Tirofiban combined with Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction (STRATEGY): protocol for a multicentre, randomised controlled trial

Background Perforating artery territorial infarction(PAI)caused by branch atheromatous disease(BAD)is prone to recurrence and early progression without an effective and well-documented antiplatelet treatment regimen.Tirofiban,an adjunctive antiplatelet agent,has shown great potential to treat acute ischaemic stroke.However,whether the combination of tirofiban and aspirin can improve the prognosis of PAI remains unclear.Aim To explore an effective and safe antiplatelet regimen for reducing the risk of recurrence and early neurological deterioration(END)in PAI caused by BAD by comparing the tirofiban and aspirin combination with placebo and aspirin combination.Methods Tirofiban combined with Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction(STRATEGY)trial is an ongoing multicentre,randomised,placebo-controlled trial in China.Eligible patients shall be randomly assigned to receive standard aspirin with tirofiban or placebo on the first day and standard aspirin from days 2 to 90.The primary endpoint is a new stroke or END within 90 days.The primary safety endpoint is severe or moderate bleeding within 90 days.Discussion The STRATEGY trial will assess whether tirofiban combined with aspirin is effective and safe in preventing recurrence and END in patients with PAI.Trial registration number NCT05310968.

Rationale and design of Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events III (TRACE III): a randomised, phase III, open- label, controlled trial

Background and purpose Recombinant human TNK tissue-type plasminogen activator(rhTNK-tPA)was not inferior to alteplase for ischaemic stroke within 4.5hours.Our study aimed to investigate the efficacy and safety of rhTNK-tPA in patients who had an ischaemic stroke due to large vessel occlusion(LVO)of anterior circulation beyond 4.5hours.Methods and design Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-III(TRACE III)is a multicentre,prospective,randomised,open-label,blind endpoint,controlled clinical trial.Patients who had an ischaemic stroke due to anterior circulation LVO(internal carotid artery,middle cerebral artery M1 and M2 segments)within 4.5–24hours from last known well(including wake-up stroke and no witness stroke)and with salvageable tissue(ischaemic core volume<70mL,mismatch ratio≥1.8 and mismatch volume≥15mL)based on CT perfusion or MRI perfusion-weighted imaging(PWI)were included and randomised to rhTNK-tPA 0.25mg/kg(single bolus)to a maximum of 25mg or standard medical therapy.Specially,we will exclude patients who are intended for direct thrombectomy.All will be followed up for 90 days.Study outcomes Primary efficacy outcome is modified Rankin Scale(mRS)score≤1 at 90 days.Secondary efficacy outcomes include ordinal distribution of mRS at 90 days,major neurological improvement defined by a decrease≥8 points compared with the initial deficit or a score≤1 on the National Institutes of Health Stroke Scale(NIHSS)at 72 hours,mRS score≤2 at 90 days,the rate of improvement on Tmax>6s at 24 hours and NIHSS score change from baseline at 7days.Safety outcomes are symptomatic intracerebral haemorrhage within 36 hours and mortality at 90 days.Discussion TRACE III will provide evidence for the efficacy and safety of rhTNK-tPA in patients who had an ischaemic strokes due to anterior circulation LVO beyond 4.5hours.Trial registration number NCT05141305.

Penumbra-targeted CircOGDH siRNA-loaded nanoparticles alleviate neuronal apoptosis in focal brain ischaemia

