Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke.

Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.

Integrating network pharmacology and transcriptomic omics reveals that akebia saponin D attenuates neutrophil extracellular traps-induced neuroinflammation via NTSR1/PKAc/PAD4 pathway after intracerebral hemorrhage.

Neutrophils and their production of neutrophil extracellular traps (NETs) significantly contribute to neuroinflammation and brain damage after intracerebral hemorrhage (ICH). Although Akebia saponin D (ASD) demonstrates strong anti-inflammatory activities and blood-brain barrier permeability, its role in regulating NETs formation and neuroinflammation following ICH is uncharted. Our research focused on unraveling the influence of ASD on neuroinflammation mediated by NETs and the mechanisms involved. We found that increased levels of peripheral blood neutrophils post-ICH are correlated with worse prognostic outcomes. Through network pharmacology, we identified ASD as a promising therapeutic target for ICH. ASD administration significantly improved neurobehavioral performance and decreased NETs production in neutrophils. Furthermore, ASD was shown to upregulate the membrane protein NTSR1 and activate the cAMP signaling pathway, confirmed through transcriptome sequencing, western blot, and immunofluorescence. Interestingly, the NTSR1 inhibitor SR48692 significantly nullified ASD's anti-NETs effects and dampened cAMP pathway activation. Mechanistically, suppression of PKAc via H89 negated ASD's anti-NETs effects but did not affect NTSR1. Our study suggests that ASD may reduce NETs formation and neuroinflammation, potentially involving the NTSR1/PKAc/PAD4 pathway post-ICH, underlining the potential of ASD in mitigating neuroinflammation through its anti-NETs properties.

Trained immunity induced by high-salt diet impedes stroke recovery.

A high-salt diet (HSD) elicits sustained sterile inflammation and worsens tissue injury. However, how this occurs after stroke, a leading cause of morbidity and mortality, remains unknown. Here, we report that HSD impairs long-term brain recovery after intracerebral hemorrhage, a severe form of stroke, despite salt withdrawal prior to the injury. Mechanistically, HSD induces innate immune priming and training in hematopoietic stem and progenitor cells (HSPCs) by downregulation of NR4a family and mitochondrial oxidative phosphorylation. This training compromises alternative activation of monocyte-derived macrophages (MDMs) without altering the initial inflammatory responses of the stroke brain. Healthy mice transplanted with bone marrow from HSD-fed mice retain signatures of reduced MDM reparative functions, further confirming a persistent form of innate immune memory that originates in the bone marrow. Loss of NR4a1 in macrophages recapitulates HSD-induced negative impacts on stroke outcomes while gain of NR4a1 enables stroke recovery in HSD animals. Together, we provide the first evidence that links HSD-induced innate immune memory to the acquisition of persistent dysregulated inflammatory responses and unveils NR4a1 as a potential therapeutic target.

Exploring causal effects and potential mediating mechanisms of genetically linked environmental senses with intracerebral hemorrhage.

The occurrence mechanism of intracerebral hemorrhage remains unclear. Several recent studies have highlighted the close relationship between environmental senses and intracerebral hemorrhage, but the mechanisms of causal mediation are inconclusive. We aimed to investigate the causal relationships and potential mechanisms between environmental senses and intracerebral hemorrhage. Multiple Mendelian randomization methods were used to identify a causal relationship between environmental senses and intracerebral hemorrhage. Gut microbiota and brain imaging phenotypes were used to find possible mediators. Enrichment and molecular interaction analyses were used to identify potential mediators and molecular targets. No causal relationship between temperature and visual perception with intracerebral hemorrhage was found, whereas long-term noise was identified as a risk factor for intracerebral hemorrhage (OR 2.95, 95% CI: 1.25 to 6.93, PIVW = 0.01). The gut microbiota belonging to the class Negativicutes and the order Selenomonadales and the brain image-derived phenotypes ICA100 node 54, edge 803, edge 1149, and edge 1323 played mediating roles. "Regulation of signaling and function in synaptic organization" is the primary biological pathway of noise-induced intracerebral hemorrhage, and ARHGAP22 may be the critical gene. This study emphasized the importance of environmental noise in the prevention, disease management, and underlying biological mechanisms of intracerebral hemorrhage.

Genetic analyses identify brain imaging-derived phenotypes associated with the risk of intracerebral hemorrhage.

