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Background: Collateral formation from the extracranial carotid artery to ischemic brain tissue determines the clinical success of superficial temporal artery (STA) to middle cerebral artery (MCA) bypass surgery in adult patients with moyamoya disease, but postoperative collateral formation (PCF) after STA-MCA bypass surgery is unpredictable. Accurate preoperative prediction of acceptable PCF could improve patient selection. This study aims to develop a prediction nomogram model for PCF in this patient population. Methods: Adult patients with moyamoya disease undergoing the STA-MCA bypass surgery between January 2013 and December 2020 at a single institution were retrospectively or prospectively enrolled in this observational study. Data including potential clinical and radiological predictors were obtained from hospital records. A nomogram was generated based on a multivariate logistic regression analysis, to identify potential predictors associated with good PCF. The performance of the nomogram was evaluated for discrimination, calibration, and clinical utility. Results: Data from 243 patients with moyamoya disease who underwent the STA-MCA bypass surgery were analyzed to build the nomogram. After 1-year follow-up, 162 (66.7%) hemispheres had good PCF and 81 (33.3%) had poor PCF. Good PCF is associated with 3 preoperative factors: age at operation, a diameter of donor branch of STA, and the preinfarction period stage. Incorporating these 3 factors, the model achieved a concordance index of 0.88 (95% CI, 0.84–0.92) and had a well-fitted calibration curve and good clinical application value. A cutoff value of 100 was determined to predict good PCF via this nomogram. Conclusions: The nomogram exhibits high accuracy in predicting good PCF after the STA-MCA bypass surgery in adult patients with moyamoya disease and may allow surgeons to better evaluate preoperatively candidacy for successful bypass surgery.

Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single-cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)–dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+/−) or CX3CR1+ myeloid cell–specific Nr4a2 (Nr4a2fl/flCx3cr1Cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacologic NR4A2 inhibition attenuated the protumorigenic TIME, and targeting the NR4A2 or SQLE enhanced the therapeutic efficacy of immune-checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2–SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer. Significance: Metabolic reprogramming of microglia in GBM informs synergistic vulnerabilities for immune-checkpoint blockade therapy in this immunologically cold brain tumor. This article is highlighted in the In This Issue feature, p. 799

Aims: To explore angiopoietin-1 (Ang-1) involved in cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (aSAH) through its effect on endoplasmic reticulum stress (ERS) and apoptosis of vascular endothelial cells (VECs). Background: CVS accounts for high morbidity and mortality of aSAH. Abnormal cellular physiological processes of VECs play a critical role in aSAH-induced CVS. In addition, Ang-1 is involved in regulating vascular structure and function. Objective: To study the role of Ang-1 played in CVS and the underlying mechanism. Methods: Blood samples of 130 aSAH patients were collected from 2016 to 2020 at West China Hospital of Sichuan University. A two-hemorrhage rodent model was employed to structure an aSAH-induced CVS rat model. Moreover, oxyHb was used to treat VECs to construct a CVS cell model in vitro. ELISA was used to measure the level of Ang-1 and HE staining to assess the rat's basilar arteries. Subsequently, CCK-8 was used to detect cell viability ability, and flow cytometry was used to test the cell apoptosis rate. Western blotting was used to determine the expression level of ERS marker and apoptosis-related proteins. Results: There was an abnormally low expression of Ang-1 in CVS patients and CVS rats; besides, oxyHb treatment decreased Ang-1 in VECs in a concentration-dependent manner. Ang-1 treatment led to the thinner basilar artery wall and lumen circumference in CVS rats; moreover, in oxyHbtreated VECs, Ang-1 treatment inhibited ERS and apoptosis. In addition, the expression of p-PI3K and p-Akt in the CVS group decreased, while the expression of p53 in the CVS group increased. The expression of p-PI3K and p-Akt in 8 CVS rats negatively correlates with the expression of Ang- 1, but the correlation between p53 and Ang-1 was positive. Furthermore, the results suggested that Ang-1 suppressed ERS and apoptosis of VECs through the regulated PI3K/Akt/p53 pathway. Conclusion: Elevated Ang-1 inhibited p53-mediated ERS and apoptosis of VECs through the activated PI3K/Akt pathway; Ang-1 might be an attractive treatment strategy for CVS.

