bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of the Relationship between Hub Genes and Immune Cell Infiltration in Vascular Endothelial Cells of Proliferative Diabetic Retinopathy Using Bioinformatics Methods
Authors: Huang Jing , Zhou Qiong
Published: February 2022

Background. Diabetic retinopathy (DR) is a serious ophthalmopathy that causes blindness, especially in the proliferative stage. However, the pathogenesis of its effect on endothelial cells, especially its relationship with immune cell infiltration, remains unclear. Methods. The dataset GSE94019 was downloaded from the Gene Expression Omnibus (GEO) database to obtain DEGs. Through aggregate analyses such as Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis, a protein-protein interaction (PPI) network was constructed to analyze the potential function of DEGs. Weighted gene coexpression network analysis (WGCNA) and Cytoscape software including molecular complex detection (MCODE) and cytoHubba plug-ins were used to comprehensively analyze and determine the hub genes. ImmuCellAI analysis was performed to further study the relationship between samples, hub genes, and 24 types of immune cell infiltration. Finally, gene-set enrichment analysis (GSEA) was employed to identify the enrichment of immune cell infiltration and endothelial cell phenotype modifications in GO biological processes (BP) based on the expression level of hub genes. Results. 2393 DEGs were identified, of which 800 genes were downregulated, and 1593 genes were upregulated. The results of functional enrichment revealed that 1398 BP terms were significantly enriched in DEGs. Three hub genes, EEF1A1, RPL11, and RPS27A, which were identified by conjoint analysis using WGCNA and Cytoscape software, were positively correlated with the number of CD4 naive T cells and negatively correlated with the numbers of B cells. The number of CD4 naive T cells, T helper 2 (Th2) cells, and effector memory T (Tem) cells were significantly higher while CD8 naive T cells and B cells significantly were lower in the diabetic group than in the nondiabetic group. Conclusions. We unearthed the DEGs and Hub genes of endothelial cells related to the pathogenesis of PDR: EEF1A1, RPL11, and RPS27A, which are highly related to each other and participate in the specific biological process of inflammation-related immune cell infiltration and endothelial cell development, chemotaxis, and proliferation, thus providing new perspectives into the diagnosis of and potential “killing two birds with one stone” targeted therapy for PDR.
Service Provisioning in Sliced Cloud Radio Access Networks
Authors: Zou Hong , Zhou Min , Cui Yaping , He Peng , Zhang Hong , Wang Ruyan
Published: February 2022

Network slicing- (NS-) based cloud radio access networks (C-RANs) have emerged as a key paradigm to support various novel applications in 5G and beyond networks. However, it is still a challenge to allocate resources efficiently due to heterogeneous quality of service (QoS) requirements of diverse services as well as competition among different network slices. In this paper, we consider a service provisioning allocation framework to guarantee resource utilization while ensuring the QoS of users. Specifically, an inter/intraslice bandwidth optimization strategy is developed to maximize the revenue of the system with multiple network slices. The proposed strategy is hierarchically structured, which decomposes into network-level slicing and packet scheduling level slicing. At the network level, resources are allocated to each slice. At the packet scheduling level, each slice allocates physical resource blocks (PRBs) among users associated with the slice. Numerical results show that the proposed strategy can effectively improve the revenue of the system while guaranteeing heterogeneous QoS requirements. For example, the revenue of the proposed strategy is 21% higher than that of the average allocation strategy.
Multifactor Stock Selection Strategy Based on Machine Learning: Evidence from China
Authors: Gao Jieying , Guo Huan , Xu Xin
Published: February 2022

Machine learning methods have been used in multifactor stock strategy for years. This paper uses three machine learning methods and linear regression method to find the most appropriate approach. First, a framework is established and 10 style factors and 30 industry factors are chosen. Second, four methods are used to forecast portfolio returns and compared by predicting returns, successful rate, and Sharpe ratio. Finally, this paper draws conclusion. The main findings are as follows: the support vector regression has the most stable successful rate for predicting, while ridge regression and linear regression have the most unstable successful rate with more extreme cases; algorithm of support vector regression fitting higher‐degree polynomials in Chinese A‐share market is optimized, compared with the traditional linear regression both in terms of stock return and retracement control; the results of support vector regression significantly outperforming the CSI 500 index prove further.
Multisensor Management Method for Ground Moving Target Tracking Based on Doppler Blind Zone Information
Authors: Zhang Yunpu , Shan Ganlin , Zhang Rui , Duan Xiusheng
Published: February 2022

Tracking ground moving target with sensors proves to be a challenge due to the uncertainty of target motion area, the existence of Doppler blind zone (DBZ), and the complex terrain. In this paper, a multisensor management method based on DBZ information is presented, in which the available sensors are selected to obtain the best operational revenues for ground moving target tracking. First, the ground target motion model is established considering the off-road/on-road state based on road topology information. Second, the sensor measurement model is given combined with the DBZ information, and a decorrelation method of measurement noise is proposed. Third, a target state estimation algorithm is derived using particle filter, in which the DBZ information is regarded as prior information. Then, combined with the variable structure interacting multiple model method, an estimation algorithm for tracking maneuvering target is proposed. Furthermore, an optimization model of nonmyopic sensor management is constructed to obtain the best sensor management scheme. Finally, the advancement and effectiveness of the proposed management method are verified in the simulations.
Influence of Coal Caving Time and Tail Beam Swing Angle on the Evolution of the Coal Gangue Boundary Line during Top Coal Caving
Authors: Zeng Qingliang , Zhu Yanpeng , Yang Yang , Li Zhe , Wan Lirong
Published: February 2022

