bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 44: Histopathological Interpretation of Vessel Wall Imaging of Intracranial Aneurysms
Authors: Hashimoto Yukishige , Matsushige Toshinori , Shimonaga Koji , Hosogai Masahiro , Kaneko Mayumi , Ono Chiaki , Mizoue Tatsuya
Published: January 2019

Background and purpose:
It remains a challenge to predict unruptured intracranial aneurysms (UIAs) that are prone to rupture. MR- Vessel wall imaging (VWI) is a current topic whether it could predict unstable aneurysms. We investigated the correlations between aneurysm wall imaging findings and aneurysmal risk factors with a focus on the histopathological vessel wall architecture to clarify the interpretation of VWI of intracranial aneurysms.

Methods:
A total of 117 intracranial aneurysms, including 21 ruptured and 96 UIAs were investigated by VWI and visualization of the aneurysm wall enhancement (AWE) was evaluated. Univariate analysis was performed to assess the correlation between VWI findings and the PHASES score (calculating patient demographic and aneurysm morphologic risk factors). Fifteen intracranial aneurysms, including 6 ruptured and 9 UIAs were available for histopathological examination.

Results:
In UIAs, AWE was identified in 30 of 96 UIAs (31%). The PHASES score was associated with AWE (9.1 ± 0.7 versus 6.0 ± 0.3, p= 0.001). Histopathological studies revealed that wall thickening accompanied by atherosclerosis, neovascularization, and macrophage infiltration corresponded to AWE. The thicken wall was characterized by loss of mural cells and mucinous degeneration as well. On contrary, AWE was identified in 17 of 21 ruptured aneurysms (81%). Three AWE patterns (focal, circumferential, and both) were identified in ruptured ones. Histopathological studies revealed that focal AWE was associated with very thin aneurysm wall and fresh intraluminal thrombus at the rupture site, whereas circumferential AWE suggested wall thickening with abundant neovascularization and inflammatory cells.

Conclusions:
In the present study, one-third of UIAs showed AWE and might not provide informative rupture risk estimation beyond PHASES score at this moment. However, VWI of intracranial aneurysms can detect what is going on in the aneurysm wall. Histopathological interpretation of VWI in ruptured aneurysms differed from that of UIAs, especially in focal AWE. Focal AWE could identify the intraluminal thrombus suggesting rupture site of the wall before treatments.
Abstract 45: Treatment Trends and Clinical Outcomes for Unruptured Cerebral Aneurysms in High vs Low Volume Centers
Authors: Inam Mehmet E , Sanzgiri Aditya A , Chen Peng Roc R , Blackburn Spiros , Bambhroliya Arvind B , Vahidy Farhaan S , Savitz Sean I , Sheth Sunil A
Published: January 2019

Background:
Prior studies have suggested that unruptured cerebral aneurysm (CA) treatments have spread from high-volume centers into lower-volume centers in the past decade, coinciding with the increase of endovascular coiling (EC) relative to surgical clipping (SC). Our understanding of outcomes from CA treatments by hospital treatment volumes is lacking.

Methods:
Using administrative data on all discharges from hospitals in New York (2005-2014) and Florida (2005-2015), we identified patients with treatments for unruptured CAs. Good outcome was defined as discharge home without intracerebral hemorrhage (ICH) and poor outcome as discharge to SNF or death. A composite weighted index of risk factors was calculated using the Charlson Comorbidity Index (CCI). Logistic regression adjusted for age, sex, smoking, diabetes and CCI were performed. Results are provided as median [IQR] or OR [95% CI].

Results:
Among 14,064 patients with treated unruptured CAs, median age was 58 [49 - 66] and 75% were female. EC was performed in 9,417 (67%), and increased over time (56% vs. 74%, 2006 vs. 2014). Annual treatments increased over the study period, with 1125 CAs treated in 2006 versus 1517 in 2014, whereas the number of treating hospitals did not (66 vs. 64, 2006 vs. 2014). In adjusted logistic regression, there was no difference in likelihood of a good outcome over time (OR 0.94 [0.86 - 1.03], 2012-2015 vs. 2005 - 2008). The likelihood of good outcome increased with annual hospital treatment volume (
Figure 1a
). This relationship was maintained for patients treated with SC and EC (ORs 1.7 [1.33 - 2.2] and 3.2 [2.5 -4.1]). The likelihood of poor outcome conversely decreased consistently with increasing annual treatment volume (
Figure 1b
).

Conclusion:
In this large cohort study, we did not observe an increase in the number of hospitals performing CA treatments. However, for patients treated with both SC and EC, treatment at higher-volume centers was associated with improved outcomes.
Abstract 46: RNA Expression Profiles From Whole Blood Associated With Vasospasm in Patients With Subarachnoid Hemorrhage
Authors: Sharp Frank R , Xu Huichun , Ander Bradley P , Stamova Boryana , Waldau Ben , Jickling Glen C , Ko Nerissa
Published: January 2019

Background and Purpose:
Though there are many biomarker studies of plasma and serum in patients with aneurysmal subarachnoid hemorrhage (SAH), few have examined cells in blood that might contribute to vasospasm and delayed ischemic neurological deficits (DIND). In this study we evaluate inflammatory and prothrombotic pathways by examining RNA expression in whole blood (including leukocytes, platelets) of SAH patients with vasospasm compared to those without vasospasm.

Methods:
Adult patients with aneurysmal SAH admitted to UCSF from 2003 to 2010 were enrolled. Patients with vasospasm (n=29) and without vasospasm (n=21) were matched for sex, race/ethnicity and aneurysm treatment method. Diagnosis of vasospasm was made by angiography. RNA expression was measured by Affymetrix Human Exon 1.0 ST Arrays. SAH patients with vasospasm were compared to those without vasospasm by ANCOVA to identify differential gene expression, exon expression and alternatively spliced transcript expression. Analyses were adjusted for age, batch, and days after SAH.

