Mapping cell diversity in human sporadic cerebral cavernous malformations.

BACKGROUND: Cerebral cavernous malformation (CCM) is a low-flow, bleeding-prone vascular disease that can cause cerebral hemorrhage, seizure and neurological deficits. Its inheritance mode includes sporadic or autosomal dominant inheritance with incomplete penetrance, namely sporadic CCM (SCCM) and familial CCM. SCCM is featured by single lesion and single affection in a family. Among CCM patients especially SCCM, the pathogenesis of the corresponding phenotypes and pathological features or candidate genes have not been fully elucidated yet. METHODS: Here, we performed in-depth single-cell RNA sequencing (scRNA-Seq) and bulk assay for transposase-accessible chromatin sequencing (ATAC-Seq) in SCCM and control patients. Further validation was conducted for the gene of interest using qPCR and RNA in situ hybridization (RNA FISH) techniques to provide further atlas and evidence for SCCM generative process. RESULTS: We identified six cell types in the SCCM and control vessels and found that the expression of NEK1, RNPC3, FBRSL1, IQGAP2, MCUB, AP3B1, ESCO1, MYO9B and PVT1 were up-regulated in SCCM tissues. Among the six cell types, we found that compared with control conditions, PVT1 showed a rising peak which followed the pseudo-time axis in endothelial cell clusters of SCCM samples, while showed an increasing trend in smooth muscle cell clusters of SCCM samples. Further experiments indicated that, compared with the control vessels, PVT1 exhibited significantly elevated expression in SCCM samples. CONCLUSION: In SCCM conditions, We found that in the process of development from control to lesion conditions, PVT1 showed a rising peak in endothelial cells and showed an increasing trend in smooth muscle cells at the same time. Overall, there was a significantly elevated expression of NEK1, RNPC3, FBRSL1, IQGAP2, MCUB, AP3B1, ESCO1, MYO9B and PVT1 in SCCM specimens compared to control samples.

Certification of stroke centers at primary hospitals and the improvement of thrombolysis n South China during 2020-2022.

INTRODUCTION: IVT use declined globally in 2020 due to the Corona Virus Disease 2019 (COVID-19) pandemic, but it increased in South China. This study was conducted to evaluate the association of establishing Stroke Prevention Centers (SPCs) at primary hospitals with IVT increase in South China. MATERIALS AND METHODS: We conducted a longitudinal observational study across 336 hospitals in 114 areas in South China during 2020-2022. Data regarding certified stroke centers, IVT volumes, and IVT rates were collected. Correlations between IVT rates and the number or density of stroke centers were accessed. IVT use was compared among areas with different levels of stroke centers or on different certification process. RESULTS: During 2020-2022, there were 83, 125, and 152 stroke centers, with 26, 65, and 92 SPCs, respectively. IVT therapies were 12,795, 17,266, and 20,411, representing a 29.8% increase/year (all p < 0.001). IVT rates increased from 7.2% in 2020 to 8.8% and 10.4% in 2021 and 2022, demonstrating a 22.2% increase/year (all p < 0.001). IVT rates correlated with the number and density of SPCs (all p < 0.05). IVT rates were higher in areas equipped with SPCs than in those without stroke centers (all p < 0.05). IVT rates consistently increased during the SPC certification process from 1 year before through the certification and subsequent maintenance (both p < 0.05). DISCUSSION AND CONCLUSION: Well-organised SPCs and IVT therapy demonstrated substantial increase during the 3-year period. Certification of SPCs at primary hospitals is associated with improved IVT therapy in South China even with city lockdown during COVID-19 pandemic.

Loss of Gucy1a3 causes poor post-stroke recovery by reducing angiogenesis via the HIF-1α/VEGFA signaling pathway in mice.