In the process of top coal caving mining, the caving time and the tail beam swing angle have an important impact on the evolution of the coal gangue boundary, which determines the top coal recovery rate and gangue content rate. Therefore, it is necessary to study the influence of the caving time and the tail beam swing angle on the top coal caving effect. For this purpose, based on Hertz–Mindlin contact theory, this paper established a simulation model of top coal caving and carried out a coal caving simulation with different caving times and tail beam swing angles. In the process of coal caving, under a specific tail beam swing angle and different caving times, this work studied the evolution characteristics of the coal gangue boundary. A simulation model of coal caving with variable time is established, and the influence mechanism of time on the coal caving effect is analyzed. Then, the evolution characteristics of the boundary are studied under different tail beam swing angles and the same caving time. A simulation model of coal caving with variable angles is established, and the influence mechanism of the tail beam swing angle on the coal caving effect is analyzed. Finally, the effects of caving time and tail beam swing angle on coal gangue discharge are studied, and the effect of coal gangue release under different working conditions is analyzed. The boundary data and the discharge data are extracted through the simulation, and contrast curves are drawn. The results show a limit position of the coal gangue boundary under the fixed working condition, which is the middle line position of the coal caving outlet. When the coal gangue boundary does not reach the limit position, there are two characteristics. First, the greater the tail beam swing angle is, the faster the deformation speed of the coal gangue boundary is. At the same caving time, the position of the coal gangue boundary will be closer to the coal caving outlet, which leads to excessive mixing of coal and gangue. Second, the longer the drawing time, the greater the deformation of the coal gangue boundary, and the easier the coal gangue is mixed, resulting in an increase in the gangue content of the discharged coal. When the coal gangue boundary reaches the limit position, the boundary will be basically stable near the top of the coal caving outlet. The limit position and shape of the coal gangue boundary are mainly affected by the density difference of coal gangue particles but not by the coal caving time and the tail beam swing angle. After the end of coal caving, the coal gangue boundary finally presents a double arch structure. The research in this paper has important reference significance for the selection of caving time and tail beam swing angle and further research.
Borderline Personality Disorder, Lived Space, and the Stimmung
Authors: Lo Monte Fabian , Englebert Jérôme
Published: February 2022

Most articles and theories about borderline personality disorder (BPD), either in the psychoanalytical field or the cognitivist one, explicitly or implicitly inscribe themselves in a topographical framework that either carry a fundamental representational a priori or give prominence to causal explanations. Less is written about the phenomenological everyday life-world of borderline people. This article aims to contribute to the description of such a world. Drawing upon clinical sequences that give prominence to the first-person perspective, we will analyse the experience of some typical “symptoms” of BPD in a phenomenological and topological way. We will be led to conclude that the borderline stimmung seems to display the following characteristics: a pervading immediacy of lived experience, a territorialization that tends towards ubiquity, a certain difficulty to deal with the unity and difference poles, a quite horizontal concern with ecstasy and elation, and a waning of reflexivity in the lived space.
What Should Be Responsible for Eryptosis in Chronic Kidney Disease?
Authors: Li Dongxin , Zheng Xujuan , Zhang Yunxia , Li Xiangling , Chen Xuexun , Yin Yonghua , Hu Jingwen , Li Jialin , Guo Min , Wang Xiangming
Published: February 2022

Background: Renal anemia is an important complication of chronic kidney disease (CKD). In addition to insufficient secretion of erythropoietin (EPO) and erythropoiesis disorders, the impact of eryptosis on renal anemia demands attention. However, a systemic analysis concerning the pathophysiology of eryptosis has not been expounded. Summary: The complicated conditions in CKD patients, including oxidative stress, osmotic stress, metabolic stress, accumulation of uremic toxins, and iron deficiency, affect the normal skeleton structure of red blood cells (RBCs) and disturbs ionic homeostasis, causing phosphatidylserine to translocate to the outer lobules of the RBC membrane that leads to early elimination and/or shortening of the RBC lifespan. Inadequate synthesis of RBCs cannot compensate for their accelerated destruction, thus exacerbating renal anemia. Meanwhile, EPO treatment alone will not reverse renal anemia. A variety of eryptosis inhibitors have so far been found, but evidence of their effectiveness in the treatment of CKD remains to be established. Key Messages: In this review, the pathophysiological processes and factors influencing eryptosis in CKD were elucidated. The aim of this review was to underline the importance of eryptosis in renal anemia and determine some promising research directions or possible therapeutic targets to correct anemia in CKD.
Suppression of Local Tumor Progression in Perivascular Hepatocellular Carcinoma by Combination Therapy with Radiofrequency Ablation and Percutaneous Ethanol Injection: A Propensity Score Matching Analysis
Authors: Takata Kazuhide , Tanaka Takashi , Anan Akira , Fukunaga Atsushi , Nagata Takahiro , Fukuda Hiromi , Yamauchi Ryo , Kunimoto Hideo , Yokoyama Keiji , Morihara Daisuke , Takeyama Yasuaki , Iwata Kaoru , Shakado Satoshi , Sakisaka Shotaro , Hirai Fumihito
Published: February 2022