Background Nanoparticles(NPs)are a class of substances that can be loaded with therapeutic agents delivered to specific areas.In our earlier research,we identified a neuron-derived circular RNA(circRNA),circular oxoglutarate dehydrogenase(CircOGDH),as a promising therapeutic target for acute ischaemic stroke.This study dedicated to explore a prospective preliminary strategy of CircOGDH-based NP delivered to the ischaemic penumbra region in middle cerebral artery occlusion/reperfusion(MCAO/R)mice.Methods Immunofluorescence in primary cortex neurons and in vivo fluorescence imaging revealed endocytosis of Poly(lactide-co-glycolide)(PLGA)poly amidoamine(PAMAM)@CircOGDH small interfering RNA(siRNA)NPs.Western blotting analysis and CCK8 assay were performed to evaluate the apoptotic level in ischaemic neurons treated with PLGA–PAMAM@CircOGDH siRNA NPs.Quantitative reverse transcription PCR experiments,mice behaviour test,T2 MRI analysis,Nissl and TdT-mediated dUTP nick end labeling(TUNEL)co-staining were performed to evaluate the apoptosis level of ischaemic penumbra neurons in MCAO/R mice.Biosafety evaluation of NPs in MCAO/R mice was detected by blood routine examination,liver and kidney function examination and HE staining.Results PLGA–PAMAM@CircOGDH siRNA NPs were successfully assembled.Endocytosis of PLGA–PAMAM@CircOGDH siRNA NPs in ischaemic neurons alleviated neuronal apoptotic level in vitro and in vivo.Furthermore,mice behaviour test showed that the neurological defects of MCAO/R mice were significantly alleviated after the tail injection of PLGA–PAMAM@CircOGDH siRNA NPs,and no toxic effects were observed.Conclusion In conclusion,our results suggest that PLGA–PAMAM@CircOGDH siRNA NPs can be delivered to the ischaemic penumbra region and alleviate neuron apoptosis in MCAO/R mice and in ischaemic neurons;therefore,our study provides a desirable approach for using circRNA-based NPs for the treatment of ischaemic stroke.

Balloon Angioplasty for Symptomatic Intracranial Artery Stenosis (BASIS): protocol of a prospective, multicentre, randomised, controlled trial

Background The superiority of balloon angioplasty plus aggressive medical management(AMM)to AMM alone for symptomatic intracranial artery stenosis(sICAS)on efficacy and safety profiles still lacks evidence from randomised controlled trials(RCTs).Aim To demonstrate the design of an RCT on balloon angioplasty plus AMM for sICAS.Design Balloon Angioplasty for Symptomatic Intracranial Artery Stenosis(BASIS)trial is a multicentre,prospective,randomised,open-label,blinded end-point trial to investigate whether balloon angioplasty plus AMM could improve clinical outcome compared with AMM alone in patients with sICAS.Patients eligible in BASIS were 35–80 years old,with a recent transient ischaemic attack within the past 90 days or ischaemic stroke between 14 days and 90 days prior to enrolment due to severe atherosclerotic stenosis(70%–99%)of a major intracranial artery.The eligible patients were randomly assigned to receive balloon angioplasty plus AMM or AMM alone at a 1:1 ratio.Both groups will receive identical AMM,including standard dual antiplatelet therapy for 90 days followed by long-term single antiplatelet therapy,intensive risk factor management and life-style modification.All participants will be followed up for 3years.Study outcomes Stroke or death in the next 30 days after enrolment or after balloon angioplasty procedure of the qualifying lesion during follow-up,or any ischaemic stroke or revascularisation from the qualifying artery after 30 days but before 12 months of enrolment,is the primary outcome.Discussion BASIS trail is the first RCT to compare the efficacy and safety of balloon angioplasty plus AMM to AMM alone in sICAS patients,which may provide an alternative perspective for treating sICAS.Trial registration number NCT03703635;https://www.clinicaltrials.gov.

Pipeline Embolization Device for intracranial aneurysms presenting with mass effect:a large Chinese cohort

Background Unruptured intracranial aneurysm treatment aims to reduce the risk of aneurysm rupture and bleeding,relieves symptoms and improve the quality of life for patients.This study aimed to assess the safety and efficacy of Pipeline Embolization Device(PED,Covidien/Medtronic,Irvine,CA)treatment for intracranial aneurysms presenting with mass effect in real-world settings.Methods We selected patients from the PED in China Post-Market Multi-Center Registry Study with mass effect presentation.The study endpoints included postoperative mass effect deterioration and mass effect relief at follow-up(3–36 months).We conducted multivariate analysis to identify factors associated with mass effect relief.Subgroup analyses by aneurysm location,size and form were also performed.Results This study included 218 patients with a mean age of 54.3±11.8 years and a female predominance of 74.0%(162/218).The postoperative mass effect deterioration rate was 9.6%(21/218).During a median follow-up period of 8.4 months,the mass effect relief rate was 71.6%(156/218).Notably,immediate aneurysm occlusion following treatment was significantly associated with mass effect relief(OR 0.392,95%CI,0.170 to 0.907,p=0.029).Subgroup analysis demonstrated that adjunctive coiling contributed to mass effect relief in cavernous aneurysms,while dense embolism impeded symptom relief in aneurysms<10mm and saccular aneurysms.Conclusions Our data confirmed the efficacy of PED in relieving mass effect.The findings of this study provide support for endovascular treatment to alleviate mass effect in unruptured intracranial aneurysms.Trial registration number NCT03831672.

