bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 212: In Vivo Molecular Imaging of Thrombosis and Thrombolysis Using a Fibrin-binding PET Probe
Authors: Blasi Francesco , Ay Ilknur , Rietz Tyson A , Rotile Nicholas J , Day Helen , Oliveira Bruno L , Looby Richard J , Caravan Peter
Published: March 2022

Background and purpose:
Thrombus formation plays a critical role in cardiovascular diseases, but thrombus imaging is still challenging. Fibrin is a major component of both arterial and venous thrombi, and represents an ideal candidate for molecular imaging of thrombosis. Here, we describe imaging properties and target uptake of a new fibrin-specific PET probe for thrombus detection in two rat models of thrombosis and stroke.

Materials and methods:
The fibrin-binding probe FBP7 was synthesized by conjugation of the cyclic peptide FHCHypY(3-CI)DLCHIL to a cross-bridge chelator (CB-TE2A), followed by labeling with copper-64. Wistar rats (4-6/group) underwent carotid crush, as a non-occlusive, mural thrombosis model, or embolic stroke as an occlusive clot model followed by thrombolysis.

Results:
FBP7 clearly detected thrombus location in both animal models, with a high PET target:background ratio that increased over time (>5-fold at 30-90’, >15-fold at 240-300’, Fig. A-B). Biodistribution confirmed the high thrombus uptake (~0.5 %ID/g), which was >5-10 folds greater than blood and other tissues of the head and thorax (C). Similar results were obtained from ex vivo autoradiography of ipsilateral vs. controlateral carotid arteries (D). PET/CT imaging allowed clot localization in the internal carotid/middle cerebral artery (ICA/MCA) segment of all stroke rats. After baseline PET acquisition, animals were infused with tPA (10 mg/kg, i.v.) or vehicle (saline) and imaged again for 90’. Time-dependent reduction of activity at the level of the thrombus was clearly detected in treated rats, but not in vehicle group (E). Brain autoradiography confirmed clot dissolution in tPA-treated animals, but enduring high thrombus activity in ipsilateral ICA/MCA of control rats (F-G).

Conclusions:
We demonstrated that FBP7 is suitable for molecular imaging of thrombosis and thrombolysis in vivo, and represents a very promising candidate for bench-to-bedside translation.
Abstract 215: Hyperhomocysteinemia as a Model of Vascular Dementia and Its Effects on Amyloid Pathology in a Transgenic Mouse Model
Authors: Lee Tiffany , Weekman Erica , Wilcock Donna M
Published: March 2022

Vascular dementia is the second leading form of dementia after Alzheimer’s disease. There is a relative lack of animal models in which to study the mechanisms underlying cerebrovascular disease leading to dementia. In addition, cerebrovascular disease is a common co-morbidity in Alzheimer’s patients, yet its impact on Alzheimer’s pathology and clinical outcome is unknown. We aimed to develop a model of vascular dementia that could allow us to create a model of cerebrovascular disease / amyloid pathology co-morbidity.

We Induced hyperhomocysteinemia through dietary deficiency of B-vitamins and enrichment of methionine in 3 month old wildtype mice for fourteen weeks. We also used the same methods to induce hyperhomocysteinemia in 6 month old APP/PS1 mice for four and six months. We performed T2* MRI, histology and biochemistry to assess outcomes.

In the wildtype mice on diet for fourteen weeks we observed significant microhemorrhages by T2* MRI imaging that was confirmed by Prussian blue staining. We found that the MRI detects a smaller number of microhemorrhages than does the Prussian blue staining. The hyperhomocysteinemic mice had significant neuroinflammation, as demonstrated by increased expression of IL-1β, TNFα, IL-6 and IL-12. Importantly, we found increased expression and activity of the matrix metalloproteinases MMP2 and MMP9.

In the APP/PS1 mice we have found that hyperhomocysteinemia induces an increase in total brain Aβ, detected both biochemically and immunohistochemically. Of note, was a greater increase in Aβ1-40 than Aβ1-42. We have also found increased cerebral amyloid angiopathy with hyperhomocysteinemia, and an exacerbated neuroinflammatory response. The numbers of microhemorrhages were comparable between wildtype and APP/PS1 hyperhomocysteinemic mice, but the microhemorrhages appear larger in the APP/PS1 mice.

Overall, we believe our data indicates that cerebrovascular disease co-morbid with amyloid pathology, exacerbates the cerebrovascular amyloid pathology and could have implications to therapeutic development for the treatment of Alzheimer’s disease.
Abstract 23: Neuroimaging and Echocardiographic Predictors of Paroxysmal Atrial Fibrillation on Outpatient Mobile Cardiac Outpatient Telemetry in Cryptogenic Ischemic Stroke and TIA Patients
Authors: Kass-Hout Omar , Kass-Hout Tareq , Parikh Ankit , Hoskins Michael , Noorian Ali , Rangaraju Srikant , Anderson Aaron , Belagaje Samir , Ayala Lauren , Blanke Debra , Bamford Laura , Frankel Michael , Yepes Manuel , Nahab Fadi
Published: March 2022

Background:
The objective of our study was to identify factors on MRI neuroimaging and echocardiography as part of routine workup of patients with cryptogenic ischemic stroke (IS) or transient ischemic attack (TIA) to identify those patients who are likely to have paroxysmal atrial fibrillation (PAF) as detected by subsequent outpatient mobile cardiac outpatient telemetry (MCOT).

Methods:
All cryptogenic IS or TIA patients seen at Emory University Hospital and The Emory Clinic from 2009-2013 and who underwent outpatient MCOT were included in this analysis.Using logistic regression, we analyzed the association between lesions seen on MRI FLAIR sequences with PAF and categorized them as the following: Cortical lesions (CL), defined as T2-hyperintense cortical-based infarcts; high subcortical (HS) T2-hyperintense lesions, defined as <5mm beneath the cortex without any cortical involvement, or none. Left atrium (LA) functional and dimensional echocardiographic parameters were evaluated to determine their association with PAF.

