bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 104: Cytochrome B5 Reductase 3 Regulates The Erythropoietin Response To Ischemic Stroke In A Mouse Model Of Chronic Anemia And Oxidative Stress
Authors: Wood Katherine C , Yuan Shuai , Schmidt Heidi , Hahn Scott , Ghosh Samit , Ofori-Acquah Solomon , Straub Adam C
Published: February 2023

Introduction:
Cytochrome b5 reductase 3 (Cyb5R3) is a heme iron reductase that reverses oxidized soluble guanylate cyclase (sGC) heme iron (Fe
3+
Fe
2+
) to preserve nitric oxide signaling. Under oxidative stress, such as occurs with sickle cell disease (SCD) and ischemic stroke, Cyb5R3 redox signaling provides resilience against tissue damage. A loss-of-function (roughly 50%) Cyb5R3 missense variant (T117S) occurs with high frequency (0.23 minor allele) in persons of African ancestry, who also suffer a greater burden of sickle cell anemia and ischemic stroke than other races. We hypothesized that Cyb5R3 regulates the erythropoietin response to ischemic stroke in a mouse model of SCD.

Methods:
Age-matched male SCD mice with wild-type Cyb5R3 (SS
WT
) or T117S Cyb5R3 (SS
T117S
) underwent middle cerebral artery occlusion (55 min) and reperfusion (48 hr). Blood was sampled at baseline and 48h reperfusion for hematology measurements. Brains were stained with 2,3,5-triphenyltetrazolium chloride to quantify infarct volume. Erythropoietin (EPO), heme oxygenase 1 (HMOX1) and sGC were assayed by Western blot.

Results:
We found brain infarct volume to be greater in SS
T117S
vs SS
WT
(63 vs 27 cm
3
, respectively; P=0.003). Red cells, hematocrit and hemoglobin decreased in SS
T117S
post-stroke, which was opposite to SS
WT
(red cells: -13% vs 13%, P=0.01; hematocrit: -20% vs 0%, P=0.03; hemoglobin: -18% vs 3%, P=0.02, respectively). In the absence of stroke (age-matched controls), SS
WT
had elevated HMOX1 protein compared to SS
T117S
, which normalized in post-stroke SS
WT
but was unchanged in post-stroke SS
T117S
. Kidney and plasma EPO levels significantly increased in SS
WT
post-stroke, but not in SS
T117S
. In vitro studies using HEK293 cells showed EPO and HMOX1 decrease with Cyb5R3 knockdown by siRNA.

Conclusion:
Our findings suggest a modifying role for Cyb5R3 in brain-kidney crosstalk during ischemic stroke, wherein loss of T117S Cyb5R3 activity negatively impacts renal and plasma EPO levels and resilience against infarct of ischemic brain tissue. The Cyb5R3 axis on which the brain-kidney-blood response to stroke in SCD turns represents a novel target for precision medicine approaches to managing stroke risk and pathology in SCD carriers of the T117S variant.
Abstract 108: Stroke Amplifies Cerebrovascular Matrix Metalloproteinase-3 (MMP3) Activity In Diabetes: Potential Sex Differences And Impact On Endothelial To Mesenchymal Transition (EndMT)
Authors: Abdelsaid Kareem , Abdul Yasir , Jamil Sarah , Li Weiguo , Ergul Adviye
Published: February 2023

Both female sex and diabetes increase the risk of poor stroke recovery, but underlying mechanisms are unclear. We reported that inhibition of MMP3 with UK356618 prevents hemorrhagic transformation (HT) in male diabetic rats, and female diabetic rats develop greater HT than males. Emerging evidence suggests that MMP3 may contribute to the regulation of EndMT, a process associated with scarring and impaired healing. We tested the hypotheses that: 1) MMP3 activity is amplified to a greater extent in the cerebrovasculature of female diabetic rats, especially after stroke; 2) EndMT occurs in female brain endothelial cells (BMVECs), and 3) MMP3 inhibition in stroke and diabetes-like conditions improves cell integrity/survival in female BMVECs.

Methods:
Cerebral microvascular homogenates were prepared from control and diabetic male and female rats subjected to sham or 60-min middle cerebral artery occlusion. MMP3 expression/activity was measured. EndMT /endothelial integrity were assessed by immunoblotting in male and female BMVECs cultured in normal, diabetes or ischemia-like conditions.

Results (Table):
Cerebrovascular MMP3 expression/activity is higher in females. TGF-β, a major EndMT inducer, significantly decreased VE-Cadherin and increased EndMT markers αSMA and p-SMAD2 to a greater extent in female cells. Ongoing studies suggested that MMP3 inhibitor UK356618 improved the expression of tight junction protein occludin and cell survival, which was associated with a decrease in transforming growth factor receptor-1 (TGFβR1).

Conclusions:
The impact of long-term MMP3 inhibition on EndMT, neurovascular restoration, and post-stroke recovery in females and diabetes needs to be further explored.
Abstract 116: Cortical Thickness Estimation From Clinical T1 Weighted Magnetic Resonance Images To Predict Functional Outcomes After Mechanical Thrombectomy
Authors: Kawas Mohammad Iyas , Atcheson Kyle , Kim Jeongchul , Kittel Carol , Whitlow Christopher , Quintero Wolfe Stacey C
Published: February 2023

Background:
Endovascular treatment (EVT) is the standard of care for acute ischemic stroke caused by large vessel occlusion (LVO). However, successful EVT does not result in functional independence in many patients. This may be due to pre-existing cortical atrophy that might reduce compensatory plasticity and attenuate recovery. Identifying patients who will most benefit from EVT may be possible using baseline cortical thickness measures as a marker of brain health and providing additional prognostic utility for clinical T1-weighted (T1w) MRI.

Objective:
Estimate hemispheric and regional cortical thickness from clinical T1w-MRI and determine its influence on functional outcomes post successful EVT.