Results:
At the gene level there were 276 differentially expressed between SAH with vasospasm compared to patients without (P<0.05,
Abstract 55: Interleukin 4 Improves White Matter Repair After Stroke By Promoting Oligodendrocyte Differentiation
Authors: Zhang Qingxiu , Zhu Wen , Yu Fang , Gao Yanqin , Chen Jun , Hu Xiaoming
Published: January 2019

Introduction:
White matter (WM) injury is an important cause of long-term deficits after stroke. This study explores a novel action of IL-4 on promoting WM integrity after stroke and elucidates the underlying mechanisms.

Hypothesis:
IL-4 promotes WM repair and enhances long-term neurological recovery after ischemic stroke by targeting both OPC differentiation and microglial polarization.

Methods:
Cerebral ischemia was induced by transient (60 min) middle cerebral artery occlusion (tMCAO) in wild type, IL-4 knockout and oligodendrocyte precursor cell (OPC)-specific PPARγ KO mice. The animals were then randomly assigned to vehicle or IL-4 treatment. IL-4 was delivered intranasally 6h after stroke and repeated every day at 1-7d, 14d, 21d, and 28d after tMCAO. Sensorimotor deficits were determined by adhesive removal, rotarod test and corner test. Cognitive deficits were determined by water maze test. A combined approach including cell-specific depletion, immunohistology staining, electron microscopy (EM), diffusion tensor imaging (DTI) and electrophysiology, was applied to evaluate WM integrity.

Results:
IL-4 knockout (KO) mice exhibited worse sensorimotor deficits and deteriorated WM injury over 14 days after tMCAO. In contrast, intraventricular infusion of IL-4 beginning 6h after MCAO attenuated long-term sensorimotor and cognitive deficits and improved WM integrity, as revealed by immunohistology staining, EM, DTI and electrophysiology. In addition to promoting microglia/macrophage M2 polarization, IL-4 treatment enhanced OPC differentiation in the ischemic brain and in organotypic cultures. Interestingly, IL-4-afforded oligodendrogenesis was still potent in microglia depleted (with PLX5662) mice. In vitro study confirmed that IL-4 directly induced the differentiation of primary OPCs into mature oligodendrocytes. This effect was mediated through the activation of PPARγ. The therapeutic efficacy of IL-4 on OPC differentiation and white matter protection was significantly reduced in OPC-specific PPARγ KO mice.

Conclusions:
IL-4 promotes oligodendrogenesis and white matter repair in an PPARγ-dependent manner. IL-4 may represent a novel recovery-enhancing strategy to promote functional recovery after ischemic stroke.
Abstract 63: Plasma Biomarkers of Cavernous Angioma With Symptomatic Hemorrhage (CASH)
Authors: Girard Romuald , Lyne Seán , Koskimäki Janne , Zeineddine Hussein A , Cao Ying , Stadnik Agnieszka , Li Yan , Moore Thomas , Lightle Rhonda , Shi Changbin , Zhang Dongdong , Polster Sean P , Romanos Sharbel , Avner Kenneth , Akers Amy , Duggan Ryan , Leclerc David , Whitehead Kevin J , Li Dean Y , Awad Issam A
Published: January 2019

Introduction:
Cerebral cavernous angiomas with a documented symptomatic hemorrhage (CASH) are associated with an exceptionally high risk of recurrent hemorrhage and serious morbidity. It is unclear if peripheral blood plasma biomarkers implicated in disease biology can differentiate CASH, and whether the same or different biomarkers can distinguish cases who would rebleed.

Methods:
Eighteen plasma molecules with postulated mechanistic roles in this disease were quantified in 114 patients and 12 healthy subjects. The best biomarker combination differentiating CASH in the prior year (+/- 30 days) was derived by minimizing the Akaike Information Criterion (AIC), and was validated using statistical and machine-learning simulations. This was compared to the biomarker predicting bleeding in the subsequent year (+/- 30 days), and both explanatory and predictive biomarkers were followed longitudinally in a subset of cases.

Results:
Nine plasma molecules had significantly different levels expressed in CASH patients (p<0·05, FDR corrected). The best biomarker (AIC=75·9) included a weighted combination of 4 of these (sCD-14, VEGF, CRP, and IL-10), and distinguished CASH patients with 76% sensitivity and 80% specificity (p=0·0003). A weighed combination of two of these compounds (sCD14 and VEGF) and two others (IL-1β and sROBO-4) predicted which patients would bleed in the subsequent year with 83% sensitivity and 93% specificity (p=0·001). The CASH biomarker increased in recovering patients (p=0·01), while the predictive biomarker decreased after a bleed (p=0·01). No significant change over time was observed in stable subjects in either biomarker.

Conclusions:
Our results suggest shared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in cavernous angiomas. This may be applied for risk stratification in clinical trials, and potentially developed as a tool in clinical practice.
Abstract 66: Reduction of the Number of Endothelial Cells Harboring Mutations of AVM Causative Genes Lessens Brain AVM Severity
Authors: Shaligram Sonali S , Zhang Rui , McDougall Cameron M , Zhu Wan , Zhu Wan , Ma Li , Lawton Michael L , Su Hua
Published: January 2019

Background and purpose:
Mutation of arteriovenous malformation (AVM) causal genes in the endothelial cells (ECs) is essential for AVM formation. However, the relationship of the mutant EC-dose and AVM severity is not clear. We tested whether reduction of mutant ECs reduces bAVM severity using three mouse models that mimic human hereditary hemorrhagic telangiectasia (HHT), a familiar form of bAVM. Majority of HHT patients have
Alk1
or endoglin (
Eng
) gene mutation.

