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First-Pass Effect in M1-Occlusion Stroke Patients Treated with Combined Stent-RetrieverLarge-Bore Distal Aspiration Catheter Thrombectomy.

Combined stent-retrieverlarge-bore distal aspiration catheter (LB-DAC) thrombectomy was recently introduced to treat large-vessel occlusion however, it is unclear whether larger inner diameters improve outcomes. We compared angiographic and clinical outcomes in patients with occlusions of the M1 segment of the middle cerebral artery treated with mechanical thrombectomy using extra-LB-DAC versus LB-DAC in combination with stent-retrievers. We analyzed consecutive patients with M1 occlusion included in the ROSSETTI registry treated with non-balloon guide catheter combined LB-DACstent-retriever thrombectomy between June 2019 and April 2022. We compared demographics, baseline clinical variables, procedural variables, angiographic outcomes, and clinical outcomes National Institute of Health Stroke Scale score at 24 h (24h-NIHSS) and modified Rankin scale score at 3 months between patients treated with extra-LB-DAC (Sofia Plus, MIVI Q6, Catalyst7 inner diameter, 0.068″-0.070″) versus LB-DAC (Sofia 5F, MIVI Q5, Catalyst 6 inner diameter, 0.055″-0.064″). Primary outcome was the first-pass effect (FPE) rate, defined as near-completecomplete reperfusion (mTICI 2c-3) after a single pass of the device. We included 324 patients (extra-LB-DAC, 185, 57.1% patients). Demographics, clinical data, and clinical outcomes were similar between the two groups however, there was a trend towards improvement in National Institute of Health Stroke Scale score at 24 h (24h-NIHSS) in the cohort treated with extra-LB-DAC 9 points (IQR 416 points) vs. 12 points (IQR 418 points, P 0.083). Patients treated with extra-LB-DAC had higher FPE rate (47% vs. 30.9% P 0.003) and higher modified FPE (mTICI ≥ 2b after a single pass) rate (65.9% vs 46.8% P 0.001). The use of extra-LB-DAC was an independent factor in predicting FPE (odds ratio 1.982, 95% confidence interval 1.250-3.143, P 0.004). Our results suggest that in combined LB-DACstent-retriever thrombectomy, a larger aspiration catheter inner diameter is associated with higher rates of FPE and mFPE.

Intensive blood pressure control in older patients with hypertension-a STEP in the right direction

In November 2022, the Clinical Practice Guidelines for the Management of Hypertension in China were updated the definition of hypertension and the target of treatment was changed from 14090 mm Hg to 13080 mm Hg. This was prompted by the results of the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) study, a large multicenter randomized controlled trial conducted in China. STEP echoed the results of the American Systolic Blood Pressure Intervention Trial (SPRINT), and confirmed that intense lowering of blood pressure is on the whole beneficial. This confirmation is important for the Chinese population, in which strokes outnumber myocardial infarctions. It is also reassuring to know that treating adults aged 60 years or older to achieve a systolic blood pressure of <130 mm Hg is safe, while reducing cardiovascular events, stroke and all-cause mortality. Nevertheless, further studies are needed to delineate the risks and benefits in subgroups, such as the elderly with diabetes or a history of stroke.

Management Strategies for Acute Type A Aortic Dissection Complicated By Limb Malperfusion.

Acute type A aortic dissection complicated by limb malperfusion presents a risk of mortality to the patients. Debates exist regarding management, whether focused on reperfusion first or immediate repair. Here, we aimed to describe our experience with the management of acute type A aortic dissection (ATAAD) complicated by limb malperfusion. From January 1, 2020 to December 31, 2021, 22 consecutive patients were admitted to Xiamen Cardiovascular Hospital, due to acute type A aortic dissection complicated by limb malperfusion. All perioperative variables were recorded and analyzed. Limb malperfusion was diagnosed, according to the clinical symptoms, computed tomography angiography, and laboratory test. We adopted the clinical categories of acute limb ischemia to stratify severity of limb ischemia. Surgery strategies are as follows Reperfusion first followed by central repair, immediate central repair, and immediate central repair followed by stenting. There were 21 males and one female with an average of 53.3±11.7 years. Management strategies were as follows immediate central repair using total arch replacement with frozen elephant trunk in 15 patients, endovascular stenting followed by central repair in four patients, and endovascular stenting after central repair in two patients. The average extracorporeal circulation time was 258.8 ± 70.5 min the average aortic cross-clamp time was 177.9 ± 54.2 min and the average circulatory arrest time was 45.5 ± 13.1 min. The early mortality rate was 13.6% (322). Two patients left the hospital voluntarily, due to cerebral infarction and bleeding. One patient underwent fasciotomy for osteofascial compartment syndrome and uneventfully was discharged. Six patients underwent continuous renal replacement therapy and hemoperfusion. Central repair is safe and feasible for ATAAD complicated with limb malperfusion. For serious limb malperfusion, endovascular stenting followed by central repair is a good choice with continuous renal replacement therapy (CRRT) and hemoperfusion. Hospital mortality rate is high in cases with multiple organ malperfusion.

Effects of Percutaneous Coronary Intervention and Coronary Artery Bypass Grafting on Clinical Outcomes in Patients with Reduced Ejection Fraction Heart Failure and Coronary Heart Disease A Meta-Analysis.

To clarify the effects of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) on the clinical outcomes of patients with coronary heart disease (CHD) complicated with reduced ejection fraction heart failure (HFrEF) through meta-analysis. Three major literature databases - PubMed, Web of Science, and Cochrane - were searched by search terms and the literature retrieval time was publications dating from January 2007 to December 2021. To search for observational studies and randomized controlled trials (RCT) comparing the efficacy of PCI and CABG in patients with CHD and HFrEF, the abstract or full text of the literature was read and the final included literature was determined, according to inclusion and exclusion criteria. The quality of the included literature was evaluated using the Ottawa scale and data extraction was further completed. Data analysis was made using RevMan5.4 and R4.1 software relevant forest plots and funnel plots were made, according to the extracted data. Eggers test was used to evaluate whether the data had publication bias. Outcomes were the major adverse cardiovascular events (MACE). A total of 10 studies were included and 11,032 subjects were included, made up of 5,521 cases of PCI and 5,511 cases of CABG. The results showed no significant difference between the two groups in cardiac mortality (CM) (RR1.13, 95% CI 0.98-1.30, P 0.10) and in overall all-cause mortality (ACM) (RR1.12, 95% CI 0.92-1.37, P 0.25). In the subgroup analysis of ACM, in the subgroups with left ventricular ejection fraction (LVEF) less than 35% and exceeding 35% and less than 50% (RR1.12, 95% CI 0.92-1.37, P 0.25) between the two groups, there was no statistical difference. However, among other MACE, compared with the PCI group, the CABG group had a lower risk of MACE (RR1.58, 95%CI 1.49-1.70, P < 0.00001), myocardial infarction (MI) (RR1.99, 95% CI 1.02-3.88, P 0.04), heart failure (HF) (RR1.29, 95% CI 1.17-1.43, P < 0.00001) and revascularization (RR2.74, 95% CI 1.93-3.90, P < 0.00001). Finally in the CABG group, the risk of stroke or transient ischemic attack (TIA) was higher (RR0.71, 95% CI 0.58-0.86, P 0.0006) than the PCI group. The mortality rates of PCI and CABG were similar in patients with CHD complicated with HFrEF. Compared with PCI, CABG had a lower incidence of MACE, MI, HF, and revascularization, and a higher incidence of stroke or TIA.

Cognitive trajectories and incident dementia after a cardiovascular event in older adults.

Cardiovascular disease (CVD) is a recognized risk factor for dementia. Here we determined the extent to which an incident CVD event modifies the trajectory of cognitive function and risk of dementia. 19,114 adults (65) without CVD or dementia were followed prospectively over 9 years. Incident CVD (fatal coronary heart disease, nonfatal myocardial infarction MI, stroke, hospitalization for heart failure) and dementia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) were adjudicated by experts. Nine hundred twenty-two participants had incident CVD, and 44 developed dementia after CVD (4.9% vs. 4.4% for participants without CVD). Following a CVD event there was a short-term drop in processing speed (-1.97, 95% confidence interval CI -2.57 to -1.41), but there was no significant association with longer-term processing speed. In contrast, faster declines in trajectories of global function (-0.56, 95% CI -0.76 to -0.36), episodic memory (-0.10, 95% CI -0.16 to -0.04), and verbal fluency (-0.19, 95% CI -0.30 to -0.01) were observed. Findings highlight the importance of monitoring cognition after a CVD event.

Revascularization methods in patients with carotid stenosis and concomitant coronary heart disease.

A major feature of the atherosclerotic process is its systemic and progressive character. The plaque pathogenetic mechanisms, morphology, evolution, and predilection site (bifurcation zones) determine the frequent coincidence of carotid and coronary atherosclerosis in the same patient.The present overview chronologically traces the history, effectiveness, and benefit of surgical and continuously improving interventional carotid revascularization. It thereby analyzes the indications, results, and complications based on a number of randomized clinical trials, industry-sponsored registries, and large single-center series in the last 3 decades. Carotid endarterectomy (CEA) and percutaneous carotid angioplasty (CAS) have evolved from dubious procedures to a modern strategy resulting in a significantly lower incidence of stroke and death compared to medical treatment only. Although almost every second patient with carotid stenosis and indications for CAS has coronary atherosclerosis, studies on therapeutic modeling in such a combination are few, showing controversial results. Having both CHD and CS doubles the risk of myocardial infarction, stroke, HF, and death. An isolated revascularization approach compromises the results of therapeutic strategies and worsens patient survival. The high risk associated with coronary heart disease in CAS and CEA is a fact and minimization requires both an individualized and uniform stepwise revascularization strategy.

Contemporary prevalence estimates of undiagnosed and diagnosed atrial fibrillation in the United States.

Atrial fibrillation (AF) prevalence estimates vary and have been based on cohorts with clinically established or diagnosed disease. Undiagnosed AF prevalence estimates are less certain as they are based on nongeneralizable convenience samples. Because AF is often asymptomatic, it my remain undiagnosed until the development of complications such as stroke or heart failure. Consequently, the observed prevalence of diagnosed AF from the literature may underestimate total disease burden. We therefore sought to estimate the total prevalence of both diagnosed and undiagnosed AF. We performed a retrospective cohort study from 2012 to 2017 using data from five US medical claims data sets. Undiagnosed AF prevalence was estimated based on the observed incidence of ischemic stroke, systemic embolism (SE), and AF incidence after a strokeSE. The diagnosed AF cohort included AF patients between Q1 2014 and Q3 2015. The undiagnosed AF cohort were patients with assumed undiagnosed AF in the year before a strokeSE and who were newly diagnosed with AF in the 3-month poststrokeSE. StrokeSE incidence was calculated among all AF patients and the ratio of number of undiagnosed AF patients to stroke rate was created. Age- and sex-adjusted estimates were stratified by period of assumed undiagnosed AF before poststrokeSE AF diagnosis (1 or 2 years). The estimated US prevalence of AF (diagnosed and undiagnosed) in Q3 2015 was 5 628 000 cases, of which 591 000 cases (11%) were undiagnosed. The assumed 2-year undiagnosed AF prevalence was 23% (1 531 000) of the total prevalent patients with AF (6 568 000). Undiagnosed (vs. diagnosed) AF patients were older and had higher CHA2DS2-VASc scores. Of undiagnosed AF, 93% had CHA2DS2-VASc ≥2 and met OAC criteria. These contemporary estimates demonstrate the high prevalence of undiagnosed AF in the United States. Undiagnosed AF patients are composed of primarily elderly individuals who if diagnosed, would meet criteria for stroke prevention therapy.

Comparative study of extracellular vesicles derived from mesenchymal stem cells and brain endothelial cells attenuating blood-brain barrier permeability via regulating Caveolin-1-dependent ZO-1 and Claudin-5 endocytosis in acute ischemic stroke.

Blood-brain barrier (BBB) disruption is a major adverse event after ischemic stroke (IS). Caveolin-1 (Cav-1), a scaffolding protein, played multiple roles in BBB permeability after IS, while the pros and cons of Cav-1 on BBB permeability remain controversial. Numerous studies revealed that extracellular vesicles (EVs), especially stem cells derived EVs, exerted therapeutic efficacy on IS however, the mechanisms of BBB permeability needed to be clearly illustrated. Herein, we compared the protective efficacy on BBB integrity between bone marrow mesenchymal stem cells derived extracellular vesicles (BMSC-EVs) and EVs from brain endothelial cells (BEC-EVs) after acute IS and investigated whether the mechanism was associated with EVs antagonizing Cav-1-dependent tight junction proteins endocytosis. BMSC-EVs and BEC-EVs were isolated and characterized by nanoparticle tracking analysis, western blotting, and transmission electron microscope. Oxygen and glucose deprivation (OGD) treated b. End3 cells were utilized to evaluate brain endothelial cell leakage. CCK-8 and TRITC-dextran leakage assays were used to measure cell viability and transwell monolayer permeability. Permanent middle cerebral artery occlusion (pMCAo) model was established, and EVs were intravenously administered in rats. Animal neurological function tests were applied, and microvessels were isolated from the ischemic cortex. BBB leakage and tight junction proteins were analyzed by Evans Blue (EB) staining and western blotting, respectively. Co-IP assay and Cav-1 siRNApcDNA 3.1 vector transfection were employed to verify the endocytosis efficacy of Cav-1 on tight junction proteins. Both kinds of EVs exerted similar efficacies in reducing the cerebral infarction volume and BBB leakage and enhancing the expressions of ZO-1 and Claudin-5 after 24 h pMCAo in rats. At the same time, BMSC-EVs were outstanding in ameliorating neurological function. Simultaneously, both EVs treatments suppressed the highly expressed Cav-1 in OGD-exposed b. End3 cells and ischemic cerebral microvessels, and this efficacy was more prominent after BMSC-EVs administration. Cav-1 knockdown reduced OGD-treated b. End3 cells monolayer permeability and recovered ZO-1 and Claudin-5 expressions, whereas Cav-1 overexpression aggravated permeability and enhanced the colocalization of Cav-1 with ZO-1 and Claudin-5. Furthermore, Cav-1 overexpression partly reversed the lower cell leakage by BMSC-EVs and BEC-EVs administrations in OGD-treated b. End3 cells. Our results demonstrated that Cav-1 aggravated BBB permeability in acute ischemic stroke, and BMSC-EVs exerted similar antagonistic efficacy to BEC-EVs on Cav-1-dependent ZO-1 and Claudin-5 endocytosis. BMSC-EVs treatment was superior in Cav-1 suppression and neurological function amelioration.

A short peptide exerts neuroprotective effects on cerebral ischemia-reperfusion injury by reducing inflammation via the miR-6328IKKβNF-κB axis.

Despite considerable efforts, ischemic stroke (IS) remains a challenging clinical problem. Therefore, the discovery of effective therapeutic and targeted drugs based on the underlying molecular mechanism is crucial for effective IS treatment. A cDNA-encoding peptide was cloned from RNA extracted from Rana limnocharis skin, and the mature amino acid sequence was predicted and synthesized. Hemolysis and acute toxicity of the peptide were tested. Furthermore, its neuroprotective properties were evaluated using a middle cerebral artery occlusionreperfusion (MCAOR) model in rats and an oxygen-glucose deprivationreperfusion (OGDR) model in neuron-like PC12 cells. The underlying molecular mechanisms were explored using microRNA (miRNA) sequencing, quantitative real-time polymerase chain reaction, dual-luciferase reporter gene assay, and western blotting. A new peptide (NP1) with an amino acid sequence of FLPAAICLVIKTC was identified. NP1 showed no obvious toxicities in vivo and in vitro and was able to cross the blood-brain barrier. Intraperitoneal administration of NP1 (10 nmolkg) effectively reduced the volume of cerebral infarction and relieved neurological dysfunction in MCAOR model rats. Moreover, NP1 significantly alleviated the decrease in viability and increase in apoptosis of neuron-like PC12 cells induced by OGDR. NP1 effectively suppressed inflammation by reducing interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels in vitro and in vivo. Furthermore, NP1 up-regulated the expression of miR-6328, which, in turn, down-regulated kappa B kinase β (IKKβ). IKKβ reduced the phosphorylation of nuclear factor-kappa B p65 (NF-κB p65) and inhibitor of NF-κB (I-κB), thereby inhibiting activation of the NF-κB pathway. The newly discovered non-toxic peptide NP1 (FLPAAICLVIKTC) exerted neuroprotective effects on cerebral ischemia-reperfusion injury by reducing inflammation via the miR-6328IKKβNF-κB axis. Our findings not only provide an exogenous peptide drug candidate and endogenous small nucleic acid drug candidate but also a new drug target for the treatment of IS. This study highlights the importance of peptides in the development of new drugs, elucidation of pathological mechanisms, and discovery of new drug targets.

Epigenetics and stroke role of DNA methylation and effect of aging on blood-brain barrier recovery.

Incomplete recovery of blood-brain barrier (BBB) function contributes to stroke outcomes. How the BBB recovers after stroke remains largely unknown. Emerging evidence suggests that epigenetic factors play a significant role in regulating post-stroke BBB recovery. This study aimed to evaluate the epigenetic and transcriptional profile of cerebral microvessels after thromboembolic (TE) stroke to define potential causes of limited BBB recovery. RNA-sequencing and reduced representation bisulfite sequencing (RRBS) analyses were performed using microvessels isolated from young (6 months) and old (18 months) mice seven days poststroke compared to age-matched sham controls. DNA methylation profiling of poststroke brain microvessels revealed 11,287 differentially methylated regions (DMR) in old and 9818 DMR in young mice, corresponding to annotated genes. These DMR were enriched in genes encoding cell structural proteins (e.g., cell junction, and cell polarity, actin cytoskeleton, extracellular matrix), transporters and channels (e.g., potassium transmembrane transporter, organic anion and inorganic cation transporters, calcium ion transport), and proteins involved in endothelial cell processes (e.g., angiogenesisvasculogenesis, cell signaling and transcription regulation). Integrated analysis of methylation and RNA sequencing identified changes in cell junctions (occludin), actin remodeling (ezrin) as well as signaling pathways like Rho GTPase (RhoA and Cdc42ep4). Aging as a hub of aberrant methylation affected BBB recovery processes by profound alterations (hypermethylation and repression) in structural protein expression (e.g., claudin-5) as well as activation of a set of genes involved in endothelial to mesenchymal transformation (e.g., Sox9, Snai1), repression of angiogenesis and epigenetic regulation. These findings revealed that DNA methylation plays an important role in regulating BBB repair after stroke, through regulating processes associated with BBB restoration and prevalently with processes enhancing BBB injury.