Given the paucity of data on the subependymoma, we aimed to evaluate its risk factors from the Surveillance, Epidemiology, and End Results (SEER) database.We collected survival and clinical information on patients with subependymoma diagnosed between 1975 and 2016 from the SEER database and screened them according to inclusion and exclusion criteria. Then, univariate and multivariate Cox regression analyses were used to identify significant prognostic factors, and nomograms were constructed to visualize the results. The concordance index (C-index), receiver operating characteristic (ROC), and calibration curves were used to assess the predictive ability of the nomogram. We divided the patient scores into two groups according to the high- and low-risk groups and constructed a survival curve using Kaplan-Meier analysis.A total of 731 patients were initially enrolled, including 511 (69.9%) males and 220 (30.1%) females. After screening, a total of 581 patientswere further evaluated by statistical analysis. The 5- and 10-year survival estimates were 92.0% and 81.9%, respectively. Sex (male, p=0.018; HR=2.3547, 95% CI=1.158-4.788) and age (≥56 years, p0.001; HR=5.640, 95% CI= 3.139-10.133) were identified as independent prognostic factors for overall survival. The nomogram contained 4 prognostic factors. The C-index was 0.741, and the ROC and calibration curves also indicated the good predictability of the nomogram.In this large cohort, a significant association was noted between age/sex and outcome, which could serve an important role for patient education. Even though a significant association was not found between the extent of resection and outcome, the effect of surgery on prognosis should be further explored.

The third INTEnsive care bundle with blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT3) is an international, multicenter, stepped-wedge (4 phases/3 steps) cluster randomized trial involving 110 hospitals in mainly low- and middle-income countries during 2017–2022. The aim is to determine the effectiveness of a goal-directed care bundle of intensive blood pressure (BP) lowering, glycemic control, antipyrexia, and anticoagulation reversal treatment versus usual standard of care, in patients with acute intracerebral hemorrhage (ICH). After a “usual care” period, hospitals were randomly allocated to implementing care-bundle protocols for control targets (systolic BP

Elevated blood glucose is frequently detected early after aneurysmal subarachnoid hemorrhage (aSAH). We aimed to investigate whether hyperglycemia at admission is associated with mortality in patients with aSAH.In a multicenter observational study of patients with aSAH, we defined normal glycemia, mild hyperglycemia, moderate hyperglycemia, and severe hyperglycemia as blood glucose of 4.00-6.09 mmol/L, 6.10-7.80 mmol/L, 7.81-10.00 mmol/L, and 10.00 mmol/L, respectively. We performed propensity score matching to obtain the adjusted odds ratios (OR) with 95 % confidence intervals (CI).Of 6771 patients with aSAH, 511(7.5 %) had died in hospital, and hyperglycemia at admission was observed in 4804 (70.9 %). Propensity scores matching analyses indicated that compared with normal glycemia, the odds of in-hospital mortality were slightly lower in patients with mild hyperglycemia (OR 0.89, 95 % CI 0.56-1.40), significantly higher in patients with moderate hyperglycemia (OR 1.90, 95 % CI 1.20-3.01), and in patients with severe hyperglycemia (OR 3.45, 95 % CI 2.15-5.53; P trend 0.001). Long-term survival was worse among patients with hyperglycemia and was proportional to its severity. Similar dose-response associations were evident for poor functional outcomes and major disability. Hyperglycemia was associated with an increased risk of hospital-acquired infections (OR 1.46, 95 % CI 1.29-1.66) and rebleeding (OR 1.58, 95 % CI 1.06-2.35).Among aSAH patients, hyperglycemia at admission was independently associated with increased mortality. Both moderate hyperglycemia and severe hyperglycemia were associated with an increased risk of mortality, but these associations were not seen in mild hyperglycemia (blood glucose 6.10-7.80 mmol/L).