OBJECTIVES: Ischemic stroke is a common and debilitating disease that can cause permanent neurological damage. Gucy1a3, which encodes the α1 subunit of soluble guanylyl cyclase, has been reported to be associated with functional recovery after ischemic stroke. However, the mechanism is still not well understood. In the present study, we investigated the effects of Gucy1a3 on (i) post-stroke recovery; (ii) vascular endothelial growth factor A (VEGFA) and hypoxia inducible factor 1 alpha (HIF-1α) expression; and (iii) angiogenesis after ischemic stroke. MATERIALS AND METHODS: Wild-type and Gucy1a3 knockout C57BL/6J male mice were respectively used to establish the models of permanent middle cerebral artery occlusion (pMCAO). Neurological deficit scores were evaluated at 24 h and 96 h after pMCAO. Cerebral infarct volume was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. For determining microvessel density, immunohistochemical analysis was performed with CD31. The expression of VEGFA and HIF-1α was detected by western blotting. RESULTS: Our results suggest that loss of Gucy1a3 increased the infarct volume and aggravated neurological deficits after pMCAO. In addition, the Gucy1a3 knockout brains exhibited significantly lower microvessel densities and VEGFA and HIF-1α expression levels than the wild-type brains at 96 h post-pMCAO. CONCLUSIONS: Our study indicates that GUCY1A3 might be involved in angiogenesis after ischemic stroke. Further investigation of GUCY1A3 will provide a new therapeutic target for stroke.

Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and the Risk of Leukoaraiosis in a South Chinese Han Population: A Case-Control Study.

Leukoaraiosis (LA) appears as white matter hyperintensities on T2-weighted brain magnetic resonance imaging scans. Age and hypertension are considered the primary risk factors for LA, but its pathogenesis remains uncertain. This study aims to investigate the correlation between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and LA. A total of 140 patients with LA and 136 neuroimaging alteration-free controls were recruited in a case-control study. ACE I/D polymorphism was determined using the polymerase chain reaction method. The allele and genotype distributions of the ACE I/D polymorphism were significantly different between subjects with and without LA. Significant difference was observed in the genotypic distribution between LA patients and controls for recessive and additive models. A statistically significant association remained apparent after adjusting for potential risk factors (D/D vs. I/D + I/I: adjusted OR 3.251, 95% CI 1.185-8.918; D/D vs. I/I: adjusted OR 3.277, 95% CI 1.187-9.047). Our results indicate that the D/D genotype and D allele are important risk factors for LA. Future studies with larger populations are needed to validate our results.

RNF213 loss-of-function promotes pathological angiogenesis in moyamoya disease via the Hippo pathway.

Moyamoya disease is an uncommon cerebrovascular disorder characterized by steno-occlusive changes in the circle of Willis and abnormal vascular network development. Ring finger protein 213 (RNF213) has been identified as an important susceptibility gene for Asian patients, but researchers have not completely elucidated whether RNF213 mutations affect the pathogenesis of moyamoya disease. Using donor superficial temporal artery samples, whole-genome sequencing was performed to identify RNF213 mutation types in patients with moyamoya disease, and histopathology was performed to compare morphological differences between patients with moyamoya disease and intracranial aneurysm. The vascular phenotype of RNF213-deficient mice and zebrafish was explored in vivo, and RNF213 knockdown in human brain microvascular endothelial cells was employed to analyse cell proliferation, migration and tube formation abilities in vitro. After bioinformatics analysis of both cell and bulk RNA-seq data, potential signalling pathways were measured in RNF213-knockdown or RNF213-knockout endothelial cells. We found that patients with moyamoya disease carried pathogenic mutations of RNF213 that were positively associated with moyamoya disease histopathology. RNF213 deletion exacerbated pathological angiogenesis in the cortex and retina. Reduced RNF213 expression led to increased endothelial cell proliferation, migration and tube formation. Endothelial knockdown of RNF213 activated the Hippo pathway effector Yes-associated protein (YAP)/tafazzin (TAZ) and promoted the overexpression of the downstream effector VEGFR2. Additionally, inhibition of YAP/TAZ resulted in altered cellular VEGFR2 distribution due to defects in trafficking from the Golgi apparatus to the plasma membrane and reversed RNF213 knockdown-induced angiogenesis. All these key molecules were validated in ECs isolated from RNF213-deficient animals. Our findings may suggest that loss-of-function of RNF213 mediates the pathogenesis of moyamoya disease via the Hippo pathway.