Methods:
Model 1 is
Pdgfb
iCreER;
Alk1
2f/2f
mouse that expresses an EC-specific estrogen inducible cre recombinase and has its
Alk1
gene exon 4-6 floxed.
Alk1
gene deletion was induced by treating the mice with different doses of tamoxifen (TM, 1.25, 0.75, or 0.01 mg/25g of body weight). Model 2 is RosaCreER;
Eng
2f/2f
mouse that expresses a estrogen inducible cre globally and has exon 5 and 6 of its
Eng
gene floxed. Model 3 is
Pdgfb
iCreER;
Eng
2f/2f
mice. The EC
Eng
deletion in Model 2 & 3 was induced by three doses of TM (TM 2.5M/25g) treatment. The icre in
Pdgfb
iCreER transgene has a codon mutant, which is more efficient in deletion of floxed alleles than wild-type cre. BAVMs were induced in TM treated mice through intra-brain injection of AAV-VEGF. Gene deletion efficiency was quantified by qPCR and immunostaining. BAVM phenotypes were analyzed histologically.

Results:
In model 1, reduction of TM dose reduces the number of
Alk1
null ECs and the severity of bAVM. The number of abnormal vessels in bAVM is positively correlated with the TM doses (R=0.8) and negatively correlated with Alk1 positive ECs (R=-0.9). Reduction of TM has also reduced mouse mortality. Compared to Rosa-CreER-mediated global
Eng
deletion,
pdgfb-
icreER-induced EC
Eng
deletion did not increase the number of abnormal vessels, but reduced vascular mural cell-coverage and increased hemorrhage in the bAVM lesion.

Conclusion:
Reduction of mutant ECs reduces bAVM severity.
Abstract 68: Objective Measures of Improvement From Intensive Communication Therapy by Treatment Duration, Dose, and Density
Authors: King Ben , Shamapant Shilpa , Warach Steven
Published: January 2019

Introduction:
Intensive Communication Therapy (ICT) is a technique developed to treat post-stroke aphasia in adults, which builds on the idea that more hours of therapy yields greater improvements over time. However, there is little evidence to support the duration (time in treatment), dose (person-hours of treatment), or density (person-hours/ time) of treatment necessary to demonstrate improvement in symptoms.

Method:
A retrospective sample of 150 individuals with aphasia who completed 8 or more weeks of outpatient ICT at a single provider agency in Texas was analyzed. Deficit was measured at baseline and with repeated measures of a unique, standardized screener for language, reading and writing. Improvement was defined as either a) an a priori threshold or b) any improvement over two consecutive measurement intervals. Treatment exposure was calculated as a) total hours in treatment, b) person-hours of treatment attended, and c) person-hours divided by time. Survival analysis and Kaplan Meier curves were used to determine incidence rate functions; tested by age, gender, severity, and time post-stroke.

Results:
51% of the sample was female, and the mean age at start of treatment was 58.5 (range=18-90). Of subjects with 2 consecutive measurements obtained (approximately 10 weeks apart), threshold improvement was met 75.8% of the time. The estimated rate of person-time in treatment to threshold improvement was 153 hours (IR=0.0065) and 360 hours to achieve consistent improvement over two sessions (IR=0.0028). Cases who demonstrated either measure of improvement received significantly greater treatment density during the course of their treatment up to that point (both p<0.05). Multiple tests of improvement varied by initial stroke severity and time post-stroke.

Conclusions:
These findings support the ability of ICT to improve symptoms in patients with speech or communication deficits post-stroke. However, the time in treatment required to show improvement is considerable and may vary depending on how long a survivor waits to initiate treatment and the initial severity of the stroke. Service providers and insurers may both need to examine their treatment plans and advocate for more intensive or longer durations of therapy based on these findings.
Abstract 71: The Impact of 3-month Functional Outcome on Healthcare Expenditure During the 5 Years After Acute Ischemic Stroke
Authors: Bae Hee-Joon , Lee Heeyoung , Kim Seong-Eun , Park Jong-Moo , Kang Kyusik , Cho Yong-Jin , Hong Keun-Sik , Park Hong-Kyun , Lee Kyung Bok , Park Tai Hwan , Park MooSeok , Lee Soo Joo , Kim Jae Guk , Han Moon-Ku , Kim Beom Joon , Kang Jihoon , Lee Jun , Cha Jae-Kwan , Kim Dae-Hyun , Nah Hyun-Wook , Kim Dong-Eog , Ryu Wi-Sun , Kim Joon-Tae , Choi Kang-Ho , Choi Jay Chol , Lee Byung-Chul , Yu Kyung-Ho , Oh Mi Sun , Kim Wook-Joo , Kwon Jee-Hyun , Shin Dong-Ick , Sohn Sung Il , Yoo Joonsang , Lee Ji Sung , Lee Juneyoung
Published: January 2019

Background and Purpose:
Stroke is one of the most devastating and costly health problems of today. However, there is lack of knowledge about how costly it is in a long-term perspective and how much the long-term cost differs according to 3-month functional outcome, a major primary outcome variable of acute stroke intervention trials.

