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Traumatic brain injury (TBI) exhibits high prevalence and mortality, but current treatments remain suboptimal. Traditional Chinese medicine (TCM) has long been effectively used for TBI intervention. Moreover, the recently discovered iron-dependent cell death pathway, known as ferroptosis, characterized by lipid peroxidation, as a key target in TCM-based treatments for TBI. This review provides a comprehensive overview of the latest advancements in TCM strategies targeting ferroptosis in TBI therapy, covering natural product monomers, classic formulas, and acupuncture/moxibustion. The review also addresses current challenges and outlines future research directions to further advance the development and application of TBI management strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: To assess the frequency of lymphocyte subsets and other laboratory indicators in paired cerebrospinal fluid (CSF) and peripheral blood (PB) samples from critically ill patients with intracerebral hemorrhage (ICH) who developed systemic inflammatory response syndrome (SIRS) following surgery., Introduction: Neuroinflammation and systemic inflammatory responses significantly contribute to secondary brain injury following ICH. Post-surgery SIRS is known to worsen clinical outcomes in ICH patients; however, the immune response in the CSF and PB has not been fully characterized. Understanding immunological changes in ICH patients with SIRS could lead to improved clinical management and prognostic outcomes., Methods: This study involved a retrospective analysis of data from patients with ICH who underwent surgery in the Neurological Intensive Care Unit (NICU) of Baoding No. 1 Hospital, Hebei Province, China, between January and July 2022. Patients were divided into SIRS and non-SIRS groups based on the clinical criteria. Demographic, clinical, and laboratory data, including lymphocyte subsets in CSF and PB, were collected and analyzed. This study compared lymphocyte subsets and other inflammatory markers between the SIRS and non-SIRS groups., Results: Patients with SIRS demonstrated higher systolic blood pressure (SBP) at admission, worse 90-day prognoses, elevated inflammatory markers, increased levels of complement proteins C3 and C4, and lower levels of immunoglobulin G (IgG) compared to patients without SIRS. Between 3-6 days post-surgery, SIRS patients showed higher percentages of CD3+T cells, CD4+T cells, and CD4+/CD8+ ratios in the CSF than non-SIRS patients. CD3+T cell percentages in the CSF were consistently higher than those in the PB and were independent of PB levels. In contrast, CD3-CD16+CD56+ natural killer (NK) cell percentages were lower in patients with SIRS. No significant differences in PB lymphocyte subsets were found between the two groups. A high CSF CD3+T cell percentage (≥85.68 %) was identified as the strongest predictor of critical ICH with SIRS after surgery, with an appropriate use criterion (AUC) of 0.7742, sensitivity of 77.42 %, specificity of 76.19 %, and 95 % CI of 0.6655-0.8829 (P < 0.0001)., Conclusion: Elevated levels of CD3+T lymphocytes in CSF are strongly associated with an increased risk of severe cerebral hemorrhage and SIRS following surgery. These findings suggest that monitoring CSF immune markers, particularly CD3+T lymphocytes, could serve as valuable predictors for the development of SIRS in critically ill ICH patients and inform post-surgical treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Opium use disorder is a significant health problem in our country, leading to a considerable number of health issues. Opium has several detrimental effects on its consumers. However, the effect of Opium use disorder on intracerebral hemorrhage (ICH) has not been evaluated. This study aims to evaluate the relationship between Opium use disorder and ICH., Methods: In this case-control study, 402 patients with ICH and 404 patients without ICH enrolled. Opium use disorder, other vascular risk factors including diabetes mellitus, hypertension, hyperlipidemia, and tobacco smoking was compared between these groups. Patients with ICH were divided into two groups; first group are patients with history of Opioid Use Disorder and second group are those patients without Opioid Use Disorder. ICH features including clinical and imaging characteristics and prognostic findings were compared between patients with and without Opium use disorder., Results: This case-control study of 806 participants found that hypertension (OR = 6.84, 95% CI: 5.03-9.34, p -value: <0.001), Opium use disorder (OR = 4.23, 95% CI: 2.42-7.35, p -value: <0.001) and tobacco smoking (OR = 1.47, 95% CI: 1.01-2.16, p -value: 0.049) had a higher risk of ICH. Opium-addicted subjects had higher ICH scores (2.61 ± 1.27 vs. 2.11 ± 1.29, p -value: 0.005), were more likely to have infratentorial hemorrhage (22% vs. 12%, OR = 2.13, 95% CI: 1.06-4.28, p -value: 0.038), more likely to be intubated (66% vs. 54%, OR = 1.79, 95% CI: 0.98-3.27, p -value = 0.041) and had lower GCS scores (9.58 ± 3.60 vs. 8.25 ± 3.88, p -value: 0.01). The effect of Opium use disorder independently on ICH was also shown in logistic regression (adjusted OR = 3.15, p -value = 0.001)., Conclusion: This study is the first to evaluate the effect of Opium use disorder on ICH, identifying Opium use disorder as a new potential risk factor for ICH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Saadatnia, Norouzi, Najafi, Gol Parvar, Najafian, Tabatabei, Foroughi, Esteki and Khorvash.)

Intracerebral hemorrhage (ICH) is a major health problem. It is one of the most common types of stroke and results in mortality in approximately half of patients. More than half of the fatalities occur in the first 2 days. In addition to the mass effect after ICH hemorrhage, complex pathophysiological mechanisms such as intracranial vessel vasospasm, microthrombosis, and inflammatory immune reaction also increase brain damage. Both resident (including microglia and astrocytes) and circulating immune cells (including neutrophils, macrophages, and lymphocytes) involved in the inflammatory process. The inflammatory response is especially harmful in the acute phase due to harmful substances secreted by infiltrating immune cells. The inflammatory response also has beneficial effects, especially in the later stages. Their role in pathophysiology makes immune cells important therapeutic targets. General immunosuppressive approaches and depleting cell groups such as neutrophils or keeping them away from the lesion site may not be sufficient to prevent poor outcomes after ICH. This is most likely because they suppress anti-inflammatory activities and pro-inflammatory effects. Instead, directing immune cells to the beneficial subpopulation seems like a more rational solution. The pro-inflammatory N1 subpopulation of neutrophils damages the tissue surrounding ICH. In contrast, the N2 subpopulation is associated with anti-inflammatory reactions and tissue repair. Studies show that when neutrophils are polarized toward the N2 subpopulation, clinical outcomes improve and the volume of the infarct decreases. However, more research is still needed. This study aims to evaluate the role of neutrophils as immunotherapeutic targets in ICH in light of current knowledge., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

The COVID-19 (coronavirus disease) pandemic had a severe impact on public health worldwide. A rare but serious complication after administration of adenoviral vaccines against SARS-CoV-2 (AstraZeneca-Oxford and Johnson & Johnson) is vaccine-induced immune thrombotic thrombocytopenia and thrombosis (VITT), which can lead to serious complications such as cerebral venous sinus thrombosis (CVST). CVST itself can cause subarachnoid hemorrhage (SAH) and/or intracerebral hemorrhage (ICH), leading to high mortality due to herniation of brain parenchyma. In those patients, an emergent decompressive hemicraniectomy (DC) is regularly performed. Herein, the authors want to focus on the patients who survive DC following VITT-associated CVST and shed light on the neurosurgical considerations in those patients. We herein propose a treatment algorithm regarding the timing and the perioperative management of cranioplasty. We describe an exemplary case highlighting that special circumstances may result in a more urgent need for autologous cranioplasty than usual, based on individual risk assessment.

Intracerebral hemorrhage (ICH) is the cerebrovascular disease with the highest disability and mortality rates, causing severe damage to the health of patients and imposing a significant socioeconomic burden. Aging stands as a foremost risk factor for ICH, with a significant escalation in ICH incidence within the elderly demographic, highlighting a close association between ICH and aging. In recent years, with the acceleration of the "aging society" trend, exploring the intricate relationship between aging and ICH has become increasingly urgent and worthy of in-depth attention. We have summarized the characteristics of ICH in the elderly, reviewing how aging influences the onset and development of ICH by examining its etiology and the mechanisms of damage via ICH. Additionally, we explored the potential impacts of ICH on accelerated aging, including its effects on cognitive abilities, quality of life, and lifespan. This review aims to reveal the connection between aging and ICH, providing new ideas and insights for future ICH research.