Methods:
We performed a retrospective analysis of a prospectively maintained Stroke Thrombectomy and Aneurysm Registry (n=602), collected between 2015 - 2021. We selected 213 patients (mean age 67.5 ± 14.6, 49.3% female) who had adequate quality MRI within 14 days of EVT and a record of the modified Rankin scale (mRS) at 90 days post EVT. Clinical T1w images were transformed into high-resolution images using the convolutional neural network SynthSR. Then, FreeSurfer was used to estimate hemispheric and regional mean cortical thickness from the side contralateral to the stroke, to avoid local lesion effects. In addition to hemispheric cortical thickness, we selected the insula, superior frontal gyrus (SFG), and superior temporal gyrus (STG) for the analysis due to their importance in sensorimotor processing, self-awareness, and social cognition respectively which are important during rehabilitation.

Results:
In an ordinal regression model adjusted for baseline mRS, the cortical thickness of the SFG and the STG was significantly predictive of 90-day mRS (p=0.005 and p=0.003 respectively), while hemispheric and insular cortical thickness were not. After adjusting for confounders and comorbidities, SFG and STG cortical thickness remained significant predictors of 90-day mRS (p<0.001 for both).

Conclusions:
The correlation between decreased cortical thickness in specific regions and worse functional outcomes elucidates the effects of pre-existing cortical atrophy in key areas of the brain that may be more important than others during recovery.
Abstract 117: Low-to-moderate Risk Transient Ischemic Attack Patients Can Be Safely Discharged From The Emergency Department To A Nurse Practitioner-Led Clinic
Authors: Alfandy Fnu , Brecht Mary-Lynn , Cardin Suzette , Devon Holli A
Published: February 2023

Background:
Unnecessary admissions fuel rising healthcare costs and take away resources from higher acuity patients without evidence of increased safety.

Purpose:
The purpose of this quality improvement project was to determine if the care diversion for transient ischemic attack (TIA), from inpatient to a nurse practitioner (NP)-led specialty clinic, resulted in no increase in stroke incidence at 90 days.

Methods:
The sample included all adults (18 years or older) presenting to the emergency department (ED) with TIA at low-to-moderate risk for stroke. Risks were defined by the ABCD
2
score and non-invasive vessel imaging. Patients who met the criteria were discharged and evaluated by a stroke NP at the TIA clinic within seven days. These patients were compared to those who were admitted to the hospital prior to clinic launch. Chart reviews were conducted to determine stroke incidence at 90 days post TIA. Descriptive statistics were used to evaluate clinical variables, and Fisher’s Exact test was used to assess difference in stroke rates. Patient satisfaction score was collected using the existing institutional survey.

Results:
Eighty-one participants were included, 40 in the clinic group and 41 in the admission group. The mean ages in the clinic group and the admission group were 72.8 and 75.2 years, respectively (
p
=0.37). Females comprised 45% of patients in the clinic group, compared to 51.2% in the admission group (
p
=0.58). The mean ABCD
2
scores were 4.08 and 3.95 in the clinic and admission groups, respectively (
p=
0.63). The median clinic follow-up time was six days. There was no stroke incidence in the clinic group and one incidence in the admission group (
p
=1.0) within 90 days of index TIA. Patient satisfaction score of the NP was 92.6%.

Conclusions:
In conclusion, referral to an NP-led clinic in patients with low-to-moderate risk TIA was equally safe as hospital admission.
Abstract 118: Expanded Tele-stroke Coverage In Community Hospitals Improves Care For Stroke Patients And Reduces Transfers
Authors: Alhajala Hisham , Hendricks-Jones Melinda , Ghosh-Dastidar Pratiti , Shawver Julie , Kung Vieh M , Burgess Richard , Jumaa Mouhammad A , Zaidi Syed F
Published: February 2023

Background:
Minor ischemic strokes and transient ischemic attacks account for more than a third of ER stroke admissions (21% and 15%, respectively). Most small community hospitals lack adequate coverage by stroke service necessitating transfer of stroke patients to comprehensive stroke centers.

Methods:
We studied the effect of implementing telestroke service in all regional hospitals and emergency departments affiliated with Promedica Toledo Hospital, a comprehensive stroke center (CSC). This service is carried out by stroke-trained advanced practice providers under supervision of vascular neurologists. Coverage included acute ED assessments of stroke patients, inpatient telestroke consults and follow ups. We propose that this comprehensive telestroke service will improve care of stroke patients presenting to community hospitals, decrease the number of transfers to CSC. It will improve numbers and timing of IV thrombolysis.

Results:
The total stroke alerts from affiliated locations before implementing telestroke service (2018 and 2019 and first half of 2020), and after implementing the service (since July 2020, 2021, and 2022) were 4817 and 4900, respectively. In pre-telestroke years, about 43% of patients were transferred to the CSC for acute stroke care while during post-telestroke years were 28% with 34.8% reduction on transfers. Among transferred patients, stroke mimickers' percentage decreased from 21% to 8%. There was a 14.5% increase in the number of IVT patients after implementing telestroke service but door to needle time did not change.

Conclusion:
This is the first reported experience of utilizing stroke-trained APPs to expand telestroke coverage for both ED and inpatient services at community hospitals. There was a decrease in number of transfers to CSC, keeping patients at their local communities. It also increased the number of IV thrombolytic treatments and reduced the number of stroke mimickers' transfers.
Abstract 119: Elevating The Cerebrovascular Nurse Practitioner: Program Development With Neurosurgeon Champions
Authors: Tosto-D'Antonio Gabriella , Connolly Sander , Mandigo Grace K , Lavine Sean D
Published: February 2023

Background:
The cerebrovascular nurse practitioner (NP) continues to have an ever-evolving role, particularly in neurosurgical departments. Although more NPs are obtaining their doctorate degrees, further post professional education is needed to promote specialty clinical practice. Our team developed a 16-week comprehensive educational program that addresses the main disease processes of stroke and highlights the importance of collaboration with cerebrovascular neurosurgeons.