Results:
Of 132 patients included in this analysis, 17 (13%) had evidence of newly diagnosed PAF on MCOT (mean duration of monitoring=25 days); median age was 72 (IQR: 64-79), 50% were women, diabetes was present in 23%, hypertension in 76%, dyslipidemia in 64%, and active tobacco use in 8%. CL seen on baseline MRI were found to be significant predictors of PAF (OR 5.2, 95 % CI: 1.3-19; p=0.01). HS lesions were not found to be a significant predictor of PAF. On baseline echocardiography, patients who had PAF (vs non-PAF) had significantly higher mean LA diameter (4.2 vs 3.7 cm, p=0.03), lower tissue Doppler velocity (a’) (5.5 vs 13.5 cm/s, p=0.03), a trend toward higher left atrium volume index (LAVI) (37.5 vs 29.2, p=0.07) and mean LAVI/late diastolic Doppler velocity (A) (0.67 vs. 0.37, P= 0.006). The Areas under the Curve (AUC) for the parameters were: LA diameter 71.4%, a’ 92.6%, LAVI 74.6%, LAVI/A 62.5%, LAVI/a’ 67.9%.

Conclusion:
Cortical-based infarcts seen on MRI FLAIR sequences and baseline echocardiographic variables may help to predict cryptogenic ischemic stroke or TIA patients who are likely to have PAF identified on outpatient MCOT.
Abstract 26: Agreement Between TOAST and CCS Classification in SiGN
Authors: McArdle Patrick F , Ay Hakan , Kittner Steven J , Brown Robert D , Meschia James F , Worrall Brad B ,   SiGN Investigators
Published: March 2022

Background:
The heterogeneity of ischemic stroke has relevance for determination of risk for recurrence, prediction of outcomes, and identification of genetic risk factors. Among the many systems created for classifying patients into subtypes of stroke, the Trial of Org10172 Acute Stroke Trial (TOAST) and Causative Classification of Stroke (CCS) systems are among the most commonly used. Both systems generate similar subtype diagnoses although the two systems use different criteria for subtype assignment. The purpose of this study was to assess the level of agreement between subtype classification made using these two systems.

Methods:
Study subjects included 14,106 adult men and women accrued in the NINDS Stroke Genetics Network (SiGN) across 21 centers in the US and Europe classified independently using both with TOAST and CCS. Kappa statistics were calculated for the five major ischemic stroke subtypes common to both systems.

Results:
The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; kappa = 0.60, 95% confidence interval [CI], 0.59 to 0.61). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large artery atherosclerosis (kappa, 0.71; 95% CI, 0.70 to 0.73) and lowest for small artery occlusion (kappa = 0.56, 95%CI, 0.54 to 0.58).

Conclusion:
Agreement between TOAST and CCS diagnoses was only moderate. Caution is warranted when comparing or combining results based upon the two systems. Re-phenotyping using one system should be encouraged when possible to ensure valid results.

Table:
Cross-classification of stroke subtypes by TOAST and CCS
Abstract 33: Cerebral Blood Flow in Leukoaraiosis Regions is Unaffected by Acute Lowering of Blood Pressure in Intracerebral Hemorrhage Patients.
Authors: Kate Mahesh , Gould Bronwen , McCourt Rebecca , Gioia Laura , Hill Micheal , Asdaghi Negar , Dowlatshahi Dariush , Coutts Shelagh , Demchuk Andrew , Buck Brian , Emery Derek , Jeerakathil Thomas , Butcher Kenneth
Published: March 2022

Introduction:
Leukoariosis(LA) is associated with poor prognosis in intracerebral hemorrhage (ICH) patients. Patients with chronic small vessel ischemic changes may be more vulnerable to decreases in cerebral perfusion, in both LA and perihematoma(PH) regions. We tested the hypotheses that acute blood pressure reduction (BP) in ICH patients is associated with decreased cerebral blood flow (CBF) in areas of LA and the PH region.

Methods:
In the ICH Acutely Decreasing Arterial Pressure Trial (ICH ADAPT), patients with ICH <24 hours duration were randomized to two systolic BP (SBP) target groups (<150 mmHg vs. <180 mmHg). Computed tomography (CT) perfusion imaging was performed 2 h post-randomization. LA tissue volume was planimetrically measured on the acute non-contrast CT, using Hounsfield Unit thresholds of 15-25. CBF, cerebral blood volume (CBV), and Tmax were measured in the LA regions.

Results:
Seventy-one patients were included with a mean age of 69.3±11.5 years and median (IQR) baseline NIHSS score of 10(11). LA was present in 74.6% (53/71) and the median volume was 8.5(20.6) ml. LA was associated with older age (70.9± 11.2 vs. 64.8 ±11.6, p=0.05) and larger ICH volumes (19.52(29.78) vs. 9.52(16.02) ml, p=0.007). Mean CBF in LA regions (32.5±13.5) was similar to that in normal appearing white matter (35.6±12.1, p=0.3). Despite a significant drop in SBP between aggressive (36.25(40) mmHg) and conservative (18.5(29) mmHg, p=0.01) treatment groups, relative CBF (rCBF) in LA regions was unaffected (0.88±0.1 vs. 0.89±0.09, p=0.6). Similarly, aggressive BP treatment did not affect relative CBV (0.83±0.16 vs. 0.82± 0.15, p=0.8) or Tmax (7.3±3.2 s vs. 6.5 ±2.4 s, p=0.3). The rCBF in the PH regions in patients’ with/without LA was similar (0.88±0.09 vs. 0.86±0.1, p=0.5). There was a trend to worse functional outcome at 90 days, measured with the modified Rankin Scale in patients with LA (4(4) vs. 2(1), p=0.06).

