OBJECTIVE:Microcirculatory changes contribute to delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH), but bedside assessment remains challenging. Sidestream darkfield imaging (SDF) enables direct visualization but may be difficult in critically ill patients. The objective was to evaluate the feasibility of repeated sublingual and conjunctival SDF imaging in aSAH patients and to compare microcirculatory changes at both sites. METHODS:SDF imaging was performed sublingually and conjunctivally at six timepoints after aSAH. Feasibility was assessed by completion rate, patient experience, and acquisition time. Logistic mixed models identified factors influencing completion and microvascular outcomes. Agreement between sites was assessed with Bland-Altman plot and Spearman correlation. RESULTS:Thirty patients were included. Sublingual and conjunctival imaging completion rates were 89% and 70% respectively, with the latter declining over time. Positive patient experience increased success (OR 16, 95% 3.46-74.17), while longer acquisition time reduced success (OR 0.89, 95% CI 0.80-0.98). Discomfort was the main cause of conjunctival imaging failure. Sublingual and conjunctival parameters showed distinct trajectories during follow-up. CONCLUSION:Sublingual SDF imaging is a feasible, well-tolerated method for serial microcirculatory assessment in aSAH patients. Conjunctival imaging is less tolerated and may be less suitable for repeated measurements. Microcirculatory changes differ between sites and cannot be used interchangeably.

MR CLEAN-LATE (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands for Late Arrivals) showed efficacy of endovascular treatment (EVT) in the late window (6-24 hours after stroke symptom onset or time last seen well) among patients with ischemic stroke selected based on collateral flow. Therefore, the future role of computed tomography perfusion (CTP) imaging in patient selection for late-window EVT may change. To investigate the interaction among CTP parameters (core volumes, penumbra volumes, and mismatch ratio) and the association of EVT with functional outcomes among patients in the late window after ischemic stroke selected based on collateral flow. This is a post hoc secondary analysis of MR CLEAN-LATE, a multicenter randomized clinical trial, with open-label treatment and blinded end point, conducted from February 2, 2018, to January 27, 2022, in 18 Dutch stroke intervention centers. Participants included 502 patients with anterior circulation large vessel occlusion and present collateral flow on results of computed tomographic angiography in the late window after stroke, who gave deferred consent and were included in MR CLEAN-LATE. All patients had completed follow-up at 90 days. This secondary analysis included 313 patients (62%) with available CTP results. Statistical analysis was performed in September 2023. Patients were randomized to receive EVT (EVT group) and best medical management vs best medical management alone (no EVT group). The primary outcome was functional outcome at 90 days measured by the modified Rankin Scale score. The treatment effect was analyzed in subgroups of core volumes, penumbra volume, and mismatch ratios using ordinal regression analysis. An interaction analysis was performed to assess whether CTP parameters modified the EVT effect on the modified Rankin Scale score at 90 days. All analyses were adjusted for relevant prognostic factors. Among the 313 patients (158 women [50%]) in the study, the median age was 73 years (IQR, 63-80 years), and the EVT group had fewer male participants than the no EVT group (73 of 168 [43%] vs 82 of 145 [57%]). Penumbra volumes significantly modified the association of EVT with outcomes (P < .001 for interaction), with the largest effect size among patients with penumbras of 120 mL or more (adjusted common odds ratio [ACOR], 6.89 [95% CI, 2.96-16.04]) and the smallest effect size among patients with penumbras of 72 mL or less (ACOR, 0.49 [95% CI, 0.22-1.08]). Core volume and mismatch ratio did not modify the EVT effect. Based on results from this secondary analysis of the MR CLEAN-LATE randomized clinical trial, there was a direct interaction between penumbra volume and treatment effect, and a trend toward potential harm of EVT was seen among patients with the smallest penumbras, which warrants further research. However, core volume and mismatch ratio did not seem to have additional value in patient selection. isrctn.org Identifier: ISRCTN19922220

