Functional Outcomes Associated With Blood Pressure Decrease After Endovascular Thrombectomy.

Importance: The associations between blood pressure (BP) decreases induced by medication and functional outcomes in patients with successful endovascular thrombectomy remain uncertain. Objective: To evaluate whether BP reductions induced by intravenous BP medications are associated with poor functional outcomes at 3 months. Design, Setting, and Participants: This cohort study was a post hoc analysis of the Outcome in Patients Treated With Intra-Arterial Thrombectomy-Optimal Blood Pressure Control trial, a comparison of intensive and conventional BP management during the 24 hours after successful recanalization from June 18, 2020, to November 28, 2022. This study included 302 patients who underwent endovascular thrombectomy, achieved successful recanalization, and exhibited elevated BP within 2 hours of successful recanalization at 19 stroke centers in South Korea. Exposure: A BP decrease was defined as at least 1 event of systolic BP less than 100 mm Hg. Patients were divided into medication-induced BP decrease (MIBD), spontaneous BP decrease (SpBD), and no BP decrease (NoBD) groups. Main Outcomes and Measures: The primary outcome was a modified Rankin scale score of 0 to 2 at 3 months, indicating functional independence. Primary safety outcomes were symptomatic intracerebral hemorrhage within 36 hours and mortality due to index stroke within 3 months. Results: Of the 302 patients (median [IQR] age, 75 [66-82] years; 180 [59.6%] men), 47 (15.6%)were in the MIBD group, 39 (12.9%) were in the SpBD group, and 216 (71.5%) were in the NoBD group. After adjustment for confounders, the MIBD group exhibited a significantly smaller proportion of patients with functional independence at 3 months compared with the NoBD group (adjusted odds ratio [AOR], 0.45; 95% CI, 0.20-0.98). There was no significant difference in functional independence between the SpBD and NoBD groups (AOR, 1.41; 95% CI, 0.58-3.49). Compared with the NoBD group, the MIBD group demonstrated higher odds of mortality within 3 months (AOR, 5.15; 95% CI, 1.42-19.4). The incidence of symptomatic intracerebral hemorrhage was not significantly different among the groups (MIBD vs NoBD: AOR, 1.89; 95% CI, 0.54-5.88; SpBD vs NoBD: AOR, 2.75; 95% CI, 0.76-9.46). Conclusions and Relevance: In this cohort study of patients with successful endovascular thrombectomy after stroke, MIBD within 24 hours after successful recanalization was associated with poor outcomes at 3 months. These findings suggested lowering systolic BP to below 100 mm Hg using BP medication might be harmful.

Effectiveness of endovascular treatment for in-hospital stroke vs. community-onset stroke: a propensity score-matched analysis.

BACKGROUND: The effectiveness of endovascular treatment for in-hospital stroke remains debatable. We aimed to compare the outcomes between patients with in-hospital stroke and community-onset stroke who received endovascular treatment. METHODS: This prospective registry-based cohort study included consecutive patients who underwent endovascular treatment from January 2013 to December 2022 and were registered in the Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy study and Yonsei Stroke Cohort. Functional outcomes at day 90, radiological outcomes, and safety outcomes were compared between the in-hospital and community-onset groups using logistic regression and propensity score-matched analysis. RESULTS: Of 1,219 patients who underwent endovascular treatment, 117 (9.6%) had in-hospital stroke. Patients with in-hospital onset were more likely to have a pre-stroke disability and active cancer than those with community-onset. The interval from the last known well to puncture was shorter in the in-hospital group than in the community-onset group (155 vs. 355 min, p<0.001). No significant differences in successful recanalization or safety outcomes were observed between the groups; however, the in-hospital group exhibited worse functional outcomes and higher mortality at day 90 than the community-onset group (all p<0.05). After propensity score matching including baseline characteristics, functional outcomes after endovascular treatment did not differ between the groups (OR: 1.19, 95% CI 0.78-1.83, p=0.4). Safety outcomes did not significantly differ between the groups. CONCLUSION: Endovascular treatment is a safe and effective treatment for eligible patients with in-hospital stroke. Our results will help physicians in making decisions when planning treatment and counseling caregivers or patients.

Intensive vs Conventional Blood Pressure Lowering After Endovascular Thrombectomy in Acute Ischemic Stroke: The OPTIMAL-BP Randomized Clinical Trial.

