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Background: Mortality remains a substantial problem after acute ischemic stroke, despite advances in acute stroke treatment over the past three decades. Mortality is particularly high among patients with Total Anterior Circulation Stroke (TACS), generally representing patients with middle cerebral artery occlusions. Notably however, these patients also stand to benefit most from new therapies including endovascular thrombectomy (EVT). In this study, we aimed to examine temporal trends in, and factors associated with, 30-day in-hospital mortality after TACS. Methods: Information on all patients with community-onset TACS from 1994 through 2019 was extracted from a prospective acute stroke registry. Multivariate analysis was performed on the primary outcome of 30-day in-hospital mortality, as well as secondary functional outcomes. Results: We studied 1106 patients hospitalized for community-onset TACS, 456 (41%) of whom experienced 30-day in-hospital mortality. Over the 25 years of observation, 30-day in-hospital mortality rose and then fell. Increased odds of mortality was associated with age and stroke severity. Decreased odds of mortality was associated with alteplase therapy and EVT, as well as presentation to hospital more than 12 hours after stroke onset. Treatment with alteplase, EVT, or both was associated with higher odds of functional independence and discharge home, and shorter lengths of stay in acute care. Conclusions: Patients receiving alteplase, EVT, or both had lower 30-day in-hospital mortality and better functional outcomes than those who were untreated. These observational data demonstrate the benefits of recanalization therapy in routine clinical practice.

Endovascular thrombectomy (EVT) is efficacious for ischemic stroke caused by proximal intracranial large-vessel occlusion involving the anterior cerebral circulation. However, evidence of its cost-effectiveness, especially in a real-world setting, is limited. We assessed whether EVT ± tissue plasminogen activator (tPA) was cost-effective when compared with standard care ± tPA at our center.We identified patients treated with EVT ± tPA after the Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing computed tomography to recanalization times trial from our prospective stroke registry from February 1, 2013 to January 31, 2017. Patients admitted before February 2013 and treated with standard care ± tPA constitute the controls. The sample size was 88. Cost-effectiveness was assessed using the net monetary benefit (NMB). Differences in average costs and quality-adjusted life years (QALYs) were estimated using the augmented inverse probability weighted estimator. We accounted for sampling and methodological uncertainty in sensitivity analyses.Patients treated with EVT ± tPA had a net gain of 2.89 [95% confidence interval (CI): 0.93-4.99] QALYs at an additional cost of $22,200 (95% CI: -28,902-78,244) per patient compared with the standard care ± tPA group. The NMB was $122,300 (95% CI: -4777-253,133) with a 0.85 probability of being cost-effective. The expected savings to the healthcare system would amount to $321,334 per year.EVT ± tPA had higher costs and higher QALYs compared with the control, and is likely to be cost-effective at a willingness-to-pay threshold of $50,000 per QALY.Analyse coût-efficacité de la thrombectomie endovasculaire dans un contexte réel. Objectif : La thrombectomie endovasculaire (TE) est efficace dans le cas d’accidents ischémiques cérébraux (AIC) causés par une occlusion proximale de l’artère cérébrale antérieure. Toutefois, les preuves d’un bon rapport coût-efficacité, particulièrement dans le cadre d’une pratique réelle, demeurent limitées. Nous avons ainsi évalué au sein de notre établissement dans quelle mesure la thrombectomie endovasculaire jumelée à un traitement au moyen d’un activateur tissulaire du plasminogène (t-PA) étaient davantage rentables en comparaison avec des soins usuels également jumelés à un traitement de t-PA. Méthodes : En consultant nos registres prospectifs, nous avons identifié des patients traités par une thrombectomie endovasculaire jumelée à un traitement de t-PA après avoir subi, du 1er février 2013 au 31 janvier 2017, un traitement endovasculaire destiné à un petit AVC central et ischémique à occlusion proximale avec un accent mis sur la minimisation du temps de recanalisation par tomodensitométrie. Les patients hospitalisés avant février 2013 et auxquels des soins usuels avaient été prodigués de concert avec l’administration d’un t-PA ont fait partie de notre groupe témoin. Au total, notre échantillon était formé de 88 patients. Nous avons évalué le rapport coût-efficacité au moyen du concept d’avantage monétaire net (AMN). Nous avons également estimé les différences en ce qui concerne les coûts moyens et l’indicateur QALY (quality-adjusted life years) en faisant appel à un estimateur pondéré par l’inverse de la probabilité inverse (augmented inverse probability weighted estimator). Enfin, nous avons tenu compte de l’incertitude de notre échantillonnage et de nos choix méthodologiques dans nos analyses de sensibilité. Résultats : Les patients traités par thrombectomie endovasculaire et l’administration d’un t-PA ont donné à voir un gain net de 2,89 années selon l’indicateur QALY (IC 95 % : 0,93 – 4,99) pour un coût additionnel de 22 200 $ (IC 95 % : −28,902 – 78,244) par patient si on les compare à notre groupe témoin. L’AMN s’est quant à lui élevé à 122 300 $ (IC 95 % : −4 777 – 253 133), sa probabilité d’être rentable atteignant 0,85. À cet égard, les économies annuelles pour le système de soins de santé pourraient atteindre les 321 334 $. Conclusion : Il appert que la thrombectomie endovasculaire jumelée à un traitement de t-PA entraînent des coûts plus élevés et un meilleur indicateur QALY en comparaison avec notre groupe témoin. Il est probable qu’une telle approche soit rentable en vertu d’un seuil de disposition à payer (willingness-to-pay threshold) avoisinant les 50 000 $ par année selon le QALY.