Previous observational studies have reported associations between brain imaging-derived phenotypes (IDPs) and intracerebral hemorrhage (ICH), but the causality between them remains uncertain. We aimed to investigate the potential causal relationship between IDPs and ICH by a two-sample Mendelian randomization (MR) study. We selected genetic instruments for 363 IDPs from a genome-wide association study (GWASs) based on the UK Biobank (n = 33,224). Summary-level data on ICH was derived from a European-descent GWAS with 1,545 cases and 1,481 controls. Inverse variance weighted MR method was applied in the main analysis to investigate the associations between IDPs and ICH. Reverse MR analyses were performed for significant IDPs to examine the reverse causation for the identified associations. Among the 363 IDPs, isotropic or free water volume fraction (ISOVF) in the anterior limb of the left internal capsule was identified to be associated with the risk of ICH (OR per 1-SD increase, 4.62 [95% CI, 2.18-9.81], P = 6.63 × 10-5). In addition, the reverse MR analysis indicated that ICH had no effect on ISOVF in the anterior limb of the left internal capsule (beta, 0.010 [95% CI, -0.010-0.030], P = 0.33). MR-Egger regression analysis showed no directional pleiotropy for the association between ISOVF and ICH, and sensitivity analyses with different MR models further confirmed these findings. ISOVF in the anterior limb of the left internal capsule might be a potential causal mediator of ICH, which may provide predictive guidance for the prevention of ICH. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.

Plasma Inflammation Markers Linked to Complications and Outcomes after Spontaneous Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) could trigger inflammatory responses. However, the specific role of inflammatory proteins in the pathological mechanism, complications, and prognosis of ICH remains unclear. In this study, we investigated the expression of 92 plasma inflammation-related proteins in patients with ICH (n = 55) and healthy controls (n = 20) using an Olink inflammation panel and discussed the relation to the severity of stroke, clinical complications, 30-day mortality, and 90-day outcomes. Our result showed that six proteins were upregulated in ICH patients compared with healthy controls, while seventy-four proteins were downregulated. In patients with ICH, seven proteins were increased in the severe stroke group compared with the moderate stroke group. In terms of complications, two proteins were downregulated in patients with pneumonia, while nine proteins were upregulated in patients with sepsis. Compared with the survival group, three proteins were upregulated, and one protein was downregulated in the death group. Compared with the good outcome group, eight proteins were upregulated, and four proteins were downregulated in the poor outcome group. In summary, an in-depth exploration of the differential inflammatory factors in the early stages of ICH could deepen our understanding of the pathogenesis of ICH, predict patient prognosis, and explore new treatment strategies.

Twenty Years of Sustained Improvement in Quality of Care and Outcomes for Patients Hospitalized With Stroke or Transient Ischemic Attack: Data From The Get With The Guidelines-Stroke Program.

BACKGROUND: The Get With The Guidelines-Stroke program is a quality improvement initiative designed to enhance adherence to evidence-based stroke care. Since its inception in 2003, over 2800 hospitals in the United States have participated in the program. METHODS: We examined patient characteristics, adherence to performance measures, and in-hospital outcomes in patients hospitalized for acute ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and transient ischemic attack in The Get With The Guidelines-Stroke hospitals from 2003 through 2022. We quantified temporal changes in performance measure adherence and clinical outcomes over time. Performance measure denominators consisted of patients who were eligible, excluding those with contraindications. RESULTS: Over the 20 years of the program, a total of 7837 849 stroke cases (median age 71 years, 51.0% female; 69.2% ischemic strokes, 3.9% SAHs, 11.5% ICHs, and 15.3% TIAs) were entered into the registry. Except for antithrombotics at discharge, in which the baseline performance was >92%, there was sustained improvement in all performance metrics regardless of type of cerebrovascular event (P<0.01 for all). In patients with acute ischemic stroke, large improvements were observed for anticoagulation for atrial fibrillation (55.7% in 2003 to 97.2% in 2022), smoking cessation counseling (44.7%-97.8%), dysphagia screening (53.8%-83.5%), thrombolytic treatment for patients arriving by 3.5 hours, treat by 4.5 hours (15.2%-92.9%), door-to-needle time within 60 minutes (19.0%-75.3%), and endovascular door-to-puncture time within 90 minutes (54.7%-62.8%). Similar improvements were also observed for measures relevant to patients with subarachnoid hemorrhage, intracerebral hemorrhage, and transient ischemic attack. Multivariable analysis showed that there was a sustained increase in odds of receiving each performance measure over time, independent of patient and hospital characteristics for each type of cerebrovascular event. After risk adjustment, there were temporal trends that patients were less likely to be discharged to a skilled nursing facility, and, for ischemic stroke only, more likely to be discharged directly home. CONCLUSIONS: During the first 20 years, Get With The Guidelines-Stroke participation was associated with sustained improvement in evidence-based care and outcomes for patients with stroke and transient ischemic attack in the United States.

