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Abstract: Spinels of composition LiM Y Mn2−Y O4, M=Cr3+, Co3+, or Ni2+, Y =0.1 and 1 for the Cr and Co dopants, Y =0.05 and 0.5 for the Ni sample, have been synthesized by a sucrose-aided combustion method. The samples as prepared require of an additional thermal treatment at 700°C, 1h to get stoichiometric single-phase spinels. The samples consist of aggregated particles of small size (45–50nm) as deduced from transmission electron microscopy and X-ray powder diffraction. The electrochemical behaviour of the six spinels as cathodes in lithium cells has been analysed at 5 and 4V under high current, 1C rate. At 5V the discharge capacity of LiNi0.5Mn1.5O4 is higher than the one shown by LiCrMnO4 and LiCoMnO4, and it shows an elevated cyclability, i.e. capacity retention of 85.3% after 100 cycles. At 4V the discharge capacity is similar for LiNi0.05Mn1.95O4, LiCr0.1Mn1.9O4 and LiCo0.1Mn1.9O4, and all the three spinels show similar and very high cyclability, i.e. capacity retention >90% after 100 cycles. The spinels preserve their starting capacity up to currents as high as 2C rate. The nanometric size of the samples explains the high rate capability of the synthesized spinels. [Copyright &y& Elsevier]

Currently, most acute ischemic stroke patients presenting with a large vessel occlusion are first evaluated at a nonthrombectomy-capable center before transfer to a comprehensive stroke center that performs thrombectomy. Interfacility transfer is a complex process that requires extensive coordination between the referring, transporting, and receiving facilities. As a result, long delays are common, contributing to poor clinical outcomes. In this review, we summarize the accumulating literature about the clinical as well as radiological-infarct growth, collateral change, arterial recanalization, and hemorrhagic transformation-changes during interfacility transfer for thrombectomy. Recent evidence shows that clinical/radiological changes during transfer are heterogeneous across patients and impact long-term functional outcomes, highlighting the urgent need to optimize care during this time window. We review some of the most promising therapeutic strategies-for example, penumbral protection to reduce infarct growth-that may improve clinical outcome in patients being transferred to thrombectomy-capable centers. Finally, we discuss key methodological considerations for designing clinical trials aimed at reducing infarct growth during transfer.

Background and Purpose: We aimed to report the characteristics of cerebral venous thrombosis (CVT) in elderly people (aged ≥65 years)., Methods: This multicenter retrospective cohort included elderly patients hospitalized for a first CVT in nine Paris-Ile-de-France hospitals between 2011 and 2021. The estimated incidence was compared to CVT recorded by the French health insurance data system. Lariboisière Hospital's CVT registry allowed comparisons of our elderly cohort with individuals younger than 65 years., Results: One hundred fourteen patients were included in this study (mean age = 74.2 years, range = 65-93, 61% female). The CVT annual incidence in Ile-de-France was 5.9-7.1 per million elderly individuals versus 8.5 per million nationwide. Headaches and focal deficits were the most common initial clinical features (50% and 51%, respectively), followed by seizures and confusion (40% and 27%). Treatment included anticoagulation (93%) and, rarely, endovascular procedure (2%) or craniectomy (1%). Compared with adult patients aged <65 years (younger adults), elderly patients presented fewer headaches (50% vs. 96%, p < 0.01) and intracranial hypertension (7% vs. 22%, p < 0.01) but more seizures and focal deficits (40% vs. 27% and 51% vs. 38%, respectively, p < 0.01). Underlying cancer, hemopathy, and locoregional infections were more frequent in elderly patients than among younger adults (p < 0.01). The prognosis of patients from our elderly cohort was poorer than that of younger adults; 8% died in the acute phase, and 73% had a favorable outcome at 1 year (vs. 1.7% and 87%, respectively, p < 0.01)., Conclusions: CVT in elderly patients has a specific clinical presentation, epidemiology, and risk factors such as cancer or hemopathy, justifying specialized management., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Purpose: The aim of this study was to identify factors that predict favorable functional outcomes in elderly patients with large-vessel occlusion acute ischemic stroke (LVO-AIS) who underwent mechanical thrombectomy (MT)., Methods: We conducted a retrospective observational study using the prospectively maintained Bigdata Observatory for Stroke of China (BOSC) to identify eligible patients who underwent MT for LVO-AIS at four comprehensive stroke centers between August 2019 and February 2022. Inclusion criteria included patients aged 80 years or older with a baseline modified Rankin Scale (mRS) 0-2, baseline National Institutes of Health Stroke Scale (NIHSS) > 6, baseline Alberta Stroke Program Early CT Score (ASPECTS) > 6 who received treatment within 24 h from symptom onset. Pertinent demographic, clinical, and procedural variables were collected. Multivariable regression analyses were performed to identify predictors of favorable long-term functional outcomes, defined as mRS 0-2 at 90 days., Results: A total of 63 patients were included in the study with a mean age of 83 years. Patients with previous diagnosis of atrial fibrillation were more likely to have a favorable functional outcome (OR 2.09, 95% CI 2.09-407.33, p = 0.012), while a higher baseline NIHSS was associated with a less favorable functional outcome (OR 0.64, 95% CI 0.46-0.89, p = 0.007). In addition, there was an observed trend suggesting an association between higher baseline ASPECTS and favorable functional outcomes. This association did not reach statistical significance (OR 2.49, 95% CI 0.94-6.54, p = 0.065)., Conclusion: In this study, we identified factors that predicted a favorable functional outcome in elderly LVO-AIS patients undergoing MT. A higher baseline NIHSS decreased the odds of mRS 0-2 at 90 days, whereas a history of atrial fibrillation increased the odds of a favorable functional outcome. These results emphasize the complex relationship between clinical factors and functional recovery in this vulnerable population., (© 2024. The Author(s).)

Background and Objectives: Cerebral amyloid angiopathy-related inflammation (CAA-RI) and biopsy-positive primary angiitis of the CNS (BP-PACNS) have overlapping clinicoradiologic presentations. It is unknown whether clinical and radiologic features can differentiate CAA-RI from BP-PACNS and whether both diseases have different relapse rates. The objectives of this study were to compare clinicoradiologic presentations and relapse rates in patients with CAA-RI vs BP-PACNS., Methods: Patients with CAA-RI and BP-PACNS were enrolled from 2 retrospective multicenter cohorts. Patients with CAA-RI were biopsy-positive or met probable clinicoradiologic criteria. Patients with BP-PACNS had histopathologic confirmation of CNS angiitis, with no secondary etiology. A neuroradiologist read brain MRIs, blinded to the diagnosis of CAA-RI or BP-PACNS. Clinicoradiologic features were compared using univariable logistic regression models. Relapse rates were compared using a univariable Fine-Gray subdistribution hazard model, with death as a competing risk., Results: This study enrolled 104 patients with CAA-RI (mean age 73 years, 48% female sex) and 52 patients with BP-PACNS (mean age 45 years, 48% female sex). Patients with CAA-RI more often had white matter hyperintense lesions meeting the probable CAA-RI criteria (93% vs 51%, p < 0.001), acute subarachnoid hemorrhage (15% vs 2%, p = 0.02), cortical superficial siderosis (27% vs 4%, p < 0.001), ≥1 lobar microbleed (94% vs 26%, p < 0.001), past intracerebral hemorrhage (17% vs 4%, p = 0.04), ≥21 visible centrum semiovale perivascular spaces (34% vs 4%, p < 0.01), and leptomeningeal enhancement (70% vs 27%, p < 0.001). Patients with BP-PACNS more often had headaches (56% vs 31%, p < 0.01), motor deficits (56% vs 36%, p = 0.02), and nonischemic parenchymal gadolinium enhancement (82% vs 16%, p < 0.001). The prevalence of acute ischemic lesions was 18% in CAA-RI and 22% in BP-PACNS ( p = 0.57). The features with the highest specificity for CAA-RI were acute subarachnoid hemorrhage (98%), cortical superficial siderosis (96%), past intracerebral hemorrhage (96%), and ≥21 visible centrum semiovale perivascular spaces (96%). The probable CAA-RI criteria had a 71% sensitivity (95% CI 44%-90%) and 91% specificity (95% CI 79%-98%) in differentiating biopsy-positive CAA-RI from BP-PACNS. The rate of relapse in the first 2 years after remission was lower in CAA-RI than in BP-PACNS (hazard ratio 0.46, 95% CI 0.22-0.96, p = 0.04)., Conclusion: Clinicoradiologic features differed between patients with CAA-RI and those with BP-PACNS. Specific markers for CAA-RI were hemorrhagic signs of subarachnoid involvement, past intracerebral hemorrhage, ≥21 visible centrum semiovale perivascular spaces, and the probable CAA-RI criteria. A biopsy remains necessary for diagnosis in some cases of CAA-RI. The rate of relapse in the first 2 years after disease remission was lower in CAA-RI than in BP-PACNS.