Methods:
Acute ischemic stroke patients who were registered into the multi-center stroke registry (Clinical Research Collaboration for Stroke in Korea, CRCS-K) in South Korea between 2011 and 2013 were matched to the National Health Insurance Service claim database. All the healthcare expenditure was extracted from the claim database and converted into daily cost of each individual. Yearly expenditures and cumulative expenditure up to 5 yeas were obtained and expressed in US dollars and were compared according to 3-month functional outcome (modified Rankin disability scale, mRS).Results: A total of 11,136 acute ischemic stroke patients (mean age, 68 years; men 58%) were analyzed. The median follow-up period was 1,418 days. The mean cumulative healthcare expenditure over 5 years was $74,295 (SD, $91,049) and showed a dramatic increment during the first month followed by a constant increase without a considerable change. The mean 5-year cumulative expenditure differed significantly according to 3-month functional outcome; $32,261 in those with 3-month mRS 0 and $163,244 in those with 3-month mRS 5. After adjusting for the selected potential confounders, the yearly expenditures and the cumulative one at each time point differed significantly according to 3-month mRS scores. Figure given below is showing the median 5-year cumulative daily expenditure by 3-month mRS.

Conclusions:
This study shows that the impact of 3-month functional outcome on the long-term healthcare expenditure following acute ischemic stroke may be more than expected. The efforts for improving functional outcomes are urgent.
Abstract 72: Early Outpatient Followup With Primary Care is Associated With Lower Readmission at 30 and 90 days in Patients With Ischemic Stroke
Authors: Leppert Michelle H , Sillau Stefan , Lindrooth Richard , Poisson Sharon , Campbell Jonathan , Simpson Jennifer
Published: January 2019

Background:
Readmissions after ischemic strokes are common and associated with high morbidity and cost. Whether early follow-up after stroke can reduce readmissions remains unclear. We examined the relationship between follow-up after stroke hospitalization with primary care or neurology and readmissions at 30 and 90 days.

Methods:
A retrospective cohort study was performed using PharMetrics claims database of US commercial insurers from 2009 to 2015. Inclusion: (1) inpatient admission with primary diagnosis of ischemic stroke, (2) discharge home, (3) age 18-89, (4) 1 year of enrollment prior to stroke and 3 months after discharge. Exclusion: (1) stroke transfers, (2) repeat admission for stroke. The primary outcome was all-cause 30-day and 90-day hospital readmission. Multivariable Cox models were used with primary care and neurology visits specified as time-dependent covariates, adjusting for patient demographics, comorbidities (calculated for one year prior to stroke) and stroke severity measures.

Results:
The cohort consisted of 16,965 patients (table). Readmissions at 30 days occurred in 6.56% of patients at a median (interquartile range) of 12 days (5-20). Readmissions at 90 days occurred in 13.2% of patients at a median of 31 days (12-58). By 30 days, 50.2% had a primary care visit and 17.1% had a neurology visit. Patients with a primary care visit within 30 days had a 23% lower rate of readmission than those who did not (hazard ratio [HR], 0.77; 95% confidence interval, 0.66-0.89). The association is less strong for primary care visits within 90 days and readmissions (HR 0.88; 0.80-0.98). Neurology follow-up did produce benefit but did not reach significance.

Conclusion:
Early outpatient follow-up with primary care is associated with a significant reduction in hospital readmission. Even though this was an insured population, almost half of all patients did not receive primary care follow-up at 30 days, which represents an opportunity for intervention.
Abstract 73: The True Cost of Stroke: Assessment of Direct and Indirect Cost of Stroke Among All Age Groups in United States of America From 2003 to 2014
Authors: Girotra Tarun , Lekoubou Alain , Bishu Kinfe , Ovbiagele Bruce
Published: January 2019

Introduction:
Researchers have looked at medical expenses directly associated with stroke care, however, there is a paucity of data regarding indirect costs associated with productivity loss, especially in young adults.

Methods:
Direct and indirect medical costs were compared between stroke and non-stroke patients using the 2003-2014 Medical Expenditure Panel Survey-Household components. Direct costs include expenditures from hospitalizations, emergency room/clinic visits, medications, home health services etc. Indirect costs depend on employment, wages, missed work days (limited to 18-64 age group), and productivity loss from premature death. Two-part econometric models were used to estimate the adjusted incremental direct expenditure for patients with stroke. We used a generalized linear model with family gamma, log link for the adjusted analysis of annual wage and a negative binomial regression model for the adjusted analysis of missed work day. Loss of productivity due to premature death was computed across all age groups using Present value of one life and annual number of deaths obtained from the 2014 National Vital Statistics.

Results:
We identified 8,101,160 stroke and 245,133,892 non-stroke patients of all age groups. Weighted samples of 10,175 stroke and 314,694 non-stroke patients were compared. Total adjusted incremental direct cost for a stroke patient (vs. non-stroke) was $4,317 (95% CI $3,828-4,807) causing a $35 billion increment in total direct cost annually. Stroke patients had $14,254 (95% CI $16,023-12,485) lower adjusted annual wage, 4.2 (95% CI 2.9-5.6) more missed workdays and nearly 60% (OR 0.41; 95% CI 0.36-0.46) lower employment compared to non-stroke patients yielding an estimated annual $38.1 billion indirect-cost due to productivity loss. Indirect-cost from premature death was estimated to be $30.4 billion. Total (direct + indirect) annual cost for stroke patients was $103.5 billion.