Methods:
Four clinical domains were identified- see table 1. Each week, a neurosurgeon gave a 1 hour lecture that reviewed neuroimaging and anatomy, pathophysiology, clinical care presentation, and preoperative and postoperative management. After all lectures were completed for each domain, a 1 hour journal club was held discussing the most recent stroke clinical practice guidelines. NPs were surveyed to report which domains were most clinically meaningful.

Results:
Our division delivered a comprehensive educational program, allowing the cerebrovascular NP to take on a more independent role in patient care. Of the sections presented in each clinical domain, neuroimaging and clinical management were reported as the most important section of the lectures by NPs.

Discussion:
The cerebrovascular NP plays a unique role on the clinical team, regardless if a patient is seen throughout the entire continuum as an elective case or treated emergently and later discharged to clinic. This program optimized evidence-based cerebrovascular practices, improved collaborating relationships between NP and surgeon, and promoted professional development. Future work will include course evaluation for on-boarding NPs and program implementation in other neurosurgical subspecialties.
Abstract 120: Tissue Kallikrein Attenuates Early Ischemic Edema Progression By Increasing The Glymphatic System Kinetics In Pmcao Mice
Authors: Zhang Jianying , Cao Wenjie , Dong Qiang
Published: February 2023

The glymphatic system (GS) is a perivascular fluid exchange pathway, that is crucial for maintaining brain homeostasis, and may contribute to ischemic edema. Tissue Kallikrein treatment provides cerebral infarction patients with vasodilatory activity, which may facilitate the kinetics in GS. We hypothesized that Tissue Kallikrein could attenuate early ischemic edema following blood interruption by altering the kinetics of the GS. In this study, we evaluated the effects of Tissue Kallikrein on mice acute ischemic edema in pMCAO mice. A fluorescent tracer was injected into the striatum of mice, and the proportion of area infused by the fluorescent tracer in the brain parenchyma was measured to assess the kinetics of the GS. The effect of Tissue Kallikrein on edema was determined by DWI/T2 mismatch, ischemic edema progression was indicated by a mismatch between diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI), that is, an acute ischemic lesion on DWI without a corresponding lesion on T2WI. Concurrently, correlation analysis was performed for the kinetics and the time windows of DWI/T2 mismatch. Our results indicated that Tissue Kallikrein attenuated brain edema was associated with improved GS kinetics in mice with pMCAO. In brief, this study shows the neuroprotective effects of Tissue Kallikrein in ischemic edema for the first time in pMCAO mice by boosting the GS kinetics.
Abstract 127: White Matter Hyperintensity And Atherosclerotic Cardiovascular Disease Risk
Authors: de Havenon Adam , Bangad Aaron , Prabhakaran Shyam , Sharma Richa , Yaghi Shadi , Falcone Guido J , Sheth Kevin N
Published: February 2023

Introduction:
White matter hyperintensity (WMH) is a neuroimaging manifestation of cerebrovascular disease that is associated with vascular risk factors and the development of cognitive impairment and stroke. Estimating atherosclerotic cardiovascular disease (ASCVD) risk is a method of measuring the extent of vascular risk for a given individual and, thus, there exists a potential link between ASCVD risk and WMH volume.

Methods:
We included participants in the SPRINT MIND study who underwent a research MRI with volumetric quantification of the burden of WMH in mL. We report the WMH burden by categories of 10-year ASCVD risk using the Pooled Cohort Equations CV Risk (2014 edition). The ASCVD categories include low (0-5%), borderline (5-7.49%), intermediate (7.5-19.9%), and high (>20%). We used a violin plot to show the results graphically and also report the medians and IQR. As a secondary outcome we report WMH progression, which is the difference in WMH burden between the baseline MRI and a follow-up MRI performed 48 months later.

Results:
We included 727 individuals, of which 22 (3.0%) were low, 46 (6.3%) were borderline, 370 (50.9%) were intermediate, and 289 (39.8%) were high ASCVD risk. The median (IQR) WMH burden was 1.6 mL (0.9-2.9) in the low, 1.7 mL (1.1-3.0) in the borderline, 2.7 mL (1.4-5.1) in the intermediate, and 4.7 mL (2.5-10.7) in the high ASCVD risk group (p<0.001) (Figure 1). The progression of WMH was 0.2 mL (-0.1-0.7) in the low, 0.4 mL (-.2-1.5) in the borderline, 0.6 mL (0.01-1.7) in the intermediate, and 1.1 mL (0.2-3.0) in the high ASCVD risk group (p=0.001).

Conclusions:
There is a positive association between ASCVD risk and WMH volume and progression. ASCVD risk, which can be assessed through demographic and clinical variables, may be a useful predictor of the volume of WMH, which is traditionally obtained through an MRI scan.
Abstract 128:
In Vivo
Downregulation Of Pancreatic Amylin In Diabetic Mice Improves Recognition Memory
Authors: Gopal Viswanathan Velmurugan , Verma Nirmal , D. Winford Edric , Kotiya Deepak , E. Radulescu Laura , Leibold Noah , C. Chen Kuey , Despa Sanda , A. Hill Demitrius , Muehlbauer Michael , R. Bain James , Despa Florin
Published: February 2023