Purpose: Endovascular thrombectomy (EVT) treatment for acute ischemic stroke is now recommended as a standard of care. However, implementing EVT in routine clinical practice poses many challenges, even in countries with advanced health-care systems. The aim of the current study is to delineate if EVT at our institution is an effective treatment for acute ischemic stroke. Methods: All patients who underwent EVT at our institution between December 2011 and July 2017 were retrospectively assessed from our prospective registry. Clinical and imaging (including the Alberta Stroke Program Early CT [ASPECT] score, single-phase computed tomography angiography, and computed tomography perfusion) criteria were utilized to determine EVT suitability. Primary outcomes included modified Rankin score (mRS) at 90 days and recanalization determined by the modified Treatment in Cerebral Infarction score. Effectiveness was assessed by comparing our cohort with patients receiving EVT in the ESCAPE (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke) trial. Results: Eighty-eight patients presented to our hospital after a median of 87 minutes last seen normal. Of these, median ASPECT score was 9. A majority (72%) also received intravenous alteplase. Successful recanalization (≥TICI 2b) was achieved in 79%. At 90 days, 48% (36/75) were functionally independent (mRS score of 0-2) and 28% (21/75) were disabled (mRS score of 3-5); 24% (18/75) died (mRS of 6) within 90 days. Conclusions: An audit of our initial experience with EVT for the treatment of acute ischemic stroke in a small tertiary care center yielded similar results compared to the ESCAPE trial, which is encouraging for implementing this treatment in routine clinical practice.

Objective: The Clock Drawing Test (CDT) is commonly used as a screening tool for the assessment of dementia. The association between the CDT in acute stroke and long-term functional and cognitive outcomes in this population is unknown. The present prospective study is the first to examine if CDT scores in the acute stage after stroke are related to long-term outcomes and to compare the predictive ability of two scoring systems in a large sample of stroke patients. Method: A total of 340 patients admitted to an acute stroke unit were included in the present study. Separate stepwise multiple linear regression analyses were performed with eight independent variables (demographic/pre-stroke variables - age, sex, premorbid functioning; stroke-related variables - stroke severity, localization; cognitive variables - Orientation Test, CDT [2 scoring systems]), and four dependent variables administered one year post-stroke (Barthel Index, modified Rankin Scale, Reintegration to Normal Living index, Global Deterioration Scale). Results: Although both CDT scoring methods were related to all long-term outcome measures, the more comprehensive scoring system was the only baseline variable that significantly explained the variance in outcome measures in all four multiple regression models. Conclusion: Performance on the CDT in acute stroke is related to long-term outcomes including patients' degree of independence in performing activities of daily living, the degree to which they achieved reintegration into daily occupations, and the degree of cognitive decline observed one-year post-stroke. Future studies are needed to clarify the nature of the relationship between different CDT scoring systems and post-stroke outcomes.