Background Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA).Methods MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220. Findings Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned, and 502 (94%) patients provided deferred consent or died before consent was obtained (255 in the endovascular treatment group and 247 in the control group; 261 [52%] females). The median mRS score at 90 days was lower in the endovascular treatment group than in the control group (3 [IQR 2-5] vs 4 [2-6]), and we observed a shift towards better outcomes on the mRS for the endovascular treatment group (adjusted common OR 1 center dot 67 [95% CI 1 center dot 20-2 center dot 32]). All-cause mortality did not differ significantly between groups (62 [24%] of 255 patients vs 74 [30%] of 247 patients; adjusted OR 0 center dot 72 [95% CI 0 center dot 44-1 center dot 18]). Symptomatic intracranial haemorrhage occurred more often in the endovascular treatment group than in the control group (17 [7%] vs four [2%]; adjusted OR 4 center dot 59 [95% CI 1 center dot 49-14 center dot 10]). Interpretation In this study, endovascular treatment was efficacious and safe for patients with ischaemic stroke caused by an anterior circulation large-vessel occlusion who presented 6-24 h from onset or last seen well, and who were selected on the basis of the presence of collateral flow on CTA. Selection of patients for endovascular treatment in the late window could be primarily based on the presence of collateral flow.Funding Collaboration for New Treatments of Acute Stroke consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.Copyright (c) 2023 Elsevier Ltd. All rights reserved.

Background The relationship between the interventionist’s experience and outcomes of endovascular thrombectomy (EVT) for acute ischemic stroke of the anterior circulation, is unclear. Objective To assess the effect of the interventionist’s level of experience on clinical, imaging, and workflow outcomes. Secondly, to determine which of the three experience definitions is most strongly associated with these outcome measures. Methods We analysed data from 2700 patients, included in the MR CLEAN Registry. We defined interventionist’s experience as the number of procedures performed in the year preceding the intervention (EXPfreq), total number of procedures performed (EXPno), and years of experience (EXPyears). Our outcomes were the baseline-adjusted National Institutes of Health Stroke Scale (NIHSS) score at 24–48 hours post-EVT, recanalization (extended Thrombolysis in Cerebral Infarction (eTICI) score ≥2B), and procedural duration. We used multilevel regression models with interventionists as random intercept. For EXPfreq and EXPno results were expressed per 10 procedures. Results Increased EXPfreq was associated with lower 24–48 hour NIHSS scores (adjusted (a)β:−0.46, 95% CI −0.70 to −0.21). EXPno and EXPyears were not associated with short-term neurological outcomes. Increased EXPfreq and EXPno were both associated with recanalization (aOR=1.20, 95% CI 1.11 to 1.31 and aOR=1.08, 95% CI 1.04 to 1.12, respectively), and increased EXPfreq, EXPno, and EXPyears were all associated with shorter procedure times (aβ:−3.08, 95% CI−4.32 to −1.84; aβ:−1.34, 95% CI−1.84 to −0.85; and aβ:−0.79, 95% CI−1.45 to −0.13, respectively). Conclusions Higher levels of interventionist’s experience are associated with better outcomes after EVT, in particular when experience is defined as the number of patients treated in the preceding year. Every 20 procedures more per year is associated with approximately one NIHSS score point decrease, an increased probability for recanalization (aOR=1.44), and a 6-minute shorter procedure time.

Background: Endovascular treatment (EVT) for acute ischemic stroke (AIS) is performed in intervention centers that provide the full range of neuro(endo)vascular care (level 1) and centers that only perform EVT for AIS (level 2). We compared outcomes between these center types and assessed whether differences in outcomes could be explained by center volume (CV). Patients and methods: We analyzed patients included in the MR CLEAN Registry (2014–2018), a registry of all EVT-treated patients in the Netherlands. Our primary outcome was the shift on the modified Rankin scale (mRS) after 90 days (ordinal regression). Secondary outcomes were the NIHSS 24–48 h post-EVT, door-to-groin time (DTGT), procedure time (linear regression), and recanalization (binary logistic regression). We compared outcomes between level 1 and 2 centers using multilevel regression models, with center as random intercept. We adjusted for relevant baseline factors, and in case of observed differences, we additionally adjusted for CV. Results: Of the 5144 patients 62% were treated in level 1 centers. We observed no significant differences between center types in mRS (adjusted(a)cOR: 0.79, 95% CI: 0.40 to 1.54), NIHSS (aβ: 0.31, 95% CI: −0.52 to 1.14), procedure duration (aβ: 0.88, 95% CI: −5.21 to 6.97), or DTGT (aβ: 4.24, 95% CI: −7.09 to 15.57). The probability for recanalization was higher in level 1 centers compared to level 2 centers (aOR 1.60, 95% CI: 1.10 to 2.33), and this difference probably depended on CV. Conclusions: We found no significant differences, that were independent of CV, in the outcomes of EVT for AIS between level 1 and level 2 intervention centers.