Background and Aims: Radiofrequency ablation (RFA) has replaced percutaneous ethanol injection (PEI) as the treatment of choice for hepatocellular carcinoma (HCC); however, control of local tumor progression (LTP) remains a challenge in perivascular HCC. The aim of this study was to determine whether PEI added to RFA can reduce the LTP rate in perivascular HCC patients. Methods: We retrospectively analyzed 167 patients, with 197 newly diagnosed HCC nodules with peritumoral vessels, who underwent either RFA plus PEI or RFA monotherapy as the first-line treatment between June 2001 and April 2015. Ethanol was injected inside the tumor close to the peritumoral vessels in the combination therapy group. Patients were matched 1:1 according to their propensity scores to reduce selection bias; cumulative LTP was then analyzed using log-rank tests and Cox proportional hazard regression analyses. Results: The two matched groups comprised 62 tumors each. The overall median follow-up period was 34 months (range, 1–140 months). In the RFA plus PEI group, the cumulative LTP rates were 5.7%, 15.5%, and 20.4% at 1, 3, and 5 years, respectively; in the RFA monotherapy group, the rates were 13.2%, 32.0%, and 40.2%, respectively. The rates were significantly lower in the RFA plus PEI group (p = 0.032). Cox proportional hazard regression analysis showed that PEI combination treatment was significantly associated with a reduced risk of local HCC recurrence (hazard ratio, 0.44; 95% confidence interval, 0.19–0.93; p = 0.031). Discussion/Conclusion: The risk of LTP after RFA for perivascular HCC can be significantly reduced by injecting ethanol close to the peritumoral vessels.
Geometria olímpica com GeoGebra v.1
Authors:   Universidade de São Paulo. Faculdade de Zootecnia e Engenharia de Alimentos, Linares Juan López , Santos João Paulo Martins dos ,   Academia da Força Aérea em Pirassununga/SP, Jesus Alessandro Firmiano de ,   Academia da Força Aérea em Pirassununga/SP
Published: February 2022

O livro faz parte de um projeto de longo prazo sobre treinamento de estudantes e professores com problemas relacionados às Olimpíadas de Matemáticas. Em particular, este material didático foi utilizado durante algumas das aulas do curso “Geometria Olímpica com GeoGebra” para professores de Matemática do Ensino Fundamental e Médio de todo o Brasil. O mesmo aconteceu na modalidade de Ensino à Distância (EaD) pela plataforma de Cultura e Extensão da USP. O diferencial na utilização do GeoGebra está baseado na disponibilidade gratuita do software online e de aplicativos para computadores e celulares. As construções geométricas podem ser realizadas de forma dinâmica, em que são exploradas diversas configurações de um mesmo problema. O GeoGebra serve tanto como calculadora gráfica e numérica, utilizada para a verificação, como ferramenta para a apresentação, passo a passo, de uma demonstração rigorosa. O GeoGebra também convida o leitor a interagir, a pôr “as mãos na massa”.
Web of Science’s Citation Median Metrics Overcome the Major Constraints of the Journal Impact Factor
Authors: Daugherty Alan , Hegele Robert A. , Lu Hong S. , Mackman Nigel , Rader Daniel J. , Weber Christian
Published: February 2022

There are many metrics to evaluate the performance and status of journals. Among these, the journal impact factor (JIF) has become the dominant metric. The influence of JIF is illustrated by its widespread use to evaluate academic status, compensation, and funding decisions. However, as noted by Clarivate Analytics, the parent company of the Web of Science (WoS), the JIF should not be used without careful attention to the many phenomena that influence citation rates. To facilitate transparency, Clarivate Analytics provides all data used to determine the JIF. In addition, WoS provides other metrics for journal evaluation, including the article citation median and the review citation median. These metrics are represented as medians to minimize the confounding influence of a small number of highly cited articles that may occur when data are represented as means. Another feature of these WoS metrics is that data are separated according to different publication types of article (original research and review). To systematically compare these selected metrics, we used the data provided on the WoS web site to analyze 25 top ranked cardiovascular journals in the same mode as represented in the WoS citation distribution window. The results indicate that the article citation median and review citation median overcome several concerns that have been raised about the JIF and seem to provide enhanced objectivity as an indicator of journal impact in publishing original research and reviews. Therefore, we advocate that these additional WoS metrics might be preferentially considered as indicators of journal performance.
Gut Microbiome and Neuroinflammation in Hypertension
Authors: Richards Elaine M. , Li Jing , Stevens Bruce R. , Pepine Carl J. , Raizada Mohan K.
Published: February 2022