A Mendelian randomisation,propensity score matching study to investigate causal association between serum homocysteine and intracranial aneurysm

Background and purpose Recent observational studies have reported that serum total homocysteine(tHcy)is associated with intracranial aneurysms(IAs).However,the causal effect of tHcy on IAs is unknown.We leveraged large-scale genetic association and real-world data to investigate the causal effect of tHcy on IA formation.Methods We performed a two-sample Mendelian randomisation(MR)using publicly available genome-wide association studies summary statistics to investigate the causal relationship between tHcy and IAs,following the recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology-MR statement.Furthermore,a propensity score matching(PSM)analysis was conducted to evaluate the detailed effects of tHcy on risk of IA formation by utilizing real-world multicentre data,including 9902 patients with and without IAs(1:1 matched).Further interaction and subgroup analyses were performed to elucidate how tHcy affects risk of IA formation.Results MR analyses indicated that genetically determined tHcy was causally associated with IA risk(OR,1.38,95%CI 1.07 to 1.79;p=0.018).This is consistent with the more conservative weighted median analysis(OR,1.41,95%CI 1.03 to 1.93;p=0.039).Further sensitivity analyses showed no evidence of horizontal pleiotropy or heterogeneity of single nucleotide polymorphisms in causal inference.According to the PSM study,we found that,compared with low tHcy(≤15μmol/L),moderate tHcy(>15-30μmol/L)(OR 2.13,95%CI 1.93 to 2.36)and high tHcy(>30μmol/L)(OR 3.66,95%CI 2.71 to 4.95)were associated with a higher IA risk(p trend<0.001).Subgroup analyses demonstrated significant ORs of tHcy in each subgroup when stratified by traditional cardiovascular risk factors.Furthermore,there was also a synergistic effect of tHcy and hypertension on IA risk(p interaction<0.001;the relative excess risk due to interaction=1.65,95%CI 1.29 to 2.01).Conclusion Both large-scale genetic evidence and multicentre real-world data support a causal association between tHcy and risk of IA formation.Serum tHcy may serve as a biomarker to identify high-risk individuals who would particularly benefit from folate supplementation.

Trendelenburg position for acute anterior circulation ischaemic stroke with large artery atherosclerosis aetiology(HOPES 3):rationale and design

Rationale The effect of the head position as a non-pharmacological therapy on acute ischaemic stroke(AIS)remains inconclusive.Our recent Head dOwn-Position for acutE moderate ischaemic Stroke with large artery atherosclerosis(HOPES 2)suggested the safety,feasibility and potential benefit of the head-down position(HDP)in AIS.Aim To investigate the benefit of HDP in acute moderate ischaemic stroke patients with large artery atherosclerosis(LAA).Sample size estimates Based on a two-sided 0.05 level of significance,600 patients are expected to yield the superiority hypothesis with 80%power,stratified by age,sex,history of diabetes,baseline systolic blood pressure,location of index vessel,National Institutes of Health Stroke Scale Score at randomisation,onset to randomisation time,progression to moderate neurological deficit due to early neurological deterioration and degree of responsible vessel stenosis.Design Head dOwn-Position for acutE moderate ischaemic Stroke with large artery atherosclerosis(HOPES 3)is a prospective,randomised,open-label,blinded endpoint and multicentre study.Eligible patients who had an ischaemic stroke will be randomly assigned(1:1)into the HDP group receiving-20°Trendelenburg plus standard medical care in compliance with national guidelines,or control group only receiving standard medical care in compliance with national guidelines.Outcome The primary outcome is favourable functional outcome,defined as modified Rankin Scale 0–2 at 90 days.Safety outcomes are HDP-related adverse events.All outcomes will have blinded assessment and will be analysed on the intention-to-treat basis.Conclusions The results of HOPES 3 will provide evidence for the effect of HDP in acute moderate ischaemic stroke patients with LAA within 24 hours of onset or in patients with progression from mild neurological deficit within 24 hours.Trial registration number NCT06010641.