Lactate dehydrogenase (LDH) has been reported to be associated with outcomes after surgery in patients with aneurysmal subarachnoid hemorrhage (aSAH), but it is unclear if this is independent from other biomarkers and across all aSAH treatments. This study aims to assess whether LDH is an independent predictor of mortality in patients with aSAH and test whether the inclusion of LDH in a well-established prediction model can improve discrimination and reclassification.This was a retrospective observational study at a tertiary academic medical center. This study measured baseline LDH levels taken at admission and longitudinal LDH levels (up to a month postadmission) to assess median, max, and trajectory LDH levels. The primary outcome was mortality at 90 days. Multivariable regression analyses were used to evaluate associations between LDH and outcomes. The full original Subarachnoid Hemorrhage International Trialists' (SAHIT) model was used as the reference model.In total, 3524 patients with aSAH were included. LDH at admission was independently associated with mortality at 90 days (quartile 4 vs. 1: odds ratio 1.60; 95% CI 1.08-2.37) and mortality at the longest follow-up (quartile 4 vs. 1: hazard ratio1.72; 95% CI 1.34-2.20). Compared with the SAHIT model, the addition of three LDH (admission, max, and median) levels to the SAHIT model significantly improved the area under the curve and categorical net reclassification improvement for prediction mortality.In patients with aSAH, LDH level is an independent predictor of all-cause mortality. The incorporation of LDH into a well-established prediction model improved the ability to predict the risk of death in patients with aSAH.

As the second most common primary intracranial neoplasms, about 40% of pituitary adenomas (PAs) exhibit aggressive behaviors and resulting in poor patient prognosis. The molecular mechanisms underlying the aggressive behaviors of PAs are not yet fully understood. Biochemical studies have reported that programmed cell death 10 (PDCD10) is a component of the striatin-interacting phosphatase and kinase (STRIPAK) complex and plays a dual role in cancers in a tissue or disease-specific manner. In the present study, we report for the first time that the role of PDCD10 in PAs. Cell proliferation, migration and invasion were either enhanced by overexpressing or inhibited by silencing PDCD10 in PA cells. Moreover, PDCD10 significantly promoted epithelial–mesenchymal transition (EMT) of pituitary adenoma cells. Mechanistically, we showed that the expression of CXCR2, together with phosphorylation levels of AKT and ERK1/2 were regulated by PDCD10. Activation of CXCR2 inversed inactivation of AKT/ERK signal pathways and the tumor-suppressive effects induced by PDCD10 silencing. Finally, the pro-oncogenic effect of PDCD10 was confirmed by in vivo tumor grafting. Taken together, we demonstrate for the first time that PDCD10 can induce aggressive behaviors of PAs by promoting cellular proliferation, migration, invasion and EMT through CXCR2-AKT/ERK signaling axis CA extern

Background and Objective: The potential impact of rebleeding and delayed cerebral ischemia (DCI) on long-term survival in patients with aneurysmal subarachnoid hemorrhage (aSAH) remained unclear. This study aimed to investigate whether DCI and rebleeding increase the risk of long-term all-cause mortality in patients with aSAH who survived the follow-up period of one year. Methods: We retrospectively collected data on patients with atraumatic aSAH who were still alive 12 months after aSAH occurrence between December 2013 and June 2019 from the electronic health system. Patients were then classified by the occurrence of rebleeding or DCI during hospitalization. Death records were obtained from an administrative database, the Chinese Household Registration Administration System, until April 20, 2021. Multivariable Cox proportional hazards models were used to compare overall survival in different groups. Sensitivity analysis was performed with propensity-score matching (PSM). Results: A total of 2,607 patients were alive one year after aSAH. The crude annual death rate from any cause among patients who had rebleeding (7.2 per 100 person-years) and patients who had DCI (3.7 per 100 person-years) during hospitalization was higher than that of patients with neither event (2.1 per 100 person-years). Multivariate analysis showed that rebleeding is an independent risk factor for long-term mortality (adjusted hazard ratio (aHR), 2.37; 95% confidence interval (CI), 1.47- 3.81). DCI was an independent prognostic factor of poorer overall survival (aHR, 2.09; 95% CI, 1.54-2.84). Conclusions: Amongst patients alive one year after aSAH, rebleeding and DCI during hospitalization were independently associated with higher rates of long-term mortality.