Computed tomography derived cervical fat-free muscle fraction as an imaging-based outcome marker in patients with acute ischemic stroke a pilot study.

Outcome assessment in stroke patients is essential for evidence-based stroke care planning. Computed tomography (CT) is the mainstay of diagnosis in acute stroke. This study aimed to investigate whether CT-derived cervical fat-free muscle fraction (FFMF) as a biomarker of muscle quality is associated with outcome parameters after acute ischemic stroke. In this retrospective study, 66 patients (mean age 76 ± 13 years, 30 female) with acute ischemic stroke in the anterior circulation who underwent CT, including CT-angiography, and endovascular mechanical thrombectomy of the middle cerebral artery between August 2016 and January 2020 were identified. Based on densitometric thresholds, cervical paraspinal muscles covered on CT-angiography were separated into areas of fatty and lean muscle and FFMF was calculated. The study cohort was binarized based on median FFMF (cutoff value < 71.6%) to compare clinical variables and outcome data between two groups. Unpaired t test and Mann-Whitney U test were used for statistical analysis. National Institute of Health Stroke Scale (NIHSS) (12.2 ± 4.4 vs. 13.6 ± 4.5, P 0.297) and modified Rankin scale (mRS) (4.3 ± 0.9 vs. 4.4 ± 0.9, P 0.475) at admission, and pre-stroke mRS (1 ± 1.3 vs. 0.9 ± 1.4, P 0.489) were similar between groups with high and low FFMF. NIHSS and mRS at discharge were significantly better in patients with high FFMF compared to patients with low FFMF (NIHSS 4.5 ± 4.4 vs. 9.5 ± 6.7 P 0.004 and mRS 2.9 ± 2.1 vs.3.9 ± 1.8 P 0.049). 90-day mRS was significantly better in patients with high FFMF compared to patients with low FFMF (3.3 ± 2.2 vs. 4.3 ± 1.9, P 0.045). Cervical FFMF obtained from routine clinical CT might be a new imaging-based muscle quality biomarker for outcome prediction in stroke patients.

Quantification of left ventricular ejection fraction and cardiac output using a novel semi-automated echocardiographic method a prospective observational study in coronary artery bypass patients.

Echocardiographic quantification of ejection fraction (EF) by manual endocardial tracing requires training, is time-consuming and potentially user-dependent, whereas determination of cardiac output by pulmonary artery catheterization (PAC) is invasive and carries a risk of complications. Recently, a novel software for semi-automated EF and CO assessment (AutoEF) using transthoracic echocardiography (TTE) has been introduced. We hypothesized that AutoEF would provide EF values different from those obtained by the modified Simpsons method in transoesophageal echocardiography (TOE) and that AutoEF CO measurements would not agree with those obtained via VTI In 167 patients undergoing coronary artery bypass graft surgery (CABG), TTE cine loops of apical 4- and 2-chamber views were recorded after anaesthesia induction under steady-state conditions. Subsequently, TOE was performed following a standardized protocol, and CO was determined by thermodilution. EF and CO were assessed by TTE AutoEF as well as TOE, using the modified Simpsons method, and Doppler measurements via velocity time integral in the LV outflow tract (VTI AutoEF and the modified Simpsons method in TOE showed moderate EF correlation (r 0.38, p < 0.01) with a bias of -12.6% (95% limits of agreement (95%LOA) -36.6 - 11.3%). AutoEF CO correlated poorly both with VTI AutoEF correlated moderately with TOE EF determined by the modified Simpsons method but poorly both with VTI German Register for Clinical Trials (DRKS-ID DRKS00010666, date of registration 08072016).

Brain reserve contributes to distinguishing preclinical Alzheimers stages 1 and 2.

In preclinical Alzheimers disease, it is unclear why some individuals with amyloid pathologic change are asymptomatic (stage 1), whereas others experience subjective cognitive decline (SCD, stage 2). Here, we examined the association of stage 1 vs. stage 2 with structural brain reserve in memory-related brain regions. We tested whether the volumes of hippocampal subfields and parahippocampal regions were larger in individuals at stage 1 compared to asymptomatic amyloid-negative older adults (healthy controls, HCs). We also tested whether individuals with stage 2 would show the opposite pattern, namely smaller brain volumes than in amyloid-negative individuals with SCD. Participants with cerebrospinal fluid (CSF) biomarker data and bilateral volumetric MRI data from the observational, multi-centric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study were included. The sample comprised 95 amyloid-negative and 26 amyloid-positive asymptomatic participants as well as 104 amyloid-negative and 47 amyloid-positive individuals with SCD. Volumes were based on high-resolution T2-weighted images and automatic segmentation with manual correction according to a recently established high-resolution segmentation protocol. In asymptomatic individuals, brain volumes of hippocampal subfields and of the parahippocampal cortex were numerically larger in stage 1 compared to HCs, whereas the opposite was the case in individuals with SCD. MANOVAs with volumes as dependent data and age, sex, years of education, and DELCODE site as covariates showed a significant interaction between diagnosis (asymptomatic versus SCD) and amyloid status (Aß4240 negative versus positive) for hippocampal subfields. Post hoc paired comparisons taking into account the same covariates showed that dentate gyrus and CA1 volumes in SCD were significantly smaller in amyloid-positive than negative individuals. In contrast, CA1 volumes were significantly (p 0.014) larger in stage 1 compared with HCs. These data indicate that HCs and stages 1 and 2 do not correspond to linear brain volume reduction. Instead, stage 1 is associated with larger than expected volumes of hippocampal subfields in the face of amyloid pathology. This indicates a brain reserve mechanism in stage 1 that enables individuals with amyloid pathologic change to be cognitively normal and asymptomatic without subjective cognitive decline.

Identifying blood biomarkers for type 2 diabetes subtyping a report from the ORIGIN trial.

Individuals with diabetes can be clustered into five subtypes using up to six routinely measured clinical variables. We hypothesised that circulating protein levels might be used to distinguish between these subtypes. We recently used five of these six variables to categorise 7017 participants from the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial into these subtypes severe autoimmune diabetes (SAID, n241), severe insulin-deficient diabetes (SIDD, n1594), severe insulin-resistant diabetes (SIRD, n914), mild obesity-related diabetes (MOD, n1595) and mild age-related diabetes (MARD, n2673). Forward-selection logistic regression models were used to identify a subset of 233 cardiometabolic protein biomarkers that were independent determinants of one subtype vs the others. We then assessed the performance of adding identified biomarkers (one after one, from the most discriminant to the least) to predict each subtype vs the others using area under the receiver operating characteristic curve (AUC ROC). Models were adjusted for age, sex, ethnicity, C-peptide level, diabetes duration and glucose-lowering medication usage at blood collection. A total of 25 biomarkers were independent determinants of subtypes, including 13 for SIDD, 2 for SIRD, 7 for MOD and 11 for MARD (all p<4.3 × 10 We identified 25 serum biomarkers, as independent determinants of type 2 diabetes subtypes, that could be combined into a diagnostic test for subtyping. ORIGIN trial, ClinicalTrials.gov NCT00069784.

Psychometric properties of Indonesian version of sleep condition indicator for screening poststroke insomnia.

No study has examined the psychometric properties of the sleep condition indicator (SCI) for screening poststroke insomnia in the Indonesian population. We aimed to develop the Indonesian version of the sleep condition indicator (ISCI) and to examine its psychometric properties for screening adult patients in late sub-acute and chronic periods after stroke. This was a cross-sectional study with two stages. In the first stage, the English version of the SCI was translated into the ISCI using standard procedures. The psychometric properties of the ISCI were tested in the second stage. Internal consistency and test-retest reliability of ISCI were used to evaluate reliability. A confirmatory factor analysis (CFA) was performed to test construct validity. To test concurrent and convergent validity, the Indonesian version of the insomnia severity index (ISI-INA), generalized anxiety disorder questionnaire (IGAD-7), and patient health questionnaire (IPHQ-9) were used. A receiver operating characteristic (ROC) analysis was conducted to calculate the optimal cutoff score of the ISCI on the basis of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for insomnia. A total of 160 adults with a diagnosis of stroke for more than 3 months were included (median age of 58.5 years, 31% met the DSM-5 criteria for insomnia). The ISCI had a satisfactory Cronbachs alpha of 0.89 and test-retest reliability of 0.78. The CFA revealed that the ISCI exhibited a satisfactory model fit and was associated with the ISI-INA, IGAD-7, and IPHQ-9 (r -0.81, -0.32, and -0.52, respectively all P < .001). The ROC test revealed that the optimal cutoff point of ≤23 yielded the highest sensitivity (94%) and specificity (97%). The study results revealed that the 8-item ISCI is a reliable and valid screening tool for detecting insomnia symptoms according to the DSM-5 criteria in the chronic period after stroke.

Dying transplanted neural stem cells mediate survival bystander effects in the injured brain.

Neural stem and progenitor cell (NSPC) transplants provide neuroprotection in models of acute brain injury, but the underlying mechanisms are not fully understood. Here, we provide evidence that caspase-dependent apoptotic cell death of NSPCs is required for sending survival signals to the injured brain. The secretome of dying NSPCs contains heat-stable proteins, which protect neurons against glutamate-induced toxicity and trophic factor withdrawal in vitro, and from ischemic brain damage in vivo. Our findings support a new concept suggesting a bystander effect of apoptotic NSPCs, which actively promote neuronal survival through the release of a protective farewell secretome. Similar protective effects by the secretome of apoptotic NSPC were also confirmed in human neural progenitor cells and neural stem cells but not in mouse embryonic fibroblasts (MEF) or human dopaminergic neurons, suggesting that the observed effects are cell type specific and exist for neural progenitorstem cells across species.

Non-occupational physical activity and risk of cardiovascular disease, cancer and mortality outcomes a dose-response meta-analysis of large prospective studies.

To estimate the dose-response associations between non-occupational physical activity and several chronic disease and mortality outcomes in the general adult population. Systematic review and cohort-level dose-response meta-analysis. PubMed, Scopus, Web of Science and reference lists of published studies. Prospective cohort studies with (1) general population samples >10 000 adults, (2) ≥3 physical activity categories, and (3) risk measures and CIs for all-cause mortality or incident total cardiovascular disease, coronary heart disease, stroke, heart failure, total cancer and site-specific cancers (head and neck, myeloid leukaemia, myeloma, gastric cardia, lung, liver, endometrium, colon, breast, bladder, rectum, oesophagus, prostate, kidney). 196 articles were included, covering 94 cohorts with >30 million participants. The evidence base was largest for all-cause mortality (50 separate results 163 415 543 person-years, 811 616 events), and incidence of cardiovascular disease (37 results 28 884 209 person-years, 74 757 events) and cancer (31 results 35 500 867 person-years, 185 870 events). In general, higher activity levels were associated with lower risk of all outcomes. Differences in risk were greater between 0 and 8.75 marginal metabolic equivalent of task-hours per week (mMET-hoursweek) (equivalent to the recommended 150 minweek of moderate-to-vigorous aerobic physical activity), with smaller marginal differences in risk above this level to 17.5 mMET-hoursweek, beyond which additional differences were small and uncertain. Associations were stronger for all-cause (relative risk (RR) at 8.75 mMET-hoursweek 0.69, 95% CI 0.65 to 0.73) and cardiovascular disease (RR at 8.75 mMET-hoursweek 0.71, 95% CI 0.66 to 0.77) mortality than for cancer mortality (RR at 8.75 mMET-hoursweek 0.85, 95% CI 0.81 to 0.89). If all insufficiently active individuals had achieved 8.75 mMET-hoursweek, 15.7% (95% CI 13.1 to 18.2) of all premature deaths would have been averted. Inverse non-linear dose-response associations suggest substantial protection against a range of chronic disease outcomes from small increases in non-occupational physical activity in inactive adults.

Association of diabetes mellitus and its types with in-hospital management and outcomes of patients with acute myocardial infarction.

Diabetes mellitus (DM) is an important risk factor for adverse outcomes following acute myocardial infarction (AMI), but large-scale studies investigating the differential impact of Type 1 DM (T1DM) and Type 2 DM (T2DM) on AMI outcomes are lacking. All adult discharges for AMI in the National Inpatient Sample (October 2015 to December 2018) were included and stratified into T1DM, T2DM and non-DM (NDM) groups. Outcomes of interests were all-cause mortality, major adverse cardiovascular and cerebrovascular events (MACCE), major bleeding and acute ischemic stroke, as well as invasive management. Binomial hierarchical multilevel multivariable logistic regression with adjusted odds ratios (aOR) and 95 % confidence intervals (95 % CI) was used to investigate the association between DM and its subtypes with the AMI outcomes. Out of 2,587,615 patients, there were 29,250 (1.1 %) T1DM and 1,032,925 (39.9 %) T2DM patients. After multivariable adjustment, patients with T1DM had increased odds of MACCE (aOR 1.20, 95 % CI 1.09-1.31), all-cause mortality (aOR 1.20, 95 % CI 1.08-1.33) and major bleeding (aOR 1.28, 95 % CI 1.13-1.44), whilst T2DM patients had increased odds of MACCE (aOR 1.03, 95 % CI 1.01-1.05) and ischemic stroke (aOR 1.09, 95 % CI 1.05-1.13), compared to NDM patients. The adjusted odds of receiving percutaneous coronary intervention were lower in both T1DM and T2DM patients (aOR 0.70, 95 % CI 0.66-0.75 and aOR 0.95, 95 % CI 0.94-0.96, respectively), but T2DM patients showed higher utilization of composite percutaneous and surgical revascularization (aOR 1.03, 95 % CI 1.03-1.04) compared to NDM patients. DM patients presenting with AMI have worse in-hospital clinical outcomes compared to NDM patients. There are important DM type-related differences with T1DM patients having overall worse outcomes and receiving less overall revascularization.

Homocysteine impedes neurite outgrowth recovery after intracerebral haemorrhage by downregulating pCAMK2A.

Hyperhomocysteinemia (HHcy) is independently associated with poorer long-term prognosis in patients with intracerebral haemorrhage (ICH) however, the effect and mechanisms of HHcy on ICH are still unclear. Here, we evaluated neurite outgrowth and neurological functional recovery using simulated models of ICH with HHcy in vitro and in vivo. We found that the neurite outgrowth velocity and motor functional recovery in the ICH plus HHcy group were significantly slower than that in the control group, indicating that homocysteine (Hcy) significantly impedes the neurite outgrowth recovery after ICH. Furthermore, phosphoproteomic data and signalome analysis of perihematomal brain tissues suggested that calmodulin-dependent protein kinases 2 (CAMK2A) kinase substrate pairs were significantly downregulated in ICH with HHcy compared with autologous blood injection only, both western blot and immunofluorescence staining confirmed this finding. Additionally, upregulation of pCAMK2A significantly increased neurite outgrowth recovery in ICH with HHcy. Collectively, we clarify the mechanism of HHcy-hindered neurite outgrowth recovery, and pCAMK2A may serve as a therapeutic strategy for promoting neurological recovery after ICH.

Derivation and validation of pragmatic clinical models to predict hospital length of stay after cardiac surgery in Ontario, Canada a population-based cohort study.

Cardiac surgery is resource intensive and often requires multidisciplinary involvement to facilitate discharge. To facilitate evidence-based resource planning, we derived and validated clinical models to predict postoperative hospital length of stay (LOS). We used linked, population-level databases with information on all Ontario residents and included patients aged 18 years or older who underwent coronary artery bypass grafting, valvular or thoracic aorta surgeries between October 2008 and September 2019. The primary outcome was hospital LOS. The models were derived by using patients who had surgery before Sept. 30, 2016, and validated after that date. To address the rightward skew in LOS data and to identify top-tier resource users, we used logistic regression to derive a model to predict the likelihood of LOS being more than the 98th percentile (> 30 d), and γ regression in the remainder to predict continuous LOS in days. We used backward stepwise variable selection for both models. Among 105 193 patients, 2422 (2.3%) had an LOS of more than 30 days. Factors predicting prolonged LOS included age, female sex, procedure type and urgency, comorbidities including frailty, high-risk acute coronary syndrome, heart failure, reduced left ventricular ejection fraction and psychiatric and pulmonary circulatory disease. The C statistic was 0.92 for the prolonged LOS model and the mean absolute error was 2.4 days for the continuous LOS model. We derived and validated clinical models to identify top-tier resource users and predict continuous LOS with excellent accuracy. Our models could be used to benchmark clinical performance based on expected LOS, rationally allocate resources and support patient-centred operative decision-making.

Parameter inference in a computational model of haemodynamics in pulmonary hypertension.

Pulmonary hypertension (PH), defined by a mean pulmonary arterial pressure (mPAP) greater than 20 mmHg, is characterized by increased pulmonary vascular resistance and decreased pulmonary arterial compliance. There are few measurable biomarkers of PH progression, but a conclusive diagnosis of the disease requires invasive right heart catheterization (RHC). Patient-specific cardiovascular systems-level computational models provide a potential non-invasive tool for determining additional indicators of disease severity. Using computational modelling, this study quantifies physiological parameters indicative of disease severity in nine PH patients. The model includes all four heart chambers, the pulmonary and systemic circulations. We consider two sets of calibration data static (systolic and diastolic values) RHC data and a combination of static and continuous, time-series waveform data. We determine a subset of identifiable parameters for model calibration using sensitivity analyses and multi-start inference and perform posterior uncertainty quantification. Results show that additional waveform data enables accurate calibration of the right atrial reservoir and pump function across the PH cohort. Model outcomes, including stroke work and pulmonary resistance-compliance relations, reflect typical right heart dynamics in PH phenotypes. Lastly, we show that estimated parameters agree with previous, non-modelling studies, supporting this type of analysis in translational PH research.

Evaluation of the effect of mesenchymal stem cells injection in the nucleus accumbens on the morphine reinstatement behavior in a conditioned place preference model in Wistar rat Expression changes of NMDA receptor subunits and NT-3.

Mesenchymal stem cells (MSCs) have been recently shown to improve functional recovery in animal models of CNS disorders and are currently being examined in clinical studies for sclerosis, stroke, and CNS lesions. The activation of endogenous CNS protection and repair mechanisms is unclear. MSC-based approaches are considered a new potential target for neurodegenerative disorders. This study was designed to discover the effect of MSCs injection in the nucleus accumbens (NAc) on the reinstatement of behavior in morphine-induced conditioned place preference (CPP) in male rats. The CPP was induced via intra-peritoneal (i.p.) morphine injection (5 mgkg) for three consecutive days. After being tested for CPP induction, animals received MSCs or culture medium (DMEM F-12) in their NAc using stereotaxic surgery. Following extinction, a priming dose of morphine (2 mgkg) was administered to induce reinstatement. Expression of GluN1, GluN2A, and GluN2B subunits of the NMDA receptor and the NT-3 gene in the NAc was assessed on the last day of extinction and following CPP reinstatement. The results showed that local injection of MSCs attenuated reinstatement after receiving a priming dose of morphine, and also shortened the period of CPP extinction. The mRNA expression of the NT-3 gene in the group receiving MSCs was increased compared to control animals, as was observed for GluN1 and GluN2B, but not GluN2A. It is concluded that intra-NAc injection of MSCs may facilitate morphine extinction and alleviate reinstatement behavior which may be via expression changes in NMDA receptor subunits and NT-3 gene.