Background Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke. Methods We did an open-label, multicentre, randomised controlled trial with a 2 x 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, >= 18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621. Findings Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1.95 [95% CI 1.13-3.35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1.98 [1.14-3.46]). Both aspirin (adjusted common OR 0.91 [95% CI 0.69-1.21]) and unfractionated heparin (0.81 [0.61-1.08]) led to a non-significant shift towards worse modified Rankin Scale scores. Interpretation Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome. Copyright (C) 2022 Published by Elsevier Ltd. All rights reserved.

INTRODUCTION: There are two treatment modalities for aneurysmal subarachnoid hemorrhage: endovascular treatment (EVT) and neurosurgical clipping. Results of economic evaluations are needed to gain insight into the relationship between clinical effectiveness and costs of these treatment modalities. This important information can inform both clinical decision-making processes and policymakers in facilitating Value-Based Healthcare.EVIDENCE ACQUISITION: Databases (PubMed, Embase, Cochrane Library, the Centre for Reviews and Dissemination, EBSCO, and Web of Science) were searched for studies published until October 2020 that had performed economic evaluations in aneurysmal subarachnoid hemorrhage patients by comparing EVT with neurosurgical clipping. The quality of reporting and methodology of these evaluations was assessed using the associated instruments (i.e. CHEERS statement and CHEC-list, respectively).EVIDENCE SYNTHESIS: A total of 6 studies met the inclusion criteria. All included studies reported both effects and costs, however five did not relate effects to costs. Only one study related effects directly to costs, thus conducted a full economic evaluation. The reporting quality scored 81% and the methodological quality scored 30%.CONCLUSIONS: The quality of published cost-effectiveness studies on the treatment of aneurysmal subarachnoid hemorrhage is poor. Six studies reported both outcomes and costs, however only one study performed a full economic evaluation comparing EVT to neurosurgical clipping. Although the reporting quality was sufficient, the methodological quality was poor. Further research that relates health-related quality of life measures to costs of EVT and neurosurgical clipping is required - specifically focusing on both reporting and methodological quality. Different subgroup analyses and modeling could also enhance the findings.

Five concentrations (50–860 mg/kg) of residues obtained after distillation and lyophilization of commercial tequila were injected into mice for evaluation of chromosome aberrations, sister-chromatid exchanges, and proliferation kinetics in mouse bone marrow cells. Appropriate positive and negative controls were included. Our results showed significant dose-related increases of chromosomal aberrations starting at 50 mg/kg and for sister-chromatid exchanges at 430 mg/kg. Cellular proliferation kinetics showed no alterations. With these data we demonstrated that the residues of tequila are genotoxic in vivo.

Abstract Background Endovascular treatment (EVT) has greatly improved the prognosis of acute ischemic stroke (AIS) patients with a proximal intracranial large vessel occlusion (LVO) of the anterior circulation. Currently, there is clinical equipoise concerning the added benefit of intravenous alteplase administration (IVT) prior to EVT. The aim of this study is to assess the efficacy and safety of omitting IVT before EVT in patients with AIS caused by an anterior circulation LVO. Methods MR CLEAN-NO IV is a multicenter randomized open-label clinical trial with blinded outcome assessment (PROBE design). Patients ≥ 18 years of age with a pre-stroke mRS < 3 with an LVO confirmed on CT angiography/MR angiography eligible for both IVT and EVT are randomized to receive either IVT (0.9 mg/kg) followed by EVT, or direct EVT in a 1:1 ratio. The primary objective is to assess superiority of direct EVT. Secondarily, non-inferiority of direct EVT compared to IVT before EVT will be explored. The primary outcome is the score on the modified Rankin Scale at 90 days. Ordinal regression with adjustment for prognostic variables will be used to estimate treatment effect. Secondary outcomes include reperfusion graded with the eTICI scale after EVT and stroke severity (National Institutes of Health Stroke Scale) at 24 h. Safety outcomes include intracranial hemorrhages scored according to the Heidelberg criteria. A total of 540 patients will be included. Discussion IVT prior to EVT might facilitate early reperfusion before EVT or improved reperfusion rates during EVT. Conversely, among other potential adverse effects, the increased risk of bleeding could nullify the beneficial effects of IVT. MR CLEAN-NO IV will provide insight into whether IVT is still of added value in patients eligible for EVT. Trial registration www.isrctn.com : ISRCTN80619088 . Registered on 31 October 2017.