Real-world analysis of two ischaemic stroke and TIA systolic blood pressure goals on 12-month mortality and recurrent vascular events

Introduction Whether obtaining the more intensive goal systolic blood pressure(SBP)of<130mm Hg,rather than a less intensive SBP goal of<140mm Hg poststroke/transient ischaemic attack(TIA)is associated with incremental mortality and recurrent vascular event benefit is largely unexplored using real-world data.Lowering SBP excessively may result in poorer outcomes.Methods This is a retrospective cohort study of 26368 Veterans presenting to a Veterans Administration Medical Center(VAMC)with a stroke/TIA between October 2015 and July 2018.Patients were excluded from the study if they had missing or extreme BP values,receiving dialysis or palliative care,left against medical advice had a cancer diagnosis,were cared for in a VAMC enrolled in a stroke/TIA quality improvement initiative,died or had a cerebrovascular or cardiovascular event within 90 days after their index stroke/TIA.The analytical sample included 12337 patients.Average SBP during 90 days after discharge was assessed in categories(≤105mm Hg,106–115mm Hg,116–130mm Hg,131–140mm Hg and>140mm Hg).Separate multivariable Cox proportional hazard regressions were used to examine the relationship between average SBP groups and time to:(1)mortality and(2)any recurrent vascular event,from 90 days to up to 365 days after discharge from the index emergency department visit or inpatient admission.Results Compared with those with SBP>140mm Hg,patients with SBP between 116 and 130mm Hg had a significantly lower risk of recurrent stroke/TIA(HR 0.77,95%CI 0.60 to 0.99)but not cardiovascular events.Patients with SBP lower than 105mm Hg,compared with those with>140mm Hg demonstrated a statistically significant higher risk of death(HR 2.07,95%CI 1.43 to 3.00),but no statistical differences were found in other SBP groups.Discussion Data support a more intensive SBP goal to prevent recurrent cerebrovascular events among stroke/TIA patients by 90 days poststroke/TIA compared with less intensive goal.Very low SBPs were associated with increased mortality risk.

Thrombolysis for ischaemic stroke despite direct oral anticoagulation

Intravenous thrombolysis is not recommended in anticoagulated patients receiving direct oral anticoagulants(DOACs)and a recent intake within the last 48hours in US and European guidelines.However,three observational studies now suggest safety of thrombolysis in patients with recent intake of DOACs,and thus support previous experimental data.In this perspective,the current evidence and practical consequences are discussed.

Safety and efficacy of glibenclamide on cerebral oedema following aneurysmal subarachnoid haemorrhage: a randomised, double- blind, placebo- controlled clinical trial

Background Glibenclamide has garnered attention due to its multifaceted neuroprotective effects in cases of acute central nervous system injury.We initiated a trial to explore the effectiveness and safety of a high dose of glibenclamide in the management of cerebral oedema following aneurysmal subarachnoid haemorrhage(aSAH).Methods This trial constituted a single-centre,randomised clinical study.Half of the 56 patients assigned to the glibenclamide group received 15mg of glibenclamide tablets daily for 10 days(5mg,three times/day).The primary outcome was the proportion of patients achieving the subarachnoid haemorrhage early brain oedema score dichotomy(defined as Subarachnoid Haemorrhage Early Brain Oedema Score 0–2)at the 10-day postmedication.The secondary outcome of cerebral oedema was the concentration of sulfonylurea receptor 1-transient receptor potential melastatin 4(SUR1-TRPM4)in the plasma and cerebrospinal fluid.Results We enrolled 56 patients diagnosed with aSAH,who were admitted to the neurosurgery intensive care unit between 22 August 2021 and 25 April 2023.The primary outcome revealed that the glibenclamide group exhibited a notably higher proportion of mild cerebral oedema in comparison to the placebo group(60.7%vs 42.9%,adjusted OR:4.66,95%CI 1.14 to 19.10,p=0.032).Furthermore,the concentration of SUR1-TRPM4 in the cerebrospinal fluid of the glibenclamide group was significantly higher than the placebo group(p=0.0002;p=0.026),while the plasma TRPM4 concentration in the glibenclamide group was significantly lower than the placebo group(p=0.001).Conclusion Oral administration of high-dose glibenclamide notably reduced radiological assessment of cerebral oedema after 10 days of medication.Significant alterations were also observed in the concentration of SUR1-TRPM4 in plasma and cerebrospinal fluid.However,it is worth noting that glibenclamide was associated with a higher incidence of hypoglycaemia.Larger trials are warranted to evaluate the potential benefits of glibenclamide in mitigating swelling and then improving neurological function.Trial registration number ChiCTR2100049908.