Association of Anticoagulant Use With Hemorrhage Location and Etiology in Incident Spontaneous Intracerebral Hemorrhage.

BACKGROUND: It is unknown whether hypertensive microangiopathy or cerebral amyloid angiopathy (CAA) predisposes more to anticoagulant-associated intracerebral hemorrhage (AA-ICH). The purpose of our study was to determine whether AA-ICH is associated with lobar location and probable CAA. METHODS: This was a cross-sectional analysis of patients with first-ever spontaneous ICH admitted to a tertiary hospital in Boston, between 2008 and 2023. Univariable and multivariable logistic regression were used to investigate the association between anticoagulation use and both lobar hemorrhage location and probable CAA on magnetic resonance imaging (MRI) by Boston Criteria 2.0 or computed tomography by Simplified Edinburgh Criteria. RESULTS: A total of 1104 patients (mean [SD] age, 73 [12]; 499 females [45.0%]) were included. Of the 1104 patients, 268 (24.3%) had AA-ICH: 148 (55.2%) with vitamin K antagonists and 107 (39.9%) with direct oral anticoagulants. Brain MRI was performed in 695 (63.0%) patients. The proportion of patients with lobar hemorrhage was not different between those with and without AA-ICH (121/268 [45.1%] versus 424/836 [50.7%]; odds ratio [OR], 0.80 [95% CI, 0.61-1.05]; P=0.113). Patients with AA-ICH were less likely to have probable CAA on MRI (17/146 [11.6%] versus 127/549 [23.1%]; OR, 0.44 [95% CI, 0.25-0.75]; P=0.002) and probable CAA on MRI or computed tomography if MRI not performed (27/268 [10.0%] versus 200/836 [23.9%]; OR, 0.36 [95% CI, 0.23-0.55]; P<0.001). Among patients with AA-ICH, there were no differences in the proportion with lobar hemorrhage (63/148 [42.6%] versus 46/107 [43.0%]; OR, 1.02 [95% CI, 0.62-1.68]; P=0.946) or probable CAA on MRI (10/72 [13.9%] versus 7/69 [10.1%]; OR, 0.70 [95% CI, 0.25-1.96]; P=0.495) between vitamin K antagonists and direct oral anticoagulant users. CONCLUSIONS: AA-ICH was not associated with lobar hemorrhage location but was associated with reduced odds of probable CAA. These results suggest that hypertensive microangiopathy may predispose more toward incident AA-ICH than CAA and emphasize the importance of blood pressure control among anticoagulant users. These findings require replication in additional cohorts.

The proteomic signature of circulating extracellular vesicles following intracerebral hemorrhage: Novel insights into mechanisms underlying recovery.

Circulating extracellular vesicles (EVs) can participate in innate repair processes triggered after intracerebral hemorrhage (ICH). We aimed to describe changes in the proteomic profile of circulating EVs between the acute and subacute phases of ICH and to compare the findings depending on outcomes, as an approach to unraveling such repair mechanisms. This was a prospective observational study including patients with non-traumatic supratentorial ICH. Exclusion criteria were previous disability, signs of herniation on baseline computed tomography, or limited life expectancy. EVs were isolated from blood samples at 24 h and 7 days after symptom onset. After 6-months' follow-up, patients were dichotomized into poor and good outcomes, defining good as an improvement of >10 points or > 50 % on the National Institutes of Health Stroke Scale and a modified Rankin Scale of 0-2. The protein cargo was analyzed by quantitative mass spectrometry and compared according to outcomes. Forty-four patients completed follow-up, 16 (35.5 %) having good outcomes. We identified 1321 proteins in EVs, 37 with differential abundance. In patients with good outcomes, proteins related to stress response (DERA, VNN2, TOMM34) and angiogenesis (RHG01) had increased abundance at 7 days. EVs from patients with poor outcomes showed higher levels of acute-phase reactants (CRP, SAA2) at 7 days compared with 24 h. In conclusion, the protein content of circulating EVs in patients with ICH changes over time, the changes varying depending on the clinical outcome, with greater abundance of proteins potentially involved in the repair processes of patients with good outcomes.

