bluuebunny/crossref_metadata_2025 huggingface dataset:
Sacubitril/valsartan is associated with improvements in quality of life in adult congenital heart disease patients with systemic right ventricular failure
Authors: Neijenhuis Ralph M.L. , Nederend Marieke , van Groningen Anna E. , Jongbloed Monique R.M. , Vliegen Hubert W. , Jukema J. Wouter , Kiès Philippine , Egorova Anastasia D.
Published: January 2025

Background

Short-term improvements in quality of life (QOL) have been reported in adult congenital heart disease patients with systemic right ventricle (sRV) failure after treatment with sacubitril/valsartan. This study aimed to evaluate the medium-term QOL changes in sRV failure patients treated with sacubitril/valsartan.

Methods

In this single-centre, prospective cohort study, patients with symptomatic sRV failure completed the Netherlands Organisation for Applied Scientific Research/Academic Hospital Leiden Questionnaire for Adult’s Health-Related Quality of Life (TAAQOL) at baseline and after starting treatment with sacubitril/valsartan. The TAAQOL was taken at structured outpatient follow-up moments after 6, 12, 24 and 36 months of treatment. Linear mixed effects models were used to evaluate the medium-term changes in 12 QOL domains.

Results

Of 40 sRV failure patients initiated on sacubitril/valsartan, 35 completed the titration phase, and 31 filled in a total of 98 TAAQOL questionnaires (response rate 77.5%). Significant improvements in gross motoric functioning (p=0.008), cognitive function (p=0.002), sleep (p=0.041), social functioning (p<0.001) and daily activities (p=0.001) were observed during follow-up. No significant changes were observed in fine motoric functioning, pain, sexuality, vitality, positive, depressive or aggressive emotions. Of interest, periods with restrictions relating to the COVID-19 pandemic did not significantly influence changes over time in any of the 12 QOL domains.

Conclusions

Sacubitril/valsartan treatment was associated with persistent medium-term QOL improvements in gross motoric functioning, cognitive function, sleep, social functioning and daily activities domains in sRV failure patients. Self-perceived QOL of sRV failure patients may be amenable to improvement with sacubitril/valsartan.
Warp drives and Martel–Poisson charts
Authors: Chowdhury Abhishek
Published: January 2025

We extend the construction of Alcubierre–Natário class of warp drives to an infinite class of spacetimes with similar properties. This is achieved by utilising the Martel–Poisson charts which closely resembles the Weak Painlevé–Gullstrand form for various background metrics (Mink, AdS, dS). The highlight of this construction is the non-flat intrinsic metric which in three dimensional spacetimes introduce conical singularities at the origin and in higher dimensions generates non-zero Ricci scalar for the spatial hypersurfaces away from the origin. We analyse the expansion/contraction of space and the (NEC) violations associated with these warp drives and find interesting scalings due to the global imprints of the conical defects. Other properties like tilting of light cones, event horizons and several generalisations are also discussed.
New Families of Frequency-Hopping Sequence Sets with Optimal Hamming Correlation
Authors: Xu Shanding
Published: January 2025

With the advantage of transmitting messages efficiently along with switching frequencies at set intervals by each user, frequency-hopping sequence (FHS) has been widely applied in the frequency-hopping multiple access spread spectrum systems. In such systems, the Hamming correlation property of FHS is an important standard to measure the system performance. In this paper, a combinatorial description of difference-balanced function from [Formula: see text] onto [Formula: see text] is given, and the sizes of its preimage sets are determined without resorting to [Formula: see text]-homogeneous property, where [Formula: see text] and [Formula: see text] are two positive integers with [Formula: see text]. Afterwards, we construct new near-optimal FHSs and optimal FHS sets by virtue of the Chinese Remainder Theorem and [Formula: see text]-homogeneous functions with difference-balanced property, which generalize some earlier constructions of optimal FHS sets and produce optimal FHS sets which are not covered in the foregoing literature.
Asymptotic properties of some Freud polynomials
Authors: Min Chao , Wang Liwei , Chen Yang
Published: January 2025

In this paper, we study the asymptotic properties of monic orthogonal polynomials (OPs) with respect to some Freud weights when the degree of the polynomial tends to infinity, including the asymptotics of the recurrence coefficients, the nontrivial leading coefficients of the monic OPs, the associated Hankel determinants and the squares of [Formula: see text]-norm of the monic OPs. These results are derived from the combination of the ladder operator approach, Dyson’s Coulomb fluid approach and some recent results in the literature.
Separation of Duty in Information Security
Authors: Groll Sebastian , Fuchs Ludwig , Pernul Günther
Published: January 2025

Separation of Duty (SoD) is a fundamental security principle that ensures critical tasks or functions are divided among multiple users to prevent fraud. The topic of SoD spans over many different areas, such as Identity and Access Management, Workflows, Petri nets, or high-level enterprise management. In this survey article, we conduct a systematic and stand-alone literature review on SoD. We develop a multi-level classification scheme and analyze the state-of-the-art and current trends in SoD research as well as the current challenges and potential research gaps. To the best of our knowledge, this is the first effort to comprehensively survey and structure SoD literature.
Cardiac MRI in Heart Transplantation: Approaches and Clinical Insights
Authors: Quinn Sandra , Catania Roberta , Appadurai Vinesh , Wilcox Jane E. , Weinberg Richard L. , Lee Daniel C. , Carr James C. , Markl Michael , Allen Bradley D. , Avery Ryan
Published: January 2025

Cardiac MRI provides comprehensive insights into orthotopic heart transplant (OHT) allograft structure and function with advanced tissue characterization and quantitative myocardial perfusion techniques and can be considered a complementary noninvasive tool for investigation and monitoring of major complications that limit the durability of OHT.
Table 2 from Evaluating Ovarian Cancer Risk–Reducing Salpingectomy Acceptance: A Survey
Authors: Lukey Alexandra , Sowamber Ramlogan , Huntsman David , Pearce Celeste Leigh , Howard A. Fuchsia , Meza Rafael , Law Michael R. , Phung Minh Tung , Hanley Gillian E.
Published: January 2025