Rnf-213 Knockout Induces Pericyte Reduction and Blood-Brain Barrier Impairment in Mouse.

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive occlusion of the internal carotid artery and the formation of an abnormal compensatory capillary network at the base of the brain. Genomics studies identified Ring finger protein 213 (RNF213) as a common genetic factor that increases the susceptibility to MMD in East Asian people. However, the function of RNF213 and its roles in pathogenesis of MMD is unclear. Here, we showed that genetic knockout of Rnf213 in mice causes significant pericyte reduction and blood-brain barrier impairment in the cortex. These phenotypes are accompanied with microglia activation and elevated level of proinflammatory cytokines. Additionally, Rnf213-deficient mice showed reduced expression of tight junction proteins, including Occludin, Claudin-5, and ZO-1. Together, these data suggested that RNF213 might contribute to the pathogenesis of MMD through disruption of pericyte homeostasis and blood-brain barrier integrity by dysregulation of inflammatory responses and tight junction formation.

Bioinformatic Analysis of Coexpressed Differentially Expressed Genes and Potential Targets for Intracerebral and Subarachnoid Hemorrhage.

BACKGROUND: Secondary brain injury following intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) is life threatening, and effective therapeutic strategies are lacking. This study aimed to understand the molecular pathogenesis of ICH- or SAH-induced secondary brain injury and provide insights regarding potential therapeutic options. METHODS: Original data of tissue microarray studies were downloaded from the Gene Expression Omnibus database. We identified the differentially expressed genes (DEGs) for each disease and common DEGs between ICH and SAH. Functional enrichment analyses were then analyzed, and a protein-protein interaction network was constructed to strictly select hub genes. Additionally, immune infiltration analyses were used to identify the common differently distributed cells in both diseases. Finally, animal model microarrays were used for external validation. RESULTS: We identified 158 common DEGs. The common DEGs were significantly enriched in cytotoxicity and inflammation pathways. The top 10 hub genes were then filtered through the protein-protein interaction networks. Moreover, natural regulatory T, T helper 17, and dendritic cells and monocytes and macrophages were identified as common differentially distributed immune cells. Additionally, target microRNAs and related drugs of hub genes were predicted. CONCLUSIONS: This study identified a variety of key genes and their respective molecular functions involved in both ICH and SAH for better understanding of the cytotoxic and inflammatory pathogenesis of secondary brain injury. The predicted targeted microRNAs and related drugs of hub genes not only could provide insights into the novel therapeutic strategies, but also could aid in future studies and drug discovery.

Impact of stroke center certification on rt-PA thrombolysis after acute ischemic stroke in South China from 2015 to 2020.

BACKGROUND AND PURPOSE: In China, stroke center certification was launched in 2015, but little is known about its impact on intravenous thrombolysis. This study aimed to evaluate the effects of stroke center certification on the use of intravenous thrombolysis during a five-year period in South China. METHODS: We retrospectively collected data regarding the use of recombinant tissue plasminogen activator (rt-PA) in 21 cities of Guangdong from 2015 to 2020. The annual thrombolysis rate was defined as the number of patients who underwent intravenous rt-PA therapy divided by the number of those who had acute ischemic stroke within the same year. The density of stroke centers was calculated as the number of stroke centers divided by the corresponding residents. Spearman's correlation analysis was used to determine the correlations between the annual thrombolysis rates and the number/density of stroke centers. Paired t-test was used to compare differences in growth in annual thrombolysis rates before and after having stroke centers. RESULTS: From 2015 to 2020, the annual rt-PA thrombolysis rates of Guangdong increased from 1.4% to 7.2%, which was accompanied by an increase in the number of stroke centers from 0 to 82 and density of stroke centers from 0.00 to 0.71 per million population. The average annual rt-PA use in stroke centers was higher than that in non-stroke centers from 2016 to 2020 (all P < 0.05). There was a positive correlation of annual thrombolysis rates with the number of stroke centers (r = 1.00, P = 0.0028) and with the density of stroke centers in the 21 cities from 2018 to 2020 (all P < 0.05). The growth in annual thrombolysis rates significantly accelerated at the city-level after having stroke centers (1.55%/y vs. 0.77%/y, P < 0.001). CONCLUSIONS: Stroke center certification may partially drive the increased use of rt-PA thrombolysis. Stroke center certification should be continually promoted to facilitate access to intravenous thrombolysis for patients with acute ischemic stroke.