Importance: Optimal blood pressure (BP) control after successful reperfusion with endovascular thrombectomy (EVT) for patients with acute ischemic stroke is unclear. Objective: To determine whether intensive BP management during the first 24 hours after successful reperfusion leads to better clinical outcomes than conventional BP management in patients who underwent EVT. Design, Setting, and Participants: Multicenter, randomized, open-label trial with a blinded end-point evaluation, conducted across 19 stroke centers in South Korea from June 2020 to November 2022 (final follow-up, March 8, 2023). It included 306 patients with large vessel occlusion acute ischemic stroke treated with EVT and with a modified Thrombolysis in Cerebral Infarction score of 2b or greater (partial or complete reperfusion). Interventions: Participants were randomly assigned to receive intensive BP management (systolic BP target <140 mm Hg; n = 155) or conventional management (systolic BP target 140-180 mm Hg; n = 150) for 24 hours after enrollment. Main Outcomes and Measures: The primary outcome was functional independence at 3 months (modified Rankin Scale score of 0-2). The primary safety outcomes were symptomatic intracerebral hemorrhage within 36 hours and death related to the index stroke within 3 months. Results: The trial was terminated early based on the recommendation of the data and safety monitoring board, which noted safety concerns. Among 306 randomized patients, 305 were confirmed eligible and 302 (99.0%) completed the trial (mean age, 73.0 years; 122 women [40.4%]). The intensive management group had a lower proportion achieving functional independence (39.4%) than the conventional management group (54.4%), with a significant risk difference (-15.1% [95% CI, -26.2% to -3.9%]) and adjusted odds ratio (0.56 [95% CI, 0.33-0.96]; P = .03). Rates of symptomatic intracerebral hemorrhage were 9.0% in the intensive group and 8.1% in the conventional group (risk difference, 1.0% [95% CI, -5.3% to 7.3%]; adjusted odds ratio, 1.10 [95% CI, 0.48-2.53]; P = .82). Death related to the index stroke within 3 months occurred in 7.7% of the intensive group and 5.4% of the conventional group (risk difference, 2.3% [95% CI, -3.3% to 7.9%]; adjusted odds ratio, 1.73 [95% CI, 0.61-4.92]; P = .31). Conclusions and Relevance: Among patients who achieved successful reperfusion with EVT for acute ischemic stroke with large vessel occlusion, intensive BP management for 24 hours led to a lower likelihood of functional independence at 3 months compared with conventional BP management. These results suggest that intensive BP management should be avoided after successful EVT in acute ischemic stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT04205305.

Aortic carboxypeptidase-like protein, a putative myokine, stimulates the differentiation and survival of bone-forming osteoblasts.

A new target that stimulates bone formation is needed to overcome limitations of current anti-osteoporotic drugs. Myokines, factors secreted from muscles, may modulate it. In this study, we investigated the role of aortic carboxypeptidase-like protein (ACLP), which is highly expressed in skeletal muscles, on bone formation. MC3T3-E1 cells and/or calvaria osteoblasts were treated with recombinant N-terminal mouse ACLP containing a signal peptide [rmACLP (N)]. The expression and secretion of ACLP were higher in skeletal muscle and differentiated myotube than in other tissues and undifferentiated myoblasts, respectively. rmACLP (N) increased bone formation, ALP activity, and phosphorylated p38 mitogen-activated protein (MAP) kinase in osteoblasts; reversal was achieved by pre-treatment with a TGF-ß receptor inhibitor. Under H2 O2 treatment, rmACLP (N) increased osteoblast survival, phosphorylated p38 MAP kinase, and the nuclear translocation of FoxO3a in osteoblasts. H2 O2 treatment caused rmACLP (N) to suppress its apoptotic, oxidative, and caspase-9 activities. rmACLP (N)-stimulated osteoblast survival was reversed by pre-treatment with a p38 inhibitor, a TGF-ß-receptor II blocking antibody, and a FoxO3a shRNA. Conditioned media (CM) from muscle cells stimulated osteoblast survival under H2 O2 treatment, in contrast to CM from ACLP knockdown muscle cells. rmACLP (N) increased the expressions of FoxO3a target anti-oxidant genes such as Sod2, Trx2, and Prx5. In conclusion, ACLP stimulated the differentiation and survival of osteoblasts. This led to the stimulation of bone formation by the activation of p38 MAP kinase and/or FoxO3a via TGF-ß receptors. These findings suggest a novel role for ACLP in bone metabolism as a putative myokine.