Background: Yi-Qi-Huo-Xue Decoction (YQHXD), a traditional Chinese medicine formula, has demonstrated efficacy in the clinical treatment of intracerebral hemorrhage (ICH) for over a decade. Nevertheless, the precise pharmacotherapeutic compounds of YQHXD capable of penetrating into cerebral tissue and the pharmacological underpinnings of YQHXD remain ambiguous., Methods: The active components of YQHXD in rat brains was analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. The potential targets, pathways and biological progresses of YQHXD ameliorating ICH induced injury was predicted by network pharmacology. Moreover, collagenase-induced ICH rat model, primary cortex neurons exposed to hemin and molecular docking were applied to validate the molecular mechanisms of YQHXD., Results: Eleven active components of YQHXD were identified within the brains. Employing the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, our investigation concentrated on the roles of autophagy and the BDNF/TrkB signaling pathway in the pharmacological context. The pharmacological results revealed that YQHXD alleviated neurological dysfunction, brain water content, brain swelling, and pathological injury caused by ICH. Meanwhile, YQHXD inhibited autophagy influx and autophagosome in vivo, and regulated cortex neuronal autophagy and TrkB/BDNF pathway both in vivo and in vitro. Subsequently, N-acetyl serotonin (NAS), a selective TrkB agonist, was employed to corroborate the significance of the BDNF/TrkB pathway in this process. The combination of NAS and YQHXD did not further enhance the protective efficacy of YQHXD in ICH rats. Additionally, outcomes of molecular docking analysis revealed that nine compounds of YQHXD exhibited potential regulatory effects on TrkB., Conclusions: Ipsilateral neuronal autophagy and BDNF/TrkB pathway were activated 72 h after ICH. YQHXD effectively resisted injury induced by ICH, which was related with suppression of ipsilateral neuronal autophagy via BDNF/TrkB pathway. This study provides novel insights into the therapeutic mechanisms of traditional Chinese medicine in the context of ICH treatment., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objective: The role of MMP-2 in patients with ICH is controversial and the impact of plasma MMP-2 level on clinical outcome is still unclear., Materials and Methods: In this study, the peripheral venous blood was acquired from 93 patients with ICH and 88 healthy controls within 24 h of hospitalization and at enrollment. We retrospectively investigated plasma MMP-2 levels of patients and healthy controls. The edema volume, the NIHSS score, the GCS score, and mRS were used to assess and quantify neurological deficit following ICH. Logistic regression analysis was configured to determine the independent relation of plasma MMP-2 levels with clinical outcomes. In addition, the plasma MMP-14 levels and complement C4 level were tested to explore the relationship with plasma MMP-2 level., Results: There was a significant reduction of plasma MMP-2 levels in ICH patients than that in healthy controls (38.02 ± 1.71 vs. 54.03 ± 2.15, p  < 0.0001), and MMP-2 is negatively correlated with the edema volume ( r  = -0.2187, p  < 0.05), NIHSS score ( r  = -0.2194, p  < 0.05), blood leucocyte count ( r  = -0.2549, p  = 0.012), and complement C4 level ( r  = -0.2723, p  = 0.005). There is positive correlation between MMP-2 level and GCS score ( r  = 0.2451, p  = 0.01) and MMP-14 level ( r  = 0.7013, p  = 0.005). The multivariate analysis revealed that reduced plasma MMP-2 level is associated with elevated edema volume (OR = 0.2604, 95% CI [0.07 to 0.84], p  = 0.02)., Conclusion: The plasma MMP-2 level in patients with ICH is significantly lower than that of healthy controls, and plasma MMP-2 level may be a prognostic factor. Plasma MMP-2 levels are correlated with the clinical outcomes of patients and negatively correlated with blood leucocyte count and complement C4 level in patients with ICH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yu, Peng, Chen, Li, Yang, Wu, Zhang and Wu.)

Objective: To study the prevalence of cognitive impairment in survivors of intracerebral hemorrhage (ICH)., Methods: Survivors of spontaneous ICH were followed up in the neurology outpatient department when they reported for follow-up after 6 months. Neuroimaging records at the onset and at follow-up visits are studied for the location of ICH, volume of ICH, intraventricular extension, and hydrocephalus. The volume of ICH is calculated by ABC/2 method on a CT scan. All patients underwent cognitive assessment with Addenbrooke's cognitive examination ACE III and were categorized as patients having cognitive impairment (or) no cognitive impairment., Results: A total of 120 patients were studied, out of which 77 (64%) are males and 43 (36%) are females with age groups ranging from 26 to 75 years. In the study population, the mean age was found to be 62.3 years. Specifically, the mean age for males was 56.9 years, while for females it was 63.4 years. Cognitive impairment was noted in 34 of 120 patients (28%) during 6 to 12 months of examination, of which 11 of 19 were in lobar location, 21 of 94 were in sub-cortical location, and 2 of 7 were in infratentorial location., Conclusion: It was found that 28% of survivors of ICH were cognitively impaired. Hence, it is essential to assess cognition in post-ICH patients during follow-up, so that suitable adjustments can be made in their employment, and also in educating family members in providing a good quality of life., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Annals of Indian Academy of Neurology.)

Background: Intraventricular hemorrhage (IVH) after intracerebral hemorrhage (ICH) is a strong independent predictor of poor outcomes. Although the location and volume of ICH are associated with IVH, our knowledge concerning the mechanism of IVH after ICH is still limited. This study aimed to investigate the relationship between hematoma morphology and IVH in patients with supratentorial deep ICH., Methods: We retrospectively analyzed adult patients (aged ≥18 years) with spontaneous supratentorial deep ICH who underwent computed tomography (CT) within 48 h after ICH symptom onset in Peking University First Hospital between January 2017 and August 2022. We collected the clinical and imaging data of the patients and assessed hematoma morphology using several quantitative radiological parameters including hematoma volume, sphericity index, A/B ratio (A: the largest area of hematoma; B: the largest diameter 90° to A on the same slice), and our newly proposed largest diameter-midline angle (LMA). Multivariable logistic regression analysis was used to analyze the relationship between these parameters and the presence of IVH on the initial CT scan., Results: Among 114 patients with spontaneous supratentorial deep ICH, 41 (36.0%) had IVH. In patients with IVH, the sphericity index was lower than that in individuals without IVH, while the LMA was larger. Multivariate logistic regression analysis showed that sphericity index [0.1-unit odds ratio (OR) =0.252; 95% CI: 0.089-0.709; P=0.009] and the LMA (10-unit OR =1.281; 95% CI: 1.007-1.630; P=0.04) were independently associated with the presence of IVH in patients with supratentorial deep ICH. Univariate analyses showed that hematoma volume, A/B ratio, sphericity index, and the LMA were significantly associated with poor outcomes at discharge., Conclusions: Two quantitative parameters of hematoma morphology, sphericity index and the LMA, were significantly associated with the presence of IVH in patients with supratentorial deep ICH. Further prospective studies with larger sample sizes are needed to validate our results., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-266/coif). The authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Intracerebral hemorrhage (ICH) remains the most lethal type of stroke, and effective clinical therapies that can speed up hematoma resolution after ICH are still lacking. While the beneficial effects of IL-10 on ICH recovery have been demonstrated, the clinical translation of IL-10 requires effective delivery methods by which sufficient IL-10 can be delivered to ICH-affected regions in the brain. Here we report the use of a phosphatidylserine (PS) liposome (PSL)-based nanoparticle system for microglia/macrophage-targeted delivery of IL-10 in ICH. We first prepared IL-10-conjugated PSL (PSL-IL10) and characterized their immunomodulating effects in vitro. Then we evaluated the therapeutic effects, including hematoma absorption, short-term outcomes, and neuroinflammation, of intranasally administered PSL-IL10 (3 μg IL-10 per mouse, 2 h post-ICH) in a collagenase-induced ICH mouse model. We also isolated microglia/macrophages from the mouse brains with ICH to analyze their morphology, phagocytosis ability, and polarization. Our study reveals that, 1) PSL-IL10 treatment resulted in significantly improved outcomes and accelerated hematoma resolution in the acute phase of ICH; 2) PSL-IL10 inhibited glial activation and down-regulated pro-inflammatory cytokine production; 3) PSL-IL10 induced Iba1 + cells with a stronger phagocytosis ability; 4) PSL-IL10 activated STAT3 and upregulated CD36 expression in microglia/macrophage. These findings collectively show that PSL-IL10 is a promising nanotherapeutic for effectively ameliorating ICH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction Medullary infarctions (MI) are a rare medical entity that is classified mainly as the more commonly lateral medullary infarcts (LMI) and the less common medial medullary infarcts (MMI). Lateral medullary syndrome, also known as Wallenberg syndrome, results when the medulla oblongata is affected and predominantly occurs secondary to atherosclerotic occlusion of the vertebrobasilar arteries. Previous studies have focused more on the anatomical, clinical, and topographical aspects of medullary infarcts. We describe the incidence of their presentation, radiological findings, etiology, treatment, and outcome at our comprehensive stroke center. Material and method This is a retrospective cohort study of 108 medullary stroke patients with confirmed clinical and radiological diagnoses of MI at Hamad General Hospital, Doha, between January 1, 2018 and December 31, 2020. We evaluated the electronic medical records of all stroke patients. Result During the selected period, a total of 2,912 ischemic strokes were reported. Of these, 843 (28.8%) were posterior circulation strokes. Only 108 (3.7%) patients had medullary strokes. Commonly encountered neurological features were dizziness (94.4%), limb ataxia (84.3%), dysarthria (44.4%), ipsilateral facial sensory loss (32.4%), headache (32.4%), contralateral limb sensory loss (25%), ipsilateral hemiparesis (24%), dysphagia (19.4%), and hiccups (13%). Most strokes reported were either minor (73% with National Institutes of Health Stroke Scale [NIHSS] 1-4) or moderate (26% with NIHSS 5-15). LMIs (87.9%) were the most common, followed by medial paramedian MI (10%). Twenty-five percent had extramedullary involvement, predominantly of the cerebellum (17.6%). Out of the total number of patients, 44 (40.7%) had large vessel atherosclerotic disease, followed by 41 (37.6%) whose stroke was due to small vessel disease, 15 (13.8 %) due to undetermined etiology, and 6 (5.5%) due to arterial dissection. Twenty-eight patients (25.4%) underwent 48-hour Holter monitoring, which detected atrial fibrillation in two patients (1.85%). The majority of patients (98.2%, or 106 patients) received antiplatelet therapy, while 68.5% (74 patients) received single antiplatelet therapy (SAPT), and 29.6% (32 patients) received dual antiplatelet therapy (DAPT). Noteworthy is that only 2.7% (three patients) received thrombolysis as an acute reperfusion therapy. Forty-seven percent (51 patients) were discharged home (mRS 0-2), and 51.9% (56 patients) were transferred to rehabilitation facilities. Follow-up assessments were performed at the stroke clinic for 57.4% (62) of the patients. The assessments found that 46 of the follow-up patients were functionally independent at that time (mRS 0-2). Conclusion This is the first large local study of medullary strokes to determine their frequency, presentation, etiology, treatment, and clinical outcome. Medullary strokes represent 3.7% of total ischemic strokes at our comprehensive stroke center. MI is rare and could present with a variety of neurological and non-specific symptoms that mimic common benign conditions. Prompt and early recognition with a high index of suspicion, the use of posterior NIHSS (POST-NIHSS), and urgent MRI-diffusion-weighted imaging (DWI) of the brain in acute settings can improve early diagnosis and the rate of reperfusion therapy. Further studies are needed to enable the early recognition and treatment of medullary infarcts., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Muhammad et al.)