Logistic regression analysis of factors associated with accepting risk-reducing surgery (RRS) for ovarian cancer when the lifetime risk is less than 4%, compared with greater than or equal to 4%, using hot deck imputation
Prognostic Factors, FLT-3 Mutations, and Treatment Outcomes with pediatric inspired protocols in adolescent and young adults (AYA) and adult patients with Acute Lymphoblastic Leukemia
Authors: Oanunu Uriel , Gross Even Zohar Noa , Aumann Shlomzion , Vainstein Vladimir , Gural Alexander , Gatt Moshe E. , Haran Arnon , Nachmias Boaz
Published: January 2025

Introduction: The treatment protocols of adolescent and young adults (AYA) patients with acute lymphoblastic leukemia (ALL) have evolved, with the advent of pediatric-based regimens, measurable residual disease monitoring and mutation analysis. Among the latter, previous reports have identified FLT-3 mutations in up to 5% of pediatric patients, however the full clinical significance of these mutations in the non-pediatric population is still uncertain.
Methods: Our cohort includes AYA patients with ALL treated with the NY-II and BFM protocols at different time periods, allowing analysis of prognostic factors and survival outcomes. Additionally, we analyzed DNA samples for FLT-3 mutations, focusing on the potential prognostic implications and treatment responses within our cohort.
Results: No significant differences were found in overall survival (OS) or progression-free survival (PFS) between the two treatment protocols. However, a higher rate of hematopoietic stem-cell transplantation (HSCT) was noted in the NY-II patients. Older age and high WBC count at presentation were identified as adverse prognostic factors using multivariate analysis. FLT-3 mutations were identified in 4 patients (5%) of the cohort, with only one patient having FLT-3 internal tandem duplication (ITD) mutation and three patients having FLT-3-tyrosine kinase domain (TKD) mutations.
Conclusions: The low rate and variability of FLT-3 mutations in an Israeli cohort precludes broad conclusions regarding their prognostic significance. In our cohort, age and WBC count, but not treatment protocol or FLT-3 mutations influenced survival.
Autodeterminação informativa e sociedade de controle: um estudo sobre as relações entre liberdade e poder na era da informação
Authors:   Universidade de São Paulo. Faculdade de Direito, Carvalho Cesar Augusto Rodrigues de
Published: January 2025

A obra é composta por quatro capítulos que analisam, de forma interdisciplinar, os impactos da Era da Informação nas diferentes esferas sociais. No primeiro capítulo, aborda-se a Era da Informação, destacando suas características históricas e o impacto da digitalização. O segundo capítulo centra-se na proteção de dados pessoais e no princípio da autodeterminação informativa, traçando suas origens e evolução legislativa e jurisprudencial no Brasil e no mundo. No terceiro capítulo, discute-se o conceito de "sociedade de controle", de Gilles Deleuze, evidenciando como a inteligência artificial e outras tecnologias da informação sustentam uma nova forma de organização social. O quarto capítulo conecta o princípio de liberdade, na modernidade, à privacidade, proteção de dados e autodeterminação informativa. A conclusão aponta que as legislações atuais, inclusive aquelas que versam sobre a proteção de dados e que disciplinam o uso da internet no Brasil, são insuficientes diante das dinâmicas de controle e dominação no ambiente informacional. Defende-se uma revisão normativa robusta, capaz de enfrentar as desigualdades e injustiças estruturais intensificadas pela sociedade de controle.
High Glucose Treatment Induces Nuclei Aggregation of Microvascular Endothelial Cells via the
foxo1a
-
klf2a
Pathway
Authors: Wang Xiaoning , Kang Xinyi , Li Bowen , Chen Changsheng , Chen Liping , Liu Dong
Published: January 2025

BACKGROUND:

Hyperglycemia is a major contributor to endothelial dysfunction and blood vessel damage, leading to severe diabetic microvascular complications. Despite the growing body of research on the underlying mechanisms of endothelial cell (EC) dysfunction, the available drugs based on current knowledge fall short of effectively alleviating these complications. Therefore, our endeavor to explore novel insights into the cellular and molecular mechanisms of endothelial dysfunction is crucial for the field.

METHODS:

In this study, we performed a high-resolution imaging and time-lapse imaging analysis of the behavior of ECs in
Tg(kdrl:ras-mCherry::fli1a:nGFP
) zebrafish embryos upon high glucose treatment. Genetic manipulation and chemical biology approaches were utilized to analyze the underlying mechanism of high glucose–induced nuclei aggregation and aberrant migration of zebrafish ECs and cultured human ECs. Bioinformatical analysis of single-cell RNA-sequencing data and molecular biological techniques was performed to identify the target genes of
foxo1a
.

RESULTS:

In this study, we observed that the high glucose treatment resulted in nuclei aggregation of ECs in zebrafish intersegmental vessels. Additionally, the aberrant migration of microvascular ECs in high glucose–treated embryos, which might be a cause of nuclei aggregation, was discovered. High glucose induced aggregation of vascular endothelial nuclei via
foxo1a
downregulation in zebrafish embryos. Then, we revealed that high glucose resulted in the downregulation of
foxo1a
expression and increased the expression of its direct downstream effector,
klf2a
, through which the aberrant migration and aggregation of vascular endothelial nuclei were caused.