Although the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke caused by intracranial anterior circulation large vessel occlusion (LVO) is proven, demonstration of local effectiveness is critical for health system planning and resource allocation because of the complexity and cost of this treatment.Using our prospective registry, we identified all patients who underwent EVT for out-of-hospital LVO stroke from February 1, 2013 through January 31, 2017 (n = 44), and matched them 1:1 in a hierarchical fashion with control patients not treated with EVT based on age (±5 years), prehospital functional status, stroke syndrome, severity, and thrombolysis administration. Demographics, in-hospital mortality, discharge disposition from acute care, length of hospitalization, and functional status at discharge from acute care and at follow-up were compared between cases and controls.For EVT-treated patients (median age 66, 50% women), the median onset-to-recanalization interval was 247 min, and successful recanalization was achieved in 30/44 (91%). Alteplase was administered in 75% of cases and 57% of controls (p = 0.07). In-hospital mortality was 11% among the cases and 36% in the control group (p = 0.006); this survival benefit persisted during follow-up (p = 0.014). More EVT patients were discharged home from acute care (50% vs. 18%, p = 0.002). Among survivors, there were nonsignificant trends in favor of EVT for median length of hospitalization (14 vs. 41 days, p = 0.11) and functional independence at follow-up (51% vs. 32%, p = 0.079).EVT improved survival and decreased disability. This demonstration of single-center effectiveness may help facilitate expansion of EVT services in similar health-care jurisdictions.Étude cas-témoin portant sur la thrombectomie endovasculaire dans un centre canadien de prise en charge des AVC. Contexte : Bien qu’on ait prouvé l’efficacité de la thrombectomie endovasculaire dans le cas d’accidents ischémiques cérébraux aigus causés par l’occlusion de grosses artères affectant la circulation antérieure intracrânienne, la démonstration de son efficacité sur le terrain est essentielle à la planification du réseau la santé et à l’allocation des ressources en raison de la complexité de ce traitement et des coûts qui y sont associés. Méthodes : À l’aide d’un registre prospectif, nous avons identifié tous les patients ayant bénéficié (n = 44), du 1er février 2013 au 31 janvier 2017, d’une thrombectomie endovasculaire à la suite d’un AVC survenu en dehors d’un établissement de la santé, AVC causé par l’occlusion de grosses artères. De manière hiérarchique, nous avons fait correspondre nos patients dans un rapport de 1 à 1 à nos témoins non traités par thrombectomie endovasculaire, et ce, en nous basant sur leur âge (± 5 ans), sur leur situation fonctionnelle avant d’être admis, sur les signes cliniques et la gravité de leur AVC, et sur l’administration d’un traitement thrombolytique. Nous avons également comparé leurs caractéristiques démographiques, leur taux de mortalité hospitalière, les modalités d’obtention d’un congé des soins intensifs, la durée de leur hospitalisation et leur situation fonctionnelle au moment de quitter les soins intensifs et à l’occasion d’un suivi. Résultats : Dans le cas de nos patients traités par thrombectomie endovasculaire (âge médian : 66 ans ; 50 % de femmes), l’intervalle médian entre les premiers signes d’un AVC et la recanalisation a été de 247 minutes. Fait à souligner, une recanalisation réussie a été accomplie dans 30 cas sur 44 (91 %). L’altéplase a été administré dans 75 % des cas et chez 57 % des témoins (p = 0,07). En ce qui concerne le taux de mortalité hospitalière, il a été de 11 % parmi tous nos cas et de 36 % chez nos témoins (p = 0,006) ; À noter que cet avantage en termes de survie a persisté au moment des suivis (p = 0,014). Plus de patients traités par thrombectomie endovasculaire ont obtenu leur congé des soins intensifs et sont revenus à la maison (50 % contre 18 % ; p = 0,002). Parmi les survivants à ces AVC, on a noté des tendances non significatives en faveur des patients traités par thrombectomie endovasculaire pour ce qui est de la durée médiane d’hospitalisation (14 jours contre 41 jours ; p = 0,11) et de l’autonomie fonctionnelle au moment des suivis (51 % contre 32 % ; p = 0,079). Conclusion : En somme, la thrombectomie endovasculaire a permis d’améliorer le taux de survie des patients ainsi que leur niveau d’autonomie fonctionnelle. Effectuée dans un seul établissement hospitalier, cette démonstration de l’efficacité de ce traitement pourrait contribuer à faciliter l’essor des traitements de thrombectomie endovasculaire dans d’autres systèmes de santé similaires.