Identification of immune-associated gene signature and immune cell infiltration related to overall survival in progressive multiple sclerosis.

BACKGROUND: Delayed diagnosis and noneffective treatment contribute to the shorter life expectancy in patients with progressive multiple sclerosis (PMS). Studies demonstrate the key role of autoimmunity in PMS, but the prognostic value of immune-associated factors remains unknown. Thus, this study aimed to develop an immune-associated gene (IAG) signature related to overall survival (OS) and conduct an immune cell infiltration analysis using PMS data. METHODS: The differentially expressed IAGs were identified based on gene expression profiles (from the Gene Expression Omnibus database) and IAGs (from the ImmPort database). Univariate and least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analyses were used to develop the IAG signature related to OS. Kaplan-Meier analyses were conducted, and receiver operating characteristic (ROC) curves were generated to assess the performance. Additionally, the differential distribution of immune cells was identified by Wilcoxon rank-sum tests and correlations with IAGs were analyzed using Spearman correlation analyses. Moreover, univariate and multivariate Cox regression analyses were used to identify the independent prognostic factors to develop a prognostic nomogram. RESULTS: The training group, consisting of 57 PMS lesions and 52 control tissues, was obtained through batch normalization to remove the inter-batch difference. A total of 206 differentially expressed IAGs were identified, and 38 of them were associated with OS. Thereafter, a 4-IAG signature was constructed to calculate the risk score and thus classify PMS patients into high- and low-risk groups according to mean risk score. Patients in the high-risk group had a lower survival time than those in the low-risk group. The Kaplan-Meier plots and ROC curves demonstrated a good performance in both the training and internal validation groups. Additionally, five differentially abundant immune cell types were identified and their relationships with IAGs were analyzed. Finally, risk score, cortical region, and naive B cells were identified as independent prognostic factors, and a nomogram incorporating these factors was developed to predict the OS in PMS. CONCLUSION: The novel IAG signature may be a reliable tool for assisting neurologists in predicting the OS for PMS patients in clinical settings. These findings may facilitate personalized treatment and provide insights into the complex mechanism of PMS.

N6-Methyladenosine RNA modification in cerebrospinal fluid as a novel potential diagnostic biomarker for progressive multiple sclerosis.

