X-ray diffracted intensity for double reflection channel cut Ge monochromators at extremely asymmetric diffraction conditions

The width and the integrated intensity of the 220 x-ray double diffraction profile and the shift of the Bragg condition due to refraction have been measured in a channel cut Ge crystal in an angular range near the critical angle of total external reflection. The Bragg angle and incidence condition were varied by changing the x-ray energy. In agreement with the extended dynamical theory of x-ray diffraction, the integrated intensity of the double diffraction remained almost constant even for grazing incidence condition very close to the critical angle C for total external reflection. A broadening of the diffraction profile not predicted by the extended theory of x-ray diffraction was observed when the Bragg condition was at angles of incidence lower than 0.6?. Plane wave topographs revealed a contrast that could be explained by a slight residual crystal surface undulation of 0.3 degrees due to the etching to remove the cutting damage and the increasing effect of refraction at glancing angles close to the critical angle. These findings confirm that highly asymmetric channel cut Ge crystals can work as efficient monochromators or image magnifiers also at glancing angles close to the critical angle and that the main limitation is the crystal surface preparation

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke

Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01–2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies

Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial

Background: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. Methods: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. Findings: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77–1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80–1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79–1·60; p=0·53). Interpretation: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care

The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis

Background A growing body of research identifies the harmful effects that adverse childhood experiences (ACEs; occurring during childhood or adolescence; eg, child maltreatment or exposure to domestic violence) have on health throughout life. Studies have quantified such effects for individual ACEs. However, ACEs frequently co-occur and no synthesis of findings from studies measuring the effect of multiple ACE types has been done. Methods In this systematic review and meta-analysis, we searched five electronic databases for cross-sectional, case-control, or cohort studies published up to May 6, 2016, reporting risks of health outcomes, consisting of substance use, sexual health, mental health, weight and physical exercise, violence, and physical health status and conditions, associated with multiple ACEs. We selected articles that presented risk estimates for individuals with at least four ACEs compared with those with none for outcomes with sufficient data for meta-analysis (at least four populations). Included studies also focused on adults aged at least 18 years with a sample size of at least 100. We excluded studies based on high-risk or clinical populations. We extracted data from published reports. We calculated pooled odds ratios (ORs) using a random-effects model. Findings Of 11 621 references identified by the search, 37 included studies provided risk estimates for 23 outcomes, with a total of 253 719 participants. Individuals with at least four ACEs were at increased risk of all health outcomes compared with individuals with no ACEs. Associations were weak or modest for physical inactivity, overweight or obesity, and diabetes (ORs of less than two); moderate for smoking, heavy alcohol use, poor self-rated health, cancer, heart disease, and respiratory disease (ORs of two to three), strong for sexual risk taking, mental ill health, and problematic alcohol use (ORs of more than three to six), and strongest for problematic drug use and interpersonal and self-directed violence (ORs of more than seven). We identified considerable heterogeneity (I 2 of > 75%) between estimates for almost half of the outcomes. Interpretation To have multiple ACEs is a major risk factor for many health conditions. The outcomes most strongly associated with multiple ACEs represent ACE risks for the next generation (eg, violence, mental illness, and substance use). To sustain improvements in public health requires a shift in focus to include prevention of ACEs, resilience building, and ACE-informed service provision. The Sustainable Development Goals provide a global platform to reduce ACEs and their life-course effect on health. Funding Public Health Wales. © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licens

Consensus statements and recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 11-13 November 2018