Cathepsin B as a key regulator of ferroptosis in microglia following intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a subtype of stroke marked by elevated mortality and disability rates. Recently, mounting evidence suggests a significant role of ferroptosis in the pathogenesis of ICH. Through a combination of bioinformatics analysis and basic experiments, our goal is to identify the primary cell types and key molecules implicated in ferroptosis post-ICH. This aims to propel the advancement of ferroptosis research, offering potential therapeutic targets for ICH treatment. Our study reveals pronounced ferroptosis in microglia and identifies the target gene, cathepsin B (Ctsb), by analyzing differentially expressed genes following ICH. Ctsb, a cysteine protease primarily located in lysosomes, becomes a focal point in our investigation. Utilizing in vitro and in vivo models, we explore the correlation between Ctsb and ferroptosis in microglia post-ICH. Results demonstrate that ICH and hemin-induced ferroptosis in microglia coincide with elevated levels and activity of Ctsb protein. Effective alleviation of ferroptosis in microglia after ICH is achieved through the inhibition of Ctsb protease activity and protein levels using inhibitors and shRNA. Additionally, a notable increase in m6A methylation levels of Ctsb mRNA post-ICH is observed, suggesting a pivotal role of m6A methylation in regulating Ctsb translation. These research insights deepen our comprehension of the molecular pathways involved in ferroptosis after ICH, underscoring the potential of Ctsb as a promising target for mitigating brain damage resulting from ICH.

Signature and function of plasma exosome-derived circular RNAs in patients with hypertensive intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is one of the major causes of death and disability, and hypertensive ICH (HICH) is the most common type of ICH. Currently, the outcomes of HICH patients remain poor after treatment, and early prognosis prediction of HICH is important. However, there are limited effective clinical treatments and biomarkers for HICH patients. Although circRNA has been widely studied in diseases, the role of plasma exosomal circRNAs in HICH remains unknown. The present study was conducted to investigate the characteristics and function of plasma exosomal circRNAs in six HICH patients using circRNA microarray and bioinformatics analysis. The results showed that there were 499 differentially expressed exosomal circRNAs between the HICH patients and control subjects. According to GO annotation and KEGG pathway analyses, the targets regulated by differentially expressed exosomal circRNAs were tightly related to the development of HICH via nerve/neuronal growth, neuroinflammation and endothelial homeostasis. And the differentially expressed exosomal circRNAs could mainly bind to four RNA-binding proteins (EIF4A3, FMRP, AGO2 and HUR). Moreover, of differentially expressed exosomal circRNAs, hsa_circ_00054843, hsa_circ_0010493 and hsa_circ_00090516 were significantly associated with bleeding volume and Glasgow Coma Scale score of the subjects. Our findings firstly revealed that the plasma exosomal circRNAs are significantly involved in the progression of HICH, and could be potent biomarkers for HICH. This provides the basis for further research to pinpoint the best biomarkers and illustrate the mechanism of exosomal circRNAs in HICH.

Minimally invasive surgeries for spontaneous hypertensive intracerebral hemorrhage (MISICH): a multicenter randomized controlled trial.

