and 402 in the Oxford vascular study had carotid imaging, with similar rates up to the age of 80. The incidence of ≥ 50% symptomatic stenosis increased steeply with age, particularly in those aged ≥ 80. Compared with investigations in patients in the Oxford vascular study, the rates of carotid imaging (relative rate 0.36, 95% confidence interval 0.28 to 0.46, P < 0.0001), diagnosis of ≥ 50% symptomatic stenosis (0.33, 0.16 to 0.69, P = 0.004), and carotid endarterectomy (0.19, 0.06 to 0.63, P = 0.007) in this age group in routine clinical practice were all substantially lower.
Conclusions Incidence of symptomatic carotid stenosis increases steeply with age, but, despite good evidence of major benefit from endarterectomy in elderly patients and a willingness to have surgery, there is substantial underinvestigation in routine clinical practice in patients aged ≥ 80 with transient ischaemic attack or ischaemic stroke.
doi:10.1136/bmj.38895.646898.55
PMCID: PMC1562473  PMID: 16849366
18.  Lead editorial: Trials – using the opportunities of electronic publishing to improve the reporting of randomised trials 
Trials  2006;7:6.
This editorial introduces the new online, open access, peer-reviewed journal Trials. The journal considers manuscripts on any aspect of the design, performance, and findings of randomised controlled trials in any discipline related to health care, and also encourages the publication of protocols. Trialists will be able to provide the necessary detail for a true and complete scientific record. They will be able to communicate not only all outcome measures, as well as varying analyses and interpretations, but also in-depth descriptions of what they did and honest reflections about what they learnt.
Trials also encourages articles covering generic issues related to trials, for example focussing on the design, conduct, analysis, interpretation, or reporting.
doi:10.1186/1745-6215-7-6
PMCID: PMC1449870  PMID: 16556322
19.  Timing of birth and risk of multiple sclerosis: population based study 
BMJ : British Medical Journal  2005;330(7483):120.
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.
doi:10.1136/bmj.38301.686030.63
PMCID: PMC544426  PMID: 15585537
20.  Stroke: Working toward a Prioritized World Agenda 
Background and Purpose
The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.
Methods
Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.
Results
Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent ‘silo’ mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (e.g., social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a ‘Brain Health’ concept that enables promotion of preventive measures.
Conclusions
To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress
doi:10.1111/j.1747-4949.2010.00442.x
PMCID: PMC3712839  PMID: 20636706
Prevention; Rehabilitation; Stroke; Translational; Treatment
21.  Stroke: Working Toward a Prioritized World Agenda 
Background and Purpose
The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.
Methods
Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.
Results
Recommendations of the Synergium are:
Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent “silo” mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science.
Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques.
Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks.
Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery.
Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries.
Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care.
Educate and energize professionals, patients, the public and policy makers by using a “Brain Health” concept that enables promotion of preventive measures.
Conclusions
To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.
doi:10.1161/STROKEAHA.110.586156
PMCID: PMC3712843  PMID: 20498453
prevention; rehabilitation; stroke; translational; treatment
23.  Ischemic Stroke Is Associated with the ABO Locus: The EuroCLOT Study 
Annals of Neurology  2013;73(1):16-31.
Objective
End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
Methods
Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).
Results
Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10–8) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10–186), rs10665 with FVII (p = 2.4 × 10–47), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10–57) and factor VIII (p = 1.2 × 10–36). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88–0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).
Interpretation
ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype. Ann Neurol 2013
doi:10.1002/ana.23838
PMCID: PMC3582024  PMID: 23381943
24.  Population-based study of capsular warning syndrome and prognosis after early recurrent TIA 
Neurology  2012;79(13):1356-1362.
Objective:
Many guidelines recommend emergency assessment for patients with ≥2 TIAs within 7 days, perhaps in recognition of the capsular warning syndrome. However, it is unclear whether all patients with multiple TIAs are at high early risk of stroke and whether treatable underlying pathologies are more prevalent in this group.