Cancer Prediction With Machine Learning of Thrombi From Thrombectomy in Stroke: Multicenter Development and Validation.

BACKGROUND: We aimed to develop and validate machine learning models to diagnose patients with ischemic stroke with cancer through the analysis of histopathologic images of thrombi obtained during endovascular thrombectomy. METHODS: This was a retrospective study using a prospective multicenter registry which enrolled consecutive patients with acute ischemic stroke from South Korea who underwent endovascular thrombectomy. This study included patients admitted between July 1, 2017 and December 31, 2021 from 6 academic university hospitals. Whole-slide scanning was performed for immunohistochemically stained thrombi. Machine learning models were developed using transfer learning with image slices as input to classify patients into 2 groups: cancer group or other determined cause group. The models were developed and internally validated using thrombi from patients of the primary center, and external validation was conducted in 5 centers. The model was also applied to patients with hidden cancer who were diagnosed with cancer within 1 month of their index stroke. RESULTS: The study included 70 561 images from 182 patients in both internal and external datasets (119 patients in internal and 63 in external). Machine learning models were developed for each immunohistochemical staining using antibodies against platelets, fibrin, and erythrocytes. The platelet model demonstrated consistently high accuracy in classifying patients with cancer, with area under the receiver operating characteristic curve of 0.986 (95% CI, 0.983-0.989) during training, 0.954 (95% CI, 0.937-0.972) during internal validation, and 0.949 (95% CI, 0.891-1.000) during external validation. When applied to patients with occult cancer, the model accurately predicted the presence of cancer with high probabilities ranging from 88.5% to 99.2%. CONCLUSIONS: Machine learning models may be used for prediction of cancer as the underlying cause or detection of occult cancer, using platelet-stained immunohistochemical slide images of thrombi obtained during endovascular thrombectomy.

Fatty acid amides as potential circulating biomarkers for sarcopenia.

BACKGROUND: Sarcopenia is characterized by a progressive decrease in skeletal muscle mass and function with age. Given that sarcopenia is associated with various metabolic disorders, effective metabolic biomarkers for its early detection are required. We aimed to investigate the metabolic biomarkers related to sarcopenia in elderly men and perform experimental studies using metabolomics. METHODS: Plasma metabolites from 142 elderly men, comprising a sarcopenia group and an age-matched control group, were measured using global metabolome profiling. Muscle and plasma samples from an aging mouse model of sarcopenia, as well as cell media and cell lysates during myoblast differentiation, were analysed based on targeted metabolome profiling. Based on these experimental results, fatty acid amides were quantified from human plasma as well as human muscle tissues. The association of fatty acid amide levels with sarcopenia parameters was evaluated. RESULTS: Global metabolome profiling showed that fatty acid amide levels were significantly different in the plasma of elderly men with sarcopenia (all Ps < 0.01). Consistent with these results in human plasma, targeted metabolome profiling in an aging mouse model of sarcopenia showed decreased levels of fatty acid amides in plasma but not in muscle tissue. In addition, the levels of fatty acid amides increased in cell lysates during muscle cell differentiation. Targeted metabolome profiling in men showed decreased docosahexaenoic acid ethanolamide (DHA EA) levels in the plasma (P = 0.016) but not in the muscle of men with sarcopenia. DHA EA level was positively correlated with sarcopenia parameters such as skeletal muscle mass index (SMI) and handgrip strength (HGS) (P = 0.001, P = 0.001, respectively). The area under the receiver-operating characteristic curve (AUC) for DHA EA level ≤ 4.60 fmol/µL for sarcopenia was 0.618 (95% confidence interval [CI]: 0.532-0.698). DHA EA level ≤ 4.60 fmol/µL was associated with a significantly greater likelihood of sarcopenia (odds ratio [OR]: 2.11, 95% CI: 1.03-4.30), independent of HGS. The addition of DHA EA level to age and HGS significantly improved the AUC from 0.620 to 0.691 (P = 0.0497). CONCLUSIONS: Our study demonstrated that fatty acid amides are potential circulating biomarkers in elderly men with sarcopenia. DHA EA, in particular, strongly related to muscle mass and strength, can be a key metabolite to become a reliable metabolic biomarker for sarcopenia. Further research on fatty acid amides will provide insights into the metabolomic changes relevant to sarcopenia from an aging perspective.