Plasma β-alanine is positively associated with the risk of ischemic stroke a nested case-control study.

Previous studies suggested that β-alanine as a neurotransmitter could affect the pathogenesis of ischemic damage. However, the association between circulating β-alanine and ischemic stroke (IS) risk has not been evaluated in populations. We aimed to examine the association between β-alanine and IS risk in a nested case-control study. We performed a case-control study nested within a prospective community-based cohort (n16457, median follow-up time 5.3 years), which included 321 incident IS cases and 321 controls matched by age and sex. Β-alanine and other metabolites were measured in plasma after overnight fasting by liquid chromatography-tandem mass spectrometry. The association of β-alanine with the risk of IS was evaluated by conditional logistic regression. Body mass index, current smoking, educational attainment, physical activity, total energy intake, family history of stroke, hypertension, diabetes, hyperlipidemia, and estimated glomerular filtration rate were adjusted for in multivariable models. There was a significant Spearman partial correlation between β-alanine and 4-pyridoxic acid (ρ 0.239, P <0.001). Participants with elevated β-alanine levels were more likely to develop IS with an adjusted odds ratio of 1.26 (95% CI 1.06-1.51, P 0.011) (per standard deviation increment). This association remained significant after excluding the first two years of follow-up, and after further adjustment for red meat intake, total protein intake, medications use, or vitamin B6 indicators. Our novel findings revealed that plasma β-alanine at baseline was positively associated with risk of IS, and may function as an early biomarker of IS risk.

Impaction procedure influences primary stability of acetabular press-fit components.

The aim of the study was to investigate whether the primary stability of press-fit acetabular components can be improved by altering the impaction procedure. Three impaction procedures were used to implant acetabular components into human cadaveric acetabula using a powered impaction device. An impaction frequency of 1 Hz until complete component seating served as reference. Overimpaction was simulated by adding ten strokes after complete component seating. High-frequency implantation was performed at 6 Hz. The lever-out moment of the acetabular components was used as measure for primary stability. Permanent bone deformation was assessed by comparison of double micro-CT (µCT) measurements before and after impaction. Acetabular component deformation and impaction forces were recorded, and the extent of bone-implant contact was determined from 3D laser scans. Overimpaction reduced primary acetabular component stability (p 0.038) but did not significantly increase strain release after implantation (p 0.117) or plastic deformations (p 0.193). Higher press-fits were associated with larger polar gaps for the 1 Hz reference impaction (p 0.002, R

Paradoxical Emboli as a Cause of Stroke.

Cerebrovascular embolic strokes are responsible for significant morbidity. 40% of strokes have no inciting cause and are thought to be the result of paradoxical emboli (PDE) passing into the arterial system by way of intra-cardiac or pulmonary vascular defects. We present two cases of PDE resulting in acute ischemic events. A 63-year-old female presented for evaluation of left upper extremity numbness. Imaging was significant for an acute right middle cerebral artery infarct and evidence of a large saddle pulmonary embolism. The patients stroke was postulated to have been secondary to a patent foramen ovale (PFO). An 87-year-old male presented for evaluation of chest pain. The patient underwent three-vessel CABG and experienced an acute left hemispheric stroke post-operatively. Transthoracic echocardiogram demonstrated a biatrial thrombus transversing a PFO and was postulated to have been the cause. The prompt diagnosis of PDE is paramount to preventing the morbidity associated with repeat ischemic events.

General Approach to Identify, Assess, and Characterize Inhibitors of Lipid Peroxidation and Associated Cell Death.

Lipid peroxidation (LPO) is associated with a variety of pathologies and drives a form of regulated necrosis called ferroptosis. There is much interest in small-molecule inhibitors of LPO as potential leads for therapeutic development for neurodegeneration, stroke, and acute organ failure, but this has been hampered by the lack of a universal high-throughput assay that can identify and assess candidates. Herein, we describe the development and validation of such an approach. Phosphatidylcholine liposomes loaded with ∼10% phospholipid hydroperoxide and STY-BODIPY, a fluorescent signal carrier that co-autoxidizes with polyunsaturated phospholipids, are shown to autoxidize at convenient and constant rates when subjected to an optimized Fe

Exploring the experiences of people who had a stroke and therapists who managed people with stroke during the COVID-19 pandemic An exploratory qualitative study.

To explore experiences, needs and rehabilitation priorities of patients who had their stroke and the experiences of therapists managing stroke patients during the COVID-19 pandemic. Exploratory qualitative study. Acute, sub-acute and community stroke facilities. Twenty-two participants. Twelve therapists (all female, mean age 38.5 years) and ten patients (9 female, mean age 51.1 years) who were involved in stroke rehabilitation during the pandemic were interviewed. Individual semi-structured interviews were conducted. Interviews were recorded and transcribed before being analysed using a reflexive thematic analysis approach. Four main themes demonstrate the modifications in the care system as a result of COVID-19, impact on the stroke patients at different stage, needs and priorities of stroke rehabilitation, and management strategies that have been used in stroke rehabilitation. Remote rehabilitation and self-management strategies were recommended to deliver care for stroke patients. However, therapists seemed unsatisfied with the quality of care delivered and patients suggested face to face delivery of care with proper personal protection equipment to better address their physical and mental health needs. The findings of this study explored the impact of the pandemic on stroke care from the perspective of the patients and therapists and provides suggestions for improved delivery of care in similar situations. Future research is warranted to examine the long-term effects on people who had inadequate post-stroke rehabilitation during covid pandemic and urgent measures taken to reduce the impact the pandemic has had on the physical and mental issues for these patients.

Transcranial magnetic stimulation to frontal but not occipital cortex disrupts endogenous attention.

Covert endogenous (voluntary) attention improves visual performance. Human neuroimaging studies suggest that the putative human homolog of macaque frontal eye fields (FEF) is critical for this improvement, whereas early visual areas are not. Yet, correlational MRI methods do not manipulate brain function. We investigated whether rFEF or V1V2 plays a causal role in endogenous attention. We used transcranial magnetic stimulation (TMS) to alter activity in the visual cortex or rFEF when observers performed an orientation discrimination task while attention was manipulated. On every trial, they received double-pulse TMS at a predetermined site (stimulated region) around V1V2 or rFEF. Two cortically magnified gratings were presented, one in the stimulated region (contralateral to the stimulated area) and another in the symmetric (ipsilateral) nonstimulated region. Grating contrast was varied to measure contrast response functions (CRFs) for all attention and stimulation combinations. In experiment 1, the CRFs were similar at the stimulated and nonstimulated regions, indicating that early visual areas do not modulate endogenous attention during stimulus presentation. In contrast, occipital TMS eliminates exogenous (involuntary) attention effects on performance A. Fernández, M. Carrasco,

Musculoskeletal pain and its impact on prognosis following acute coronary syndrome or stroke A linked electronic health record cohort study.

Musculoskeletal painful conditions are a risk factor for cardiovascular disease (CVD), but less is known about whether musculoskeletal pain also worsens prognosis from CVD. The objective was to determine whether patients with musculoskeletal pain have poorer prognosis following acute coronary syndrome (ACS) or stroke. The study utilised UK electronic primary care records (CPRD Aurum) with linkage to hospital and mortality records. Patients aged ≥45 years admitted to hospital with incident ACSstroke were categorised by healthcare use for musculoskeletal pain (inflammatory conditions, osteoarthritis OA, and regional pain) based on primary care consultations in the prior 24 months. Outcomes included mortality, length of stay, readmission and management of index condition (ACSstroke). There were 171,670 patients with incident ACS and 138,512 with stroke 30% consulted for musculoskeletal pain prior to ACSstroke and these patients had more comorbidity than those without musculoskeletal pain. Rates of mortality and readmission, and length of stay were higher in those with musculoskeletal pain, particularly OA and inflammatory conditions, in ACS. Readmission was also higher for patients with musculoskeletal pain in stroke. However, increased risks associated with musculoskeletal pain did not remain after adjustment for age and polypharmacy. Inflammatory conditions were associated with increased likelihood of prescriptions for dual anti-platelets (ACS only) and anti-coagulants. Patients with musculoskeletal pain have higher rates of poor outcome from ACS which relates to being older but also increased polypharmacy. The high rates of comorbidity including polypharmacy highlight the complexity of patients with musculoskeletal pain who have new onset ACSstroke.

Perinatal brain damage - what the obstetrician needs to know.

Perinatal brain damage is still one of the leading contributors to perinatal death and postnatal disability worldwide. However, the term perinatal brain damage encompasses very different aetiological entities that result in an insult to the developing brain and does not differentiate between the onset, cause and severity of this insult. Hypoxic-ischemic encephalopathy (HIE), intraventricular haemorrhage, periventricular leukomalacia and perinatal stroke are often listed as the major aetiologies of perinatal brain damage. They differ by type and timing of injury, neuropathological and imaging findings and their clinical picture. Along the timeline of neurodevelopment

Establishment of a reproducible and minimally invasive ischemic stroke model in swine.

The need for new advances in the managementtreatment options for ischemic stroke patients requires that upcoming preclinical research uses animals with more human-like brain characteristics. The porcine brain is considered appropriate although the presence of the rete mirabile (RM) prevents direct catheterization of the intracranial arteries to produce focal cerebral ischemia. To develop a reproducible minimally invasive porcine stroke model, a catheterguide was introduced through the femoral artery until reaching the left RM. Using the pressure cooker technique (PCT), Squid-12 embolization material was deposited to fill, overflow and occlude the left RM, the left internal carotid artery (ICA) and left circle of Willis (CW) wing up to the origins of the middle cerebral arteries (MCAs), thus mimicking the occlusion produced in the filament model in rodents. Longitudinal multimodal cerebral MR imaging was conducted to assess the brain damage and cerebral blood supply. The technique we describe here occluded up to the origins of the MCAs in 7 out of 8 swine, inducing early damage 90 min post-occlusion that later evolved to a large cerebral infarction, and producing no mortality during the intervention. This novel minimally invasive ischemic stroke model in swine produced reproducible infarcts and shows translational features common to human stroke.

Reduction of in-hospital non-COVID-19 pneumonia in stroke patients during the COVID-19 pandemic.

Measures adopted to contain the spread of SARS-CoV-2 could have led to a reduction in the rate of non-COVID-19 infections. We assessed whether a similar reduction was present in patients with stroke. We performed a hospital-based study nested in a prospective population-based registry. We compared prevalence of infections and in-hospital mortality in subjects admitted for acute stroke between the first pandemic year (study period, from March 2020 to February 2021) and the pre-pandemic year (control period, from March 2019 to February 2020). Infections were reported as pneumonia (PNA), urinary tract infections (UTI), and any infection (INF). From the control (n 677) to the study period (n 520), the prevalence of INF decreased from 11.5 to 4.6% (p < 0.001) and that of PNA decreased from 6.9 to 2.5% (p 0.001). No changes in in-hospital mortality and length of hospital stay were observed between the two periods. The observed reduction of in-hospital pneumonias in patients with stroke was likely attributable to the use of protective measures and limitation of hospital visits. Maintaining some of those measures in the long term may contribute to control infections in hospitalized patients with stroke.

Delayed Chronic Acidic Postconditioning Improves Poststroke Motor Functional Recovery and Brain Tissue Repair by Activating Proton-Sensing TDAG8.

Acidic postconditioning by transient CO

A strange case of double stroke Dr. Jekyll and Mr. Hyde.

The etiological diagnosis of ischemic stroke is crucial for secondary prevention, but often complex for the patients cardiovascular comorbidities, each of which may cause a stroke. We report the case of an 84-year-old patient with severe left ventricular systolic dysfunction due to dilated cardiomyopathy and implantable cardioverter-defibrillator in primary prevention, hospitalized for atherothrombotic ischemic stroke treated conservatively and later by carotid thromboendarterectomy for ulcerated plaque of the right internal carotid artery. A week after discharge, an embolic ischemic stroke occurred due to thrombosis of the left atrial appendage in absence of atrial fibrillation. A careful analysis of the patients cardiovascular risk factors, clinical signs and neuroimages allowed for the etiological diagnosis of both cerebral ischemic events. The case is also peculiar because of left atrial appendage thrombus formation in the context of severe left ventricular systolic dysfunction in absence of atrial fibrillation. In the same patient, the recurrent stroke was not due to the same cause and, owing to the complexity of the differential diagnosis, a multidisciplinary neurological and cardiological approach is pivotal for the management of these patients.

Cerebral Microbleeds-Long-Term Outcome After Cerebrospinal Fluid Shunting in Idiopathic Normal Pressure Hydrocephalus.

Cerebral microbleeds (CMBs) are common in idiopathic normal pressure hydrocephalus (INPH) and have been suggested as radiological markers of a brain prone to bleeding. The presence of CMBs might be relevant when selecting patients for shunt surgery. To evaluate whether CMBs increases long-term risk of hemorrhagic complications and mortality or affects outcomes after cerebrospinal fluid shunt surgery in a cohort of patients with INPH. One hundred and forty nine shunted patients with INPH (mean age, 73 years) were investigated with MRI (T2 or susceptibility-weighted imaging sequences) preoperatively. CMBs were scored with the Microbleed Anatomic Rating Scale. Patients were observed for a mean of 6.5 years (range 2 weeks to 13 years) after surgery. Hemorrhagic events and death were noted. Improvement in gait was evaluated 3 to 6 months after surgery. At baseline, 74 patients (50%) had CMBs. During follow-up, 7 patients (5%) suffered a hemorrhagic stroke and 43 (29%) suffered a subdural hematomahygroma with a median time from surgery of 30.2 months (IQR 50). Overall, having CMBs was not associated with suffering a subdural hematomahygroma or hemorrhagic stroke during follow-up with 1 exception that an extensive degree of CMBs (≥50 CMB) was more common in patients suffering a hemorrhagic stroke (P .03). CMBs were associated with increased mortality (P .02, Kaplan-Meier, log-rank test). The presence of CMBs did not affect gait outcome (P .28). CMBs were associated with hemorrhagic stroke and mortality. CMBs do not seem to reduce the possibility of gait improvement after shunt surgery or contribute to the risk of hemorrhagic complications regarding subdural hematoma or hygroma.

Effect of Alteplase on Ischemic Stroke Mortality is Dependent on Stroke Severity.

Although intravenous Alteplase (IV-tPA) has a beneficial effect on functional outcome after ischemic stroke (IS), prior studies of IV-tPAs impact on post-stroke mortality did not have sufficient representation of more severe stroke. We determined if the interaction between baseline NIH Stroke Scale (NIHSS) and IV-tPA modified the risk of mortality after IS in two cohorts 1) National Inpatient Sample 2016-2020 and 2) a harmonized cohort of IS patients from the NINDS IV-tPA, ALIAS part 2, SHINE, FAST-MAG, IMS-III, POINT, and DEFUSE 3 trials. We fit logistic regression models to the outcome of in-hospital mortality (NIS cohort) or mortality within 90 days (harmonized cohort), adjusted for baseline variables. We included 198,668 patients in the NIS cohort of which 14.0% received IV-tPA and 3.4% had in-hospital death. We included 7,138 patients in the harmonized cohort of which 33.2% received IV-tPA and 9.4% had death by 90 days. Mortality in the NIS cohort was associated with older age, female sex, non-Hispanic white race, atrial fibrillation, and higher NIHSS. In the harmonized cohort, mortality was associated with older age, diabetes, atrial fibrillation, and higher NIHSS. In both cohorts, the interaction between NIHSS and IV-tPA was significant. In the NIS cohort the separation became significant at NIHSS 15 and in the harmonized cohort at NIHSS 23, at which point IV-tPA began to have a significant benefit for both in-hospital and 90-day mortality, respectively. IV-tPA is associated with a reduction in both in-hospital and 90-day mortality for patients with more severe IS. This article is protected by copyright. All rights reserved.

Choosing Transcatheter Aortic Valve Replacement in Porcelain Aorta Outcomes Versus Surgical Replacement.

Porcelain aorta complicates aortic valve replacement and is an indication for transcatheter approaches. No study has compared surgical and transcatheter valve replacement in the setting of porcelain aorta. We characterize porcelain aorta patients undergoing aortic valve replacement and the association of aortic calcification and outcomes. Patients undergoing aortic valve replacement with porcelain aorta were identified. Aortic calcium volume was determined using 3-D computed tomography thresholding techniques. Propensity scoring was performed to assess the effect of surgical versus transcatheter approaches. Risk factors for composite major hospital complications (death, stroke, and dialysis) were identified using random forest machine learning. From 012006 to 012015, 164 patients with porcelain aorta underwent aortic valve replacement (105 64% surgical replacement, 59 36% transcatheter replacement). Propensity scoring matched 29 pairs (49% of transcatheter patients). Before matching 5-year survival was 41% (43% surgical, 35% transcatheter, plog-rank0.9). After matching, mortality for surgical versus transcatheter replacement was 3.4% (n 1) versus 10% (n 3), stroke 14% (n 4) versus 3.4% (n 1), and dialysis 6.9% (n 2) versus 11% (n 3). Matched 5-year survival was 40% after surgical replacement and 29% after transcatheter replacement (plog-rank0.4). Total aortic calcium volume was greater in transcatheter than surgical patients (188.0 mL vs 177.7 mL) and was associated with more major hospital complications after either approach. Surgical and transcatheter approaches are complementary options for aortic stenosis with porcelain aorta. Surgical valve replacement remains an effective treatment for patients requiring concomitant procedures. Quantifying aortic calcium volume is a helpful risk predictor in all patients with porcelain aorta.

DL-3-n-butylphthalide Attenuates Cerebral Ischemia-Reperfusion Injury By Inhibiting Mitochondrial OmiHtrA2-Mediated Apoptosis.