Background and purpose: This study aimed to investigate the differences in intracerebral hemorrhage (ICH) between Jews and Arabs residing in northern Israel, focusing on risk factors, hemorrhage volume, and functional outcome. Methods: A retrospective analysis was conducted utilizing a population-based registry to investigate intracerebral hemorrhage (ICH) characteristics, risk factors, and outcomes. The registry consisted of inpatients diagnosed with hemorrhagic stroke. Due to the wide variation in data on ICH characteristics and the limited availability of population-based data on predictors of ICH survival and functional outcomes, we collected retrospective data on all adult patients admitted to the Galilee Medical Center with a diagnosis of ICH. Data were obtained from the registry covering the period from 2013 to 2019. Ethnic differences and risk factors associated with intracranial hemorrhage (ICH) were examined within a diverse population of 241 patients, comprising 52.70% Jews ( n = 127) and 47.30% Arabs ( n = 114). Results: The results of this study revealed significant differences in age, obesity rates, and intracerebral hemorrhage (ICH) location between the two ethnic groups. Hypertension emerged as the most prevalent condition among ICH patients in both ethnic groups (76.70%), followed primarily by anticoagulant use (63.60%), dyslipidemia (60.70%), diabetes (44.60%), obesity (30.60%), smoking (24.60%), and a history of cardiovascular disease (21.80%). Furthermore, 20.90% of the patients had a history of previous cerebrovascular accidents (CVA). Arab patients with ICH were generally younger (62.90 ± 16.00 years) and exhibited higher rates of obesity (38.70%) compared to Jewish patients with ICH (70.17 ± 15.24 years, 23% obesity; p = 0.001, p = 0.013, respectively). Hemorrhage volume was identified as a crucial determinant of patient outcomes, with larger volumes associated with poorer Modified Rankin Scale (mRS) scores at discharge and higher mortality rates. Interestingly, patients without hypertension had higher hemorrhage volumes compared to those with hypertension. The extent of hemorrhage into the ventricles did not significantly correlate with mRS at discharge in our dataset. Conclusions: This study highlights significant differences in the characteristics and outcomes of intracranial hemorrhage (ICH) between Jews and Arabs in northern Israel. The findings reveal variations in age, obesity rates, and ICH location between the two groups. While hypertension was the most prevalent risk factor for both populations, other risk factors differed. Notably, hemorrhage volume emerged as a crucial prognostic factor, aligning with previously published data. These findings underscore the necessity for tailored approaches that consider ethnic-specific factors in the risk assessment, prevention, and management of ICH. Further research is warranted to elucidate the underlying mechanisms and develop interventions aimed at improving outcomes and enhancing healthcare practices in ICH management.

Objectives: Poor immune-nutritional status has been associated with an unfavorable outcome in critical illness. The Osaka prognostic score (OPS) and the Naples prognostic score (NPS), based on inflammatory and nutritional status, has been shown to predict prognosis following cancer and other diseases. The aim of this study was to investigate the relationship between the OPS and NPS and the short-term outcomes of patients with intracerebral hemorrhage (ICH)., Methods: We retrospectively analyzed the clinical data of patients hospitalized with spontaneous ICH (n = 340) at The Second Affiliated Hospital of Chongqing Medical University between August 2016 and August 2021. Inclusion criteria included patients aged between 18 and 70, and if a blood sample was taken for laboratory testing within 24 h of admission (serum C-reactive protein, albumin, total cholesterol, and counts for neutrophils, lymphocytes, and monocytes were collected on admission). Exclusion criteria included a non-spontaneous cause of ICH and patient death during hospitalization. Patients were divided into four groups based on OPS or five groups according to NPS. Outcomes were evaluated by the modified Rankin Scale (mRS) at six months post-ICH hospitalization. An unfavorable outcome was defined as a mRS score ≥ 3., Results: A total of 289 patients met our inclusion criteria. The unfavorable outcome group had older age, a lower Glasgow Coma Scale score, a higher rate of complications and cerebral herniation, a longer hospital stay, and higher OPS and NPS when compared with the favorable outcome group. Univariate analysis showed that both OPS and NPS were strongly correlated with mRS (r = 0.196,P < 0.001; r = 0.244, P = 0.001, respectively). Multivariate analysis further showed that OPS and NPS were both independent predictors of unfavorable outcomes for patients with ICH with adjusted odds ratios of 1.802 (95% confidence interval [CI]:1.140-2.847, P = 0.012) and 1.702 (95% CI: 1.225-2.635, P = 0.02), respectively. The area under the curve (AUC) of NPS for predicting a poor outcome was 0.732 (95% CI: 0.665-0.799), which was similar to the AUC of OPS 0.724 (95% CI: 0.657-0.792)., Conclusions: In this cohort, a higher OPS and NPS on admission was associated with poor outcome at six months following ICH, supporting their potential role as markers for predicting the outcome of patients with ICH., (© 2023. The Author(s).)

Background and Purpose: Intracerebral hemorrhage (ICH) enhances neurogenesis in the subventricular zone (SVZ); however, the mechanism is not fully understood. We investigated the role of brain-derived neurotrophic factor (BDNF) in post-ICH neurogenesis in a rodent model and in patients with ICH using cerebrospinal fluid (CSF)., Methods: A rat model of ICH was constructed via stereotaxic injection of collagenase into the left striatum. Patients with ICH receiving an external ventricular drain were prospectively enrolled. CSF was collected from rats and patients at different post-ICH times. Primary cultured rat neural stem cells (NSCs) were treated with CSF with or without BDNF-neutralized antibody. Immunohistochemistry and immunocytochemistry were used to detect NSC proliferation and differentiation. The BDNF concentration in CSF was quantified using enzyme-linked immunosorbent assays (ELISA)., Results: In the rat model of ICH, the percentage of proliferating NSCs and neuroblasts in SVZ was elevated in bilateral hemispheres. The cultured rat NSCs treated with CSF from both rats and patients showed an increased capacity for proliferation and differentiation toward neuroblasts. BDNF concentration was higher in CSF collected from rats and patients with ICH than in controls. Blocking BDNF decreased the above-noted promotion of proliferation and differentiation of cultured NSCs by CSF treatment. In patients with ICH, the BDNF concentration in CSF and the neurogenesis-promoting capacity of post-ICH CSF correlated positively with ICH volume., Conclusion: BDNF in CSF contributes to post-ICH neurogenesis, including NSC proliferation and differentiation toward neuroblasts in a rat model and patients with ICH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lin, Tsai, Chen, Young, Wu, Chiang, Kao, Huang, Hsu, Chen and Tsai.)

Background: Intracerebral hemorrhage (ICH) is a potentially devastating condition with elevated early mortality rates, poor functional outcomes, and high costs of care. Standard of care involves intensive supportive therapy to prevent secondary injury. To date, there is no randomized control study demonstrating benefit of early evacuation of supratentorial ICH., Methods: The Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH) Trial was designed to evaluate the minimally invasive trans-sulcal parafascicular surgery (MIPS) approach, a technique for safe access to deep brain structures and ICH removal using the BrainPath ® and Myriad ® devices (NICO Corporation, Indianapolis, IN). ENRICH is a multi-centered, two-arm, randomized, adaptive comparative-effectiveness study, where patients are block randomized by ICH location and Glasgow Coma Score (GCS) to early ICH evacuation using MIPS plus standard guideline-based management vs. standard management alone to determine if MIPS results in improved outcomes defined by the utility-weighted modified Rankin score (UWmRS) at 180 days as the primary endpoint. Secondary endpoints include clinical and economic outcomes of MIPS using cost per quality-adjusted life years (QALYs). The inclusion and exclusion criteria aim to capture a broad group of patients with high risk of significant morbidity and mortality to determine optimal treatment strategy., Discussion: ENRICH will result in improved understanding of the benefit of MIPS for both lobar and deep ICH affecting the basal ganglia. The ongoing study will lead to Level-I evidence to guide clinicians treatment options in the management of acute treatment of ICH., Trial Registration: This study is registered with clinicaltrials.gov (Identifier: NCT02880878)., Competing Interests: Authors BS and RL are employed by Berry Consultants LLC. Berry Consultants LLC supports the SLT with the study's adaptive clinical trial design. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ratcliff, Hall, Porto, Saville, Lewis, Allen, Frankel, Wright, Barrow and Pradilla.)

Monitoring ferroptosis-related miRNAs is crucial for the treatment and prognosis of patients with intracerebral hemorrhage. In this work, a novel hydrophobic paper (h-paper)-based plasmonic substrate was produced by dropping DS Au nanorods with a narrow range of sizes and morphologies onto h-paper. Raman reporter molecules were adsorbed to the array surface, and surface-enhanced Raman scattering spectra at randomly selected points reveal uniform and significant SERS enhancement. Hairpin DNAs labelled with Raman reporters and hybridized with placeholder DNAs were decorated on SERS substrate to fabricate SERS biosensor. Target miRNAs initiated the "inverse Molecular Sentinel" process. During the process, PHs were removed and the conformation of HPs changed toward the hairpin structure, thus eliciting the proximity of Raman reporter to substrate and a stronger SERS signal. The proposed SERS biosensor performs well in terms of stability, reproducibility, and selectivity. The limits of detection of miR-122-5p and miR-140-5p in serum were 4.17 aM and 4.49 aM, respectively. Finally, the fabricated SERS biosensor was applied to detect miR-122-5p and miR-140-5p in ICH patients and healthy subjects, and the results obtained by SERS were consistent with the results from quantitative real-time polymerase chain reaction, revealing the accuracy of the method. This simple, rapid approach offers great potential for the simultaneous detection of miRNAs in practical clinical applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Chen, Fan and Wang.)

