Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Restoring brain function after stroke - bridging the gap between animals and humans

Stroke is the leading cause of complex adult disability in the world. Recovery from stroke is often incomplete, which leaves many people dependent on others for their care. The improvement of long-term outcomes should, therefore, be a clinical and research priority. As a result of advances in our understanding of the biological mechanisms involved in recovery and repair after stroke, therapeutic opportunities to promote recovery through manipulation of poststroke plasticity have never been greater. This work has almost exclusively been carried out in preclinical animal models of stroke with little translation into human studies. The challenge ahead is to develop a mechanistic understanding of recovery from stroke in humans. Advances in neuroimaging techniques now enable us to reconcile behavioural accounts of recovery with molecular and cellular changes. Consequently, clinical trials can be designed in a stratified manner that takes into account when an intervention should be delivered and who is most likely to benefit. This approach is expected to lead to a substantial change in how restorative therapeutic strategies are delivered in patients after stroke

Impact of national lockdown on the hyperacute stroke care and rapid transient ischaemic attack outpatient service in a comprehensive tertiary stroke centre during the COVID-19 pandemic

Background: The COVID-19 pandemic is having major implications for stroke services worldwide. We aimed to study the impact of the national lockdown period during the COVID-19 outbreak on stroke and transient ischemic attack (TIA) care in London, UK. Methods: We retrospectively analyzed data from a quality improvement registry of consecutive patients presenting with acute ischemic stroke and TIA to the Stroke Department, Imperial College Health Care Trust London during the national lockdown period (between March 23rd and 30th June 2020). As controls, we evaluated the clinical reports and stroke quality metrics of patients presenting with stroke or TIA in the same period of 2019. Results: Between March 23rd and 30th June 2020, we documented a fall in the number of stroke admissions by 31.33% and of TIA outpatient referrals by 24.44% compared to the same period in 2019. During the lockdown, we observed a significant increase in symptom onset-to-door time in patients presenting with stroke (median = 240 vs. 160 min, p = 0.020) and TIA (median = 3 vs. 0 days, p = 0.002) and a significant reduction in the total number of patients thrombolysed [27 (11.49%) vs. 46 (16.25%, p = 0.030)]. Patients in the 2020 cohort presented with a lower median pre-stroke mRS (p = 0.015), but an increased NIHSS (p = 0.002). We registered a marked decrease in mimic diagnoses compared to the same period of 2019. Statistically significant differences were found between the COVID and pre-COVID cohorts in the time from onset to door (median 99 vs. 88 min, p = 0.026) and from onset to needle (median 148 vs. 126 min, p = 0.036) for thrombolysis whilst we did not observe any significant delay to reperfusion therapies (door-to-needle and door-to-groin puncture time). Conclusions: National lockdown in the UK due to the COVID-19 pandemic was associated with a significant decrease in acute stroke admission and TIA evaluations at our stroke center. Moreover, a lower proportion of acute stroke patients in the pandemic cohort benefited from reperfusion therapy. Further research is needed to evaluate the long-term effects of the pandemic on stroke care

Outcomes of different anesthesia techniques in nonagenarians treated with mechanical thrombectomy for anterior circulation large vessel occlusion: An inverse probability weighting analysis

Introduction: There is a lack of evidence for the optimal type of anesthesia technique in patients ⩾ 90 years with acute ischemic stroke undergoing mechanical thrombectomy (MT) as this subgroup of patients was often excluded or under-represented in previous trials. We aimed to compare outcomes between general anesthesia (GA) and non-GA techniques in patients ⩾ 90 years with large vessel occlusion (LVO) undergoing MT. Patients and methods: Our study included patients ⩾ 90 years with anterior circulation LVO, NIHSS ⩾ 6, ASPECTS ⩾ 5 consecutively treated with MT within 6 h after stroke onset in three thrombectomy capable centers between January 1st, 2016 and March 30th, 2023. Inverse probability weighting (IPW) was used to reduce bias by indication of the anesthesia type on study outcomes. We used a weighted ordinal robust logistic regression analysis to explore the primary outcome of modified Rankin Scale (mRS) shift at 90 days in GA versus non-GA treated patients. Secondary outcomes included 90-day mortality, symptomatic intracranial hemorrhage (sICH) and TICI score of 2b, 2c, or 3. Results: We included 139 patients ⩾ 90 years treated with MT, 62 were in GA group and 77 in non-GA group. There was a significant shift for worse mRS scores at 90-day in non-GA treated patients (cOR 3.65, 95% CI 1.77–7.77, p = 0.001). The weighted logistic regression showed that non-GA technique was an independent predictor of 90-day mortality (OR 7.49, 95% CI 2.00–28.09; p = 0.003). Conclusion: Our study indicated that nonagenarians with acute ischemic stroke treated with MT without GA have a worse prognosis than their counterparts undergoing MT with GA. Further studies in larger cohorts are warranted to evaluate the optimal type of anesthesia in this patient population