Conclusion:
Two-thirds of the estimated $103.5 billion annual cost involved with stroke patients is attributed to indirect expenditures. Loss of productivity due to premature death is heavily concentrated in the economically productive age group. Our findings renew the call for greater emphasis on stroke prevention strategies.
Abstract 75: Predictors of Poor Outcome After Intracerebral Hemorrhage: Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) Study
Authors: Woo Daniel , Comeau Mary , Venema Simone U , Anderson Christopher , Flaherty Matthew L , Testai Fernando D , Kittner Steven , Frankel Michael R , James Micahel L , Sung Gene , Elkind Mitchell S , Worrall Bradford B , Kidwell Chelsea S , Gonzales Nicole R , Koch Sebastian , Hall Christiana , Birnbaum Lee , Mayson Douglas , Coull Bruce M , Malkoff Marc , Sheth Kevin N , Chong Ji Y , McCauley Jacob L , Osborne Jennifer , Wethington Misty , Gilkerson Lee A , Behymer Tyler P , Coleman Elisheva R , Sekar Padmini , Moomaw Charles J , Rosand Jonathan , Langefeld Carl D
Published: January 2019

Introduction:
Intracerebral hemorrhage (ICH) is the most severe subtype of stroke with a high mortality rate and majority of survivors suffering significant disability. The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study prospectively recruited 1000 white, 1000 black and 1000 Hispanic spontaneous ICH cases. Herein, we report the main results of the predictors of 3 month outcome after ICH.

Hypothesis:
We hypothesized that ICH Score variables of age, ICH volume, ICH location, presence of intraventricular hemorrhage (IVH), and presenting Glasgow Coma Scale would predict long-term disability in addition to prior validation of mortality.

Methods:
Between 2010-2015, cases were prospectively recruited with uniform phenotype definitions, centralized neuroimaging review and with telephone follow-up at 3 months. Apolipoprotein E genotyping was performed centrally. Individual characteristics were screened for association under a logistic regression model, 90-day mRS ≥ 4 versus 0-3, and those meeting P<0.2 were entered into multivariate model building where the final model was determined by minimum AIC score. Analyses were repeated removing subjects with withdrawal of care.

Results:
The Table presents the prevalence/average of each variable entering the final multivariate model for association with poor (mRS 4-6) compared to good (mRS 0-3) outcome at 3 months. When analyses were repeated excluding withdrawal of care, overall Graeb (IVH) score fell out of the model (with presence of IVH replacing it) but the remaining variables were retained and in the same direction of effect. C-statistic for the multivariate model = 0.884 compared to 0.763 for ICH score alone (p=1.7E-22).

Conclusion:
ICH score elements were validated as predictive of 3 month outcome. Novel baseline characteristics such as white matter hyperintensity as well as subsequent clinical events that may affect outcomes were identified. Location specific results to be presented.
Abstract 76: Intensive Blood Pressure Reduction is Associated With Reduced Hematoma Expansion in Deep Intracerebral Hemorrhage: A Secondary Analysis of ATACH-2
Authors: Leasure Audrey C , Qureshi Adnan I , Goldstein Joshua N , Murthy Santosh B , Kamel Hooman , Woo Daniel , Matouk Charles C , Sansing Lauren H , Sheth Kevin N , Falcone Guido J
Published: January 2019

Introduction:
Hypertension is the strongest risk factor for spontaneous intracerebral hemorrhage (ICH) involving deep brain regions. We tested the hypothesis that intensive blood pressure (BP) treatment reduces hematoma expansion and improves functional outcomes in deep ICH, and evaluated whether this effect is modified by the specific deep structure involved (thalamus versus basal ganglia).

Methods:
We performed a secondary analysis of data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial, which randomly assigned ICH patients with symptom onset within 4.5 hours and hematoma volume <60mL to either intensive treatment (systolic BP target 110-139 mm Hg) or standard treatment (target 140-179 mm Hg). Significant hematoma expansion was defined as a >33% increase in volume between baseline and 24-hour CT. We used chi-square and Mann–Whitney U tests and logistic and ordinal logistic regression models as appropriate.

Results:
Of 1000 trial subjects, 870 (87%) had deep ICH, of whom 780 (90%) had complete neuroimaging/outcome data (thalamus n=336, basal ganglia n=444) and 405 (52%) were randomized to intensive treatment. Significant hematoma expansion was less frequent in the intensive vs standard arm (17% vs 26%, p=0.008). Intensive treatment was associated with a lower risk of significant hematoma expansion (OR 0.6, 95% CI 0.4-0.9; p=0.01) even in multivariable models (OR 0.6, 95% CI 0.4-0.9; p=0.01) including age, sex, baseline INR and time to scan. This treatment effect was modified by the specific deep location of the ICH (interaction p=0.02): there was less hematoma expansion with intensive versus standard treatment among basal ganglia bleeds (0.4 [IQR 2] mL vs 0.9 [IQR 6] mL, p=0.002) but not among thalamic bleeds (0.3 [IQR 2] mL vs 0.4 [IQR 2] mL, p=0.48). Intensive treatment was not associated with a shift in the distribution of 3-month modified Rankin Scale scores (overall p=0.9, basal ganglia p=0.9, thalamus p=0.8).

Conclusions:
Compared to standard treatment, intensive BP reduction was associated with less hematoma expansion in deep ICH, specifically among hemorrhages located in the basal ganglia. In this underpowered subgroup analysis, intensive BP reduction was not associated with improved outcomes.
Abstract 77: Perihematomal Edema Expansion Rate is Associated With Poor Functional Outcomes in Basal Ganglia Intracerebral Hemorrhage
Authors: Leasure Audrey C , Qureshi Adnan I , Goldstein Joshua N , Murthy Santosh B , Kamel Hooman , Woo Daniel , Matouk Charles C , Sansing Lauren H , Falcone Guido J , Sheth Kevin N
Published: January 2019

Background:
Perihematomal edema (PHE) has been associated with poor outcomes in deep spontaneous intracerebral hemorrhage (ICH). However, it is unknown if specific deep location (thalamus versus basal ganglia) modifies the effect of PHE on functional outcome.

Methods:
We used data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial. We included patients who had deep ICH and available neuroimaging and 3-month functional outcome data. We calculated the 24-hour PHE expansion rate as the difference in PHE volume between baseline and 24-hour CT scan divided by hours between scans. We used logistic regression models to evaluate the relationship between PHE expansion rate (natural-log transformed) and poor outcome (3-month modified Rankin Scale [mRS] score 4-6), with subgroup analyses to determine the effect of thalamic vs basal ganglia location on this association.