Background and Objectives: IV tenecteplase is an alternative to alteplase before mechanical thrombectomy (MT) in patients with large-vessel occlusion (LVO) ischemic stroke. Little data are available on its use in patients with large ischemic core. We aimed to compare the efficacy and safety of both thrombolytics in this population., Methods: We conducted a retrospective analysis of patients with anterior circulation LVO strokes and diffusion-weighed imaging Alberta Stroke Program Early CT Score (DWI-ASPECTS) ≤5 treated with tenecteplase or alteplase before MT from the TETRIS (tenecteplase) and ETIS (alteplase) French multicenter registries. Primary outcome was reduced disability at 3 months (ordinal analysis of the modified Rankin scale [mRS]). Safety outcomes were 3-month mortality, parenchymal hematoma (PH), and symptomatic intracranial hemorrhage (sICH). We used propensity score overlap weighting to reduce baseline differences between treatment groups., Results: We analyzed 647 patients (tenecteplase: n = 194; alteplase: n = 453; inclusion period 2015-2022). Median (interquartile range) age was 71 (57-81) years, with NIH Stroke Scale score 19 (16-22), DWI-ASPECTS 4 (3-5), and last seen well-to-IV thrombolysis and puncture times 165 minutes (130-226) and 260 minutes (203-349), respectively. After MT, the successful reperfusion rate was 83.1%. After propensity score overlap weighting, all baseline variables were well balanced between both treatment groups. Compared with patients treated with alteplase, patients treated with tenecteplase had better 3-month mRS (common odds ratio [OR] for reduced disability: 1.37, 1.01-1.87, p = 0.046) and lower 3-month mortality (OR 0.52, 0.33-0.81, p < 0.01). There were no significant differences between thrombolytics for PH (OR 0.84, 0.55-1.30, p = 0.44) and sICH incidence (OR 0.70, 0.42-1.18, p = 0.18)., Discussion: Our data are encouraging regarding the efficacy and reassuring regarding the safety of tenecteplase compared with that of alteplase in bridging therapy for patients with LVO strokes and a large ischemic core in routine clinical care. These results support its consideration as an alternative to alteplase in bridging therapy for patients with large ischemic cores., Trials Registration Information: NCT03776877 (ETIS registry) and NCT05534360 (TETRIS registry)., Classification of Evidence: This study provides Class III evidence that patients with anterior circulation LVO stroke and DWI-ASPECTS ≤5 treated with tenecteplase vs alteplase before MT experienced better functional outcomes and lower mortality at 3 months.

Background and Purpose: Patients with acute ischaemic stroke and a large vessel occlusion who present to a non-endovascular-capable centre often require inter-hospital transfer for thrombectomy. Whether the inter-hospital transfer time is associated with 3-month functional outcome is poorly known., Methods: Acute stroke patients enrolled between January 2015 and December 2022 in the prospective French multicentre Endovascular Treatment of Ischaemic Stroke registry were retrospectively analysed. Patients with an anterior circulation large vessel occlusion transferred from a non-endovascular to a comprehensive stroke centre for thrombectomy were eligible. Inter-hospital transfer time was defined as the time between imaging in the referring hospital and groin puncture for thrombectomy. The relationship between transfer time and favourable 3-month functional outcome (modified Rankin Scale 0-2) was assessed through a mixed logistic regression model adjusting for centre and symptom-onset-to-referring-hospital imaging time, age, sex, diabetes, referring hospital National Institutes of Health Stroke Scale score, Alberta Stroke Programme Early Computed Tomography Score, occlusion site and intravenous thrombolysis use., Results: Overall, 3769 patients were included (median inter-hospital transfer time 161 min, interquartile range 128-195; 46% with favourable outcome). A longer transfer time was independently associated with lower rates of favourable outcome (p < 0.001). Compared to patients with transfer time below 120 min, there was a 15% reduction in the odds of achieving favourable outcome for transfer times between 120 and 180 min (adjusted odds ratio 0.85; 95% confidence interval 0.67-1.07), and a 36% reduction for transfer times beyond 180 min (adjusted odds ratio 0.64; 95% confidence interval 0.50-0.81)., Conclusions: A shorter inter-hospital transfer time is strongly associated with favourable 3-month functional outcome. A speedier inter-hospital transfer is of critical importance to improve outcome., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Objectives: Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke are controversial. With the publication of several randomized controlled trials (RCTs) and the recent results of the RESIST trial, it may be possible to identify the patient population that may (or may not) benefit from RIC. This systematic review and meta-analysis aims to evaluate the effectiveness and safety of RIC in patients with ischemic stroke receiving different treatments by pooling data of all randomized controlled studies to date., Methods: We searched the PubMed, Embase, Cochrane, Elsevier, and Web of Science databases to obtain articles in all languages from inception until May 25, 2023. The primary outcome was the modified Rankin Scale (mRS) score at the specified endpoint time in the trial. The secondary outcomes were change in NIH Stroke Scale (NIHSS) and recurrence of stroke events. The safety outcomes were cardiovascular events, cerebral hemorrhage, and mortality. The quality of articles was evaluated through the Cochrane risk assessment tool. This study was registered in PROSPERO (CRD42023430073)., Results: There were 7,657 patients from 22 RCTs included. Compared with the control group, patients who received RIC did not have improved mRS functional outcomes, regardless of whether they received medical management, reperfusion therapy with intravenous thrombolysis (IVT), or mechanical thrombectomy (MT). In the medical management group, patients who received RIC had decreased incidence of stroke recurrence (risk ratio 0.63, 95% CI 0.43-0.92, p = 0.02) and lower follow-up NIHSS score by 1.72 points compared with the control group ( p < 0.00001). There was no increased risk of adverse events including death or cerebral hemorrhage in the IVT or medical management group., Discussion: In patients with ischemic stroke who are not eligible for reperfusion therapy, RIC did not affect mRS functional outcomes but significantly improved the NIHSS score at the follow-up endpoint and reduced stroke recurrence, without increasing the risk of cerebral hemorrhage or death. In patients who received IVT or MT, the benefit of RIC was not observed.

