Peter M Rothwell

Oxford University Hospitals NHS Trust, Oxford, England, United Kingdom

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Publications (428)4025.48 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Lack of reduced cognitive impairment with blood pressure (BP) lowering in trials may reflect use of the Mini-Mental State Examination (MMSE), which is insensitive to mild cognitive impairment after cerebrovascular events compared with the Montreal Cognitive Assessment. We determined relationships between impairment on MMSE versus Montreal Cognitive Assessment (MoCA) with the major physiological determinant of vascular cognitive impairment: hypertension and hypertensive arteriopathy.
    09/2014;
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    ABSTRACT: -Prevalence of atrial fibrillation (AF) is over 10% at age ≥80 years, but the impact of population ageing on rates of AF-related ischaemic events is uncertain.
    Circulation 09/2014; · 15.20 Impact Factor
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    ABSTRACT: Risk of recurrent stroke is high in the first few weeks after transient ischemic attack or stroke and clinical risk prediction tools have only limited accuracy, particularly after the hyperacute phase. Previous studies of the predictive value of biomarkers have been small, been done in selected populations, and have not concentrated on the acute phase or on intensively treated populations. We aimed to determine the predictive value of a panel of blood biomarkers in intensively treated patients early after transient ischemic attack and stroke.
    08/2014;
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    ABSTRACT: Visit-to-visit variability in systolic blood pressure (SBP) is associated with an increased risk of stroke and was reduced in randomized trials by calcium channel blockers and diuretics but not by renin-angiotensin system inhibitors. However, time of day effects could not be determined. Day-to-day variability on home BP readings predicts stroke risk and potentially offers a practical method of monitoring response to variability-directed treatment.
    08/2014;
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    ABSTRACT: Objectives: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases. Methods: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.
    Neurology 08/2014; 83(8):678-685. · 8.25 Impact Factor
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    ABSTRACT: We investigated the incidence of stroke and stroke subtypes in a population-based cohort of patients in France treated with growth hormone (GH) for short stature in childhood.
    Neurology 08/2014; · 8.25 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5610 27), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05–1.32); meta-analysis p = 2.6610 28). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2610 215 ; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p,0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.
    PLoS Genetics 07/2014; 219201920(10). · 8.52 Impact Factor
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    ABSTRACT: Diabetes accelerates progression of atherosclerotic disease, but data on associations between diabetes and advanced atherosclerotic plaque composition are scarce.
    Atherosclerosis 06/2014; 235(2):418-423. · 3.71 Impact Factor
  • Ruth E Langley, Peter M Rothwell
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    ABSTRACT: The purpose of this review is to assess recent evidence that demonstrates that aspirin has the potential to be an effective preventive and therapeutic agent in gastrointestinal malignancy.
    Current opinion in oncology 05/2014; · 4.09 Impact Factor
  • Annals of cardiothoracic surgery. 05/2014; 3(3):278-84.
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    ABSTRACT: Although the research linking cardiovascular disorders to geomagnetic activity is accumulating, robust evidence for the impact of geomagnetic activity on stroke occurrence is limited and controversial. We used a time-stratified case-crossover study design to analyze individual participant and daily geomagnetic activity (as measured by Ap Index) data from several large population-based stroke incidence studies (with information on 11 453 patients with stroke collected during 16 031 764 person-years of observation) in New Zealand, Australia, United Kingdom, France, and Sweden conducted between 1981 and 2004. Hazard ratios and corresponding 95% confidence intervals (CIs) were calculated. Overall, geomagnetic storms (Ap Index 60+) were associated with 19% increase in the risk of stroke occurrence (95% CI, 11%-27%). The triggering effect of geomagnetic storms was most evident across the combined group of all strokes in those aged <65 years, increasing stroke risk by >50%: moderate geomagnetic storms (60-99 Ap Index) were associated with a 27% (95% CI, 8%-48%) increased risk of stroke occurrence, strong geomagnetic storms (100-149 Ap Index) with a 52% (95% CI, 19%-92%) increased risk, and severe/extreme geomagnetic storms (Ap Index 150+) with a 52% (95% CI, 19%-94%) increased risk (test for trend, P<2×10(-16)). Geomagnetic storms are associated with increased risk of stroke and should be considered along with other established risk factors. Our findings provide a framework to advance stroke prevention through future investigation of the contribution of geomagnetic factors to the risk of stroke occurrence and pathogenesis.