Background Accurately predicting the outcome of isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) remains hitherto challenging. This study aims to Construct and Validate a Robust Prognostic Model for IDH wild-type GBM (COVPRIG) for the prediction of overall survival using a novel metric, gene-gene (G×G) interaction, and explore molecular and cellular underpinnings. Methods Univariate and multivariate Cox regression of four independent trans-ethnic cohorts containing 800 samples. Prediction efficacy was comprehensively evaluated and compared with previous models by a systematic literature review. The molecular underpinnings of COVPRIG were elucidated by integrated analysis of several bulk-tumor and single-cell expression profiles. Results Using a Cox-ph model-based method, six of the 93,961 G×G interactions were screened to form an optimal combination which, together with age, comprised the COVPRIG model. COVPRIG was designed for RNA-seq and microarray, respectively, and effectively identified patients at high risk of mortality. The predictive performance of COVPRIG was satisfactory, with aera under the curve (AUC) ranging from 0.56 (CGGA693, RNA-seq, 6-month survival) to 0.79 (TCGA RNAseq, 18-month survival), which can be further validated by decision curves. Nomograms were constructed for individual risk prediction for RNA-seq and microarray-based cohorts, respectively. Besides, the prognostic significance of COVPRIG was also validated in GBM including the IDH mutant samples. Notably, COVPRIG was comprehensively evaluated and externally validated, and a systemic review disclosed that COVPRIG outperformed current validated models with an integrated discrimination improvement (IDI) of 6~16% when calibrating to the same condition. Moreover, integrative bioinformatics analysis predicted an essential role of METTL1+ neural-progenitor-like (NPC-like) malignant cell in driving unfavorable outcome. Conclusion This study provided a powerful tool for the outcome prediction for IDH wild-type GBM, and preliminary molecular underpinnings for future research.

Background Short stature homeobox 2 (SHOX2) is significant gene in the development and progression of multiple types of tumors. Nonetheless, the biological role of SHOX2 within pan-cancer datasets has not been investigated. Thus, comprehensive bioinformatics analyses of pan-cancer datasets were conducted to explore how SHOX2 regulates tumorigenesis. Methods A variety of tumor datasets and online analytical tools, including SangerBox, TIMER2, LinkedOmic, GEPIA2 and cBioPortal, were applied to explore SHOX2 expression in various tumors. To ascertain the connections between SHOX2 expression and genetic alterations, SHOX2-related genes and tumor immunity, the pan-cancer datasets were examined. In vitro assays were applied to verify the biological functions of SHOX2 in glioma cells via CCK-8, wound healing, Transwell and colony formation assays. Results Analyses found that SHOX2 was overexpressed in multiple cancer types. SHOX2 expression level was significantly correlated with isocitrate dehydrogenase (IDH), 1p/19q, O6-methylguanine DNA methyltransferase (MGMT) status and new types of glioma patients. High mRNA expression levels of SHOX2 were associated with a poor prognosis in multiple tumor patients. KEGG enrichment analysis showed that SHOX2-related genes were associated with cell cycle and DNA damage repair. Genetic alterations of SHOX2 were identified in multiple types of cancers, including duplications and deep mutations. Immune analysis showed that SHOX2 was closely correlated with the tumor mutation burden (TMB), microsatellite instability (MSI), neoantigen and neoantigens and immune checkpoint (ICP) in a variety of tumors and could influence the immunotherapy sensitivity of cancers. CCK-8, wound healing, Transwell and colony formation experiments showed that SHOX2 knockdown inhibited glioma cell proliferation, migration, invasion and colony formation abilities. Conclusion SHOX2 was overexpressed in multiple cancer types in TCGA cohort. SHOX2 knockdown inhibited glioma cell proliferation, migration and colony formation ability. Our study showed that SHOX2 may be an immunotherapeutic and promising prognostic biomarker in certain types of tumors.

BackgroundIntracranial aneurysms (IA) is a common condition and may ultimately result in life-threatening hemorrhagic strokes. A precise understanding of the cellular and gene expression perturbations in human IA tissue may enlighten additional therapeutics for unruptured IA.MethodsA total of 21,332 qualified cells were obtained from four cell-sparse ruptured and unruptured human IA tissues. Detailed cell atlas and dynamics, gene expression perturbations, and inflammation features were thoroughly investigated using multiple machine learning-based algorithms.ResultsEndothelial cells, smooth muscle cells (SMCs), fibroblasts and, for the first time, pericytes have been identified in human IA tissue. A significant proportion of immune cells are also identified, with the number of monocyte/macrophages and neutrophils being notably higher in ruptured IA. By leveraging external datasets, macrophages characterized by transcriptional activation of NF-κB and HIVEP2 is most strongly associated with IA rupture. Interestingly, the recruitment and activation of macrophages and their functional characteristics in terms of TNFα and chemokine production remain consistent between unruptured and ruptured IA.ConclusionsThis study provides insights into the pathophysiology and molecular underpinnings of the IA wall and may motivate novel therapeutic options for unruptured IA.