Rationale: Mechanical thrombectomy (MT) associated with the best medical treatment (BMT) has recently shown efficacy for the management of acute ischemic stroke (AIS) secondary to a large vessel occlusion. However, evidence is lacking regarding the benefit of MT for more distal occlusions., Aim: To evaluate the efficacy in terms of good clinical outcome at 3 months of MT associated with the BMT over the BMT alone in AIS related to a distal occlusion., Methods: The DISCOUNT trial is a multicenter open-label randomized controlled trial involving French University hospitals. Adult patients (⩾18 years) with an AIS involving the anterior or posterior circulation secondary to a distal vessel occlusion within 6 h of symptom onset or within 24 h if no hyperintense signal on fluid attenuation inversion recovery acquisition will be randomized 1:1 to receive either MT associated with the BMT (experimental group) or BMT alone (control group). The number of patients to be included is 488., Study Outcomes: The primary outcome is the rate of good clinical outcome at 3 months defined as a modified Rankin scale (mRS) ⩽2 and evaluated by an independent assessor blinded to the intervention arm. Secondary outcomes include recanalization of the occluded vessel within 48 h, angiographic reperfusion in the experimental group, 3-month excellent clinical outcome (mRS ⩽ 1), all adverse events, and death. A cost utility analysis will estimate the incremental cost per quality-adjusted life year (QALY) gained., Discussion: If positive, this study will open new insights in the management of AISs., Trial Registration: ClinicalTrials.gov: NCT05030142 registered on 1 September 2021., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: B.G. has received grants from the French Ministry of Health and is the primary investigator of the TITAN, DIRECT ANGIO, and IA-RESCUE trial, and consulting fees from Boerhinger Ingelheim, Air Liquide, MIVI, Medtronic, Microvention, and Penumbra. A.S. reports conflicts of interest with Medtronic, Balt Extrusion, and Microvention (consultant). F.C. reports conflicts of interest with Medtronic, Balt Extrusion (consultant), ClinSearch (core lab), Penumbra, Stryker (payment for reading), and Artedrone (Board). J.-C.G. reports conflicts of interest with Stryker (consultant), Medtronic (consultant), Microvention (consultant), Balt, and Intradys (consultant). I.D.-Z. reports a conflict of interest with Medtronic (honoraria for research, lecturing and acting as an advisor). G.T. reports a conflict of interest with Guerbet France (Lecturing fees). N.B. reports a conflict of interest with Stryker and QApel (consultant). I.S. reports a conflict of interest with Sanofi Synthé-Labo, Servier, Boheringer Ingelheim, Astra-Zeneca, Novonordisk, Medtronic (consultant), and BMS-Pfizer (Lecturing fees). Prof. Cognard reports a conflict of interest with Medtronic, Stryker, Microvention, Cerenovus, and MIVI (consultant). S.A. reports a conflict of interest with Boehringer Ingelheim, Astra-Zeneca, Pfizer, and Amgen (participation in advisory meetings and satellite symposia). S.A. is also the principal investigator of the Tenecteplase treatment in Ischemic Stroke (TETRIS) registry (financial support from Boehringer Ingelheim) and of the ToGiac trial (supported by a research grant from Roche-Shugai). S.R. reports conflict of interest with Boheringer Ingelheim, Bristol-Myers Squibb (scientific expertise), and Acticor (study coordination).

Background: The choice of the first-line technique in vertebrobasilar occlusions (VBOs) remains challenging. We aimed to report outcomes in a large cohort of patients and to compare the efficacy and safety of contact aspiration (CA) and combined technique (CoT) as a first-line endovascular technique in patients with acute VBOs., Methods: We retrospectively analyzed clinical and neuroradiological data of patients with VBOs from the prospective, multicenter, observational Endovascular Treatment in Ischemic Stroke (ETIS) Registry in France between January 2015 and August 2023. The primary outcome was the first pass effect (FPE) rate, whereas modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3 and 2c-3, number of passes, need for rescue strategy, modified Rankin Scale (mRS) 0-2, mortality, and symptomatic intracranial hemorrhage (sICH) were secondary outcomes. We performed univariate and multivariate analyses to investigate differences between the two groups., Results: Among the 583 included patients (mean age 66.2 years, median National Institutes of Health Stroke Scale (NIHSS) 13, median posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS) 8), 393 were treated with CA alone and 190 with CoT. Procedures performed with CA were shorter compared with CoT (28 vs 47 min, P<0.0001); however, no differences were observed in terms of FPE (CA 43.3% vs CoT 38.4%, P=0.99), and successful final recanalization (mTICI 2b-3, CA 92.4% vs CoT 91.8%, P=0.74) did not differ between the two groups. Functional independence and sICH rates were also similar, whereas mortality was significantly lower in the CA group (34.5% vs 42.9%; OR 1.79, 95% CI 1.03 to 3.11)., Conclusions: We observed no differences in FPE, mTICI 2b-3, sICH, and functional independence between the two study groups. First-line CA was associated with shorter procedures and lower mortality rates than CoT., Competing Interests: Competing interests: JC is a consultant for Balt, Medtronic, Stryker. GM is a consultant for Balt USA, Bracco Imaging, Johnson&Johnson Medical Devices&Diagnostics Group, Medtronic, MicroVention, Phenox, Stryker., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although carotid web (CaW) is increasingly diagnosed as a cause of cryptogenic stroke, data are still limited to monocentric small sample cohort. To broaden knowledge on symptomatic CaW, CAROWEB registry has been recently implemented., Aims: In a large cohort of symptomatic CaW patients, we described epidemiologic characteristics, admission clinical and imaging features, and the current management including the secondary preventive strategy choice made in comprehensive French Stroke Units., Methods: CAROWEB is an ongoing French observational multicenter registry enrolling consecutive CaW patients diagnosed after an ipsilateral ischemic stroke (IS) or transient ischemic attack (TIA). Submitted cases were validated by two experienced neurologist and neuroradiologist. Clinical, imaging, and management features were collected for this study., Results: Between June 2019 and December 2021, 244 cases were submitted by 14 centers, 42 rejected, and 202 included (IS, 91.6%; TIA, 7.9%; retinal infarction, 0.5%; mean age, 50.8 ± 12.2 years; female, 62.9%; Caucasian, 47.5%; Afro-Caribbean, 20.3%). IS patients showed median (interquartile range (IQR)) admission National Institutes of Health Stroke Scale (NIHSS) score, 8 (2-15); intracranial artery occlusion, 71.8%; ipsilateral chronic cerebral infarction (CCI), 16.3%; and reperfusion treatment, 57.3%. CaW was not identified during the mechanical thrombectomy procedure in 30 of 85 (35.3%) patients. Secondary prevention was invasive in 55.6% (stenting, n = 80; surgery, n = 30). In multivariable analysis, the invasive therapeutic option was associated with ipsilateral CCI (odds ratio (OR): 4.24 (1.27-14.2), p = 0.019) and inversely associated with risk factors (OR: 0.47 (0.24-0.91), p = 0.025) and admission NIHSS score (OR: 0.93 (0.89-0.97), p = 0.001)., Conclusion: CaW must be considered in all ethnic groups including Caucasians. Secondary prevention is heterogeneous in large French Stroke Centers. The absence of risk factors, milder severity strokes, and ipsilateral CCI were predictive variables of secondary invasive treatment. The high rate of invasive treatment suggests that medical treatment alone is deemed ineffective to avoid recurrence and emphasize the need of randomized trials., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background & Purpose: Carotid Web (CaW) is a growingly recognized cause of ischemic stroke, associated with a high recurrence risk. Several therapeutic strategies have been proposed as a tertiary prevention including carotid stenting, endarterectomy and antithrombotic medications. Among these, carotid stenting with dual-layer stent may be promising to adequately cover the focal arterial dysplasia. Our aim was to investigate the safety and efficacy of the Casper stent in the treatment of symptomatic CaW., Methods: We conducted a retrospective analysis of consecutive patients presenting with a symptomatic CaW and included in the ongoing prospective observational multicenter CAROWEB registry. The study period was January 2015 to December 2021. Inclusion criteria were CaW treated with dual-layer Casper stent. Patients treated with other types of carotid stent, endarterectomy or antithrombotic medication were excluded. Clinical and radiological initial data and outcomes were recorded., Results: twenty-seven patients (with 28 caw) were included. median age was 52 (iqr: 46-68). median delay between index cerebrovascular event and cervical stenting was 9 days (IQR: 6-101). In all cases, the cervical carotid stenting was successfully performed. No major perioperative complication was recorded. No recurrent stroke or transient ischemic attack was observed during a median follow-up time of 272 days (IQR: 114-635). Long-term imaging follow-up was available in 25/28 (89.3%) stented CaW with a median imaging follow-up of 183 days (IQR: 107-676; range: 90-1542). No in-stent occlusion or stenosis was detected., Conclusion: In this study, carotid stenting with dual-layer Casper stent in the treatment of symptomatic CaW was effective regarding stroke recurrence prevention and safe, without procedural nor delayed detected adverse event. However, the optimal therapeutic approach of symptomatic CaW still needs to be explored through randomized trials., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Though there is increasing evidence on the effect of long working hours (LWH) and stroke, few studies have distinguished stroke subtypes. We examined the associations between LWH and ischaemic or haemorrhagic stroke after adjusting for cardiovascular risk factors., Methods: From a national population-based cohort CONSTANCES, baseline questionnaires and initial health examinations were used to retrieve sociodemographic and cardiovascular risk factors from 2012 to 2018. LWH were defined as self-reported working time≥10 hours daily for at least 50 days per year. Incident cases of stroke were collected using International Classification of Disease codes recorded in the National Health Data System. Associations between LWH and stroke were investigated using multinomial models adjusted for cardiovascular risk factors., Results: Among the 160 751 participants who were free from stroke at baseline, exposure to LWH≥10 years was reported by 20 723 participants, and 190 incident cases of stroke were identified, including 134 ischaemic and 56 haemorrhagic. Exposure to LWH was associated with an elevated odds of ischaemic stroke (OR=1.61 (1.04-2.49)) and haemorrhagic stroke (OR=2.50 (1.38-4.53)) in unadjusted models. In adjusted multivariable models, only the LWH association with haemorrhagic stroke remained significant (aOR=1.92 (1.01-3.09))., Conclusions: LWH were associated with stroke, though it remained significant for haemorrhagic stroke only after adjustments. Differences in direct and indirect biological pathways and lack of power in the ischaemic subgroup may explain these results and further studies on the impact of mediating and effect measure modifying factors are needed. Nevertheless, policies that attenuate effects of both LWH and cardiovascular risks factor are warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Cerebral venous sinus thrombosis (CVST) is a rare disease with highly variable clinical presentation and outcomes. Clinical studies suggest a role of inflammation and coagulation in CVST outcomes. The aim of this study was to investigate the association of inflammation and hypercoagulability biomarkers with CVST clinical manifestations and prognosis., Methods: This prospective multicenter study was conducted from July 2011 to September 2016. Consecutive patients referred to 21 French stroke units and who had a diagnosis of symptomatic CVST were included. High-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), D-dimer, and thrombin generation using calibrated automated thrombogram system were measured at different time points until 1 month after anticoagulant therapy discontinuation., Results: Two hundred thirty-one patients were included. Eight patients died, of whom 5 during hospitalization. The day 0 hs-CRP levels, NLR, and D-dimer were higher in patients with initial consciousness disturbance than in those without (hs-CRP: 10.2 mg/L [3.6-25.5] vs 23.7 mg/L [4.8-60.0], respectively; NLR: 3.51 [2.15-5.88] vs 4.78 [3.10-9.59], respectively; D-dimer: 950 μg/L [520-2075] vs 1220 μg/L [950-2445], respectively). Patients with ischemic parenchymal lesions (n = 31) had a higher endogenous thrombin potential 5pM than those with hemorrhagic parenchymal lesions (n = 31): 2025 nM min (1646-2441) vs 1629 nM min (1371-2090), respectively ( P  = .0082). Using unadjusted logistic regression with values >75th percentile, day 0 hs-CRP levels of >29.7 mg/L (odds ratio, 10.76 [1.55-140.4]; P  = .037) and day 5 D-dimer levels of >1060 mg/L (odds ratio, 14.63 [2.28-179.9]; P  = .010) were associated with death occurrence., Conclusion: Two widely available biomarkers measured upon admission, especially hs-CRP, could help predict bad prognosis in CVST in addition to patient characteristics. These results need to be validated in other cohorts., (© 2023 The Authors.)