    Stroke 04/2014; · 6.16 Impact Factor
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    ABSTRACT: Treatment with statins reduces the rate of cardiovascular events in high-risk patients, but residual risk persists. At least part of that risk may be attributable to atherogenic dyslipidemia characterized by low high-density lipoprotein cholesterol (≤40 mg/dL) and high triglycerides (triglycerides ≥150 mg/dL). We studied subjects with stroke or transient ischemic attack in the Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM; n=19 100) and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL; n=4731) trials who were treated with a statin and who had high-density lipoprotein cholesterol and triglycerides measurements 3 months after randomization (n=10 498 and 2900, respectively). The primary outcome measure for this exploratory analysis was the occurrence of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). We also performed a time-varying analysis to account for all available high-density lipoprotein cholesterol and triglyceride measurements. A total of 10% of subjects in PERFORM and 9% in SPARCL had atherogenic dyslipidemia after ≥3 months on start statin therapy. After a follow-up of 2.3 years (PERFORM) and 4.9 years (SPARCL), a major cardiovascular event occurred in 1123 and 485 patients in the 2 trials, respectively. The risk of major cardiovascular events was higher in subjects with versus those without atherogenic dyslipidemia in both PERFORM (hazard ratio, 1.36; 95% confidence interval, 1.14-1.63) and SPARCL (hazard ratio, 1.40; 95% confidence interval, 1.06-1.85). The association was attenuated after multivariable adjustment (hazard ratio, 1.23; 95% confidence interval, 1.03-1.48 in PERFORM and hazard ratio, 1.24; 95% confidence interval, 0.93-1.65 in SPARCL). Time-varying analysis confirmed these findings. The presence of atherogenic dyslipidemia was associated with higher residual cardiovascular risk in PERFORM and SPARCL subjects with stroke or transient ischemic attack receiving statin therapy. Specific therapeutic interventions should now be trialed to address this residual risk.
    Stroke 04/2014; · 6.16 Impact Factor
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    ABSTRACT: Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.
    The American Journal of Human Genetics 04/2014; 94(4):511-21. · 11.20 Impact Factor
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    ABSTRACT: Patients with genetic background for high circulating oxidized low-density lipoprotein (oxLDL) levels might be at an increased risk of cerebrovascular disease (CVD). The association of oxLDL-variant rs676210 with CVD events was studied in patients undergoing coronary angiography (study A; N = 2913 [271 cases]). We sought to replicate the results in a large genome-wide association study meta-analysis of ischaemic stroke (study B; N = 3548 cases, 5972 controls). In study A, the prevalence of hypertension, diabetes and >50% carotid stenosis as well as the levels of LDL cholesterol differed significantly between cases and controls. In a logistic regression model adjusted for the significant covariates, rs676210 associated with CVD events (p = 0.030; odds ratio = 1.29 [95% confidence interval 1.03‒1.63] for risk allele G). In study B, rs676210 did not associate with the history of ischaemic stroke. The oxLDL levels increasing variant rs676210 associates with CVD events in patients undergoing coronary angiography.
    Atherosclerosis 03/2014; 234(1):214-217. · 3.71 Impact Factor
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    ABSTRACT: 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. 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. 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). 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. Wellcome Trust, Wolfson Foundation, UK Medical Research Council, Stroke Association, British Heart Foundation, National Institute for Health Research.
    The Lancet Neurology 02/2014; · 23.92 Impact Factor
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    ABSTRACT: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification. A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.