Background: Chinese medicine usually acts as "multi-ingredients, multi-targets and multi-pathways" on complex diseases, and these action modes reflect the coordination and integrity of the treatment process with traditional Chinese medicine (TCM). System pharmacology is developed based on the cross-disciplines of directional pharmacology, system biology, and mathematics, has the characteristics of integrity and synergy in the treatment process of TCM. Therefore, it is suitable for analyzing the key ingredients and mechanisms of TCM in treating complex diseases. Intracerebral Hemorrhage (ICH) is one of the leading causes of death in China, with the characteristics of high mortality and disability rate. Bring a significant burden on people and society. An increasing number of studies have shown that Chinese medicine prescriptions have good advantages in the treatment of ICH, and Ditan Decoction (DTT) is one of the commonly used prescriptions in the treatment of ICH. Modern pharmacological studies have shown that DTT may play a therapeutic role in treating ICH by inhibiting brain inflammation, abnormal oxidative stress reaction and reducing neurological damage, but the specific key ingredients and mechanism are still unclear., Methods: To solve this problem, we established PPI network based on the latest pathogenic gene data of ICH, and CT network based on ingredient and target data of DTT. Subsequently, we established optimization space based on PPI network and CT network, and constructed a new model for node importance calculation, and proposed a calculation method for PES score, thus calculating the functional core ingredients group (FCIG). These core functional groups may represent DTT therapy for ICH., Results: Based on the strategy, 44 ingredients were predicted as FCIG, results showed that 80.44% of the FCIG targets enriched pathways were coincided with the enriched pathways of pathogenic genes. Both the literature and molecular docking results confirm the therapeutic effect of FCIG on ICH via targeting MAPK signaling pathway and PI3K-Akt signaling pathway., Conclusions: The FCIG obtained by our network pharmacology method can represent the effect of DTT in treating ICH. These results confirmed that our strategy of active ingredient group optimization and the mechanism inference could provide methodological reference for optimization and secondary development of TCM., (© 2023. The Author(s).)

The method of iron-dependent cell death known as ferroptosis is distinct from apoptosis. The suppression of ferroptosis after intracerebral hemorrhage (ICH) will effectively treat ICH and improve prognosis. This paper primarily summarizes the mechanism of ferroptosis after ICH, with an emphasis on lipid peroxidation, the antioxidant system, iron metabolism, and other pathways. In addition, regulatory targets and drug molecules were described. Although there has been some progress in the field of study, there are still numerous gaps. The mechanism by which non-heme iron enters neurons through the blood-brain barrier (BBB), the mitochondrial role in ferroptosis, and the specific mechanism by which lipid peroxidation induces ferroptosis remain unclear and require further study. In addition, the inhibitory effect of many drugs on ferroptosis after ICH has only been demonstrated in basic experiments and must be translated into clinical trials. In summary, research on ferroptosis following ICH will play an important role in the treatment of ICH.

Background: Early hematoma growth is associated with poor functional outcomes in patients with intracerebral hemorrhage (ICH). We aimed to explore whether quantitative hematoma heterogeneity in non-contrast computed tomography (NCCT) can predict early hematoma growth., Methods: We used data from the Risk Stratification and Minimally Invasive Surgery in Acute Intracerebral Hemorrhage (Risa-MIS-ICH) trial. Our study included patients with ICH with a time to baseline NCCT <12 h and a follow-up CT duration <72 h. To get a Hounsfield unit histogram and the coefficient of variation (CV) of Hounsfield units (HUs), the hematoma was segmented by software using the auto-segmentation function. Quantitative hematoma heterogeneity is represented by the CV of hematoma HUs. Multivariate logistic regression was utilized to determine hematoma growth parameters. The discriminant score predictive value was assessed using the area under the ROC curve (AUC). The best cutoff was determined using ROC curves. Hematoma growth was defined as a follow-up CT hematoma volume increase of >6 mL or a hematoma volume increase of 33% compared with the baseline NCCT., Results: A total of 158 patients were enrolled in the study, of which 31 (19.6%) had hematoma growth. The multivariate logistic regression analysis revealed that time to initial baseline CT ( P = 0.040, odds ratio [OR]: 0.824, 95 % confidence interval [CI]: 0.686-0.991), "heterogeneous" in the density category ( P = 0.027, odds ratio [OR]: 5.950, 95 % confidence interval [CI]: 1.228-28.828), and CV of hematoma HUs ( P = 0.018, OR: 1.301, 95 % CI: 1.047-1.617) were independent predictors of hematoma growth. By evaluating the receiver operating characteristic curve, the CV of hematoma HUs (AUC = 0.750) has a superior predictive value for hematoma growth than for heterogeneous density (AUC = 0.638). The CV of hematoma HUs had an 18% cutoff, with a specificity of 81.9 % and a sensitivity of 58.1 %., Conclusion: The CV of hematoma HUs can serve as a quantitative hematoma heterogeneity index that predicts hematoma growth in patients with early ICH independently., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Huang, Huang, Lin, He, Zheng, Gao, Cai, Ye, Chen, Wu, Fang, Wang, Lin, Kang and Yu.)

Background: Noncontrast computed tomography (NCCT) is often performed for patients with a suspected spontaneous intracerebral hemorrhage (ICH) at the time of admission. Both clinical and radiomic features on the initial NCCT can predict the outcomes of those with ICH, but satisfactory model performance remains challenging., Methods: A total of 258 acute ICH patients from the Central Hospital of Wuhan (CHW) between January 2018 and December 2020 were retrospectively assigned to training and internal validation cohorts at a ratio of 7:3. An independent external testing cohort of 87 patients from January 2021 to July 2021 from the Fifth Affiliated Hospital of Nanchang University (FAHNU) was also used. Based on the least absolute shrinkage and selection operator (LASSO) algorithm, radiomics (rad)-scores were generated from 9 quantitative features on the initial NCCT images. Three models (radiomics, clinical, and hybrid) were established using stepwise logistic regression analysis. The Akaike information criterion and the likelihood ratio test were used to compare the goodness of fit of the three models. Receiver operating characteristic (ROC) curve analysis was performed and bar charts were constructed to evaluate the discrimination of constructed model for predicting a poor outcome following ICH., Results: The three cohorts had similar baseline clinical characteristics, including demographic features and outcomes. In the clinical model, hematoma expansion [2.457 (0.297, 2.633); P=0.014], intracerebral ventricular hemorrhage [2.374 (0.180, 1.882); P=0.018], and location [-2.268 (-2.578, -0.188); P=0.023] were independently associated with a poor clinical outcome. In the hybrid model, location [-2.291 (-2.925, -0.228); P=0.022], and rad-score [5.255 (0.680, 11.460); P<0.001] were independently associated with a poor outcome. The hybrid model achieved satisfactory discriminability, with areas under curve (AUCs) of 0.892 [95% confidence interval (CI): 0.847 to 0.937], 0.893 (95% CI: 0.820 to 0.966), and 0.838 (95% CI: 0.755 to 0.920) in the training, internal validation, and external testing cohorts, respectively. The hybrid model also achieved good discriminability in the prediction of 30-day mortality, with AUCs of 0.840, 0.823, and 0.883 in the training, internal validation, and external testing cohorts, respectively. The rad-score [2.861 (1.940, 4.220); P<0.001] was the predominant risk factor associated with 30-day mortality., Conclusions: Radiomic analysis based on initial NCCT scans showed added value in predicting a poor outcome after ICH. A clinical-radiomics model yielded improved accuracy in predicting a poor outcome and 30-day death following ICH compared with radiomics alone., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-128/coif). JC is employed by GE and only provided technical support during the research. The other authors have no conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background and Objectives: Treatment-limiting decisions (TLDs) are employed to actively withhold treatment/invasive interventions from patients in whom clinicians feel they would derive little to no benefit and/or suffer detrimental effects. Data regarding the employment of TLDs in patients with spontaneous intracerebral hemorrhage (ICH) remain sparse. Accordingly, this study sought to investigate both the prevalence of TLDs and factors driving TLDs in patients suffering from spontaneous ICH. Materials and Methods: This was a retrospective study of 249 consecutive patients with ICH treated from 2018−2019 at the Neurovascular Center of the University Hospital Bonn. Reasons deemed critical in the decision-making process with regard to TLD were ultimately extracted/examined via chart review of qualifying patients. Results: A total of 249 patients with ICH were included within the final analyses. During the time period examined, 49 patients (20%) had advanced directives in place, whereas in 53 patients (21%) consultation with relatives or acquaintances was employed before further treatment decisions. Overall, TLD ultimately manifested in 104 patients (42%). TLD was reached within 6 h after admission in 52 patients (50%). Congruent with severity of injury and expected outcomes, TLDs were more likely in patients with signs of cerebral herniation and an ICH score > 3 (p < 0.001). Conclusions: The present study examines details associated with TLDs in patients with spontaneous ICH. These data provide insight into key decisional processes and reinforce the need for further structured investigations in an effort to help guide patients and their families.