Prediction of Mortality Among Patients With Isolated Traumatic Brain Injury Using Machine Learning Models in Asian Countries: An International Multi-Center Cohort Study.

Abstract Traumatic brain injury (TBI) is a significant healthcare concern in several countries, accounting for a major burden of morbidity, mortality, disability, and socioeconomic losses. Although conventional prognostic models for patients with TBI have been validated, their performance has been limited. Therefore, we aimed to construct machine learning (ML) models to predict the clinical outcomes in adult patients with isolated TBI in Asian countries. The Pan-Asian Trauma Outcome Study registry was used in this study, and the data were prospectively collected from January 1, 2015, to December 31, 2020. Among a total of 6540 patients (≥ 15 years) with isolated moderate and severe TBI, 3276 (50.1%) patients were randomly included with stratification by outcomes and subgrouping variables for model evaluation, and 3264 (49.9%) patients were included for model training and validation. Logistic regression was considered as a baseline, and ML models were constructed and evaluated using the area under the precision-recall curve (AUPRC) as the primary outcome metric, area under the receiver operating characteristic curve (AUROC), and precision at fixed levels of recall. The contribution of the variables to the model prediction was measured using the SHapley Additive exPlanations (SHAP) method. The ML models outperformed logistic regression in predicting the in-hospital mortality. Among the tested models, the gradient-boosted decision tree showed the best performance (AUPRC, 0.746 [0.700-0.789]; AUROC, 0.940 [0.929-0.952]). The most powerful contributors to model prediction were the Glasgow Coma Scale, O2 saturation, transfusion, systolic and diastolic blood pressure, body temperature, and age. Our study suggests that ML techniques might perform better than conventional multi-variate models in predicting the outcomes among adult patients with isolated moderate and severe TBI.

Comparing carotid endarterectomy and carotid artery stenting: retrospective single-center analysis.

BACKGROUND: Extracranial cerebrovascular diseases represent approximately 20% of ischemic stroke cases. Carotid endarterectomy (CEA) was the gold standard procedure for carotid artery stenosis treatment until the introduction of carotid artery stenting (CAS) in the 1980s. While there have been several multicenter randomized trials comparing CEA and CAS, a more efficacious procedure has not been conclusively distinguished. This study reports the results of CAS versus CEA in patients with symptomatic or asymptomatic carotid stenosis and compares them with those from other studies. METHODS: This study is a single-center retrospective study and included patients who underwent CAS and CEA as elective surgery between January 2012 and December 2020. The final analysis included patient baseline characteristics, postoperative complications, and patient outcomes. RESULTS: The 235 patients included were assigned to the CAS (n=128) and CEA (n=107) groups. Within 30 days postoperatively, no significant differences were noted in myocardial infarction [n=1, 0.8% (CAS); n=1, 0.9% (CEA); P=0.899], cerebral infarction [n=4, 3.1% (CAS); n=1, 0.9% (CEA); P=0.247], and patient mortality [n=1, 0.8% (CAS); n=0, 0% (CEA); P=0.247]. CONCLUSIONS: In elective surgery, CAS and CEA had the same effect of preventing cerebral infarction with no difference in postoperative complications.

Association between CHADS2, CHA2DS2-VASc, ATRIA, and Essen Stroke Risk Scores and Functional Outcomes in Acute Ischemic Stroke Patients Who Received Endovascular Thrombectomy.

Background: CHADS2, CHA2DS2-VASc, ATRIA, and Essen stroke risk scores are used to estimate thromboembolism risk. We aimed to investigate the association between unfavorable outcomes and stroke risk scores in patients who received endovascular thrombectomy (EVT). Methods: This study was performed using data from a nationwide, multicenter registry to explore the selection criteria for patients who would benefit from reperfusion therapies. We calculated pre-admission CHADS2, CHA2DS2-VASc, ATRIA, and Essen scores for each patient who received EVT and compared the relationship between these scores and 3-month modified Rankin Scale (mRS) records. Results: Among the 404 patients who received EVT, 213 (52.7%) patients had unfavorable outcomes (mRS 3−6). All scores were significantly higher in patients with unfavorable outcomes than in those with favorable outcomes. Multivariable logistic regression analysis indicated that CHADS2 and the ATRIA score were positively correlated with unfavorable outcomes after adjusting for body mass index and variables with p < 0.1 in the univariable analysis (CHADS2 score: odds ratio [OR], 1.484; 95% confidence interval [CI], 1.290−1.950; p = 0.005, ATRIA score, OR, 1.128; 95% CI, 1.041−1.223; p = 0.004). Conclusions: The CHADS2 and ATRIA scores were positively correlated with unfavorable outcomes and could be used to predict unfavorable outcomes in patients who receive EVT.