Abstract Background Endovascular therapy (EVT) for acute ischemic stroke due to proximal occlusion of the anterior intracranial circulation, started within 6 h from symptom onset, has been proven safe and effective. Recently, EVT has been proven effective beyond the 6-h time window in a highly selected population using CT perfusion or MR diffusion. Unfortunately, these imaging modalities are not available in every hospital, and strict selection criteria might exclude patients who could still benefit from EVT. The presence of collaterals on CT angiography (CTA) may offer a more pragmatic imaging criterion that predicts possible benefit from EVT beyond 6 h from time last known well. The aim of this study is to assess the safety and efficacy of EVT for patients treated between 6 and 24 h from time last known well after selection based on the presence of collateral flow. Methods The MR CLEAN-LATE trial is a multicenter, randomized, open-label, blinded endpoint trial, aiming to enroll 500 patients. We will investigate the efficacy of EVT between 6 and 24 h from time last known well in acute ischemic stroke due to a proximal intracranial anterior circulation occlusion confirmed by CTA or MRA. Patients with any collateral flow (poor, moderate, or good collaterals) on CTA will be included. The inclusion of poor collateral status will be restricted to a maximum of 100 patients. In line with the current Dutch guidelines, patients who fulfill the characteristics of included patients in DAWN and DEFUSE 3 will be excluded as they are eligible for EVT as standard care. The primary endpoint is functional outcome at 90 days, assessed with the modified Rankin Scale (mRS) score. Treatment effect will be estimated with ordinal logistic regression (shift analysis) on the mRS at 90 days. Secondary endpoints include clinical stroke severity at 24 h and 5–7 days assessed by the NIHSS, symptomatic intracranial hemorrhage, recanalization at 24 h, follow-up infarct size, and mortality at 90 days, Discussion This study will provide insight into whether EVT is safe and effective for patients treated between 6 and 24 h from time last known well after selection based on the presence of collateral flow on CTA. Trial registration NL58246.078.17 , ISRCTN19922220 , Registered on 11 December 2017

The glycocalyx is an important constituent of blood vessels located between the bloodstream and the endothelium. It plays a pivotal role in intercellular interactions in neuroinflammation, reduction of vascular oxidative stress, and provides a barrier regulating vascular permeability. In the brain, the glycocalyx is closely related to functions of the blood-brain barrier and neurovascular unit, both responsible for adequate neurovascular responses to potential threats to cerebral homeostasis. An aneurysmal subarachnoid hemorrhage (aSAH) occurs following rupture of an intracranial aneurysm and leads to immediate brain damage (early brain injury). In some cases, this can result in secondary brain damage, also known as delayed cerebral ischemia (DCI). DCI is a life-threatening condition that affects up to 30% of all aSAH patients. As such, it is associated with substantial societal and healthcare-related costs. Causes of DCI are multifactorial and thought to involve neuroinflammation, oxidative stress, neuroinflammation, thrombosis, and neurovascular uncoupling. To date, prediction of DCI is limited, and preventive and effective treatment strategies of DCI are scarce. There is increasing evidence that the glycocalyx is disrupted following an aSAH, and that glycocalyx disruption could precipitate or aggravate DCI. This review explores the potential role of the glycocalyx in the pathophysiological mechanisms contributing to DCI following aSAH. Understanding the role of the glycocalyx in DCI could advance the development of improved methods to predict DCI or identify patients at risk for DCI. This knowledge may also alter the methods and timing of preventive and treatment strategies of DCI. To this end, we review the potential and limitations of methods currently used to evaluate the glycocalyx, and strategies to restore or prevent glycocalyx shedding.