BACKGROUND: Intracerebral hemorrhage (ICH) is a common stroke type with high morbidity and mortality. There are mainly three surgical methods for treating ICH. Unfortunately, thus far, no specific surgical method has been proven to be the most effective. We carried out this study to investigate whether minimally invasive surgeries with endoscopic surgery or stereotactic aspiration (frameless navigated aspiration) will improve functional outcomes in patients with supratentorial ICH compared with small-bone flap craniotomy. METHODS: In this parallel-group multicenter randomized controlled trial conducted at 16 centers, patients with supratentorial hypertensive ICH were randomized to receive endoscopic surgery, stereotactic aspiration, or craniotomy at a 1:1:1 ratio from July 2016 to June 2022. The follow-up duration was 6 months. Patients were randomized to receive endoscopic evacuation, stereotactic aspiration, or small-bone flap craniotomy. The primary outcome was favorable functional outcome, defined as the proportion of patients who achieved a modified Rankin scale (mRS) score of 0-2 at the 6-month follow-up. RESULTS: A total of 733 patients were randomly allocated to three groups: 243 to the endoscopy group, 247 to the aspiration group, and 243 to the craniotomy group. Finally, 721 patients (239 in the endoscopy group, 246 in the aspiration group, and 236 in the craniotomy group) received treatment and were included in the intention-to-treat analysis. Primary efficacy analysis revealed that 73 of 219 (33.3%) in the endoscopy group, 72 of 220 (32.7%) in the aspiration group, and 47 of 212 (22.2%) in the craniotomy group achieved favorable functional outcome at the 6-month follow-up (P = .017). We got similar results in subgroup analysis of deep hemorrhages, while in lobar hemorrhages the prognostic outcome was similar among three groups. Old age, deep hematoma location, large hematoma volume, low preoperative GCS score, craniotomy, and intracranial infection were associated with greater odds of unfavorable outcomes. The mean hospitalization expenses were ¥92,420 in the endoscopy group, ¥77,351 in the aspiration group, and ¥100,947 in the craniotomy group (P = .000). CONCLUSIONS: Compared with small bone flap craniotomy, endoscopic surgery and stereotactic aspiration improved the long-term outcome of hypertensive ICH, especially deep hemorrhages. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02811614.

Mas receptor activation facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating neurological disease causing severe sensorimotor dysfunction and cognitive decline, yet there is no effective treatment strategy to alleviate outcomes of these patients. The Mas axis-mediated neuroprotection is involved in the pathology of various neurological diseases, however, the role of the Mas receptor in the setting of ICH remains to be elucidated. METHODS: C57BL/6 mice were used to establish the ICH model by injection of collagenase into mice striatum. The Mas receptor agonist AVE0991 was administered intranasally (0.9 mg/kg) after ICH. Using a combination of behavioral tests, Western blots, immunofluorescence staining, hematoma volume, brain edema, quantitative-PCR, TUNEL staining, Fluoro-Jade C staining, Nissl staining, and pharmacological methods, we examined the impact of intranasal application of AVE0991 on hematoma absorption and neurological outcomes following ICH and investigated the underlying mechanism. RESULTS: Mas receptor was found to be significantly expressed in activated microglia/macrophages, and the peak expression of Mas receptor in microglia/macrophages was observed at approximately 3-5 days, followed by a subsequent decline. Activation of Mas by AVE0991 post-treatment promoted hematoma absorption, reduced brain edema, and improved both short- and long-term neurological functions in ICH mice. Moreover, AVE0991 treatment effectively attenuated neuronal apoptosis, inhibited neutrophil infiltration, and reduced the release of inflammatory cytokines in perihematomal areas after ICH. Mechanistically, AVE0991 post-treatment significantly promoted the transformation of microglia/macrophages towards an anti-inflammatory, phagocytic, and reparative phenotype, and this functional phenotypic transition of microglia/macrophages by Mas activation was abolished by both Mas inhibitor A779 and Nrf2 inhibitor ML385. Furthermore, hematoma clearance and neuroprotective effects of AVE0991 treatment were reversed after microglia depletion in ICH. CONCLUSIONS: Mas activation can promote hematoma absorption, ameliorate neurological deficits, alleviate neuron apoptosis, reduced neuroinflammation, and regulate the function and phenotype of microglia/macrophages via Akt/Nrf2 signaling pathway after ICH. Thus, intranasal application of Mas agonist ACE0991 may provide promising strategy for clinical treatment of ICH patients.

Single-cell RNA sequencing reveals the evolution of the immune landscape during perihematomal edema progression after intracerebral hemorrhage.