Anti-stroke biologics:from recombinant proteins to stem cells and organoids

The use of biologics in various diseases has dramatically increased in recent years.Stroke,a cerebrovascular disease,is the second most common cause of death,and the leading cause of disability with high morbidity worldwide.For biologics applied in the treatment of acute ischaemic stroke,alteplase is the only thrombolytic agent.Meanwhile,current clinical trials show that two recombinant proteins,tenecteplase and non-immunogenic staphylokinase,are most promising as new thrombolytic agents for acute ischaemic stroke therapy.In addition,stem cell-based therapy,which uses stem cells or organoids for stroke treatment,has shown promising results in preclinical and early clinical studies.These strategies for acute ischaemic stroke mainly rely on the unique properties of undifferentiated cells to facilitate tissue repair and regeneration.However,there is a still considerable journey ahead before these approaches become routine clinical use.This includes optimising cell delivery methods,determining the ideal cell type and dosage,and addressing long-term safety concerns.This review introduces the current or promising recombinant proteins for thrombolysis therapy in ischaemic stroke and highlights the promise and challenges of stem cells and cerebral organoids in stroke therapy.

Efficacy and safety of dual antiplatelet therapy in the elderly for stroke prevention: a subgroup analysis of the CHANCE- 2 trial

Objectives Evidence of the optimal antiplatelet therapy for elderly patients who had a stroke is limited,especially those elder than 80 years.This study aimed to explore the efficacy and safety of dual antiplatelet therapy(DAPT)in old-old patients compared with younger patients in the ticagrelor or Clopidogrel with aspirin in High-risk patients with Acute Non-disabling Cerebrovascular Events-II(CHANCE-2)trial.Methods CHANCE-2 was a randomised,double-blind,placebo-controlled trial in China involving patients with high-risk transient ischaemic attack or minor stroke with CYP2C19 loss-of-function alleles.In our substudy,all enrolled patients were stratified by age:old-old(≥80 years),young-old(65–80 years)and younger(<65 years).The primary outcomes were stroke recurrence and moderate to severe bleeding within 90 days,respectively.Results Of all the 6412 patients,406(6.3%)were old-old,2755(43.0%)were young-old and 3251(50.7%)were younger.Old-old patients were associated with higher composite vascular events(HR 1.41,95%CI 1.00 to 1.98,p=0.048),disabling stroke(OR 2.43,95%CI 1.52 to 3.88,p=0.0002),severe or moderate bleeding(HR 8.40,95%CI 1.95 to 36.21,p=0.004)and mortality(HR 7.56,95%CI 2.23 to 25.70,p=0.001)within 90 days.Ticagrelor-aspirin group was associated with lower risks of stroke recurrence within 90 days in younger patients(HR 0.68,95%CI 0.51 to 0.91,p=0.008),which was no differences in old-old patients.Conclusion Elderly patients aged over 80 in CHANCE-2 trial had higher risks of composite vascular events,disabling stroke,severe or moderate bleeding and mortality within 90 days.Genotype-guided DAPT might not be as effective in old-old patients as in younger ones.Trial registration number NCT04078737.

CSA declaration of next- generation reperfusion therapy for ischaemic stroke

Cerebrovascular disease is a significant health concern that threatens people’s health and life. About 80% of its burden comes from ischaemic stroke. Early reperfusion therapy is the key to timely restore blood flow to salvageable ischaemic brain tissue.

