Laminin Receptors in the CNS and Vasculature

Stroke, Ahead of Print. Laminin exerts a variety of important functions via binding to its receptors, including integrins and dystroglycan. With the advance in gene-targeting technology, many integrin/dystroglycan knockout/mutant mice were generated in the past 3 decades. These mutants enable loss-of-function studies and have substantially enriched our knowledge of integrin/dystroglycan functions. In this review, we summarize the functions of laminin receptors during embryonic development and in the CNS and vasculature. First, the biochemical properties of integrins and dystroglycan are briefly introduced. Next, we discuss loss-of-function studies on laminin receptors, including integrin-α3, integrin-α6, integrin-α7, integrin-β1, integrin-β4, and dystroglycan, focusing on embryonic development, the CNS, and vasculature. The phenotypes of compound knockout mice are described and compared with that of single mutants. Last, important questions and challenges in the field as well as potential future directions are discussed. Our goal is to provide a synthetic review on loss-of-function studies of laminin receptors in the CNS and vasculature, which could serve as a reference for future research, encourage the formation of new hypotheses, and stimulate new research in this field.

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Explaining the multifaceted experiences of family caregivers of stroke survivors: a qualitative study in Iran

Objectives
As the family caregivers of stroke survivors are typically subjected to care burden, spirituality has been advocated to protect them from its negative effects. The purpose of this study was to describe the caregiving experiences of family caregivers of stroke survivors.

Design
This qualitative study was conducted from December 2023 to June 2024 in Iran. Data were analysed using the conventional content analysis method.

Setting
The study was conducted in the neurology wards of two referral hospitals affiliated with Shahid Beheshti University of Medical Sciences in Tehran, Iran.

Participants
After meeting the inclusion criteria, a total of 17 family caregivers of stroke survivors were recruited using the purposive sampling technique with maximum variation. Data were then collected through 17 in-depth semistructured interviews, each lasting 30–60 min.

Results
Four themes emerged from the study participants’ statements: (1) ‘challenges and struggles’, (2) ‘religious coping strategies’, (3) ‘psychological coping strategies’ and (4) ‘social and relational dynamics’. The core concept of ‘balancing hope and hardship’ was then introduced.

Conclusion
The study findings highlight the need to develop comprehensive support programmes for family caregivers of stroke survivors to minimise their caregiving burden. Healthcare planners and providers are encouraged to use these findings to improve the health outcomes of these families and reduce the burden of caregiving.

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Study protocol for an internahaational prospective non-randomised trial evaluating the long-term outcomes of transcatheter aortic valve implantation versus surgical aortic valve replacement for aortic-valve stenosis in patients at risk to severe valve obstruction: the TAVISAR trial

Background
Aortic valve stenosis (AVS) represents the most prevalent primary valvular lesion necessitating surgical intervention or transcatheter intervention in Europe and North America. Its prevalence is increasing at a rapid rate as a consequence of the ageing population. A variety of mechanical interventions are available to determine the management of AVS; however, there is currently a paucity of robust data with which to perform a comparative analysis of the efficacy of surgical aortic valve replacement (SAVR) and that of conventional stented xenograft bioprostheses (BP) or sutureless aortic valves (SAV) and transcatheter aortic valve implantation (TAVI). The present study aims to compare the effectiveness and clinical outcomes of SAVR using BP or SAV technique and TAVI in patients with severe AVS.

Methods and analysis
A collaboration between three cardiac surgery centres across two European countries has resulted in the conception of the Transcatheter Aortic Valve Implantation vs Surgical Aortic Valve Replacement trial. This prospective non-randomised trial is designed to evaluate the long-term outcomes of TAVI in comparison to SAVR for AVS in patients at risk of severe valve obstruction. The registry will enrol successive patients who have undergone mechanical intervention for AVS between January 2015 and December 2025. Investigators will assess the difference between replacement procedures for both the standard surgical approach and the transcatheter procedure. The principal clinical outcome under consideration will be the composite degree of all-cause mortality, ischaemic stroke or rehospitalisation at 10 years. The present study will also have a number of secondary endpoints, including all-cause mortality, followed by functional status, hospitalisation, neurocognition, physiological measures (echocardiographic assessment), adverse events and reoperation.

Ethics and dissemination
It is hypothesised that the nature of the trials will serve to minimise bias related to institutional volume and surgical experience. Each participating centre is required to have an aortic valve programme that enables proper follow-up and management of any late aortic events following replacement surgery for the AVS. The data collected will provide valuable insight into the comparative effectiveness of various surgical approaches, both standardised and advanced, in aortic valve surgery and TAVI. This comprehensive analysis will contribute significantly to the development of robust international guidelines.