Ischemic stroke is a major cause of death and disability worldwide and results from inadequate cerebrovascular blood supply mitochondrial dysfunction plays an essential role in its pathogenesis. DL-3-n-butylphthalide (NBP) is an effective medicine for ischemic stroke that reduces cell apoptosis and improves long-term prognosis. Whether and how NBP regulates mitochondria-associated apoptosis in cerebral ischemia-reperfusion injury remains unclear. Male Sprague Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) stroke and treated with low (20 mgkg) or high (80 mgkg) concentrations of NBP. The OmiHtrA2 inhibitor UCF-101 was used as a positive control. Cerebral infarction, neuron injury and neuronal apoptosis were assessed to determine the efficacy of NBP compared to UCF-101. We assessed the expression of the OmiHtrA2 signaling pathway by western blotting and tested the mRNA expression of mitochondrial metabolism-related genes by PCR. Compared to the MCAO group, both low and high concentrations of NBP substantially improved cerebral infarction, neuron injury, and neuronal apoptosis high concentrations of NBP were more potent than low concentrations. The expression of proteins of the mitochondrial OmiHtrA2 signaling pathway, including OmiHtrA2, XIAP, PARL, OPA1, CHOP, and ClpP, was inhibited in the NBP group. Overall, early application of NBP attenuated cerebral ischemia-reperfusion injury by inhibiting mitochondrial OmiHtrA2-mediated apoptosis in rats. Our study supports a novel neuroprotective mechanism of NBP, making it a promising therapeutic agent for ischemic stroke.

Cost-utility and budget impact analysis of CPAP therapy compared to no treatment in the management of moderate to severe obstructive sleep apnea in Colombia from a third-party payer perspective.

To conduct cost-utility and budget impact analysis of providing Continuous Positive Airway Pressure (CPAP) therapy versus no treatment for moderate to severe obstructive sleep apnea (OSA) in Colombia from a third-party payer perspective. We used a Markov model to assess the cost-utility and budget impact analysis of CPAP in patients over 40 years old with moderate to severe OSA. Data on effectiveness and utility values were obtained from published literature. A discount rate of 5% was applied for outcomes and costs. ICER was calculated and compared against the threshold estimated for Colombia, which is 86% of the GDP per capita. Over a lifetime horizon, the base case analysis showed the incremental cost per quality-adjusted life-years (QALYs) gained with CPAP therapy was COP$3,503,804 (USD$1,011 in 2020 prices). The budget impact analysis showed that the adoption of CPAP therapy in the target population would lead to a cumulative net budget impact of COP$411,722 million (USD$118,784,412 in, 2020 prices) over five years of time horizon. CPAP was cost-effective compared to no-treatment in OSA. According to the budget impact analysis, adopting this technology would require a budget allocation that is partially offset by reduced number of strokes and traffic accident events.

Using Epidemiological Data to Inform Clinical Trial Feasibility Assessments A Case Study.

Clinical trial enrollment and completion is challenging, with nearly half of all trials not being completed or not completed on time. In 2014, the National Institutes of Health StrokeNet in collaboration with stroke epidemiologists from GCNKSS (Greater CincinnatiNorthern Kentucky Stroke Study) began providing proposed clinical trials with formal trial feasibility assessments. Herein, we describe the process of prospective feasibility analyses using epidemiological data that can be used to improve enrollment and increase the likelihood a trial is completed. In 2014, DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trialists, National Institutes of Health StrokeNet, and stroke epidemiologists from GCNKSS collaborated to evaluate the initial inclusionexclusion criteria for the DEFUSE 3 study. Trial criteria were discussed and an assessment was completed to evaluate the percent of the stroke population that might be eligible for the study. The DEFUSE 3 trial was stopped early with the publication of DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct), and the Wilcoxon rank-sum statistic was used to analyze whether the trial would have been stopped had the proposed changes not been made, following the DEFUSE 3 statistical analysis plan. After initial epidemiological analysis, 2.4% of patients with acute stroke in the GCNKSS population would have been predicted to be eligible for the study. After discussion with primary investigators and modifying 4 key exclusion criteria (upper limit of age increased to 90 years, baseline modified Rankin Scale broadened to 0-2, time since last well expanded to 16 hours, and decreased lower limit of National Institutes of Health Stroke Scale score to <6), the number predicted to be eligible for the trial increased to 4%. At the time of trial conclusion, 57% of the enrolled patients qualified only by the modified criteria, and the trial was stopped at an interim analysis that demonstrated efficacy. We estimated that the Wilcoxon rank-sum value for the unadjusted predicted enrollment would not have crossed the threshold for efficacy and the trial not stopped. Objectively assessing trial inclusionexclusion criteria using a population-based resource in a collaborative and iterative process including epidemiologists can lead to improved recruitment and can increase the likelihood of successful trial completion.

Practice Patterns and Outcomes Associated With Anticoagulation Use Following Sepsis Hospitalizations With New-Onset Atrial Fibrillation.

Practice patterns and outcomes associated with the use of oral anticoagulation for arterial thromboembolism prevention following a hospitalization with new-onset atrial fibrillation (AF) during sepsis are unclear. Retrospective, observational cohort study of patients ≥40 years of age discharged alive following hospitalization with new-onset AF during sepsis across 21 hospitals in the Kaiser Permanente Northern California health care delivery system, years 2011 to 2018. Primary outcomes were ischemic stroketransient ischemic attack (TIA), with a safety outcome of major bleeding events, both within 1 year of discharge alive from sepsis hospitalization. Adjusted risk differences for outcomes between patients who did and did not receive oral anticoagulation within 30 days of discharge were estimated using marginal structural models fitted by inverse probability weighting using Super Learning within a target trial emulation framework. Among 82 748 patients hospitalized with sepsis, 3992 (4.8%) had new-onset AF and survived to hospital discharge mean age was 78±11 years, 53% were men, and 70% were White. Patients with new-onset AF during sepsis averaged 45±33% of telemetry monitoring entries with AF, and 27% had AF present on the day of hospital discharge. Within 1 year of hospital discharge, 89 (2.2%) patients experienced strokeTIA, 225 (5.6%) had major bleeding, and 1011 (25%) died. Within 30 days of discharge, 807 (20%) patients filled oral anticoagulation prescriptions, which were associated with higher 1-year adjusted risks of ischemic strokeTIA (5.69% versus 2.32% risk difference, 3.37% 95% CI, 0.36-6.38) and no significant difference in 1-year adjusted risks of major bleeding (6.51% versus 7.10% risk difference, -0.59% 95% CI, -3.09 to 1.91). Sensitivity analysis of ischemic stroke-only outcomes showed a risk difference of 0.15% (95% CI, -1.72 to 2.03). After hospitalization with new-onset AF during sepsis, oral anticoagulation use was uncommon and associated with potentially higher strokeTIA risk. Further research to inform mechanisms of stroke and TIA and management of new-onset AF after sepsis is needed.

Right hemispheric structural connectivity and poststroke language recovery.

Poststroke aphasia typically results from brain damage to the left-lateralized language network. The contribution of the right-lateralized homologues in aphasia recovery remains equivocal. In this longitudinal observational study, we specifically investigated the role of right hemisphere structural connectome in aphasia recovery. Twenty-two patients with aphasia after a left hemispheric stroke underwent comprehensive language assessment at the early subacute and chronic stages. A novel structural connectometry approach, using multi-shell diffusion-weighted MRI data collected at the early subacute stage, was used to evaluate the relationship between right hemisphere white matter connectome and language production and comprehension abilities at early subacute stage. Moreover, we evaluated the relationship between early subacute right hemisphere white matter connectome and longitudinal change in language production and comprehension abilities. All results were corrected for multiple comparisons. Connectometry analyses revealed negative associations between early subacute stage right hemisphere structural connectivity and language production, both cross-sectionally and longitudinally (p

Resting-state functional alterations in patients with brain arteriovenous malformations involving language areas.

Brain arteriovenous malformations (AVMs) may involve language areas but usually do not lead to aphasia. This study evaluated resting-state functional alterations and investigated the language reorganization mechanism in AVM patients. Thirty-nine patients with AVMs involving language areas and 32 age- and sex-matched healthy controls were prospectively enrolled. The AVM patients were categorized into three subgroups according to lesion location the frontal (15 patients), temporal (14 patients), and parietal subgroups (10 patients). All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI), and the amplitude of low-frequency fluctuation (ALFF) approach was applied to analyze rs-fMRI data. Language abilities were normal in all participants based on the Western Aphasia Battery. Compared with those of healthy subjects, ALFF values significantly increased (FDR corrected p < .01) in the anterior part of the right putamen in the frontal AVM subgroup, in the posterior part of the right inferior and middle temporal gyrus in the temporal AVM subgroup, and in the inferior lateral part of the left cerebellar hemisphere (lobule VIII) and the right inferior parietal lobule in the parietal AVM subgroup. Functional annotation using Neurosynth indicated that the ALFF t-map was only significantly positively associated with the language-related domain (FDR corrected p < .01). In patients with AVMs involving the language cortex, language network reorganization occurs to maintain normal language abilities. The brain areas recruited into the reorganized language network were located in the right cerebral and left cerebellar hemispheres, both of which are nondominant hemispheres. Differences in lesion location led to distinct reorganization patterns.

Effect of small vessel disease severity on blood pressure management after endovascular therapy in the BP TARGET trial.

Acute ischemic stroke patients with cerebral small vessel disease (CSVD), including cerebral microbleeds (CMB) and white matter hyperintensities (WMH), have worse outcomes. We investigated the effect of two BP strategies (intensive versus standard) and BP variability (BPV) after reperfusion according to CSVD burden in the BP-TARGET trial. We included patients with available magnetic resonance imaging at baseline. We described CMB as absent or present and WMH severity according to the Fazekas classification (0-1, absent-mild 2-3, moderate-to-severe). Outcomes consisted of any ICH at 24 hours and favorable outcome at 90 days (modified Rankin Scale between 0-2). We included 246 patients. The intensive SBP target was not associated with lower rates of ICH or favorable outcome according to CSVD subgroups (all p-values>0.35). Several BPV parameters were associated with increased odds of ICH in patients with CMB but not in patients without CMB (diastolic blood pressure -DBP- coefficient of variation -CV-, OR 95%CI2.06 1.13-3.77 in patients with >1 CMB vs 0.94 0.68-1.31 in patients without CMB, p We found no effect of the SBP management strategy on ICH occurrence or functional outcome according to CSVD burden. BPV was associated with higher odds of ICH in patients with CMB and worse outcome in patients with moderate-to-severe WMH.

The impact of funding on the quality and interpretation of systematic reviews of mechanical thrombectomy in stroke patients.

Funding may impact the quality and findings of systematic reviews (SRs). We aimed to compare the methodological quality of funded and non-funded SRs that investigated the outcomes in ischemic stroke patients undergoing mechanical thrombectomy. We conducted a comprehensive search strategy in different databases, including Ovid Cochrane Central Register of Controlled Trials, Ovid Embase, Ovid Medline (including epub ahead of print, in-process other non-indexed citations), PubMed, Scopus and Web of Science Core Collection to retrieve all relevant SRs. Random sequence generation matched each funded SR with a non-funded one. A Measurement Tool to Assess Systematic Reviews (AMSTAR)-2 tool was used to assess the bias and quality of the included SRs. We also used uni- and multivariate analysis to perform our analysis, and results were expressed in odds ratio (OR) and 95% confidence interval (CI). We retrieved 150 articles, which were randomized and matched into 100 SRs, including 50 funded and 50 non-funded studies. By multivariate analysis, we found that including randomized clinical trials (RCTs) (OR 5.7 95% CI 1.8-17.8 p 0.003) and reporting conflict of interests (OR 5.2 95 CI 1.1-24 p 0.036) were the only significant differences between funded and non-funded SRs. No significant differences were found regarding the overall confidence for low-quality (OR 0.54 95% CI 0.09-3.2 p 0.49) and moderatehigh-quality SRs (OR 0.17 95% CI 0.02-1.87 p 0.14). Funded studies tend to include RCTs more often and report conflict of interests with no significant impact on overall confidence.

Srs11-92, a ferrostatin-1 analog, improves oxidative stress and neuroinflammation via Nrf2 signal following cerebral ischemiareperfusion injury.

Ferroptosis is increasingly becoming to be considered as an important mechanism of pathological cell death during stroke, and specific exogenous ferroptosis inhibitors have the ability to reverse cerebral ischemiareperfusion injury. However, research on Srs11-92 (AA9), a ferrostatin-1 (Fer-1) analog, in preclinical studies is limited. In the middle cerebral artery occlusion-reperfusion (MCAOR) mice model or oxygen-glucose deprivationreperfusion (OGDR) cell model, Fer-1, AA9, andor ML385 were administered, and brain infarct size, neurological deficits, neuronal damage, oxidative stress, and neuroinflammation were determined after the damage, in vitro and in vivo. Fer-1 and AA9 improved brain infarct size, neuronal damage, and neurological deficits in mice model of MCAOR, and inhibited the overloaded iron deposition, ROS accumulation, and neuroinflammation response it also increased the expression of GPx4, Nrf2, and HO-1 and suppressed the expression of HMGB1 and NF-κB p65 in the epicenter of injured hippocampal formation. However, Nrf2 inhibitor ML385 reversed the neuroprotective effect of AA9, including the oxidative stress and neuroinflammation. In vitro studies showed that AA9 relieved OGDR-induced neuronal oxidative stress and neuroinflammation via the Nrf2 pathway, which was impaired by ML385 in primary neurons. The findings imply that Fer-1 analog AA9 may be suitable for further translational studies for the protection of neuronal damage via Nrf2 signal pathway-mediated oxidative stress and neuroinflammation in stroke and others neurological diseases.

Influence of Acupuncture and Other Clinical Factors on the Recovery of Limb Motor Function in Patients After Stroke A Retrospective Study.

Limb motor disorders after stroke are very common, and the clinical related factors of improving limb motor function are still unclear. As a part of comprehensive rehabilitation strategy, acupuncture has been widely used in rehabilitation after stroke in China. But more evidence is needed for the influence of acupuncture and some other clinical factors on post-stroke motor disorders. A retrospective study was conducted using the database of patients with post-stroke motor disorders admitted to the Neurological Rehabilitation Unit of the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine. The included patients were grouped according to whether NIHSS improved or muscle strength improved. The positive logistic regression was used to analyze the influencing factors of possible NIHSS improvement. Combined with the influencing factors of NIHSS improvement and muscle strength improvement, the influencing factors of limb motor function recovery after stroke were obtained. When analyzing the baseline of the included patients, it was found that patients with NIHSS improvement had earlier acupuncture intervention time (M, (IQR)13.5 (14), OR0.716, 95% CI 0.591-0.869, p0.001), more cumulative acupuncture treatment times (M,(IQR)29 (12), OR0.744, 95% CI 0.608-0.910, p0.004), and less hypertension history (OR0.256, 95% CI 0.082-0.801, p0.019). Smoking history only has positive significance in univariate and multivariate analysis of NIHSS, not muscle strength (OR0.274, 95% CI 0.097-0.779, p0.015). The earlier acupuncture intervention and the more cumulative acupuncture treatment times are, the more beneficial the limb function of stroke patients with motor disorders will be. The previous history of hypertension is the influencing factor of limb motor function not improving in patients with limb motor disorder after a stroke. The effect of smoking history on limb movement function of patients with limb motor disorder after stroke needs further study.

Association between carotid intima media thickness and acute ischemic stroke at an Indonesian tertiary referral hospital.

A high prevalence of tobacco smoking contributes to a high incidence of acute ischemic stroke (AIS) in Indonesia. Large-artery atherosclerosis is known to be a significant cause of AIS. The present study was aimed at evaluating the association between AIS and atherosclerosis on the basis of carotid intima-media thickness (CIMT) measurements in a tertiary care hospital in Indonesia. A total of 79 patients with AIS (case study group) and 79 individuals without AIS (control group) were included. Chi-squared tests and odds ratios were used to compare the groups and determine associations. We also considered factors such as age, body mass index (BMI), sex, type-2 diabetes mellitus (T2DM), hypertension, smoking status, dyslipidemia, socioeconomic status, and educational level in the statistical analyses. A p-value <0.05 was considered statistically significant. Stratification of atherosclerosis into case study and control groups with respect to all study variables indicated a significant relationship (p > 0.05) between atherosclerosis and all variables except low socioeconomic status (p 0.265) and low educational level (p 0.180). Regression analysis demonstrated that a BMI ≥25 kgm AIS was associated with atherosclerosis, on the basis of CIMT measurements, according to age, BMI, sex, T2DM, hypertension, smoking status, dyslipidemia, socioeconomic status, and education level in the Indonesian population. يساهم الانتشار المرتفع لتدخين التبغ في ارتفاع معدل الإصابة بالسكتة الدماغية الحادة في إندونيسيا. من المعروف أن تصلب الشرايين الكبير هو سبب مهم للسكتة الدماغية الحادة. هدفت الدراسة الحالية إلى تقييم العلاقة بين السكتة الدماغية الحادة وتصلب الشرايين بناءً على قياسات سماكة الطبقة الداخلية للشريان السباتي في مستشفى المستشفيات التخصصية الإندونيسية. إجمالا، تم تضمين 79 مريضا يعانون من السكتة الدماغية الحادة (مجموعة دراسة الحالة) و 79 فردا بدون سكتة إقفارية حادة (مجموعة التحكم). تم استخدام اختبار كاي تربيع ونسب الأرجحية لمقارنة المجموعات وتحديد ارتباطها. أخذنا في الاعتبار أيضا عوامل مثل العمر، ومؤشر كتلة الجسم، والجنس، وداء السكري من النوع 2، وارتفاع ضغط الدم، وعادات التدخين، وعسر شحميات الدم، والحالة الاجتماعية والاقتصادية، والمستوى التعليمي في التحليلات الإحصائية. أظهر التقسيم الطبقي لتصلب الشرايين في دراسة الحالة ومجموعات الضبط فيما يتعلق بجميع متغيرات الدراسة علاقة معنوية بين تصلب الشرايين وجميع المتغيرات باستثناء الحالة الاجتماعية والاقتصادية المنخفضة والمستوى التعليمي المنخفض. أظهر تحليل الانحدار أن مؤشر كتلة الجسم 25 كجم م 2 كان مرتبطا بخطر الإصابة بتصلب الشرايين بمقدار 2.139 ضعفا من مؤشر كتلة الجسم الطبيعي. ارتبطت السكتة الدماغية الحادة بتصلب الشرايين على أساس قياسات سماكة الطبقة الداخلية للشريان السباتي مع مراعاة العمر، ومؤشر كتلة الجسم، والجنس، وارتفاع ضغط الدم من النوع 2، وعادات التدخين، وخلل شحميات الدم، والحالة الاجتماعية والاقتصادية، ومستوى التعليم لدى السكان الإندونيسيين.

Spatiotemporal profile of neutrophil extracellular trap formation in a mouse model of ischemic stroke.

