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  • Patient behavior immediately after transient ischemic attack according to clinical characteristics, perception of the event, and predicted risk of stroke.

    17 May 2018

    BACKGROUND AND PURPOSE: Little research has been done on patients' behavior after transient ischemic attack (TIA). Recent data on the high early risk of stroke after TIA mean that emergency action after TIA is essential for effective secondary prevention. We therefore studied patients' behavior immediately after TIA according to their perceptions, clinical characteristics, and predicted stroke risk. METHODS: Consecutive patients with TIA participating in the Oxford Vascular Study or attending dedicated hospital clinics in Oxfordshire, UK, were interviewed. Predicted stroke risk was calculated using 2 validated scores. RESULTS: Of 241 patients, 107 (44.4%) sought medical attention within hours of the event, although only 24 of these attended the emergency department. A total of 107 (44.4%) delayed seeking medical attention for > or =1 day. Correct recognition of symptoms (42.2% of patients) was not associated with less delay. However, patients with motor symptoms or duration of symptoms > or =1 hour were more likely to seek emergency attention (hazard ratio, 2.1; 95% CI, 1.4 to 3.2; P=0.00005), as were those at higher predicted stroke risk (P=0.001). The other main correlate with delay was the day of the week on which the TIA occurred (P<0.001), with greater delays at the weekend. Delay was unrelated to age, sex, or other vascular risk factors. CONCLUSIONS: Many patients delay seeking medical attention after a TIA irrespective of correct recognition of symptoms, although patients at higher predicted risk of stroke do act more quickly. Public education about both the urgency and nature of TIA is required.

  • Prognosis and management in the first few days after a transient ischemic attack or minor ischaemic stroke.

    8 December 2017

    The risk of recurrent stroke during the first few days after a transient ischaemic attack (TIA) or minor stroke is very much higher than previously estimated. However, there is considerable international variation in how patients with suspected TIA or minor stroke are managed in the acute phase, some healthcare systems providing immediate emergency inpatient care and others providing non-emergency outpatient clinic assessment. This review considers what is known about the early prognosis after TIA and minor ischaemic stroke, what factors identify individuals at particularly high early risk of stroke, and what evidence there is that urgent preventive treatment is likely to be effective in reducing the early risk of stroke.

  • Systematic review and pooled analysis of published and unpublished validations of the ABCD and ABCD2 transient ischemic attack risk scores.

    23 May 2018

    BACKGROUND AND PURPOSE: The ABCD system was derived to predict early risk of stroke after transient ischemic attack. Independent validations have reported conflicting results. We therefore systematically reviewed published and unpublished data to determine predictive value and generalizability to different clinical settings and users. METHODS: Validations of the ABCD and ABCD2 scores were identified by searching electronic databases, reference lists, relevant journals, and conference abstracts. Unpublished tabulated data were obtained where available. Predictive value, expressed as pooled areas under the receiver operator characteristic curves (AUC), was calculated using random-effects meta-analysis, and analyses for heterogeneity were performed by categorization according to study setting and method. RESULTS: Twenty cohorts were identified reporting the performance of the ABCD system in 9808 subjects with 456 strokes at 7 days. Among the 16 studies of both the ABCD and ABCD2 scores, pooled AUC for the prediction of stroke at 7 days were 0.72 (0.66 to 0.78) and 0.72 (0.63 to 0.82), respectively (P diff=0.97). The pooled AUC for the ABCD and ABCD2 scores in all cohorts reporting relevant data were 0.72 (0.67 to 0.77) and 0.72 (0.63 to 0.80), respectively (both P<0.001). Predictive value varied significantly between studies (P<0.001), but 75% of the variance was accounted for by study method and setting, with the highest pooled AUC for face-to-face clinical evaluation and the lowest for retrospective extraction of data from emergency department records. CONCLUSION: Independent validations of the ABCD system showed good predictive value, with the exception of studies based on retrospective extraction of nonsystematically collected data from emergency department records.

  • Prediction and prevention of stroke after transient ischemic attack in the short and long term.

    8 December 2017

    Over the last 5 years, a number of studies have shown the early risk of stroke following transient ischemic attack (TIA) to be of the order of 5-10% at 1 week and 10-20% at 3 months, considerably higher than previously estimated. Because these studies have been carried out in a variety of different clinical settings, their findings are likely to be generalizable. Various independent prognostic factors for this early risk of stroke have been identified and models, based on clinical features at presentation, have been derived and validated to predict risk of stroke within 7 and 90 days after TIA. At the same time, diffusion-weighted magnetic resonance imaging and carotid imaging provide prognostic information and are likely to refine risk prediction further, although no unified model combining clinical and imaging data currently exists. Uncertainty continues surrounding the most effective secondary prevention in the hyperacute phase after TIA, especially in the choice of antiplatelet agents, although clinical trials to address this question are ongoing. However, the need for carotid endarterectomy in patients with symptomatic carotid stenosis is well established. The risk of vascular disease in the medium term (1-5 years) following TIA has been more widely studied, and predictive models for this are available. Recent data on the long-term (10 years and beyond) vascular risk after TIA demonstrate ongoing mortality from both cerebrovascular and cardiovascular causes, highlighting the need for continued secondary prevention.