Background: N6-methyladenosine (m6A) and 5-methylcytosine (m5C) are the main RNA methylation modifications involved in the oncogenesis of cancer. However, it remains obscure whether m6A/m5C-related long non-coding RNAs (lncRNAs) affect the development and progression of low grade gliomas (LGG). Methods: We summarized 926 LGG tumor samples with RNA-seq data and clinical information from the Cancer Genome Atlas and Chinese Glioma Genome Atlas. 105 normal brain samples with RNA-seq data from the Genotype Tissue Expression project were collected for control. 39 m6A/m5C-related genes were used to draw co-expressed lncRNAs network. We obtained a molecular classification cluster from the expression pattern of sreened lncRNAs. The least absolute shrinkage and selection operator (LASSO) Cox regression was employed to construct a m6A/m5C-related lncRNAs prognostic signature of LGG. In vitroexperiments were employed to validate the biological functions of lncRNAs in our risk model. Results: The expression pattern of 14 sreenedhighly correlated lncRNAs could cluster samples into two groups, in which various clinicopathological features and the tumor immune microenvironment were significantly distinct. The survival time of cluster 1 was significantly reduced compared with cluster 2. This prognostic signature is based on 8 m6A/m5C-related lncRNAs (GDNF-AS1, HOXA-AS3, LINC00346, LINC00664, LINC00665, MIR155HG, NEAT1, RHPN1-AS1). Patients in the high-risk group harbored shorter survival times. Time-ROC curve analysis was confirmed that our model had promising predictive power in survival prediction for both the TCGA (AUC at 1/3/5years respectively: 0.86, 0.84 and 0.77) and CGGA cohorts (AUC at 1/3/5years respectively: 0.73, 0.76 and 0.76). Notably, WHO class II, IDH mutation, 1p/19q co-deletion and MGMT promoter methylation were decreased in the high-risk group. Immunity microenvironment analysis showed B cells, CD4+ T cells, macrophages, and myeloid-derived DC cells were significantly increased in the high-risk group. In addition, patients in high-risk group possessed more CNVs, and higher G-score. Patients in high-risk group had the worse overall survival time regardless of followed TMZ therapy or radiotherapy. All observed results from the TCGA-LGG cohort could be validated in CGGA cohort. Afterwards, we investigated the biological functions of LINC00664 in glioma cells in vitro. LINC00664 was found to promote cell viability, invasion and migration ability of glioma cells. Conclusion: Our study elucidated a prognostic prediction model of LGG by 8 m6A/m5C methylated lncRNAs and a critical lncRNA regulation function involved in LGG progression. High-risk patients have shorter survival times and a pro-tumor immune microenvironment.

Supplemental Figure S4 describes that NR4A2-knockdown affects lipid metabolism and promotes antigen presentation of microglia.

Supplemental Figure S1 describes elevated oxidative stress challenge in the microglia of glioma.

Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single-cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)–dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+/−) or CX3CR1+ myeloid cell–specific Nr4a2 (Nr4a2fl/flCx3cr1Cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacologic NR4A2 inhibition attenuated the protumorigenic TIME, and targeting the NR4A2 or SQLE enhanced the therapeutic efficacy of immune-checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2–SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer.Significance:Metabolic reprogramming of microglia in GBM informs synergistic vulnerabilities for immune-checkpoint blockade therapy in this immunologically cold brain tumor.This article is highlighted in the In This Issue feature, p. 799

Table S2 describes information of key research agents, data deposition and software versions.

Supplemental Figure S6 describes that inhibition of NR4A2 or SQLE improves the therapeutic efficacy of immune checkpoint blockade.

Supplemental Figure S2 describes that oxidative stress in microglia promotes the immunosuppressive functions of microglia.

Supplemental Figure S7 describes that oxidative stress in microglia as an independent predictor for clinical outcome in glioma patients.

Table S4 describes list of literature-based immune marker panel selected to identity cell types of obtained clusters.

Table S3 describes primer information for qPCR analysis.