Hypertension is a worldwide problem with major impacts on health including morbidity and mortality, as well as consumption of health care resources. Nearly 50% of American adults have high blood pressure, and this rate is rising. Even with multiple antihypertensive drugs and aggressive lifestyle modifications, blood pressure is inadequately controlled in about 1 of 5 hypertensive individuals. This review highlights a hypothesis for hypertension that suggests alternative mechanisms for blood pressure elevation and maintenance. A better understanding of these mechanisms could open avenues for more successful treatments. The hypothesis accounts for recent understandings of the involvement of gut physiology, gut microbiota, and neuroinflammation in hypertension. It includes bidirectional communication between gut microbiota and gut epithelium in the gut-brain axis that is involved in regulation of autonomic nervous system activity and blood pressure control. Dysfunction of this gut-brain axis, including dysbiosis of gut microbiota, gut epithelial dysfunction, and deranged input to the brain, contributes to hypertension via inflammatory mediators, metabolites, bacteria in the circulation, afferent information alterations, etc resulting in neuroinflammation and unbalanced autonomic nervous system activity that elevates blood pressure. This in turn negatively affects gut function and its microbiota exacerbating the problem. We focus this review on the gut-brain axis hypothesis for hypertension and possible contribution to racial disparities in hypertension. A novel idea, that immunoglobulin A-coated bacteria originating in the gut with access to the brain could be involved in hypertension, is raised. Finally, minocycline, with its anti-inflammatory and antimicrobial properties, is evaluated as a potential antihypertensive drug acting on this axis.
Impact of Atrial Tachyarrhythmia Recurrence on the Development of Long‐Term Adverse Clinical Events Following Catheter Ablation in Patients With Atrial Fibrillation With Systolic Impairment: A Single‐Center Observational Study
Authors: Ishiguchi Hironori , Yoshiga Yasuhiro , Shimizu Akihiko , Ueyama Takeshi , Ono Makoto , Fukuda Masakazu , Kato Takayoshi , Fujii Shohei , Hisaoka Masahiro , Uchida Tomoyuki , Omuro Takuya , Shimokawa Mototsugu , Okamura Takayuki , Kobayashi Shigeki , Yano Masafumi
Published: February 2022

Background

Catheter ablation can improve long‐term prognosis of patients with atrial fibrillation with systolic impairment. However, atrial tachyarrhythmia (ATA) recurrence increases during long‐term follow‐up. We aimed to investigate the impact of ATA recurrence on the development of long‐term adverse clinical events following catheter ablation for atrial fibrillation and to identify predictors for the development of adverse clinical events.

Methods and Results

This single‐center observational study included 75 patients with systolic impairment (left ventricular ejection fraction <50%) who underwent the first catheter ablation procedure for atrial fibrillation at our institution (median follow‐up period: 3.5 [range: 2.4–4.7] years). We compared the cumulative incidence of adverse clinical events (all‐cause death, heart failure hospitalization, stroke, or acute myocardial infarction) between the groups with and without ATA recurrence following the first and last procedures. Multivariable analyses were performed to identify predictors for developing adverse clinical events. Twenty‐one patients (28%) developed adverse clinical events at a median of 2.2 (range: 0.64–2.8) years following the first procedure. The proportion of freedom from adverse clinical events following the first procedure was significantly lower in the ATA recurrence group than in the nonrecurrence group (41% [n=40] versus 95% [n=35],
P
<0.0005); the proportion following the last procedure also showed a similar tendency (35% [n=26] versus 57% [n=49],
P
<0.0001). ATA recurrence emerged as an independent predictor for adverse clinical events following both procedures after multivariable adjustment.

Conclusions

ATA recurrence following catheter ablation procedure could predict adverse clinical events in patients with atrial fibrillation with systolic impairment.
Microbial DNA Enrichment Promotes Adrenomedullary Inflammation, Catecholamine Secretion, and Hypertension in Obese Mice
Authors: Gao Hong , Jin Zhongmou , Tang Kechun , Ji Yudong , Suarez Jorge , Suarez Jorge A. , Cunha e Rocha Karina , Zhang Dinghong , Dillmann Wolfgang H. , Mahata Sushil K. , Ying Wei
Published: February 2022

Background

Obesity is an established risk factor for hypertension. Although obesity‐induced gut barrier breach leads to the leakage of various microbiota‐derived products into host circulation and distal organs, the roles of microbiota in mediating the development of obesity‐associated adrenomedullary disorders and hypertension have not been elucidated. We seek to explore the impacts of microbial DNA enrichment on inducing obesity‐related adrenomedullary abnormalities and hypertension.

Methods and Results

Obesity was accompanied by remarkable bacterial DNA accumulation and elevated inflammation in the adrenal glands. Gut microbial DNA containing extracellular vesicles (mEVs) were readily leaked into the bloodstream and infiltrated into the adrenal glands in obese mice, causing microbial DNA enrichment. In lean wild‐type mice, adrenal macrophages expressed CRIg (complement receptor of the immunoglobulin superfamily) that efficiently blocks the infiltration of gut mEVs. In contrast, the adrenal CRIg+ cell population was greatly decreased in obese mice. In lean CRIg
−/−
or C3
−/−
(complement component 3) mice intravenously injected with gut mEVs, adrenal microbial DNA accumulation elevated adrenal inflammation and norepinephrine secretion, concomitant with hypertension. In addition, microbial DNA promoted inflammatory responses and norepinephrine production in rat pheochromocytoma PC12 cells treated with gut mEVs. Depletion of microbial DNA cargo markedly blunted the effects of gut mEVs. We also validated that activation of cGAS (cyclic GMP‐AMP synthase)/STING (cyclic GMP–AMP receptor stimulator of interferon genes) signaling is required for the ability of microbial DNA to trigger adrenomedullary dysfunctions in both in vivo and in vitro experiments. Restoring CRIg+ cells in obese mice decreased microbial DNA abundance, inflammation, and hypertension.