Stacking ensemble learning model to predict 6-month mortality in ischemic stroke patients.

Patients with acute ischemic stroke can benefit from reperfusion therapy. Nevertheless, there are gray areas where initiation of reperfusion therapy is neither supported nor contraindicated by the current practice guidelines. In these situations, a prediction model for mortality can be beneficial in decision-making. This study aimed to develop a mortality prediction model for acute ischemic stroke patients not receiving reperfusion therapies using a stacking ensemble learning model. The model used an artificial neural network as an ensemble classifier. Seven base classifiers were K-nearest neighbors, support vector machine, extreme gradient boosting, random forest, naive Bayes, artificial neural network, and logistic regression algorithms. From the clinical data in the International Stroke Trial database, we selected a concise set of variables assessable at the presentation. The primary study outcome was all-cause mortality at 6 months. Our stacking ensemble model predicted 6-month mortality with acceptable performance in ischemic stroke patients not receiving reperfusion therapy. The area under the curve of receiver-operating characteristics, accuracy, sensitivity, and specificity of the stacking ensemble classifier on a put-aside validation set were 0.783 (95% confidence interval 0.758-0.808), 71.6% (69.3-74.2), 72.3% (69.2-76.4%), and 70.9% (68.9-74.3%), respectively.

Impact of Renal Function on Short-Term Outcome After Reperfusion Therapy in Patients With Ischemic Stroke.

BACKGROUND: A high and low estimated glomerular filtration rate (eGFR) could affect outcomes after reperfusion therapy for ischemic stroke. This study aimed to determine whether renal function based on eGFR affects mortality risk in patients with ischemic stroke within 6 months following reperfusion therapy. METHODS: This prospective registry-based cohort study included 2266 patients who received reperfusion therapy between January 2000 and September 2019 and were registered in the SECRET (Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy) study or the Yonsei Stroke Cohort. A high and low eGFR were based on the Chronic Kidney Disease Epidemiology Collaboration equation and defined, respectively, as the 5th and 95th percentiles of age- and sex-specific eGFR. Occurrence of death within 6 months was compared among the groups according to their eGFR such as low, normal, or high eGFR. RESULTS: Of the 2266 patients, 2051 (90.5%) had a normal eGFR, 110 (4.9%) a low eGFR, and 105 (4.6%) a high eGFR. Patients with high eGFR were younger or less likely to have hypertension, diabetes, or atrial fibrillation than the other groups. Active cancer was more prevalent in the high-eGFR group. During the 6-month follow-up, there were 24 deaths (22.9%) in the high-eGFR group, 37 (33.6%) in the low-eGFR group, and 237 (11.6%) in the normal-eGFR group. After adjusting for variables with P<0.10 in the univariable analysis, 6-month mortality was independently associated with high eGFR (hazard ratio, 2.22 [95% CI, 1.36-3.62]; P=0.001) and low eGFR (HR, 2.29 [95% CI, 1.41-3.72]; P=0.001). These associations persisted regardless of treatment modality or various baseline characteristics. CONCLUSIONS: High eGFR as well as low eGFR were independently associated with 6-month mortality after reperfusion therapy. Kidney function could be considered a prognostic factor in patients with ischemic stroke after reperfusion therapy.

Lumican, an Exerkine, Protects against Skeletal Muscle Loss.

