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BACKGROUND AND PURPOSE: There is a paucity of evidence regarding the safety of endovascular treatment for patients with acute ischemic stroke due to primary medium-vessel occlusion. The aim of this study was to examine the willingness among stroke physicians to perform endovascular treatment in patients with mild-yet-disabling deficits due to medium-vessel occlusion. MATERIALS AND METHODS: In an international cross-sectional survey consisting of 7 primary medium-vessel occlusion case scenarios, participants were asked whether the presence of personally disabling deficits would influence their decision-making for endovascular treatment despite the patients having low NIHSS scores (100 endovascular treatments per year (risk ratio = 1.63; 95% CI, 1.22–2.17). CONCLUSIONS: The presence of a patient-relevant deficit in low-NIHSS acute ischemic stroke due to medium-vessel occlusion is an important factor for endovascular treatment decision-making. This may have relevance for the conduct and interpretation of low-NIHSS endovascular treatment in randomized trials.

Recent evidence points toward a link between lean body mass (LBM) and cardiovascular capacity in women. This study aimed at determining the sex-specific relationship of LBM with central and peripheral circulatory variables in healthy women and men ( n =70) matched by age (60±12 years versus 58±15 years), physical activity, and cardiovascular risk factors. Regional (legs, arms, and trunk) and whole-body (total) body composition were assessed via dual-energy x-ray absorptiometry. Cardiac structure, function, and central/peripheral hemodynamics were measured via transthoracic echocardiography and the volume-clamp method at rest and peak incremental exercise. Regression analyses determined sex-specific relationships between LBM and cardiovascular variables. Regional and total LBM were lower in women than men ( P r ≥0.53, P ≤0.002) but not men ( P ≥0.156). Leg, arm, and total LBM only associated with LV relaxation in women ( r ≥0.43, P ≤0.013). All LBM variables strongly associated with LV volumes at peak exercise in women ( r ≥0.54, P ≤0.001) but not men and negatively associated with total peripheral resistance at peak exercise in women ( r ≥0.43, P ≤0.023). Adjustment by adiposity-related or cardiovascular risk factors did not alter results. In conclusion, leg and arm LBM independently associate with internal cardiac dimensions, ventricular relaxation, and systemic vascular resistance in a sex-specific manner, with these relationships exclusively present in women.

Background Intravenous thrombolysis with alteplase is widely used in patients with acute ischemic stroke presenting early after symptom onset. Recent phase II trials have suggested that intravenous tenecteplase may be safer and associated with higher early reperfusion rates as compared with alteplase. This study investigates whether intravenous tenecteplase is noninferior to intravenous alteplase for the treatment of acute ischemic stroke. Methods This is a pragmatic, registry‐linked, prospective, randomized (1:1) controlled, open‐label parallel group clinical trial (AcT [Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke]) with blinded end point assessment of 1600 patients to test if intravenous tenecteplase (0.25 mg/kg body weight, maximum dose 25 mg) is noninferior to intravenous alteplase (0.9 mg/kg body weight; maximum dose, 90 mg) in patients with acute ischemic stroke eligible for intravenous thrombolysis in clinical routine. Patients are recruited from comprehensive and primary stroke centers and enrolled using deferral of consent. The proposed sample has at least 90% power with a noninferiority margin of 5%, assuming incidence of the 90‐day modified Rankin Scale score of 0 to 1 is 38% in the tenecteplase and 35% in the alteplase groups, and a loss to follow‐up rate Results The blinded primary end point is the proportion of subjects achieving a 90‐day modified Rankin Scale score of 0 to 1. Key safety outcomes include 24‐hour symptomatic intracerebral hemorrhage and 90‐day all‐cause mortality. All serious adverse events within a 24‐hour period will be reported and coded using the Medical Dictionary for Regulatory Activities. Outcomes are collected either centrally (primary, key secondary, and safety end points) or through ongoing Canadian stroke registries. The primary analysis is a simple unadjusted comparison of proportions. Conclusions Results from the trial will provide real‐world evidence of the effectiveness of intravenous tenecteplase versus alteplase in patients with acute ischemic stroke presenting early after stroke onset.