Conclusions

The leakage of gut mEVs leads to adrenal enrichment of microbial DNA that are pathogenic to induce obesity‐associated adrenomedullary abnormalities and hypertension. Recovering the CRIg+ macrophage population attenuates obesity‐induced adrenomedullary disorders.
Abstract 10: Recurrent Ischemic Infarcts And Hemorrhages On MRI Within 30 Days Of Anticoagulation Commencement For Ischemic Stroke: Preliminary Results From The Attune Registry
Authors: Sharobeam Angelos , Lam Christina , Garcia-Esperon Carlos , Krause Martin , Wong Andrew A , Lee Andrew , Shah Darshan , Lee-Archer Matthew , Tan Meng , Gawarikar Yash , Gilligan Amanda , Parsons Mark , Yan Bernard
Published: February 2022

Introduction:
Anticoagulation reduces recurrent ischemic stroke based on clinical definitions in patients with atrial fibrillation (AF). However, neuroimaging registries suggested a significant proportion developed ischemic lesions on magnetic resonance imaging (MRI) at 12 months follow up. The rate of early recurrent ischemic stroke identified by MRI remains unclear. ATTUNE (Atrial fibrillation in stroke - Utility of Neuroimaging Evaluation) is a prospective, multicentre study of clinical and radiological outcomes in patients commenced on anticoagulation after ischaemic stroke or TIA. We aimed to investigate the incidence of early ischemic stroke on MRI in this group of patients who were anticoagulated.

Aims/Methods:
We performed an interim analysis of the ATTUNE database to determine the proportion of patients with radiological evidence of infarction and haemorrhage on (MRI), one month after index ischemic stroke or transient ischemic attack (TIA). MRIs performed at one month were analysed independently by two experienced neuroimage assessors and the number of new infarcts and haemorrhages determined for each patient.

Results:
A total of 216 patients were analysed. The median age was 74 (IQR 68-81). Anticoagulation was commenced a median of 4 days after index event (IQR 2-6). Twenty-eight patients had new infarcts on follow-up MRI (13%). Fifty-six had new haemorrhage on follow up MRI (26%). Of these, 41 patients had hemorrhagic transformation of the initial infarct and 15 had a remote haemorrhage.

Conclusion:
There is a high rate of recurrent ischemic lesions and haemorrhages on MRI in patients commenced on anticoagulation within 30 days of index stroke or TIA.
Abstract 103: Burden Of Ischemic And Hemorrhagic Stroke Across The Us From 1990-2019: A Global Burden Of Disease Study
Authors: Leasure Audrey C , Acosta Julian , Sharma Richa , Krumholz Harlan M , de Havenon Adam , Falcone Guido J , Sheth Kevin N
Published: February 2022

Introduction:
We sought to present burden estimates of ischemic and hemorrhagic stroke in the US in 2019 and to describe trends from 1990 to 2019 by age, sex, and geographic location.

Methods:
We performed an analysis of the Global Burden of Disease (GBD) 2019 study. Data on stroke incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) from 1990 to 2019 were obtained from the GBD results tool. We measured crude and age-standardized incidence, prevalence, mortality, and DALYs per 100,000 (with 95% uncertainty intervals) for all stroke, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage from 1990 to 2019.

Results:
In the US in 2019, there were 0.46 million (0.40-0.52) incident strokes, of which 67.5% were ischemic (0.31 million [0.26-0.38]), 0.19 million (0.17-0.21) stroke-related deaths and 3.83 million (3.47-4.16) stroke-attributable DALYs. The crude number of incident strokes, prevalent strokes, mortality, and DALYs increased from 1990 to 2019 but age-standardized stroke burden measures declined or remained flat (Figure 1). Trends in stroke incidence, prevalence, mortality, and DALYs varied by age group and geographic location, with stroke incidence decreasing in older adults nationwide and increasing in younger adults (15-49 years) in the South and Midwest US (Figure 2).

Conclusions:
While age-standardized measures of stroke burden are decreasing, there is a large and increasing number of people affected by stroke in the US, especially among younger populations in the South and Midwest.Public health efforts to reduce stroke burden across the lifespan should incorporate location-specific stroke trends.
Abstract 109: Biological Pathways Enriched For Genes Associated With Lesion Burden In Cerebral Cavernous Malformation
Authors: Sriram Aditya , Weinsheimer Shantel , Nelson Jeffrey , Mabray Marc , Zabramski Joseph M , Akers Amy , Hart Blaine , Morrison Leslie , McCulloch Charles E , Kim Helen ,   Brain Vascular Malformation Consortium CCM Investigator Group
Published: February 2022

Introduction:
Familial Cerebral Cavernous Malformation (CCM) is an autosomal dominant disorder caused by mutations in
KRIT1
,
CCM2
and
PDCD10
. CCMs can result in seizures, neurological deficits, and intracranial hemorrhage. Our prior research identified genetic modifiers that contribute to CCM progression. We hypothesized that genes associated with CCM progression (lesion burden, large lesion size, and hemorrhage) are enriched in biological pathways. We performed a functional enrichment analysis of top associated genes from a genome-wide panel to identify pathways that, when dysregulated, may contribute to CCM progression.

Methods:
Familial CCM cases (n=335) enrolled in the Brain Vascular Malformation Consortium were genotyped using Affymetrix Axiom Genome-Wide LAT1 Human Arrays. Logistic regression analysis was performed using an additive model, adjusting for age at enrollment and sex, to identify genetic variants associated with total lesion burden, large lesion burden (≥5mm), or hemorrhage. For nominally associated variants (P<0.001) mapping +/-5kb to genes, we performed an over-representation analysis using WebGestalt to identify enrichment of genes in KEGG biological pathways using a false discovery rate (FDR)
<
0.15.