Conclusion:
LA is associated with larger baseline ICH volumes, but no differences in perihematoma CBF or the response to BP reduction. CBF in LA tissue is also unaffected by BP reduction. These data do not support a less aggressive approach to BP reduction in elderly patients with imaging evidence of chronic small vessel ischemia.
Abstract 44: Global Hypomethylation and Promoter Hypomethylation of
Flt1
Concurrently Occurred Iin Atherosclerotic Tissues
Authors: Kim JeeYeon , Hwang Jun Ha , Jeong Hye Seon , Kwon Sun Uck , Kim Geun-Eun , Kim Jei
Published: March 2022

Background and objectives:
Epigenetic alterations have been suggested as a pathological mechanism in atherosclerosis development. However, global and gene-specific epigenetic changes have not been well-known in atherosclerotic tissues yet. We evaluated whether the global methylation and promoter methylation of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) genes of atherosclerotic tissues was different from peripheral leukocytes in carotid stenosis patients.

Methods:
We used carotid endarterectomy (CEA) tissues and peripheral leukocytes (WBC) collected from 27 patients, who received CEA to remove athoerslcerotic plaque from proximal internal carotid artery. To evaluate global methylation status in the CEA tissue and WBC of each patient, pyrosequencing for long-interspersed nuclear element (LINE) sequence was performed. The evaluation of gene-specific promoter methylation status targeted to angiogenesis-related genes including VEGF, VEGFR1 (Flt1), and VEGFR2 (KDR). The methylation status of each gene was evaluated using methylation specific polymerase chain reaction. The differences of global and gene-specific methylation status of each tested gene were compared between CEA and WBC of all patients.

Results:
On global methylation status evaluation, LINE methylation was lower in CEA than WBC (CEA, 63.7±1.7; WBC, 65.8±3.3%, p=0.002). CEA tissues also showed significantly lower promoter methylations in VEGFR1 (CEA, 5.3±7.1; WBC, 11.9±9.4%, p=0.007). The methylation status of VEGFR2 (CEA, 21.4±11.5; WBC, 25.5±13.5%, p=0.220) and VEGF (CEA, 19.3±11.8; WBC, 18.0±9.9%, p=0.561) was not statistically different between CEA and WBC samples of the patients.

Conclusion:
The concurrent decrease pattern of LINE and VEGFR1 suggested that the hypomethylation occurred globally and gene-specifically in angiogenesis-related genes of proximal ICA stenosis. In particular, the VEGFR1 promoter hypomethylation in atherosclerotic tissues might be an epigenetic evidence to explain the increase of angiogenesis increasing inside of atherosclerotic plaque.
Abstract 55: Trans-Ethnic Meta-Analysis of Genome-Wide Association Studies on Cerebral White Matter Lesions Identifies New Loci
Authors: Verhaaren Benjamin F , Seshadri Sudha , Ikram M. Arfan , Fornage Myriam ,   on behalf of the NeuroCHARGE working group
Published: March 2022

Introduction:
Cerebral white matter lesions (WML) increase the risk of stroke and dementia. WML burden is highly heritable, but few genetic variants have been identified to date, which explain a small proportion of the trait variance. To identify novel genetic loci for cerebral white matter lesions, we conducted a trans-ethnic meta-analysis of genome-wide association studies.

Methods:
We included 21,079 people of European (N=17,936), Afro-American (N=1,943), Hispanic (N=795), Chinese (N=204) and Malay (N=201) descent from 22 population-based cohorts in the middle-aged and elderly. People with dementia or stroke were excluded. WML burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study was imputed to the 1000 Genomes reference panel. We investigated the relationship between each SNP and WML burden with linear regression models, adjusted for age, sex and intracranial volume. A fixed-effects meta-analysis was conducted using a z-score based method for each ethnicity separately and for the total sample.

Results:
In the European sample, we confirmed a previously known locus on chr17q25 (p=3.9E-19) and identified two novel loci: on chr2p21 (p=4.1E-08) and chr10q24 (p=9.4E-10). Two additional loci, on chr1q22 (p=4.6E-08) and chr2p16 (p=1.6E-08), were identified in the trans-ethnic meta-analysis. The novel loci contain genes that are involved in the extracellular matrix (chr2p16), ubiquitination (chr1q22) and apoptosis (chr10q24) and have been implicated in Huntington’s disease (chr2p21), multiple sclerosis (chr2p21), medulloblastoma (chr10q24) and glioma (chr10q24, chr2p16). Suggestive associations (p<10-6) include loci on chr2q33 containing a gene involved in gliomas, and chr7q31 containing a gene implicated in autism and schizophrenia.

Conclusions:
We identified four novel loci for WML burden in a trans-ethnic meta-analysis of genome-wide association studies and confirmed a previously identified locus.
Abstract 60: Inpatient Statin Use in Intracerebral Hemorrhage is Strongly Associated With Improved Survival
Authors: Flint Alexander , Kamel Hooman , Rao Vivek , Faigeles Bonnie , Klingman Jeff , Hemphill J Claude , Johnston S Claiborne
Published: March 2022

Introduction:
Inpatient statin use is associated with improved outcomes after ischemic stroke. The impact of inpatient statin use after intracerebral hemorrhage (ICH) is less clear.

Methods:
We measured the impact of inpatient and outpatient statin use on 30-day survival among 3,481 patients with a primary discharge diagnosis of ICH over a 10-year period at 19 hospitals in an integrated care delivery system. We used multivariate logistic regression modeling mortality, controlling for patient characteristics, and allowing an interaction between inpatient and outpatient statin use. We also used last prior treatment analysis (LPTA), an instrumental variable reflecting local geographic and temporal treatment environment, to control for potential confounding in probit models.