Hypersecretion of amylin, a β-cell hormone that regulates satiation, is common in individuals with prediabetes and is associated with pancreatic amyloid deposition and type-2 diabetes. Evidence has emerged that increased circulating levels of amyloid-forming human amylin may potentially impair brain function. Because mouse amylin is non-amyloidogenic, we generated transgenic mice with
conditional
pancreatic expression of amyloid-forming human amylin to study how
in vivo
knockdown of human amylin expression influences brain function during the development of type-2 diabetes. Males and females were fed a high-fat diet starting at 3 months of age to induce amylin hypersecretion and glucose dysregulation. Males developed hyperglycemia at 5 months of age, whereas females showed glucose dysregulation 3-4 months later. At 5 months of age, human amylin-expressing male mice were randomly assigned to either amylin downregulation group (by peritoneal tamoxifen injection) or control group (maintained amylin expression) (n = 10/group). Two months later, we assessed brain function with the novel object recognition test and performed comparative non-targeted metabolomics and global RNA-seq analyses of hippocampal tissue. Mice with downregulated human amylin show enhanced recognition memory index (p < 0.001) and lower blood glucose levels (p < 0.001) compared to those that continued to express human amylin. This was associated with increased hippocampal levels of glycolysis metabolites, including lactic acid (p < 0.01), glucose-6-phosphate (p = 0.06), and fructose (p = 0.07). Hippocampal gene-expression patterns between the two mouse groups revealed extensive compensatory changes in gene expression related to glucose metabolism. In conclusion, amylin downregulation in diabetic mice improves systemic glucose homeostasis and memory. Molecular processes associated with improved memory involve increased hippocampal glycolytic fluxes and compensatory gene expression.
Abstract 14: Determinants Of Withdrawal Of Life-sustaining Therapy After Acute Stroke
Authors: Alkhachroum Ayham , Zhou Lili , Asdaghi Negar , Gardner Hannah , Ying Hao , Gutierrez Carolina M , Samano Daniel , Bass Danielle , Foster Dianne , Sur Nicole B , Massad Nina , Kottapally Mohan , Merenda Amedeo , Starke Robert , O'Phelan Kristine , Romano Jose G , Claassen Jan , Sacco Ralph L , Rundek Tatjana
Published: February 2023

Introduction:
The decision to withhold or withdraw life-sustaining therapy (WLST) is common after acute stroke. Factors that may influence the decision are not well determined. We aimed to investigate factors associated with WLST in hospitalized acute stroke patients.

Methods:
Patients with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) were included across 152 Florida hospitals participating in the prospective Florida Stroke Registry from 2008-2021. Importance plots were performed to generate the predictive factors associated with WLST. AUC-ROC curves were generated for the performance of logistic regression (LR) and random forest (RF) models. We used 75/15/15 for training/testing/validation.

Results:
Among 309,393 AIS patients, 47,485 ICH patients, and 16,694 SAH patients; 9%, 28%, and 19% subsequently had WLST during hospitalization. Patients who had WLST were older (77 vs. 69 years), more women (57% vs. 49%), more White (76% vs. 67%), greater stroke severity at presentation NIHSS ≥ 5 (29% vs.19%), more likely to be treated in comprehensive stroke centers (52% vs. 44%), more likely to have Medicare insurance (53% vs. 44%), less likely to be uninsured (8% vs. 13%), more likely to undergo surgical treatments (1.2% vs 0.3%), and more likely to have impaired level of consciousness (38% vs. 12%). The most predictive factors associated with the decision to WLST in AIS were age, stroke severity, state region, insurance status, stroke center type, race, and level of consciousness (RF AUC of .93 and LR AUC of .85). The most predictive factors in ICH were age, impaired level of consciousness, state region, race, insurance status, stroke center type, and ambulation status at baseline (RF AUC of .76 and LR AUC of .71). Most predictive factors in SAH were age, impaired level of consciousness, state region, insurance status, race, and stroke center type (RF AUC of .82 and LR AUC of .72).

Conclusion:
Among acute hospitalized stroke patients; age, level of consciousness, state region, race, insurance status, ambulation status at baseline, and stroke center type could contribute to the decision to WLST.
Abstract 140: The Incidence Of Stroke In Indigenous Populations Of Countries With A Very High Human Development Index: A Systematic Review.
Authors: Balabanski Anna H , Dos Santos Angela , Woods John A , Mutimer Chloe A , Thrift Amanda G , Kleinig Timothy J , Suchy-Dicey Astrid M , Ragnhild Siri Susanna , Boden-Albala Bernadette , Krishnamurthi Rita V , Feigin Valery L , Buchwald Dedra , Ranta Anna , Mienna Christina S , Zavaleta Carol , Churilov Leonid , Burchill Luke J , Zion Deborah , Longstreth W T , Tirschwell David L , Anand Sonia S , Parsons Mark W , Brown Alex , Warne Donald K , Harwood Matire , Barber Alan , Katzenellenbogen Judith M
Published: February 2023

Introduction:
Despite known socioeconomic and health disparities affecting Indigenous populations in developed countries, stroke incidence data are sparse. With Indigenous Advisory Board oversight, we undertook a systematic review to compare Indigenous with non-Indigenous stroke incidence rates in countries with a very high Human Development Index (HDI).

Methods:
We identified population-based stroke incidence studies published from 1990-2022 in Indigenous adult populations of developed countries using PubMed, EMBASE and Global Health databases, without language restriction. We excluded non-peer-reviewed sources, studies with <10 Indigenous people, or studies not covering a 35-64 year minimum age range. Two reviewers independently screened titles, abstracts, and full texts, and extracted data. We assessed quality using "ideal" criteria for population-based stroke incidence studies, the Newcastle-Ottawa Scale for risk of bias, and CONSIDER criteria for Indigenous research.

Results:
Among 13,041 publications, 24 studies (19 full text, 5 abstracts) from 7 countries met inclusion criteria. Compared with respective non-Indigenous populations (Fig 1), age-standardised incidence rates were greater in Aboriginal and Torres Strait Islander Australians (ratios ranging from 1.7-3.2), American Indians (1.2), Sámi of Sweden/Norway (1.08-2.14), and Singaporean Malay (1.7-1.9), with higher rate ratios at younger ages. Studies had substantial heterogeneity in design and risk of bias. Few investigators reported Indigenous stakeholder involvement.