    Stroke 02/2014; 45(2):394-402. · 6.16 Impact Factor
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    ABSTRACT: Background High blood pressure is a prognostic factor for acute stroke, but blood pressure variability might also independently predict outcome. We assessed the prognostic value of blood pressure variability in participants of INTERACT2, an open-label randomised controlled trial (ClinicalTrials.gov number NCT00716079). Methods INTERACT2 enrolled 2839 adults with spontaneous intracerebral haemorrhage (ICH) and high systolic blood pressure (150–220 mm Hg) without a definite indication or contraindication to early intensive treatment to reduce blood pressure. Participants were randomly assigned to intensive treatment (target systolic blood pressure <140 mm Hg within 1 h using locally available intravenous drugs) or guideline-recommended treatment (target systolic blood pressure <180 mm Hg) within 6 h of onset of ICH. The primary outcome was death or major disability at 90 days (modified Rankin Scale score ≥3) and the secondary outcome was an ordinal shift in modified Rankin Scale scores at 90 days, assessed by investigators masked to treatment allocation. Blood pressure variability was defined according to standard criteria: five measurements were taken in the first 24 h (hyperacute phase) and 12 over days 2–7 (acute phase). We estimated associations between blood pressure variability and outcomes with logistic and proportional odds regression models. The key parameter for blood pressure variability was standard deviation (SD) of systolic blood pressure, categorised into quintiles. Findings We studied 2645 (93·2%) participants in the hyperacute phase and 2347 (82·7%) in the acute phase. In both treatment cohorts combined, SD of systolic blood pressure had a significant linear association with the primary outcome for both the hyperacute phase (highest quintile adjusted OR 1·41, 95% CI 1·05–1·90; ptrend=0·0167) and the acute phase (highest quintile adjusted OR 1·57, 95% CI 1·14–2·17; ptrend=0·0124). The strongest predictors of outcome were maximum systolic blood pressure in the hyperacute phase and SD of systolic blood pressure in the acute phase. Associations were similar for the secondary outcome (for the hyperacute phase, highest quintile adjusted OR 1·43, 95% CI 1·14–1·80; ptrend=0·0014; for the acute phase OR 1·46, 95% CI 1·13–1·88; ptrend=0·0044). Interpretation Systolic blood pressure variability seems to predict a poor outcome in patients with acute intracerebral haemorrhage. The benefits of early treatment to reduce systolic blood pressure to 140 mm Hg might be enhanced by smooth and sustained control, and particularly by avoiding peaks in systolic blood pressure. Funding National Health and Medical Research Council of Australia.
    The Lancet Neurology 01/2014; · 23.92 Impact Factor
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    ABSTRACT: Background and purpose Patients with genetic background for high circulating oxidized low-density lipoprotein (oxLDL) levels might be at an increased risk of cerebrovascular disease (CVD). Methods The association of oxLDL-variant rs676210 with CVD events was studied in patients undergoing coronary angiography (study A; N = 2913 [271 cases]). We sought to replicate the results in a large genome-wide association study meta-analysis of ischaemic stroke (study B; N = 3548 cases, 5972 controls). Results In study A, the prevalence of hypertension, diabetes and >50% carotid stenosis as well as the levels of LDL cholesterol differed significantly between cases and controls. In a logistic regression model adjusted for the significant covariates, rs676210 associated with CVD events (p = 0.030; odds ratio = 1.29 [95% confidence interval 1.03‒1.63] for risk allele G). In study B, rs676210 did not associate with the history of ischaemic stroke. Conclusions The oxLDL levels increasing variant rs676210 associates with CVD events in patients undergoing coronary angiography.
    Atherosclerosis 01/2014; 234(1):214–217. · 3.71 Impact Factor
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    ABSTRACT: In many countries, stroke is a lower priority than other diseases despite its public health impact. One issue is a lack of readily accessible comparative data to help make the case for the development of national stroke strategies. To assist in this process, we need to have a common repository of the latest published information on the impact of stroke worldwide. We aim to provide a repository of the most current incidence and mortality data on stroke available by country and illustrate the gaps in these data. We plan to update this repository annually and expand the scope to address other aspects of the burden of stroke. Data were compiled using two approaches: (1) an extensive literature review with a major focus on published systematic reviews on stroke incidence (between 1980 and May 14, 2013); and (2) direct acquisition and collation of data from the World Health Organization to present the most current estimates of stroke mortality for each country recognized by the World Health Organization. For mortality, ICD8, ICD9, and ICD10 mortality codes were extracted. Using population denominators crude stroke mortality was calculated, as well as adjusting for the World Health Organization world population. We used only the most recent year reported to the World Health Organization. Incidence rates for stroke were available for 52 countries, with some countries having incidence studies undertaken in more than one region. When adjusted to the World Health Organization world standard population, incidence rates for stroke ranged from 41 per 100 000 population per year in Nigeria (1971-74) to 316/ 100 000/year in urban Dar-es-Salaam (Tanzania). Some regions had three to fivefold greater incidence than other countries. Of the 123 countries reporting mortality data, crude mortality was greatest in Kazhakstan (in 2003). In many regions data were very old or nonexistent. Such country-level data are important for citizens, clinicians, and policy makers so that local and global strategies to reduce the overall burden of stroke can be implemented. Through this first annual review of country-specific stroke epidemiology, we hope to promote discussion and provide insights into the worldwide burden of stroke.