Results:
Kaplan-Meier analysis showed significant differences in survival after ICH among statin users before and during hospitalization (n=769), statin non-users before and during hospitalization (n=1,896), and patients who underwent statin withdrawal (n=391) (see Figure). Controlling for patient characteristics including initial severity, inpatient statin use was associated with lower mortality after ICH (odds ratio [OR] = 0.40, 95% C.I. 0.25 - 63, P<0.001) and withdrawal from statins was associated with higher mortality (OR = 2.30, 95% C.I. 1.40 - 3.91, P=0.002). LPTA models confirmed the association of inpatient statins with lower mortality (OR = 0.28, 95% C.I. 0.26 - 0.32, P=0.01).

Conclusions:
Inpatient statin use is associated with improved survival after ICH, particularly among patients already on a statin as an outpatient at the time of the ICH.
Abstract 63: Risk of Malnutrition on Admission Predicts Mortality, Length of Hospital Stay and Hospitalisation Costs at 6 Months Post Stroke
Authors: Gomes Filomena , Emery Peter W , Weekes Christine E
Published: March 2022

INTRODUCTION
Malnutrition is related with poor outcomes after stroke which justifies the need for screening to identify and treat nutritionally vulnerable patients; however, no nutrition screening tool has been validated for this population. This study aimed to establish the predictive validity of the Malnutrition Universal Screening Tool (MUST) in stroke patients, using several outcomes: mortality, cumulative length of hospital stay (LOS) and hospitalisation costs at 6 months post stroke.

METHODS
Patients were recruited from consecutive admissions at 2 hyper-acute stroke units in London and were screened for their risk of malnutrition (low, medium and high) according to MUST. Outcomes were obtained for each patient through a national database that contains details of all hospital admissions.

RESULTS
Of 543 recruited patients, 537 were screened within 72h of admission with MUST, 51% were males and 87% had an ischaemic stroke, with a mean age of 74.7years (range 22-99). Results (see table) showed a strong positive association between risk of malnutrition and mortality rate (Chi square test,
p<0.001
), which remained significant after adjustment for possible confounders (Multivariable Cox Proportional Hazards Model,
p<0.001
). For patients who survived, there was a strong positive association between the risk of malnutrition and both LOS and hospitalisation costs (Kruskal-Wallis test,
p<0.001
and
p=0.049
, respectively), which again remained significant after adjustment for possible confounders (univariate analysis of variance,
p<0.001
and
p=0.001
, respectively).

CONCLUSION
Risk of malnutrition (as assessed by MUST) is an independent strong predictor of mortality, LOS and hospitalisation costs at 6 months post stroke, supporting the routine screening of stroke patients for risk of malnutrition on admission.
Abstract 66: MRI Predictors of Stroke Recurrence in Patients With Recent Lacunar Stroke: The SPS3 Trial
Authors: Benavente Oscar R , Pearce Lesly A , Anderson David , Bazan Carlos , Hart Robert G
Published: March 2022

Background:
Brain infarcts (BIs) and white matter hyperintesities (WMHs) have been associated with an increased risk of stroke. However, neither has been investigated in a well characterized cohort of patients with cerebral small vessel disease. Our objective was to identify MRI predictors of recurrent stroke in the SPS3 cohort.

Methods:
SPS3 was a multicenter trial that enrolled 3020 patients with recent lacunar stroke verified by MRI. Baseline MRIs were centrally read, including presence of index infarct, old subcortical brain infarcts (also called lacunar infarcts) (BIs), and WMHs using the ARWMC score, and independent predictors of recurrent stroke identified. A stratification scheme for stroke risk was developed based on MRI findings and previously identified clinical risk factors (RF) of prior stroke/TIA, black race, male, diabetes.

Results:
2980 MRIs were included in these analyses. BIs (HR 1.5, 95% CI 1.2, 1.9) and more severe WMHs (HR 1.4, CI 1.2, 1.6) were independently associated with recurrent stroke, and remained independent after including clinical RF and assigned treatments in the Cox PH model. Anatomical localization of the index stroke was not associated with stroke recurrence. Annualized recurrent stroke rates were 5.2 %/pt-yr (95% CI 4.3, 6.2), 2.7% (95% CI 2.2, 3.4), and 1.7% (95% CI 1.1, 1.7) respectively in high (> 2 of the following: prior stroke/TIA, BIs, severe WMD, or all 3 other clinical RF), moderate (not high risk; prior stroke/TIA or 2 clinical RF), and low (not moderate or high risk; 0-1 clinical RF) risk patients.

Conclusions:
In this large, well-characterized cohort of recent lacunar strokes, old subcortical infarcts and WMHs on MRI are shown to be independent predictors of stroke recurrence. Stratification schemes may help to identify patients at different risk and select the most appropriate therapeutic intervention for stroke reduction.
Abstract 73: Resistance to Iv Thrombolysis and Prognostic Impact of Metabolic Syndrome in Middle Cerebral Artery Ischemic Stroke
Authors: Dorado Laura , Arenillas Juan F , López-Cancio Elena , Hernández-Pérez María , Pérez de la Ossa Natàlia , Gomis Meritxell , Millán Mònica , Galán Amparo , Dávalos Antonio
Published: March 2022

Background:
Metabolic Syndrome (MetS) may confer higher resistance to early arterial recanalization after intravenous (IV) thrombolysis and a poor impact in other prognostic variables after stroke. We aimed to test this hypothesis evaluating not only the clinical syndrome but also some relevant biomarkers associated with MetS and insulin resistance.