Results:
Our CCM GWAS study identified genes nominally associated with total lesion burden (n=298), large lesion burden (n=287), and hemorrhage (n=200). We found no significantly over-represented pathways for genes associated with large lesion burden and hemorrhage. However, six pathways were enriched for genes associated with total lesion burden, all with FDR=0.12: oxytocin signaling, synaptic vesicle cycle, HIF-1 signaling, neomycin, kanamycin and gentamicin biosynthesis, adrenergic signaling in cardiomyocytes, and gastric acid secretion. Interestingly, the HIF-1 pathway interacts with several pathways of interest in CCM, e.g., mTOR and PI3K-Akt.

Conclusions:
Genetic variants associated with total lesion burden in familial CCM map to genes that are likely enriched in KEGG biological pathways. These findings expand the list of candidate genetic modifiers for CCM lesion progression, including genes in the HIF-1 pathway, and necessitate further investigation in other independent CCM patient cohorts.
Abstract 110: Inhibition Of VEGF Signaling Prevents

KRAS
G12V

-induced Brain Arteriovenous Malformations
Authors: Park Eunsu , Kim Sehee , Koerbelin Jakob , Chen Peng R , Kim Eunhee
Published: February 2022

Introduction:
Brain arteriovenous malformations (bAVMs) are a major risk factor of cerebral hemorrhages in young patients. Recently, somatic KRAS mutation has identified ~60% of human bAVMs, and we confirmed the causal role of endothelial

KRAS
G12V

mutation in bAVM development using a mouse model. Excessive uncontrolled angiogenesis is associated with the abnormal vascular outgrowth in bAVMs. While abnormal VEGF signaling is involved in pathologic angiogenesis, the role in mutant KRAS-induced bAVMs has not been studied. Here, we hypothesized that KRAS mutation induces bAVMs via activation of VEGF signaling, and tested if VEGF inhibition prevents

KRAS
G12V

-induced bAVM development.

Methods:
We induced bAVMs in mice by systemic injection of AAV-BR1 carrying

KRAS
G12V

mutation (KRAS
G12V
mice). To determine the effect of KRAS mutation on VEGF signaling, we tested the expression of VEGF-A and VEGFR2 in

KRAS
G12V

-induced bAVMs
in vivo
and cultured mouse endothelial cells (ECs) overexpressing

KRAS
G12V

in vitro
. Furthermore, we performed the tube formation assay to test angiogenesis by

KRAS
G12V

mutation in the cultured EC. Finally, we treated VEGFR2 inhibitor (SU5416) in the KRAS
G12V
mice and measured the bAVM size and numbers in the latex-casted brains.

Results:
We found that the expression of VEGF-A, VEGFR2, and phospho(p)-VEGFR2 were significantly increased in KRAS
G12V
-induced bAVMs in mice. We also found that KRAS
G12V
transfection up-regulates expression of VEGF-A, VEGFR2, and p-VEGFR2, and increased tube formation in cultured ECs. Finally, we confirmed that SU5416 treatment significantly reduced the numbers and size of bAVMs in KRAS
G12V
mice.

Conclusions:
Our data show that endogenous VEGF signaling is activated by KRAS mutation. The VEGF inhibition study suggests that the endogenously activated VEGF signaling would be essential to mediate the mutant KRAS-induced bAVM development.
Abstract 116: Unmet Need In Acute Ischemic Stroke Patients Not Treated With Alteplase
Authors: Mac Grory Brian , Xian Ying , Solomon Nicole , Matsouaka Roland , Decker-Palmer Marquita , Fonarow Gregg C , Smith Eric E , Schwamm Lee H
Published: February 2022

Introduction:
Early administration of intravenous tissue plasminogen activator (IV alteplase) improves functional outcomes in patients with acute ischemic stroke (AIS), yet many patients are not treated with IV alteplase. There is a need to understand the reasons for non-treatment and the short- and long-term outcomes in this patient population.

Methods:
We analyzed patients ≥65 years old with a primary diagnosis of AIS presenting within 24 hours of time last known well (LKW) but not treated with IV alteplase from 1,630 Get With The Guidelines-Stroke Hospitals in the United States between January 2016 and December 2016. We report clinical characteristics, reasons for withholding treatment, in-hospital mortality, 90-day and 1-year outcomes including Medicare costs, stratified by time from LKW to presentation (≤4.5 hours, >4.5-6 hours and >6-24 hours).

Results:
Of 39,760 patients (median age 80 [25
th
-75
th
quartiles: 73-87], 56.7% female), 19,391 (48.8%) presented within 4.5 hours of LKW. In those with documented reasons for withholding IV alteplase, the most common reasons were rapid improvement of symptoms (3,985/14,782, 27.0%) and mild symptoms (3,791/14,782, 25.6%). In 1,100 out of 1,174 (93.7%) patients presenting in the >3.0-4.5-hour time window, the most common reason for not treating was a delay in patient arrival. The most common discharge location for those presenting ≤4.5 hours since LKW was home (8,660/19,391, 44.7%). The 90-day mortality and re-admission rates were 18.9% and 23.0% in those presenting ≤4.5 hours since LKW, 19.0% and 22.2% in those presenting between 4.5 and 6 hours, and 19.1% and 23.2% in those presenting between 6 and 24 hours. Median 90-day total in-hospital costs remained relatively high at $9,471 (IQR: $5,622-$21,356) in patients presenting ≤4.5 hours since LKW.