Results:
Out of 1000 subjects enrolled in ATACH-2, 870 (87%) had supratentorial, deep ICH. Of these, 754 (87%) had complete neuroimaging and outcome data (thalamus n=324, basal ganglia n=430). Overall, PHE expansion rate was associated with poor outcome in univariable (OR 1.3, 1.2-1.5, p<0.001) but not multivariable models (OR 1.1, 0.9-1.3, p=0.24). Median PHE expansion rate was faster in basal ganglia versus thalamic ICH (0.03 [0.09] mL/hr vs 0.01 [0.04] mL/hr, p<0.001). In basal ganglia ICH, PHE expansion rate was associated with poor outcome (OR 1.4, 1.1-1.8, p=0.01) in a multivariable model including age, sex, race, admission GCS, ICH volume (natural log-transformed), presence of intraventricular hemorrhage (IVH), hematoma expansion, time to baseline scan, and treatment group. In thalamic ICH, PHE expansion rate was not associated with poor outcome in multivariable analysis (OR 0.9, 0.7-1.2, p=0.44).

Conclusions:
In the ATACH-2 trial population, 24-hour PHE expansion rate was associated with poor functional outcome among basal ganglia, but not thalamic, bleeds. These results provide further evidence that PHE is associated with functional outcomes and supports the existence of effect modification by the specific deep location involved.
Abstract 79: Preliminary Efficacy and Safety of Intravenous Recombinant Human Pro-urokinase (rhpro-UK) for Acute Ischemic Stroke:AMulticenter Phase IIa, Randomized, Open, Positive Controlled, Trial(rhpro-UK STROKEIIa)
Authors: Song Haiqing , Wang Yuan , Ma Qingfeng , Ji Xunming , Chen Fei , Ding Jianping , Ren Yi , Zhang Qian , Dong Kai , Chu Changbiao , Yu Zhipeng , Fan Chunqiu , Xue Sufang , Huang Xiaoqin , Xie Yunyan , Wang Yuping
Published: January 2019

Objective:
To investigate preliminary efficacy and safety of intravenous recombinant human pro-urokinase (rhpro-UK) in patients with acute ischemic stroke (AIS).

Methods:
In the 23-center phase IIa, time window stratified, randomized, open, positive controlled, clinical trial, patients within 6 hours after the onset of AIS were stratified into two therapeutic time windows. Patients within 4.5 h were randomized to receive intravenous rhpro-UK 50mg, 35mg, or recombinant tissue plasminogen activator (rt-PA; 0.9 mg/kg, maximum 90 mg). Patients within 4.5-6 h were randomized to receive rhpro-UK 50mg or 35mg. Primary outcome was a modified Rankin scale (mRS) score ≤1at 90 days. Secondary outcome was the treatment response based on ≥ 4-point reduction from the baseline National Institutes of Health stroke scale score at 24 hours after treatment. Safety outcomes included symptomatic intracerebral hemorrhage (sICH), death due to any cause, and other serious adverse events.

Results:
We enrolled 190 patients (Figure 1A). Within 4.5 h, the proportion of patients with a mRS score ≤1 at 90 days did not differ significantly among groups (57.9%, 55.6% and 52.6%, P=0.92). Similarly, there was no statistical significance among groups in term of treatment response at 24 hours (P=0.85). In the 4.5-6 h time window, the rates of functional independence of rhpro-UK 50mg and 35mg were 59.0% and 69.2% (P=0.34). The proportion of patients with functional response to treatment were 28.2% and 33.3% (P=0.62) (Figure1B, 1C). sICH occurred in one patient in the 50mg rphro-UK group within 4.5 h within 30 days after the intervention. There was no significant difference among the five groups in death and rate of other serious adverse events.

Conclusion:
As compared with rt-PA, intravenous rhpro-UK at two dose within the 4.5 hours after onset of symptoms showed similar efficacy and safety profiles in patients withAIS. Similarly, these two dose groups did not differ in efficacy and safety between 4.5-6.0 hours.
Abstract 8: Increasing Rate of Stroke From Infective Endocarditis Related to Opioid Abuse in the U.S.
Authors: Salehi Omran Setareh , Chatterjee Abhinaba , Chen Monica L , Lerario Michael P , Merkler Alexander E , Kamel Hooman
Published: January 2019

Background:
There has been a recent sharp rise in opioid-related deaths in the U.S. Intravenous opioid use can lead to infective endocarditis which can result in stroke. There are scant data on recent trends in this neurological complication of opioid abuse. We investigated whether increasing opioid abuse has led to a higher incidence of stroke from opioid-related endocarditis.

Methods:
We used the 1993 to 2015 releases of the National Inpatient Sample and validated

International Classification of Diseases, 9
th
Revision, Clinical Modification

codes to identify patients hospitalized with the combination of opioid abuse, infective endocarditis, and stroke (defined as ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage). Survey weights provided by the NIS were used to calculate nationally representative estimates, and population estimates from the U.S. census were used to calculate age- and sex-adjusted annual hospitalization rates per 10 million person-years. Joinpoint regression was used to assess trends.

Results:
From 1993 through 2015, 5,283 patients were hospitalized with stroke from endocarditis secondary to opioid abuse. Across this period, the incidence of such strokes increased from 2.4 (95% confidence interval [CI], 0.5 to 4.3) to 18.8 (95% CI, 14.4 to 23.3) hospitalizations per 10 million U.S. residents. Joinpoint regression detected two segments: no significant change in incidence was apparent from 1993 to 2008 (annual percentage change, 2%; 95% CI, -2% to 6%), and then the incidence significantly increased from 2008 to 2015 (annual percentage change, 20%; 95% CI, 11% to 31%) (Figure 1).