Conclusions:
In countries with a very high HDI, available data suggest marked disparities in stroke incidence in Indigenous populations, although there are gaps in data availability and quality. Indigenous stakeholder involvement in studies is infrequently reported. A greater understanding of stroke incidence in these populations is imperative for informing effective societal responses.
Abstract 144: Cancer And The Risk Of Perioperative Arterial Ischemic Events
Authors: Navi Babak B , Zhang Cenai , Kamel Hooman
Published: February 2023

Background:
An estimated 40% of Americans will develop cancer in their lifetime, and most will require one or multiple surgeries for diagnosis and treatment. We sought to determine whether cancer is an independent risk factor for perioperative arterial ischemic events.

Methods:
We performed a retrospective cohort study of patients who had major inpatient or outpatient surgery registered in the National Surgical Quality Improvement Program (NSQIP) between 2006-2016. The study exposure was disseminated cancer. The study outcome was a perioperative arterial ischemic event, defined as an ischemic stroke or myocardial infarction within 30 days of surgery. Multivariable Cox regression was used to evaluate the association between the study exposure and outcome while adjusting for potential confounders. Various sensitivity analyses were conducted.

Results:
Among 5,609,675 NSQIP cases, 122,221 (2.2%) surgeries involved patients with disseminated cancer. Patients’ mean age was 56 years (SD, 17); 57% were women. The Kaplan-Meier 30-day perioperative arterial ischemic event rate was 0.96% (95% CI, 0.91-1.02%) among patients with disseminated cancer vs 0.48% (95% CI, 0.47-0.49%) among patients without disseminated cancer (HR, 2.0; 95% CI, 1.9-2.1) (Figure). In Cox regression analyses adjusting for demographics, functional status, comorbidities, surgical setting, anesthesia type, and relevant clinical factors, disseminated cancer remained associated with a perioperative arterial ischemic event (HR, 1.3; 95% CI, 1.2-1.4). This association persisted across analyses excluding neurosurgical and cardiac surgeries, restricting to elective surgeries, and restricting to patients with functional independence before surgery.

Conclusions:
In a large, nationwide, surgical registry, comorbid cancer was associated with an estimated 20-40% increased risk of perioperative arterial ischemic events.
Abstract 148: Genetically-Determined LDL Negatively Impacts Clinical Evolution Of Ischemic Stroke Survivors
Authors: Wu Kane , Rivier Cyprien , Demarais Zachariah , Conlon Carolyn , Renedo Daniela , Torres Lopez Victor , Sharma Richa , De Havenon Adam H , Sheth Kevin N , Falcone Guido J
Published: February 2023

Introduction:
Ischemic Stroke survivors are at high risk of stroke recurrence. Understanding the genetic risk factors for stroke recurrence will help guide future prevention strategies.

Hypothesis:
Genetically-elevated LDL-cholesterol (LDL-c) negatively impact clinical trajectories after stroke, leading to higher risk of post-stroke acute vascular events.

Methods:
We analyzed clinical and genetic data from the Vitamin Intervention Stroke Prevention (VISP) clinical trial, which examined high-dose vitamins in stroke survivors. Genetic susceptibility to increased LDL-c was modeled through a polygenic risk score built with genetic data on 38 known genetic risk variants for LDL-cholesterol (variants influencing other lipid traits were excluded). We divided the LDL-related polygenic risk score into 0-20, 20-80, and 80-100 percentile categories labeled as low, intermediate and high genetic predisposition to high LDL. We fitted multivariable (adjusting for age, sex, vascular risk factors, and statin treatment) Cox proportional hazards and logistic regression models to test whether higher polygenic risk for elevated LDL-c was associated with observed LDL-c, ischemic stroke recurrence, and composite risk of ischemic stroke and myocardial infarction.

Results:
Of the 2,164 stroke survivors enrolled in VISP, 1,567 (72%) had available LDL-c and genetic data. The mean LDL in the low, intermediate and high polygenic risk categories was 114.5 (SD 2.21), 123.2 (SD 1.23), and 128.8 (SD 2.35), respectively (unadjusted p<0.001). Compared to stroke survivors with low polygenic risk, those with intermediate (HR 1.52, 95% CI 0.91-2.54) and high (HR 2.03, 95% CI 1.14-3.61) polygenic risk had significantly higher risk of stroke recurrence (p test-for-trend 0.01). We observed similar associations when evaluating the composite risk of stroke and myocardial infarction (all p<0.05) and when conducting these analyses using logistic regression (all p<0.05).

Conclusions:
A higher polygenic risk for increased LDL-c is associated with worse clinical trajectories after stroke. Further research is needed to determine whether stroke survivors with an elevated genetic risk benefit from unique care pathways with additional monitoring and treatment.
Abstract 149: Trajectories Of Patient Centred, Cognitive And Functional Outcomes In Survivors Of Severe Intracerebral And Intraventricular Hemorrhage
Authors: Shah Vishank A
Published: February 2023

Objective:
To describe trajectories of patient-centered, cognitive and functional outcomes and identify timepoints at which recovery plateaus after severe intracerebral and intraventricular hemorrhage (ICH/IVH).

Methods:
In this post-hoc analysis of CLEAR III and MISTIE III trials, all day-30 survivors were included (n=872). One-year trajectories of EuroQol 5-Dimensions (EQ5D), Visual Analog Scale (EQVAS), Mini Mental Status (MMSE), Barthel Index (BI), NIHSS and mRS were compared between patients with good (mRS0-3) vs. poor (mRS4-5) functional outcome at day-30, using mixed effects linear regression models.