BACKGROUND: Progressive multiple sclerosis (PMS) is an uncommon and severe subtype of MS that worsens gradually and leads to irreversible disabilities in young adults. Currently, there are no applicable or reliable biomarkers to distinguish PMS from relapsing-remitting multiple sclerosis (RRMS). Previous studies have demonstrated that dysfunction of N6-methyladenosine (m6A) RNA modification is relevant to many neurological disorders. Thus, the aim of this study was to explore the diagnostic biomarkers for PMS based on m6A regulatory genes in the cerebrospinal fluid (CSF). METHODS: Gene expression matrices were downloaded from the ArrayExpress database. Then, we identified differentially expressed m6A regulatory genes between MS and non-MS patients. MS clusters were identified by consensus clustering analysis. Next, we analyzed the correlation between clusters and clinical characteristics. The random forest (RF) algorithm was applied to select key m6A-related genes. The support vector machine (SVM) was then used to construct a diagnostic gene signature. Receiver operating characteristic (ROC) curves were plotted to evaluate the accuracy of the diagnostic model. In addition, CSF samples from MS and non-MS patients were collected and used for external validation, as evaluated by an m6A RNA Methylation Quantification Kit and by real-time quantitative polymerase chain reaction. RESULTS: The 13 central m6A RNA methylation regulators were all upregulated in MS patients when compared with non-MS patients. Consensus clustering analysis identified two clusters, both of which were significantly associated with MS subtypes. Next, we divided 61 MS patients into a training set (n = 41) and a test set (n = 20). The RF algorithm identified eight feature genes, and the SVM method was successfully applied to construct a diagnostic model. ROC curves revealed good performance. Finally, the analysis of 11 CSF samples demonstrated that RRMS samples exhibited significantly higher levels of m6A RNA methylation and higher gene expression levels of m6A-related genes than PMS samples. CONCLUSIONS: The dynamic modification of m6A RNA methylation is involved in the progression of MS and could potentially represent a novel CSF biomarker for diagnosing MS and distinguishing PMS from RRMS in the early stages of the disease.

Development and Validation of a Nomogram to Predict the Individual Future Stroke Risk for Adult Patients With Moyamoya Disease: A Multicenter Retrospective Cohort Study in China.

Background: Studies exploring the predictive performance of major risk factors associated with future stroke events are insufficient, and a useful tool to predict individual risk is not available. Therefore, personalized advice for preventing future stroke in patients with moyamoya disease (MMD) cannot provide evidence-based recommendations. The aim of this study was to develop a novel nomogram with reliable validity to predict the individual risk of future stroke for adult MMD patients. Methods: This study included 450 patients from seven medical centers between January 2013 and December 2018. Follow-ups were performed via clinical visits and/or telephone interviews from initial discharge to December 2019. The cohort was randomly assigned to a training set (2/3, n = 300) for nomogram development and a test set (1/3, n = 150) for external validation. The Kaplan-Meier analyses and receiver operating characteristic (ROC) curves were applied to assess the clinical benefits of this nomogram. Results: Diabetes mellitus, a family history of MMD, a past history of stroke or transient ischemic attack, clinical manifestation, and treatment were identified as major risk factors via the least absolute shrinkage and selection operator (LASSO) method. A nomogram including these predictors was established via a multivariate Cox regression model, which displayed excellent discrimination [Harrell's concordance index (C-index), 0.85; 95% confidence interval (CI): 0.75-0.96] and calibration. In the external validation, the nomogram was found to have good discrimination (C-index, 0.81; 95% CI: 0.68-0.94) and calibration. In the subgroup analysis, this predictive nomogram also showed great performance in both ischemic-type (C-index, 0.90; 95% CI: 0.77-1.00) and hemorrhagic-type MMD (C-index, 0.72; 95% CI: 0.61-0.83). Furthermore, the nomogram was shown to have potential in clinical practice through Kaplan-Meier analyses and ROC curves. Conclusions: We developed a novel nomogram incorporating several clinical characteristics with relatively good accuracy, which may have considerable potential for evaluating individual future stroke risk and providing useful management recommendations for adult patients with MMD in clinical practice.

Associations between SNP83 of phosphodiesterase 4D gene and carotid atherosclerosis in a southern Chinese Han population: a case-control study.