Background: Laminopathies are caused by rare alterations in LMNA , leading to a wide clinical spectrum. Though muscular dystrophy begins at early ages, disease progression is different in each patient. We investigated variability in laminopathy phenotypes by performing a targeted genetic analysis of patients diagnosed with LMNA -related muscular dystrophy to identify rare variants in alternative genes, thereby explaining phenotypic differences. Methods: We analyzed 105 genes associated with muscular diseases by targeted sequencing in 26 pediatric patients of different countries, diagnosed with any LMNA -related muscular dystrophy. Family members were also clinically assessed and genetically analyzed. Results: All patients carried a pathogenic rare variant in LMNA . Clinical diagnoses included Emery-Dreifuss muscular dystrophy (EDMD, 13 patients), LMNA -related congenital muscular dystrophy (L-CMD, 11 patients), and limb-girdle muscular dystrophy 1B (LGMD1B, 2 patients). In 9 patients, 10 additional rare genetic variants were identified in 8 genes other than LMNA . Genotype-phenotype correlation showed additional deleterious rare variants in five of the nine patients (3 L-CMD and 2 EDMD) with severe phenotypes. Conclusion: Analysis f known genes related to muscular diseases in close correlation with personalized clinical assessments may help identify additional rare variants of LMNA potentially associated with early onset or most severe disease progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cesar, Coll, Fiol, Fernandez-Falgueras, Cruzalegui, Iglesias, Moll, Perez-Serra, Martínez-Barrios, Ferrer-Costa, Olmo, Puigmulè, Alcalde, Lopez, Pico, Berrueco, Brugada, Zschaeck, Natera-de Benito, Carrera-García, Exposito-Escudero, Ortez, Nascimento, Brugada, Sarquella-Brugada and Campuzano.)

Molecular screening for pathogenic mutations in sudden cardiac death (SCD)-related genes is common practice for SCD cases. However, test results may lead to uncertainty because of the identification of variants of unknown significance (VUS) occurring in up to 70% of total identified variants due to a lack of experimental studies. Genetic variants affecting potential splice site variants are among the most difficult to interpret. The aim of this study was to examine rare intronic variants identified in the exonic flanking sequence to meet two main objectives: first, to validate that canonical intronic variants produce aberrant splicing; second, to determine whether rare intronic variants predicted as VUS may affect the splicing product. To achieve these objectives, 28 heart samples of cases of SCD carrying rare intronic variants were studied. Samples were analyzed using 85 SCD genes in custom panel sequencing. Our results showed that rare intronic variants affecting the most canonical splice sites displayed in 100% of cases that they would affect the splicing product, possibly causing aberrant isoforms. However, 25% of these cases (1/4) showed normal splicing, contradicting the in silico results. On the contrary, in silico results predicted an effect in 0% of cases, and experimental results showed >20% (3/14) unpredicted aberrant splicing. Thus, deep intron variants are likely predicted to not have an effect, which, based on our results, might be an underestimation of their effect and, therefore, of their pathogenicity classification and family members’ follow-up.