Results:
Patients with good day-30 outcome (n=148), reported none to only moderate problems across all EQ5D dimensions. Mobility, selfcare and activity dimension mean scores improved significantly from day-30 to 180 (ß-slope, activity=-0.36, mobility=-0.25, selfcare=-0.27; all p<0.001), but did not improve from day-180 to 365 (all p>0.05). Contrarily, ICH/IVH survivors with poor day-30 outcome (n=724), reported extreme anxiety/depression, pain, inability to perform selfcare and usual activities at day-30, but, all mean scores improved significantly through 1-year (ß-slope for 1-year vs. day-30: mobility= -1.3; anxiety= -0.9, pain= -1.2; activities= -1.2; selfcare= -1.6; p<0.001). Likewise, significant cognitive recovery occurred through 1-year in poor day-30 outcome survivors (mean day-30 MMSE,11.5; ß-slope through 1-year=8.7, p<0.001), whereas good day-30 outcome survivors had peak cognitive recovery by day-180 (mean day-30 MMSE, 25; ß-slope=2.0, p<0.001). Similar trajectories were noted for EQVAS and other outcomes. The gap across all domains between survivors with good versus poor day-30 outcome narrowed significantly by one-year, but mean scores remained different between the two groups.

Conclusion:
In addition to functional disability, severe ICH/IVH survivors have significant anxiety, depression, pain, cognitive impairment and inability to perform selfcare or usual activities in the early phase, all of which improve significantly over time. While patients with early functional recovery plateau by 6-months, those with severe disability at day-30 continue to improve across all domains through 1-year.
Abstract 152: Relationship Between Gait Function And Damage To Descending Motor Pathways After Stroke
Authors: Bishop Lauri , Dicarlo Julie A , Parlman Kristin , Winstein Carolee J , Boyne Pierce , Lin David
Published: February 2023

Introduction:
Descending motor pathways, namely the corticospinal (CST) and corticoreticular tracts (CRT), are important for normal gait function and have been implicated in gait recovery after stroke. However, the relationship of structural injury to these tracts and gait function in the acute and chronic stage post-stroke remains unclear.

Methods:
Gait velocity was recorded the first week (acute) after stroke (n=127) and one year later (n= 50). CST and CRT injury were measured using weighted lesion load (wLL). The impact of CST and CRT injury on ambulation status (non-ambulatory vs. ambulatory) and gait velocity was assessed with multivariate logistic and linear regression models, respectively, acutely and chronically, controlling for wLL and lesion size.

Results:
Greater CRT injury resulted in a higher odds of ambulation loss acutely post-stroke (odds ratio [95% CI, p value]: CRT wLL, 1.06 [1.02-1.12, 0.007]; CST wLL 0.97 [0.95-0.99, 0.04]; lesion volume 1.00 [0.99-1.00, 0.96]). Conversely, greater CST injury had higher odds of ambulation loss at one-year (CST wLL, 1.09 [1.01-1.21, 0.04]; CRT wLL, 0.98 [0.84-1.13, 0.75]; lesion volume, 1.00 [0.99-1.00, 0.81]). For walkers (N=51 [acute] and 46 [chronic]), gait velocity was not significantly associated with CRT nor CST wLL at either time. Multicollinearity results denoted lesion measures provided independent information (maximum variance inflation factors 3.4 (acute), 4.2 (one-year)).

Conclusion:
Results suggest CRT injury is the dominant correlate of ambulation loss acutely, with CST the dominant correlate of persistent loss after one-year. Gait velocity is not well explained by damage to either tract. The results imply that the CRT may be the primary cortical projection for normal (pre-stroke) gait. Yet, the nervous system has sufficient redundancy to compensate for unilateral CRT injury, while CST injury may have a more enduring negative impact on gait function.
Abstract 156: Establishing An Informatics Framework For Longitudinal Cerebrovascular And Neurological Disease Research
Authors: Pan Alan P , Wozny Joseph , Schaefer Caroline , Nicolas Charlie , Bako Abdulaziz , Potter Thomas B , Tannous Jonika , Caballero Elizabeth , Nair Rejani R , Ganduglia-Cazaban Cecilia , Vahidy Farhaan
Published: February 2023

Background:
Although developments in computational big data methods have enhanced the ability to meaningfully extract information from hospital EMRs, there are inherent gaps in understanding care utilization and long-term patient outcomes outside of in-patient milieu, particularly across hospital systems.

Methods:
Utilizing registry data from a 7-hospital stroke certified healthcare system serving a large metropolitan, cohorts were identified for Medicare-insured patients with primary discharge diagnoses of acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), or cerebral amyloid angiopathy (CAA). In collaboration with a CMS Qualified Entity which houses health care utilization data for over 80% of the state population (including 100% of Medicare Fee-for-Service), patient records were securely matched and linked. Socio-demographic and enrollment characteristics for matched cohorts are reported.

Results:
Medical records and claims data were matched for 98.4% of patients (n=6,531) admitted between 05/2016 and 12/2020 (n=5,789 AIS; 696 ICH; 46 CAA). Across all matched patients, the median (IQR) age at hospital admission was 76.0 (69.0-84.0) (54% female; 56% non-Hispanic White; 24% non-Hispanic Black; 13% Hispanic/Latino; median [IQR] Area Deprivation Index: 4 [2-6]). Age-based standard enrollment represented 86% of patients, with the remainder enrolled due to disability or health complications. Median (IQR) number of total years for patients with Part AB and D coverage was 6.9 (5.0-7.0) and 5.4 (2.9-7.0) years, respectively. At the time of reporting, all-cause death rates among Medicare enrollees who sought care are: 33% (AIS), 55% (ICH), and 41% (CAA).

Conclusion:
In the absence of systematically captured long-term outcomes data, health informatic pipelines that create linkages across multimodal sources provide a valuable framework for enabling longitudinal research on patients throughout and after stroke hospitalizations.
Abstract 161: Racial And Ethnic Differences In The Risk Of Ischemic Stroke After Intracerebral Hemorrhage
Authors: Simonetto Marialaura , Merkler Alexander E , Parikh Neal S , Sheth Kevin N , Sacco Ralph L , Ziai Wendy C , Fink Matthew E , Kamel Hooman , Zhang Cenai , Murthy Santosh
Published: February 2023

Background:
Intracerebral hemorrhage (ICH) is associated with an increased risk of ischemic stroke. Whether there are racial and ethnic disparities in the risk of ischemic stroke after ICH is poorly understood.