When treating acute ischaemic stroke of LVO type,time window prevails over tissue window

Time is brain.How fast an occluded cerebral artery can be reopened is directly related to how many brain cells can be saved.The iden-tification of a tissue window as indicated by the presence of a penumbra on multimodality imaging study has opened the time window of treatment to 24 hours after the onset.1 From 2019 to 2022,the issue of direct intra-arterial(IA)mechanical thrombectomy(MT)is non-inferior to bridging therapy or not has been settled.2 Bridging therapy may have slight advantage in re-opening the occluded arteries than direct IA MT.3 Recently published data on IA MT to treat acute ischaemic stroke(AIS)from a large vessel occlusion but with a low Alberta Stroke Programme Early CT(ASPECT)score indicated that in these patients,performing a multimodality imaging study may not be necessary.Multimodality imaging study including MRI of head,MRA of head and neck and magnetic resonance perfusion(MRP)of head or CT of head,CTA of head and neck and CT perfusion(CTP)of head are must-to do tests when evaluating patients with AIS with an onset time between 6 and 24 hours in current clinical practice.

Tenecteplase thrombolysis for stroke up to 24 hours after onset with perfusion imaging selection:the umbrella phase IIa CHABLIS-T randomised clinical trial

Background The performance of intravenous tenecteplase in patients who had an acute ischaemic stroke with large/medium vessel occlusion or severe stenosis in an extended time window remains unknown. We investigated the promise of efficacy and safety of different doses of tenecteplase manufactured in China, in patients who had an acute ischaemic stroke with large/ medium vessel occlusion beyond 4.5- hour time window. Methods The CHinese Acute tissue- Based imaging selection for Lysis In Stroke- Tenecteplase was an investigator- initiated, umbrella phase IIa, open- label, blinded- endpoint, Simon’s two- stage randomised clinical trial in 13 centres across China's Mainland. Participants who had salvageable brain tissue on automated perfusion imaging and presented within 4.5-24 hours from time of last seen well were randomised to receive 0.25 mg/ kg tenecteplase or 0.32 mg/kg tenecteplase, both with a bolus infusion over 5-10 s. The primary outcome was proportion of patients with promise of efficacy and safety defined as reaching major reperfusion without symptomatic intracranial haemorrhage at 24-48 hours after thrombolysis. Assessors were blinded to treatment allocation. All participants who received tenecteplase were included in the analysis. Results A total of 86 patients who had an acute ischaemic stroke identified with anterior large/medium vessel occlusion or severe stenosis were included in this study from November 2019 to December 2021. All of the 86 patients enrolled either received 0.25 mg/kg (n=43) or 0.32 mg/kg (n=43) tenecteplase, and were available for primary outcome analysis. Fourteen out of 43 patients in the 0.25 mg/kg tenecteplase group and 10 out of 43 patients in the 0.32 mg/kg tenecteplase group reached the primary outcome, providing promise of efficacy and safety for both doses based on Simon’s two- stage design. Discussion Among patients with anterior large/medium vessel occlusion and significant penumbral mismatch presented within 4.5-24 hours from time of last seen well, tenecteplase 0.25 mg/kg and 0.32 mg/kg both provided sufficient promise of efficacy and safety.

Treatment practice of vasospasm during endovascular thrombectomy: an international survey