Background and Purpose: Though peripheral artery disease (PAD) is a well-known risk factor for ischemic events, better outcomes have been described in acute ischemic stroke patients with co-existing PAD. This paradoxical association has been attributed to remote ischemic preconditioning (RIPC) and might be related to better collateral blood flow. The aim of this study is to compare outcomes after endovascular thrombectomy (EVT) in acute stroke patients with and without PAD and to assess the relation between PAD and collateral grades. Methods: We analyzed acute ischemic stroke patients treated with EVT for an anterior circulation large artery occlusion, included in the Dutch, prospective, multicenter MR CLEAN Registry between March 2014 and November 2017. Collaterals were scored on CT angiography, using a 4-point collateral score. We used logistic regression analysis to estimate the association of PAD with collateral grades and functional outcome, assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included mortality at 90 days, symptomatic intracranial hemorrhage, and stroke progression. Results: We included 2,765 patients for analysis, of whom 254 (9.2%) had PAD. After adjustment for potential confounders, multivariable regression analysis showed no association of PAD with functional outcome [mRS cOR 0.90 (95% CI, 0.7-1.2)], collateral grades (cOR 0.85, 95% CI 0.7-1.1), or safety outcomes. Conclusion: In the absence of an association between the presence of PAD and collateral scores or outcomes after EVT, it may be questioned whether PAD leads to RIPC in patients with acute ischemic stroke due to large vessel occlusion.

Background:Endovascular treatment (EVT) with or without intravenous thrombolysis (IVT) is effective and safe in is-chemic stroke caused by large vessel occlusion, but IVT might delay time to EVT or increase risk of intracranial hemorrhage (ICH). We assessed the influence of prior IVT on time to treatment and risk of ICH in patients treated with EVT.Methods:We analyzed data from the MR CLEAN Registry and included patients with an anterior circulation occlusion treated with EVT who presented directly to an intervention center, between 2014 and 2017. Primary endpoint was the door to groin time. Secondary outcomes were workflow time intervals and safety outcomes. We compared patients who received EVT only with patients who received IVT prior to EVT.Results:We included 1,427 patients directly referred to an intervention center of whom 1,023 (72%) received IVT + EVT. Adjusted door to CT imaging and door to groin time were shorter in IVT + EVT patients (difference 5.7 min [95% CI: 4.6-6.8] and 7.0 min [95% CI: 2.4-12], respectively) while CT imaging to groin time was similar between the groups. Early recanalization on digital subtraction angiography before EVT was seen more often after prior IVT (11 vs. 5.2%, aOR 2.4 [95% CI: 1.4-4.2]). Rates of symptomatic ICH were similar.Conclusion:Prior IVT did not delay door to groin times and was associated with higher rates of early recanalization, without increasing the risk of ICH. Our results do not warrant withholding IVT prior to EVT.

Background and Purpose-To assess the effect of inter-hospital transfer on time to treatment and functional outcome after endovascular treatment (EVT) for acute ischemic stroke, we compared patients transferred from a primary stroke center to patients directly admitted to an intervention center in a large nationwide registry. Methods-MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry is an ongoing, prospective, observational study in all centers that perform EVT in the Netherlands. We included adult patients with an acute anterior circulation stroke who received EVT between March 2014 to June 2016. Primary outcome was time from arrival at the first hospital to arterial groin puncture. Secondary outcomes included the 90-day modified Rankin Scale score and functional independence (modified Rankin Scale score of 0-2). Results-In total 821/1526 patients, (54%) were transferred from a primary stroke center. Transferred patients less often had prestroke disability (227/800 [28%] versus 255/699 [36%]; P=0.02) and more often received intravenous thrombolytics (659/819 [81%] versus 511/704 [73%]; P<0.01). Time from first presentation to groin puncture was longer for transferred patients (164 versus 104 minutes; P<0.01, adjusted delay 57 minutes [95% CI, 51-62]). Transferred patients had worse functional outcome (adjusted common OR, 0.75 [95% CI, 0.62-0.90]) and less often achieved functional independence (244/720 [34%] versus 289/681 [42%], absolute risk difference -8.5% [95% CI, -8.7 to -8.3]). Conclusions-Interhospital transfer of patients with acute ischemic stroke is associated with delay of EVT and worse outcomes in routine clinical practice, even in a country where between-center distances are short. Direct transportation of patients potentially eligible for EVT to an intervention center may improve functional outcome.