Trial registration number
Clinical Trial Gov.Com. ID: NCT05261204 IRB. ID: 2022011057

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Targeting osteosarcopenia and multimorbidity for frailty prevention through identification and deep phenotyping methods in healthy ageing and high-burden disease cohorts (OPTIMA-C): a longitudinal observational cohort study protocol for neuromusculoskeletal muscle health

Introduction
Sarcopenia and frailty have been identified as negative predictors of health outcomes. Patients with stroke, traumatic brain injury (TBI), knee osteoarthritis (OA) and breast cancer commonly experience low physical activity levels in the chronic phase of recovery. This prospective study aims to explore the feasibility of multimodal screening and longitudinal tracking of various biomarkers from the acute to chronic phase of disease to determine the relationship with frailty outcomes.

Methods and analysis
A prospective longitudinal observational cohort study involving Asian populations is planned over 3 years. Enrolled participants with index conditions of acute stroke, TBI, knee OA and breast cancer will be recruited from rehabilitation hospitals and clinics and followed longitudinally. Reference thresholds from the Asian Working Group on Sarcopenia will be used. Variables include self-reported questionnaires, disease and comorbidity characteristics, anthropometric measurements, appetite questionnaires, muscle ultrasound (MUS), muscle/bone mass, blood biomarkers and markerless gait motion systems. In particular, physical performance (short physical performance battery and hand grip strength), sarcopenia (SARC-F questionnaire) and frailty assessment (FRAIL score, clinical frailty scale), four-region MUS, body composition analysis, dual X-ray absorptiometry, bone mineral densitometry, physical activity levels (International Physical Activity Questionnaire for the elderly [IPAQ-E], fitness trackers) and health-related quality of life assessment (EuroQoL-5D questionnaire five level [EQ5D-5L]) will be used. Blood biomarkers measuring metabolic health (eg, glycated haemoglobin, cholesterol, fasting glucose and 25-OH vitamin D) and inflammation (eg, Tumor Necrosis Factor-alpha [TNF-α] and Monocyte Chemoattractant Protein-1 [MCP-1]) will be measured at baseline. Data collection will take place at postrecruitment baseline (hospital admission), 1, 6 months, 12 months and 2 years postrecruitment (inpatient) and at postrecruitment baseline, 6 months, 12 months and 2 years postrecruitment (outpatient).

Ethics and dissemination
Ethical approval has been obtained from the National Healthcare Group Domain Specific Review Board (2023/00105). Findings will be disseminated through conference presentations and publication in scientific journals.

Trial registeration number
NCT06073106.

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How do we measure dysarthria after stroke? A systematic review to guide the core outcome set for dysarthria

Objectives
A consensus study to establish a Core Outcome Set for dysarthria after stroke identified four key outcome domains that should be measured in research and clinical practice: (1) intelligibility of speech, (2) ability to participate in conversations, (3) living well with dysarthria and (4) communication partners skills and knowledge (where relevant). This review aimed to systematically identify corresponding measurement instruments and to examine their clinical utility and psychometric properties.

Design
Systematic review conducted in alignment with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Data sources
CINAHL, EMBASE, MEDLINE, PsycInfo and Cochrane Stroke Group Trials Register, CENTRAL, Linguistics and Language Behavioral Abstracts (LLBA). Major trials registers: WHO ICTRP, ISRCTN registry and ClinicalTrials.gov searched March 2024.

Eligibility criteria for selecting studies
We included trials that developed or used measurement instruments for poststroke dysarthria. We identified studies that could be included in an update of the Cochrane systematic review of interventions for non-progressive dysarthria to identify what measurement instruments were used in therapy trials for poststroke dysarthria.

Data extraction and synthesis
Records were screened independently by three authors. Psychometric data were extracted, by two authors, from included studies and methodological quality was evaluated using Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) and Core Outcome Measures in Effectiveness Trials (COMET) guidance. Assessment of clinical utility followed Outcome Measures in Rheumatology (OMERACT) guidance.

Results
Following screening, 19 publications reporting 12 measurement instruments were identified. According to COSMIN standards, all 19 publications were rated as having low, very low or unknown quality of evidence. Three measurement instruments were identified as having the most relevant clinical utility to the population, the highest quality of evidence and had the potential to measure some specific aspects from three of the four agreed domains, intelligibility, conversations and living well with dysarthria from the patient and clinician perspective. These were the Frenchay Dysarthria Assessment II, the Communication Outcomes After Stroke Scale and the Therapy Outcome Measures for Dysarthria.