CONCLUSIONS:

High glucose treatment caused the nuclei of ECs to aggregate in vivo, which resembles the crowded nuclei of ECs in microaneurysms. High glucose suppresses
foxo1a
expression and increases the expression of its downstream effector,
klf2a
, thereby causing the aberrant migration and aggregation of vascular endothelial nuclei. Our findings provide a novel insight into the mechanism of microvascular complications in hyperglycemia.
Abstract 109: Geographical Trends in Cerebrovascular Disease Mortality in the United States, 1999-2020
Authors: Pasia Lorenzo Gabriel , Tran Joseph , Flores Sanchez Dajhanna , Westhoff John
Published: January 2025

Introduction:
Cerebrovascular disease, a leading cause of death in the U.S., presents ongoing public health challenges, particularly in understanding geographic and demographic disparities in mortality. Although mortality trends by sex, race, and ethnicity are well-documented, geographic variations across the U.S. remain underexplored. This study describes cerebrovascular disease mortality trends from 1999 to 2020, focusing on state and urban-rural differences.

Methods:
This retrospective cohort study analyzed 5,387,782 death certificates from 1999 to 2020, obtained from the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) database, focusing on cerebrovascular disease, defined by ICD-10 codes I60-I69. Age-adjusted mortality rates (AAMRs) per 100,000 were calculated based on the 2000 U.S. standard population. Temporal trends in mortality rates, stratified by urban-rural classification (large central metro, large fringe metro, medium metro, small metro, rural) and state, were characterized using the Joinpoint Regression Program, version 5.2.0 (National Cancer Institute). Statistical analyses were performed using RStudio 4.4.1, with p < 0.05 indicating significance. This study used deidentified, publicly available data and was deemed not human research by the University of Nevada, Reno IRB.

Results:
From 1999 to 2020, the overall U.S. AAMR for cerebrovascular disease declined, with an average annual percent change (AAPC) of -2.03% (95% CI: -2.34 to -1.80, p < 0.001). Rural areas consistently had the highest AAMRs throughout the 22-year study period, though they decreased from 113.9 per 100,000 in 1999 to 78.6 in 2020. A significant upward trend was observed from 2018 onwards across all urban-rural classifications, with rural areas experiencing a 5.31% (95% CI: 2.53 to 6.95, p < 0.001) increase in AAMR between 2018 and 2020. State-level analysis showed significant variability among states, with states like Mississippi having persistently high AAMRs, despite overall declines.

Conclusion:
This study highlights a significant overall decline in U.S. cerebrovascular disease mortality from 1999 to 2020, alongside a recent concerning increase beginning in 2018, particularly in rural areas and certain states. These findings underscore the need for targeted public health interventions to address emerging disparities in cerebrovascular disease outcomes by region and urbanization level.
Abstract 141: Clinical Trial Emulation Leveraging Genetic Effects: A Proof-of-Concept Application to SPRINT
Authors: Clocchiatti-Tuozzo Santiago , Rivier Cyprien , Huo Shufan , Shoamanesh Ashkan , Kamel Hooman , Murthy Santosh , de Havenon Adam , Sansing Lauren , Gill Thomas , Sheth Kevin , Falcone Guido
Published: January 2025

Introduction:
Randomized clinical trials (RCTs) are the gold standard for evaluating treatment effects, but they are costly, time-consuming, and complex. Therefore, selecting the most promising novel treatments for RCTs is vital. Genetic variants, randomly distributed during meiosis, create true 'experiements of nature' for the traits they influence. Drugs backed by genomic evidence are twice as likely to gain FDA approval, yet genomics have not been used to formally emulate RCTs. In this study, we present a genomic proof-of-concept emulation of the SPRINT RCT.

Methods:
We conducted SPRINT-e, a genomic emulation of the SPRINT RCT, using UK Biobank data. SPRINT originally randomized 9,361 hypertensive individuals without diabetes into two groups: intensive treatment (SBP<120 mmHg, n=4,678) and standard treatment (SBP<140 mmHg, n=4,683). We selected participants meeting SPRINT’s criteria and used a validated polygenic risk score for SBP to emulate treatment effects. Starting with the 4,678 participants with the lowest genetic risk, we iteratively replaced low-risk participants with higher-risk ones until we matched SPRINT’s SBP difference (15 mmHg) and standard treatment arm size. Finally, we used Cox models, as in SPRINT, to assess whether intensive treatment reduced the risk of stroke, myocardial infarction, coronary artery disease, and cardiovascular death.

Results:
Like SPRINT, SPRINT-e included 4678 participants assigned to intensive genetic treatment, 4683 participants assigned to standard genetic treatment (both mean age 63, 42% female), and a follow-up time of 4.8 years. The number of events in the intensive treatment group of SPRINT and SPRINT-e was 243(5.2%) and 220(4.7%), respectively, while in the standard treatment groups was 319(6.8%) and 270(5.8%), respectively. In SPRINT and SPRINT-e, Cox proportional hazard models estimated that intensive versus standard treatment led to risk reductions in the composite outcome of 35%(HR: 0.75, 95%CI: 0.64-0.89) and 34%(HR: 0.76, 95%CI: 0.62–0.92), respectively (Figure 1).

Conclusion:
Our genomic-based RCT emulation framework accurately reproduced the primary result of SPRINT. Although the absolute event rate in SPRINT-e was lower than in SPRINT, the relative risk reductions were nearly identical. This framework could be valuable for simulating RCTs that target continuous and highly heritable physiological variables. Utilizing these genomic tools could significantly improve the success rate of future RCTs.
Abstract 42: Statin Use in Cervical Artery Dissection and Subsequent Ischemic Stroke
Authors: Lodhi Omair ul haq , Yaghi Shadi , Shu Liqi , Chung Natali , Leon Guerrero Christopher , Engelter Stefan , Kaufmann Josefin Emelie , Traenka Christopher , Kam Wayneho , Zubair Adeel , AlMajali Mohammad , Affan Muhammad
Published: January 2025

Introduction:
Cervical artery dissection (CAD) is a significant etiology of ischemic stroke, especially in individuals under 50, accounting for up to 25% of cases in this age group. While antithrombotic therapy is the primary treatment for CAD, the role of statins in preventing recurrent ischemic strokes in these patients remains unclear. This study, a secondary analysis of the Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection (STOP-CAD) trial, investigates the impact of statin therapy on subsequent ischemic stroke.