AIMS Intrinsic sex differences in fundamental blood attributes have long been hypothesized to contribute to the gap in cardiorespiratory fitness between men and women. This study experimentally assessed the role of blood volume and oxygen (O2) carrying capacity on sex differences in cardiac function and aerobic power. METHODS AND RESULTS Healthy women and men (n = 60) throughout the mature adult lifespan (42-88 yr) were matched by age and physical activity levels. Transthoracic echocardiography, central blood pressure and O2 uptake were assessed throughout incremental exercise (cycle ergometry). Main outcomes such as left ventricular end-diastolic volume (LVEDV), stroke volume (SV), cardiac output (Q), and peak O2 uptake (VO2peak), as well as blood volume (BV) were determined with established methods. Measurements were repeated in men following blood withdrawal and O2 carrying capacity reduction matching women's levels. Prior to blood normalization, BV and O2 carrying capacity were markedly reduced in women compared with men (P

The AcT trial (Alteplase Compared to Tenecteplase) compares alteplase or tenecteplase for patients with acute ischemic stroke. All eligible patients are enrolled by deferral of consent. Although the use of deferral of consent in the AcT trial meets the requirements of Canadian policy, we sought to provide a more explicit and rigorous approach to the justification of deferral of consent organized around 3 questions. Ultimately, the approach we outline here could become the foundation for a general justification for deferral of consent.

Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care.In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual.Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI - 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis.Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

Background : Intravenous thrombolysis with alteplase is widely used in acute ischemic stroke patients presenting early after symptom onset. Recent phase II trials have suggested that intravenous tenecteplase may be safer and associated with higher early reperfusion rates as compared to alteplase. This study investigates whether intravenous tenecteplase is non‐inferior to intravenous alteplase for the treatment of acute ischemic stroke. Methods : This is a pragmatic, registry‐linked, prospective, randomized (1:1) controlled, open‐label parallel group clinical trial with blinded endpoint assessment of 1600 patients to test if intravenous tenecteplase (0.25 mg/kg body weight, max dose 25 mg) is non‐inferior to intravenous alteplase (0.9 mg/kg body weight, max dose 90 mg) in patients with acute ischemic stroke eligible for intravenous thrombolysis in clinical routine. Patients are recruited from comprehensive and primary stroke centers and enrolled using deferral of consent. The proposed sample has at least 90% power with a non‐inferiority margin of 5%, assuming incidence of 90‐day mRS 0–1 is 38% in the tenecteplase and 35% in the alteplase groups, and a loss to follow‐up rate < 5%. Results : The blinded primary endpoint is the proportion of subjects achieving a 90‐day mRS (modified Rankin scale) of 0–1. Key safety outcomes include 24‐hour symptomatic intracerebral hemorrhage and 90‐day all‐cause mortality. All serious adverse events within 24‐hour period will be reported and coded using MedDRA. Outcomes are collected either centrally (primary, key secondary and safety endpoints) or through ongoing Canadian stroke registries. The primary analysis is a simple unadjusted comparison of proportions. Conclusion : Results from the trial will provide real‐world evidence of the effectiveness of intravenous tenecteplase vs. alteplase in patients with acute ischemic stroke presenting early after stroke onset. Clinical Trial Registration: NCT03889249 https://clinicaltrials.gov/ct2/show/NCT03889249 This article is protected by copyright. All rights reserved

Background Whether the fundamental hematological and cardiac variables determining cardiorespiratory fitness and their intrinsic relationships are modulated by major constitutional factors, such as sex and age remains unresolved. Methods Transthoracic echocardiography, central hemodynamics and pulmonary oxygen (O2) uptake were assessed in controlled conditions during submaximal and peak exercise (cycle ergometry) in 85 healthy young (20–44 year) and older (50–77) women and men matched by age-status and moderate-to-vigorous physical activity (MVPA) levels. Main outcomes such as peak left ventricular end-diastolic volume (LVEDVpeak), stroke volume (SVpeak), cardiac output (Qpeak) and O2 uptake (VO2peak), as well as blood volume (BV), BV–LVEDVpeak and LVEDVpeak–SVpeak relationships were determined with established methods. Results All individuals were non-smokers and non-obese, and MVPA levels were similar between sex and age groups (P ≥ 0.140). BV per kg of body weight did not differ between sexes (P ≥ 0.118), but was reduced with older age in men (P = 0.018). Key cardiac parameters normalized by body size (LVEDVpeak, SVpeak, Qpeak) were decreased in women compared with men irrespective of age (P ≤ 0.046). Older age per se curtailed Qpeak (P ≤ 0.022) due to lower heart rate (P 2peak was reduced with older age in both sexes (P peak than older men (P = 0.024). Conclusions Sex and age interact on the crucial circulatory relationship between total circulating BV and peak cardiac filling, with older women necessitating more BV to fill the exercising heart than age- and physical activity-matched men.