Introduction Debate exists as to whether wake-up stroke (WUS) (i.e. symptoms first noted on waking) differs from stroke developing while awake [awake onset stroke (AOS)]. Unknown onset stroke (UOS) with unclear symptom onset time is infrequently studied. Aims This study aimed to examine differences in stroke characteristics and outcomes in these three groups. Methods The stroke registry database from Halifax Infirmary, Canada, was interrogated for hospitalised stroke patients between 1999–2011. Information was available on demographics, stroke characteristics, and functional status at discharge and six months (modified Rankin score [mRS]). Results Of 3890 patients, 65% had AOS, 21% WUS and 14% UOS. UOS patients were significantly older, more commonly female and living alone than AOS patients, with no difference between AOS and WUS. UOS rates increased from 10 to 16% of patients during the study period ( P < 0·0001). UOS but not WUS had a higher stroke severity than AOS. Intracerebral hemorrhage was less common (9 vs. 13%) and lacunar stroke more common (23 vs. 19%) in WUS compared to AOS. In UOS left hemisphere location was more likely, and lacunar stroke less common. Excellent outcomes were slightly lower for WUS. UOS had significantly higher rates of in-hospital mortality (23 vs. 16%, P < 0·0001) and poorer functional outcome six months after stroke (mRS < 3 in 26% of UOS and 46% of AOS, P = 0·02). Conclusion WUS has lower rates of ICH but similar stroke severity and outcomes to AOS. UOS prevalence appears to be increasing, with higher stroke severity and worse prognosis.