Thromboinflammatory processes modulate the complex pathophysiology of cerebral ischemia-reperfusion (IR) injury in ischemic stroke, but the exact underlying mechanisms remain poorly understood. Emerging evidence indicates that neutrophil extracellular traps (NETs) might play an important role in the thromboinflammatory cascade. In addition, the link between von Willebrand factor (VWF) and neutrophil recruitment in the ischemic brain might promote thromboinflammation, possibly by the formation of NETs. To study NET formation in a murine model of cerebral IR injury in ischemic stroke. The filament-induced transient middle cerebral artery occlusion model was used to induce 60 minutes of focal cerebral ischemia after which reperfusion was allowed. At different time points postischemia, NETs were identified in the ischemic mouse brain using quantitative immunofluorescence microscopy. NETs could be identified in the ipsilateral brain hemisphere. Interestingly, NETs could already be detected at 6 hours poststroke. Their presence increased at 12 hours, was highest at 24 hours, and decreased again 48 hours postischemia. Remarkably, NETs were predominantly localized within the brain vasculature postischemia, suggesting that NETs play a role in secondary microthrombosis. Strikingly, NET formation was significantly decreased in VWF-deficient mice compared to littermate wild-type mice 24 hours postischemia, indicating a possible role for VWF in promoting NETosis in the ischemic brain. This study identified the spatiotemporal profile of NET formation in a mouse model of cerebral IR injury in ischemic stroke. NETs, potentially in combination with VWF, might be attractive targets for the development of novel therapeutic strategies in ischemic stroke treatment.

Antiplatelet treatment patterns and outcomes of secondary stroke prevention in the United States.

Patients who have an ischemic stroke (IS) or transient ischemic attack (TIA) are at risk of having a secondary stroke. Single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT) may be recommended for secondary stroke prevention (SSP), depending on severity and etiology. This study evaluated outpatient antiplatelet treatment patterns for SSP and outcomes after first hospitalization for ISTIA among adults without atrial fibrillation in the United States. This retrospective observational study utilized data from an adjudicated administrative health claims database. Eligible patients had an imputed National Institutes of Health Stroke Scale index event score ≤7. Over-the-counter medication use (eg, aspirin) was not captured. Of 154,273 patients, 41,622 (27%) were prescribed antiplatelet therapy within 90 days of the event 93.8% received SAPT, 6.1% received DAPT. The first line of antiplatelet therapy after discharge was started a mean of 17.0 days after the event mean treatment duration was 61.9 days. The incidence rate for secondary IS was 5.53, 2.03, and 1.17 per person-year 90-days, 1-year, and 3-years following treatment initiation, respectively. Among patients matched for demographic and clinical characteristics, the risk of secondary IS was increased with DAPT versus SAPT (hazard ratio 95% CI 1.27 1.20-1.34 p < 0.0001). Many patients were not prescribed or discontinued antiplatelet therapy within 90 days of hospitalization for ISTIA and, in most cases, prescriptions were not compliant with SSP consensus guidelines. Patients remained at risk for IS, which was highest within 90 days. More effective strategies for SSP are needed to improve outcomes in this patient population.

Improved Balance, Gait, and Lower Limb Motor Function in a 58-Year-Old Man with Right Hemiplegic Traumatic Brain Injury Following Virtual Reality-Based Real-Time Feedback Physical Therapy.

BACKGROUND This report presents the case of a 58-year-old man with right hemiplegia who improved his gait and lower limb motor function following virtual reality (VR)-based physical therapy. The use of augmented reality or VR-based technology is being increasingly used to support physical therapy in patients with motor deficits and to improve gait, and can be used in small hospitals and outpatient departments. CASE REPORT A 58-year-old man was diagnosed with left hemiplegia due to traumatic brain injury (TBI). He received 20 minutes of VR-based real-time feedback gait training and 30 minutes of general physical therapy, 5 times a week for 8 weeks. BioRescue was used for measurement of balance, GAITRite was used for measurement of gait, and Fugl-Meyer assessment was used for lower extremity motor function measurement. These were measured before the intervention and at 2, 4, 6, and 8 weeks after the intervention. After the intervention, center of pressure and limits of stability also increased. The affected step length, stride length, affected single support, and cadence were significantly increased after VR-based real-time feedback. Additionally, his lower extremity motor function score increased from 18 to 23 points. CONCLUSIONS This case report supports recent studies that have shown the value of VR-based methods as part of a physical therapy program in patients with problems with gait and motor function, including patients with stroke. VR-based real-time feedback showed favorable effects on rehabilitation following a TBI.

Investigation of Neurological Complications after COVID-19 Vaccination Report of the Clinical Scenarios and Review of the Literature.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), broke out in 2019 and became a pandemic in 2020. Since then, vaccines have been approved to prevent severe illness. However, vaccines are associated with the risk of neurological complications ranging from mild to severe. Severe complications such as vaccine-induced immune thrombotic thrombocytopenia (VITT) associated with acute ischaemic stroke have been reported as rare complications post-COVID-19 vaccination. During the pandemic era, VITT evaluation is needed in cases with a history of vaccination within the last month prior to the event. Cerebral venous sinus thrombosis (CVST) should be suspected in patients following immunization with persistent headaches who are unresponsive to analgesics. In this article, we investigated neurological complications after COVID-19 vaccination and provided more subsequent related clinical studies of accurate diagnosis, pathophysiological mechanisms, incidence, outcome, and management.

Video-based Goniometer Applications for Measuring Knee Joint Angles during Walking in Neurological Patients A Validity, Reliability and Usability Study.

Easy-to-use evaluation of Range Of Motion (ROM) during walking is necessary to make decisions during neurological rehabilitation programs and during follow-up visits in clinical and remote settings. This study discussed goniometer applications (DrGoniometer and Angles - Video Goniometer) that measure knee joint ROM during walking through smartphone cameras. The primary aim of the study is to test the inter-rater and intra-rater reliability of the collected measurements as well as their concurrent validity with an electro-goniometer. The secondary aim is to evaluate the usability of the two mobile applications. A total of 22 patients with Parkinsons disease (18 males, age 72 (8) years), 22 post-stroke patients (17 males, age 61 (13) years), and as many healthy volunteers (8 males, age 45 (5) years) underwent knee joint ROM evaluations during walking. Clinicians and inexperienced examiners used the two mobile applications to calculate the ROM, and then rated their perceived usability through the System Usability Scale (SUS). Intraclass correlation coefficients (ICC) and correlation coefficients (corr) were calculated. Both applications showed good reliability (ICC > 0.69) and validity (corr > 0.61), and acceptable usability (SUS > 68). Smartphone-based video goniometers could be used to assess the knee ROM during walking in neurological patients, because of their acceptable degree of reliability, validity and usability.

On the Role of Training Data for SVM-Based Microwave Brain Stroke Detection and Classification.

The aim of this work was to test microwave brain stroke detection and classification using support vector machines (SVMs). We tested how the nature and variability of training data and system parameters impact the achieved classification accuracy. Using experimentally verified numerical models, a large database of synthetic training and test data was created. The models consist of an antenna array surrounding reconfigurable geometrically and dielectrically realistic human head phantoms with virtually inserted strokes of arbitrary size, and different dielectric parameters in different positions. The generated synthetic data sets were used to test four different hypotheses, regarding the appropriate parameters of the training dataset, the appropriate frequency range and the number of frequency points, as well as the level of subject variability to reach the highest SVM classification accuracy. The results indicate that the SVM algorithm is able to detect the presence of the stroke and classify it (i.e., ischemic or hemorrhagic) even when trained with single-frequency data. Moreover, it is shown that data of subjects with smaller strokes appear to be the most suitable for training accurate SVM predictors with high generalization capabilities. Finally, the datasets created for this study are made available to the community for testing and developing their own algorithms.

Multi Modal Feature Extraction for Classification of Vascular Dementia in Post-Stroke Patients Based on EEG Signal.

Dementia is a term that represents a set of symptoms that affect the ability of the brains cognitive functions related to memory, thinking, behavior, and language. At worst, dementia is often called a major neurocognitive disorder or senile disease. One of the most common types of dementia after Alzheimers is vascular dementia. Vascular dementia is closely related to cerebrovascular disease, one of which is stroke. Post-stroke patients with recurrent onset have the potential to develop dementia. An accurate diagnosis is needed for proper therapy management to ensure the patients quality of life and prevent it from worsening. The gold standard diagnostic of vascular dementia is complex, includes psychological tests, complete memory tests, and is evidenced by medical imaging of brain lesions. However, brain imaging methods such as CT-Scan, PET-Scan, and MRI have high costs and cannot be routinely used in a short period. For more than two decades, electroencephalogram signal analysis has been an alternative in assisting the diagnosis of brain diseases associated with cognitive decline. Traditional EEG analysis performs visual observations of signals, including rhythm, power, and spikes. Of course, it requires a clinician expert, time consumption, and high costs. Therefore, a quantitative EEG method for identifying vascular dementia in post-stroke patients is discussed in this study. This study used 19 EEG channels recorded from normal elderly, post-stroke with mild cognitive impairment, and post-stroke with dementia. The QEEG method used for feature extraction includes relative power, coherence, and signal complexity the evaluation performance of normal-mild cognitive impairment-dementia classification was conducted using Support Vector Machine and K-Nearest Neighbor. The results of the classification simulation showed the highest accuracy of 96% by Gaussian SVM with a sensitivity and specificity of 95.6% and 97.9%, respectively. This study is expected to be an additional criterion in the diagnosis of dementia, especially in post-stroke patients.

Effects of bihemispheric transcranial direct current stimulation on motor recovery in subacute stroke patients a double-blind, randomized sham-controlled trial.

Bihemispheric transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) can simultaneously modulate bilateral corticospinal excitability and interhemispheric interaction. However, how tDCS affects subacute stroke recovery remains unclear. We investigated the effects of bihemispheric tDCS on motor recovery in subacute stroke patients. We enrolled subacute inpatients who had first-ever ischemic stroke at subcortical regions and moderate-to-severe baseline Fugl-Meyer Assessment of Upper Extremity (FMA-UE) score 2-56. Participants between 14 and 28 days after stroke were double-blind, randomly assigned (11) to receive real (n 13) or sham (n 14) bihemispheric tDCS (with ipsilesional M1 anode and contralesional M1 cathode, 20 min, 2 mA) during task practice twice daily for 20 sessions in two weeks. Residual integrity of the ipsilesional corticospinal tract was stratified between groups. The primary efficacy outcome was the change in FMA-UE score from baseline (responder as an increase ≥ 10). The secondary measures included changes in the Action Research Arm Test (ARAT), FMA-Lower Extremity (FMA-LE) and explorative resting-state MRI functional connectivity (FC) of target regions after intervention and three months post-stroke. Twenty-seven participants completed the study without significant adverse effects. Nineteen patients (70%) had no recordable baseline motor-evoked potentials (MEP-negative) from the paretic forearm. Compared with the sham group, the real tDCS group showed enhanced improvement of FMA-UE after intervention (p < 0.01, effect size η Bihemispheric tDCS during task-oriented training may facilitate motor recovery in subacute stroke patients, even with compromised corticospinal tract integrity. Further studies are warranted for tDCS efficacy and network-specific neuromodulation. This study is registered with ClinicalTrials.gov (ID NCT02731508).

ADSC-derived exosomes attenuate myocardial infarction injury by promoting miR-205-mediated cardiac angiogenesis.

Acute myocardial infarction is a major health problem and is the leading cause of death worldwide. Myocardial apoptosis induced by myocardial infarction injury is involved in the pathophysiology of heart failure. Therapeutic stem cell therapy has the potential to be an effective and favorable treatment for ischemic heart disease. Exosomes derived from stem cells have been shown to effectively repair MI injury-induced cardiomyocyte damage. However, the cardioprotective benefits of adipose tissue-derived mesenchymal stem cell (ADSC)-Exos remain unknown. This study aimed to investigate the protective effects of exosomes from ADSC on the hearts of MI-treated mice and to explore the underlying mechanisms. Cellular and molecular mechanisms were investigated using cultured ADSCs. On C57BL6J mice, we performed myocardial MI or sham operations and assessed cardiac function, fibrosis, and angiogenesis 4 weeks later. Mice were intramyocardially injected with ADSC-Exos or vehicle-treated ADSCs after 25 min following the MI operation. Echocardiographic experiments showed that ADSC-Exos could significantly improve left ventricular ejection fraction, whereas ADSC-Exos administration could significantly alleviate MI-induced cardiac fibrosis. Additionally, ADSC-Exos treatment has been shown to reduce cardiomyocyte apoptosis while increasing angiogenesis. Molecular experiments found that exosomes extracted from ADSCs can promote the proliferation and migration of microvascular endothelial cells, facilitate angiogenesis, and inhibit cardiomyocytes apoptosis through miRNA-205. We then transferred isolated exosomes from ADSCs into MI-induced mice and observed decreased cardiac fibrosis, increased angiogenesis, and improved cardiac function. We also observed increased apoptosis and decreased expression of hypoxia-inducible factor-1α and vascular endothelial growth factor in HMEC-1 transfected with a miRNA-205 inhibitor. In summary, these findings show that ADSC-Exos can alleviate cardiac injury and promote cardiac function recovery in MI-treated mice via the miRNA-205 signaling pathway. ADSC-Exos containing miRNA205 have a promising therapeutic potential in MI-induced cardiac injury.

Effect of goal-directed fluid therapy based on plasma colloid osmotic pressure on the postoperative pulmonary complications of older patients undergoing major abdominal surgery.

As an important component of accelerated rehabilitation surgery, goal-directed fluid therapy (GDT) is one of the optimized fluid therapy strategies and is closely related to perioperative complications and mortality. This article aimed to study the effect of combining plasma colloid osmotic pressure (COP) with stroke volume variation (SVV) as a target for intraoperative GDT for postoperative pulmonary complications in older patients undergoing major abdominal surgery. In this study, older patients (n 100) undergoing radical resection of gastroenteric tumors were randomized to three groups Group C (n1 31) received a conventional infusion regimen, Group S1 (n2 34) received GDT based on SVV, and Group S2 (n3 35) received GDT based on SVV and COP. The results were recorded, including the lung injury score (LIS) PaO The patients in the S2 group had fewer postoperative pulmonary complications than those in the C group (P < 0.05) and the proportion of pulmonary complications of grade 1 and higher than grade 2 in S2 group was significantly lower than that in C group (P <0.05) the patients in the S2 group had a higher PaO The findings of our study show that intraoperative GDT based on COP and SVV can reduce the incidence of pulmonary complications and conducive to shortening the hospital stay in older patients after gastrointestinal surgery. Chinese Clinical Trial. no. ChiCTR2100045671. Registry at www.chictr.org.cn on April 20, 2021.

Predictors of outcome after endovascular treatment for tandem occlusions a single center retrospective analysis.

The endovascular treatment procedure in tandem occlusions (TO) is complex compared to single occlusion (SO) and optimal management remains uncertain. The aim of this study was to identify clinical and procedural factors that may be associated to efficacy and safety in the management of TO and compare functional outcome in TO and SO stroke patients. This is a retrospective single center study of medium (MeVO) and large vessel occlusion (LVO) of the anterior circulation. Clinical, imaging, and interventional data were analyzed to identify predictive factors for symptomatic intracranial hemorrhage (sICH) and functional outcome after endovascular treatment (EVT) in TO. Functional outcome in TO and SO patients was compared. Of 662 anterior circulation stroke patients with MeVO and LVO stroke, 90 (14%) had TO. Stenting was performed in 73 (81%) of TO patients. Stent thromboses occurred in 8 (11%) patients. Successful reperfusion with modified thrombolysis in cerebral infarction (mTICI) ≥ 2b was achieved in 82 (91%). SICH occurred in seven (8%). The strongest predictors for sICH were diabetes mellitus and number of stent retriever passes. Good functional clinical outcome (mRS ≤ 2) at 90-day follow up was similar in TO and SO patients (58% vs 59% respectively). General anesthesia (GA) was associated with good functional outcome whereas hemorrhage in the infarcted tissue, lower mTICI score and history of smoking were associated with poor outcome. The risk of sICH was increased in patients with diabetes mellitus and those with extra stent-retriever attempts. Functional clinical outcomes in patients with TO were comparable to patients with SO.

Effect of direct endovascular treatment versus standard bridging therapy in large artery anterior circulation stroke (DEVT) 18-month follow-up of a randomized controlled trial.

Two trials in Chinese population showed that endovascular treatment (EVT) alone was noninferior to alteplase follow by EVT at 90 days. However, results of long-term clinical outcomes remain unknown. We reported the results of prespecified 18-month analysis of the DEVT trail. We assessed clinical outcomes 18 months after patients were randomly assigned to receive EVT alone or bridging therapy for acute ischemic stroke (AIS). The primary outcome was the proportion of functional independence modified Rankin scale (mRS), 0-2 at 18 months. Secondary outcomes included all-cause mortality and the quality of life at 18 months as measured by means of a health utility index according to the European Quality of Life 5-Dimension 5-level scale (EQ-5D-5L). Kaplan-Meier event curves were used to investigate the risk of mortality in participants with EVT alone or bridging therapy. Among 234 patients (EVT alone, n 116 bridging therapy, n 118) in the DEVT trial, only 231 (98.7%) patients were extended follow-up to 18 months. A total of 60 (51.7%) patients in the EVT alone achieved functional independence vs 56 (47.5%) patients in the bridging therapy (difference, 4.3% 1-sided 97.5% CI, - 8.4% to ∞, P for noninferiority 0.014). No significant between-group difference was detected in EQ-5D-5L score (0.81 vs 0.73 difference, 0 95% CI, 0 to 0.005). The cumulative mortality was 27.6% in the EVT alone and 28.8% in the bridging therapy. At 18 months follow-up, EVT alone was noninferior to bridging therapy regarding favorable functional outcome in patients with AIS. Trial was registered on Chinese Clinical Trial Registry (ChiCTR-IOR-17013568) on 27112017.

Non-invasive assessment of Pulse Wave Transit Time (PWTT) is a poor predictor for intraoperative fluid responsiveness a prospective observational trial (best-PWTT study).