BACKGROUND: Perihematomal edema (PHE) after post-intracerebral hemorrhage (ICH) has complex pathophysiological mechanisms that are poorly understood. The complicated immune response in the post-ICH brain constitutes a crucial component of PHE pathophysiology. In this study, we aimed to characterize the transcriptional profiles of immune cell populations in human PHE tissue and explore the microscopic differences between different types of immune cells. METHODS: 9 patients with basal ganglia intracerebral hemorrhage (hematoma volume 50-100 ml) were enrolled in this study. A multi-stage profile was developed, comprising Group1 (n = 3, 0-6 h post-ICH, G1), Group2 (n = 3, 6-24 h post-ICH, G2), and Group3 (n = 3, 24-48 h post-ICH, G3). A minimal quantity of edematous tissue surrounding the hematoma was preserved during hematoma evacuation. Single cell RNA sequencing (scRNA-seq) was used to map immune cell populations within comprehensively resected PHE samples collected from patients at different stages after ICH. RESULTS: We established, for the first time, a comprehensive landscape of diverse immune cell populations in human PHE tissue at a single-cell level. Our study identified 12 microglia subsets and 5 neutrophil subsets in human PHE tissue. What's more, we discovered that the secreted phosphoprotein-1 (SPP1) pathway served as the basis for self-communication between microglia subclusters during the progression of PHE. Additionally, we traced the trajectory branches of different neutrophil subtypes. Finally, we also demonstrated that microglia-produced osteopontin (OPN) could regulate the immune environment in PHE tissue by interacting with CD44-positive cells. CONCLUSIONS: As a result of our research, we have gained valuable insight into the immune-microenvironment within PHE tissue, which could potentially be used to develop novel treatment modalities for ICH.

Extracellular vesicle encapsulated Homer1a as novel nanotherapeutics against intracerebral hemorrhage in a mouse model.

Homer1a and A2 astrocytes are involved in the regulation of inflammation induced by intracerebral hemorrhage (ICH). However, there is no anticipated treatment strategy based on the anti-inflammatory effect of Homer1a and A2 astrocytes. Here, we successfully induced A2 astrocytes in vitro, and then we report an efficient method to prepare Homer1a+ EVs derived from A2 astrocytes which making it more stable, safe, and targetable to injured neurons. Homer1a+ EVs promotes the conversion of A1 to A2 astrocytes in ICH mice. Homer1a+ EVs inhibits activation and nuclear translocation of NF-κB, thereby regulating transcription of IL-17A in neurons. Homer1a+ EVs inhibits the RAGE/NF-κB/IL-17 signaling pathway and the binding ability of IL-17A: IL17-AR and RAGE: DIAPH1. In addition, Homer1a+ EVs ameliorates the pathology, behavior, and survival rate in GFAPCreHomer1fl/-Homer1a± and NestinCreRAGEfl/fl ICH mice. Our study provides a novel insight and potential for the clinical translation of Homer1a+ EVs in the treatment of ICH.

Development and validation of a machine learning-based predictive model for assessing the 90-day prognostic outcome of patients with spontaneous intracerebral hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (sICH) is associated with significant mortality and morbidity. Predicting the prognosis of patients with sICH remains an important issue, which significantly affects treatment decisions. Utilizing readily available clinical parameters to anticipate the unfavorable prognosis of sICH patients holds notable clinical significance. This study employs five machine learning algorithms to establish a practical platform for the prediction of short-term prognostic outcomes in individuals afflicted with sICH. METHODS: Within the framework of this retrospective analysis, the model underwent training utilizing data gleaned from 413 cases from the training center, with subsequent validation employing data from external validation center. Comprehensive clinical information, laboratory analysis results, and imaging features pertaining to sICH patients were harnessed as training features for machine learning. We developed and validated the model efficacy using all the selected features of the patients using five models: Support Vector Machine (SVM), Logistic Regression (LR), Random Forest (RF), XGboost and LightGBM, respectively. The process of Recursive Feature Elimination (RFE) was executed for optimal feature screening. An internal five-fold cross-validation was employed to pinpoint the most suitable hyperparameters for the model, while an external five-fold cross-validation was implemented to discern the machine learning model demonstrating the superior average performance. Finally, the machine learning model with the best average performance is selected as our final model while using it for external validation. Evaluation of the machine learning model's performance was comprehensively conducted through the utilization of the ROC curve, accuracy, and other relevant indicators. The SHAP diagram was utilized to elucidate the variable importance within the model, culminating in the amalgamation of the above metrics to discern the most succinct features and establish a practical prognostic prediction platform. RESULTS: A total of 413 patients with sICH patients were collected in the training center, of which 180 were patients with poor prognosis. A total of 74 patients with sICH were collected in the external validation center, of which 26 were patients with poor prognosis. Within the training set, the test set AUC values for SVM, LR, RF, XGBoost, and LightGBM models were recorded as 0.87, 0.896, 0.916, 0.885, and 0.912, respectively. The best average performance of the machine learning models in the training set was the RF model (average AUC: 0.906 ± 0.029, P < 0.01). The model still maintains a good performance in the external validation center, with an AUC of 0.817 (95% CI 0.705-0.928). Pertaining to feature importance for short-term prognostic attributes of sICH patients, the NIHSS score reigned supreme, succeeded by AST, Age, white blood cell, and hematoma volume, among others. In culmination, guided by the RF model's variable importance weight and the model's ROC curve insights, the NIHSS score, AST, Age, white blood cell, and hematoma volume were integrated to forge a short-term prognostic prediction platform tailored for sICH patients. CONCLUSION: We constructed a prediction model based on the results of the RF model incorporating five clinically accessible predictors with reliable predictive efficacy for the short-term prognosis of sICH patients. Meanwhile, the performance of the external validation set was also more stable, which can be used for accurate prediction of short-term prognosis of sICH patients.