The purpose of the European Stroke Organisation-Karolinska Stroke Update Conference is to provide updates on recent stroke therapy research and to give an opportunity for the participants to discuss how these results may be implemented into clinical routine. The meeting started 22 years ago as Karolinska Stroke Update, but since 2014 it is a joint conference with European Stroke Organisation. Importantly, it provides a platform for discussion on the European Stroke Organisation guidelines process and on recommendations to the European Stroke Organisation guidelines committee on specific topics. By this, it adds a direct influence from stroke professionals otherwise not involved in committees and work groups on the guideline procedure. The discussions at the conference may also inspire new guidelines when motivated. The topics raised at the meeting are selected by the scientific programme committee mainly based on recent important scientific publications. This year's European Stroke Organisation-Karolinska Stroke Update Meeting was held in Stockholm on 11-13 November 2018. There were 11 scientific sessions discussed in the meeting including two short sessions. Each session except the short sessions produced a consensus statement (Full version with background, issues, conclusions and references are published as web-material and at and ) and recommendations which were prepared by a writing committee consisting of session chair(s), scientific secretary and speakers. These statements were presented to the 250 participants of the meeting. In the open meeting, general participants commented on the consensus statement and recommendations and the final document were adjusted based on the discussion from the general participants Recommendations (grade of evidence) were graded according to the 1998 Karolinska Stroke Update meeting with regard to the strength of evidence. Grade A Evidence: Strong support from randomised controlled trials and statistical reviews (at least one randomised controlled trial plus one statistical review). Grade B Evidence: Support from randomised controlled trials and statistical reviews (one randomised controlled trial or one statistical review). Grade C Evidence: No reasonable support from randomised controlled trials, recommendations based on small randomised and/or non-randomised controlled trials evidence.Peer reviewe

Implementation and outcome of thrombolysis with alteplase 3–4·5 h after an acute stroke: an updated analysis from SITS-ISTR

Background In September, 2008, the European Acute Stroke Study III (ECASS III) randomised trial and the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) observational study reported the efficacy and safety of the extension of the time window for intravenous alteplase treatment from within 3 h to within 4.5 h after stroke onset. We aimed to assess the implementation of the wider time window, its effect on the admission-to-treatment time, and safety and functional outcome in patients recorded in SITS-ISTR. Methods Patients treated according to the criteria of the European Summary of Product Characteristics, except for the time window, were included. Patients were grouped according to whether they were registered into SITS-ISTR before or after October, 2008. We measured admission-to-treatment time and rates of symptomatic intracerebral haemorrhage, mortality, and functional independence at 3 months. Findings 23 942 patients were included in SITS-ISTR between December, 2002, and February, 2010, of whom 2376 were treated 3-4.5 h after symptom onset. The proportion of patients treated within 3-4.5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs 67 of 1023 [7%]). The median admission-to-treatment time was 65 min both for patients registered before and after October, 2008 (p=0.94). 352 (2%) of 21 204 patients treated within 3 h and 52 (2%) of 2317 treated within 3-4.5 h of stroke had symptomatic intracerebral haemorrhage at 3 months (adjusted odds ratio [OR] 1.44, 95% CI 105-1.97; p=0.02). 2287 (12%) of 18 583 patients who were treated within 3 h and 218 (12%) of 1817 who were treated within 3-4.5 h had died by the 3-month follow-up (adjusted OR 1.26, 95% CI 1.07-1. 49; p=0.005); 10 531 (57%) of 18 317 patients treated within 3 h of stroke and 1075 (60%) of 1784 who were treated within 3-4.5 h were functionally independent at 3 months (adjusted OR 0.84, 95% CI 0.75-0.95; p=0.005). Interpretation Since October, 2008, thrombolysis within 3-4.5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased. Safety and functional outcomes are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier. Thrombolysis should be initiated within 4.5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset

Delivery of acute ischaemic stroke treatments in the European region in 2019 and 2020.

INTRODUCTION We assessed best available data on access and delivery of acute stroke unit (SU) care, intravenous thrombolysis (IVT) and endovascular treatment (EVT) in the European region in 2019 and 2020. PATIENTS AND METHODS We compared national data per number of inhabitants and per 100 annual incident first-ever ischaemic strokes (AIIS) in 46 countries. Population estimates and ischaemic stroke incidence were based on United Nations data and the Global Burden of Disease Report 2019, respectively. RESULTS The estimated mean number of acute SUs in 2019 was 3.68 (95% CI: 2.90-4.45) per one million inhabitants (MIH) with 7/44 countries having less than one SU per one MIH. The estimated mean annual number of IVTs was 21.03 (95% CI: 15.63-26.43) per 100,000 and 17.14% (95% CI: 12.98-21.30) of the AIIS in 2019, with highest country rates at 79.19 and 52.66%, respectively, and 15 countries delivering less than 10 IVT per 100,000. The estimated mean annual number of EVTs in 2019 was 7.87 (95% CI: 5.96-9.77) per 100,000 and 6.91% (95% CI: 5.15-8.67) of AIIS, with 11 countries delivering less than 1.5 EVT per 100,000. Rates of SUs, IVT and EVT were stable in 2020. There was an increase in mean rates of SUs, IVT and EVT compared to similar data from 2016. CONCLUSION Although there was an increase in reperfusion treatment rates in many countries between 2016 and 2019, this was halted in 2020. There are persistent major inequalities in acute stroke treatment in the European region. Tailored strategies directed to the most vulnerable regions should be prioritised

Colchicine for prevention of vascular inflammation in Non-CardioEmbolic stroke (CONVINCE) - study protocol for a randomised controlled trial.