Background and Purpose- Previous studies have reported less favorable outcome and less effect of endovascular treatment (EVT) after ischemic stroke in women than in men. Our aim was to study the influence of sex on outcome and on the effect of EVT for ischemic stroke in recent randomized trials on EVT. Methods- We used data from 7 randomized controlled trials on EVT within the HERMES collaboration. The primary outcome was 90-day functional outcome (modified Rankin Scale). We compared baseline characteristics and outcomes between men and women. With ordinal logistic regression, we evaluated the association between EVT and 90-day functional outcome for men and women separately, adjusted for potential confounders. We tested for interaction between sex and EVT. Results- We included 1762 patients in the analyses, of whom 833 (47%) were women. Women were older (median, 70 versus 66 years; P<0.001), were smoking less often (30% versus 44%; P<0.001), and had higher collateral grades (grade 3: 46% versus 35%; P<0.001) than men. Functional independence (modified Rankin Scale score, 0-2) at 90 days was reached by 318 women (39%) and 364 men (39%). The effect of EVT on the ordinal modified Rankin Scale was similar in women (adjusted common odds ratio [acOR], 2.13; 95% CI, 1.47-3.07) and men (acOR, 2.16; 95% CI, 1.59-2.96), with a P for interaction of 0.926. Conclusions- Sex does not influence clinical outcome after EVT and does not modify treatment effect of EVT. Therefore, sex should not be a consideration in the selection of patients for EVT.

Background and Purpose-Endovascular treatment (EVT) of patients with acute ischemic stroke because of large vessel occlusion involves complicated logistics, which may cause a delay in treatment initiation during off-hours. This might lead to a worse functional outcome. We compared workflow intervals between endovascular treatment-treated patients presenting during off- and on-hours. Methods-We retrospectively analyzed data from the MR CLEAN Registry, a prospective, multicenter, observational study in the Netherlands and included patients with an anterior circulation large vessel occlusion who presented between March 2014 and June 2016. Off-hours were defined as presentation on Monday to Friday between 17:00 and 08:00 hours, weekends (Friday 17:00 to Monday 8:00) and national holidays. Primary end point was first door to groin time. Secondary end points were functional outcome at 90 days (modified Rankin Scale) and workflow time intervals. We stratified for transfer status, adjusted for prognostic factors, and used linear and ordinal regression models. Results-We included 1488 patients of which 936 (62.9%) presented during off-hours. Median first door to groin time was 140 minutes (95% CI, 110-182) during off-hours and 121 minutes (95% CI, 85-157) during on-hours. Adjusted first door to groin time was 14.6 minutes (95% CI, 9.3-20.0) longer during off-hours. Door to needle times for intravenous therapy were slightly longer (3.5 minutes, 95% CI, 0.7-6.3) during off-hours. Groin puncture to reperfusion times did not differ between groups. For transferred patients, the delay within the intervention center was 5.0 minutes (95% CI, 0.5-9.6) longer. There was no significant difference in functional outcome between patients presenting during off- and on-hours (adjusted odds ratio, 0.92; 95% CI, 0.74-1.14). Reperfusion rates and complication rates were similar. Conclusions-Presentation during off-hours is associated with a slight delay in start of endovascular treatment in patients with acute ischemic stroke. This treatment delay did not translate into worse functional outcome or increased complication rates.

Introduction: We aimed to develop and validate a prognostic score for disability at discharge and functional outcome at three months in patients with acute ischemic stroke based on clinical information available on admission. Patients and methods: The Dutch Stroke Score (DSS) was developed in 1227 patients with ischemic stroke included in the Paracetamol (Acetaminophen) In Stroke study. Predictors for Barthel Index (BI) at discharge ('DSS-discharge') and modified Rankin Scale (mRS) at three months ('DSS-3 months') were identified in multivariable ordinal regression. The models were internally validated with bootstrapping techniques. The DSS-3 months was externally validated in the PRomoting ACute Thrombolysis in Ischemic StrokE study (1589 patients) and the Preventive Antibiotics in Stroke Study (2107 patients). Model performance was assessed in terms of discrimination, expressed by the area under the receiver operating characteristic curve (AUC), and calibration. Results: At model development, the strongest predictors of Barthel Index at discharge were age per decade over 60 (odds ratio = 1.55, 95% confidence interval (CI) 1.41-1.68), National Institutes of Health Stroke Scale (odds ratio = 1.24 per point, 95% CI 1.22-1.26) and diabetes (odds ratio = 1.62, 95% CI 1.32-1.91). The internally validated AUC was 0.76 (95% CI 0.75-0.79). The DSS-3 months, additionally consisting of previous stroke and atrial fibrillation, performed similarly at internal (AUC 0.75, 95% CI 0.74-0.77) and external validation (AUC 0.74 in PRomoting ACute Thrombolysis in Ischemic StrokE (95% CI 0.72-0.76) and 0.69 in Preventive Antibiotics in Stroke Study (95% CI 0.69-0.72)). Observed outcome was slightly better than predicted. Discussion: The DSS had satisfactory performance in predicting BI at discharge and mRS at three months in ischemic stroke patients. Conclusion: If further validated, the DSS may contribute to efficient stroke unit discharge planning alongside patients' contextual factors and therapeutic needs.