Aim of this study is to test the predictive value of Pulse Wave Transit Time (PWTT) for fluid responsiveness in comparison to the established fluid responsiveness parameters pulse pressure (ΔPP) and corrected flow time (FTc) during major abdominal surgery. Forty patients undergoing major abdominal surgery were enrolled with continuous monitoring of PWTT (LifeScope® Modell J BSM-9101 Nihon Kohden Europe GmbH, Rosbach, Germany) and stroke volume (Esophageal Doppler Monitoring CardioQ-ODM®, Deltex Medical Ltd, Chichester, UK). In case of hypovolemia (difference in pulse pressure ∆PP ≥ 9%, corrected flow time FTc ≤ 350 ms) a fluid bolus of 7 mlkg ideal body weight was administered. Receiver operating characteristics (ROC) curves and corresponding areas under the curve (AUCs) were used to compare different methods of determining PWTT. A Wilcoxon test was used to discriminate fluid responders (increase in stroke volume of ≥ 10%) from non-responders. The predictive value of PWTT for fluid responsiveness was compared by testing for differences between ROC curves of PWTT, ΔPP and FTc using the methods by DeLong. AUCs (area under the ROC-curve) to predict fluid responsiveness for PWTT-parameters were 0.61 (raw c finger Q), 0.61 (raw c finger R), 0.57 (raw c ear Q), 0.53 (raw c ear R), 0.54 (raw non-c finger Q), 0.52 (raw non-c finger R), 0.50 (raw non-c ear Q), 0.55 (raw non-c ear R), 0.63 (∆ c finger Q), 0.61 (∆ c finger R), 0.64 (∆ c ear Q), 0.66 (∆ c ear R), 0.59 (∆ non-c finger Q), 0.57 (∆ non-c finger R), 0.57 (∆ non-c ear Q), 0.61 (∆ non-c ear R) raw measurements vs. ∆ respiratory variation c corrected measurements according to Bazetts formula vs. non-c uncorrected measurements Q vs. R start of PWTT-measurements with Q- or R-wave in ECG finger vs. ear pulse oximetry probe location. Hence, the highest AUC to predict fluid responsiveness by PWTT was achieved by calculating its respiratory variation (∆PWTT), with a pulse oximeter attached to the earlobe, using the R-wave in ECG, and correction by Bazetts formula (AUC best-PWTT 0.66, 95% CI 0.54-0.79). ∆PWTT was sufficient to discriminate fluid responders from non-responders (p 0.029). No difference in predicting fluid responsiveness was found between best-PWTT and ∆PP (AUC 0.65, 95% CI 0.51-0.79 p 0.88), or best-PWTT and FTc (AUC 0.62, 95% CI 0.49-0.75 p 0.68). ΔPWTT shows poor ability to predict fluid responsiveness intraoperatively. Moreover, established alternatives ΔPP and FTc did not perform better. Prior to enrolement on clinicaltrials.gov (NC T03280953 date of registration 13092017).

Risk factors for early neurologic deterioration in single small subcortical infarction without carrier artery stenosis predictors at the early stage.

This study aimed to assess the epidemiological features and explore the potential risk factors for early neurological deterioration (END) in patients with acute single small subcortical infarction (SSSI) who underwent antiplatelet therapy without carotid artery stenosis. Patients with SSSI, as confirmed by cranial magnetic resonance imaging (MRI), who were hospitalized within 48 h after the onset of symptoms were enrolled. END was mainly defined as increment in the National Institutes of Health Stroke Scale (NIHSS) score of ≥ 2 points or any new neurological deficit. Poor functional outcome was defined as modified Rankin Scale (mRS) score of > 2 points at 3-month after the onset. The association of END with multiple indicators was assessed at the early stage of admission using multivariate logistic regression analysis, and adjusted odds ratios (aORs) were calculated. A total of 280 patients were enrolled from June 2020 to May 2021, of whom, END occurred in 44 (15.7%) patients (median age, 64 years 70.5% male), while END occurred during sleep in 28 (63.6%) patients. History of hypertension (aOR 4.82, p 0.001), infarction in internal capsule (aOR 3.35, p 0.001), and elevated level of low-density lipoprotein cholesterol (LDL-C aOR 0.036, p 0.0016) were significantly associated with the risk of END. Patients with END (aOR 5.74, p 0.002), history of diabetes (aOR 2.61, p 0.020), and higher NIHSS scores at discharge (per 1-score increase, aOR 1.29, p 0.026) were associated with the poor functional outcome at 3-month after the onset. Patients with a history of hypertension, infarction in internal capsule or a higher level of LDL-C were found to be at a higher risk of END.

The artificial sweetener erythritol and cardiovascular event risk.

Artificial sweeteners are widely used sugar substitutes, but little is known about their long-term effects on cardiometabolic disease risks. Here we examined the commonly used sugar substitute erythritol and atherothrombotic disease risk. In initial untargeted metabolomics studies in patients undergoing cardiac risk assessment (n 1,157 discovery cohort, NCT00590200 ), circulating levels of multiple polyol sweeteners, especially erythritol, were associated with incident (3 year) risk for major adverse cardiovascular events (MACE includes death or nonfatal myocardial infarction or stroke). Subsequent targeted metabolomics analyses in independent US (n 2,149, NCT00590200 ) and European (n 833, DRKS00020915 ) validation cohorts of stable patients undergoing elective cardiac evaluation confirmed this association (fourth versus first quartile adjusted hazard ratio (95% confidence interval), 1.80 (1.18-2.77) and 2.21 (1.20-4.07), respectively). At physiological levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo. Finally, in a prospective pilot intervention study ( NCT04731363 ), erythritol ingestion in healthy volunteers (n 8) induced marked and sustained (>2 d) increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies. Our findings reveal that erythritol is both associated with incident MACE risk and fosters enhanced thrombosis. Studies assessing the long-term safety of erythritol are warranted.

Restoration of Adult Neurogenesis by Intranasal Administration of Gangliosides GD3 and GM1 in The Olfactory Bulb of A53T Alpha-Synuclein-Expressing Parkinsons-Disease Model Mice.

Parkinsons disease (PD) is the second most common neurodegenerative disorder affecting the body and mind of millions of people in the world. As PD progresses, bradykinesia, rigidity, and tremor worsen. These motor symptoms are associated with the neurodegeneration of dopaminergic neurons in the substantia nigra. PD is also associated with non-motor symptoms, including loss of smell (hyposmia), sleep disturbances, depression, anxiety, and cognitive impairment. This broad spectrum of non-motor symptoms is in part due to olfactory and hippocampal dysfunctions. These non-motor functions are suggested to be linked with adult neurogenesis. We have reported that ganglioside GD3 is required to maintain the neural stem cell (NSC) pool in the subventricular zone (SVZ) of the lateral ventricles and the subgranular layer of the dentate gyrus (DG) in the hippocampus. In this study, we used nasal infusion of GD3 to restore impaired neurogenesis in A53T alpha-synuclein-expressing mice (A53T mice). Intriguingly, intranasal GD3 administration rescued the number of bromodeoxyuridine (BrdU )Sox2 NSCs in the SVZ. Furthermore, the administration of gangliosides GD3 and GM1 increases doublecortin (DCX)-expressing immature neurons in the olfactory bulb, and nasal ganglioside administration recovered the neuronal populations in the periglomerular layer of A53T mice. Given the relevance of decreased ganglioside on olfactory impairment, we discovered that GD3 has an essential role in olfactory functions. Our results demonstrated that intranasal GD3 infusion restored the self-renewal ability of the NSCs, and intranasal GM1 infusion promoted neurogenesis in the adult brain. Using a combination of GD3 and GM1 has the potential to slow down disease progression and rescue dysfunctional neurons in neurodegenerative brains.

Development of evaluation system for cerebral artery occlusion in emergency medical services noninvasive measurement and utilization of pulse waves.

Rapid reperfusion therapy can reduce disability and death in patients with large vessel occlusion strokes (LVOS). It is crucial for emergency medical services to identify LVOS and transport patients directly to a comprehensive stroke center. Our ultimate goal is to develop a non-invasive, accurate, portable, inexpensive, and legally employable in vivo screening system for cerebral artery occlusion. As a first step towards this goal, we propose a method for detecting carotid artery occlusion using pulse wave measurements at the left and right carotid arteries, feature extraction from the pulse waves, and occlusion inference using these features. To meet all of these requirements, we use a piezoelectric sensor. We hypothesize that the difference in the left and right pulse waves caused by reflection is informative, as LVOS is typically caused by unilateral artery occlusion. Therefore, we extracted three features that only represented the physical effects of occlusion based on the difference. For inference, we considered that the logistic regression, a machine learning technique with no complex feature conversion, is a reasonable method for clarifying the contribution of each feature. We tested our hypothesis and conducted an experiment to evaluate the effectiveness and performance of the proposed method. The method achieved a diagnostic accuracy of 0.65, which is higher than the chance level of 0.43. The results indicate that the proposed method has potential for identifying carotid artery occlusions.

Current situation of telemedicine research for cardiovascular risk in Japan.

Hypertension continues to be a principal risk factor for the occurrence of cardiovascular disorders, stroke, and kidney diseases. Although more than 40 million subjects suffer from hypertension in Japan, its optimal control is achieved only a subpopulation of patients, highlighting the need for novel approaches to manage this disorder. Toward the better control of blood pressure, the Japanese Society of Hypertension has developed the Future Plan, in which the application of the state-of-art information and communication technology, including web-based resources, artificial intelligence, and big data analysis, is considered as one of the promising solutions. In fact, the rapid advance of digital health technologies, as well as ongoing coronavirus disease 2019 pandemic, has triggered the structural changes in the healthcare system globally, increasing demand for the remote delivery of the medical services. Nonetheless, it is not entirely clear what evidence exists that support the widespread use of telemedicine in Japan. Here, we summarize the current status of telemedicine research, particularly in the field of hypertension and other cardiovascular risk factors. We note that there have been very few interventional studies in Japan that clearly showed the superiority or noninferiority of telemedicine over standard care, and that the methods of online consultation considerably varied among studies. Clearly, more evidence is necessary for wide implementation of telemedicine in hypertensive patients in Japan, and also those with other cardiovascular risk factors.

A neurodevelopmental epigenetic programme mediated by SMARCD3-DAB1-Reelin signalling is hijacked to promote medulloblastoma metastasis.

How abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled 1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus. We further identify that a core set of transcription factors, enhancer of zeste homologue 2 (EZH2) and nuclear factor I X (NFIX), coordinates with the cis-regulatory elements at the SMARCD3 locus to form a chromatin hub to control SMARCD3 expression in the developing cerebellum and in metastatic MB. Increased SMARCD3 expression activates Reelin-DAB1-mediated Src kinase signalling, which results in a MB response to Src inhibition. These data deepen our understanding of how neurodevelopmental programming influences disease progression and provide a potential therapeutic option for patients with MB.

Delta (B1.617.2) variant of SARS-CoV-2 induces severe neurotropic patterns in K18-hACE2 mice.

A highly contagious virus, severe acute respiratory syndrome coronavirus 2, caused the coronavirus disease 19 (COVID-19) pandemic (SARS-CoV-2). SARS-CoV-2 genetic variants have been reported to circulate throughout the COVID-19 pandemic. COVID-19 symptoms include respiratory symptoms, fever, muscle pain, and breathing difficulty. In addition, up to 30% of COVID-19 patients experience neurological complications such as headaches, nausea, stroke, and anosmia. However, the neurotropism of SARS-CoV-2 infection remains largely unknown. This study investigated the neurotropic patterns between the B1.617.2 (Delta) and Hu-1 variants (Wuhan, early strain) in K18-hACE2 mice. Despite both the variants inducing similar pathogenic patterns in various organs, B1.617.2-infected K18-hACE2 mice demonstrated a higher range of disease phenotypes such as weight loss, lethality, and conjunctivitis when compared to those in Hu-1-infected mice. In addition, histopathological analysis revealed that B1.617.2 infects the brain of K18-hACE2 mice more rapidly and effectively than Hu-1. Finally, we discovered that, in B1.617.2-infected mice, the early activation of various signature genes involved innate cytokines and that the necrosis-related response was most pronounced than that in Hu-1-infected mice. The present findings indicate the neuroinvasive properties of SARS-CoV-2 variants in K18-hACE2 mice and link them to fatal neuro-dissemination during the disease onset.

Direct Oral Anticoagulants Versus Vitamin K Antagonists for the Treatment of Left Ventricular Thrombi-Insights from a Swiss Multicenter Registry.

Current guidelines recommend vitamin K antagonists (VKAs) for the treatment of a left ventricular thrombus (LVT). However, direct oral anticoagulants (DOACs) show superior safety and efficacy compared with VKAs in most thromboembolic disorders. Nevertheless, DOACs remain poorly investigated for the treatment of LVT. To describe the thrombus resolution rate and clinical efficacy of DOACs versus VKAs in patients with LVT, we analyzed consecutive patients with confirmed LVT from a multicenter echocardiography database. Echocardiograms and clinical end points were evaluated independently. The thrombus resolution rate and clinical outcomes were compared according to the underlying anticoagulation regimen. In total, 101 patients were included (17.8% women, mean age 63.3 ± 13.2 years), 50.5% had recently experienced a myocardial infarction. The mean left ventricular ejection fraction was 36.6 ± 12.2%. DOACs versus VKAs were used in 48 and 53 patients, respectively. The median follow-up was 26.6 (interquartile range 11.841.2) months. Among patients receiving VKAs compared with DOACs, the thrombus resolved more rapidly within the first month in those taking VKAs (p 0.049). No differences were seen between the 2 groups with respect to major bleedings, strokes, and other thromboembolic events. In each group, LVT recurred in 3 of the subjects (a total of 6) after discontinuation of anticoagulation. In conclusion, DOACs appear to be a safe and effective alternative to VKAs for the treatment of LVTs, but the rate of thrombus dissolution within 1 month after initiation of anticoagulation appears to be higher with VKAs. A sufficiently powered randomized trial is required to definitively define the role of DOACs in the treatment of LVT.

Oral health and functional outcomes following mechanical thrombectomy for ischemic stroke.

An association between poor dentition and the risk of ischemic stroke has previously been reported in the literature. In this study we assessed oral hygiene (OH), including tooth loss and the presence of dental disease, to determine if an association exists with functional outcomes following mechanical thrombectomy (MT) for large-vessel ischemic stroke. A retrospective review was conducted of consecutive adult patients at a single comprehensive stroke center who underwent MT from 2012 to 2018. Inclusion criteria included availability of CT imaging to radiographically assess OH. A multivariate analysis was performed, with the primary outcome being 90-day post-thrombectomy modified Rankin Scale (mRS) score >2. A total of 276 patients met the inclusion criteria. The average number of missing teeth was significantly higher in patients with a poor functional outcome (mean (SD) 10 (11) vs 4 (6), p<0.001). The presence of dental disease was associated with poor functional outcome, including cavities (21 (27%) vs 13 (8%), p<0.001), periapical infection (18 (23%) vs 11 (6.7%), p<0.001), and bone loss (27 (35%) vs 11 (6.7%), p<0.001). Unadjusted, missing teeth was a univariate predictor of poor outcome (OR 1.09 (95% CI 1.06 to 1.13), p<0.001). After adjustment for recanalization scores and use of tissue plasminogen activator (tPA), missing teeth remained a predictor of poor outcome (OR 1.07 (95% CI 1.03 to 1.11), p<0.001). Missing teeth and the presence of dental disease are inversely correlated with functional independence following MT, independent of thrombectomy success or tPA status.

Facilitators and barriers to atrial fibrillation (AF) screening in primary care a qualitative descriptive study of general practitioners in primary care in Ireland.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major risk factor for stroke. Atrial fibrillation is often asymptomatic making it difficult to diagnose. Globally, stroke is a leading cause of morbidity and mortality. Opportunistic atrial fibrillation screening has been recommended in clinical practice within Ireland and internationally, the optimal mode and location remains under investigation. Currently, there is no formal atrial fibrillation screening programme. Primary care has been proposed as a suitable setting. This study aimed to identify the facilitators and barriers to atrial fibrillation screening in primary care from the perspective of general practitioners (GPs). A qualitative descriptive study design was adopted. 54 GPs were invited from 25 practices insouthern Ireland to participate in individual interviews at their practices, rural and urban. A topic guide was developed to guide the interview content towards identification of facilitators and barriers to atrial fibrillation screening. The interviews were conducted in-person, audio-recorded, transcribed verbatim and analysed using framework analysis. Eight GPs from five practices participated in an interview. Three GPs, two male and one female, were recruited from two rural practices and five GPs, two male and three female, were recruited from three urban practices. All eight GPs expressed a willingness to engage in atrial fibrillation screening. Time pressures and the need for additional staff to support were identified as barriers. Programme structure and patient awareness campaignseducation wereidentified as facilitators.The results have been integrated into a pilot primary care-based screening programme for atrial fibrillation.

Mastering the Learning Curve for Robotic-Assisted Coronary Artery Bypass Surgery.

Previous studies have evaluated the learning curve to achieve competency but have not identified thresholds for mastery. Robotic-assisted coronary artery bypass grafting (CABG) is a minimally-invasive alternative to sternotomy CABG. The purpose of this study was to evaluate the short- and long-term outcomes of this procedure and to estimate the threshold for achieving mastery. From 2009-2020, 1,000 robotic-assisted CABG procedures were performed at a single institution. Robotic left internal mammary artery (LIMA) harvest, followed by off-pump, LIMA-left anterior descending grafting via a 4cm thoracotomy was performed. Short-term outcomes were obtained from the STS database and long-term follow-up was obtained by telephone questionnaires from dedicated research nurses for all patients >1 year from surgery. The mean age was 64±11 years, STS predicted risk of mortality was 1.1±1.5%, and 76% (758) of patients were male. Thirty-day mortality occurred in 6 patients (0.6%, OE 0.53), 5 (0.5%) experienced a postoperative stroke, and postoperative LIMA patency was 97.2% (491505). Mean procedure time decreased from 195 minutes to 176 minutes, and conversion to sternotomy decreased from 4.4% (22500) to 1.6% (8500) after 500 cases. Short-term outcomes suggest expertise was reached between 250-500 cases. Long-term follow up was completed in 97% (873896) of patients with a median follow-up of 3.9 years, Q1-Q3(1.8, 5.8) and the overall survival was 89% (777). Robotic-assisted CABG can be performed safely with excellent results even during a surgeons early experience. However, the learning curve to achieve mastery is longer than required to achieve competency with a threshold of approximately 250-500 cases.

Rapid Change in the Direction of Hand Movement to Increase Hand Propulsion During Front Crawl Swimming.

This study aims to investigate the difference in hand acceleration induced by rapid changes in hand movement directions and propulsion between fast and slow groups of swimmers during front crawl swimming. Twenty-two participants, consisting of 11 fast and 11 slow swimmers, performed front crawl swimming at their maximal effort. Hand acceleration and velocity and the angle of attack were measured using a motion capture system. The dynamic pressure approach was used to estimate hand propulsion. In the insweep phase, the fast group attained significantly higher hand acceleration than the slow group in the lateral and vertical directions (15.31 3.44 m·s-2 vs 12.23 2.60 m·s-2 and 14.37 1.70 m·s-2 vs 12.15 1.21 m·s-2), and the fast group exerted significantly larger hand propulsion than the slow group (53 5 N vs 44 7 N). Although the fast group attained large hand acceleration and propulsion during the insweep phase, the hand velocity and the angle of attack were not significantly different in the 2 groups. The rapid change in hand movement direction could be considered in the technique of underwater arm stroke, particularly in the vertical direction, to increase hand propulsion during front crawl swimming.