Background: Intravenous administration of recombinant tissue plasminogen activator (rt-PA) fails to succeed in a subset of acute ischemic stroke (AIS) patients, while in approximately 6-8% of cases intracerebral hemorrhage (ICH) occurs as side effect., Objective: Here, we aimed to investigate α2-plasmin inhibitor (α2-PI) levels during thrombolysis and to find out whether they predict therapy outcomes in AIS patients., Patients/methods: In this prospective, observational study, blood samples of 421 AIS patients, all undergoing i.v. thrombolysis by rt-PA within 4.5 h of their symptom onset, were taken before and 24 h after thrombolysis. In a subset of patients ( n = 131), blood was also obtained immediately post-lysis. α2-PI activity and antigen levels were measured by chromogenic assay and an in-house ELISA detecting all forms of α2-PI. α2-PI Arg6Trp polymorphism was identified in all patients. Stroke severity was determined by NIHSS on admission and day 7. Therapy-associated ICH was classified according to ECASSII. Long-term outcomes were defined at 3 months post-event by the modified Rankin Scale (mRS)., Results: Median α2-PI activity and antigen levels showed a significant drop immediately post-lysis and increased to subnormal levels at 24 h post-event. Admission α2-PI levels showed a significant negative stepwise association with stroke severity. Patients with favorable long-term outcomes (mRS 0-1) had significantly higher admission α2-PI antigen levels (median:61.6 [IQR:55.9-70.5] mg/L) as compared to patients with poor outcomes (mRS 2-5: median:59.7 [IQR:54.5-69.1] and mRS 6: median:56.0 [IQR:48.5-61.0] mg/L, p < 0.001). In a Kaplan-Meier survival analysis, patients with an α2-PI antigen in the highest quartile on admission showed significantly better long-term survival as compared to those with α2-PI antigen in the lowest quartile (HR: 4.54; 95%CI:1.92-10.8, p < 0.001); however, in a multivariate analysis, a low admission α2-PI antigen did not prove to be an independent risk factor of poor long-term outcomes. In patients with therapy-related ICH ( n = 34), admission α2-PI antigen levels were significantly, but only marginally, lower as compared to those without hemorrhage., Conclusions: Low α2-PI antigen levels on admission were associated with more severe strokes and poor long-term outcomes in this cohort. Our results suggest that in case of more severe strokes, α2-PI may be involved in the limited efficacy of rt-PA thrombolysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Székely, Orbán-Kálmándi, Szegedi, Katona, Baráth, Czuriga-Kovács, Lóczi, Vasas, Fekete, Fekete, Berényi, Oláh, Csiba and Bagoly.)

Background: In patients with spontaneous supratentorial intracerebral hemorrhage (ICH), open craniotomy has failed to improve a functional outcome. Innovative minimally invasive neurosurgery (MIS) may improve a health outcome and reduce healthcare costs., Aims: Before starting phase-III trials, we aim to assess conditions that need to be met to reach the potential cost-effectiveness of MIS compared to usual care in patients with spontaneous supratentorial ICH., Methods: We used a state-transition model to determine at what effectiveness and cost MIS would become cost-effective compared to usual care in terms of quality-adjusted life-years (QALYs) and direct healthcare costs. Threshold and two-way sensitivity analyses were used to determine the minimal effectiveness and maximal costs of MIS, and the most cost-effective strategy for each combination of cost and effectiveness. Scenario and probabilistic sensitivity analyses addressed model uncertainty., Results: Given €10,000 of surgical costs, MIS would become cost-effective when at least 0.7-1.3% of patients improve to a modified Rankin Scale (mRS) score of 0-3 compared to usual care. When 11% of patients improve to mRS 0-3, surgical costs may be up to €83,301-€164,382, depending on the population studied. The cost-effectiveness of MIS was mainly determined by its effectiveness. In lower mRS states, MIS needs to be more effective to be cost-effective compared to higher mRS states., Conclusion: MIS has the potential to be cost-effective in patients with spontaneous supratentorial ICH, even with relatively low effectiveness. These results support phase-III trials to investigate the effectiveness of MIS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schreuder, Scholte, Ulehake, Sondag, Rovers, Dammers, Klijn and Grutters.)

Introduction: The role of commensal microbiota in systemic diseases, including brain diseases, has attracted increasing attention. Oral infectious diseases, such as dental caries and periodontitis, are also involved in cerebrovascular diseases and cognitive impairment. Cerebral microbleeds (CMBs) and intracerebral hemorrhage due to small vessel disease (SVD), are presumably associated with a high risk of vascular cognitive impairment and stroke. We previously reported that Streptococcus mutans ( S. mutans , the main pathogen of dental caries), harboring the cnm gene that encodes the collagen-binding protein Cnm, is associated with the development of hypertensive intracerebral hemorrhage and aggravation of CMBs. We also proposed a mechanism by which the circulating Cnm-expressing S. mutans causes intracerebral hemorrhage or CMBs; it binds to denuded basement membranes mainly composed of collagen IV through damaged tight junctions or it directly invades endothelial cells, resulting in blood-brain barrier injury. In November 2018, we initiated a multicenter, prospective cohort study (RAMESSES: Risk Assessment of Cnm-positive S. mutans in Stroke Survivors; UMIN Clinical Trials Registry: UMIN000045559) to explore the longitudinal association between Cnm-positive S. mutans and CMBs with comprehensive dental findings, which should determine the effect of Cnm-positive S. mutans in the oral cavity on the risk of CMB development and cognitive decline., Methods: Fifteen domestic institutes will be enlisted to enroll 230 patients who have at least one CMB in the deep brain area and develop a stroke within the past year. The prevalence of Cnm-positive S. mutans based on oral specimens and dental hygiene will be examined. The primary outcome is the number of newly developed deep CMBs. The secondary outcomes include the new development of lobar, subtentorial, or any type of CMBs; symptomatic intracerebral hemorrhage or ischemic stroke; changes in cognitive function or frailty; major bleeding; all-cause mortality; and antibody titers against periodontal pathogens. The observation period will be 2 years., Discussion: The 2-year longitudinal prospective cohort study is expected to establish the role of Cnm-positive S. mutans in SVD including CMBs and intracerebral hemorrhage from the perspective of the "brain-oral axis" and provide guidance for novel prophylactic strategies against Cnm-positive S. mutans -induced SVD., Competing Interests: MI reports personal fees from Daiichi Sankyo, Eisai, and Bayer, and grants from Panasonic, Bristol-Myers Squibb, and Otsuka Pharmaceutical, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hosoki, Hattori, Saito, Takegami, Tonomura, Yamamoto, Ikeda, Hosomi, Oishi, Morita, Miyamoto, Nomura, Nakano and Ihara.)

Background and Purpose: Intracerebral hemorrhage (ICH) is a subtype of stroke and results in neurological deficits in patients without any effective treatments. Artemisinin (ART), a well-known antimalarial Chinese medicine, exerts multiple essential roles in the central and peripheral nervous system due to its antioxidative and anti-inflammation properties. Neural cell adhesion molecule L1 (L1CAM, L1) is considered to be implicated in neural development, functional maintenance, and neuroprotection during disease. However, whether these two essential molecules are neuroprotective in ICH remains unclear., Methods: Therefore, the present study investigated the influence of ART on the recovery of neurological deficits in a mouse model of ICH induced by collagenase and the underlying mechanism., Results: It was revealed that ART is capable of upregulating L1 expression to alleviate brain edema, reduce oxidative stress, and inhibit inflammation to alleviate ICH-induced brain injury to improve the neurological outcome in mice suffering from ICH., Conclusion: These results may lay the foundation for ART to be a novel candidate treatment for ICH., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Intracerebral hemorrhage (ICH) refers to hemorrhage caused by non-traumatic vascular rupture in the brain parenchyma, which is characterized by acute onset, severe illness, and high mortality and disability. The influx of blood into the brain tissue after cerebrovascular rupture causes severe brain damage, including primary injury caused by persistent hemorrhage and secondary brain injury (SBI) induced by hematoma. The mechanism of brain injury is complicated and is a significant cause of disability after ICH. Therefore, it is essential to understand the mechanism of brain injury after ICH to develop drugs to prevent and treat ICH. Studies have confirmed that many traditional Chinese medicines (TCM) can reduce brain injury by improving neurotoxicity, inflammation, oxidative stress (OS), blood-brain barrier (BBB), apoptosis, and neurological dysfunction after ICH. Starting from the pathophysiological process of brain injury after ICH, this paper summarizes the mechanisms by which TCM improves cerebral injury after ICH and its comparison with conventional western medicine, so as to provide clues and a reference for the clinical application of TCM in the prevention and treatment of hemorrhagic stroke and further research and development of new drugs., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Intracerebral hemorrhage (ICH) is a type of stroke which results in a high disability and mortality rate and has a poor prognosis. Tongqiao Huoxue Decoction (TQHXD) is a classical Chinese prescription. Clinical practice has proven that TQHXD can promote blood circulation and can effectively treat ICH and its sequelae. However, the current mechanism is still unclear., Methods: The chemical components and target genes of TQHXD were collected from the Traditional Chinese medicine (TCM) Systems Pharmacology and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine analysis platforms, and the gene expression data of ICH tissues were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to obtain differentially co-expressed gene pairs and build a drug-target-disease network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the obtained target genes and shared genes. Finally, molecular docking was carried out to further clarify the utility of TQHXD for the treatment of ICH., Results: A total of 304 differentially expressed genes in ICH, 42 TQHXD active ingredients, and 279 predicted targets of its active compounds were obtained. Bioinformatics analysis showed that they were involved in angiogenesis, the regulation of wound healing, and other biological processes. Furthermore, their participation in fluid shear stress and the atherosclerosis signaling pathway indicated their close association with the pathological processes of ICH. Finally, molecular docking was carried out to further confirm the tightly binding structural sites of the effective components of TQHXD and key proteins., Conclusions: In summary, the results of this study suggest that the mechanism of action of TQHXD in the treatment of ICH involves multiple targets and signaling pathways related to its occurrence and development. This study not only provides a new theoretical basis for the treatment of ICH with traditional Chinese medicine, but also provides new ideas for the research and development of drugs for the treatment of ICH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-1403/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: Chinese herbal medicine (CHM) is characterized by "multi- compounds, multi-targets and multi-pathway", which has advanced benefits for preventing and treating complex diseases, but there still exists unsolved issues, mainly include unclear material basis and underlying mechanism of prescription. Integrated pharmacology is a hot cross research area based on system biology, mathematics and poly-pharmacology. It can systematically and comprehensively investigate the therapeutic reaction of compounds or drugs on pathogenic genes network, and is especially suitable for the study of complex CHM systems. Intracerebral Hemorrhage (ICH) is one of the main causes of death among Chinese residents, which is characterized with high mortality and high disability rate. In recent years, the treatment of ICH by CHM has been deeply researched. Xue Fu Zhu Yu Decoction (XFZYD), one of the commonly used prescriptions in treating ICH at clinic level, has not been clear about its mechanism., Methods: Here, we established a strategy, which based on compounds-targets, pathogenetic genes, network analysis and node importance calculation. Using this strategy, the core compounds group (CCG) of XFZYD was predicted and validated by in vitro experiments. The molecular mechanism of XFZYD in treating ICH was deduced based on CCG and their targets., Results: The results show that the CCG with 43 compounds predicted by this model is highly consistent with the corresponding Compound-Target (C-T) network in terms of gene coverage, enriched pathway coverage and accumulated contribution of key nodes at 89.49%, 88.72% and 90.11%, respectively, which confirmed the reliability and accuracy of the effective compound group optimization and mechanism speculation strategy proposed by us., Conclusions: Our strategy of optimizing the effective compound groups and inferring the mechanism provides a strategic reference for explaining the optimization and inferring the molecular mechanism of prescriptions in treating complex diseases of CHM., (© 2022. The Author(s).)