Exerkines are soluble factors secreted by exercised muscles, mimicking the effects of exercise in various organs, including the muscle itself. Lumican is reportedly secreted from muscles; however, its roles in skeletal muscle remain unknown. Herein, we found that lumican mRNA expression in the extensor digitorum longus was significantly higher in exercised mice than in unloading mice, and lumican stimulated myogenesis in vitro. Additionally, lumican knockdown significantly decreased muscle mass and cross-sectional area (CSA) of the muscle fiber in the gastrocnemius muscle of exercised mice. Lumican upregulated phosphorylation of p38 mitogen-activated protein kinase (MAPK) and a p38 inhibitor near completely blocked lumican-stimulated myogenesis. Inhibitors for integrin α2ß1 and integrin ανß3 also prevented lumican-stimulated myogenesis. Systemic lumican treatment, administered via the tail vein for 4 weeks, significantly increased relative muscle masses by 36.1% in ovariectomized mice. In addition, intramuscular lumican injection into unloaded muscles for 2 weeks significantly increased muscle mass by 8.5%. Both intravenous and intramuscular lumican treatment significantly increased muscle CSA. Our in vitro and in vivo experiments indicate that lumican is a muscle-secreted exerkine that affords protection against muscle loss by activating p38 MAPK via integrin receptors.

Diagnostic and prognostic value of presepsin and procalcitonin in non-infectious organ failure, sepsis, and septic shock: a prospective observational study according to the Sepsis-3 definitions.

BACKGROUND: We investigated the diagnostic and prognostic value of presepsin among patients with organ failure, including sepsis, in accordance with the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). METHODS: This prospective observational study included 420 patients divided into three groups: non-infectious organ failure (n = 142), sepsis (n = 141), and septic shock (n = 137). Optimal cut-off values of presepsin to discriminate between the three groups were evaluated using receiver operating characteristic curve analysis. We determined the optimal cut-off value of presepsin levels to predict mortality associated with sepsis and performed Kaplan-Meier survival curve analysis according to the cut-off value. Cox proportional hazards model was performed to determine the risk factors for 30-day mortality. RESULTS: Presepsin levels were significantly higher in sepsis than in non-infectious organ failure cases (p < 0.001) and significantly higher in patients with septic shock than in those with sepsis (p = 0.002). The optimal cut-off value of the presepsin level to discriminate between sepsis and non-infectious organ failure was 582 pg/mL (p < 0.001) and between sepsis and septic shock was 1285 pg/mL (p < 0.001). The optimal cut-off value of the presepsin level for predicting the 30-day mortality was 821 pg/mL (p = 0.005) for patients with sepsis. Patients with higher presepsin levels (≥ 821 pg/mL) had significantly higher mortality rates than those with lower presepsin levels (< 821 pg/mL) (log-rank test; p = 0.004). In the multivariate Cox proportional hazards model, presepsin could predict the 30-day mortality in sepsis cases (hazard ratio, 1.003; 95% confidence interval 1.001-1.005; p = 0.042). CONCLUSIONS: Presepsin levels could effectively differentiate sepsis from non-infectious organ failure and could help clinicians identify patients with sepsis with poor prognosis. Presepsin was an independent risk factor for 30-day mortality among patients with sepsis and septic shock.

Association between CHADS2, CHA2DS2-VASc, ATRIA, and Essen Stroke Risk Scores and Unsuccessful Recanalization after Endovascular Thrombectomy in Acute Ischemic Stroke Patients.

BACKGROUND: The CHADS2, CHA2DS2-VASc, ATRIA, and Essen scores have been developed for predicting vascular outcomes in stroke patients. We investigated the association between these stroke risk scores and unsuccessful recanalization after endovascular thrombectomy (EVT). METHODS: From the nationwide multicenter registry (Selection Criteria in Endovascular Thrombectomy and Thrombolytic therapy (SECRET)) (Clinicaltrials.gov NCT02964052), we consecutively included 501 patients who underwent EVT. We identified pre-admission stroke risk scores in each included patient. RESULTS: Among 501 patients who underwent EVT, 410 (81.8%) patients achieved successful recanalization (mTICI ≥ 2b). Adjusting for body mass index and p < 0.1 in univariable analysis revealed the association between all stroke risk scores and unsuccessful recanalization (CHADS2 score: odds ratio (OR) 1.551, 95% confidence interval (CI) 1.198-2.009, p = 0.001; CHA2DS2VASc score: OR 1.269, 95% CI 1.080-1.492, p = 0.004; ATRIA score: OR 1.089, 95% CI 1.011-1.174, p = 0.024; and Essen score: OR 1.469, 95% CI 1.167-1.849, p = 0.001). The CHADS2 score had the highest AUC value and differed significantly only from the Essen score (AUC of CHADS2 score; 0.618, 95% CI 0.554-0.681). CONCLUSION: All stroke risk scores were associated with unsuccessful recanalization after EVT. Our study suggests that these stroke risk scores could be used to predict recanalization in stroke patients undergoing EVT.