Methods:
Prospective, observational study in consecutive stroke patients with MCA occlusion and who received IV tPA in a single tertiary-care center. MetS was diagnosed following the unified criteria of the last Joint Interim Statement 2009. We measured PAI-1, adiponectin and CRP levels at admission (before treatment). Primary outcome variable was resistance to thrombolysis defined as the absence of complete MCA recanalization at 2 hours after tPA infusion assessed by transcranial color-coded duplex or when rescue mechanical thrombectomy after IV tPA was needed. Secondary outcome variables were dramatic neurological improvement (decrease in ≥10 points in the NIHSS score in the first 24 hours), poor outcome (mRS score >2 at 3 months), symptomatic intracerebral hemorrhage (SICH) following ECASS II criteria and infarct volume (AXBXC/2).

Results:
A total of 234 patients (55.6% men, mean age 69.5±13.3 years, median baseline NIHSS 16 [10-20]) were included and 146 (62.4%) fulfilled MetS criteria. After multivariate analysis MetS was an independent predictor of resistance to thrombolysis (OR 2.2 [1.3-4.2] p=0.01) and absence of early neurological recovery (OR 0.5 [0.28-0.97] p=0.04). In addition, MetS conferred poorer functional outcome at three months, higher SICH rate and increased infarct volume although these associations disappeared after adjustment for covariates. Adiponectin levels in women and CRP and PAI-1 levels in the whole sample were significantly associated with MetS but we found no influence of those biomarkers in resistance to thrombolysis, SICH, infarct volume or early neurological improvement. However, CRP levels were higher in patients with poor functional outcome.

Conclusions:
MetS is an independent predictor of resistance to clot dissolution after tPA administration in patients with acute MCA occlusions and it is associated with poorer neurologic outcome.
Abstract 79: Effect of Carotid Revascularization Endarterectomy Versus Stenting Trial Results on Performance of Carotid Artery Stent Placement and Carotid Endarterectomy in United States
Authors: Siddiq Farhan , Adil Malik M , Malik Ahmed A , Chaudhry Saqib A , Qureshi Adnan I
Published: March 2022

Introduction:
Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) results, published in 2010, showed no difference in composite outcome (stroke, myocardial infarction, or death) between carotid artery stent placement (CAS) and carotid endarterectomy (CEA). The impact of these results on the pre-existing practices has not been studied. The aim of our study is to determine whether any change in utilization and outcomes of CAS and CEA subsequent to the CREST results.

Methods:
We estimated the frequency of CAS and CEA procedures in the years 2009 (pre-CREST period) and 2011 (post-CREST period), using data from the National In-patient Sample (NIS). Pre- and post-CREST CAS and post-CREST CEA rates and outcomes were compared with pre-CREST CEA (reference).

Results:
A total of 225,191 patients underwent CEA or CAS in pre- and post-CREST period. The frequency of CAS did not change after CREST publication. In the pre-CREST period, CAS group (compared with CEA) were younger .Neurological complications, and in-hospital mortality was higher in the CAS group compared to CEA group in the pre-CREST analysis (p=0.008, 0.0003, 0.0004, respectively. In the post-CREST period, the frequency of CAS has remained unchanged in comparison to CEA. Neurological complications were more frequently reported in the post-CREST group (p<0.0001 and 0.005, respectively). Post-procedure cardiac complications were not different in both pre and post CREST CAS group when compared with reference CEA group (p=0.8 and 0.6, respectively). After adjusting for age, gender and risk factors, the Odds ratio (OR) for moderate to severe disability was 1.0 (95% CI 0.8-1.2) in the pre-CREST CAS group and 0.7 (95%CI 0.6-0.9) in the post-CREST CAS group compared with the reference. Adjusted OR for neurological complications in the pre-CREST CAS group was 0.6 (95%CI 0.6-0.9) and 0.7 (95%CI 0.5-0.9) in the post-CREST CAS group.

Conclusion:
The frequency of CAS and CEA for carotid artery stenosis has not changed after the publication of CREST trial. The demographics, pre-treatment co-morbidity profile and in-hospital complications remain unchanged during the two time periods. CAS continues to have higher risk of post-operative neurological complications as reported in CREST trial.
Abstract 8: APE1 Upregulation Reduces Oxidative DNA Damage and Protects Hippocampal Neurons from Ischemic Injury
Authors: Li Peiying , Leak Rehana , Zhang Feng , Cao Guodong , Gao Yanqin , Chen Jun
Published: March 2022

Background and purpose:
Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme that participates in base-excision repair of oxidative DNA damage and the redox activation of transcription factors. We tested the hypotheses that APE1 upregulation protects neuronal structure and function against transient global cerebral ischemia (tGCI).

Methods:
Transient GCI was induced for 12 min in male Sprague-Dawley rats with the 4-vessel occlusion method. Low-dose proton irradiation or transgenic overexpression was generated to upregulate APE1. Lentiviral vectors expressing shRNA against rat APE1 were stereotaxically infused in the dorsal hippocampus to knockdown APE1 expression. Golgi staining and immunofluorescence staining of synaptophysin-1 and PSD-95 were used to label dendritic spines and synapses. Field excitatory postsynaptic potentials in the Schaffer collateral pathway were measured to assess the hippocampal synaptic function. Morris water maze was performed 22-27 days after tGCI to assess the learning and memory deficits.

Results:
Upregulation of APE1 protected hippocampal CA1 neurons against tGCI-induced cell loss and reduced apurinic/apyrimidinic sites and DNA fragmentation. Conversely, APE1 knockdown attenuated irradiation-afforded protection. APE1 overexpression inhibited the DNA damage response, as evidenced by lower phospho-histone H2A (H2AX) and p53 upregulated modulator of apoptosis (PUMA) levels. APE1 overexpression also partially rescued CA1 dendritic spines after tGCI and attenuated the decrease in field excitatory postsynaptic potentials in the Schaffer collateral pathway. Presynaptic and postsynaptic markers were reduced following tGCI and this effect was also blunted in APE1 transgenics. The Morris water maze test revealed that APE1 protected against learning and memory deficits for at least 27 days post-injury. Animals expressing DNA repair-disabled mutant APE1 (D210A) exhibited more DNA damage than controls and were not protected against tGCI-induced cell loss.