  • Transient ischaemic attack: clinical relevance, risk prediction and urgency of secondary prevention.

    8 May 2018

    PURPOSE OF REVIEW: Transient ischaemic attack (TIA) is increasingly recognized as a harbinger of stroke and an important opportunity for secondary prevention. We have reviewed recent evidence on the burden of TIA and prediction and prevention of stroke in the acute phase. RECENT FINDINGS: Although recent data on the incidence and prevalence of TIA are lacking, available data suggest that the burden of TIA is higher than previously estimated and may be expected to increase with the ageing of the population. Prospective prognostic studies have shown that the early risk of stroke after TIA is approximately 5% at 7 days and 10-15% at 90 days depending on clinical settings and study methodology. This risk can be reliably predicted by risk scores based on clinical features (the ABCD system), TIA aetiology and findings on brain imaging, although the optimal combined prognostic strategy is uncertain because the interaction between individual predictors is not established. Studies of the urgent assessment and initiation of secondary prevention in specialist centres suggest that the early risk of stroke after TIA can be reduced by up to 80%. SUMMARY: The risk of stroke after TIA is considerable. However, recent advances have shown that this risk can be predicted for individuals and substantially reduced by appropriate secondary prevention measures.

  • Early stroke risk and ABCD2 score performance in tissue- vs time-defined TIA: a multicenter study.

    23 May 2018

    OBJECTIVES: Stroke risk immediately after TIA defined by time-based criteria is high, and prognostic scores (ABCD2 and ABCD3-I) have been developed to assist management. The American Stroke Association has proposed changing the criteria for the distinction between TIA and stroke from time-based to tissue-based. Research using these definitions is lacking. In a multicenter observational cohort study, we have investigated prognosis and performance of the ABCD2 score in TIA, subcategorized as tissue-positive or tissue-negative on diffusion-weighted imaging (DWI) or CT imaging according to the newly proposed criteria. METHODS: Twelve centers provided data on ABCD2 scores, DWI or CT brain imaging, and follow-up in cohorts of patients with TIA diagnosed by time-based criteria. Stroke rates at 7 and 90 days were studied in relation to tissue-positive or tissue-negative subcategorization, according to the presence or absence of brain infarction. The predictive power of the ABCD2 score was determined using area under receiver operator characteristic curve (AUC) analyses. RESULTS: A total of 4,574 patients were included. Among DWI patients (n = 3,206), recurrent stroke rates at 7 days were 7.1%(95% confidence interval 5.5-9.1) after tissue-positive and 0.4% (0.2-0.7) after tissue-negative events (p diff < 0.0001). Corresponding rates in CT-imaged patients were 12.8% (9.3-17.4) and 3.0% (2.0-4.2), respectively (p diff < 0.0001). The ABCD2 score had predictive value in tissue-positive and tissue-negative events (AUC = 0.68 [95% confidence interval 0.63-0.73] and 0.73 [0.67-0.80], respectively; p sig < 0.0001 for both results, p diff = 0.17). Tissue-positive events with low ABCD2 scores and tissue-negative events with high ABCD2 scores had similar stroke risks, especially after a 90-day follow-up. CONCLUSIONS: Our findings support the concept of a tissue-based definition of TIA and stroke, at least on prognostic grounds.

  • Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study).