Background: Hyperintense Acute Reperfusion Marker (HARM) is a hyperintense subarachnoid signal on FLAIR MRI sequence caused by gadolinium contrast leakage into the subpial space. While, on FLAIR, HARM may mimic subarachnoid hemorrhage, it is differentiated from it on computed tomography (CT) and SWAN MRI sequences. Cerebral microbleeds are black, rounded spots on SWAN caused by blood-products deposition following red blood cell leakage from small cerebral vessels brain. Both microbleeds and HARM carry important prognostic implication as they are associated with blood-brain barrier disruption and an increased risk of intracerebral hemorrhage., Case Presentation: A 79-year-old man presented with aphasia and right hemiparesis due to ischemic stroke with left middle cerebral artery occlusion. Admission NIHSS score was 7, and he was successfully treated by intravenous thrombolysis and mechanical thrombectomy. On day 1, his clinical condition worsened, and he had an urgent gadolinium-enhanced MRI. There was no evidence of early recurrence, nor of hemorrhage on SWAN or on FLAIR. Left middle cerebral artery was permeable. The patient was anticoagulated for newly diagnosed atrial fibrillation, and a second MRI following a generalized tonic-clonic seizure showed multiple left hemispheric diffusion-weighted imaging (DWI) hyperintense spots and a left hemispheric sub-arachnoid hyperintensity on FLAIR, compatible with a subarachnoid hemorrhage. This diagnosis was excluded by SWAN MRI sequence and a normal cerebral CT the same day. The diagnosis of HARM was retained. At day 9, patient's condition improved, and a control MRI did not show evidence of HARM. However, numerous microbleeds were detected in the left hemisphere only (ipsilateral with HARM and stroke)., Conclusions: This case highlights first of all the importance of differentiating HARM and subarachnoid hemorrhage, especially in an anticoagulated patient with clinical aggravation. Secondly, it is crucial to identify microbleeds and understand their pathophysiology, as they are associated with higher risk of hemorrhage and stroke recurrence in ischemic stroke patients. Finally, the mono-hemispheric appearance of microbleeds in this case suggests for the first time that, in some acute ischemic stroke patients, a relationship between HARM and cerebral microbleeds may exist., (© 2022. The Author(s).)

Background and Purpose: Ischemic stroke is one of the most common causes of morbidity and mortality and has numerous clinical mimics. Previous studies have suggested a potential role of the tryptophan-serotonin (5-HT)-kynurenine (TSK) axis in ischemic stroke. Studies assessing this axis in the hyperacute phase of ischemic stroke (<4.5 h) are lacking. This prospective study thus evaluates the TSK axis in transient ischemic attack (TIA) and hyperacute ischemic stroke (AIS) patients. Methods: This study included 28 patients (24 AIS and 4 TIA) and 29 controls. The blood and urine samples of patient were collected within 4.5 h of symptoms onset (day 0, D0), then at 24 h and 3 months. Control blood and urine samples were collected once (D0). The TSK axis markers measured were platelet serotonin transporter (SERT) and 5-HT 2A receptor (5-HT 2A R) densities and platelet, plasma, and urinary 5-HT, plasma and urinary 5-hydroxyindole acetic acid (5-HIAA), and plasma kynurenine and tryptophan (TRP) levels. Results: At D0, patients exhibited a lower ( p = 10 -5 ) platelet SERT density, higher ( p < 10 -6 ) platelet 5-HT 2A R density, higher ( p = 10 -5 ) plasma kynurenine/tryptophan (K/T) ratio, and higher urinary 5-HT ( p = 0.011) and 5-HIAA ( p = 0.003) levels than controls. Conclusions: We observed, for the first time, a hyperacute dysregulation of the serotonergic axis, and hyperacute and long-lasting activation of the tryptophan-kynurenine pathway in brain ischemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saccaro, Pico, Chadenat, Richard, Launay, Bastenaire, Jullien, Lambert, Feuga, Macquet, Callebert, Lambert and Spreux-Varoquaux.)

Background and Objectives: We aimed to analyze the epidemiologic, clinical, and paraclinical features of adolescents with cerebral venous thrombosis (CVT) and its therapeutic management and outcome., Methods: This multicenter retrospective cohort included patients 10 to 18 years of age hospitalized for a first episode of CVT in 2 French regions between 1999 and 2019. The number of cases was compared to the number recorded by the French health insurance system. The CVT registry of the Lariboisière hospital allowed comparisons with adults., Results: One hundred two patients were included (52.9% female; median age 15.1 years). Estimated incidence was 0.37 to 0.38 per 100,000 adolescents per year; 45.5% of patients presented with focal deficits or seizures or in a coma. Male patients were younger than female patients (14.2 vs 15.6 years; p < 0.01) and more often admitted to intensive care (52.1% vs 24.1%; p = 0.0,035). The lateral sinus was the most common CVT location (72.3%), and 29.4% of adolescents had associated venous infarction or hematoma. Most patients (94.1%) received anticoagulation. Treatment also included an endovascular procedure (2.9%), decompressive craniectomy (4.9%), and CSF shunt (6.9%). The most frequently identified CVT-associated condition was local infection in male (18.6%) and systemic disease in female (14.8%; p < 0.001) patients. The proportion of CVTs in adolescents without an identified associated condition or risk factor was low (1.9% vs 11.4% in adults; p < 0.002). Adverse outcome at 1 year was more frequent than in adults (33.3% vs 11.8%; p = 0.0,001)., Discussion: CVT in adolescents is rare and complex with specific epidemiology, including differences in clinical presentation and associated conditions between sexes, and more severe outcomes than in adults. Careful specialized management and follow-up are therefore recommended., (© 2021 American Academy of Neurology.)

Introduction: Cerebral venous thrombosis (CVT) is a rare disease with highly variable clinical presentation and outcome. Etiological assessment may be negative. The clinical and radiological presentation and evolution can be highly variable. The mechanisms involved in this variability remain unknown. Objective: The aim of this multicenter French study registered on ClinicalTrials.gov (NCT02013635) was therefore to prospectively recruit a cohort of patients with cerebral venous thrombosis (FPCCVT) in order to study thrombin generation and clot degradation, and to evaluate their influence on clinical radiological characteristics. The first part of the study was to compare our cohort with a reference cohort. Methods: This prospective, multicenter, French study was conducted from July 2011 to September 2016. Consecutive patients (aged >15 years) referred to the stroke units of 21 French centers and who had a diagnosis of symptomatic CVT were included. All patients gave their written informed consent. The diagnosis of CVT had to be confirmed by imaging. Clinical, radiological, biological, and etiological characteristics were recorded at baseline, at acute phase, at 3 months and at last follow-up visit. Thrombophilia screening and the choice of treatment were performed by the attending physician. All data were compared with data from the International Study on CVT published by Ferro et al. Results: Two hundred thirty-one patients were included: 117 (50.6%) had isolated intracranial hypertension, 96 (41.5%) had focal syndrome. During hospitalization, 229 (99.1%) patients received anticoagulant treatment. Median length of hospital stay was 10 days. Five patients died during hospitalization (2.2%). At 3 months, 216 patients (97.0%) had follow-up with neurological data based on an outpatient visit. The mean duration of antithrombotic treatment was 9 months, and the mean time to last follow-up was 10.5 months. At the end of follow-up, eight patients had died, and 26 patients were lost to follow-up. At least one risk factor was identified in 200 patients. Conclusions: We demonstrated that the FPCCVT cohort had radiological, biological, and etiological characteristics similar to the historical ISCVT cohort. Nevertheless, the initial clinical presentation was less severe in our study probably due to an improvement in diagnostic methods between the two studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Triquenot Bagan, Crassard, Drouet, Barbieux-Guillot, Marlu, Robinet-Borgomino, Morange, Wolff, Grunebaum, Klapczynski, André-Kerneis, Pico, Martin-Bastenaire, Ellie, Menard, Rouanet, Freyburger, Godenèche, Allano, Moulin, Mourey, Derex, Berruyer, Runavot, Trichet, Viader, Le Querrec, Husein, Cluet-Dennetiere, Macian-Montoro, Donnard, Guillon, Ternisien, Zuber, Laplanche, Tassan, Peeltier, Canaple, Roussel, Gaillard, Scavazza and Le Cam Duchez.)