Background and aim The clinical importance and management of vasospasm as a complication during endovascular stroke treatment(EVT)has not been well studied.We sought to investigate current expert opinions in neurointervention and therapeutic strategies of iatrogenic vasospasm during EVT.Methods We conducted an anonymous international online survey(4 April 2023 to 15 May 2023)addressing treatment standards of neurointerventionalists(NIs)practising EVT.Several illustrative cases of patients with vasospasm during EVT were shown.Two study groups were compared according to the NI’s opinion regarding the potential influence of vasospasm on patient outcome after EVT using descriptive analysis.Results In total,534 NI from 56 countries responded,of whom 51.5%had performed>200 EVT.Vasospasm was considered a complication potentially influencing the patient’s outcome by 52.6%(group 1)whereas 47.4%did not(group 2).Physicians in group 1 more often added vasodilators to their catheter flushes during EVT routinely(43.7%vs 33.9%,p=0.033)and more often treated severe large-vessel vasospasm with vasodilators(75.3%vs 55.9%;p<0.001),as well as extracranial vasospasm(61.4%vs 36.5%,p<0.001)and intracranial medium-vessel vasospasm(27.1%vs 11.2%,p<0.001),compared with group 2.In case of a large-vessel vasospasm and residual and amenable medium-vessel occlusion during EVT,the study groups showed different treatment strategies.Group 2 continued the EVT immediately more often,without initiating therapy to treat the vasospasm first(9.6%vs 21.1%,p<0.001).Conclusion There is disagreement among NIs about the clinical relevance of vasospasm during EVT and its management.There was a higher likelihood of use of preventive and active vasodilator treatment in the group that perceived vasospasm as a relevant complication as well as differing interventional strategies for continuing an EVT in the presence of a large-vessel vasospasm.

Real- world evaluation of Brainomix e- Stroke software

Background and purpose Brainomix e-Stroke is an artificial intelligence-based decision support tool that aids the interpretation of CT imaging in the context of acute stroke.While e-Stroke has the potential to improve the speed and accuracy of diagnosis,real-world validation is essential.The aim of this study was to prospectively evaluate the performance of Brainomix e-Stroke in an unselected cohort of patients with suspected acute ischaemic stroke.Methods The study cohort included all patients admitted to the University College London Hospital Hyperacute Stroke Unit between October 2021 and April 2022.For e-ASPECTS and e-CTA,the ground truth was determined by a neuroradiologist with access to all clinical and imaging data.For e-CTP,the values of the core infarct and ischaemic penumbra were compared with those derived from syngo.via,an alternate software used at our institution.Results 1163 studies were performed in 551 patients admitted during the study period.Of these,1130(97.2%)were successfully processed by e-Stroke in an average of 4min.For identifying acute middle cerebral artery territory ischaemia,e-ASPECTS had an accuracy of 77.0%and was more specific(83.5%)than sensitive(58.6%).The accuracy for identifying hyperdense thrombus was lower(69.1%),which was mainly due to many false positives(positive predictive value of 22.9%).Identification of acute haemorrhage was highly accurate(97.8%)with a sensitivity of 100%and a specificity of 97.6%;false positives were typically caused by areas of calcification.The accuracy of e-CTA for large vessel occlusions was 91.5%.The core infarct and ischaemic penumbra volumes provided by e-CTP strongly correlated with those provided by syngo.via(ρ=0.804—0.979).Conclusion Brainomix e-Stroke software provides rapid and reliable analysis of CT imaging in the acute stroke setting although,in line with the manufacturer’s guidance,it should be used as an adjunct to expert interpretation rather than a standalone decision-making tool.

Intra-arterial tenecteplase during thrombectomy for acute stroke(BRETIS-TNK II):rationale and design

Background Our recent pilot study suggests intra-arterial tenecteplase(TNK)during the first pass of endovascular treatment(EVT)seems safe,may increase first-pass reperfusion and good outcome in acute ischaemic stroke(AIS)patients with large-vessel occlusion(LVO).Aims To determine the efficacy and safety of intra-arterial TNK administration during EVT in AIS-LVO patients presenting up to 24 hours from symptom onset.Sample size estimates A maximum of 380 patients are required to test the superiority hypothesis with 80%power according to a two-side 0.05 level of significance,stratified by age,gender,baseline systolic blood pressure,prestroke modified Rankin Scale(mRS),baseline National Institute of Health stroke scale,baseline ASPECTS,time from onset to groin puncture,intravenous thrombolysis before EVT,stroke territory and stroke aetiology.Design Intra-arterial TNK during thrombectomy for acute stroke(BRETIS-TNK II)study is a prospective,randomised,adaptive enrichment,open-label,blinded end point,multicentre study.Eligible AIS-LVO patients are randomly assigned into the experimental group and control group with a ratio of 1:1.The experimental group will be treated with intra-arterial infusion of TNK during EVT.The control group will be treated with standard EVT.Outcome The primary end point is a favourable outcome,defined as an mRS score of 0–2 at 90 days.The primary safety end point is symptomatic intracranial haemorrhage within 48 hours,which is defined as an increase in the National Institutes of Health Stroke Scale score of≥4 points as a result of the intracranial haemorrhage.Conclusions The results of BRETIS-TNK II will provide evidence for the efficacy and safety of intra-arterial TNK administration during EVT in AIS patients with LVO.