Supplemental Figure S5 describes that genetic knockout of Nr4a2 in microglia reverses immunosuppressive state.

Supplemental Figure S3 describes that inhibiting nuclear translocation of NR4A2 hampers immunosuppressive functions and promotes antigen presentation capacities of microglia.

Background and purposeThough hypertension disorders of pregnancy (HDP) are recognized as independent pregnancy-associated stroke risk factors, few studies have considered their impact on stroke prognosis. Therefore, we intended to evaluate the impact of HDP on short- and long-term outcomes of pregnancy-associated hemorrhagic stroke (HS).MethodsWe conducted a retrospective analysis of patients admitted to our hospital from May 2009 to December 2021 with a diagnosis of pregnancy-associated HS. After dividing patients into two groups by the presence of a diagnosis of HDP or not, the short- (at the time of discharge) and long-term (after discharge follow-up) outcomes were compared by mRS (modified Rankin Scale) scores, and poor functional outcome defined as mRS > 2. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were reported.ResultsTwenty-two HDP and 72 non-HDP pregnancy-associated HS patients were enrolled and follow-up after 4.7 ± 3.6 years. There was no significant difference between the two groups regarding short-term outcomes, but patients with HDP were more likely to reach poor functional outcomes at long-term follow-up (aOR = 4.47, 95% CI = 1.28–15.67, p = 0.019).ConclusionsIn this retrospective study, women with hypertension disorders of pregnancy did not show worse short-term outcomes of pregnancy-associated hemorrhagic stroke compared to those without but had poorer long-term functional outcomes. This underlines the importance of prevention, recognition, and treatment of hypertension disorders in these women.

BACKGROUND: The molecular subtype of breast cancer is one of the most important factors affecting patient prognosis. The study aimed to analyze the association between quantitative and qualitative features of contrast-enhanced mammography (CEM) images and breast cancer molecular subtypes. METHODS: This retrospective double-center study included women who underwent CEM between November 2017 and April 2020. Each patient had at least 1 malignant lesion confirmed by pathology. The CEM images were evaluated by 2 radiologists to obtain quantitative and qualitative image features. The molecular subtypes were studied as dichotomous outcomes, including luminal versus non-luminal, human epidermal growth factor receptor (HER2)-enriched versus non-HER2-enriched, and triple-negative breast cancer (TNBC) versus non-TNBC subtypes. The association between the image features and molecular subtypes was analyzed by multivariate logistic regression, with odds ratios (ORs) and 95% confidence intervals (CIs) provided. RESULTS: A total of 151 patients with 160 malignant lesions were included in the study. For quantitative features, a higher standard deviation of lesion density was associated with non-luminal (OR =0.88, 95% CI: 0.81 to 0.96, P=0.004) and HER2-enriched breast cancers (OR =1.16, 95% CI: 1.04 to 1.28, P=0.006). The relative degree of enhancement (RDE) and contrast-to-noise ratio (CNR) were not associated with molecular subtypes. However, a higher CNR/lesion size (OR =1.06, 95% CI: 1.01 to 1.12, P=0.012) was associated with luminal subtype cancers, and a higher RDE/lesion size (OR =0.94, 95% CI: 0.88 to 1.00, P=0.035) or a higher CNR/lesion size (OR =0.94, 95% CI: 0.88–1.00, P=0.038) was associated with non-TNBCs. For qualitative features, the presence of calcification was associated with HER2-enriched breast cancers (OR =2.91, 95% CI: 1.10 to 7.67, P=0.031). The presence of architectural distortion was associated with luminal cancer (OR =14.50, 95% CI: 1.91 to 110.14, P=0.010) and non-TNBC (OR =0.05, 95% CI: 0.00 to 0.43, P=0.022). Non-mass enhancement (OR =2.78, 95% CI: 1.08 to 7.14, P=0.033) was associated with HER2-enriched breast cancers. An association remained after adjustments for age, breast thickness, and breast density (all adjusted P