Acute myocardial infarction and ischemic stroke are leading causes of morbidity and mortality worldwide. Although reperfusion therapies have greatly improved the outcomes of patients with these conditions, many patients die or are severely disabled despite complete reperfusion. It is therefore important to identify interventions that can prevent progression to ischemic necrosis and limit ischemia-reperfusion injury. A possible strategy is ischemic conditioning, which consists of inducing ischemia - either in the ischemic organ or in another body site [i.e., remote ischemic conditioning (RIC), e.g., by inflating a cuff around the patient's arm or leg]. The effects of ischemic conditioning have been studied, alone or in combination with revascularization techniques. Based on the timing (before, during, or after ischemia), RIC is classified as pre-, per-/peri-, or post-conditioning, respectively. In this review, we first highlight some pathophysiological and clinical similarities and differences between cardiac and cerebral ischemia. We report evidence that RIC reduces circulating biomarkers of myocardial necrosis, infarct size, and edema, although this effect appears not to translate into a better prognosis. We then review cutting-edge applications of RIC for the treatment of ischemic stroke. We also highlight that, although RIC is a safe procedure that can easily be implemented in hospital and pre-hospital settings, its efficacy in patients with ischemic stroke remains to be proven. We then discuss possible methodological issues of previous studies. We finish by highlighting some perspectives for future research, aimed at increasing the efficacy of ischemic conditioning for improving tissue protection and clinical outcomes, and stratifying myocardial infarction and brain ischemia patients to enhance treatment feasibility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Saccaro, Aimo, Emdin and Pico.)

Introduction: Long QT syndrome is the main arrhythmogenic disease responsible for sudden death in infants, especially in the first days of life. Performing an electrocardiogram in newborns could enable early diagnosis and adoption of therapeutic measures focused on preventing lethal arrhythmogenic events. However, the inclusion of an electrocardiogram in neonatal screening protocols still remains a matter of discussion. To comprehensively analyse the potential clinical value of performing an electrocardiogram and subsequent follow-up in a cohort of newborns. Methods: Electrocardiograms were performed in 685 neonates within the first week of life. One year follow-up was performed if QTc > 450 ms identified. Comprehensive genetic analysis using massive sequencing was performed in all cases with QTc > 470 ms. Results: We identified 54 neonates with QTc > 450 ms/ <470 ms; all normalized QTc values within 6 months. Eight cases had QTc > 480 ms at birth and, if persistent, pharmacological treatment was administrated during follow-up. A rare variant was identified as the potential cause of long QT syndrome in five cases. Three cases showed a family history of sudden arrhythmogenic death. Conclusions: Our prospective study identifies 0.14% of cases with a definite long QT, supporting implementation of electrocardiograms in routine pediatric protocols. It is an effective, simple and non-invasive approach that can help prevent sudden death in neonates and their relatives. Genetic analyses help to unravel the cause of arrhythmogenic disease in diagnosing neonates. Further, clinical assessment and genetic analysis of relatives allowed early identification of family members at risk of arrhythmias helping to adopt preventive personalized measures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sarquella-Brugada, García-Algar, Zambrano, Fernández-Falgueres, Sailer, Cesar, Sebastiani, Martí-Almor, Aurensanz, Cruzalegui, Merchan, Coll, Pérez-Serra, Olmo, Fiol, Iglesias, Ferrer-Costa, Puigmulé, Lopez, Pico, Arbelo, Jordà, Brugada, Brugada and Campuzano.)

Background and Aims: Complex aortic atheroma (CAA) is a common cause of acute brain ischemia (BI), including ischemic stroke (IS) and transient ischemic attack (TIA), and is associated with recurrence. The CHA2DS2-VASc score is a useful tool for predicting stroke in patients with atrial fibrillation (AF), and can also predict cardiovascular events in other populations, including non-AF populations. The ADAM-C score is a new risk score for predicting the diagnostic yield of transesophageal echocardiography (TEE) after BI. We aimed to evaluate the ability of CHA2DS2-VASc and ADAM-C scores to predict CAA after BI., Methods: This prospective, multicenter, observational study included 1479 patients aged over 18 years who were hospitalized for BI. CAA was defined as the presence of one or more of the following criteria: thrombus, ulcerated plaque, or plaque thickening ≥ 4 mm., Results: CAA was diagnosed in 216 patients (14.6%). CHA2DS2-VASc and ADAM-C scores were significantly higher in the CAA group versus the non-CAA group (P < .0001 for both). The CHA2DS2-VASc and ADAM-C scores appear to be good predictors of CAA (AUC 0.699 [0.635, 0.761] and 0.759 [0.702, 0.814], respectively). The sensitivity, specificity, predictive positive value (PPV), and negative predictive value (NPV) of the scores for detecting CAA were 94%, 22%, 17%, and 96%, respectively, for a CHA2DS2-VASc score < 2, and 90%, 46%, 22%, and 96%, respectively, for an ADAM-C score < 3 CONCLUSIONS: CHA2DS2-VASc and ADAM-C scores are able to predict CAA after BI. CHA2DS2-VASc < 2 and ADAM-C < 3 both have an interesting NPV of 96%., (© 2021 Wiley Periodicals LLC.)