The main purpose of the study was to explore a reliable way to automatically handle emergency cases, such as intracerebral hemorrhage (ICH). Therefore, an artificial intelligence (AI) system, named, H-system, was designed to automatically recognize medical text data of ICH patients and output the treatment plan. Furthermore, the efficiency and reliability of the H-system were tested and analyzed. The H-system, which is mainly based on a pretrained language model Bidirectional Encoder Representations from Transformers (BERT) and an expert module for logical judgment of extracted entities, was designed and founded by the neurosurgeon and AI experts together. All emergency medical text data were from the neurosurgery emergency electronic medical record database (N-eEMRD) of the First Affiliated Hospital of Chongqing Medical University, Chongqing Emergency Medical Center, and Chongqing First People's Hospital, and the treatment plans of these ICH cases were divided into two types. A total of 1,000 simulated ICH cases were randomly selected as training and validation sets. After training and validating on simulated cases, real cases from three medical centers were provided to test the efficiency of the H-system. Doctors with 1 and 5 years of working experience in neurosurgery (Doctor-1Y and Doctor-5Y) were included to compare with H-system. Furthermore, the data of the H-system, for instance, sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and the area under the receiver operating characteristics curve (AUC), were calculated and compared with Doctor-1Y and Doctor-5Y. In the testing set, the time H-system spent on ICH cases was significantly shorter than that of doctors with Doctor-1Y and Doctor-5Y. In the testing set, the accuracy of the H-system's treatment plan was 88.55 (88.16-88.94)%, the specificity was 85.71 (84.99-86.43)%, and the sensitivity was 91.83 (91.01-92.65)%. The AUC value of the H-system in the testing set was 0.887 (0.884-0.891). Furthermore, the time H-system spent on ICH cases was significantly shorter than that of doctors with Doctor-1Y and Doctor-5Y. The accuracy and AUC of the H-system were significantly higher than that of Doctor-1Y. In addition, the accuracy of the H-system was more closed to that of Doctor-5Y. The H-system designed in the study can automatically recognize and analyze medical text data of patients with ICH and rapidly output accurate treatment plans with high efficiency. It may provide a reliable and novel way to automatically and rapidly handle emergency cases, such as ICH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Deng, Zhu, Sun, Xie, Dan, Zhan, Xia, Liang, Li, Shi and Jiang.)

Background: This study aimed to systematically compare the discrimination and calibration of 5 clinical scores for stroke-associated pneumonia (SAP) after intracerebral hemorrhage (ICH)., Methods: We derived a validation cohort from the Beijing Registration of Intracerebral Hemorrhage. SAP was then diagnosed according to the Center for Disease Control and Prevention's criteria for hospital-acquired pneumonia. The area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow goodness-of-fit test were used to assess model discrimination and calibration., Results: A total of 1964 patients were enrolled in the study. The mean age was 56.8±14.4 years, and 67.6% were male. The median National Institutes of Health Stroke Scale (NIHSS) score at admission was 11 [interquartile range (IQR), 3-21], while the median length of stay (LOS) was 16 days (IQR, 8-22 days). A total of 575 (29.2%) patients were diagnosed with in-hospital SAP after ICH. The AUROC of the 5 clinical scores ranged from 0.732 to 0.800. In comparing these scores, we found that the ICH-associated pneumonia score-B (ICH-APS-B 0.800; 95% CI: 0.780-0.820; P<0.001) showed a statistically better discrimination than did the other risk models (all P<0.001). Furthermore, all clinical scores performed better in patients with an LOS >72 h. The ICH-APS-B (0.827; 95% CI: 0.806-0.848; P<0.001) still showed statistically better discrimination than did the other risk models in patients with an LOS longer than 72 hours. The Hosmer-Lemeshow test also revealed that the ICH-APS-B. had the largest Cox and Snell R2 result for in-hospital SAP after ICH., Conclusions: Among the 5 models for predicting SAP after ICH, the ICH-APS-B showed the best predictive performance, suggests it may be a useful tool for implementing the personalized care of patients and conducting clinical trials of SAP after ICH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-4046/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Introduction and Aim: Data remain limited on sex-differences in patients with oral anticoagulant (OAC)-related intracerebral hemorrhage (ICH). We aim to explore similarities and differences in risk factors, acute presentation, treatments, and outcome in men and women admitted with OAC-related ICH., Method: This study was a retrospective observational study based on 401 consecutive patients with OAC-related ICH admitted within 24 h of symptom onset. The study was registered on osf.io. We performed logarithmic regression and cox-regression adjusting for age, hematoma volume, Charlson Comorbidity Index (CCI), and pre-stroke modified Ranking Scale (mRS). Gender and age were excluded from CHA 2 DS 2 -VASc and CCI was not adjusted for age., Results: A total of 226 men and 175 women were identified. More men were pre-treated with vitamin K-antagonists (73.5% men vs . 60.6% women) and more women with non-vitamin K-antagonist oral anticoagulants (26.5% men vs . 39.4% women), p = 0.009. Women were older (mean age 81.9 vs . 76.9 years, p < 0.001). CHA 2 DS 2 -VASc and CCI were similar in men and women.Hematoma volumes (22.1 ml in men and 19.1 ml in women) and National Institute of Health Stroke Scale (NIHSS) scores (13 vs . 13) were not statistically different, while median Glasgow Coma Scale (GCS) was lower in women, (14 [8;15] vs . 14 [10;15] p = 0.003).Women's probability of receiving reversal agents was significantly lower (adjusted odds ratio [ aOR ] = 0.52, p = 0.007) but not for surgical clot removal ( aOR = 0.56, p = 0.25). Women had higher odds of receiving do-not-resuscitate (DNR) orders within a week ( aOR = 1.67, p = 0.04). There were no sex-differences in neurological deterioration ( aOR = 1.48, p = 0.10), ability to walk at 3 months ( aOR = 0.69, p = 0.21) or 1-year mortality (adjusted hazard ratio = 1.18, p = 0.27)., Conclusion: Significant sex-differences were observed in age, risk factors, access to treatment, and DNRs while no significant differences were observed in comorbidity burden, stroke severity, or hematoma volume. Outcomes, such as adjusted mortality, ability to walk, and neurological deterioration, were comparable. This study supports the presence of sex-differences in risk factors and care but not in presentation and outcomes., Competing Interests: CO has received a travel grant from Merck, Sharp, and Dohme. HC has received personal honoraria for speaking/educational activities from Boehringer-Ingelheim, Bristol-Myers-Squibb, Bayer, Daichi-Sanko and has received honoraria paid to her institution for services as National Lead in trials sponsored by Bayer and Alexion. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Grundtvig, Ovesen, Steiner, Carcel, Gaist, Christensen, Marstrand, Meden, Rosenbaum, Iversen, Kruuse, Christensen, Ægidius, Havsteen and Christensen.)