Hypothesis:
Non-Hispanic Black and Hispanic ICH patients have a higher risk of ischemic stroke compared to White ICH patients.

Methods:
We retrospectively analyzed data from the Healthcare Cost and Utilization Project on all hospitalizations at all nonfederal hospitals in Florida from 2005 to 2018 and New York from 2006 to 2016. We included patients with an ICH, and without a prior or concomitant diagnosis of ischemic stroke. ICH and ischemic stroke were ascertained using validated ICD-9-CM and ICD-10-CM codes. Using Cox proportional hazard models, we studied the relationship between race and risk of ischemic stroke, after adjustment of demographics and comorbidities.

Results:
We included 55,582 patients with ICH- 66% Non-Hispanic White, 19% Non-Hispanic Black, and 13% Hispanic. Black and Hispanic patients were younger and had a higher prevalence of cardiovascular comorbidities; however, atrial fibrillation was more prevalent among White patients. During a median follow up period of 3.6 years (IQR 0.7-7.2), an incident ischemic stroke occurred in 3,361 (9%) Non-Hispanic White, 1,308 (12%) Non-Hispanic Black, and 858 (12%) Hispanic patients (p<.001). In adjusted Cox models, the risk of an ischemic stroke was significantly higher among Non-Hispanic Black patients (HR 1.6; 95% CI,1.4-1.7) and Hispanic patients (HR 1.4; 95% CI,1.2-1.5]), compared to non-Hispanic White patients.

Conclusions:
Among patients with ICH, Non-Hispanic Black and Hispanic patients had a significantly higher risk of ischemic stroke compared to Non-Hispanic White patients.
Abstract 165: Nationwide Seasonal Variations And Increases In Incidence Of Intracerebral Hemorrhage And Acute Ischemic Stroke: An Analysis Of Pre-pandemic 16-year National Data
Authors: Baig Eman , Tannous Jonika , Potter Thomas B , Pan Alan P , Britz Gavin W , Vahidy Farhaan S , Bako Abdulaziz T
Published: February 2023

Introduction:
There is paucity of evidence on long-term nationwide trends and seasonal variation in incidence of Intracerebral Hemorrhage (ICH) and Acute Ischemic Stroke (AIS).

Methods:
Using the Nationwide Inpatient Sample (2004 - 2019), we identified adults (≥ 18 years) discharged with primary diagnosis of ICH and AIS. We aggregated hospitalizations across quarters: Jan - Mar (Q1); Apr - Jun (Q2); Jul - Sep (Q3) and Oct - Dec (Q4). We used survey weights to calculate nationally representative estimates of quarter-specific incidence across age, sex, and race/ethnicity sub-cohorts and obtained time-specific denominators from the US Census Bureau. We calculated per quarter incidence rate (IR) across Q1-Q4 and Q2-Q3. We used multivariable Poisson regression model to report the adjusted incidence rate ratio (aIRR) and 95% confidence interval (CI) for the differences in quarterly incidence between Q1Q4 and Q2Q3.

Results:
Across 16 years, 985 959 ICH and 7 067 178 AIS hospitalizations were evaluated. The average quarterly crude IR of ICH in Q1Q4 of 6 per 100 000 was higher than the average rate of 5.4 per 100 000 observed in Q2Q3 (aIRR, CI: 1.10, 1.09 - 1.10). However, for AIS the average quarterly IR of ICH in Q1Q4 (41.2 per 100 000) was similar to the incidence rate in Q2Q3 (41.2 per 100 000) (aIRR, CI: 1.00, 1.00 - 1.00). Furthermore, we observed that average quarterly incidence is increasing overtime (aIRR, CI) for both ICH (1.01, 1.01 - 1.01) and AIS (1.03, 1.03 -1.03). The aIRR and CI for age, race, and sex are provided in the figure.

Conclusion:
Both stroke phenotypes demonstrate an increasing nationwide incidence. However, unlike AIS, ICH incidence is consistently and significantly higher in the months of October to March. Additional evaluation of factors such as holiday stress, seasonal variations in health behaviors (diet, physical activity, medication adherence) and physiological parameters (blood pressure, blood viscosity, fibrinogen, and cholesterol levels) is warranted.
Abstract 18: A Novel Neutrophil Subpopulation Mediates Neuroprotection In The Late Phases Of Cerebral Ischemia
Authors: Garcia-Bonilla Lidia , Sciortino Rose , Racchumi Gianfranco M , Iadecola Costantino , Anrather Josef
Published: February 2023