3D biological scaffold delivers Bergenin to reduce neuroinflammation in rats with cerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a severe form of stroke characterized by high incidence and mortality rates. Currently, there is a significant lack of effective treatments aimed at improving clinical outcomes. Our research team has developed a three-dimensional (3D) biological scaffold that incorporates Bergenin, allowing for the sustained release of the compound. METHODS: This 3D biological scaffold was fabricated using a combination of photoinitiator, GEMA, silk fibroin, and decellularized brain matrix (dECM) to encapsulate Bergenin through advanced 3D bioprinting techniques. The kinetics of drug release were evaluated through both in vivo and in vitro studies. A cerebral hemorrhage model was established, and a 3D biological scaffold containing Bergenin was transplanted in situ. Levels of inflammatory response, oxidative stress, and apoptosis were quantified. The neurological function of rats with cerebral hemorrhage was assessed on days 1, 3, and 5 using the turning test, forelimb placement test, Longa score, and Bederson score. RESULTS: The 3D biological scaffold incorporating Bergenin significantly enhances the maintenance of drug concentration in the bloodstream, leading to a marked reduction in inflammatory markers such as IL-6, iNOS, and COX-2 levels in a cerebral hemorrhage model, primarily through the inhibition of the NF-κB pathway. Additionally, the scaffold effectively reduces the expression of hypoxia-inducible factor 1-alpha (HIF-1α) in primary cultured astrocytes, which in turn decreases the production of reactive oxygen species (ROS) and inhibits IL-6 production induced by hemin. Subsequent experiments reveal that the 3D biological scaffold containing Bergenin promotes the activation of the Nrf-2/HO-1 signaling pathway, both in vivo and in vitro, thereby preventing cell death. Moreover, the application of this 3D biological scaffold has been demonstrated to improve drug retention in the bloodstream. CONCLUSION: This strategy effectively mitigates inflammation, oxidative stress, and cell death in rats with cerebral hemorrhage by inhibiting the NF-κB pathway while concurrently activating the Nrf-2/HO-1 pathway.

Circ-AGTPBP1 promotes white matter injury through miR-140-3p/Pcdh17 axis role of Circ-AGTPBP1 in white matter injury.