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice

Background Low-intensity focused ultrasound stimulation(LIFUS)has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents.However,the cellular and molecular mechanisms of neurological repair and remodelling after LIFUS in ischaemic stroke are unclear.Methods Ultrasound stimulation was treated in adult male mice 7 days after transient middle cerebral artery occlusion.Angiogenesis was measured by laser speckle imaging and histological analyses.Electromyography and fibre photometry records were used for synaptogenesis.Brain atrophy volume and neurobehaviour were assessed 0–14 days after ischaemia.iTRAQ proteomic analysis was performed to explore the differentially expressed protein.scRNA-seq was used for subcluster analysis of astrocytes.Fluorescence in situ hybridisation and Western blot detected the expression of HMGB1 and CAMK2N1.Results Optimal ultrasound stimulation increased cerebral blood flow,and improved neurobehavioural outcomes in ischaemic mice(p<0.05).iTRAQ proteomic analysis revealed that the expression of HMGB1 increased and CAMK2N1 decreased in the ipsilateral hemisphere of the brain at 14 days after focal cerebral ischaemia with ultrasound treatment(p<0.05).scRNA-seq revealed that this expression pattern belonged to a subcluster of astrocytes after LIFUS in the ischaemic brain.LIFUS upregulated HMGB1 expression,accompanied by VEGFA elevation compared with the control group(p<0.05).Inhibition of HMGB1 expression in astrocytes decreased microvessels counts and cerebral blood flow(p<0.05).LIFUS reduced CAMK2N1 expression level,accompanied by increased extracellular calcium ions and glutamatergic synapses(p<0.05).CAMK2N1 overexpression in astrocytes decreased dendritic spines,and aggravated neurobehavioural outcomes(p<0.05).Conclusion Our results demonstrated that LIFUS promoted angiogenesis and synaptogenesis after focal cerebral ischaemia by upregulating HMGB1 and downregulating CAMK2N1 in a subcluster of astrocytes,suggesting that LIFUS activated specific astrocyte subcluster could be a key target for ischaemic brain therapy.

Discontinuation of antiplatelet therapy after stent-assisted coil embolisation of cerebral aneurysm:a nationwide cohort study

Introduction Stent-assisted coil embolisation(SACE)for the treatment of unruptured cerebral aneurysms has been increasingly used.Long-term advantages of antiplatelet therapy(APT)post-SACE treatment are still not well understood.We investigated the long-term effects of APT on clinical prognosis after SACE.Patients and methods We conducted a retrospective study using nationwide health insurance claims data from South Korea,including patients with cerebral aneurysm treated with SACE from January 2009 to December 2020.The study outcomes consisted of the occurrence of cerebral infarction and major haemorrhage.To evaluate the impact of APT,we employed a multivariable time-dependent Cox proportional hazards regression model for each of the three distinct periods:1–12 months,12–24 months and>24 months after SACE.Results This study included 17692 unruptured cerebral aneurysm patients treated with SACE.During the mean follow-up of 4.2 years,there were 379(2.1%)patients with cerebral infarction and 190(1.1%)patients with major haemorrhage.The percentage of patients receiving APT was 79.5%at 1year,which gradually decreased to 58.3%at 2 years after SACE.APT was beneficial in preventing cerebral infarction within 12 months after SACE(adjusted HR(aHR)0.56;95%CI,0.35 to 0.89;p=0.014).After 12 months,this association was not evident.APT increased the risk of haemorrhage after 24 months(aHR 1.76;95%CI 1.11 to 2.87;p=0.016).Discussion and conclusion Our findings suggest that in patients with unruptured cerebral aneurysm treated with SACE,the reasonable duration of APT for preventing cerebral infarction might be 1year after SACE.