Atherosclerosis was an important pathophysiological basis of atherothrombotic stroke, and phosphodiesterase 4D (PDE4D) polymorphism (SNP83/rs966221) was reported to be associated with the susceptibility to atherothrombotic stroke. Aim of the present study was to explore the potential association between SNP83 and carotid atherosclerosis (CAS). 204 southern Chinese Han participants were divided into two groups according to the carotid intima-media thickness (IMT) of the carotid artery: CAS group (carotid IMT ≥ 1.0 mm) and non-CAS group (carotid IMT < 1.0 mm). Carotid IMT was measured by color Doppler ultrasound. The PDE4D SNP83 polymorphism was determined by SNaPshot technique. Our study found that SNP83 was associated significantly with CAS susceptibility under the dominant, overdominant and codominant models. After adjusting for age, gender, low-density lipoprotein cholesterol, Hemoglobin A1c, cigarette smoking, hypertension history, and diabetes mellitus history, the association still remained significant (dominant model: crude OR = 2.373, 95% CI: 1.268-4.442, P = 0.007; adjusted OR = 3.129, 95% CI: 1.104-8.866, P = 0.032; overdominant model: crude OR = 1.968, 95% CI: 1.043-3.714, P = 0.037; adjusted OR = 2.854, 95% CI: 1.005-8.108, P = 0.049; codominant: crude OR = 2.102, 95% CI: 1.110-3.979, P = 0.023; adjusted OR = 2.984, 95% CI: 1.047-8.502, P = 0.041). Carotid IMT of carriers with CT + CC genotypes was higher than carriers with TT genotype (P = 0.016). Our results indicated that the SNP83/rs966221 located on PDE4D gene was significantly associated between CAS susceptibility and carotid IMT independently of conventional risk factors in a southern Chinese Han population.

Mutations of RNF213 are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish.

Although familial forms of cerebral cavernous malformation are mainly attributed to three CCM genes (KRIT1, CCM2 and PDCD10), no mutation is identified in sporadic cerebral cavernous malformation cases with a unique lesion, indicating additional genes for sporadic cerebral cavernous malformation. To screen the candidate genes, we conducted whole exome sequencing in 31 sporadic cerebral cavernous malformation patients and 32 healthy controls, and identified 5 affected individuals carrying 6 heterozygous deleterious mutations in RNF213 but no RNF213 mutation in healthy individuals. To further confirm RNF213 was associated with cerebral cavernous malformation, we generated rnf213a homozygous knockout zebrafish and found mutation of rnf213a in zebrafish led to a mulberry-like cluster of disordered-flow vascular channels which was reminiscent of human cerebral cavernous malformation. In addition, we revealed kbtbd7 and anxa6 were significantly downregulated due to rnf213a mutation through transcriptomic sequencing and RT-qPCR analysis. Based on the mulberry-like phenotype partly rescued by mRNA of kbtbd7 as well as anxa6, we suggested that rnf213a promoted mulberry-like cluster via downregulation of kbtbd7 and anxa6. Altogether, we firstly demonstrate RNF213is a novel candidate gene for sporadic cerebral cavernous malformation and the mutation of rnf213a is responsible for the mulberry-like cluster in zebrafish.

Development and Validation of a Five-Gene Signature to Predict Relapse-Free Survival in Multiple Sclerosis.

Background: Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system with a variable natural history of relapse and remission. Previous studies have found many differentially expressed genes (DEGs) in the peripheral blood of MS patients and healthy controls, but the value of these genes for predicting the risk of relapse remains elusive. Here we develop and validate an effective and noninvasive gene signature for predicting relapse-free survival (RFS) in MS patients. Methods: Gene expression matrices were downloaded from Gene Expression Omnibus and ArrayExpress. DEGs in MS patients and healthy controls were screened in an integrated analysis of seven data sets. Candidate genes from a combination of protein-protein interaction and weighted correlation network analysis were used to identify key genes related to RFS. An independent data set (GSE15245) was randomized into training and test groups. Univariate and least absolute shrinkage and selection operator-Cox regression analyses were used in the training group to develop a gene signature. A nomogram incorporating independent risk factors was developed via multivariate Cox regression analyses. Kaplan-Meier methods, receiver-operating characteristic (ROC) curves, and Harrell's concordance index (C-index) were used to estimate the performance of the gene signature and nomogram. The test group was used for external validation. Results: A five-gene signature comprising FTH1, GBP2, MYL6, NCOA4, and SRP9 was used to calculate risk scores to predict individual RFS. The risk score was an independent risk factor, and a nomogram incorporating clinical parameters was established. ROC curves and C-indices demonstrated great performance of these predictive tools in both the training and test groups. Conclusions: The five-gene signature may be a reliable tool for assisting physicians in predicting RFS in clinical practice. We anticipate that these findings could not only facilitate personalized treatment for MS patients but also provide insight into the complex molecular mechanism of this disease.