Methods:
STOP-CAD was a multicenter retrospective observational study that included 4023 patients with non-major trauma-related CAD. For this substudy, we included 2610 patients with ischemic stroke, excluding those with non-ischemic presentations for example isolated horner’s syndrome and those lacking statin information (Figure 1.0). Patients were stratified based on statin use at hospital discharge and a sensitivity analysis was conducted based on intensity: high-intensity, moderate-intensity, low-intensity, or no statin.

Primary outcome assessed was the incidence of subsequent ischemic stroke, secondary outcomes were major hemorrhage, mortality and 90-day functional outcomes, defined by the Modified Rankin Scale (mRS ≤ 2). Statistical analyses included univariate analyses, Cox regression models to evaluate odds and hazard ratios.

Results:
There was no significant difference in the incidence of subsequent ischemic strokes between the statin group (3.1%) and the no statin group (3.3%) with an adjusted hazard ratio (HR) of 0.736 (95% CI, 0.434-1.248, p=0.256). Similarly, the incidence of major hemorrhage, mortality and 90-day functional outcomes showed no significant differences between the groups (Table 1.0). However, a sensitivity analysis revealed a significantly lower mortality rate in the high-intensity statin group compared to the low-to-moderate intensity statin and no statin groups (p=0.009)(Table 2).

Conclusion:
Statin therapy did not significantly reduce the risk of subsequent ischemic stroke, major hemorrhage, functional outcome, or mortality rates. This study underscores that while statin therapy is beneficial in reducing vascular events and improving outcomes in ischemic stroke population, its specific benefits in CAD-related ischemic strokes are less clear. These findings highlight the need for individualized treatment strategies and further research to optimize secondary prevention in CAD-related stroke.
Abstract 46: Rapid Implementation of Endovascular Thrombectomy Is Associated with Improved Health Equity in Stroke Outcomes: An Analysis of the Get With The Guidelines®-Stroke Registry
Authors: Lusk Jay , Liu Bo , Obrien Emily , Hasan David , Fonarow Gregg , Sheth Kevin , Schwamm Lee , Xian Ying , Albers Gregory , Saver Jeffrey , Li Fan , Mac Grory Brian
Published: January 2025

Introduction:
The introduction of novel therapeutics into clinical practice could improve or worsen equity in health outcomes with respect to socioeconomic status, race, ethnicity, or sex. Our objective was to determine whether the introduction of endovascular thrombectomy (EVT) for treatment of acute ischemic stroke impacted equity in health outcomes.

Methods:
This was a retrospective, observational, cohort study in the American Heart Association’s Get With The Guidelines®-Stroke (GWTG-Stroke) Program based on two epochs: January 2010 to December 2014 and January 2016 to December 2019. From 2,272 hospitals in the United States, 173,049 patients who were potentially eligible for EVT were included. Our exposure was availability of EVT at system level defined by degree of implementation of EVT by each hospital after balancing key patient and hospital characteristics with overlap weighting. The primary endpoint was difference in in-hospital mortality for patients from ZIP codes with median income >$60,000 vs <$60,000. Secondary endpoints were differences in in-hospital mortality by race/ethnicity, sex, insurance status, county-level poverty, and county-level educational attainment, as well as differences in ambulatory status at hospital discharge and a composite of in-hospital mortality/discharge to hospice.

Results:
Of 173,049 patients potentially eligible for EVT (median age 75; 53.9% female), 39,196 (22.7%) received EVT (7,572 [10.0% of potentially eligible patients] between 2010-2014 and 31,624 [32.6% of potentially eligible patients] between 2016-2019 (Table 1). In 2010-2014, 1,565 (20.7%) of patients and in 2016-2019 5,158 (16.3%) who received EVT died in-hospital (Table 2). For the primary endpoint and exposure, rapid implementation of EVT was associated with decreased disparities in mortality rates for patients from counties with median income >$60,000 versus <$60,000 (ARD 3.9%, 95% CI 0.53-7.3%, p=0.02). For secondary analyses, after overlap weighting, rapid implementation of EVT was not associated in changes in health equity in any endpoints by race/ethnicity, sex, county poverty rates, county educational attainment, or insurance status (Table 3).

Conclusions:
Rapid implementation of EVT was associated with improvements in health equity by community median income and was not associated with new or worsening disparities in any health outcome by race/ethnicity, sex, insurance status, or other county-level socioeconomic markers.
Abstract 56: Intravenous Glyburide in Large Core, Endovascular-Treated Stroke Patients: An Analysis of the CHARM Trial
Authors: Sheth Kevin , Albers Greg , Saver Jeffrey , Campbell Bruce , Molyneaux Bradley , Hinson H.E. , Cordonnier Charlotte , Steiner Thorsten , Toyoda Kazunori , Wintermark Max , Nogueira Raul , Simard J Marc , Jacobson Sven , Kimberly W Taylor
Published: January 2025

Introduction:
Recent large core stroke trials show a benefit for endovascular treatment (EVT) of acute ischemic stroke up to approximately 125 mL. Consequently, clinical trials evaluating neuroprotection in EVT populations may best test proof of concept under this volume threshold. The CHARM trial evaluated the safety and efficacy of intravenous glyburide as a treatment for large hemispheric infarction (LHI) patients at high risk for cerebral edema.

Hypothesis:
The objective of this analysis was to examine the treatment effect of IV glyburide in EVT patients with baseline infarcts up to 125 mL.