Background and Purpose-Subfebrile body temperature and fever in the first days after stroke are strongly associated with unfavorable outcome. A subgroup analysis of a previous trial suggested that early treatment with paracetamol may improve functional outcome in patients with acute stroke and a body temperature of 36.5 degrees C. In the present trial, we aimed to confirm this finding. Methods-PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2) was a multicenter, randomized, double-blind, placebo-controlled clinical trial. We aimed to include 1500 patients with acute ischemic stroke or intracerebral hemorrhage within 12 hours of symptom onset. Patients were treated with paracetamol in a daily dose of 6 g or matching placebo for 3 consecutive days. The primary outcome was functional outcome at 3 months, assessed with the modified Rankin Scale and analyzed with multivariable ordinal logistic regression. Because of slow recruitment and lack of funding, the study was stopped prematurely. Results-Between December 2011 and October 2015, we included 256 patients, of whom 136 (53%) were allocated to paracetamol. In this small sample, paracetamol had no effect on functional outcome (adjusted common odds ratio, 1.15; 95% confidence interval, 0.74-1.79). There was no difference in the number of serious adverse events (paracetamol n=35 [26%] versus placebo n=28 [24%]). Conclusions-Treatment with high-dose paracetamol seemed to be safe. The effect of high-dose paracetamol on functional outcome remains uncertain. Therefore, a large trial of early treatment with high-dose paracetamol is still needed.

Background There is conflicting evidence about the influence of sex on outcome after spontaneous intracerebral hemorrhage (sICH) and the majority of the research focused on mortality and short-term outcome only. We investigated sex differences in long-term functional outcome after sICH. Methods We used data from a prospective hospital registry and included all consecutive patients with ICH admitted to our institution between January 2006 and July 2014. Functional outcome was assessed by modified Rankin Scale evaluated 3 and 12 months after ICH. We explored the influence of sex on long-term functional outcome using multivariable regression models and additionally by means of propensity score matching. Results We analyzed 823 patients, of whom 380 (46%) women. Women were on average three years older (p < 0.001), men had more often deep hematomas (p = 0.01). Unadjusted mortality rates were significantly increased in women at three months (42% vs. 35%; odds ratio (OR): 1.35; 95% confidence interval (CI): 1.02-1.80). After adjusting for baseline prognostic factors there were no differences between men and women in short- and long-term mortality (OR = 1.01; 95% CI = 0.66-1.54 and OR = 1.04; 95%CI = 0.69-1.57, respectively) and short- and long-term unfavorable outcome (OR = 1.02; 95%CI = 0.67-1.55 and OR = 0.96; 95% CI = 0.62-1.48, respectively). Conclusion We found no sex-related differences in long-term functional outcome in patients with sICH. The apparently worse functional outcome in women can be explained by differences in age.

Background and Purpose— Subfebrile body temperature and fever in the first days after stroke are strongly associated with unfavorable outcome. A subgroup analysis of a previous trial suggested that early treatment with paracetamol may improve functional outcome in patients with acute stroke and a body temperature of ≥36.5°C. In the present trial, we aimed to confirm this finding. Methods— PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2) was a multicenter, randomized, double-blind, placebo-controlled clinical trial. We aimed to include 1500 patients with acute ischemic stroke or intracerebral hemorrhage within 12 hours of symptom onset. Patients were treated with paracetamol in a daily dose of 6 g or matching placebo for 3 consecutive days. The primary outcome was functional outcome at 3 months, assessed with the modified Rankin Scale and analyzed with multivariable ordinal logistic regression. Because of slow recruitment and lack of funding, the study was stopped prematurely. Results— Between December 2011 and October 2015, we included 256 patients, of whom 136 (53%) were allocated to paracetamol. In this small sample, paracetamol had no effect on functional outcome (adjusted common odds ratio, 1.15; 95% confidence interval, 0.74–1.79). There was no difference in the number of serious adverse events (paracetamol n=35 [26%] versus placebo n=28 [24%]). Conclusions— Treatment with high-dose paracetamol seemed to be safe. The effect of high-dose paracetamol on functional outcome remains uncertain. Therefore, a large trial of early treatment with high-dose paracetamol is still needed. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR2365.