Prevalence of RNF213 variants in symptomatic intracranial arterial stenosis/occlusion in China.

The ring finger protein 213 gene (RNF213) rs112735431 was significantly associated with intracranial artery stenosis/occlusion disease (ICASO) in Japan and Korea and to a lesser degree in China. We conducted a case-control study to examine the prevalence and correlates of the RNF213 rare variants in Chinese patients with symptomatic ICASO. A total of 503 cases including 390 ischemic stroke patients (ICASO-IS), 113 intracranial hemorrhage patients (ICASO-ICH) and 227 control subjects were recruited. The snapshot technique was used for RNF213 rare variants analysis, including rs112735431, rs148731719, rs37144111 and rs138130613. Moreover, a meta-analysis was performed to explore the relationship between RNF213 variants and ICASO in Asian. In our case-control study, we found that the rs138130613 variant was significantly associated with ICASO-IS (OR = 9.92, 95% CI 1.24-79.19, p = 0.03). The mean age of first ischemic stroke onset of variant carriers was earlier than the noncarriers (51.3 ± 18.0 versus 66.0 ± 12.9 years old, p = 0.02), but the conventional atherosclerotic risk factors and the characteristics of artery stenosis did not differ between them. In addition, the meta-analysis showed significant association between the rs112735431 polymorphism and the ICASO or ICASO-IS, and this variant was found more often in women and young-onset patients in Asia. This study suggests that the RNF213 rs112735431 and rs138130613 are genetic risk variants for ischemic stroke with intracranial artery stenosis/occlusion in China and rs112735431 is also associated with the high risk of ICASO in Asia. Further large-scale investigation of the RNF213 gene will provide new insights into pathogenetic mechanisms of symptomatic ICASO.

Efficacy and Safety of Antiplatelet Agents for Adult Patients With Ischemic Moyamoya Disease.

Background: The use of antiplatelet agents in ischemic moyamoya disease (MMD) is controversial. This study aimed to investigate the effectiveness and safety of antiplatelet therapy compared with conservative treatment and surgical revascularization in ischemic MMD patients. Methods: Ischemic MMD patients were retrospectively enrolled from eight clinical sites from January 2013 to December 2018. Follow-up was performed through clinical visits and/or telephone interviews from first discharge to December 2019. The primary outcome was the episodes of further ischemic attacks, and the secondary outcome was the individual functional status. Risk factors for future stroke were identified by the LASSO-Cox regression model. Propensity score matching was applied to assemble a cohort of patients with similar baseline characteristics using the TriMatch package. Results: Among 217 eligible patients, 159 patients were included in the analyses after a 1:1:1 propensity score matching. At a mean follow-up of 33 months, 12 patients (7.5%) developed further incident cerebral ischemic events (surgical:antiplatelet:conservative = 1:3:8; p = 0.030), 26 patients (16.4%) developed a poor functional status (surgical:antiplatelet:conservative = 7:12:7; p = 0.317), and 3 patients (1.8%) died of cerebral hemorrhage (surgical:antiplatelet:conservative = 1:2:0; p = 0.361). The survival curve showed that the risk of further cerebral ischemic attacks was lowest with surgical revascularization, while antiplatelet therapy was statistically significant for preventing recurrent risks compared with conservative treatment (χ2 = 8.987; p = 0.011). No significant difference was found in the functional status and bleeding events. The LASSO-Cox regression model revealed that a family history of MMD (HR = 6.93; 95% CI: 1.28-37.52; p = 0.025), a past history of stroke or transient ischemic attack (HR = 4.35; 95% CI: 1.09-17.33; p = 0.037), and treatment (HR = 0.05; 95% CI: 0.01-0.32; p = 0.001) were significantly related to the risk of recurrent strokes. Conclusions: Antiplatelet agents were effective and safe in preventing further cerebral ischemic attacks in adult patients with ischemic MMD. They may be a replacement therapy for patients with surgical contraindications and for patients prior to revascularization.