Methods:
CHARM subjects who were enrolled with CTP or DWI volume 80-125 mL and underwent EVT were included in this analysis. The primary endpoint was a shift analysis on the 90-day modified Rankin Scale (mRS) and included participants aged ≤70 years who received any study drug. Independent variables included age, sex, baseline NIHSS, world region, and tPA. We also examined the frequency of decompressive craniectomy and the amount of midline shift (mm) by treatment group.

Results:
For a total of 34 subjects (mean age 56 years, 32% female, baseline NIHSS 20, 41% received thrombolysis), the time to thrombectomy was 4.5±2.0 hours and time to study drug was 9.6±1.4 hours. glyburide-treated patients received study drug later than placebo by an average of 1 hour (
P
=0.036). The baseline infarct volume was 94±20 mL, which did not differ by treatment arm. glyburide-treated subjects had a favorable outcome (n=18, cOR 7.13, 95%CI 1.51-33.7,
P
=0.013) relative to placebo (see figure). 90-day mortality occurred less frequently in glyburide treated subjects compared to placebo (5.6% vs 31%,
P
=0.05). There were no decompressive craniectomies in glyburide treated patients, whereas there were 4 decompressions among the placebo-treated subjects (
P
=0.021). The mean midline shift was 4.2 ± 2.5 mm in IV glyburide-treated subjects and 7.6 ± 5.5 mm among placebo-treated subjects (
P
=0.024).

Conclusions:
There is evidence of benefit for IV glyburide in large core EVT treated subjects with a baseline stroke volume ≤125 mL. Although IV glyburide may also have benefit among non-EVT treated subjects, the evolving standard of care of EVT for large core stroke indicates that an efficient, feasible trial design should focus on EVT patients.
Abstract 67: How dark is too dark? A multicentric retrospective study exploring the role of Net-Water-Uptake in predicting futile recanalization following mechanical thrombectomy.
Authors: Carone Davide , Brinjikji Waleed , Perry Alistair , Al Halak Abdulrahman , Vaclavik Daniel , ZAMARRO JOAQUIN , Rai Ansaar , Kallmes David F , Harston George
Published: January 2025

Background:
Acute stroke lesions become more hypodense on non-contrast CT as the ischemic injury matures. Lesions transition to established infarcts at which time recanalization treatment is thought to be futile, if not harmful. As it is not possible to directly quantify the degree of injury progression, eligibility for treatment is determined using temporal criteria. In this study we used an AI approach to segment and quantify the degree of hypoattenuation of acute stroke lesions on baseline CTs, and explored its impact on clinical outcome following mechanical thrombectomy.

Methods:
Imaging was collected from a multicentric registry (across 4 US and 5 EU sites) of consecutive large vessel occlusion (LVO) stroke patients who underwent mechanical thrombectomy. Baseline NCCT scans were processed using Brainomix 360 to automatically segment the ischemic core. Lesion hypoattenuation was then quantified by in-house software using the mean Net-Water-Uptake (NWU). Multivariate models were used to explore the association between NWU and clinical outcome (3-month modified Rankin scale–mRS), controlling for e-ASPECTS scores, age, and recanalization status. Interaction models were also used to examine the relationship between NWU e-ASPECTS scores.

Results:
Of the 1363 patients included (age: median 70, IQR: 50-79; 571 females), successful recanalization (mTICI 2b-3) was achieved for 1119 patients. Multivariate analysis found NWU (p=<.001, t=4.62; Fig1) to remain an independent predictor of outcome. There was a significant interaction effect between and ASPECTS score (p=0.029, Fig 2), suggesting that degree of hypoattenuation played a larger role in patients with lower aspects value. In subgroup analysis, NWU was not a significant predictor of outcome in patients that did not achieve successful recanalizion (mTICI 0-2a).

Conclusions:
These findings suggest that stroke lesion hypodensity measured using NWU might help identify patients at risk of futile recanalization, and that incorporating this information might be more relevant in patients with lower ASPECTS. The ability to determine treatment eligibility using information extracted from routine imaging would allow safe extension of treatment to patients with unclear onset time, and would account for differences in rates of infarct progression.
Abstract 70: Machine Learning for Identification of Fast Progressors of Acute Anterior Circulation Ischemic Strokes in the Early Window Without CT Perfusion
Authors: Lin Sidney , Raince Avtar , Byrns Kory
Published: January 2025

Purpose:
Fast progressors (FP) of infarct growth in anterior circulation occlusions at 0-6 hours from onset (early window) have been associated with reduced rates of favorable outcome post endovascular thrombectomy (EVT). FP can be identified by using CT perfusion (CTP) derived infarct core volume (ICV) to calculate infarct growth rate (IGR), but has disadvantages of added time/radiation and susceptibility to motion. CTP is often performed with CT angiography (CTA) but AHA/ASA guidelines do not require perfusion imaging in the early window for EVT decision making. Our aim was to determine if machine learning (ML) can identify FP with only clinical, laboratory, CT, and CTA variables, without using CTP data.

Methods:
We retrospectively included consecutive stroke patients arriving 0-6 hours from symptom onset with ICA and/or MCA occlusion on CTA and had concurrent CTP. RAPID AI generated maps of ICV and hypoperfusion volume with criteria of rCBF <30% and Tmax >6 seconds. IGR was calculated as ICV/onset-to-CT time. FP was defined as IGR ≥10 mL/hour. Eight ML algorithms for binary classification were used with 11 selected features including age, NIHSS, lab values, ASPECTS, clot burden score (CBS), and dichotomized collateral score (Tan method 0-1 vs 2-3). Data was randomly split 70:30 for training and testing. Synthetic Minority Oversampling Technique was used to balance the class distribution in the training set. 10-fold cross validation was assessed during training. The performance of the models during testing was compared using ROC AUC, precision (PPV), recall (sensitivity), and accuracy. Relative weights of features during testing were examined with Shapley Additive Explanations (SHAP).