Background & Purpose Neurovascular research is underfunded, imposing substantial challenges on clinical researchers in the field of neurovascular diseases. We explored what physicians perceive to be the greatest challenges with regard to neurovascular research funding, and how they think the funding crisis in neurovascular research could be overcome. Methods We performed an international, multi-disciplinary survey among physicians involved in the medical care of patients with neurovascular diseases. After providing their demographic data, physicians were asked closed-ended questions on their personal opinion regarding challenges in neurovascular research funding, and how these challenges could be overcome. Physicians also described in their own words what they perceived to be the biggest challenges in obtaining funding. Data were analyzed using descriptive statistics and response clustering. Results Of 233 participating physicians (70.4% male,82.8% senior staff) from 48 countries, 217(97.4%) perceived the discrepancy between required and available funding to be a problem;172(73.8%) considered it a major problem. High competitiveness (61/118 available free text responses[51.7%]), time-consuming application processes (28/118[23.7%]) and administrative requirements (25/118[21.1%]) were identified as key obstacles. Traditional big funding agencies were perceived to be most capable of closing the neurovascular research funding gap, followed by specialty-specific organizations and industry, while philanthropy and crowdfunding were perceived to be less important. Conclusion The gap between required and available funding was perceived to be a major problem in neurovascular research, with high competitiveness, time-consuming funding processes and excessive administrative requirements being the key obstacles to obtaining funding. Traditional funding agencies were perceived to be most capable of closing this funding gap.

Supplemental Digital Content is available in the text., OBJECTIVES: The reduced orthostatic tolerance (OT) that is characteristic of the female sex may be explained by multiple phenotypic differences between sexes. This study aimed to elucidate the mechanistic role of blood volume (BV) and oxygen carrying capacity on sex differences in OT. DESIGN: Experimental intervention. SETTING: University of Calgary, Main Campus, Calgary, AB, Canada. SUBJECTS: Healthy women and men (n = 90) throughout the adult lifespan (20–89 yr) matched by age and physical activity. INTERVENTIONS: Incremental lower body negative pressure (LBNP) in all individuals. Blood withdrawal and oxygen carrying capacity reduction in men to match with women’s levels. MEASUREMENTS AND MAIN RESULTS: Transthoracic echocardiography and central blood pressures were assessed throughout incremental LBNP for 1 hour or until presyncope. Blood uniformization resulted in a precise sex match of BV and oxygen carrying capacity (p ≥ 0.598). A third of women (14/45) and two thirds of men (31/45) prior to blood uniformization completed the orthostatic test without presyncopal symptoms (p-for-sex < 0.001). After blood uniformization, seven out of 45 men completed the test (p-for-sex = 0.081). Left ventricular end-diastolic volume (LVEDV) and stroke volume (SV) were progressively reduced with LBNP in both sexes, with women showing markedly lower volumes than men (p < 0.001). Blood uniformization did not eliminate sex differences in LVEDV and SV. CONCLUSIONS: Sex differences in OT are not present when BV and oxygen carrying capacity are experimentally matched between sexes throughout the adult lifespan.

Blood donation entails acute reductions of cardiorespiratory fitness in healthy men. Whether these effects can be extrapolated to blood donor populations comprising women remains uncertain. The purpose of this study was to comprehensively assess the acute impact of blood withdrawal on cardiac function, central hemodynamics and aerobic capacity in women throughout the mature adult lifespan. Transthoracic echocardiography and O2 uptake were assessed at rest and throughout incremental exercise (cycle ergometry) in healthy women (n = 30, age: 47–77 yr). Left ventricular end-diastolic volume (LVEDV), stroke volume (SV), cardiac output (Q̇) and peak O2 uptake (V̇O2peak), and blood volume (BV) were determined with established methods. Measurements were repeated following a 10% reduction of BV within a week period. Individuals were non-smokers, non-obese and moderately fit (V̇O2peak = 31.4 ± 7.3 mL·min–1·kg–1). Hematocrit and BV ranged from 38.0 to 44.8% and from 3.8 to 6.6 L, respectively. The standard 10% reduction in BV resulted in 0.5 ± 0.1 L withdrawal of blood, which did not alter hematocrit (P = 0.953). Blood withdrawal substantially reduced cardiac LVEDV and SV at rest as well as during incremental exercise (≥10% decrements, P ≤ 0.009). Peak Q̇ was proportionally decreased after blood withdrawal (P < 0.001). Blood withdrawal induced a 10% decrement in V̇O2peak (P < 0.001). In conclusion, blood withdrawal impairs cardiac filling, Q̇ and aerobic capacity in proportion to the magnitude of hypovolemia in healthy mature women. Novelty: The filling of the heart and therefore cardiac output are impaired by blood withdrawal in women. Oxygen delivery and aerobic capacity are reduced in proportion to blood withdrawal.