Conclusions
This review provides a comprehensive overview and appraisal of dysarthria measurement instruments to align with a Core Outcome Set. We only included English language-based measurement instruments. Many dysarthria measurement instruments were developed for non-stroke populations, including progressive dysarthria, with limited psychometric data for stroke. Measurement instruments with uncertain quality of evidence can still be considered for inclusion with a Core Outcome Set and three have been suggested. There is a need for further psychometric testing of these and the development of new measurement instruments to cover all aspects of intelligibility, conversations, living well with dysarthria and communication partner skills.

PROSPERO registration number
CRD42022302998.

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Rationale and design of 'discontinuing statins in multimorbid older adults without cardiovascular disease (STREAM): study protocol of a randomised non-inferiority clinical trial

Introduction
Statins are among the most widely used drugs. While they are effective for primary and secondary prevention of cardiovascular (CV) disease in middle-aged subjects, their benefits for prevention in older adults (aged ≥70 years) without CV disease are uncertain, particularly for those with multimorbidity. Statin side effects and drug interactions are common in older patients and may negatively impact quality of life. To date, the only randomised controlled trial (RCT) investigating statin discontinuation in older adults has demonstrated no difference in survival but did note a small improvement in quality of life for those who discontinued statins. However, this trial exclusively enrolled patients with a life expectancy

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Inhibition of Ipsilesional M1 β Oscillations by Contralesional M1 Following Acute Ischemic Stroke: A TMS-EEG Study

Stroke, Ahead of Print. BACKGROUND:This study aimed to investigate neurophysiological mechanisms underlying functional impairment and recovery after acute ischemic stroke using transcranial magnetic stimulation combined with electroencephalography, focusing on interhemispheric interactions and oscillatory dynamics.METHODS:This single-center case-control study (December 2022 to May 2024) included 19 ischemic stroke patients within 14 days of symptom onset (mean age, 47.95±12.41 years; 15 [79%] males) with 3-month poststroke follow-up. Sixteen age-matched healthy controls (53.56±9.83 years; 12 [80%] males) were included. Transcranial magnetic stimulation-evoked electroencephalography potentials, local mean field power during 25 ms and 35 ms (local mean field power25–35 ms), and power spectral density of the ipsilesional primary motor cortex (ilM1) were calculated when single-pulse transcranial magnetic stimulation was sequentially applied to the contralesional M1 (clM1) and ilM1. Spearman correlation analysis evaluated associations between transcranial magnetic stimulation combined with electroencephalography parameters and clinical outcomes: Fugl-Meyer assessment, Fugl-Meyer assessment-upper extremity subscale, National Institutes of Health Stroke Scale, and National Institutes of Health Stroke Scale changes from baseline to 3 months poststroke.RESULTS:Stroke patients exhibited simplified transcranial magnetic stimulation-evoked electroencephalography potential waveforms with reduced amplitudes compared with healthy controls. The contralesional resting motor threshold of stroke patients was significantly lower compared with healthy controls (t=−2.79;P=0.009). The contralesional resting motor threshold was positively associated with the local mean field power25–35 msof ilM1 with stimulation on ilM1 (r=0.482;P=0.018). The power and power spectral density of β oscillations were negatively associated with the Fugl-Meyer assessment (r=−0.557,P=0.014;r=−0.417,P=0.038, respectively) and Fugl-Meyer assessment-upper extremity (r=−0.503,P=0.014;r=−0.389,P=0.05, respectively), but the power of β oscillations was positively associated with changes in the National Institutes of Health Stroke Scale (r=0.507;P=0.027) with stimulation on clM1.CONCLUSIONS:Increased excitability of the clM1 is associated with decreased excitability of the ilM1. The inhibition of β oscillations in the ilM1 by the clM1 serves as a biomarker for poststroke functional impairment and recovery. Neuromodulation of the clM1 to enhance the β oscillations of ilM1 may be a promising treatment strategy.

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StrokeCog-15 Is an Efficient Neuropsychological Battery to Screen for Cognitive Impairment in Chronic Stroke