Diffuse midline glioma-H3K27M mutant (DMG) and glioblastoma (GBM) are the most lethal brain tumors that primarily occur in pediatric and adult patients, respectively. Both tumors exhibit significant heterogeneity, shaped by distinct genetic/epigenetic drivers, transcriptional programs including RNA splicing, and microenvironmental cues in glioma niches. However, the spatial organization of cellular states and niche-specific regulatory programs remain to be investigated. Here, we perform a spatial profiling of DMG and GBM combining short- and long-read spatial transcriptomics, and single-cell transcriptomic datasets. We identify clinically relevant transcriptional programs, RNA isoform diversity, and multi-cellular ecosystems across different glioma niches. We find that while the tumor core enriches for oligodendrocyte precursor-like cells, radial glial stem-like (RG-like) cells are enriched in the neuron-rich invasive niche in both DMG and GBM. Further, we identify niche-specific regulatory programs for RG-like cells, and functionally confirm that FAM20C mediates invasive growth of RG-like cells in a neuron-rich microenvironment in a human neural stem cell derived orthotopic DMG model. Together, our results provide a blueprint for understanding the spatial architecture and niche-specific vulnerabilities of DMG and GBM.

BackgroundSchwannomas of the trochlear nerve with the absence of systemic neurofibromatosis are considerably uncommon, especially complicated by intra-tumoral hemorrhage. Due to the lack of typical clinical manifestations and imaging findings, a definite diagnosis of trochlear schwannomas before surgery is particularly difficult.Case presentationWe report the case of a 64-year-old female patient who presented with a unilaterally intermittent headache of 2-month duration and without a remarkable neurological deficit at admission. Imaging studies revealed a well-demarcated cystic-solid lesion with mixed signals beside the brainstem and suprasellar cisterna. The patient underwent a surgical operation with total resection of the tumor by a subtemporal surgical approach. The tumor was intraoperatively found to originate from the trochlear nerve and was pathologically confirmed as a hemorrhagic schwannoma with cystic degeneration.ConclusionsWe describe this case in detail and conduct a concomitant survey of the literature, summarizing the clinical presentations, radiological features, surgical treatment, and the possible mechanisms of hemorrhage in relevance to trochlear nerve schwannoma.

Low serum albumin levels have been identified as a predictor of infectious complications in critically ill patients. However, the association in patients with aneurysmal subarachnoid hemorrhage (aSAH) remains unclear. We aimed to evaluate the prognostic value of hypoalbuminemia using blood samples at admission in patients with aSAH.In a multicenter observational study of patients with aSAH, serum albumin counts were collected on admission. Hypoalbuminemia was defined as a total albumin level 35 g/L. Multivariable logistic regression analyses and propensity score matching were performed to obtain the adjusted odds ratios (ORs) with 95% confidence intervals (CI) for the primary outcome of hospital-acquired infections.A total of 5448 patients were included in the observational cohort study. The odds of hospital-acquired infections were significantly higher in patients with albumin levels 30-34.9 g/L (OR 1.62, 95% CI 1.38-1.90), 25-29.9 g/L (OR 1.97, 95% CI 1.54-2.51), and 24.9 g/L (OR 2.43, 95% CI 1.53-3.86) compared with patients with albumin level ≥ 35 g/L. The odds of hospital-acquired infections with a change in albumin levels from admission to 48-72 h later of lower than - 10 g/L and - 10 to - 5 g/L were 1.67 (95% CI 1.41-1.86) and 1.24 (95% CI 1.05-1.46), respectively, compared with a change in albumin levels of - 5 to 5 g/L.In this large study of matched patients with aSAH, hypoalbuminemia at admission was associated with hospital-acquired infections. A decrease in serum albumin levels within 72 h of admission was associated with higher hospital-acquired infections.

To verify whether mesenchymal stem cells cocultured with tanshinone IIA may ameliorate Alzheimer's disease by inhibiting oxidative stress.Sixty male Sprague-Dawley rats were randomly divided into 4 groups named Sham, Aβ25-35, mesenchymal stem cells, and mesenchymal stem cells (tanshinone IIA). The rats were treated according to different groups. The neurobehavioral performance of Sprague-Dawley rats was evaluated via Morris water maze test. Histological changes were checked via hematoxylin-eosin staining. The levels of total antioxidant activity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and malondialdehyde in hippocampus were assayed by ELISA kit. The levels of Aβ, p-tau/tau, and p-AMP-activated protein kinase/AMP-activated protein kinase in hippocampus were checked by Western blot.Our research showed that the injection of mesenchymal stem cells (tanshinone IIA) into the hippocampus alleviated learning and memory deficits and reduced hippocampal neuronal injury in the Alzheimer's disease rats. Moreover, mesenchymal stem cells (tanshinone IIA) treatment suppressed oxidative stress, attenuated Aβ accumulation reduced Tau hyperphosphorylation, and enhanced the activity of AMP-activated protein kinase in the hippocampus of the Alzheimer's disease rats. However, there were almost no significant difference between the mesenchymal stem cells and Aβ25-35 groups.Mesenchymal stem cells (tanshinone IIA) transplantation may be a potential treatment for curing Alzheimer's disease, which may be related to the inhibition of oxidative stress.