Methods:
We studied clinical characteristics, Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and risk of stroke in 1,000 consecutive patients with incident and recurrent TIAs in a prospective, population-based study (Oxford Vascular Study).
Results:
Of 1,000 patients with TIAs, 170 had a further TIA within 7 days (105 within 24 hours). Multiple TIAs were not associated with carotid stenosis or atrial fibrillation, and much of the 10.6 (95% confidence interval [CI] 6.5−15.9) risk of stroke during the 7 days after the first TIA was due to patients with small-vessel disease (SVD) etiology (10 of 24 vs 8 of 146, odds ratio [OR] = 12.3, 95% CI 3.7–41.9, p < 0.0001), particularly those with motor weakness (i.e., capsular warning syndrome) compared with hemisensory events (9 of 15 [60%], 95% CI 35.3–84.7 vs 1 of 9 [11.1%], 95% CI 0–31.7, p = 0.03). The 7-day risk of stroke after a recurrent TIA was similar to the risk after a single TIA in patients with non-SVD TIA (8 of 146 [5.5%] vs 76 of 830 [9.2%], OR = 0.58, 95% CI 0.25–1.3, p = 0.20). Of the 9 patients with stroke after a capsular warning syndrome, all had the recurrent TIA within 24 hours after the first TIA, and the subsequent stroke occurred within 72 hours of the second TIA in 8. The ABCD2 scores of all preceding TIAs were ≥4 in all 9 patients with capsular warning syndrome before stroke.
Conclusions:
Capsular warning syndrome is rare (1.5% of TIA presentations) but has a poor prognosis (7-day stroke risk of 60%). Otherwise, recurrent TIA within 7 days is not associated with a greater stroke risk than that after a single TIA.
doi:10.1212/WNL.0b013e31826c1af8
PMCID: PMC3448742  PMID: 22972645
25.  Age- and sex-specific rates of leukoaraiosis in TIA and stroke patients 
Neurology  2012;79(12):1215-1222.
Objective:
To determine any sex differences in age-specific prevalence or severity of leukoaraiosis, a marker of white matter ischemia, in population-based and clinic cohorts of TIA/stroke and in a systematic review of the literature.
Methods:
Age-specific sex differences were calculated for both CT and MRI in the Oxford Vascular Study (OXVASC) and in an MRI-based clinic cohort. We pooled odds ratios (ORs) for leukoaraiosis in women vs men from published studies by fixed-effect meta-analysis, stratified by patient characteristics (stroke vs nonstroke) and CT vs MRI.
Results:
Among 10 stroke studies (all CT-based), leukoaraiosis was most frequent in women (OR = 1.42, 95% confidence interval [CI] 1.27–1.57, p < 0.0001), with little heterogeneity between studies (p = 0.28). However, no such excess was seen in 10 reports of nonstroke cohorts (0.91, 0.67–1.24, p = 0.56). Moreover, excess leukoaraiosis in women on CT-imaging in OXVASC (1.38, 1.15–1.67, p = 0.001) was explained by their older age (age-adjusted OR = 1.01, 0.82–1.25, p = 0.90). Leukoaraiosis was more severe in older (≥75) women (CT-1.50, 1.14–1.97, p = 0.004 in OXVASC; MRI-1.70, 1.17–2.48, p = 0.006 in OXVASC and clinic cohort). However, leukoaraiosis was independently associated with early mortality (hazard ratio = 1.46, 1.23–1.73, p < 0.0001), suggesting that comparisons in older age groups will be biased by prior premature death of men with leukoaraiosis. Sex differences in severity of leukoaraiosis were not addressed in previous studies.
Conclusions:
Previously reported excess leukoaraiosis in women with TIA/stroke is likely to be confounded by age and apparently greater severity in older women is likely to be biased by premature death in men with leukoaraiosis.
doi:10.1212/WNL.0b013e31826b951e
PMCID: PMC3440447  PMID: 22955138

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