Stroke, Ahead of Print. BACKGROUND:Poststroke cognitive impairment can significantly impact functional outcomes and quality of life. While comprehensive neuropsychological evaluations are valuable in characterizing this impairment, their time-intensive nature is not always feasible. Thus, we set out to develop a brief cognitive battery that is sensitive to poststroke cognitive impairment.METHODS:Neuropsychological testing was completed in a validation sample of 126 participants with chronic ischemic stroke (median days since stroke, 337 [interquartile range, 235–1057]) as part of StrokeCog, a prospective observational cohort study. This comprehensive 60-minute cognitive battery contained 9 tests covering 5 cognitive domains. A partial least square regression analysis informed the selection of a brief, 15-minute battery of 4 tests (StrokeCog-15) covering 4 cognitive domains: language, memory, working memory, and processing speed/executive functioning. We then compared StrokeCog-15 with Montreal Cognitive Assessment and an established 30-minute battery in its ability to detect cognitive impairment as identified by the comprehensive battery. Finally, we assessed the utility of StrokeCog-15 in an external validation sample of 61 participants (median days since stroke, 210 [interquartile range, 193–230]) enrolled in the parallel Stroke-IMPaCT study.RESULTS:Cognitive impairment was common, occurring in 50% (n=61) and 66% (n=40) of the 2 cohorts. Deficits occurred most frequently in the memory and processing speed/executive functioning domains. In the derivation sample, StrokeCog-15 demonstrated high sensitivity (0.97) and adequate specificity (0.78) in detecting cognitive impairment on the comprehensive battery, outperforming both Montreal Cognitive Assessment (sensitivity, 0.77; specificity, 0.73) and the 30-minute battery (sensitivity, 0.97; specificity, 0.35). StrokeCog-15 similarly demonstrated high sensitivity (0.93) and adequate specificity (0.67) in the validation sample.CONCLUSIONS:A brief 15-minute battery of tests has high sensitivity to detect cognitive impairment as identified on a longer neuropsychological test battery. StrokeCog-15 assesses multiple cognitive domains commonly impacted by stroke and represents an efficient yet effective means to identify chronic poststroke cognitive impairment.

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Preventive Effects of Prasugrel on Cerebrovascular Events Following Percutaneous Coronary Intervention

Stroke, Ahead of Print. BACKGROUND:Dual antiplatelet drug administration is recommended after percutaneous coronary intervention (PCI) stent placement. Although prasugrel, a newer P2Y12 inhibitor, reportedly suppresses cardiovascular events more effectively than the traditional agent clopidogrel, its preventive effects on cerebrovascular disorders remain a topic of ongoing debate. This study aimed to examine the cerebrovascular efficacy and safety of post-PCI prasugrel and clopidogrel using extensive real-world data in Japan.METHODS:Using the CLIDAS (Clinical Deep Data Accumulation System) database, 7412 post-PCI patients who received dual antiplatelet therapy between April 2013 and March 2019 were identified. The primary end point was defined as the incidence of any stroke, while secondary end points included individual ischemic and hemorrhagic cerebrovascular events. The incidence of cerebrovascular events was compared between the prasugrel (2.5–3.75 mg daily; n=2219) and clopidogrel (75 mg daily; n=5193) groups using propensity-score inverse probability of treatment weighting and Fine and Gray models to account for competing risks.RESULTS:Within 1 year after PCI, the prasugrel group had a significantly lower incidence of cerebrovascular events (subdistribution hazard ratio, 0.46 [95% CI, 0.24–0.91];P=0.027) than the clopidogrel group. The subgroup analyses did not show significant differences in the incidence of ischemic (subdistribution hazard ratio, 0.54 [95% CI, 0.25–1.14];P=0.11) and hemorrhagic cerebrovascular events (subdistribution hazard ratio, 0.30 [95% CI, 0.084–1.10];P=0.070) between the use of prasugrel and clopidogrel. One-year health care costs between patients treated with prasugrel and those treated with clopidogrel showed no significant differences.CONCLUSIONS:Our data suggest that post-PCI prasugrel use was associated with lower cerebrovascular events compared with the use of clopidogrel in combination with aspirin. Further research is necessary to substantiate the potential of prasugrel in lowering cerebrovascular risks after post-PCI while upholding a satisfactory safety profile.

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ARISE II Consensus on the Management of Intracranial Atherosclerotic Disease

Stroke, Volume 56, Issue 6, Page 1636-1641, June 1, 2025. Intracranial atherosclerotic disease (ICAD) is one of the leading causes of ischemic stroke worldwide. Despite advances in its diagnosis and management, there is no clear consensus on best practices to manage ICAD. This report summarizes the ARISE II (Roundtable Discussion With Industry and Stroke Experts) consensus in treating ICAD. The consensus underscored the importance of lifestyle modification and medical management in patients with ICAD. Patients who fail medical management are candidates for endovascular treatment. Open surgery is not recommended in patients who lack demonstrated hemodynamic insufficiency. The consensus also identified gaps in knowledge about the optimal duration of antithrombotics, the effect of the CYP2C19 genotype on medical management, the need for newer devices, and the standardization of antithrombotic protocols before stenting in an acute setting. Optical coherence tomography requires additional clinical data before defining its role in the diagnosis of ICAD.

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