White matter injury (WMI) resulting from intracerebral hemorrhage (ICH) is closely associated with adverse prognoses in ICH patients. Although Circ-AGTPBP1 has been reported to exhibit high expression in the serum of premature infants with WMI, its effects and mechanisms in ICH-induced WMI remain unclear. This study aimed to investigate the role of circ-AGTPBP1 in white matter injury after intracerebral hemorrhage. An intracerebral hemorrhage rat model was established by injecting autologous blood into rat left ventricles and circ-AGTPBP1 was knocked down at the ICH site using recombinant adeno-associated virus, AAV2/9. Magnetic resonance imaging (MRI) and gait analysis were conducted to assess long-term neurobehavioral effects. Primary oligodendrocyte progenitor cells (OPCs) were isolated from rats and overexpressed with circ-AGTPBP1. Downstream targets of circ-AGTPBP1 in OPCs were investigated using CircInteractome, qPCR, FISH analysis, and miRDB network. Luciferase gene assay was utilized to explore the relationship between miR-140-3p and Pcdh17 in OPCs and HEK-293T cells. Finally, CCK-8 assay, EdU staining, and flow cytometry were employed to evaluate the effects of mi-RNA-140-3p inhibitor or silencing of sh-pcd17 on the viability, proliferation, and apoptosis of OPCs. Low expression of circ-AGTPBP1 alleviates white matter injury and improves neurological functions in rats after intracerebral hemorrhage. Conversely, overexpression of circ-AGTPBP1 reduces the proliferative and migrative potential of oligodendrocyte progenitor cells and promotes apoptosis. CircInteractome web tool and qPCR confirmed that circ-AGTPBP1 binds with miR-140-3p in OPCs. Additionally, miRDB network predicted Pcdh17 as a downstream target of miR-140-3p. Moreover, pcdh17 expression was increased in the brain tissue of rats with intracerebral-induced white matter injury. Furthermore, inhibiting miR-140-3p suppressed the proliferation and migration of OPCs and facilitated apoptosis through Pcdh17. Circ-AGTPBP1 promotes white matter injury through modulating the miR-140-3p/Pcdh17 axis. The study provides a new direction for developing therapeutic strategies for white matter injury.

Predictors of extubation failure and prolonged mechanical ventilation among patients with intracerebral hemorrhage after surgery.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a condition associated with high mortality and morbidity. Survivors may require prolonged intubation with mechanical ventilation (MV). The aim of this study was to analyze the predictors of extubation failure and prolonged MV in patients who undergo surgical evacuation. METHODS: This retrospective study was conducted on adult patients with ICH who underwent MV for at least 48 h and survived > 14 days after surgery. The demographics, clinical characteristics, laboratory tests, and Glasgow Coma Scale score were analyzed. RESULTS: A total of 134 patients with ICH were included in the study. The average age of the patients was 60.34 ± 15.59 years, and 79.9% (n = 107) were extubated after satisfying the weaning parameters. Extubation failure occurred in 11.2% (n = 12) and prolonged MV in 48.5% (n = 65) patients. Multivariable regression analysis revealed that a white blood cell count > 10,000/mm3 at the time of extubation was an independent predictor of reintubation. Meanwhile, age and initial Glasgow Coma Scale scores were predictors of prolonged MV. CONCLUSIONS: This study provided the first comprehensive characterization and analysis of the predictors of extubation failure and prolonged MV in patients with ICH after surgery. Knowledge of potential predictors is essential to improve the strategies for early initiation of adequate treatment and prognosis assessment in the early stages of the disease.

Diverging Trends in Survival and Functional Outcome between Males and Females after Intracerebral Hemorrhage.

BACKGROUND: Compared to ischemic stroke, sex differences in patient outcomes following intracerebral hemorrhage (ICH) are underreported. We aimed to determine sex differences in mortality and functional outcomes in a large, unselected Swedish cohort. METHODS: In this observational study, data on 22,789 patients with spontaneous ICH registered in the Swedish Stroke Register between 2012 and 2019 were used to compare sex differences in 90-day mortality and functional outcome using multivariable Cox and logistic regression analyses, adjusting for relevant confounders. Multiple imputation was used to impute missing data. RESULTS: The crude 90-day mortality rate was 36.7% in females (3,820/10,405) and 31.7% in males (3,929/12,384) (female hazard ratio [HR] 1.20 95% confidence interval [CI]: 1.15-1.25). In multivariable analysis, the HR for 90-day mortality following ICH in females was 0.89 (95% CI: 0.85-0.94). Age was an important driving factor for the effect of sex on mortality. After adjustment for age, vascular risk factors, and stroke severity, the 90-day functional outcome in pre-stroke independent patients was worse in females compared to males (odds ratio: 1.27 95% CI: 1.16-1.40). CONCLUSION: In this large observational study, despite lower 90-day mortality, the female sex was independently associated with a worse functional outcome compared to males after ICH, even after adjusting for significant covariates. These diverging trends have not been previously reported for ICH. Given the observational design, our findings should be interpreted with caution, thus further external validation is warranted.