Contexte: Entre 33 et 77% des patients qui survivent a un accident vasculaire cerebral (AVC) eprouvent de la fatigue. Il n'existe pas de consensus concernant les facteurs de risque de la fatigue post AVC, ce qui temoigne peut-etre des multiples facettes de la fatigue. Nous avons caracterise la fatigue post AVC au moyen de l'Echelle des repercussions de la fatigue (ERF), un questionnaire valide qui englobe les aspects physiques, cognitifs et psychosociaux de la fatigue. Methode: Le Stroke Outcomes Study a recrute de facon prospective des patients atteints d'un AVC ischemique en 2001-2002. Les donnees demographiques, le niveau de fonction premorbide (Oxford Handicap Scale, OHS), la severite de l'AVC (Stroke Severity Scale, SSS), le sous-type d'AVC (Oxfordshire Community Stroke Project Classification, OCSP) et le niveau de fonctionnement au moment du conge hospitalier (OHS; Indice de Barthel, IB) ont ete colliges. Une entrevue a ete effectuee 12 mois apres l'AVC pour evaluer le fonctionnement (IB; score de Rankin modifie, SRm), la qualite de vie (Indice de reintegration a la vie normale, IRVN), la depression (echelle de depression geriatrique, EDG) et la fatigue (ERF). Resultats: Nous avons recrute 522 patients atteints d'un AVC ischemique et 228 des patients (57,6%) survivants ont participe au suivi d'un an post AVC. Trente-six pour cent des patients accusaient de la fatigue et 59,5% d'entre eux la consideraient comme l'un des pires symptomes post AVC. L'analyse de regression lineaire a montre une association entre un âge inferieur et une frequence de la fatigue plus elevee ( β = ―0,20 ; p = 0,01), plus prolongee (β =-0,22 ; p < 0,01) et plus invalidante (β = -0,24; p < 0,01). Les patients plus jeunes etaient plus susceptibles de decrire la fatigue comme l'un des pires symptomes post AVC (β = -0,24 ; p < 0,05). Les patients plus jeunes accusaient un impact plus considerable de la fatigue sur la fonction cognitive (β = 0,-27; p < 0,05) et sur la fonction psychosociale (β = -0,27 ; p < 0,05). La fatigue etait correlee aux symptomes depressifs et alterait leur qualite de vie. La fatigue sans depression etait presente chez 49,0% des repondants dont la fatigue etait l'un des pires symptomes bien qu'ils n'avaient pas un score GDS eleve. Conclusions: L'âge etait le seul facteur de prediction constant de la severite de la fatigue lors du suivi un an apres l'AVC: les participants plus jeunes accusaient une fatigue cognitive et psychosociale plus severe.

Background:weaimedtoassesswhethertheperformanceofstrokeoutcomemodelscomprisingsimpleclinicalvariablescould beimprovedbytheadditionofmorecomplexclinicalvariablesandinformationfromthe firstcomputedtomography(CT)scan. Methods: 538 consecutive acute ischaemic and haemorrhagic stroke patients were enrolled in a Stroke Outcome Study between 2001 and 2002. Independent survival (modified Rankin scale ≤2) was assessed at 6 months. Models based on clinical and radiological variables from the first assessment were developed using multivariate logistic regression analysis. Results: three models were developed (I–III). Model I included age, pre-stroke independence, arm power and a stroke severity score (area under a receiver operating characteristic curve, AUC = 0.882) but performed no better than Model II, which comprised age, pre-stroke independence, normal verbal component of the Glasgow coma score, arm power and being able to walk without assistance (AUC 0.876). Model III, including two radiological variables and clinical variables, was not statistically superior to model II (AUC 0.901, P = 0.12). Model II was externally validated in two independent datasets (AUCs of 0.773 and 0.787). Conclusion: this study demonstrates an externally validated stroke outcome prediction model using simple clinical variables. Outcome prediction was not significantly improved with CT-derived radiological variables or more complex clinical variables.

BackgroundCaregiver burden following stroke can have significant adverse health consequences for caregivers and threatens the recovery and successful rehabilitation of patients. Our objective was to identify patient factors that contribute to higher levels of caregiver burden.MethodsWe prospectively studied patients admitted to our stroke unit over a 2-year period (2001-2002). Data were collected at baseline and at 1 year. Caregiver burden was measured at 1 year using the Relatives Stress Scale (completed by 155 caregivers) and the Bakas Caregiver Outcomes Scale (143 caregivers). Explanatory patient factors at baseline included sociodemographic status, stroke severity, stroke sub-type, functional disability (Barthel Index), functional handicap (Oxford Handicap Scale and Modified Rankin Scale), and cognitive status (orientation, clock drawing). At 1 year, mental health and health-related quality of life were assessed using the Fatigue Impact Scale, Geriatric Depression Scale, Global Deterioration Scale, and 36-item Short Form Health Survey.ResultsThe baseline patient factors predictive of caregiver burden by multiple regression analysis were older patient age ( PConclusionsThe functional status of patients can be used to identify caregivers at risk of caregiver burden. Patient demographic variables, cognitive function, and mental health status may further expose vulnerable caregivers. These factors should be considered in the development of strategies to offset caregiver burden.