AND score: a simple tool for predicting infection in acute ischemic stroke patients without a ventilator in the Chinese population.

OBJECTIVE: We aimed to develop a simple and user-friendly scoring system to predict all-cause hospital-acquired infections (HAIs) after acute ischemic stroke (AIS) in the Chinese population. METHODS: AIS patients from a retrospective cohort study at our center were included from January 2016 to December 2018. HAIs were diagnosed based on the current criteria from Ministry of Health of the People's Republic of China. Stepwise logistic regression models were performed to screen independent predictors of HAI after AIS. A scoring system was developed by including each of the above significant predictors. RESULTS: Among 1211 patients, 76 patients (6.28%) developed HAI. Age, baseline National Institute of Health stroke scale (NIHSS) score, and dysphagia were independent predictors of HAI. For the AND score, A refers to age, N refers to NIHSS, and D refers to dysphagia. The AND score showed a high area under the receiver operating characteristics (AUROC) curve (0.679), which comprised age (65-74 years was 4 points, 75-84 years was 6 points, ≥85 years was 8 points), NIHSS score ≥10 (5 points), and dysphagia (6 points). CONCLUSIONS: We developed a simple scoring system to predict all-cause infections after AIS patients without a ventilator in the Chinese population.

Bilateral cerebral infarction associated with severe arteriosclerosis in the A1 segment: a case report.

Large artery atherosclerosis and cardioembolism are the two major subtypes of ischemic stroke. We herein describe a 75-year-old man with acute complete cerebral infarction in the typical territories of the bilateral anterior cerebral artery (ACA) and left middle cerebral artery. Brain magnetic resonance angiography showed that the right A1 segment of the ACA was affected by severe arteriosclerosis and that the right ACA other than the A1 segment was compensated by the left ACA through the anterior communicating artery. Acute cardioembolism only occluded the left anterior circulation but simultaneously blocked the right ACA due to decompensation. We presume that the bilateral cerebral infarctions were caused by chronic atherosclerosis and acute cardioembolism.

Decreased Pituitary Height and Stunted Linear Growth After Radiotherapy in Survivors of Childhood Nasopharyngeal Carcinoma Cases.

To examine the morphological changes of the pituitary glands and linear growth of childhood nasopharyngeal carcinoma (NPC) cases who accepted radiotherapy. A total of 90 children (i.e., age less than 18 years) who were diagnosed as NPC at Sun Yat-sen University Cancer Center from January 2009 to January 2016 were identified by reviewing medical records. Two radiologists reviewed and measured the pre-radiation, post-radiation, and the latest available pituitary gland heights independently. Patients' current height information was collected by telephone interviews. We compared the pituitary height differences using paired t-tests and estimated the pituitary height trajectories within each sex by mixed regression models. Height-for-age Z-score was calculated for each patient using the WHO growth reference data for 5-19 years as reference. Most of the included participants were of male sex (75.6%) and over half were diagnosed at stage IV (58.4%). Among the 90 included participants, 89 had one repeated measurement of the pituitary height and 79 had two repeated measurements of the pituitary height. Seventy six of the 89 childhood NPC participants had reduced pituitary heights after radiation and accounted for 85.4% of the whole population. The means of the pituitary heights before and after radiotherapy were 6.4 ± 1.3 mm and 5.6 ± 1.2 mm (P < 0.001), respectively. The mean of height-for-age Z-score for childhood NPC cases was significantly below zero (-0.54, 95% CI = -0.74, -0.34). We concluded that childhood NPC cases had decreased pituitary heights and stunted linear growth after radiotherapy.