Conclusion:
APE1 upregulation, either endogenously or through transgene overexpression, protects DNA, neuronal structures, synaptic function, and behavioral output from ischemic injury.
Abstract 88: A Prospective Evaluation of Efficacy of a Nurse-led Tia Clinic in Hong Kong
Authors: Chung Tsang, Mick Yu , Chun Kong Chan , Yin Ming Tam , Ping Wing Ng
Published: March 2022

Background:
Patients with transient ischemic attacks(TIAs) are at risk of developing ischemic stroke and therefore early management is of paramount importance. An alternative to the conventional physician-led assessment is nurse-led TIA clinic which can provide rapid access to evaluation and diagnostic investigations of TIA.

Objective:
To evaluate the efficacy of nurse-led TIA clinic in cardiovascular risk factors control and prevention of ischemic stroke

Methods:
A prospective study was conducted in a nurse-led TIA clinic in the United Christian Hospital of Hong Kong between January and July 2013. The referral sources included emergency room, medical wards and outpatient clinics. TIA patients were first screened by stroke nurse upon receiving the referrals, and then protocol-driven investigations and treatment were initiated quickly before further assessment by stroke physician. The efficacy endpoints were measured by healthcare utilization, changes in biomedical parameters, lifestyle modification and patients’ satisfaction score at 3 months.

Results:
A total of 213 patients were referred to stroke nurse for screening.95 patients were recruited and managed first in the nurse-led TIA clinic. 85 patients were diagnosed to be TIA after review by stroke physician. At 3 months(n=33), there were 3 patients hospitalized for non-vascular events,1 patient for recurrent TIA and none for non-stroke vascular events. The 3-month mortality was 0%. For biomedical parameters,significant reduction in mean total cholesterol(p=0.001), mean low-density lipoprotein(p<0.001), mean systolic blood pressure(p=0.011) and mean diastolic blood pressure(p=0.002). 3(38%) out of 8 active smokers ceased smoking. There was no change in the mean BMI. The mean patients’ satisfaction score was 9.1 out of 10(range 8 to 10)

Conclusion:
Nurse-led TIA clinic is efficient in triaging TIA referrals and providing early access to initial evaluation and diagnostic workup. Combined with physician’s treatment, TIA patients can achieve significant improvement in cardiovascular risk factors control and low incidence rate of ischemic stroke at 3 months. Our TIA patients are satisfied with this modality of assessment pathway and this can serve as a model of care for future TIA services
Abstract 9: Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) deficiency Attenuates Phagocytic Activities of Microglia and Exacerbates Ischemic Damage in Experimental Stroke
Authors: Kawabori Masahito , Kacimi Rachid , Kauppinen Tiina , Calosing Cyrus , Kim Jong Youl , Christine Christine , Nakamura Mary , Yenari Midori
Published: March 2022

Clearing cellular debris after brain injury represents an important mechanism to re-attain tissue homeostasis and promote functional recovery. Triggering receptor expressed by myeloid cells-2 (TREM2) is involved in the innate immune system, and carries out surveillance functions by binding and phagocytosing pathogens. TREM2 is expressed on macrophages and microglia, and promotes the phagocytosis of apoptotic brain cells. Deficiency of functional TREM2 leads to accelerated dementia, and mutations in the TREM2 gene have been linked to Alzheimer’s. Here we explore the significance of TREM2 in a in-vitro and in-vivo stroke model. Cultures of neurons and microglia were subjected to OGD. TREM2-knockout (KO) and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion ischemic model. TREM2 knockdown in microglia by siRNA led to decreased transformation to an amoeboid morphology following co-culture and OGD exposure, but no effect on overall neuron death. OGD-exposed and nuclear lysates from neurons led to TREM2 signaling. In vivo, phagocytosis and infarcted brain tissue resorption was observed in wild-type mice by 14d, but no phagocytosis and little infarcted brain resorption was seen in TREM2 KO mice (p < 0.01)(Fig). TREM2 KO mice also had worsened neurological recovery (p < 0.05), and decreased viable brain tissue in the ipsilateral hemisphere. Numbers of activated microglia and macrophages in KO mice were decreased compared to WT, and oil red staining to identify foamy macrophages was nearly absent in the KO brains. These findings establish the relevance of TREM2 in phagocytosis of the infarcted brain and emphasize the importance of phagocytosis in neurological outcome following experimental stroke.
Abstract 92: Prevalence and Predictors of Apparent Treatment-Resistant Hypertension among Individuals with a History of Physician-Diagnosed Stroke or TIA
Authors: Howard Virginia J , Tanner Rikki M , Irvin Marguerite R , Calhoun David A , Anderson Aaron , Lackland Daniel T , Oparil Suzanne , Muntner Paul
Published: March 2022

Background:
Uncontrolled blood pressure (BP) and use of multiple antihypertensive medication classes are common among persons with a history of stroke, suggesting prevalence of resistant hypertension may be high in this population. In a cohort of persons with hypertension, we sought to determine prevalence of apparent treatment-resistant hypertension (aTRH) among those with a history of stroke and/or TIA. Additionally, demographics and clinical factors associated with aTRH were determined.

Methods:
This cross-sectional analysis used data from REGARDS, a national, population-based, longitudinal study of 30,239 black and white adults ≥ 45 years, enrolled 2003-2007. Baseline data collection included centralized telephone interview for medical history, including self-report of physician diagnosed stroke or TIA. Analysis was restricted to 14,160 participants with hypertension, defined as SBP ≥ 140 mmHg, DBP ≥ 90 mmHg, or self-reported use of antihypertensive medications. aTRH was defined as: 1) uncontrolled BP (systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg) with concurrent use of ≥ 3 antihypertensive medication classes, or 2) use of ≥ 4 antihypertensive medication classes, regardless of BP level. We used Poisson regression to calculate predictors of aTRH.