Conclusions:
Patients within the GWTG-Stroke registry not treated with IV alteplase have a high risk of re-admission and mortality and have high total in-hospital and post-discharge costs. This study may inform future efforts to address the unmet need to improve the scope of IV alteplase delivery along with other aspects of AIS care and, consequently, outcomes in this patient population.
Abstract 117: Contrast-enhanced Transcranial Doppler Ultrasonography Versus Transesophageal Echocardiography As Screening Tool In Embolic Stroke
Authors: Fourcand Farah , Gadallah Nancy , Ghori Arifa , Torres Danisette , panezai spozhmy , Suhan Laura B , Mehta Siddhart , Kirmani Jawad F
Published: February 2022

Introduction:
Right-to-left (RtL) intracardiac and intrapulmonary shunts are associated with embolic stroke. Although contrast-enhanced transcranial doppler ultrasonography (ceTCD) and transesophageal echocardiography (TEE) are used in embolic stroke work up, there are no standardized guidelines as to which test should be considered as ‘gold standard’. Our objective is to evaluate the sensitivity of contrast-enhanced TCD and TEE in detecting right-to-left shunt to determine respective utilities as screening tools.

Methods:
Electronic medical records of subjects presenting with acute neurological symptoms who had ceTCD and TEE were evaluated. Sensitivity and specificity were calculated. Based on the respective prevalence of intracardiac and intrapulmonary shunts, positive predictive value, negative predictive value, and test accuracy were determined for ceTCD and TEE. Social Science Statistics was used for data analysis.

Results:
From June 2016 to August 2021, of 7,498 ischemic stroke patients, 260 patients were suspected of having strokes related to right to left shunts and underwent ceTCD and TEE for detection of cardioembolic sources for stroke. A positive right-to-left shunt was detected in 83 subjects. Detection by ceTCD was confirmed by the operator for 81 patients while 2 were considered false positive results (delayed sporadic High Intensity Transient Signals (HITS)). Sensitivity of ceTCD was 97.65% (95% CI [91.76%, 99.71%]). No safety concerns were identified in patients undergoing ceTCD. Of those with positive ceTCD (68.57%, n=35) were detected by Valsalva, and all of those 35 patients had negative TEE. TEE had sensitivity of 70.34% (95% CI [61.23%, 78.39%]).

Conclusion:
Contrast-enhanced TCD has superior sensitivity, is cost-effective, practical, and a safe alternative to TEE in identifying intracardiac or intrapulmonary shunts. Screening superiority of ceTCD may lie in ability to elicit shunts during Valsalva maneuvers. To our knowledge this is the largest single center series confirming ceTCD as a gold standard tool for screening of right to left shunts.
Abstract 118: Cerebral Venous Reflux And Dilated Basal Ganglia Perivascular Space In Hypertensive Small Vessel Disease
Authors: Tsai Hsin-hsi C , Lee Bo-ching , Chen Ya-Fang , Jeng Jiann , Tsai Li-Kai
Published: February 2022

Background:
Cerebral venous flow alterations have been considered as a contributor in white matter ischemia and cognitive impairment, but their role in small vessel disease has never been investigated.

Method:
297 patients with spontaneous hypertensive intracerebral hemorrhage who underwent brain MRI were included. Presence of cerebral venous reflux (CVR) was defined as abnormal signal intensity in the dural venous sinus (cavernous, inferior petrosal, sigmoid or transverse sinus) or internal jugular vein using MR angiography (Figure). Dilated basal ganglia (BG) perivascular spaces (PVS) was defined as the number of PVS >20 or any PVS with size > 3mm in short axis (L-PVS). The association between CVR and dilated BG-PVS were evaluated in univariate and multivariable models. Stroke recurrence was also analyzed in cox regression model.

Results:
Compared to patients without CVR, patients with CVR (n=37, 12,5%) had similar demographics, but showed a trend toward more severe SVD markers including microbleeds, white matter hyperintensities and lacunes. In addition, presence of CVR is significantly associated with dilated BG-PVS (BG-PVS > 20, 62.2% vs. 34.6%,
P
= 0.002; L-PVS, 48.6% vs. 18.8%,
P
< 0.001). In multivariable model, the presence of CVR remained independently associated with dilated BG-PVS (odds ratio 4.03 [1.68-9.68], p=0.002) after adjustment for age and other SVD markers. In cox model, CVR predicts higher risk of stroke recurrence independent of conventional SVD markers (odds ratio 2.32 [1.00-5.34],
P
= 0.049).

Conclusion:
We demonstrated a close relationship between CVR and dilated BG PVS, suggesting the potential role of venous drainage dysfunction in the formation of enlargement of PVS in hypertensive SVD.
Abstract 12: CT Perfusion For Lesion-Symptom Mapping In Emergent Large Vessel Occlusion
Authors: Neuhaus Ain A , Brinjikji Waleed , Rabinstein Alejandro A , Harston George , Joly Olivier , Abbasi Mehdi , Kallmes David F
Published: February 2022

Introduction:
Selection criteria for endovascular thrombectomy (EVT) for emergent large-vessel occlusion (ELVO) stroke increasingly rely on CT perfusion (CTP) findings at presentation. While perfusion imaging is used to estimate the likelihood of deriving long-term functional benefit from EVT, there is comparatively little data on how perfusion deficits relate to domains of neurological function. Here, we investigated region-specific hypoperfusion as a driver of neurological dysfunction through correspondence between NIHSS items and CTP.