Background Inflammation contributes to unstable atherosclerotic plaque and stroke. In randomised trials in patients with coronary disease, canukinumab (an interleukin-1B antagonist) and colchicine (a tubulin inhibitor with pleiotropic anti-inflammatory effects) reduced recurrent vascular events.Hypothesis: Anti-inflammatory therapy with low-dose colchicine plus usual care will reduce recurrent vascular events in patients with non-severe, non-cardioembolic stroke and TIA compared with usual care alone. Design CONVINCE is a multi-centre international (in 17 countries) Prospective, Randomised Open-label, Blinded-Endpoint assessment (PROBE) controlled Phase 3 clinical trial in 3154 participants. The intervention is colchicine 0.5 mg/day and usual care versus usual care alone (antiplatelet, lipid-lowering, antihypertensive treatment, lifestyle advice). Included patients are at least 40 years, with non-severe ischaemic stroke (modified Rankin score ≤3) or high-risk TIA (ABCD2 > 3, or positive DWI, or cranio-cervical artery stenosis) within 72 hours-28 days of randomisation, with qualifying stroke/TIA most likely caused by large artery stenosis, lacunar disease, or cryptogenic embolism. Exclusions are stroke/TIA caused by cardio-embolism or other defined cause (e.g. dissection), contra-indication to colchicine (including potential drug interactions), or incapacity for participation in a clinical trial. The anticipated median follow-up will be 36 months. The primary analysis will be by intention-to-treat. Outcome The primary outcome is time to first recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation with unstable angina (non-fatal or fatal). Summary CONVINCE will provide high-quality randomised data on the efficacy and safety of anti-inflammatory therapy with colchicine for secondary prevention after stroke. Schedule First-patient first-visit was December 2016. Recruitment to complete in 2021, follow-up to complete in 2023

Design of a PROspective multi-national CLOTBUST collaboration on reperfusion therapies for stroke (CLOTBUST-PRO)

Background The benefit of intravenous (i.v.) tissue plasminogen activator (tPA) in acute ischemic stroke (IS) is attributable to lysis of thrombus and restoration of perfusion to ischemic but not yet infarcted brain. Aims Our multicentre collaborative group prospectively implemented a protocol for transcranial Doppler assessment of intracranial recanalization with tPA treatment based on the CLOTBUST clinical trial (CLOTBUST-PRO). We aim to determine whether early recanalization (within 1 h from tPA bolus) is independently associated with better 3-month outcome in patients with intracranial arterial occlusions and correlates to a shorter time interval elapsed from symptom onset to tPA bolus. Subjects and methods Consecutive patients with acute IS due to intracranial arterial occlusions will be treated with standard i.v.-tPA and continuously monitored with 2 MHz Transcranial Doppler for arterial recanalization. Early recanalization will be determined with the previously validated Thrombolysis in Brain Ischemia flow-grading system within 60 min after tPA bolus. Power calculations are based on the assumption of alpha=0.05 (two-sided test) and probabilities of functional independence at 3 months of 0.50 and 0.35 in patients with early complete recanalization and persisting occlusion, respectively. Detection of a 15% difference with a power of 0.824 requires an estimated sample of 480 patients of whom 25% are expected to achieve early recanalization while 75% will have persisting occlusion at 1 h after tPA bolus. We also plan to test prespecified secondary hypotheses within the projected study sample. Conclusions CLOTBUST-PRO is designed to determine if the timing (within 1 h from tPA bolus) of tPA-induced arterial recanalization is an independent determinant of 3-month functional recovery. We also seek to demonstrate that the sooner the tPA is given to stroke patients, the earlier the recanalization occurs and the greater is the likelihood of functional independence at 3 months