Background: The cerebrospinal fluid circulation of patients with intracerebral hemorrhage (ICH) can be blocked by blood clots, resulting in acute hydrocephalus. However, current research on chronic hydrocephalus (CH) is lacking., Methods: A total of 253 patients with ICH combined with coma treated at The Third People's Hospital of Gansu Province after emergency hematoma removal from January 2018 to January 2020 were included. Patients were divided into the CH group (n=48) and the control group (n=205) depending on whether hydrocephalus occurred or not within 3-12 months after operation. The main clinical characteristics of the two groups were compared, and the risk factors for CH were analyzed. Counting data of the two groups were expressed as "n (%)", and multivariate logistic regression analysis was used to explore the risk factors for CH., Results: Compared with the control group, the proportion of patients with modified Graeb score ≥5 points in the CH group increased significantly (52.08% vs. 21.95%, P=0.000). The proportion of patients with preoperative cerebral hernia increased significantly (37.5% vs. 19.51%, P=0.008). The proportion of patients with preoperative obstructive hydrocephalus increased (43.75% vs. 24.39%, P=0.007). The proportion of patients with postoperative subdural effusion increased (41.67% vs. 13.66%, P=0.000). Multivariate logistic regression analysis showed that a modified Graeb score ≥5 points and postoperative subdural effusion were risk factors for the formation of CH in patients with ICH complicated by coma after emergency hematoma removal (P<0.05). The modified Graeb score has diagnostic value for the formation of CH in patients with ICH combined with coma after emergency hematoma removal, and the area under the curve was 0.653 [P=0.001, 95% confidence interval (CI): 0.561-0.744]. There was no significant difference in preoperative neurological deficit score between the control group and the CH group (19.75±3.03 vs. 19.86±3.01, P=0.113). Compared with the control group, the neurological deficit score at 12 months after operation in the CH group was significantly higher (12.73±2.99 vs. 10.64±2.82, P=0.000)., Conclusions: A modified Graeb score >5 points and postoperative subdural effusion are risk factors for the formation of CH in patients with ICH combined with coma after emergency hematoma removal. The formation of CH affects postoperative neurological rehabilitation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-128/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Purpose: To determine whether spectral detector CT (SDCT) with a plain non-enhanced monochromatic CT, a water-weighted image after iodine removal, an iodine map, and Mono energetic images changes the diagnosis and classification of intracranial hemorrhage based on single energy CT after endovascular treatment (EVT) for ischemic stroke., Methods: Two readers evaluated single energy and SD CT data collected from 63 patients within one week after EVT. They diagnosed ICH or contrast staining, and graded ICH according to the Heidelberg and Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) classification. Differences in diagnosis between single energy and SD CT were tested with Pearson's chi-squared test. Diagnostic values of single energy CT were calculated. Interrater agreement was based on Cohen's Kappa., Results: When spectral data were added to single energy CT, the diagnosis of ICH changed in 8 CT scans (13%): in 4, the diagnosis of ICH was rejected and in 4, initially undetected ICH was diagnosed. In an additional 3 patients, the ICH grade was modified. CT alone had 88% sensitivity, 87% specificity, 88% positive diagnostic value, 87% negative diagnostic value, and 87% overall accuracy for ICH compared to SDCT. Interreader agreement on the presence of ICH was 0.84 (95% CI 0.51-0.86) for spectral CT and 0.84 (95% CI 0.73-0.97) for single energy CT., Conclusion: SD CT after endovascular treatment contributes to the distinction between intracranial hemorrhage and contrast staining., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The Alberta Stroke Program Early CT Score (ASPECTS) is widely used to guide thrombolytic therapy and predict the functional outcome of patients with acute ischemic stroke (AIS). Whether ASPECTS can predict the functional outcome of patients with intracerebral hemorrhage (ASPECTS-H) remains unclear., Methods: Patients with primary intracerebral hemorrhage (ICH) were collected and retrospectively analyzed. ASPECTS-H was assessed at admission. Patients were followed up at 30 days and 90 days after the onset of ICH. Occurrence of death within 90 days after ICH was the primary endpoint. Modified Rankin Scale (mRS) ≥ 3 was considered a poor functional outcome., Results: A total of 149 patients met eligibility criteria; 61 (40.9%) had poor functional outcome at 30 days, and 37 (24.8%) had poor functional outcome at 90 days. Using binary logistic regression modeling, we found that a low ASPECTS-H was associated with a poor functional outcome. The risk ratio of a low ASPECTS-H was 2.31 at 30 days ( P = 0.000; 95% CI, 1.560-3.421) and 2.711 at 90 days ( P = 0.000; 95% CI, 1.677-4.381). The optimal cutoff value of ASPECTS-H to discriminate good and poor 30-day and 90-day outcomes was 7.5 (Sensitivity 30-day  = 0.636, 1-Specificity 30 - day  = 0.311; Sensitivity 90-day  = 0.580, 1-Specificity 90-day  = 0.270)., Conclusions: A low ASPECTS-H was an indicator of poor short-term and long-term functional outcomes of ICH.

Background: Intracerebral hemorrhage (ICH) is a severe cerebrovascular disease with high morbidity and mortality rates. Oxidative stress and inflammation are important pathological mechanisms of secondary brain injury (SBI) after ICH. Brain and muscle Arnt-like protein 1 (BMAL1), which forms the core component of the circadian clock, was previously shown to be involved in many diseases and to participate in oxidative stress and inflammatory responses. However, the role of BMAL1 in SBI following ICH is unknown. In addition, treatments targeting miR-155 and its downstream signaling pathway may exert a beneficial effect on SBI after ICH, while miR-155 may regulate Bmal1 mRNA stability and translation. Nevertheless, researchers have not clearly determined whetheantagomir-155 upregulates BMAL1 expression and subsequently attenuates ICH-induced brain injury in rats., Methods: After establishing an ICH rat model by injecting autologous blood, the time course of changes in levels of the BMAL1 protein after ICH was analyzed. Subsequently, this study was designed to investigate the potential role and mechanisms of BMAL1 in SBI following ICH using lentiviral overexpression and antagomir-155 treatments., Results: BMAL1 protein levels were significantly decreased in the ICH group compared to the sham group. Genetic overexpression of BMAL1 alleviated oxidative stress, inflammation, brain edema, blood-brain barrier injury, neuronal death, and neurological dysfunction induced by ICH. On the other hand, we observed that inhibiting miRNA-155 using antagomir-155 promoted the expression of BMAL1 and further activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway to attenuate brain injury after ICH., Conclusions: These results reveal that BMAL1 serves as a neuroprotective agent in ICH and upregulation of BMAL1 attenuates ICH-induced SBI. Therefore, BMAL1 may be a promising therapeutic target for SBI following ICH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-1863). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Phillyrin, a natural plant extract, has significant antioxidant and anti-apoptotic effects. However, its effect on intracerebral hemorrhage (ICH) remains unclear. In this study, we investigated a potential role for phillyrin in the regulation of the oxidative stress and apoptosis induced by ICH. A model of ICH was induced by collagenase IV (0.2 U in 1 μl sterile normal saline) in male C57BL/6J (B6) mice and different doses of phillyrin (5, 15, or 30 mg/kg) were intraperitoneally (i.p.) injected at 30 min, 6 h, and 22 h after modeling. We found that phillyrin significantly reduced neural function and lesion volume, improved injury of white and grey matter around the lesion, decreased apoptosis and oxidative stress, increased the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase 1(HO-1), NADPH quinone oxidoreductase 1 (NQO1) and Superoxide Dismutase-1(SOD-1) in vitro and in vivo, and protected neurons from the stimulation of hemin by promoting Nrf2 nuclear translocation. Treatment with ML385 (Nrf2 inhibitor) completely reversed the protective effects of phillyrin in vivo after ICH injury. Based on our findings, we conclude that phillyrin treatment alleviates ICH injury-induced apoptosis and oxidative stress via activation of the Nrf2 signaling pathway, highlighting a potential role for phillyrin as an ICH therapeutic., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Microglia plays a vital role in neuroinflammation, contributing to the pathogenesis of intracerebral hemorrhage (ICH)-induced brain injury. Mesenchymal stem cells (MSCs) hold great potential for treating ICH. We previously revealed that MSCs ameliorate the microglial pyroptosis caused by an ischemic stroke. However, whether MSCs can modulate microglial pyroptosis after ICH remains unknown. This study aimed to investigate the neuroprotective effects of hypoxia-preconditioned olfactory mucosa MSCs (OM-MSCs) on ICH and the possible mechanisms., Methods: ICH was induced in mice via administration of collagenase IV. At 6 h post-ICH, 2-4×10 5 normoxic/hypoxic OM-MSCs or saline were intracerebrally administered. To evaluate the neuroprotective effects, the behavioral outcome, apoptosis, and neuronal injury were measured. Microglia activation and pro-inflammatory cytokines were applied to detect neuroinflammation. Microglial pyroptosis was determined by western blotting, immunofluorescence staining, and transmission electron microscopy (TEM)., Results: The two OM-MSC-transplanted groups exhibited significantly improved functional recovery and reduced neuronal injury, especially the hypoxic OM-MSCs group. Hypoxic OM-MSCs attenuated microglial activation as well as the levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Moreover, we found that hypoxia-preconditioned OM-MSCs ameliorated pyroptosis by diminishing the levels of pyroptosis-associated proteins in peri-hematoma brain tissues, decreasing the expression of the microglial nod-like receptor family protein 3 (NLRP3) and caspase-1, and reducing the membrane pores on microglia post-ICH., Conclusions: Our study showed that hypoxic preconditioning augments the therapeutic efficacy of OM-MSCs, and hypoxia-preconditioned OM-MSCs alleviate microglial pyroptosis in the ICH model., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-2590). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background and Objective: Clinicians working in intensive care frequently report perceptions of inappropriate care (PIC) situations. Intracerebral haemorrhage (ICH) is associated with high rates of mortality and morbidity. Prognosticating after ICH is complex and may be influenced by clinicians' subjective impressions and biases, which may, in turn, influence decision making regarding the level of care provided. The aim of this study was to qualitatively explore perceptions of neurocritical care in relation to the expected functional outcome for ICH patients., Design: Qualitative study using semi-structured interviews with neurocritical care doctors and nurses., Setting: Neurocritical care (NCC) department in a UK neuroscience tertiary referral center., Subjects: Eleven neurocritical care nurses, five consultant neurointensivists, two stroke physicians, three neurosurgeons., Intervention: None., Measurements and Main Results: We conducted 21 semi-structured interviews and identified five key themes: (1) prognostic uncertainty (2) subjectivity of good versus poor outcome (3) perceived inappropriate care (PIC) situations (including for frail elderly patients) (4) challenging nature of decision-making (5) clinician distress., Conclusions: Caring for severely affected ICH patients in need of neurocritical care is challenging, particularly with frail elderly patients. Awareness of the challenges could facilitate interventions to improve decision-making for this group of stroke patients and their families, as well as measures to reduce the distress on clinicians who care for this patient group. Our findings highlight the need for effective interdisciplinary shared decision making involving the family, taking into account patients' previously expressed values and preferences and incorporating these into bespoke care planning., (© 2020. The Author(s).)