Outcome in Patients Treated with Intra-arterial thrombectomy: The optiMAL Blood Pressure control (OPTIMAL-BP) Trial.

RATIONALE: Very early stage blood pressure (BP) levels may affect outcome in stroke patients who have successfully undergone recanalization following intra-arterial treatment, but the optimal target of BP management remains uncertain. AIM: We hypothesized that the clinical outcome after intensive BP-lowering is superior to conventional BP control after successful recanalization by intra-arterial treatment. SAMPLE-SIZE ESTIMATES: We aim to randomize 668 patients (334 per arm), 1:1. METHODS AND DESIGN: We initiated a multicenter, prospective, randomized, open-label trial with a blinded end-point assessment (PROBE) design. After successful recanalization (thrombolysis in cerebral infarction score ≥ 2 b), patients with elevated systolic BP level, defined as the mean of two readings ≥ 140 mmHg, will be randomly assigned to the intensive BP-lowering (systolic BP < 140 mm Hg) group or the conventional BP-lowering (systolic BP, 140-180 mm Hg) group. STUDY OUTCOMES: The primary efficacy outcomes are from dichotomized analysis of modified Rankin Scale (mRS) scores at three months (mRS scores: 0-2 vs. 3-6). The primary safety outcomes are symptomatic intracerebral hemorrhage and death within three months. DISCUSSION: The OPTIMAL-BP trial will provide evidence for the effectiveness of active BP control to achieve systolic BP < 140 mmHg during 24 h in patients with successful recanalization after intra-arterial treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04205305.

SLIT3 promotes myogenic differentiation as a novel therapeutic factor against muscle loss.

BACKGROUND: Sarcopenia and osteoporosis frequently co-occur in the elderly and have common pathophysiological determinants. Slit guidance ligand 3 (SLIT3) has been recently discovered as a novel therapeutic factor against osteoporosis, and a SLIT3 fragment containing the second leucine-rich repeat domain (LRRD2) had a therapeutic efficacy against osteoporosis. However, a role of SLIT3 in the skeletal muscle is unknown. METHODS: Skeletal muscle mass, strength, and/or physical activity were evaluated in Slit3-/- , ovariectomized, and aged mice, based on the measurements of muscle weight and grip strength, Kondziella's inverted hanging test, and/or wheel-running test. Skeletal muscles were also histologically evaluated by haematoxylin and eosin staining and/or immunofluorescence. The ovariectomized and aged mice were intravenously injected with recombinant SLIT3 LRRD2 for 4 weeks. C2C12 cells were used to know cellular effects of SLIT3, such as in vitro myogenesis, fusion, cell viability, and proliferation, and also used to evaluate its molecular mechanisms by immunocytochemistry, immunoprecipitation, western blotting, real-time PCR, siRNA transfection, and receptor-ligand binding ELISA. RESULTS: Slit3-deficient mice exhibited decreased skeletal muscle mass, muscle strength, and physical activity. The relative masses of gastrocnemius and soleus were lower in the Slit3-/- mice (0.580 ± 0.039% and 0.033 ± 0.003%, respectively) than those in the WT littermates (0.622 ± 0.043% and 0.038 ± 0.003%, respectively) (all, P < 0.05). Gastrocnemius of Slit3-/- mice showed the reduced number of Type I and Type IIa fibres (all, P < 0.05), but not of Type IIb and Type IIx fibres. SLIT3 activated ß-catenin signalling by promoting its release from M-cadherin, thereby increasing myogenin expression to stimulate myoblast differentiation. In vitro experiments involving ROBO2 expression, knockdown, and interaction with SLIT3 indicated that ROBO2 functions as a SLIT3 receptor to aid myoblast differentiation. SLIT3 LRRD2 dissociated M-cadherin-bound ß-catenin and up-regulated myogenin expression to increase myoblast differentiation, in a manner similar to full-length SLIT3. Systemic treatment with SLIT3 LRRD2 increased skeletal muscle mass in both ovariectomized and aged mice (all, P < 0.05). The relative masses of gastrocnemius and soleus were higher in the treated aged mice (0.548 ± 0.045% and 0.033 ± 0.005%, respectively) than in the untreated aged mice (0.508 ± 0.016% and 0.028 ± 0.003%, respectively) (all, P < 0.05). SLIT3 LRRD2 treatment increased the hanging duration of the aged mice by approximately 1.7-fold (P < 0.05). CONCLUSIONS: SLIT3 plays a sarcoprotective role by activating ß-catenin signalling. SLIT3 LRRD2 can potentially be used as a therapeutic agent against muscle loss.