Methods:
We included 169 patients with ELVO presenting to Mayo Clinic Rochester or Jacksonville, who had baseline CTP and itemised NIHSS data. Perfusion was quantified as mean transit time using e-CTP (Brainomix Ltd., Oxford, UK) and thresholded to ≥5 s for lesion masking. Voxel-wise lesion-symptom mapping (VLSM) was performed using sparse canonical correlations analysis (Lesymap package, R).

Results:
Total NIHSS was most strongly predicted by left MCA territory hypoperfusion, corresponding to language-eloquent cortical areas and dominant hemisphere motor tracts (figure 1). Contralateral limb motor deficits (NIHSS 5 and 6) were mainly associated with subcortical and white matter hypoperfusion; there was an additional strong signal for left frontal cortex in language function (NIHSS 9). The remaining NIHSS items were less well localised.

Conclusions:
Expanding on previous pilot data, our results provide further evidence for the feasibility of hypoperfusion-to-symptom mapping in ELVO. This could allow for more nuanced clinical-imaging mismatch determination, and selection of patients based on specific neurological deficits that may be reversible.
Abstract 124: Effects Of Dual Antiplatelet Therapy Using Cilostazol In Patients With Extracranial Or Intracranial Arterial Stenosis: A Subgroup Analysis Of The Csps.com Trial
Authors: Uchiyama Shinichiro , Toyoda Kazunori , Okamura Satomi , Omae Katsuhiro , Kimura Kazumi , Hoshino Haruhiko , Yamaguchi Takenori
Published: February 2022

Background:
The CSPS.com trial showed that dual antiplatelet therapy (DAPT) using cilostazol was superior to single antiplatelet therapy (SAPT) with aspirin or clopidogrel for the long-term prevention of recurrent ischemic stroke and vascular events in high-risk Japanese patients with ischemic stroke. We conducted a subgroup analysis of the CSPS.com trial in order to investigate the effects of extracranial or intracranial arterial stenosis on the benefit of cilostazol.

Methods:
We compared the risk of recurrent ischemic stroke and vascular events including stroke, myocardial infarction, and vascular death between DAPT with cilostazol and aspirin or clopidogrel and SAPT with aspirin or clopidogrel in patients with or without at least 50% stenosis of the extracranial or intracranial artery among patients recruited to the CSPS.com trial.

Results:
The median follow-up period was 1.4 years. The risk of recurrent stroke did not differ between DAPT and SAPT among 246 patients with extracranial arterial stenosis (8.04% vs 7.46%, HR 1.05, 95% CI 0.43-2.58), while it was lower in DAPT than in SAPT among 547 patients with intracranial arterial stenosis (5.8% vs 11.9%, HR 0.47, 95% CI 0.23-0.95), and among 944 patients without any arterial stenosis (2.91% vs 7.13%, HR 0.44, 95% CI 0.17-0.74). The risk of vascular events did not differ between DAPT and SAPT among patients with extracranial arterial stenosis (8.93% vs 8.96%, HR 0.97, 95% CI 0.42-2.24), while it was lower in DAPT than in SAPT among patients with intracranial arterial stenosis (7.70% vs 14.5%, HR 0.48, 95% CI 0.26-0.96), and among patients without any arterial stenosis (3.33% vs 7.56%, HR 0.47, 95% CI 0.26-0.85). The risk of major bleeding did not differ between DAPT and SAPT among any category of patients.

Conclusions:
DAPT using cilostazol might not be beneficial for the long-term prevention of recurrent stroke and vascular events in patients with extracranial arterial stenosis, while it might be beneficial in patients with intracranial arterial stenosis or in those without any arterial stenosis.
Abstract 125: 3d Time-of-flight Mr Angiography At 3.0 Tesla Underestimates Disease Stage Compared To Digital Subtraction Angiography In The Evaluation Of Moyamoya Disease
Authors: Rizvi Ahmed , Larson Anthony , Rinaldo Lorenzo , Klaas James P , Lanzino Giuseppe S , Lehman Vance , Meyer Fredric , Savastano Luis , Brinjikji Waleed
Published: February 2022

Introduction:
Digital subtraction angiography (DSA) is currently the gold standard for evaluation of moyamoya disease (MMD) and is the basis for several grading systems. Non-invasive modalities such as MRA are also used in assessment of MMD. Accurate implementation of these staging systems for use with MRA would imply a less-invasive method of MMD monitoring.

Methods:
This was a single-center retrospective study that compared MRA to reference DSA studies in determining MMD severity using Berlin and modified Suzuki (mSG) grading systems A single reviewer assigned modified Suzuki and Berlin grades to all included hemispheres on both MRA and DSA. The mean difference between MRA and DSA grades for each DSA reference grade was determined utilizing both grading systems. The distribution of scores was also compared between MRA and DSA using both grading systems.

Results:
A total of 166 cerebral hemispheres in 90 patients were included: The mean age at MMD diagnosis was 34.8 years (standard deviation [SD] = 14.2), and fifty-three patients (63.9%) were male. Mean MRA grades were significantly lower than DSA reference grades 3 and 4 utilizing the mSG system (p = <0.0001 in both cases); A similar pattern was observed for Berlin grades 2 and 3 (p = <0.0001,
Table 1
). The distribution of modified Suzuki grades on MRA was skewed toward relatively lower grades as compared to DSA (p = <0.0001): This pattern was also true for Berlin grades as well (p = <0.0001,
Table 2
).

Conclusions:
DSA is essential in the evaluation of MMD, as MRA is shown to underestimate disease stage, with a greater degree of underestimation in more severe disease. We suggest DSA be performed in order to aid in appropriate treatment planning.