The differential placental expression of ERp44 and pre-eclampsia association with placental zinc, the ERAP1 and the renin-angiotensin-system.

Endoplasmic reticulum resident protein 44 (ERp44) is a zinc-metalloprotein, regulating Endoplasmic reticulum aminopeptidase 1 (ERAP1) and Angiotensin II (Ang II). We explored placental ERp44 expression and components of the renin-angiotensin-system (RAS) in pre-eclampsia (PE), correlating these to ERAP1 expression and placental zinc concentrations. Placental tissue, taken at time of delivery in normotensive women or women with PE (n 12group), were analysed for ERp44, AT1R, AT2R and AT4R by qPCR. Protein ERp44 expression was measured by immunohistochemistry and compared to previously measured ERAP1 expression. Placental zinc was measured by inductively-coupled-mass-spectrometry. ERp44 geneprotein expression were increased in PE (P < 0.05). AT1R expression was increased (P 0.02) but AT4R decreased (P 0.01) in PE, compared to normotensive controls. A positive association between ERp44 and AT2R expression was observed in all groups. ERp44 was negatively correlated with ERAP1 protein expression in all samples. Placental zinc concentrations were lower in women with PE (P 0.001) and negatively associated with ERp44 gene expression. Increased placental ERp44 could further reduce ERAP1 release in PE, potentially preventing release of Ang IV and thus lowering levels of Ang IV which consequently diminishes the possibility of counterbalancing the activity of vasoconstrictive, Ang II. The lower placental zinc may contribute to dysfunction of the ERp44ERAP1 complex, exacerbating the hypertension in PE.

Effects of constraint induced movement therapy in patients with multiple sclerosis A systematic review.

Multiple sclerosis (MS) is a chronic neurodegenerative disorder of the central nervous system (CNS) that commonly affects young and middle-aged adults. Neurodegeneration of the CNS affects its functions such as sensorimotor, autonomic and cognitive functions. Affectation of motor function can result in disability in performance of daily life activities. Thus, effective rehabilitation interventions are needed to help prevent disability in patients with MS. One of these interventions is the constraint induced movement therapy (CIMT). The CIMT is used to improve motor function in patients with stroke and other neurological conditions. Recently, its use in patients with MS is gaining ground. The aim of this study is to carry out a systematic review and meta-analysis to determine from the literature, the effects of CIMT on upper limb function in patients with MS. PubMED, Embase, Web of Science (WoS), PEDro, and CENTRAL were searched until October 2022. Randomized controlled trials in patients with MS who were 18 years and above were included. Data on the characteristics of the study participants such as disease duration, type of MS, the mean scores of the outcomes of interest such as motor function and use of the arm in daily activities, and white matter integrity were extracted. Methodological quality and risks of bias of the included studies were assessed using PEDro scale and Cochrane risks of bias tool. The data was analysed using both narrative and quantitative syntheses. In the quantitative synthesis, random effect model meta-analysis of the mean and standard deviation of the scores on the outcomes of interest and the study sample size (for both the CIMT and the control group) post intervention was carried out. In addition, percentage of variation across the studies due to heterogeneity (I Two studies comprising of 4 published articles with good methodological quality were included in the study. The results showed that, CIMT is safe and improved white matter integrity, motor function, muscle strength, dexterity, real-world arm use and biomechanical parameters post intervention. However, although there was a trend towards better improvement in the CIMT group in all the outcomes, there was no statistically significant difference between groups in motor function (SMD0.44, 95% CI-0.20 to 1.07, p 0.18) and quality of movement (SMD0.96, -1.15 to 3.07, p 0.37). CIMT can be used in patients with MS since it is safe as well as effective at improving functional outcomes. However, more studies are required to confirm its safety and effectiveness.

Centerline depth world for left atrial appendage orifice localization using reinforcement learning.

Left atrial appendage (LAA) occlusion (LAAO) is a minimally invasive implant-based method to prevent cardiovascular stroke in patients with non-valvular atrial fibrillation. Assessing the LAA orifice in preoperative CT angiography plays a crucial role in choosing an appropriate LAAO implant size and a proper C-arm angulation. However, accurate orifice localization is hard because of the high anatomic variation of LAA, and unclear position and orientation of the orifice in available CT views. With the major research focus being on LAA segmentation, the only existing computational method for orifice localization utilized a rule-based decision. Nonetheless, using such a fixed rule may yield high localization error due to the varied anatomy of LAA. While deep learning-based models usually show improvements under such variation, learning an effective localization model is difficult because of the tiny orifice structure compared to the vast search space of CT volume. In this paper, we propose a centerline depth-based reinforcement learning (RL) world for effective orifice localization in a small search space. In our scheme, an RL agent observes the centerline-to-surface distance and navigates through the LAA centerline to localize the orifice. Thus, the search space is significantly reduced facilitating improved localization. The proposed formulation could result in high localization accuracy compared to the expert annotations. Moreover, the localization process takes about 7.3 s which is 18 times more efficient than the existing method. Therefore, this can be a useful aid to physicians during the preprocedural planning of LAAO.

Outcomes in Patients With Early Menopause Who Underwent Transcatheter Aortic Valve Implantation.

Early menopause is associated with an increased risk of cardiovascular diseases, including aortic stenosis (AS). We sought to investigate the prevalence and impact of early menopause on clinical outcomes in patients who underwent transcatheter aortic valve implantation (TAVI) for severe symptomatic AS. Womens International TAVI is a multinational, prospective, observational registry of women who underwent TAVI for severe symptomatic AS (n 1,019). Patients were divided into 2 groups based on age of menopause early menopause (age ≤45 years) and regular menopause (age >45 years). The primary outcome of interest was Valve Academic Research Consortium 2 efficacy end point, a composite of mortality, stroke, myocardial infarction, hospitalization for valve-related symptoms, or heart failure or valve-related dysfunction at 1-year follow-up. Of 732 patients with available data on menopause age, 173 (23.6%) were classified as having early menopause. These patients presented for TAVI at a younger age (81.6 ± 6.9 vs 82.7 ± 5.9, p 0.05) and had a significantly lower Society of Thoracic Surgeons score (6.6 ± 4.8 vs 8.2 ± 7.1, p 0.03) than those with regular menopause. However, the total valve calcium volume was smaller among patients with early versus regular menopause (731.8 ± 850.9 mm

Microglia phagocytosis mediates the volume and function of the rat sexually dimorphic nucleus of the preoptic area.

The sexually dimorphic nucleus of the preoptic area (SDN-POA) is the oldest and most robust sex difference reported in mammalian brain and is singular for its presence across a wide range of species from rodents to ungulates to man. This small collection of Nissl-dense neurons is reliably larger in volume in males. Despite its notoriety and intense interrogation, both the mechanism establishing the sex difference and the functional role of the SDN have remained elusive. Convergent evidence from rodent studies led to the conclusion that testicular androgens aromatized to estrogens are neuroprotective in males and that higher apoptosis (naturally occurring cell death) in females determines their smaller SDN. In several species, including humans, a smaller SDN correlates with a preference for mating with males. We report here that this volume difference is dependent upon a participatory role of phagocytic microglia which engulf more neurons in the female SDN and assure their destruction. Selectively blocking microglia phagocytosis temporarily spared neurons from apoptotic death and increased SDN volume in females without hormone treatment. Increasing the number of neurons in the SDN in neonatal females resulted in loss of preference for male odors in adulthood, an effect paralleled by dampened excitation of SDN neurons as evidenced by reduced immediate early gene (IEG) expression when exposed to male urine. Thus, the mechanism establishing a sex difference in SDN volume includes an essential role for microglia, and SDN function as a regulator of sexual partner preference is confirmed.

Association of Time of Day With Outcomes Among Patients Triaged for a Suspected Severe Stroke in Nonurban Catalonia.

We aim to assess whether time of day modified the treatment effect in the RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion Trial), a cluster-randomized trial that did not demonstrate the benefit of direct transportation to a thrombectomy-capable center versus nearest local stroke center for patients with a suspected large vessel stroke triaged in nonurban Catalonia between March 2017 and June 2020. We performed a post hoc analysis of RACECAT to evaluate if the association between initial transport routing and functional outcome differed according to trial enrollment time daytime (800 am-859 pm) and nighttime (900 pm-759 am). Primary outcome was disability at 90 days, as assessed by the shift analysis on the modified Rankin Scale score, in patients with ischemic stroke. Subgroup analyses according to stroke subtype were evaluated. We included 949 patients with an ischemic stroke, of whom 258 patients(27%) were enrolled during nighttime. Among patients enrolled during nighttime, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days (adjusted common odds ratio acOR, 1.620 95% CI, 1.020-2.551) no significant difference between trial groups was present during daytime (acOR, 0.890 95% CI, 0.680-1.163 Among patients evaluated during nighttime for a suspected acute severe stroke in non-urban areas of Catalonia, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days. This association was only evident in patients with confirmed large vessel occlusion on vascular imaging. Time delays in alteplase administration and interhospital transfers might mediate the observed differences in clinical outcome. URL httpswww. gov Unique identifier NCT02795962.

Reperfusion Treatments in Disabling Versus Nondisabling Mild Stroke due to Anterior Circulation Vessel Occlusion.

The benefit of distinguishing between disabling versus nondisabling deficit in mild acute ischemic stroke due to endovascular thrombectomy-targetable vessel occlusion (EVT-tVO including anterior circulation large and medium-vessel occlusion) is unknown. We compared safety and efficacy of acute reperfusion treatments in disabling versus nondisabling mild EVT-tVO. From the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register, we included consecutive acute ischemic stroke patients (2015-2021) treated within 4.5 hours, with full NIHSS items availability and score ≤5, evidence of intracranial internal carotid artery, M1, A1-2, or M2-3 occlusion. After propensity score matching, we compared efficacy (3-month modified Rankin Scale score of 0-1, modified Rankin Scale score of 0-2, and early neurological improvement) and safety (nonhemorrhagic early neurological deterioration, any intracerebral or subarachnoid hemorrhage, symptomatic intracranial hemorrhage, and death at 3-month) outcomes in disabling versus nondisabling patients-adopting an available definition. We included 1459 patients. Propensity score matched analysis of disabling versus nondisabling EVT-tVO (n336 per group) found no significant differences in efficacy (modified Rankin Scale score 0-1 67.4% versus 71.5%, We found similar safety and efficacy outcomes after acute reperfusion treatment in disabling versus nondisabling mild EVT-tVO our findings suggest to adopt similar acute treatment approaches in the 2 groups. Randomized data are needed to clarify the best reperfusion treatment in mild EVT-tVO.

Impact of Time to Treatment on Endovascular Thrombectomy Outcomes in the Early Versus Late Treatment Time Windows.

The impact of time to treatment on outcomes of endovascular thrombectomy (EVT) especially in patients presenting after 6 hours from symptom onset is not well characterized. We studied the differences in characteristics and treatment timelines of EVT-treated patients participating in the Florida Stroke Registry and aimed to characterize the extent to which time impacts EVT outcomes in the early and late time windows. Prospectively collected data from Get With the Guidelines-Stroke hospitals participating in the Florida Stroke Registry from January 2010 to April 2020 were reviewed. Participants were EVT patients with onset-to-puncture time (OTP) of ≤24 hours and categorized into early window treated (OTP ≤6 hours) and late window treated (OTP >6 and ≤24 hours). Association between OTP and favorable discharge outcomes (independent ambulation, discharge home and to acute rehabilitation facility) as well as symptomatic intracerebral hemorrhage and in-hospital mortality were examined using multilevel-multivariable analysis with generalized estimating equations. Among 8002 EVT patients (50.9% women median age ±SD, 71.5 ±14.5 years 61.7% White, 17.5% Black, and 21% Hispanic), 34.2% were treated in the late time window. Among all EVT patients, 32.4% were discharged home, 23.5% to rehabilitation facility, 33.7% ambulated independently at discharge, 5.1% had symptomatic intracerebral hemorrhage, and 9.2% died. As compared with the early window, treatment in the late window was associated with lower odds of independent ambulation (odds ratio OR, 0.78 0.67-0.90) and discharge home (OR, 0.71 0.63-0.80). For every 60-minute increase in OTP, the odds of independent ambulation reduced by 8% (OR, 0.92 0.87-0.97 In routine practice, just over one-third of EVT-treated patients independently ambulate at discharge and only half are discharged to homerehabilitation facility. Increased time from symptom onset to treatment is significantly associated with lower chance of independent ambulation and ability to be discharged home after EVT in the early time window.

Research Opportunities in Stroke Prevention for Atrial Fibrillation A Report From a National Heart, Lung, and Blood Institute Virtual Workshop.

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas (1) improving risk stratification tools for stroke and intracranial hemorrhage (2) addressing challenges with oral anticoagulants and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closureexcision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.

Emerging Roles of Endothelial Nitric Oxide in Preservation of Cognitive Health.

eNOS (endothelial nitric oxide synthase) is critically important enzyme responsible for regulation of cardiovascular homeostasis. Under physiological conditions, constitutive eNOS activity and production of endothelial nitric oxide (NO) exert essential neurovascular protective functions. In this review, we first discuss the roles of endothelial NO in prevention of neuronal amyloid accumulation and formation of neurofibrillary tangles, hallmarks of Alzheimer disease pathology. Next, we review existing evidence suggesting that NO released from endothelium prevents activation of microglia, stimulates glycolysis in astrocytes, and increases biogenesis of mitochondria. We also address major risk factors for cognitive impairment including aging and ApoE4 (apolipoprotein 4) genotype with focus on their detrimental effects on eNOSNO signaling. Relevant to this review, recent studies suggested that aged eNOS heterozygous mice are unique model of spontaneous cerebral small vessel disease. In this regard, we review contribution of dysfunctional eNOS to deposition of Aβ (amyloid-β) into blood vessel wall leading to development of cerebral amyloid angiopathy. We conclude that endothelial dysfunction manifested by the loss of neurovascular protective functions of NO may significantly contribute to development of cognitive impairment.

Comparison of Stroke Care Costs in Urban and Nonurban Hospitals and Its Association With Outcomes in New Zealand A Nationwide Economic Evaluation.

Although geographical differences in treatment and outcomes after stroke have been described, we lack evidence on differences in the costs of treatment between urban and nonurban regions. Additionally, it is unclear whether greater costs in one setting are justified given the outcomes achieved. We aimed to compare costs and quality-adjusted life years in people with stroke admitted to urban and nonurban hospitals in New Zealand. Observational study of patients with stroke admitted to the 28 New Zealand acute stroke hospitals (10 in urban areas) recruited between May and October 2018. Data were collected up to 12 months poststroke including treatments in hospital, inpatient rehabilitation, other health service utilization, aged residential care, productivity, and health-related quality of life. Costs in New Zealand dollars were estimated from a societal perspective and assigned to the initial hospital that patients presented to. Unit prices for 2018 were obtained from government and hospital sources. Multivariable regression analyses were conducted when assessing differences between groups. Of 1510 patients (median age 78 years, 48% female), 607 presented to nonurban and 903 to urban hospitals. Mean hospital costs were greater in urban than nonurban hospitals ($13 191 versus $11 635, Better outcomes following initial presentation to urban hospitals were associated with greater costs compared to nonurban hospitals. These findings may inform greater targeted expenditure in some nonurban hospitals to improve access to treatment and optimize outcomes.

Cerebral Small Vessel Disease-Related Dementia More Questions Than Answers.

Cerebral small vessel disease (CSVD) has emerged as a common factor driving age-dependent diseases, including stroke and dementia. CSVD-related dementia will affect a growing fraction of the aging population, requiring improved recognition, understanding, and treatments. This review describes evolving criteria and imaging biomarkers for the diagnosis of CSVD-related dementia. We describe diagnostic challenges, particularly in the context of mixed pathologies and the absence of highly effective biomarkers for CSVD-related dementia. We review evidence regarding CSVD as a risk factor for developing neurodegenerative disease and potential mechanisms by which CSVD leads to progressive brain injury. Finally, we summarize recent studies on the effects of major classes of cardiovascular medicines relevant to CSVD-related cognitive impairment. Although many key questions remain, the increased attention to CSVD has resulted in a sharper vision for what will be needed to meet the upcoming challenges imposed by this disease.

Hippocampal Vascular Supply and Its Role in Vascular Cognitive Impairment.

The incidence of age-related dementia is increasing as the world population ages and due to lack of effective treatments for dementia. Vascular contributions to cognitive impairment and dementia are increasing as the prevalence of pathologies associated with cerebrovascular disease rise, including chronic hypertension, diabetes, and ischemic stroke. The hippocampus is a bilateral deep brain structure that is central to learning, memory, and cognitive function and highly susceptible to hypoxicischemic injury. Compared with cortical brain regions such as the somatosensory cortex, less is known about the function of the hippocampal vasculature that is critical in maintaining neurocognitive health. This review focuses on the hippocampal vascular supply, presenting what is known about hippocampal hemodynamics and blood-brain barrier function during health and disease, and discusses evidence that supports its contribution to vascular cognitive impairment and dementia. Understanding vascular-mediated hippocampal injury that contributes to memory dysfunction during healthy aging and cerebrovascular disease is essential to develop effective treatments to slow cognitive decline. The hippocampus and its vasculature may represent one such therapeutic target to mitigate the dementia epidemic.

Blood-Brain Barrier Dysfunction in Normal Aging and Neurodegeneration Mechanisms, Impact, and Treatments.

Cerebral endothelial cells and their linking tight junctions form a unique, dynamic and multi-functional interface, the blood-brain barrier (BBB). The endothelium is regulated by perivascular cells and components forming the neurovascular unit. This review examines BBB and neurovascular unit changes in normal aging and in neurodegenerative disorders, particularly focusing on Alzheimer disease, cerebral amyloid angiopathy and vascular dementia. Increasing evidence indicates BBB dysfunction contributes to neurodegeneration. Mechanisms underlying BBB dysfunction are outlined (endothelium and neurovascular unit mediated) as is the BBB as a therapeutic target including increasing the uptake of systemically delivered therapeutics across the BBB, enhancing clearance of potential neurotoxic compounds via the BBB, and preventing BBB dysfunction. Finally, a need for novel biomarkers of BBB dysfunction is addressed.

Domain-Specific Outcome Measures in Clinical Trials of Therapies Promoting Stroke Recovery A Suggested Blueprint.