Introduction: Carotid atherosclerosis represents 8 to 15% of ischemic strokes in relation to the concept of "vulnerable" plaque. Contrast enhanced ultrasound (CEUS) can detect moving microbubbles within the plaque corresponding to neovessels that constitute "precursors" of vulnerable plaque and intraplaque hemorrhage. CEUS was not studied specifically in acute ischemic strokes. The aim of this study is to analyse the prevalence of CEUS carotid plaque ipsilateral at the ischemic stroke as well as the main characteristics of contrast-plaques., Method: A single-centre prospective pilot study involving 33 consecutive patients with a stroke ≤10 days, diagnosed by an MRI with positive diffusion sequence and having a carotid plaque thickness ≥2.5mm with low or heterogeneous echogenicity, located in the ipsilateral carotid territory at the stroke. Plaque echogenicity was done by visual analysis and by measurement of the gray scale median (GSM). A transcranial Doppler monitoring was carried out in search of HITS. The contrast ultrasound was performed after 2.5 cc IV injection of SonoVue®. A video clip was recorded after injection which was used for interpretation by visual analysis in 3 grades, provided by two independent expert readers., Results: The population consisted of 10 women and 23 men aged 73 on average. The topography of strokes in the carotid territory was located on the right in 11 (33%) cases and on the left in 22 (67%) cases. Seventeen patients had carotid stenosis between 0 and 49% according to the Nascet method and 16 patients had stenosis of 50 to 99%. The visual characterisation of the plaques had echolucent dominance (Type 1-2) in 18 cases and echogenic dominance (Type 3-4a) in 15 cases. Cardiovascular risk factors were common with no difference by sex. The inter-observer agreement of plaque enhancement was moderate in first reading (k=0.48) and excellent at consensus (k=0.91). Only one disagreement was found. Contrast agent enhancement of carotid plaque was observed in 11/32 patients, representing a prevalence of 34.4% - CI95% [17.9-50.9]. Variables associated with contrast plaque included the absence of antiplatelet drug (63.6% vs. 23.8%, P=0.05) and the presence of a regular edge on the plaque (91% vs. 48%, P=0.04). There was no difference in contrast enhancement for stenosis>or<50% in diameter and neither for the type of plaque., Conclusion: In a consecutive cohort of 33 patients, the prevalence of CEUS from an ipsilateral carotid plaque to a recent acute ischemic stroke was 34.4%. There was a statistically significant association between the contrast enhancement of the plaque and the absence of antiplatelet drug (P=0.05) and also the presence of a regular edge on the plaque (P=0.04). There was no correlation between plaque contrast and clinical and biological characteristics of patients or the presence of HITS., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing joint estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates), with contributions from a large network of individual experts. Evidence from mechanistic data and prior studies suggests that exposure to long working hours may cause stroke. In this paper, we present a systematic review and meta-analysis of parameters for estimating the number of deaths and disability-adjusted life years from stroke that are attributable to exposure to long working hours, for the development of the WHO/ILO Joint Estimates., Objectives: We aimed to systematically review and meta-analyse estimates of the effect of exposure to long working hours (three categories: 41-48, 49-54 and ≥55 h/week), compared with exposure to standard working hours (35-40 h/week), on stroke (three outcomes: prevalence, incidence, and mortality)., Data Sources: A protocol was developed and published, applying the Navigation Guide to systematic reviews as an organizing framework where feasible. We searched electronic databases for potentially relevant records from published and unpublished studies, including Ovid MEDLINE, PubMed, EMBASE, Scopus, Web of Science, CISDOC, PsycINFO, and WHO ICTRP. We also searched grey literature databases, Internet search engines, and organizational websites; hand-searched reference lists of previous systematic reviews; and consulted additional experts., Study Eligibility and Criteria: We included working-age (≥15 years) individuals in the formal and informal economy in any WHO and/or ILO Member State but excluded children (aged < 15 years) and unpaid domestic workers. We included randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies with an estimate of the effect of exposure to long working hours (41-48, 49-54 and ≥55 h/week), compared with exposure to standard working hours (35-40 h/week), on stroke (prevalence, incidence or mortality)., Study Appraisal and Synthesis Methods: At least two review authors independently screened titles and abstracts against the eligibility criteria at a first review stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. Missing data were requested from principal study authors. We combined relative risks using random-effects meta-analysis. Two or more review authors assessed the risk of bias, quality of evidence and strength of evidence, using the Navigation Guide and GRADE tools and approaches adapted to this project., Results: Twenty-two studies (20 cohort studies, 2 case-control studies) met the inclusion criteria, comprising a total of 839,680 participants (364,616 females) in eight countries from three WHO regions (Americas, Europe, and Western Pacific). The exposure was measured using self-reports in all studies, and the outcome was assessed with administrative health records (13 studies), self-reported physician diagnosis (7 studies), direct diagnosis by a physician (1 study) or during a medical interview (1 study). The outcome was defined as an incident non-fatal stroke event in nine studies (7 cohort studies, 2 case-control studies), incident fatal stroke event in one cohort study and incident non-fatal or fatal ("mixed") event in 12 studies (all cohort studies). Cohort studies were judged to have a relatively low risk of bias; therefore, we prioritized evidence from these studies, but synthesised evidence from case-control studies as supporting evidence. For the bodies of evidence for both outcomes with any eligible studies (i.e. stroke incidence and mortality), we did not have serious concerns for risk of bias (at least for the cohort studies). Eligible studies were found on the effects of long working hours on stroke incidence and mortality, but not prevalence. Compared with working 35-40 h/week, we were uncertain about the effect on incidence of stroke due to working 41-48 h/week (relative risk (RR) 1.04, 95% confidence interval (CI) 0.94-1.14, 18 studies, 277,202 participants, I 2 0%, low quality of evidence). There may have been an increased risk for acquiring stroke when working 49-54 h/week compared with 35-40 h/week (RR 1.13, 95% CI 1.00-1.28, 17 studies, 275,181participants, I 2 0%, p 0.04, moderate quality of evidence). Compared with working 35-40 h/week, working ≥55 h/week may have led to a moderate, clinically meaningful increase in the risk of acquiring stroke, when followed up between one year and 20 years (RR 1.35, 95% CI 1.13 to 1.61, 7 studies, 162,644 participants, I 2 3%, moderate quality of evidence). Compared with working 35-40 h/week, we were very uncertain about the effect on dying (mortality) of stroke due to working 41-48 h/week (RR 1.01, 95% CI 0.91-1.12, 12 studies, 265,937 participants, I 2 0%, low quality of evidence), 49-54 h/week (RR 1.13, 95% CI 0.99-1.29, 11 studies, 256,129 participants, I 2 0%, low quality of evidence) and 55 h/week (RR 1.08, 95% CI 0.89-1.31, 10 studies, 664,647 participants, I 2 20%, low quality of evidence). Subgroup analyses found no evidence for differences by WHO region, age, sex, socioeconomic status and type of stroke. Sensitivity analyses found no differences by outcome definition (exclusively non-fatal or fatal versus "mixed") except for the comparison working ≥55 h/week versus 35-40 h/week for stroke incidence (p for subgroup differences: 0.05), risk of bias ("high"/"probably high" ratings in any domain versus "low"/"probably low" in all domains), effect estimate measures (risk versus hazard versus odds ratios) and comparator (exact versus approximate definition)., Conclusions: We judged the existing bodies of evidence for human evidence as "inadequate evidence for harmfulness" for all exposure categories for stroke prevalence and mortality and for exposure to 41-48 h/week for stroke incidence. Evidence on exposure to 48-54 h/week and ≥55 h/week was judged as "limited evidence for harmfulness" and "sufficient evidence for harmfulness" for stroke incidence, respectively. Producing estimates for the burden of stroke attributable to exposures to working 48-54 and ≥55 h/week appears evidence-based, and the pooled effect estimates presented in this systematic review could be used as input data for the WHO/ILO Joint Estimates. PROTOCOL IDENTIFIER: https://doi.org/10.1016/j.envint.2018.06.016., Prospero Registration Number: CRD42017060124., (Copyright © 2020 , , , , , , , , , , , , , , , , , , , , , , , , , , , World Health Organization and International Labour Organization. Published by Elsevier Ltd.. All rights reserved.)

Over the last ten years, analysis of copy number variants has increasingly been applied to the study of arrhythmogenic pathologies associated with sudden death, mainly due to significant advances in the field of massive genetic sequencing. Nevertheless, few published reports have focused on the prevalence of copy number variants associated with sudden cardiac death. As a result, the frequency of these genetic alterations in arrhythmogenic diseases as well as their genetic interpretation and clinical translation has not been established. This review summarizes the current available data concerning copy number variants in sudden cardiac death-related diseases., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background Long-working hours (LWH) are a probable risk factor for ischemic heart diseases (IHD); however, no previous study has considered duration of exposure to LWH when addressing this topic. We aimed to determine the association between cumulative exposure to LWH and IHD while accounting for relevant confounders. Methods and Results In this retrospective study, we included all baseline participants from the French population-based cohort CONSTANCES. Part-time employees and those who reported a cardiac event in the 5 years before LWH exposure were excluded. From self-administered questionnaires and clinical examinations, we obtained participants' age, sex, body mass index, occupational status, smoking habits, high blood pressure, diabetes mellitus, familial history of cardiovascular disease, dyslipidemia, exposure to LWH, and its duration. We defined LWH as working for >10 hours daily for at least 50 days per year. The main outcome was reported history of IHD, ie, myocardial infarction or angina pectoris, during a clinical examination. Of 137 854 included participants, 69 774 were men. There were 1875 cases (1.36%) of IHD, and exposure to LWH was reported by 42 462 subjects (30.8%) among whom 14 474 (10.50%) reported exposure for at least 10 years. Overall, exposure to LWH for ≥10 years was associated with an increased risk of IHD, adjusted odds ratio (aOR) 1.24 (1.08-1.43), P =0.0021. In stratified analyses, this effect was not observed in women, but was significant amongst men, aOR 1.28 (1.11-1.48), P =0.0008. Conclusions This large population-based study supports an association between cumulative exposure to LWH and IHD in men. Future research should consider relevant strategies for reducing LWH exposure and duration.

Background: Arterial thoracic outlet syndrome is a rare condition characterized by a subclavian artery pathology associated with a bone abnormality. It is rarely associated with thromboembolic stroke. The mechanism of cerebral embolism associated with thoracic outlet syndrome have rarely been demonstrated. We present here a fully studied case with a high probability of reverse flow embolism., Case Presentation: A 24-year-old man with a known arterial thoracic outlet syndrome presented with a right cerebral posterior artery brain infarction. An ultrasound examination depicted the compression of the right subclavian artery in the scalene defile with a post stenotic aneurysm and the presence of a floating thrombus in this aneurysm. There was a reverse flow during diastole in this aneurysm. Anticoagulation was carried out with the disappearance of the floating thrombus with no new clinical or brain MRI event. Corrective surgery of this thoracic outlet syndrome was performed one month after stroke., Conclusion: Very few cases of stroke in arterial thoracic outlet syndrome have been described with thorough dynamic vascular imaging. To our knowledge, this is the fourth reported case that advocates for a reverse flow embolism mechanism in stroke associated with thoracic outlet syndrome, and the first to realize an extensive ultrasound and doppler workup.