Percutaneous Left Atrial Appendage Occlusion Yields Favorable Neurological Outcomes in Patients with Non-Valvular Atrial Fibrillation.

BACKGROUND AND OBJECTIVES: Prior studies have shown that stroke patients treated with percutaneous left atrial appendage occlusion (LAAO) for non-valvular atrial fibrillation (NVAF) experience better outcomes than similar patients treated with warfarin. We investigated the impact of percutaneous left atrial appendage closure on post-stroke neurological outcomes in NVAF patients, compared with non-vitamin K antagonist oral anticoagulant (NOAC) therapy. METHODS: Medical records for 1,427 patients in multiple registries and for 1,792 consecutive patients at 6 Korean hospitals were reviewed with respect to LAAO or NOAC treatment. Stroke severity in patients who experienced ischemic stroke or transient ischemic attack after either treatment was assessed with modified Rankin Scale (mRS) scoring at hospital discharge and at 3 and 12 months post-stroke. RESULTS: mRS scores were significantly lower in LAAO patients at 3 (p<0.01) and 12 months (p<0.01) post-stroke, despite no significant differences in scores before the ischemic cerebrovascular event (p=0.22). The occurrences of disabling ischemic stroke in the LAAO and NOAC groups were 36.7% and 44.2% at discharge (p=0.47), 23.3% and 44.2% at 3 months post-stroke (p=0.04), and 13.3% and 43.0% at 12 months post-stroke (p=0.01), respectively. Recovery rates for disabling ischemic stroke at discharge to 12 months post-stroke were significantly higher for LAAO patients (50.0%) than for NOAC patients (5.6%) (p<0.01). CONCLUSIONS: Percutaneous LAAO was associated with more favorable neurological outcomes after ischemic cerebrovascular event than NOAC treatment.

Prediction of Early Recanalization after Intravenous Thrombolysis in Patients with Large-Vessel Occlusion.

BACKGROUND AND PURPOSE: We aimed to develop a model predicting early recanalization after intravenous tissue plasminogen activator (t-PA) treatment in large-vessel occlusion. METHODS: Using data from two different multicenter prospective cohorts, we determined the factors associated with early recanalization immediately after t-PA in stroke patients with large-vessel occlusion, and developed and validated a prediction model for early recanalization. Clot volume was semiautomatically measured on thin-section computed tomography using software, and the degree of collaterals was determined using the Tan score. Follow-up angiographic studies were performed immediately after t-PA treatment to assess early recanalization. RESULTS: Early recanalization, assessed 61.0±44.7 minutes after t-PA bolus, was achieved in 15.5% (15/97) in the derivation cohort and in 10.5% (8/76) in the validation cohort. Clot volume (odds ratio [OR], 0.979; 95% confidence interval [CI], 0.961 to 0.997; P=0.020) and good collaterals (OR, 6.129; 95% CI, 1.592 to 23.594; P=0.008) were significant factors associated with early recanalization. The area under the curve (AUC) of the model including clot volume was 0.819 (95% CI, 0.720 to 0.917) and 0.842 (95% CI, 0.746 to 0.938) in the derivation and validation cohorts, respectively. The AUC improved when good collaterals were added (derivation cohort: AUC, 0.876; 95% CI, 0.802 to 0.950; P=0.164; validation cohort: AUC, 0.949; 95% CI, 0.886 to 1.000; P=0.036). The integrated discrimination improvement also showed significantly improved prediction (0.097; 95% CI, 0.009 to 0.185; P=0.032). CONCLUSIONS: The model using clot volume and collaterals predicted early recanalization after intravenous t-PA and had a high performance. This model may aid in determining the recanalization treatment strategy in stroke patients with large-vessel occlusion.