Conclusions:
U.S. hospitalization rates for stroke from opioid-related infective endocarditis were stable for nearly two decades but then sharply increased starting in 2008, coinciding with the emergence of the opioid epidemic.
Abstract 81: Tenecteplase is Non-Inferior to Alteplase for Acute Ischemic Stroke: Formal Meta-Analysis of 5 Completed Randomized Trials
Authors: Burgos Adrian M , Saver Jeffrey L
Published: January 2019

Background:
Tenecteplase (TNK), a newer lytic easier to administer than alteplase (ALT), was recognized in the 2018 US AHA/ASA Guideline Update as an alternative to ALT in patients with acute ischemic stroke (AIS). But this recommendation was advanced based on informal consideration, rather than formal meta-analysis, of completed RCTs.

Methods:
Systematic literature search identified all RCTs comparing TNK vs ALT; formal non-inferiority meta-analysis was conducted per PRISMA guidelines. Based on a prior non-inferiority lytic AIS trial (ENCHANTED), the primary meta-analytic endpoint was disability-free (mRS 0-1) outcome at 3m, with a non-inferiority margin of 0.88. Additional efficacy and safety outcomes were also analyzed.

Results:
The systematic search identified 5 trials enrolling 1585 patients (828 TNK, 757 ALT). Across all trials, mean age was 70.8, 58.5% were male, baseline NIHSS was mean 7.0, and time from last known well to treatment start was mean 148 mins. All ALT patients received standard 0.9 mg/kg dosing, while TNK dosing was 0.1 mg/kg in 6.8%, 0.25 mg/kg in 24.6%, and 0.4 mg/kg in 68.6%. For the primary endpoint, rates of disability-free (mRS 0-1) 3m outcome were: TNK 57.9% vs ALT 55.4%, RR 1.06 (95%CI 0.98-1.16) (Figure). The lower 95%CI bound fell well within the 0.88 non-inferiority margin. Similar results were seen for the additional efficacy endpoints: functional independence (mRS 0-2): TNK 71.9% vs ALT 70.5%, RR 1.02 (95% CI 0.96-1.09); and mRS shift analysis. For safety endpoints, lower event rates reduced power, but point estimates were also consistent with non-inferiority: Symptomatic ICH - TNK 3% vs ALT 3%, RR 0.96 (95% CI 0.56-1.65). Death – TNK 7.6% vs ALT 8.1%, RR 0.86 (95% CI 0.62-1.21).

Conclusion:
Accumulated clinical trial evidence provides strong evidence indicating that TNK is non-inferior to ALT in the treatment of AIS. These findings provide formal support for the recent guideline recommendation to consider TNK an alternative to ALT.
Abstract 83: Therapeutic Hypothermia in Patients With Acute Ischemic Stroke a Systematic Review of Prospective Controlled Studies
Authors: Kuczynski Andrea , Marzoughi Sina , Al Sultan Abdulaziz S , Goyal Mayank , Demchuk Andrew , Almekhlafi Mohammed A
Published: January 2019

Background:
Therapeutic hypothermia (TH) is a potent neuroprotectant in stroke models. We investigated its effects in published studies of ischemic stroke patients.

Methods:
This is a systematic review and meta-analysis of prospective randomized and non-randomized controlled studies published till July 2018. Full manuscripts reporting the type and outcomes of TH in acute ischemic stroke patients were included. We classified TH into systemic (body cooling) and selective (brain cooling). Two reviewers independently selected eligible studies and extracted the data. The main outcomes were neurological improvement (using the baseline to follow up NIHSS difference), complications, and mortality.

Results:
Of 2850 retrieved studies, 16 prospective controlled studies (813 patients) were included. Systemic TH was used in 13 studies (8 RCTs, 5 non-randomized parallel- controlled) while selective TH in 2 studies (1 RCT, 1 parallel- controlled), and one RCT used both types. Methods of cooling were highly variable and often multiple modalities were used. Median time from onset to TH start was 6 hours (IQR 7.5). Median target temperature was 33°C (range 32-35), which was reached within a median of 4 hours (IQR 3.7) in 9 systemic TH studies; while only one selective TH study reported the time to target temperature (17 minutes). Selective TH studies did not report enough outcomes to allow comparison with systemic TH. Outcomes are summarized in the forest plot and stratified by the study design (figure). Cardiac complications were higher in the TH vs controls (pooled relative risk “RR” 1.5, 95% CI 1.2 to 1.9, p 0.001). The pooled estimates suggest non-significant higher risks of pneumonia (RR 1.2, 95% CI 0.9 to 1.7, p 0.2) and death (RR 1.1, 95% CI 0.8 to 1.6, p 0.5) with TH. Eight studies reported baseline and follow-up NIHSS. The standardized mean difference was comparable (p = 0.413).

Conclusions:
TH was associated with complications without improving recovery or mortality rates.
Abstract 85: Intravenous Application of Autologous Preconditioned Mesenchymal Stem Cells for Ischemic Stroke: Final Results of a Randomized Controlled Trial
Authors: Chung Jong-Won , Moon Gyeong Joon , Kim Suk Jae , Kim Soo-Kyoung , Lee Jin Soo , Sohn Sung Il , Chang Won Hyuk , Kim Yun-Hee , Seo Woo-Keun , Kim Gyeong-Moon , Chung Chin-Sang , Bang Oh Young
Published: January 2019

Background:
Preclinical studies showed that stroke induces a process of recovery via the activation of MSCs, and culture methods for MSCs using stroke patient’s serum obtained during the acute phase of a stroke could constitute a novel MSC activation method. The present trial was conducted to test whether modified MSCs with autologous serum improve the recovery in patients with chronic stroke.