Results:
147 patients were included with median (IQR) age 76 (67-85), onset-to-CT 2.5 hours (1.5-4), NIHSS 19 (12-24), ASPECTS 9 (8-10), CBS 7 (6-8), collateral score 1 (1-2), ICV 11 mL (0-34), hypoperfusion volume 104 mL (67-157), and IGR 3.4 mL/hour (0-12.3). 47 (32.0%) were labeled as FP with median IGR 24.0 mL/hour (13.3-40.0). 16 (34.0%) of these FP also had ICV >70 mL upon arrival. XGBoost was the best performing ML model with ROC AUC 0.90, precision 0.76, recall 0.93, and accuracy 0.89. SHAP analysis of this model ranked collateral score, time from onset, serum glucose level, systolic blood pressure, and ASPECTS as the top 5 most important features.

Conclusion:
ML can accurately identify FP in the early window without using CTP.
Abstract 83: Prognostic Value of Cortical Superficial Siderosis Among Patients with Cerebral Amyloid Angiopathy-Associated Intracerebral Hemorrhage
Authors: Das Alvin , Abramovitz Fouks Avia , Gokcal Elif , Rotschild Ofer , Regenhardt Robert , Selim Magdy , Viswanathan Anand , Goldstein Joshua , Rosand Jonathan , Steven greenberg , Gurol Edip
Published: January 2025

Introduction:
The recent update (version 2.0) to the Boston criteria for cerebral amyloid angiopathy (CAA) adds two additional neuroimaging markers to increase the sensitivity of CAA detection: multispot white matter hyperintensity (WMH) pattern and severe centrum semiovale enlarged perivascular spaces (CSO EPVS). While the presence of these novel non-hemorrhagic markers, together with well-established hemorrhagic markers such as lobar cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS), increases the likelihood of underlying CAA in patients with intracerebral hemorrhage (ICH), it is unclear whether these markers have a prognostic impact on clinical outcomes.

Methods:
Brain MRIs from a prospective database of consecutive non-traumatic ICH patients admitted to a tertiary care center were reviewed for the presence of CMBs, cSS, multispot WMH pattern, and CSO EPVS. Patients who met the diagnostic criteria for CAA were selected for inclusion in this study. Clinical and neuroimaging predictors of an unfavorable discharge outcome (modified Rankin score ≥ 4) were assessed in univariate and multivariable models.

Results:
Between 2003 and 2019, 1,791 patients were admitted with non-traumatic ICH. Of the 1,297 (72%) patients who received a brain MRI, 645 (36%) were found to have CAA (mean age 74±11 years, 49% female). An unfavorable discharge was observed in 75% of patients. Lobar CMBs occurred in 326 (51%) patients, cSS occurred in 197 (31%), multispot WMH pattern occurred in 123 (19%), and severe centrum semiovale EPVS occurred in 156 (24%). In univariate analyses, age, hypertension, diabetes, ischemic stroke history, dementia, admission Glasgow Coma Scale (GCS) scores, intubation, external ventricular drain placement, hematoma evacuation, intraventricular extension, and cSS were associated with an unfavorable discharge outcome (all
p
< 0.05). When entered into a multivariable model subjected to backward elimination, age (aOR 1.05, 95% CI 1.03–1.08), hypertension (aOR 1.66, 95% CI 1.06–2.62), dementia (aOR 8.40, 95% CI 1.97–35.81), GCS score (aOR 0.85, 95% CI 0.75–0.96), intubation (aOR 2.59, 95% CI 1.09–6.15), intraventricular extension (aOR 1.75, 95% CI 1.67–4.84), and cSS (aOR 1.75, 95% CI 1.07–2.88) remained significantly associated with an unfavorable discharge outcome.

Conclusion:
Although non-hemorrhagic imaging markers are common in CAA patients with ICH, only the presence of cSS is significantly associated with unfavorable clinical outcomes.
Abstract 86: Location-Specific Hematoma Volume Tolerance for Spontaneous Intracerebral Hemorrhage
Authors: Brissette Vincent , Ouyang Menglu , Yogendrakumar Vignan , Ramsay Timothy , Mallick Ranjeeta , Morotti Andrea , Goldstein Joshua , Anderson Craig , Dowlatshahi Dar
Published: January 2025

Background:
Hematoma volume is an important predictor of outcome in spontaneous intracerebral hemorrhage (ICH). Location-specific hematoma volume thresholds are associated with poor outcome and can inform surgical trial inclusion criteria and clinical decision rules for hematoma evacuation. In a pooled trial dataset, we evaluated associations between ICH location, hematoma volume thresholds, and patient outcomes.

Methods:
We performed a secondary analysis of the ATACH-2 clinical trial. We evaluated the associations between intraparenchymal location-specific hematoma volume cutoffs (thalamic, basal ganglia, and lobar) and poor outcome (mRS 4-6; primary outcome) or mortality (secondary outcome) at 3 months. Using semi-automated volumetric assessments of 24-hour CT scans, we applied volume cutoffs at 5 mL increments starting at ≤5 mL up to >50 mL. We also applied Youden’s method for each hematoma location to determine the optimal location-specific volume thresholds that predict outcomes. We calculated odds ratios (OR) of poor outcome through multivariable logistic regression models for each location, adjusted for age, sex, prior stroke/transient ischemic attack, hemisphere location, and intraventricular hemorrhage extension.