Isorhynchophylline (IRN), a component of traditional Chinese herb Uncaria rhynchophylla, possesses strong antioxidant activity. Ferroptosis induced by iron overload causes cell oxidative stress after intracerebral hemorrhage (ICH). Therefore, this study aims to explore the effects of IRN on the ferroptosis following ICH. In this study, mouse hippocampal HT-22 cells were treated with ferric ammonium citrate (FAC) alone or together with IRN, and we found IRN reduced the FAC-induced cell damage. Then, cells were treated with IRN following treatment with FAC after transfection with miR-122-5p inhibitor, and the results showed IRN reduced the FAC-induced decrease of miR-122-5p levels and relieved the ferroptosis by detecting ferroptotic marker proteins, iron ion concentration and oxidative stress level; after transfection with miR-122-5p inhibitor, the protective effects of IRN against FAC-induced ferroptosis in these cells were weakened. TP53 (also known as p53) was verified as a target of miR-122-5p by using dual luciferase reporter assay, and restoration of TP53 attenuated the effects of miR-122-5p on ferroptotic marker proteins expression, iron ion concentration and lipid ROS levels, as well as solute carrier family seven member 11 (SLC7A11) mRNA expression. SLC7A11 siRNA reversed the inhibitory effects of IRN on FAC-induced ferroptosis and oxidative stress levels. Subsequently, IRN increased the mNSS score, and decreased brain water content and EB content in ICH model. Moreover, IRN decreased ferroptosis and lipid ROS level, upregulated the expression of miR-122-5p and SLC7A11 mRNA, and inhibited TP53 expression. Our findings reveal that IRN protects neurocyte from ICH-induced ferroptosis via miR-122-5p/TP53/SLC7A11 pathway, which may provide a potential therapeutic mechanism for ICH.

Given the ongoing global SARS-CoV-2-vaccination efforts, clinical awareness needs to be raised regarding the possibility of an increased incidence of SARS-CoV-2-vaccine-related immune-mediated thrombocytopenia in patients with intracerebral hemorrhage (ICH) secondary to cerebral sinus and vein thrombosis (CVT) requiring (emergency) neurosurgical treatment in the context of vaccine-induced immune thrombotic thrombocytopenia (VITT). Only recently, an association of vaccinations and cerebral sinus and vein thrombosis has been described. In a number of cases, neurosurgical treatment is warranted for these patients and special considerations are warranted when addressing the perioperative coagulation. We, herein, describe the past management of patients with VITT and established a literature-guided algorithm for the treatment of patients when addressing the impaired coagulation in these patients. Increasing insights addressing the pathophysiology of SARS-CoV-2-vaccine-related immune-mediated thrombocytopenia guide physicians in developing an interdisciplinary algorithm taking into account the special considerations of this disease.

Dentin matrix protein 1 (DMP1) is an extracellular matrix phosphoprotein that is known to facilitate mineralization of collagen in bone and promote osteoblast/odontoblast differentiation. Blood-brain barrier (BBB) disruption is the major pathogenesis in secondary brain injury after intracerebral hemorrhage (ICH). This study aimed to investigate the expression pattern of DMP1 in the mouse brain and explore the role of DMP1 in BBB disruption and brain injury in a mouse model of ICH. Mice were subjected to autologous blood injection-induced ICH. Immunofluorescence staining, western blot analysis, neurobehavioral tests, brain water content measurements, Evans blue permeability assay, and transmission electron microscopy were performed. Small interfering RNA targeting DMP1 (DMP1 siRNA) was administered at 72 h prior to ICH. Results showed that DMP1 is expressed extensively in the mouse brain, and is upregulated in the ICH model. Administration of DMP1 siRNA effectively ameliorated BBB disruption, attenuated brain edema, and improved neurological function after ICH. Moreover, the expression of zonula occludens-1 (ZO-1) and occludin were upregulated, and matrix metalloproteinase-9 (MMP-9) was downregulated in the ICH model. DMP1 siRNA administration reversed the expression of ZO-1, occludin, and MMP-9. These results demonstrated that DMP1 upregulation plays an essential role in inducing BBB disruption and brain injury after ICH. The inhibition of DMP1 could be a potential therapeutic strategy for ICH treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

As a selective inhibitor of mitochondrial fission protein dynamin-related protein-1 (Drp1), mitochondrial division inhibitor 1 (mdivi-1) can cross the blood-brain barrier (BBB) and exert neuroprotection. However, it remains unclear whether mdivi-1 can attenuate intracerebral hemorrhage (ICH)-induced secondary brain injury. This study was undertaken to characterize the roles of mdivi-1 in short-term and long-term behavioral outcomes, along with synaptic plasticity changes in mice after ICH. The results indicated mdivi-1 reversed Drp1 translocation and the morphologic changes of mitochondria, as well as ameliorated short-term neurobehavioral deficits, the BBB disruption and brain edema remarkably. In addition, mdivi-1 could rescue ICH-induced motor and memory dysfunctions. Mdivi-1 could also prevent ICH-induced reductions in synaptic proteins (synapsin I, PSD95) and phosphorylated cAMP-response element binding (p-CREB). In vitro, mdivi-1 inhibited hemin-induced hippocampal neuron death and improved neurite outgrowth. In conclusion, we found that mdivi-1 can alleviate short-term and long-term neurological deficits, synaptic dysfunction. These findings demonstrate that mdivi-1 may be beneficial in the treatment of secondary brain injury, synaptic dysfunction and neurological outcomes caused by ICH.

Background: Prostaglandin E1 (PGE1) exerts various pharmacological effects such as membrane stabilization, anti-inflammatory functions, vasodilation, and platelet aggregation inhibition. We have previously demonstrated that PGE1 has a beneficial impact on patients suffering from intracerebral hemorrhage (ICH). The related mechanism underlying PGE1's beneficial effect on ICH treatment needs further exploration., Methods: The present study elucidates the mechanism of PGE1 on ICH treatment using a neuronal apoptosis model in vitro . The mouse primary cortical neurons were pretreated with different concentrations of PGE1, followed by the treatment with hemin, the main catabolite in whole blood, to mimic the clinical ICH., Results: Comparing with the vehicle-treated group, PGE1 prevented cultured cortical neurons from the accumulation of inhibited intracellular levels of reactive oxygen species (ROS), amelioration of mitochondrial membrane potential, and hemin-induced apoptosis. The reduction of ROS and apoptosis were associated with the up-regulation of Heme oxygenase-1 (HO-1) expression. Knockdown of nuclear transcription factor erythroid 2-related factor (Nrf2) by siRNA attenuated the upregulation of HO-1 as well as the protective effect of PGE1., Conclusions: Our work suggests that the Nrf2/HO-1 molecular pathway may play a crucial role in treating ICH patients with PGE1 and may represent novel molecular targets, resulting in discovering new drugs for ICH treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5839). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Necroptosis-induced neuronal damage after intracerebral hemorrhage (ICH) has been documented recently. Previous studies have reported that RIP3 and its complex are recognized as central mediators of necroptosis. In this study, the role of RIP3 in the activation of CaMKII and AIF was investigated., Methods: We induced ICH in C57BL/6 mice by injecting collagenase IV into the basal ganglia. ICH mice were pretreated with the mPTP inhibitor CsA and the CAMKII inhibitor Kn-93, RIP3 siRNA or RIP3 rAAV. Brain edema and neurobehavior were evaluated. The expression of RIP3, p-MLKL, AIF, and CaMKII proteins was evaluated by western blotting, immunofluorescence (IF) and immunoprecipitation (IP)., Results: Significant increases in RIP3, p-MLKL, CaMKII and AIF expression were observed in ICH mice, and RIP3-AIF colocalized in the nucleus. Overexpression of RIP3 by rAAV upregulated AIF expression in both the cytoplasm and nucleus, while CaMKII expression was increased in the cytoplasm. The interaction of RIP3-AIF and RIP3-CaMKII was detected after ICH injury. These complexes were inhibited by CsA with Kn-93 or RIP3 siRNA pretreatment, which reduced brain edema and neurological deficits., Conclusions: Our findings revealed that ICH induced necroptotic neuronal death through the RIP3-CaMKII complex and the RIP3-AIF signaling pathway. Moreover, blockade of mPTP opening could suppress the pathogenesis of necroptosis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Iron has a key role in the activation of the autophagic pathway in rats with intracerebral hemorrhage (ICH), and hepcidin has the ability to reduce brain iron in ICH-rats. We therefore hypothesized that hepcidin might be able to inhibit autophagy by reducing iron in an ICH brain. Here, we investigated the effects of Ad-hepcidin and/or hepcidin peptide on autophagic activities in ICH models in vitro and in vivo. We demonstrated that ad-hepcidin and hepcidin peptide both inhibited hemin-induced increase in LC3-II/LC3-I conversion ratio and reversed the reduction in p62 content in cortical neurons in vitro. We also showed that ad-hepcidin inhibited ICH-induced increase in LC3-II/LC3-I conversion ratio and reversed ICH-induced reduction in p62 content in the brain cortex of rats in vivo. Based on these findings plus previous data on the effects of ad-hepcidin and/or hepcidin peptide on iron contents in ICH models, we suggested that hepcidin-induced inhibition of autophagy might be mediated via reducing iron in hemin-treated neurons in vitro and ICH-rat brain in vivo., (Copyright © 2021 Elsevier Inc. All rights reserved.)