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016

© 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Traumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognised as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. We aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016, and to estimate the proportion of TBI and SCI cases caused by different types of injury. Methods: We used results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 to measure the global, regional, and national burden of TBI and SCI by age and sex. We measured the incidence and prevalence of all causes of injury requiring medical care in inpatient and outpatient records, literature studies, and survey data. By use of clinical record data, we estimated the proportion of each cause of injury that required medical care that would result in TBI or SCI being considered as the nature of injury. We used literature studies to establish standardised mortality ratios and applied differential equations to convert incidence to prevalence of long-term disability. Finally, we applied GBD disability weights to calculate YLDs. We used a Bayesian meta-regression tool for epidemiological modelling, used cause-specific mortality rates for non-fatal estimation, and adjusted our results for disability experienced with comorbid conditions. We also analysed results on the basis of the Socio-demographic Index, a compound measure of income per capita, education, and fertility. Findings: In 2016, there were 27·08 million (95% uncertainty interval [UI] 24·30–30·30 million) new cases of TBI and 0·93 million (0·78–1·16 million) new cases of SCI, with age-standardised incidence rates of 369 (331–412) per 100 000 population for TBI and 13 (11–16) per 100 000 for SCI. In 2016, the number of prevalent cases of TBI was 55·50 million (53·40–57·62 million) and of SCI was 27·04 million (24·98–30·15 million). From 1990 to 2016, the age-standardised prevalence of TBI increased by 8·4% (95% UI 7·7 to 9·2), whereas that of SCI did not change significantly (−0·2% [–2·1 to 2·7]). Age-standardised incidence rates increased by 3·6% (1·8 to 5·5) for TBI, but did not change significantly for SCI (−3·6% [–7·4 to 4·0]). TBI caused 8·1 million (95% UI 6·0–10·4 million) YLDs and SCI caused 9·5 million (6·7–12·4 million) YLDs in 2016, corresponding to age-standardised rates of 111 (82–141) per 100 000 for TBI and 130 (90–170) per 100 000 for SCI. Falls and road injuries were the leading causes of new cases of TBI and SCI in most regions. Interpretation: TBI and SCI constitute a considerable portion of the global injury burden and are caused primarily by falls and road injuries. The increase in incidence of TBI over time might continue in view of increases in population density, population ageing, and increasing use of motor vehicles, motorcycles, and bicycles. The number of individuals living with SCI is expected to increase in view of population growth, which is concerning because of the specialised care that people with SCI can require. Our study was limited by data sparsity in some regions, and it will be important to invest greater resources in collection of data for TBI and SCI to improve the accuracy of future assessments. Funding: Bill & Melinda Gates Foundation

A biomaterials approach to influence stem cell fate in injectable cell-based therapies

Background Numerous stem cell therapies use injection-based administration to deliver high-density cell preparations. However, cell retention rates as low as 1% have been observed within days of transplantation. This study investigated the effects of varying administration and formulation parameters of injection-based administration on cell dose recovery and differentiation fate choice of human mesenchymal stem cells. Methods The impact of ejection rate via clinically relevant Hamilton micro-syringes and biomaterial-assisted delivery was investigated. Cell viability, the percentage of cell dose delivered as viable cells, proliferation capacity as well as differentiation behaviour in bipotential media were assessed. Characterisation of the biomaterial-based cell carriers was also carried out. Results A significant improvement of in-vitro dose recovery in cells co-ejected with natural biomaterials was observed, with ejections within 2% (w/v) gelatin resulting in 87.5 ± 14% of the cell dose being delivered as viable cells, compared to 32.2 ± 19% of the dose ejected in the commonly used saline vehicle at 10 μl/min. Improvement in cell recovery was not associated with the rheological properties of biomaterials utilised, as suggested by previous studies. The extent of osteogenic differentiation was shown to be substantially altered by choice of ejection rate and cell carrier, despite limited contact time with cells during ejection. Collagen type I and bone-derived extracellular matrix cell carriers yielded significant increases in mineralised matrix deposited at day 21 relative to PBS. Conclusions An enhanced understanding of how administration protocols and biomaterials influence cell recovery, differentiation capacity and choice of fate will facilitate the development of improved administration and formulation approaches to achieve higher efficacy in stem cell transplantation