Importance: Treatment with remote ischemic perconditioning has been reported to reduce brain infarction volume in animal models of stroke. Whether this neuroprotective effect was observed in patients with acute ischemic stroke remains unknown., Objective: To determine whether treatment with remote ischemic perconditioning administered to the leg of patients with acute ischemic stroke can reduce brain infarction volume growth., Design, Setting, and Participants: This proof-of-concept multicenter prospective randomized open-label with blinded end point clinical trial was performed from January 12, 2015, to May 2, 2018. Patients were recruited from 11 stroke centers in France. Of the 188 patients who received magnetic resonance imaging within 6 hours of symptom onset and were confirmed to have carotid ischemic stroke, 93 were randomized to receive treatment with lower-limb remote ischemic perconditioning in addition to standard care (the intervention group), and 95 were randomized to receive standard care alone (the control group)., Interventions: Randomization on a 1:1 ratio to receive treatment with remote ischemic perconditioning (4 cycles of 5-minute inflations and 5-minute deflations to the thigh to 110 mm Hg above systolic blood pressure) in addition to standard care or standard care alone., Main Outcomes and Measures: The change in brain infarction volume growth between baseline and 24 hours, measured by a diffusion-weighted sequence of magnetic resonance imaging scans of the brain., Results: A total of 188 patients (mean [SD] age, 67.2 [15.7] years; 98 men [52.1%]) were included in this intention-to-treat analysis. At hospital admission, the median National Institutes of Health Stroke Scale score was 10 (interquartile range [IQR], 6-16) and the median brain infarction volume was 11.4 cm3 (IQR, 3.6-35.8 cm3); 164 patients (87.2%) received intravenous thrombolysis, and 64 patients (34.0%) underwent mechanical thrombectomy. The median increase in brain infarction growth was 0.30 cm3 (IQR, 0.11-0.48 cm3) in the intervention group and 0.37 cm3 (IQR, 0.19-0.55 cm3) in the control group (mean between-group difference on loge-transformed change, -0.07; 95% CI, -0.33 to 0.18; P = .57). An excellent outcome (defined as a score of 0-1 on the 90-day modified Rankin Scale or a score equal to the prestroke modified Rankin Scale score) was observed in 46 of 90 patients (51.1%) in the intervention group and 37 of 91 patients (40.7%) in the control group (P = .12). No significant differences in 90-day mortality were observed between the intervention and control groups (14 of 90 patients; Kaplan-Meier estimate, 15.8% vs 10 of 91 patients; Kaplan-Meier estimate, 10.4%, respectively; P = .45) or with symptomatic intracerebral hemorrhage (4 of 88 patients [4.5%] in both groups; P = .97)., Conclusions and Relevance: In this study, treatment with remote ischemic perconditioning, during or after reperfusion therapies, had no significant effect on brain infarction volume growth at 24 hours after symptom onset., Trial Registration: ClinicalTrials.gov Identifier: NCT02189928.

Objective: Adolescence represents a transition period between childhood and adulthood, and only limited information exists about stroke characteristics in this population. Our aim was to describe the clinical and neuroradiologic features, etiologies, initial management, and outcome of ischemic stroke in adolescents., Methods: This retrospective cohort study evaluated all consecutive patients 10 to 18 years with a first-ever ischemic stroke hospitalized between 2007 and 2017 in 10 French academic centers representing a population of ≈10 million. Extracted data from the national database served as validation., Results: A total of 60 patients were included (53% male, median age 15.2 years). Diagnosis at first medical contact was misevaluated in 36%, more frequently in posterior than anterior circulation strokes (55% vs 20% respectively, odds ratio 4.8, 95% confidence interval 1.41-16.40, p = 0.01). Recanalization treatment rate was high (n = 19, 32%): IV thrombolysis (17%), endovascular therapy (11.7%), or both IV and intra-arterial thrombolysis (3.3%); safety was good (only 1 asymptomatic hemorrhagic transformation). Despite thorough etiologic workup, 50% of strokes remained cryptogenic. The most common determined etiologies were cardioembolism (15%), vasculitis and autoimmune disorders (12%, occurring exclusively in female patients), and arterial dissections (10%, exclusively in male patients). Recurrent ischemic cerebrovascular events occurred in 12% (median follow-up 19 months). Recurrence rate was 50% in patients with identified vasculopathy but 0% after cryptogenic stroke. Functional outcome was favorable (Rankin Scale score 0-2 at day 90) in 80% of cases., Conclusions: Ischemic strokes in adolescents harbor both pediatric and adult features, emphasizing the need for multidisciplinary collaboration in their management. Recanalization treatments appear feasible and safe., (© 2019 American Academy of Neurology.)

Background: The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after stroke has not been well studied., Methods: In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes., Results: A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65 mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; P = 0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups., Conclusions: After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.)., (Copyright © 2019 Massachusetts Medical Society.)

Background and Purpose: Previous studies have suggested an association between stroke and meteorological factors, air pollution and acute respiratory infections as triggering factors. Often, these factors have been evaluated separately. We evaluated the association between all these environmental triggering factors and calls for suspected stroke in a suburb in west Paris from 2004 to 2015., Methods: We used data from the emergency medical dispatching center of all calls for suspected stroke (SAMU 78), climatic parameters (MétéoFrance), pollution (AIRPARIF), and data from influenza epidemic surveillance networks (GROG and Sentinelles). The association between short-term exposure (1-day lag) to environmental triggering factors and stroke occurrence was analyzed using negative-binomial log linear regression model for counting time series., Results: Between 2004 and 2015, a total of 11,037 calls for suspected stroke were recorded. In bivariate analysis, there were associations between calls for suspected stroke and temperature (mean, maximum and minimum), humidity and influenza epidemic. In multivariable analysis, only two variables were associated with calls for suspected stroke: humidity [3.93% excess relative risk (ERR) of stroke per 10% increase in humidity; 95% confidence interval (CI), 1.42 to 6.51; P<0.002] and pollution on the "Air Parif Atmo" scale (2.86% ERR of stroke per 1 unit increase; 95% CI, 1.01 to 4.75; P=0.002)., Conclusions: This study suggests that short-term exposure to air pollution and a high level of humidity are associated with a significant excess relative risk of calls for suspected stroke., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Whether reserve plays a role in Parkinson's disease (PD) patients has received less attention than in dementia and has been mainly examined in relation with cognitive function., Objective: To investigate whether reserve plays a role in the severity and progression of motor, cognitive, and nonmotor PD symptoms by examining whether education level (proxy of reserve) is associated with baseline performance and rate of progression., Methods: We used data from a longitudinal cohort of PD patients (≤5-year disease duration at baseline) annually followed up to 5 years (n = 393; 41% women; mean age = 62.3 years, standard deviation = 10.0; mean disease duration = 2.6 years, standard deviation = 1.5). We examined the relationship of education with time to reach Hoehn and Yahr stage ≥3 using Cox regression and with baseline severity and progression of motor (Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts II and III, gait speed), cognitive (Mini-Mental State Examination), and nonmotor (depression, anxiety, nonmotor symptoms scale, quality of life) symptoms using mixed models., Results: Education level was not associated with age at onset or diagnosis. Compared with the low-education group, the incidence of Hoehn and Yahr ≥3.0 was 0.42 times lower (95% confidence interval, 0.22-0.82, P = 0.012) in the high-education group. Higher education was associated with better baseline motor function (P < 0.001), but not with the rate of motor decline (P > 0.15). Similar results were observed for cognition. Education was not associated with nonmotor symptoms., Conclusions: Higher education is associated with better baseline motor/cognitive function in PD, but not with rate of decline, and with a lower risk of reaching Hoehn and Yahr ≥3 during the follow-up. Our observations are consistent with a passive reserve hypothesis for motor/cognitive symptoms. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objective: To evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS)., Methods: We enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria., Results: After a median follow-up of 50 months (IQR 25-82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement ( ≥ 3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥ 30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma., Conclusions: Our study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥ 30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)