The ability of oncolytic adenoviruses to replicate in and lyse cancer cells offers a potential therapeutic approach. However, selectivity and efficacy of adenovirus replication need to be improved. In this study, we present that loss of p21(WAF1) promotes adenovirus replication and more effective cell killing. To test our hypothesis, we took HCT116 colon cancer cell lines carrying deletions of either p21(WAF1) or p53, and infected these cell lines with wild-type adenovirus (WtD) or the oncolytic adenoviruses, ONYX-015 and Delta-24. We found that WtD, ONYX-015 and Delta-24 induced stronger cytopathic effects in HCT116 p21-/- cells compared with HCT116-WT cells. This was accompanied by increased virus production. siRNA-mediated knockdown of p21(WAF1), and similarly of p27(KIP1), in HCT116-WT cells also enhanced replication of and cell killing by these viruses. Furthermore, we found that TE7, an esophageal carcinoma cell line, also showed a strong cell-killing effect and virus production when p21(WAF1) expression was suppressed by RNA interference before adenoviruses infection. Also, H1299 and DU-145 cells transfected with p21(WAF1) siRNA showed higher virus production after ONYX-015 and Delta-24 infections. These observations suggest that p21(WAF1) plays a role in mediating replication of oncolytic viruses with potential implications for adenoviral therapy of cancer.

Contexte : Des etudes cliniques randomisees ont demontre que l'activateur du plasminogene tissulaire (tPA) administre par voie intraveineuse ameliore l'issue dans l'accident vasculaire cerebral ischemique aigu (AVCIA). Nous avons effectue une etude cas-temoin chez des patients d'un hopital presentant un AVCIA afin d'evaluer si l'efficacite potentielle du traitement par le tPA se traduit par une efficacite reelle en pratique clinique. Methodes : 151 patients, ayant subi un AVCIA et ayant ete traites par tPA entre 1996 et 2005, ont ete apparies 1:1 quant a l'âge, au sexe, au score pre-AVC a l'Oxford Handicap Scale (OHS), a la severite de l'AVC et au sous-type, et en aveugle quant a l'issue, a des temoins tires d'un registre prospectif. Les criteres d'evaluation etaient le deces pendant l'hospitalisation, l'hemorragie intracrânienne symptomatique (HICS), la duree du sejour hospitalier (DSH), le score OHS au moment du conge et la survie a long terme. Resultats : Nous n'avons constate aucune difference entre les cas et les temoins (p = 0,83) quant a la mortalite intra-hospitaliere (23% vs 24%) et a la survie a long terme (suivi median de 2 ans). 7,8% des patients traites par le tPA ont presente une HICS (IC de 95%: 4,2 a 13,5%). La DSH mediane des cas etait plus courte (13 [7-29] vs 16 [8-32] jours, p = 0,14) mais la difference n'etait pas significative. Cependant elle etait significative pour les femmes traitees par le tPA par rapport a celles qui n'avaient pas recu ce traitement (14 [7-28] vs 20 [11-34] jours, p = 0,04). Au moment du conge hospitalier, les patients traites par le tPA qui n'avaient aucune invalidite etaient de 6,6% plus nombreux (IC de 95% : 1,1 a 12,0%) que les temoins (OHS < 1,p = 0,02). Cependant, il n'y avait pas de difference quant au taux d'independance au moment du conge hospitalier ou quant a la proportion des patients qui retournaient a domicile. Conclusion: Nous demontrons qu'il existe une amelioration mineure quant a la recuperation precoce apres un AVCIA si on administre du tPA, mais l'impact est moins dramatique que celui qui a ete rapporte dans les etudes randomisees. Ceci pourrait etre du au moment ou le traitement est administre et au type de patients traites.