    3 May 2018

    BACKGROUND: The incidence of stroke is predicted to rise because of the rapidly ageing population. However, over the past two decades, findings of randomised trials have identified several interventions that are effective in prevention of stroke. Reliable data on time-trends in stroke incidence, major risk factors, and use of preventive treatments in an ageing population are required to ascertain whether implementation of preventive strategies can offset the predicted rise in stroke incidence. We aimed to obtain these data. METHODS: We ascertained changes in incidence of transient ischaemic attack and stroke, risk factors, and premorbid use of preventive treatments from 1981-84 (Oxford Community Stroke Project; OCSP) to 2002-04 (Oxford Vascular Study; OXVASC). FINDINGS: Of 476 patients with transient ischaemic attacks or strokes in OXVASC, 262 strokes and 93 transient ischaemic attacks were incident events. Despite more complete case-ascertainment than in OCSP, age-adjusted and sex-adjusted incidence of first-ever stroke fell by 29% (relative incidence 0.71, 95% CI 0.61-0.83, p=0.0002). Incidence declined by more than 50% for primary intracerebral haemorrhage (0.47, 0.27-0.83, p=0.01) but was unchanged for subarachnoid haemorrhage (0.83, 0.44-1.57, p=0.57). Thus, although 28% more incident strokes (366 vs 286) were expected in OXVASC due to demographic change alone (33% increase in those aged 75 or older), the observed number fell (262 vs 286). Major reductions were recorded in mortality rates for incident stroke (0.63, 0.44-0.90, p=0.02) and in incidence of disabling or fatal stroke (0.60, 0.50-0.73, p<0.0001), but no change was seen in case-fatality due to incident stroke (17.2% vs 17.8%; age and sex adjusted relative risk 0.85, 95% CI 0.57-1.28, p=0.45). Comparison of premorbid risk factors revealed substantial reductions in the proportion of smokers, mean total cholesterol, and mean systolic and diastolic blood pressures and major increases in premorbid treatment with antiplatelet, lipid-lowering, and blood pressure lowering drugs (all p<0.0001). INTERPRETATION: The age-specific incidence of major stroke in Oxfordshire has fallen by 40% over the past 20 years in association with increased use of preventive treatments and major reductions in premorbid risk factors.

  • Rapid antigen processing and presentation of a protective and immunodominant HLA-B*27-restricted hepatitis C virus-specific CD8+ T-cell epitope.

    10 May 2018

    HLA-B*27 exerts protective effects in hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections. While the immunological and virological features of HLA-B*27-mediated protection are not fully understood, there is growing evidence that the presentation of specific immunodominant HLA-B*27-restricted CD8+ T-cell epitopes contributes to this phenomenon in both infections. Indeed, protection can be linked to single immunodominant CD8+ T-cell epitopes and functional constraints on escape mutations within these epitopes. To better define the immunological mechanisms underlying HLA-B*27-mediated protection in HCV infection, we analyzed the functional avidity, functional profile, antiviral efficacy and naïve precursor frequency of CD8+ T cells targeting the immunodominant HLA-B*27-restricted HCV-specific epitope as well as its antigen processing and presentation. For comparison, HLA-A*02-restricted HCV-specific epitopes were analyzed. The HLA-B*27-restricted CD8+ T-cell epitope was not superior to epitopes restricted by HLA-A*02 when considering the functional avidity, functional profile, antiviral efficacy or naïve precursor frequency. However, the peptide region containing the HLA-B*27-restricted epitope was degraded extremely fast by both the constitutive proteasome and the immunoproteasome. This efficient proteasomal processing that could be blocked by proteasome inhibitors was highly dependent on the hydrophobic regions flanking the epitope and led to rapid and abundant presentation of the epitope on the cell surface of antigen presenting cells. Our data suggest that rapid antigen processing may be a key immunological feature of this protective and immunodominant HLA-B*27-restricted HCV-specific epitope.

  • APOBEC3G-induced hypermutation of human immunodeficiency virus type-1 is typically a discrete "all or nothing" phenomenon.

    14 May 2018

    The rapid evolution of Human Immunodeficiency Virus (HIV-1) allows studies of ongoing host-pathogen interactions. One key selective host factor is APOBEC3G (hA3G) that can cause extensive and inactivating Guanosine-to-Adenosine (G-to-A) mutation on HIV plus-strand DNA (termed hypermutation). HIV can inhibit this innate anti-viral defense through binding of the viral protein Vif to hA3G, but binding efficiency varies and hypermutation frequencies fluctuate in patients. A pivotal question is whether hA3G-induced G-to-A mutation is always lethal to the virus or if it may occur at sub-lethal frequencies that could increase viral diversification. We show in vitro that limiting-levels of hA3G-activity (i.e. when only a single hA3G-unit is likely to act on HIV) produce hypermutation frequencies similar to those in patients and demonstrate in silico that potentially non-lethal G-to-A mutation rates are ∼10-fold lower than the lowest observed hypermutation levels in vitro and in vivo. Our results suggest that even a single incorporated hA3G-unit is likely to cause extensive and inactivating levels of HIV hypermutation and that hypermutation therefore is typically a discrete "all or nothing" phenomenon. Thus, therapeutic measures that inhibit the interaction between Vif and hA3G will likely not increase virus diversification but expand the fraction of hypermutated proviruses within the infected host.

  • AIDS restriction HLA allotypes target distinct intervals of HIV-1 pathogenesis.

    23 May 2018

    An effective acquired immune response to infectious agents mediated by HLA-restricted T-cell recognition can target different stages of disease pathogenesis. We show here that three distinct HLA alleles known to alter the overall rate of AIDS progression act during distinct intervals after HIV-1 infection. The discrete timing of HLA allele influence suggests alternative functional mechanisms in immune defense against this dynamic and chronic immunosuppressive disease.