Cerebral ischemia triggers a powerful inflammatory reaction involving infiltration of peripheral leukocytes. Neutrophils, the first immune cells entering the ischemic brain, contribute to brain injury by limiting tissue perfusion and destabilizing the blood-brain barrier. However, recent evidence indicates that neutrophils can also participate to the repairing process. Nevertheless, the dynamics and complexity of neutrophil subsets are poorly understood. Here, we performed single-cell transcriptomics to obtain a picture of infiltrating neutrophil diversity in the mouse brain 2 (D02) and 14 days (D14) after transient middle cerebral artery occlusion (MCAo) or sham surgery (Sham). Clustering analysis of the transcripts revealed 5 neutrophil populations. In Sham, most neutrophils fell into clusters 1 and 4, characterized by expression of genes associated with neutrophil development such
Retnlg
and
Mmp8
(cluster 1) and
Camp, Ltf, Chil3
and
Lcn2
(cluster 4). After MCAo, clusters 1 and 4 gradually decreased, whereas cluster 2, identified by type I response genes (
Isg15, Ifit3, Rsad2, Ifit1, Ifi204
) and cluster 3, characterized by upregulation of chemokines/cytokines (
Ccl3
,
Ccl4
,
Csf1
), increased progressively from D02 to D14. Interestingly, we found that the number of neutrophils in the ischemic brain was 5 times higher at D14 than at D02 (Sham, 0.2 ± 0.1 x10
3
; D02: 3 ± 1.3 x10
3
; D14: 14.5 ± 3.5x10
3
cells; p=0.02 D02 vs D14; n=10-14/group). Therefore, we next investigated if neutrophil infiltration at D14 has a beneficial or adverse effect on stroke recovery. To this end, 7 days after MCAo, neutrophils depletion was induced by systemic injection of both rat anti-Ly6G (50μg/mouse, i.p) and CXCR2-antagonist SB225002 (2 mg/kg, i.p), once per day, for 7 consecutive days. We found that neutrophil depletion increased brain tissue loss (-18.7 ± 2.9
vs
-8 ± 2.6% IgG/vehicle mice; p=0.01; n=9/group). In addition, neutrophil depletion decreased ambulatory distance (p<0.05 vs vehicle; n=11/group) and stereotypic behavior (p<0.05 vs vehicle; n=11/group) without altering open field performance in sham mice. Our study unveils an unrecognized neutrophil subpopulation protecting the brain in the subacute stroke phase, opening new avenues for stroke treatment.
Abstract 20: Gut Microbiota-derived Indole Metabolites Influence Outcomes After Neonatal-Hypoxic Ischemic Encephalopathy
Authors: Korf Janelle , Blasco-Conesa Maria , Honarpisheh Pedram , Blixt Frank , Sharmeen Romana , Banerjee Anik , Mohan Eric , Lee Juneyoung , McCullough Louise D , Ganesh Bhanu P
Published: February 2023

Introduction:
Neonatal Hypoxic Ischemic Encephalopathy (nHIE) is a leading cause of infant mortality and morbidity worldwide. Males are at greater risk than females, and survivors of nHIE suffer from major disability with limited therapeutic options. Growing clinical and pre-clinical evidence shows neurological injury adversely alters the microbial populations in the gut (dysbiosis) and depletes anti-inflammatory metabolites exclusively made by the gut microbiota. Replacing key microbially-derived beneficial metabolites improves cognitive outcomes in pre-clinical models of adult stroke. However, changes in the gut microbiota and its metabolites after nHIE have not been explored and may lay the foundation for future therapies.

Hypothesis:
nHIE leads to gut dysbiosis and reduces microbial-derived metabolites, which worsens neurological outcomes in males and females.

Methods:
A modified Rice Vannucci Model on PND9 C57BL/6 mice was used to model nHIE. Fecal, plasma, gut, and brain samples were collected acutely (24hrs) and chronically (7wks) after injury.

Results:
We found a significant decrease in 3-indolepropionic acid (p=0.0190, n=4-6), inoxyl-3-sulfate (p=0.0098, n=4-6) and indoxyl acetate (p=0.0096, n=4-6) in the plasma of male mice 24hrs after HIE compared to sham controls, with no significant changes in female plasma. There was a significant increase in indole metabolites in the ischemic hemisphere in both males and females 24hrs after HIE. 7wks after nHIE, there was a significant increase in anxiety-like behavior in males (decrease in % of time immobile during tail suspension=0.018, n=6) and decreased functional ability (nest building score p=0.0147, n=6) in males with HIE compared to sham controls. No significant changes were observed in females. 16S rRNA sequencing data showed dysbiotic microbiota composition after nHIE, consistent with the microbial-metabolite changes found by mass spectroscopy analysis.

Conclusion:
nHIE induced brain injury results in gut dysbiosis, with sex-specific alterations in circulating indole metabolites and behavioral deficits. This supports our hypothesis that a sex-specific reduction in bioavailability of microbial-metabolites worsens CNS damage after nHIE.
Abstract 21: Genome Wide Association Study Of Stroke Recovery Phenotypes Defined By Serial NIH Stroke Scale Scores
Authors: Aldridge Chad M , Krishnagopal Sanjukta , Lohse Keith , Hsu Fang-Chi , Keene Keith L , Worrall Bradford B , Braun Robynne
Published: February 2023

Objective:
To perform a genome wide association study (GWAS) of stroke recovery phenotypes as defined by the trajectories of patients’ NIH stroke scale scores over time.

Background:
Stroke recovery research entails tracking multiple domains of neurologic impairment over time that are measured on differing scales. This presents challenges for analytic approaches commonly used to study stroke genetics. Here, we present a novel approach using a network science-based method, Trajectory Profile Clustering (TPC), to define stroke recovery phenotypes for GWAS.

Design/Methods:
We analyzed data from 3,679 patients in the VISP dataset (Vitamin Intervention for Stroke Prevention) on 15 NIHSS impairment measures at 6 time points spanning 24 months post-stroke. The 4 identified TPC profiles (Figure, Panel A), were used as phenotypes for a subsequent GWAS on the 2,099 genotyped VISP patients. We used a multinomial generalized regression with TPC profiles as the response variable. The model adjusted for age, sex, treatment group, and the first ten principal components.

Results:
TOPMed imputation and strict quality control resulted in 6,392,745 SNPs. Although none of our loci reached genome wide significance, the GWAS identified several suggestive loci (p<5e-6) clustering within or near genes of biological relevance (Figure, Panel B): LINC02151 (non-coding RNA 11q23.3) is associated with lipid homeostasis, sphingomyelin levels, neurofibrillary tangles and coronary artery disease. SEC63P2 (RNA-seq 4p15.1) is associated with hippocampal volume and is expressed in choroid plexus during development. IDE (10q23.33) is associated with triglyceride levels, Type 2 diabetes and BMI, and in the present analysis also differentiated among the 4 TPC-derived phenotypes (p<0.05).

Conclusion:
Phenotypes defined using TPC, even in this limited sample, identified multiple suggestive genetic associations with biological relevance for both stroke risk and stroke recovery.