Methods:
In this prospective, randomized controlled trial, patients with moderate-to-severe disabling middle cerebral artery territory infarct observed within 90 days of the onset of symptoms were assigned, in a 2:1 ratio, to receive MSC therapy (intervention group) or standard care alone (control group), and followed for 3 months. The primary outcome was the score on the mRS at 3 months of treatment.

Results:
Totals of 39 and 15 patients completed the follow-up in the intervention and control groups, respectively. The mean interval between stroke onset to randomization was 20.2±17.2 days. The mean age was 63.4±13.9 and median NIHSS score was 11 [IQR, 8-17] in the study population. The baseline characteristics were well balanced in the two groups. The median mRS score at day 90 was 3 [IQR, 3-4] in the intervention group and 4 [IQR, 3-4] in the treatment group (P = 0.879). Proportional odds ratio for good functional outcome (mRS at 3 months of treatment) with the stem cell treatment was 0.65 (95% confidence interval, 0.18-2.44; P = 0.529), after adjusting for age, gender, and initial NIHSS scores. In secondary efficacy endpoint, no significant difference was found in the two groups measured by global Fugl-Meyer assessment. However, Fugl-Meyer score in the lower motor function showed significant improvement in the intervention group (delta between baseline and 90-day, 2.3 vs. 4.7; P<0.01). In terms of secondary safety outcomes, one patient in the control group experienced recurrent stroke, and one each patients of the intervention group had transient allergic reaction and one pneumonia.

Conclusions:
Among patients with chronic stroke, treatment with autologous preconditioned MSC was feasible but did not improve long-term functional outcome. Further studies are needed to select responders to MSC therapies and to improve efficacy of stem cell therapeutics.
Abstract 86: Nationwide Differences in Care and Outcomes of Acute Ischemic Stroke
Authors: Lunagariya Abhishek , Patel Achint , Dave Mihir , Jani Vishal , Tadi Prasanna , Huisa Branko , Hemmen Thomas
Published: January 2019

Background:
Acute Ischemic Stroke (AIS) remains a leading cause of mortality and morbidity in United States, and poses a major socio-economic burden. Efforts are underway to standardize systems of care for acute stroke treatment. We aim to assess if, despite the attempts towards standardization, regional difference in stroke care practice pattern, cost and/ or outcomes persist.

Methods:
Healthcare Cost and Utilization Project's Nationwide Inpatient Sample database was reviewed from 2002 to 2014. Hospitalizations with AIS were identified using ICD-9-CM codes 433.xx-436, tPA use by procedure code 99.10. Care is determined based on tPA utilization, length of stay, and cost of hospitalization. Outcomes are determined based on discharge disposition (home or facility) and death. These were further analyzed based on regions; Northeast, South, Midwest and West. Multivariate linear regression model and Cochran Armitage trend test used for the analysis.

Results:
AIS admissions increased throughout the US, more so in the South. There is an increase in tPA utilization all regions, which is significantly higher in the West compared to other regions. Midwest and South have significantly lower cost of hospitalization compared to West despite having higher length of stay.
(Graph).

Conclusion:
AIS care is noted to be remarkably non-uniform across the USA. This lack of uniformity seems to affect outcomes. Further studies are required to determine the causation of these findings.
Abstract 90: Long-Term Impact of Mechanical Thrombectomy Randomized Trials in a Comprehensive Stroke Center: Individual Ethical Dilemmas versus Societal Benefits
Authors: Nogueira Raul G , Rodrigues Gabriel M , Frankel Michael , Haussen Diogo C
Published: January 2019

Introduction:
Despite being the best sources of evidence for clinical interventions, randomized controlled trials (RCTs) may raise individual ethical concerns as often times control groups are left without treatments that might be perceived as beneficial. This becomes particularly challenging when centers must randomize patients to non-treatment versus modalities that were previously considered their standard of care. We aim to assess the overall societal costs and benefits related to two recent thrombectomy RCTs.

Methods:
Retrospective comprehensive stroke center database analysis. The number of MT was analyzed in the year prior and the year after the SWIFT-PRIME (all cases) and DAWN (6-24h cases) trials. The societal benefit was estimated based on (1) the number of control patients in the trials, (2) the number-need-to-treat (NNT) to achieve one additional good outcome (90-day mRS 0-2), and (3) the MT growth post trial completion.

Results:
SWIFT PRIME was presented in February 2015. The number of MT increased from 149 the year prior to 258 in the subsequent year (12.4±3.5 vs 21.42±5.48 patients/month, p=<0.001). Our site enrolled 12 patients including six controls. The NNT was 4. Thus, the net result was that we missed the opportunity to provide an uncertain benefit to 1.5 individuals in order to offer a definite benefit to an additional 109 patients and definitely benefit 27 of them.

DAWN was presented in May 2017. The number of 6-24-h MT increased from 91 the year prior to 134 in the subsequent year (7.7±3.4 vs. 11.2±3.5 patients/month, p=0.02). Our site enrolled 38 patients including 16 controls. The NNT was 3. Thus, the net result was that we missed the opportunity to provide an uncertain benefit to 5.3 individuals in order to offer a definite benefit to an additional 43 patients and definitely benefit 14.3 of them.

Conclusion:
A considerable benefit from thrombectomy RCTs could be measured at our center despite pre-existent aggressive treatment protocols and outreach programs confirming that individual ethical concerns should be nullified in face of equipoise. The overall societal benefit after a scientific breakthrough vastly surpasses the alleged burden of those relative few control cases.