Results:
Out of 949 patients included for analysis, 358, 485 and 106 were diagnosed with thalamic, basal ganglia ICH and lobar ICH, respectively. Location-specific hematoma volume cutoffs most predictive of a poor outcome (mRS 4-6) calculated with Youden’s index were 6.6 mL for thalamic ICH (OR 5.72, 95% CI 3.22-10.18; p<0.0001), 23.1 mL for basal ganglia ICH (OR 14.11, 95% CI 8.21-24.27; p<0.0001) and 24.4 mL for lobar ICH (OR 8.22, 95% CI 2.3-29.36; p=0.0012). For our secondary outcome, Youden’s lobar ICH cutoff of 42.5mL was the most predictive of mortality. Predictive performances for Youden’s method are shown in Table 1, and for all thresholds shown in Figure 1.

Conclusion:
Hematoma volumes associated with poor outcome and mortality vary by location, supporting the notion that different brain regions have different “hematoma volume tolerances”; good outcomes are unlikely when ICH volume exceeds that brain region’s tolerance. Our results provide important data for location-specific hematoma volume tolerance to inform clinical trials and clinical decision rules in ICH management.
Abstract 89: A first-in-class humanized antibody fragment targeting platelet glycoprotein Ibα: a comprehensive preclinical study of CA1001 for the treatment of acute ischemic stroke
Authors: Xu Xiaohong , Lei Xi , Zhu Guangheng , Liu Zhenze , Hu Xudong , Slavkovic Sladjana , Neves Miguel , Ma Wenjing , Xie Huifang , Preeti Preeti , Yu Ruoying , Shaykhalishahi Hamed , Zhang Cheng , Shen Chuanbin , Li Bei , Tang Naping , Chang Yan , Xiang Qian , Cui Yimin , Ni Heyu
Published: January 2025

Introduction:
Platelet glycoprotein (GP) Ibα is a key receptor for thrombosis. Under high shear conditions, GPIbα-VWF interactions are required for initiating platelet adhesion and vessel occlusion. GPIbα is also an important checkpoint for thrombo-inflammation in acute ischemic stroke. It has been considered as a desirable target against ischemic stroke for decades, but no anti-GPIbα drug has been successfully developed.

Methods:
CA1001 was humanized from our unique mAb crossing different species, and manufactured under GMP-like conditions with 99.9% purity. The efficacy of CA1001 was assessed using various
in vitro
platelet functional assays with blood samples and
in vivo
models, including state-of-the-art intravital microscopy thrombosis and transient middle cerebral artery occlusion (tMCAO) models. Pharmacokinetics (PK), pharmacodynamics (PD), and a 14-day regulatory toxicology study were conducted in rats and rhesus monkeys.

Results:
CA1001 specifically recognized platelet GPIbα from human, monkeys, rats, mice, rabbits and dogs. Using platelets from rhesus monkeys, healthy volunteers, and patients with peripheral artery disease, CA1001 dose-dependently inhibited ristocetin-induced platelet aggregation
in vitro
. Using laser injury and FeCl
3
injury intravital microscopy models, CA1001 inhibited thrombosis, prevented vessel occlusion, and importantly, promoted thrombus dissolution (thrombolysis)
in vivo
. In a 60-min tMCAO models, intravenous injection of CA1001 1 hour after tMCAO significantly reduced the cerebral infarct volume at 24 hours without increasing the risk of intracerebral hemorrhage. The PD studies showed that single bolus injection of CA1001 reached maximal anti-platelet effects within 5 minutes (0.25mg/kg in rats, 4mg/kg in monkeys) which was maintained following intravenous infusion. The extent and duration of the effect were dose-dependent. Plasma concentrations increased linearly with the dose received. In toxicology studies, CA1001 was well tolerated and safe without bleeding nor platelet count reduction. The No Obvious Adverse Event Level in rats and monkeys were 25mg/kg, and 100mg/kg respectively, which are 10 and 25 times the therapeutic targeted doses.

Conclusion:
The first-in-class humanized anti-GPIbα Fab CA1001 has potent anti-thrombotic effects, consistent PK/PD properties and favorable safety and tolerability profiles warranting further clinical development in healthy volunteers and patients with acute ischemic stroke.
Abstract DP1: Intravenous thrombolysis for acute ischemic stroke patients with cerebral amyloid angiopathy
Authors: Chen Huanwen , Colasurdo Marco , Khunte Mihir , Malhotra Ajay , Gandhi Dheeraj
Published: January 2025

Background:
Cerebral amyloid angiopathy (CAA) is a hemorrhagic cerebrovascular disease that is thought to be due to excess protein deposition in vessel walls that lead to fragility and increase the risk of rupture. Whether intravenous thrombolysis (IVT) is safe and effective for acute ischemic stroke (AIS) patients with CAA is largely unknown.

Methods:
This was an explorative analysis of a nationwide database of hospitalizations in the United States. AIS patients with CAA were identified by ICD-10 codes and included in the study, and cases were divided into IVT and no-IVT groups. Propensity score matching was performed to balance treatment groups, and additional multivariable logistic regressions were used for doubly robust analyses. Primary outcome was routine discharge to home with self-care. Secondary outcomes include discharge to home, in-hospital mortality, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH).

Results:
5,100 patients were identified; 498 (9.8%) received IVT. After propensity score matching and doubly robust analyses with additional multivariable logistic regression, IVT was associated with better discharge outcomes (Figure 1), with significantly higher odds of routine discharge (adjusted OR 1.77 [95%CI 1.12-2.80], p=0.015) despite higher odds of ICH (aOR 4.00 [95%CI 2.79 to 5.75], p<0.001), and SAH (aOR 2.42 [95%CI 1.41-4.16], p=0.001). IVT was not associated with significantly different odds of home discharge (aOR 0.99 [95%CI 0.69-1.41], p=0.94) or in-hospital mortality (aOR 0.91 [95%CI 0.45-1.84], p=0.80). Mediation analyses revealed that the higher rates of ICH associated with IVT treatment led to a statistically significant suppression of IVT’s association with higher odds of routine discharge (ACME of -0.03 [-0.01 to -0.06], p=0.004 and proportion suppressed of 49.3% [95%CI 8.0% to 360.6%], p=0.038).