Introduction The optimal anaesthesia approach for endovascular treatment (EVT) in acute ischaemic stroke is currently unknown. In stroke due to medium vessel occlusions (MeVO), the occluded vessels are particularly small and more difficult to access, especially in restless or uncooperative patients. In these patients, general anaesthesia (GA) may be preferred by physicians to prevent complications due to patient movement. We investigated physicians’ approaches to anaesthesia during EVT for MeVO stroke. Methods In a worldwide, case-based, online survey, physicians’ preferred anaesthesia approach during EVT for MeVO stroke was categorized as “initial GA”, “initial GA if necessary” (depending on patient cooperation), “no initial GA, but conversion if necessary” (start with local anaesthesia or conscious sedation), and “no GA”. Preferred anaesthesia approaches were reported overall and stratified by physician and patient characteristics. Results A total of 366 survey participants provided 1464 responses to 4 primary MeVO EVT case-scenarios. One-third of responses (489/1464 [33%]) favoured no initial GA, but conversion if necessary. Both initial GA and initial GA if necessary were preferred in 368/1464 (25%) of responses respectively. No GA was favoured in 244/1464 (17%). Occlusion location, respondent specialization (interventional neuroradiology), higher age, and female respondent sex were significantly associated with GA preference. GA was more often used in Europe than in other parts of the world ( p Conclusions Anaesthesia approaches in MeVO EVT vary across world regions and patient and physician factors. Most physicians in this survey preferred to start with local anaesthesia or conscious sedation and convert to GA if necessary.

Whether average sex differences in cardiorespiratory fitness can be mainly explained by blood inequalities in the healthy circulatory system remains unresolved. This study evaluated the contribution of blood volume (BV) and oxygen (O2) carrying capacity to the sex gap in cardiac and aerobic capacities in healthy young individuals. Healthy young women and men (n = 28, age range = 20–43 years) were matched by age and physical activity. Echocardiography, blood pressures, and O2 uptake were measured during incremental exercise. Left ventricular end-diastolic volume (LVEDV), stroke volume (SV), cardiac output (Q), peak O2 uptake (VO2peak), and BV were assessed with precise methods. The test was repeated in men after blood withdrawal and reduction of O2 carrying capacity, reaching women’s levels. Before blood normalization, exercise cardiac volumes and output (LVEDV, SV, Q) adjusted by body size and VO2peak (42 ± 9 vs. 50 ± 11 ml⋅min–1⋅kg–1, P < 0.05) were lower in women relative to men. Blood normalization abolished sex differences in cardiac volumes and output during exercise (P ≥ 0.100). Likewise, VO2peak was similar between women and men after blood normalization (42 ± 9 vs. 40 ± 8 ml⋅min–1⋅kg–1, P = 0.416). In conclusion, sex differences in cardiac output and aerobic capacity are not present in experimental conditions matching BV and O2 carrying capacity between healthy young women and men.

OBJECTIVE The contribution of body composition to sex differences in strong prognostic cardiorespiratory variables remains unresolved. This study aimed to elucidate whether body composition determines sex differences in cardiac and oxygen (O2 ) uptake responses to incremental exercise. METHODS Healthy, moderately active women and men (n = 60, age = 60.7 [12.3] years) matched by age and cardiorespiratory fitness were included. Body composition was determined via dual-energy x-ray absorptiometry. Transthoracic echocardiography and O2 uptake were assessed at rest and throughout incremental exercise with established methods. Major cardiac and pulmonary outcomes were normalized by body surface area (BSA), total lean body mass (LBM), or leg LBM. RESULTS Women presented with smaller anthropometrical indices (height, weight, BSA) and LBM compared with men (p < 0.001). Peak exercise cardiac dimensions and output (i.e., peak cardiac outout [Qpeak ]), commonly normalized by BSA, were reduced in women relative to men (p ≤ 0.019). Cardiac sex differences were abolished after normalization by total or leg LBM (p ≥ 0.115). Strong linear relationships of total and leg LBM with Qpeak and peak oxygen uptake were detected exclusively in women (r ≥ 0.53, p ≤ 0.003), independent of body fat percentage. CONCLUSIONS Total and leg LBM stand out as strong independent determinants of cardiac and aerobic capacities in women, regardless of body fat percentage, relationships that are not present in age- and fitness-matched men.

OBJECTIVES To investigate the effects of blood withdrawal on cardiac, hemodynamic, and pulmonary responses to submaximal exercise in females. DESIGN AND METHODS 30 healthy females (63.8 ± 8.3 years) were recruited for this experimental study. Transthoracic echocardiography, non-invasive blood pressure monitoring, and oxygen uptake were assessed during a fixed submaximal workload (100 W) prior to (day 1) and immediately after (day 2) a 10% reduction of blood volume. Main measurements included left ventricular end-diastolic volume, stroke volume, cardiac output, mean arterial pressure, systolic blood pressure, diastolic blood pressure, and oxygen uptake. Blood volume was determined via carbon monoxide rebreathing. RESULTS Participant's blood volume ranged from 3.8 to 6.6 L. Following 10% reduction in blood volume (0.5 ± 0.1 L), left ventricular end-diastolic volume (p ≤ 0.030) and stroke volume (p