Different deficits recover to different degrees and with different time courses after stroke, indicating that plasticity differs across the brains neural systems after stroke. To capture these differences, domain-specific outcome measures have received increased attention. Such measures have potential advantages over global outcome scales, which combine recovery across many domains into a single score and so blur the ability to capture individual measures of stroke recovery. Use of a global end point to rate disability can overlook substantial recovery in specific domains, such as motor or language, and may not differentiate between good and poor recovery for specific neurological domains. In light of these points, a blueprint is proposed for using domain-specific outcome measures in stroke recovery trials. Key steps include selecting a domain in the context of preclinical data, picking a domain-specific clinical trial end point, anchoring inclusion criteria to this end point, scoring this end point both before and after treatment, and then pursuing regulatory approval on the basis of the domain-specific results. This blueprint is intended to foster clinical trials that, by using domain-specific end points, are able to demonstrate favorable results in clinical trials of therapies that promote stroke recovery.

SAYSD1 senses UFMylated ribosome to safeguard co-translational protein translocation at the endoplasmic reticulum.

Translocon clogging at the endoplasmic reticulum (ER) as a result of translation stalling triggers ribosome UFMylation, activating translocation-associated quality control (TAQC) to degrade clogged substrates. How cells sense ribosome UFMylation to initiate TAQC is unclear. We conduct a genome-wide CRISPR-Cas9 screen to identify an uncharacterized membrane protein named SAYSD1 that facilitates TAQC. SAYSD1 associates with the Sec61 translocon and also recognizes both ribosome and UFM1 directly, engaging a stalled nascent chain to ensure its transport via the TRAPP complex to lysosomes for degradation. Like UFM1 deficiency, SAYSD1 depletion causes the accumulation of translocation-stalled proteins at the ER and triggers ER stress. Importantly, disrupting UFM1- and SAYSD1-dependent TAQC in Drosophila leads to intracellular accumulation of translocation-stalled collagens, defective collagen deposition, abnormal basement membranes, and reduced stress tolerance. Thus, SAYSD1 acts as a UFM1 sensor that collaborates with ribosome UFMylation at the site of clogged translocon, safeguarding ER homeostasis during animal development.

Negami An Augmented Reality App for the Treatment of Spatial Neglect After Stroke.

A widely applied and effective rehabilitation method for patients experiencing spatial neglect after a stroke is visual exploration training. Patients improve their ipsilesional bias of attention and orientation by training exploration movements and search strategies toward the contralesional side of space. In this context, gamification can have a positive influence on motivation for treatment and thus on the success of treatment. In contrast to virtual reality applications, treatment enhancements through augmented reality (AR) have not yet been investigated, although they offer some advantages over virtual reality. This study aimed to develop an AR-based app (Negami) for the treatment of spatial neglect that combines visual exploration training with active, contralesionally oriented rotation of the eyes, head, and trunk. The app inserts a virtual element (origami bird) into the real space surrounding the patient, which the patient explores with the camera of a tablet. Subjective reports from healthy elderly participants (n10) and patients with spatial neglect after stroke (n10) who trained with the new Negami app were analyzed. Usability, side effects, and game experience were assessed by various questionnaires. Training at the highest defined difficulty level was perceived as differently challenging but not as frustrating by the group of healthy elderly participants. The app was rated with high usability, hardly any side effects, high motivation, and entertainment. The group of patients with spatial neglect after stroke consistently evaluated the app positively on the dimensions of motivation, satisfaction, and fun. The Negami app represents a promising extension by adding AR to traditional exploration training for spatial neglect. Through participants natural interaction with the physical surrounding environment during playful tasks, side effects as symptoms of cybersickness are minimized and patients motivation appeared to markedly increase. The use of AR in cognitive rehabilitation programs and the treatment of spatial neglect seems promising and should receive further investigation.

MeCP2 regulates

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and

Remote ischemic conditioning-induced hyperacute and acute responses of plasma proteome in healthy young male adults a quantitative proteomic analysis.

Long-term remote ischemic conditioning (RIC) has been proven to be beneficial in multiple diseases, such as cerebral and cardiovascular diseases. However, the hyperacute and acute effects of a single RIC stimulus are still not clear. Quantitative proteomic analyses of plasma proteins following RIC application have been conducted in preclinical and clinical studies but exhibit high heterogeneity in results due to wide variations in experimental setups and sampling procedures. Hence, this study aimed to explore the immediate effects of RIC on plasma proteome in healthy young adults to exclude confounding factors of disease entity, such as medications and gender. Young healthy male participants were enrolled after a systematic physical examination and 6-month lifestyle observation. Individual RIC sessions included five cycles of alternative ischemia and reperfusion, each lasting for 5 min in bilateral forearms. Blood samples were collected at baseline, 5 min after RIC, and 2 h after RIC, and then samples were processed for proteomic analysis using liquid chromatography-tandem mass spectrometry method. Proteins related to lipid metabolism (e.g., Apolipoprotein F), coagulation factors (hepatocyte growth factor activator preproprotein), members of complement cascades (mannan-binding lectin serine protease 1 isoform 2 precursor), and inflammatory responses (carboxypeptidase N catalytic chain precursor) were differentially altered at their serum levels following the RIC intervention. The most enriched pathways were protein glycosylation and complementcoagulation cascades. One-time RIC stimulus may induce instant cellular responses like anti-inflammation, coagulation, and fibrinolysis balancing, and lipid metabolism regulation which are protective in different perspectives. Protective effects of single RIC in hyperacute and acute phases may be exploited in clinical emergency settings due to apparently beneficial alterations in plasma proteome profile. Furthermore, the beneficial effects of long-term (repeated) RIC interventions in preventing chronic cardiovascular diseases among general populations can also be expected based on our study findings. ClinicalTrials.gov, NCT03105141.

Epigenetic Regulation of Ferroptosis in Central Nervous System Diseases.

Ferroptosis, a newly identified form of cell death, is characterized by iron overload and accumulation of lipid reactive oxygen species. Inactivation of pathways, such as glutathioneglutathione peroxidase 4, NAD(P)Hferroptosis suppressor protein 1ubiquinone, dihydroorotate dehydrogenaseubiquinol, or guanosine triphosphate cyclohydrolase-16(R)-L-erythro-5,6,7,8-tetrahydrobiopterin pathways, have been found to induce ferroptosis. The accumulating data suggest that epigenetic regulation can determine cell sensitivity to ferroptosis at both the transcriptional and translational levels. While many of the effectors that regulate ferroptosis have been mapped, epigenetic regulation in ferroptosis is not yet fully understood. Neuronal ferroptosis is a driver in several central nervous system (CNS) diseases, such as stroke, Parkinsons disease, traumatic brain injury, and spinal cord injury, and thus, research on how to inhibit neuronal ferroptosis is required to develop novel therapies for these diseases. In this review, we have summarized epigenetic regulation of ferroptosis in these CNS diseases, focusing in particular on DNA methylation, non-coding RNA regulation, and histone modification. Understanding epigenetic regulation in ferroptosis will hasten the development of promising therapeutic strategies in CNS diseases associated with ferroptosis.

DEEP MOVEMENT Deep learning of movie files for management of endovascular thrombectomy.

Treatment and outcomes of acute stroke have been revolutionised by mechanical thrombectomy. Deep learning has shown great promise in diagnostics but applications in video and interventional radiology lag behind. We aimed to develop a model that takes as input digital subtraction angiography (DSA) videos and classifies the video according to (1) the presence of large vessel occlusion (LVO), (2) the location of the occlusion, and (3) the efficacy of reperfusion. All patients who underwent DSA for anterior circulation acute ischaemic stroke between 2012 and 2019 were included. Consecutive normal studies were included to balance classes. An external validation (EV) dataset was collected from another institution. The trained model was also used on DSA videos post mechanical thrombectomy to assess thrombectomy efficacy. In total, 1024 videos comprising 287 patients were included (44 for EV). Occlusion identification was achieved with 100% sensitivity and 91.67% specificity (EV 91.30% and 81.82%). Accuracy of location classification was 71% for ICA, 84% for M1, and 78% for M2 occlusions (EV 73, 25, and 50%). For post-thrombectomy DSA (n 194), the model identified successful reperfusion with 100%, 88%, and 35% for ICA, M1, and M2 occlusion (EV 89, 88, and 60%). The model could also perform classification of post-intervention videos as mTICI < 3 with an AUC of 0.71. Our model can successfully identify normal DSA studies from those with LVO and classify thrombectomy outcome and solve a clinical radiology problem with two temporal elements (dynamic video and pre and post intervention). • DEEP MOVEMENT represents a novel application of a model applied to acute stroke imaging to handle two types of temporal complexity, dynamic video and pre and post intervention. • The model takes as an input digital subtraction angiograms of the anterior cerebral circulation and classifies according to (1) the presence or absence of large vessel occlusion, (2) the location of the occlusion, and (3) the efficacy of thrombectomy. • Potential clinical utility lies in providing decision support via rapid interpretation (pre thrombectomy) and automated objective gradation of thrombectomy outcomes (post thrombectomy).

MRI for collateral assessment pre-thrombectomy and association with outcome a systematic review and meta-analysis.

Various neuroimaging methods exist to assess the collateral circulation in stroke patients but much of the evidence is based on computed tomography. Our aim was to review the evidence for using magnetic resonance imaging for collateral status evaluation pre-thrombectomy and assess the impact of these methods on functional independence. We systematically reviewed EMBASE and MEDLINE for studies that evaluated baseline collaterals using MRI pre-thrombectomy and conducted a meta-analysis to express the relationship between good collaterals (defined variably as the presence good vs absence poor or quality ordinal scores binarized as good-moderate vs poor of collaterals) and functional independence (modified Rankin score mRS≤2) at 90 days. Outcome data were presented as relative risk (RR, 95% confidence interval, 95%CI). We assessed for study heterogeneity, publication bias, and conducted subgroup analyses of different MRI methods and affected arterial territories. From 497 studies identified, we included 24 (1957 patients) for the qualitative synthesis, and 6 (479 patients) for the metanalysis. Good pre-thrombectomy collaterals were significantly associated with favorable outcome at 90 days (RR1.91, 95%CI1.36-2.68, p 0.0002) with no difference between MRI methods and affected arterial territory subgroups. There was no evidence of statistical heterogeneity (I In stroke patients treated with thrombectomy, good pre-treatment collaterals assessed using MRI are associated with double the rate of functional independence. However, we found evidence that relevant MR methods are heterogenous and under-reported. Greater standardization and clinical validation of MRI for collateral evaluation pre-thrombectomy are required.

Correlation of systemic involvement and presence of pathological skin calcification assessed by ex vivo nonlinear microscopy in Pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE (OMIM 264800)) is an autosomal recessive connective tissue disorder mainly caused by mutations in the ABCC6 gene. PXE results in ectopic calcification primarily in the skin, eye and blood vessels that can lead to blindness, peripheral arterial disease and stroke. Previous studies found correlation between macroscopic skin involvement and severe ophthalmological and cardiovascular complications. This study aimed to investigate correlation between skin calcification and systemic involvement in PXE. Ex vivo nonlinear microscopy (NLM) imaging was performed on formalin fixed, deparaffinized, unstained skin sections to assess the extent of skin calcification. The area affected by calcification (CA) in the dermis and density of calcification (CD) was calculated. From CA and CD, calcification score (CS) was determined. The number of affected typical and nontypical skin sites were counted. Phenodex scores were determined. The relationship between the ophthalmological, cerebro- and cardiovascular and other systemic complications and CA, CD and CS, respectively, and skin involvement were analyzed. Regression models were built for adjustment to age and sex. We found significant correlation of CA with the number of affected typical skin sites (r 0.48), the Phenodex score (r 0.435), extent of vessel involvement (V-score) (r 0.434) and disease duration (r 0.48). CD correlated significantly with V-score (r 0.539). CA was significantly higher in patients with more severe eye (p 0.04) and vascular (p 0.005) complications. We found significantly higher CD in patients with higher V-score (p 0.018), and with internal carotid artery hypoplasia (p 0.045). Significant correlation was found between higher CA and the presence of macula atrophy (β - 0.44, p 0.032) and acneiform skin changes (β 0.40, p 0.047). Based on our results, the assessment of skin calcification pattern with nonlinear microscopy in PXE may be useful for clinicians to identify PXE patients who develop severe systemic complications.

Waiting more than 24 hours for hip fracture surgery is associated with increased risk of adverse outcomes for sicker patients a nationwide cohort study of 63,998 patients using the Swedish Hip Fracture Register.

Waiting time to surgery is a modifiable risk factor in hip fracture surgery. However, there is no consensus regarding the acceptable duration of waiting time. We used the Swedish Hip Fracture Register RIKSHÖFT and 3 administrative registers to explore the association between time to surgery and adverse outcomes after discharge. 63,998 patients ≥ 65 years, admitted to a hospital between January 1, 2012, and August 31, 2017 were included. Time to surgery was divided into < 12, 12-24, and > 24 hours. Diagnoses investigated were atrial fibrillationflutter (AF), congestive heart failure (CHF), pneumonia, and acute ischemia (a combination of strokeintracranial bleeding, myocardial infarction, and acute kidney injury). Crude and adjusted survival analyses were performed. Time spent in hospital following the initial hospitalization was described for the 3 groups. Waiting > 24 hours was associated with an increased risk of AF (HR 1.4, 95%CI 1.2-1.6), CHF (HR 1.3, CI 1.1-1.4) and acute ischemia (HR 1.2, CI 1.01-1.3). However, stratifying for ASA grade revealed that these associations were present only in patients with ASA 3-4. There was no association between waiting time and pneumonia after the initial hospitalization (HR 1.1, CI 0.97-1.2), but one was found with pneumonia during hospital stay OR 1.2 (CI 1.1-1.4). Time in hospital after the initial hospitalization was similar over the waiting time groups. The associations between waiting > 24 hours for hip fracture surgery and AF, CHF, and acute ischemia suggest that shorter waiting time may reduce adverse outcomes for the sicker patients.

Neuropathological features of SARS-CoV-2 delta and omicron variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continually evolving resulting in variants with increased transmissibility, more severe disease, reduced effectiveness of treatments or vaccines, or diagnostic detection failure. The SARS-CoV-2 Delta variant (B.1.617.2 and AY lineages) was the dominant circulating strain in the United States from July to mid-December 2021, followed by the Omicron variant (B.1.1.529 and BA lineages). Coronavirus disease 2019 (COVID-19) has been associated with neurological sequelae including loss of tastesmell, headache, encephalopathy, and stroke, yet little is known about the impact of viral strain on neuropathogenesis. Detailed postmortem brain evaluations were performed for 22 patients from Massachusetts, including 12 who died following infection with Delta variant and 5 with Omicron variant, compared to 5 patients who died earlier in the pandemic. Diffuse hypoxic injury, occasional microinfarcts and hemorrhage, perivascular fibrinogen, and rare lymphocytes were observed across the 3 groups. SARS-CoV-2 protein and RNA were not detected in any brain samples by immunohistochemistry, in situ hybridization, or real-time quantitative PCR. These results, although preliminary, demonstrate that, among a subset of severely ill patients, similar neuropathological features are present in Delta, Omicron, and non-Deltanon-Omicron variant patients, suggesting that SARS-CoV-2 variants are likely to affect the brain by common neuropathogenic mechanisms.

Real-Time Monitoring and Modulation of Blood Pressure in a Rabbit Model of Ischemic Stroke.

Control of blood pressure, in terms of both absolute values and its variability, affects outcomes in ischemic stroke patients. However, it remains challenging to identify the mechanisms that lead to poor outcomes or evaluate measures by which these effects can be mitigated because of the prohibitive limitations inherent to human data. In such cases, animal models can be utilized to conduct rigorous and reproducible evaluations of diseases. Here we report refinement of a previously described model of ischemic stroke in rabbits that is augmented with continuous blood pressure recording to assess the impacts of modulation on blood pressure. Under general anesthesia, femoral arteries are exposed through surgical cutdowns to place arterial sheaths bilaterally. Under fluoroscopic visualization and roadmap guidance, a microcatheter is advanced into an artery of the posterior circulation of the brain. An angiogram is performed by injecting the contralateral vertebral artery to confirm occlusion of the target artery. With the occlusive catheter remaining in position for a fixed duration, blood pressure is continuously recorded to allow for tight titration of blood pressure manipulations, whether through mechanical or pharmacological means. At the completion of the occlusion interval, the microcatheter is removed, and the animal is maintained under general anesthesia for a prescribed length of reperfusion. For acute studies, the animal is then euthanized and decapitated. The brain is harvested and processed to measure the infarct volume under light microscopy and further assessed with various histopathological stains or spatial transcriptomic analysis. This protocol provides a reproducible model that can be utilized for more thorough preclinical studies on the effects of blood pressure parameters during ischemic stroke. It also facilitates effective preclinical evaluation of novel neuroprotective interventions that might improve care for ischemic stroke patients.

Heterogeneity in diagnosis and prognosis of ischaemic stroke subtypes 9-year follow-up of 22000 cases in Chinese adults.

Reliable classification of ischaemic stroke (IS) aetiological subtypes is required in research and clinical practice, but the predictive properties of these subtypes in population studies with incomplete investigations are poorly understood. To compare the prognosis of aetiologically-classified IS subtypes and use machine learning (ML) to classify incompletely investigated IS cases. In a 9-year follow-up of a prospective study of 512,726 Chinese adults, 22,216 incident IS cases, confirmed by clinical adjudication of medical records, were assigned subtypes using a modified Causative Classification System for Ischemic Stroke (CCS) (LAA large artery atherosclerosis SAO small artery occlusion, CE cardioaortic embolism or undetermined aetiology) and classified by CCS as evident, probable, or possible IS cases. For incompletely investigated IS cases where CCS yielded an undetermined aetiology, a ML model was developed to predict IS subtypes from baseline risk factors and screening for cardioaortic sources of embolism. The 5-year risks of subsequent stroke and all-cause mortality (measured using cumulative incidence functions and 1 minus Kaplan-Meier estimates, respectively) for the ML-predicted IS subtypes were compared with aetiologically-classified IS subtypes. Among 7,443 IS subtypes with evident or probable aetiology, 66% had SAO, 32% had LAA and 2% had CE, but proportions of SAO-to-LAA cases varied by regions in China. CE had the highest rates of subsequent stroke and mortality (43.5%, 40.7%), followed by LAA (43.2%, 17.4%) and SAO (38.1%, 11.1%), respectively. ML provided classifications for cases with undetermined aetiology and incomplete clinical data (24% of all IS cases n5,276), with area under the curves (AUC) of 0.99 (0.99-1.00) for CE, 0.67 (0.64-0.70) for LAA, and 0.70 (0.67-0.73) for SAO for unseen cases. ML-predicted IS subtypes yielded comparable subsequent stroke and all-cause mortality rates to the aetiologically-classified IS subtypes. This study highlighted substantial heterogeneity in prognosis of IS subtypes and utility of ML approaches for classification of IS cases with incomplete clinical investigations.