Results:
Among all hypertensive participants, 2,208 (15.6%) had aTRH, however, 433/1,961 (22.1%) with a history of stroke/TIA had aTRH . After adjustment for age, race and sex, participants with history of stroke/TIA were more likely to have aTRH (prevalence ratio [PR] = 1.43; 95% CI: 1.30 - 1.57) although the association was partially mediated by adjustment for risk factors and socio-economic status (PR = 1.15; 95% CI: 1.04 - 1.28). Among stroke/TIA participants, aTRH was more common in blacks (PR = 1.70; 95% CI: 1.43 - 2.02), larger waists (PR = 1.31 per 15 cm; 95% CI: 1.22 - 1.42), diabetes (PR = 1.62; 95% CI: 1.37 - 1.91), albumin-to-creatinine ratio ≥ 30 mg/g (PR = 1.87; 1.59 - 2.20), and history of myocardial infarction (PR = 1.34; 95% CI: 1.12 - 1.59).

Conclusions:
In this study, over 20% of persons with stroke/TIA had aTRH. As current guidelines recommend BP reduction in these individuals, our results support identification of those who may need more intensive BP monitoring and management.
Abstract 95: The impact of Blood Pressure Variability on Stroke Recurrence: The SPS3 trial
Authors: Field Thalia S , Patton Kristopher , McClure Leslie , Sussman Craig , White Carole , Pergola Pablo , Hart Robert , Benavente Oscar ,   SPS3 Investigators
Published: March 2022

Background:
Blood pressure variability (BPV) has been identified as an independent and powerful risk factor for first and recurrent stroke. However, the role of visit-to-visit BPV in stroke patients with well-controlled blood pressure is not well defined.

Methods:
Participants from the Secondary Prevention of Small Subcortical Strokes (SPS3) trial were included. All participants had recent symptomatic MRI-proven lacunar infarcts. Visit-to-visit BPV was defined by average real variability (ARV; mean absolute difference from visit to visit), standard deviation (SD) and coefficient of variation (CV; equal to SD/mean). We analyzed the association between BPV and recurrence of stroke, myocardial infarction and death.

Results:
There were 2666 participants included in the analysis with a mean of 13.7 followup visits per patient (36498 visits overall). Mean age was 63 y and 63% were male. Mean blood pressure was 132/72 and ARV was 12/7 mm Hg. There was no relationship between systolic or diastolic BPV and all recurrent stroke, nor was there a relationship between BPV and recurrent ischemic stroke or hemorrhagic stroke. After multivariable adjustment, increased systolic BPV was associated with all-cause mortality (HR 1.05 per mm Hg, 95% CI 1.03-1.08, p=0.0001) and MI (HR 1.05, 95% CI 1.01-1.97, p=0.02). There was a weak but significant correlation between systolic and diastolic ARV and average number of antihypertensive medications during the trial (systolic Spearman rank 0.214, p<0.0001, diastolic 0.135, p<0.0001). However, there was no relationship between ARV and stroke, regardless of the number of antihypertensives a patient was taking one year after randomization.

Conclusion:
In this well-characterized population with symptomatic lacunar stroke and well-controlled blood pressure, visit-to-visit BPV was not associated with stroke recurrence. The directionality and nature of the relationship between BPV, MI and death is not well understood and requires further investigation. The lack of an association between BPV and stroke may have been precluded by aggressive and dynamic BP management in this cohort.
Abstract NS10: Prevalence of Angioedema in Patients Treated With Rt-PA Within a U.S. National Database
Authors: Doellman Traci , Heitsch Laura , Sucharew Heidi , Adeoye Opeolu , Ferioli Simona , Kleindorfer Dawn O
Published: March 2022

Introduction:
Oro-lingual angioedema has been reported to occur in 1 to 5% of AIS patients receiving rt-PA therapy, in small samples with prospective screening. We sought to describe the prevalence and predictors of angioedema within a large administrative database.

Methods:
This analysis utilized the Premier database, a representative sampling of US hospitals that includes approximately 15% of hospital discharges, with access to pharmacy records. Study period was fiscal yrs 2006-2010. Patients with primary admitting diagnosis of AIS were included (ICD 9 codes 433.x1, 434.x1, and 436), AIS patients receiving thrombolytics were identified using ICD-9 code 99.10 or pharmacy use (Alteplase, 50 or 100mg vials). Patients with angioedema were identified by code 995.1. Associations between patient demographics and angioedema were assessed using logistic regression.

Results:
A total of 257,992 ischemic stroke patients were within the database. These patients were 47 % male, 16% black, and mean age of 71 (SD 14). There were 8792 (3.4%) IS patients treated with rt-PA, these patients were more likely to be younger (mean age 69 (SD 15) vs 71 (14)), white (66% vs 63%) compared to those not treated, p-values <0.01. There were 129 (0.05%) IS patients with angioedema (0.33% in rt-PA treated, vs. .04% in not-treated, p value <0.01)
.
Multivariable model of predictors of angioedema among those patients treated with rt-PA are presented below.

Discussion:
Within a large administrative database, we found a much smaller percentage of angioedema reported among rt-PA treated patients than has been previously reported, likely in part due to under-documentation of milder angioedema events. We also found that rt-PA treated women had much higher risk of angioedema than men, which has not been reported previously. Unfortunately, admission medications are not available within this database, so concomitant angiotensin-converting enzyme medication use (a known risk factor for angioedema) is unknown.
Abstract NS11: Impact of Substance Abuse on Timely Treatment With rt-PA: A Population-Based Study
Authors: Goodall Emily B , Kimmel Pamela L , Sucharew Heidi , Alwell Kathleen , Moomaw Charles J , DE LOS RIOS LA ROSA Felipe , Woo Daniel , Flaherty Matthew , Khatri Pooja , Adeoye Opeolu , Ferioli Simona , Mackey Jason , Martini Sharyl , Kissela Brett M , Kleindorfer Dawn O
Published: March 2022

Introduction:
Acute stroke patients intoxicated or with a history of substance abuse may be more difficult to diagnose. We explored the impact of substance abuse on time to treatment with rt-PA in our population.