Modified adenoviruses represent a new approach to treatment of gastrointestinal cancer. However, their uptake by cells in many cases requires the major receptor for adenoviruses, the coxsackievirus and adenovirus receptor (CAR). Thus, lack of CAR expression is a potential cause of intrinsic resistance of tumor cells to this type of treatment. To evaluate this, we studied the localization of CAR protein in normal and malignant gastrointestinal tissues. In normal tissues, CAR was concentrated at sites of cell-cell interaction, in particular at the apico-lateral cellular surface. Expression was particularly strong around bile and pancreatic ducts, which is in agreement with CAR's physiological function as a tight-junction protein. In GI malignancies (esophageal, pancreatic, colorectal and liver cancer), expression of the receptor varied substantially. Loss of CAR expression at cell-cell junction was evident in many samples. A significant correlation between CAR expression and histological grade was found, with moderately to poorly differentiated tumors most frequently demonstrating loss or reduction of CAR expression. These data indicate that CAR expression is frequently altered in gastrointestinal malignancy, potentially reducing the efficacy of adenovirus-based therapies.

Background models to predict functional status post-stroke have utility in balancing groups in randomised trials, for outcome comparison between stroke centres and may assist in outcome prediction. This study aimed to develop models of both excellent [modified Rankin score (mRS) 0-1] and devastating outcomes (mRS of 5-6). Methods patients admitted with ischaemic or haemorrhagic stroke in 2001-02 to the Halifax Infirmary, Canada, were enrolled. Sixteen clinical variables from the first neurological assessment and six radiological variables from the acute CT scan were used to the model outcome at 6 months. Results five hundred and thirty-eight stroke patients were enrolled. Thirty per cent had an excellent outcome and 30% had a devastating outcome. Three models of the excellent outcome were developed [area under the receiver operator curve (AUC) 0.866-882] including the variables age, pre-stroke functional status, stroke severity, ability to lift both arms, walk independently, normal verbal Glasgow Coma Scale and leukoaraiosis. Predictive models of the devastating outcome (AUC of 0.859-0.874) included additional variables living alone pre-stroke and total anterior circulation stroke. The simplest models of both outcomes were externally validated (AUC of 0.856-0.885). Conclusion this study demonstrates new externally validated predictive models of both excellent and devastating outcomes. Leukoaraiosis was the only independent radiological predictor of both outcomes. Living alone pre-stroke predicted devastating outcome post-stroke.

Background and Purpose— Studies suggest that women with stroke are investigated less aggressively and receive tissue plasminogen activator less frequently than men. We tested whether gender differences in the investigation, treatment, and outcome of stroke are due to confounding factors. Methods— Gender differences in the use of investigations, trial enrollment, treatment with intravenous tissue plasminogen activator, and in-hospital outcomes were examined in data from our prospective registry using multivariate analysis to adjust for age, prestroke functional status, stroke subtype and severity, and atrial fibrillation. Results— Of 2725 consecutive hospitalized patients (1996 to 2006), 88% had ischemic stroke and 48% were women. Women were older (median age, 77 versus 70 years), had more severe strokes, and were less likely to be independent prestroke (78% versus 87%) compared with men (all P Conclusion— The majority of the gender differences in stroke were explained by confounding. More research is required to understand gender differences in stroke pathophysiology and the utilization of thrombolytic therapy.