Background: The third INTEnsive care bundle with blood pressure Reduction in Acute Cerebral Haemorrhage Trial is an ongoing international, multicentre, stepped wedge, cluster-randomized trial to determine the effectiveness of a goal-directed care bundle (early intensive blood pressure [BP] lowering, glycaemic control, treatment of pyrexia, and reversal of anticoagulation), as compared to standard of care, on patient-centred outcomes after acute intracerebral haemorrhage (ICH). An embedded process evaluation aims to identify factors related to the uptake and implementation of the intervention. Herein, we present the process evaluation results for hospital sites in China. Methods/Design: A mixed methods approach, including surveys, focused group discussions and interviews with clinicians, routine monitoring, and recruitment logs were used to collect data across purposively sampled hospitals. Medical Research Council guidance and normalization process theory were used as theoretical frameworks for design, data analysis, and synthesis. Results: Twenty quantitative surveys were completed with clinicians, and 26 interviews and 2 focus group discussions were conducted during 2019–2020. The care bundle was generally delivered as planned and acceptable by doctors and nurses, but difficulties were reported in achieving the protocol-defined target levels of BP and glycaemic control. Resistance to implementing the care bundle occurred for patients perceived to be at high risk of adverse effects. Common organizational contextual factors that impeded implementation included delayed processes and limited medication supply, while established background care procedures, expertise, and capacity influenced its integration into routine practice. Areas to facilitate implementation included optimizing workflow within available resources, having a dedicated team, and recognizing the potential benefits of the intervention. Conclusions: Varied established care protocols across sites, different levels of background expertise, and lack of staff capacity impeded the integration of goal-directed care bundle into routine practice for ICH patients in China. Ready identification, and efforts to address, these barriers could facilitate uptake of future guideline-recommended interventions for the management of patients with ICH.

Backgrounds: Previous studies reported inconsistent results regarding associations between apolipoprotein E (APOE) polymorphism and clinical outcomes after ischemic stroke (IS), intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). Thus, the study was designed to make a systematic review and meta-analysis regarding the association between APOE polymorphism and clinical outcome after IS, ICH, and SAH. Methods: To identify studies eligible for this meta-analysis, we searched for articles published before August 2021 in the databases (PubMed, Web of Science, and Google Scholar). We used STATA 12.0 software to compute hazard ratios (HRs) and their 95% confidence intervals (CIs) regarding APOE polymorphism and clinical outcome after IS, ICH, and SAH. Results: Meta-analysis showed no significant association between APOE polymorphism and functional outcome after IS with fixed effects models (ε4 carrier vs. non-ε4 carrier: HR, 1.00; 95% CI: 0.83–1.21, I2 = 29.4%, p = 0.183; ε2 carrier vs. non-ε2 carrier: HR, 0.92; 95% CI: 0.72–1.16, I2 = 15.6%, p = 0.307). Meta-analysis showed that ICH patients carrying ε4 allele have increased risk of poor outcome in Caucasian population with fixed effects models (ε4 carrier vs. non-ε4 carrier: HR, 1.75; 95% CI: 1.19–2.57, I2 = 0.0%, p = 0.543). Meta-analysis showed no significant association between APOE polymorphism and functional outcomes after SAH with random effects models (ε4 carrier vs. non-ε4 carrier: HR, 1.51; 95% CI: 0.80–2.84, I2 = 57.1%, p = 0.022). Conclusions: In conclusion, the present study demonstrated APOE ε4 carriers show worse functional outcomes after ICH, but not after IS or SAH. More large-scale studies were critical to explore the association between APOE polymorphism and clinical outcome after IS, ICH, and SAH.