    International Journal of Stroke 01/2014; 9(1):6-18. · 2.75 Impact Factor
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    ABSTRACT: The 2013 Aspirin Foundation Conference covered a range of topics from clinical and medical history, epidemiology, health economics, and the current uses of aspirin in general practice and in the treatment and prevention of cancer. The use of aspirin as primary prevention in people at risk of atherosclerotic events is now well known, but its use as a preventative agent in some cancer types is still under discussion, and data on colorectal and lung cancer were presented at this meeting. The potential use of aspirin in preventing vascular disease in HIV patients was also discussed. The cost effectiveness of aspirin as a primary prevention strategy was discussed for the first time in this series of meetings.
    ecancermedicalscience 01/2014; 8:388.

Publication Stats

15k Citations
4,025.48 Total Impact Points

Institutions

  • 2007–2014
    • Oxford University Hospitals NHS Trust
      • Department of Clinical Neurology
      Oxford, England, United Kingdom
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 1997–2014
    • University of Oxford
      • • Health Economics Research Centre (HERC)
      • • Nuffield Department of Clinical Neurosciences
      • • Department of Public Health
      Oxford, England, United Kingdom
    • Maastricht University
      • Neurologie
      Maastricht, Provincie Limburg, Netherlands
  • 2013
    • Monash University (Australia)
      • School of Public Health and Preventive Medicine
      Melbourne, Victoria, Australia
    • University of Burgundy
      Dijon, Bourgogne, France
    • ICMS
      Portage la Prairie, Manitoba, Canada
    • NIHR Oxford Biomedical Research
      Oxford, England, United Kingdom
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2012–2013
    • St George's, University of London
      • Stroke and Dementia Research Centre
      London, ENG, United Kingdom
    • University of Toronto
      Toronto, Ontario, Canada
    • University of Birmingham
      • Centre for Cardiovascular Sciences
      Birmingham, ENG, United Kingdom
    • Baker IDI Heart and Diabetes Institute
      Melbourne, Victoria, Australia
  • 2007–2012
    • Duke University Medical Center
      • • Department of Medicine
      • • Division of Medical Oncology
      Durham, NC, United States
  • 2011
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      Newcastle-on-Tyne, England, United Kingdom
    • Benedictus Krankenhaus Tutzing
      Tutzing, Bavaria, Germany
    • Inselspital, Universitätsspital Bern
      • Department of Neurology
      Bern, BE, Switzerland
  • 2008–2011
    • Chiang Mai University
      • Department of Surgery
      Chiang Mai, Chiang Mai Province, Thailand
  • 2010
    • Newcastle University
      Newcastle-on-Tyne, England, United Kingdom
    • The University of Western Ontario
      London, Ontario, Canada
  • 2007–2010
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 2009
    • Oxford Brookes University
      • Department of Sport and Health Sciences
      Oxford, ENG, United Kingdom
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      La Jolla, CA, United States
    • Nottinghamshire Healthcare NHS Trust
      Nottigham, England, United Kingdom
    • Hôpital Lariboisière - Fernand-Widal (Hôpitaux Universitaires Sant-Louis, Lariboisière, Fernand-Widal)
      Lutetia Parisorum, Île-de-France, France
  • 1994–2009
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 1994–2007
    • The University of Edinburgh
      • Division of Clinical Neurosciences
      Edinburgh, Scotland, United Kingdom
  • 2006
    • University Medical Center Utrecht
      • Julius Center for Health Sciences and Primary Care
      Utrecht, Provincie Utrecht, Netherlands
  • 2005
    • Hospital of the University of Pennsylvania
      • Department of Neurology
      Philadelphia, Pennsylvania, United States