Expression of the Coxsackie and Adenovirus Receptor (CAR) is frequently reduced in carcinomas, resulting in decreased susceptibility of such tumors to infection with therapeutic adenoviruses. Because CAR participates physiologically in the formation of tight-junction protein complexes, we examined whether molecular mechanisms known to down-regulate cell-cell adhesions cause loss of CAR expression. Transforming growth factor-β (TGF-β)–mediated epithelial-mesenchymal transition (EMT) is a phenomenon associated with tumor progression that is characterized by loss of epithelial-type cell-cell adhesion molecules (including E-cadherin and the tight junction protein ZO-1), gain of mesenchymal biochemical markers, such as fibronectin, and acquisition of a spindle cell phenotype. CAR expression is reduced in tumor cells that have undergone EMT in response to TGF-β. This down-regulation results from repression of CAR gene transcription, whereas altered RNA stability and increased proteasomal protein degradation play no role. Loss of CAR expression in response to TGF-β is accompanied by reduced susceptibility to adenovirus infection. Indeed, treatment of carcinoma cells with LY2109761, a specific pharmacologic inhibitor of TGF-β receptor types I and II kinases, resulted in increased CAR RNA and protein levels as well as improved infectability with adenovirus. This was observed in cells induced to undergo EMT by addition of exogenous TGF-β and in those that were transformed by endogenous autocrine/paracrine TGF-β. These findings show down-regulation of CAR in the context of EMT and suggest that combination of therapeutic adenoviruses and TGF-β receptor inhibitors could be an efficient anticancer strategy. (Cancer Res 2006; 66(3): 1648-57)

Recombinant adenoviruses are presently being tested clinically as a new strategy for the treatment of cancer. An important determining factor for the successful entry of such adenoviruses into target cells is expression of the coxsackievirus and adenovirus receptor (CAR) at the cell surface. Recent observations suggest that expression of this receptor, which physiologically participates in formation of cell-cell adhesions, is frequently reduced in highly malignant cancer cells. This raises the possibility that those tumors representing the greatest therapeutic challenge might be the least susceptible to infection with therapeutic adenoviruses. We explored the role of the Raf-MEK-ERK pathway on CAR expression in a panel of cancer cells because this pathway is frequently up-regulated in cancer cells and is known to down-regulate cell-cell adhesion molecules. We found that disruption of signaling through the Raf-MEK-ERK pathway by inhibition of MEK up-regulated CAR expression, which was accompanied by increased representation of the protein at the cell surface. After Raf-MEK-ERK inhibition, adenovirus entry into cells was increased and cell killing by replication competent adenoviruses was enhanced in a CAR-dependent manner. Conversely, induction of Raf-1 resulted in reduction and disruption of CAR expression at the cell surface. We conclude that loss of CAR expression in cancer cells is, at least in part, mediated through the Raf-MEK-ERK signal transduction pathway and that pharmacological restoration of CAR at the cell surface could improve adenovirus-based treatments of cancer.

Introduction Study aim: to assess what computed tomography perfusion (CTP) and CT angiography source imaging (CTA SI) add to the baseline assessment of patients with suspected acute ischaemic stroke (AIS). Hypothesis: the final volume of infarcted brain will not be smaller than that predicted by the cerebral blood volume (CBV) parameter on acute CTP imaging. Methods This was a retrospective imaging study analysing imaging data of patients admitted to the Queen Elizabeth II Health Sciences Centre via the acute stroke protocol from 1st April–31st August 2012. Clinical data from the Registry of the Capital District Stroke Program (RCDSP), and CT images from the Nova Scotia Picture Archiving and Communications Systems were used. A manual tracing technique using the “Markup Freeform” tool via AGFA IMPAX version 6.5.1.1008 was used to calculate lesion volumes. The primary outcome measure was the difference in volume between the ischaemic tissue on CTP and SI at admission, with the infarct volume on follow–up CT or diffusion–weighted imaging sequences on magnetic resonance imaging (MRI). Results For full analysis, 38 patients met inclusion/exclusion criteria. There was no difference between CTP CBV or SI and follow–up MRI/CT lesion volume (P>0.05). Lesion volumes were greater on time to peak (TTP) and cerebral blood flow (CBF) CTP images compared to follow–up MRI/CT (P Conclusions Results from HASIS suggest information from admission CTP and SI in suspected AIS patients can predict final infarct volume, where final volume of infarcted brain will not be smaller than that predicted by CTP CBV or CTA SI.