Methods:
The Greater Cincinnati Region includes five counties with a population of 1.3 million. We ascertained all stroke patients that presented to hospital emergency departments (ED) in 2005 and 2010. Patients residing in nursing or group homes were excluded. Substance abuse was defined as a history noted in the medical record, or abnormal tox screen/EtOH level on presentation. Door to Needle (DTN) was defined as ED arrival time to rt-PA administration. Wilcoxon signed rank test compared (DTN) times between substance abusers and non- abuse groups. Multivariable regression analyzed the association of DTN with demographics (age, race, and gender), history of hypertension, diabetes and atrial fibrillation, as well as the Primary Stroke Center(PSC) certification status of the presenting hospital.

Results:
In 2005, 72 non-institutionalized ischemic stroke patients received rt-PA in local EDs; in 2010, 112. Mean age for 184 patients was 70 (13 SD), 18% were black, and 51% female. Substance abuse was present in 34 (18%) patients. Median DTN for substance abusers was 73.5 minutes (25
th
, 75
th
%tile: 52.0, 93.0) vs. 77.50 minutes (61.0, 99.0) for non- abusers (p=0.25). However, if the presenting hospital was a PSC, the DTN times were substantially and significantly shorter (Table).

Discussion:
Substance abuse history or current intoxication did not impact DTN for rt-PA treated patients within our population. We did find that arriving to a Primary Stroke Center was associated with significantly shorter DTN times. This suggests that hospital systems impact DTN times more than individual patient-level factors.
Abstract NS22: Stroke Length of Stay: Life in the FAST Lane
Authors: Zimmermann Mary Beth , Trower Diane , Zwerneman Karen
Published: March 2022

The length of stay for stroke (ischemic & hemorrhagic stroke DRGs combined) was 7.04 days in a major university teaching hospital, compared to the national average of 3-5 days. The purpose was to decrease length of stay (LOS) for the stroke patient population by implementing multidisciplinary LOS guidelines. Discharge planning starts with admission, and research shows a correlation between initial National Institutes of Health Stroke Scale (NIHSS) and discharge disposition. Patients with NIHSS = 0-5 most likely go home; 6-15 most likely go to a rehabilitation facility; and 16-42 most likely will go to a Skilled Nursing Facility (SNF) or Long Term Acute Care Facility (LTAC) (Schlegel et. al., 2004; Schlegel et al., 2003). We formed a multidisciplinary team, including nursing, social work (SW), care coordination (CC), medical hospitalists, neurologist, and physical medicine staff working specifically with the stroke patient population. Each discipline developed length of stay guidelines, depicting crucial points in the care of a stroke patient on a day-to-day basis (Wojner & Alexandrov, 2000). Each specialty was included in the teaching plan, and we held educational sessions for all disciplines, including 100+ members of the medical hospitalist team. Through this education, Nursing began communicating admission NIHSS in daily huddles. Palliative care screenings were included for patients with NIHSS >25. Speech Therapy (ST) recommendations for PEG tube placement were communicated daily, and physicians were notified directly. PT/OT/ST coordinated one discharge recommendation by day 2, with variances communicated immediately to the CC. For physicians, PEG scheduling was centralized since specific GI MDs were only available on certain days. Through implementation, our length of stay for all stroke patients went from 7.04 to 5.23 days. The LOS guidelines are now used to orient new team members from all disciplines.
Abstract NS6: Factors Affecting Uncertainty in Caregivers of Stroke Survivors
Authors: Byun Eeeseung , Riegel Barbara J , Sommers Marilyn S , Tkacs Nancy C , Evans Lois K
Published: March 2022

Caregiving for stroke survivors is a known risk factor for morbidity and mortality. Little has been reported on caregiving in the early poststroke period, a time when uncertainty is probably at its highest. Uncertainty has been related to poor health outcomes in other populations. In the early poststroke period caregivers may be uncertain about the potential for recovery and their sudden assumption of the new caregiver role, but factors affecting uncertainty in these caregivers are not known.

Methods:
We conducted a prospective, longitudinal observational study and recruited 40 caregivers (68% female, mean age 58±14.22 years, 60% children) and their stroke-survivor relatives (38% male, mean age 76±7.80 years) from acute care settings in the northeastern US. We measured caregivers’ uncertainty using the Perception of Uncertainty in Illness Scale for Family Members (range: 31-155, higher scores: greater uncertainty) and collected caregiver and stroke-survivor sociodemographic, clinical and response characteristics (e.g., coping capacity, caregiver comorbidity, social support, severity of stroke and stroke-survivor functional status and comorbidity) by self-report and chart abstraction. Multivariate stepwise regression was used to examine factors affecting uncertainty within 2 weeks following stroke (T1) and at 6 weeks poststroke (T2).

Results:
Uncertainty was high in caregivers at both time points (T1: 83.73±23.47, T2: 85.23±23.94). Caregiver older age (
p
= 0.001 at T1 and T2) and lower coping capacity (
p
< 0.001 at T1 and T2) at both time points and stroke-survivor lower functional status at T1 (
p
= 0.047) were associated with greater caregiver uncertainty.

Conclusions:
Caregivers experience persistently high uncertainty during the first 6 weeks poststroke. Caregiver age and coping capacity and stroke-survivor functional status may help identify stroke-survivor caregivers at highest risk for early uncertainty. These caregivers may be in the greatest need of interventions.