Conclusion:
IVT for AIS patients with CAA was associated with higher odds of short-term excellent outcomes despite higher odds of ICH and SAH, and it did not increase the odds of early mortality.
Abstract DP14: Neuroinflammatory mechanisms linking metabolic syndrome with vascular cognitive impairment
Authors: Zhang Mengqi , Letian Anudari , Goldberg Emily , Arkelius Kajsa , SINGHAL NEEL
Published: January 2025

Background:
PCSK9, a key regulator of cholesterol metabolism, has been implicated in atherosclerosis. However, its potential role in vascular cognitive impairment and dementia (VCID) remains elusive. We hypothesized that PCSK9 overexpression, exacerbated by a high-fat diet (HFD), would promote neurovascular inflammation and recapitulate VCID pathology.

Methods:
C57 mice were stratified into control, PCSK9 overexpression, HFD, and PCSK9+HFD groups. PCSK9 overexpression was induced via AAV injection, and mice were subjected to either a normal diet or HFD for 4 months. Laser speckle contrast imaging was employed to assess CBF response to whisker stimulation. Immunofluorescence analyses were conducted to evaluate neurovascular alterations, encompassing microvascular density, glial activation, neuronal density, arteriosclerosis, and blood-brain barrier integrity. Light sheet microscopy was utilized to provide ultra-high resolution 3D imaging of the cerebrovascular architecture. Cognitive function and exploratory behavior were investigated using novel object recognition and open field tests.

Results:
PCSK9+HFD mice exhibited significantly compromised neurovascular coupling, as evidenced by attenuated CBF response to whisker stimulation. Immunofluorescence revealed profound neurovascular alterations, including markedly reduced microvascular density, exacerbated astrogliosis and microglial activation, diminished neuronal density, heightened arteriosclerosis and inflammation, and severe blood-brain barrier disruption. These changes were most pronounced in the PCSK9+HFD group, followed by the HFD and PCSK9 groups, highlighting the synergistic detrimental effects of PCSK9 overexpression and HFD. Notably, light sheet fluorescence microscopy (LSFM) unveiled a dramatically sparser and less complex 3D cerebrovascular network in PCSK9+HFD mice. Moreover, PCSK9+HFD mice displayed the most severe neurocognitive changes, as shown by impaired recognition memory and reduced exploration.

Conclusions:
This study demonstrates that metabolic syndrome induced by PCSK9 overexpression and HFD synergistically converge upon neuroinflammatory mediators to recapitulate VCID pathology. Microglial and astrocytic activation in PCSK9 overexpression and HFD is strongly associated with altered cerebral blood flow regulation. Our findings provide a preclinical platform for discovery of new therapeutic approaches for neuroinflammatory and cerebrovascular alterations associated with VCID pathology.
Abstract DP3: Thrombolysis for Ischemic Stroke after 4.5 hours without thrombectomy: A Meta-analysis of Randomized Controlled Trials
Authors: Ozaeta Jan Camille , Dadzie Samuel , Chinnatambi Christopher , Kumi Alex , Ibrahim Sammudeen , March Christopher
Published: January 2025

Background:
Current guidelines for ischemic stroke recommend initiating intravenous thrombolytic therapy within 4.5 hours after stroke onset or the last known well time. However, advancements in imaging techniques, such as CT perfusion and perfusion-diffusion magnetic resonance imaging (MRI), have improved diagnostic accuracy. These modalities can identify viable brain tissue beyond the 4.5-hour window, and reperfusion through thrombolysis has been shown to enhance functional outcomes in patients with salvageable brain tissue beyond this timeframe.

Objective:
The aim of this study is to assess the efficacy and safety of thrombolysis administered more than 4.5 hours after the onset of ischemic stroke.

Methods:
We conducted a comprehensive search of the Cochrane Central Registry of Controlled Trials, PubMed, Embase, Web of Science, and clinicalTrials.gov databases for all randomized controlled trials (RCTs) published up to July 2024 comparing thrombolysis (TPA) > 4.5 h to standard of care. The primary functional outcome was the absence of disability measured as a modified Rankin scale of 0-1. The secondary clinical endpoints included symptomatic intracranial hemorrhage (ICH), 90-day mortality, reperfusion at 24 hours, and functional independence at 90 days. The odds ratio (OR) with a 95% confidence interval (CI) was calculated for the outcomes of interest. The protocol was registered in PROSPERO (CRD42024564522).

Results:
Four RCTs were included in the analysis, comprising a total of 1,268 patients (TPA > 4.5h, n = 643; standard, n = 625) with a mean age of 70 years and 56% males. TPA > 4.5h was associated with a 42% reduction in the frequency of functional disability (OR: 1.42 [95% CI, 1.12-1.82]; p = 0.004; I
2
= 0%). There was also a 35% increase in functional independence at 90 days (OR: 1.35 [95% CI, 1.08-1.69]; p = 0.009; I
2
= 0%), and a 46% increase in reperfusion at 24 hours (OR: 1.46 [95% CI, 1.14-1.87]; p = 0.003; I
2
= 0%). There was, however, a significant increase in the risk of symptomatic ICH (OR: 2.82 [95% CI, 1.25-6.38]; p = 0.01; I
2
= 14%), but there was no significant difference in 90-day mortality (OR: 1.11 [95% CI, 0.80-1.53]; p = 0.53; I
2
= 0%).

Conclusion:
Thrombolysis administered beyond 4.5 hours after the onset of ischemic stroke is associated with improved functional outcomes and increased reperfusion rates. However, this benefit is accompanied by a higher risk of symptomatic intracranial hemorrhage.