bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 197: Practice and Preparedness for Endovascular Therapy in Acute Pediatric Stroke
Authors: Wilson Jenny L , Pergami Paola
Published: October 2018

Introduction:
Endovascular therapy (ET) for pediatric stroke has been described through case reports and series.

Hypothesis:
We aimed to determine how pediatric stroke neurologists practice regarding ET, and institutional readiness for this therapy.

Methods:
A link to a REDCap survey was emailed to the members of the International Pediatric Stroke Study (IPSS), which includes 58 centers and approximately 150 investigators, requesting responses from physicians who manage acute stroke.

Results:
We received 42 responses, with 12 countries represented. Most respondents were pediatric neurologists (n=33), with a median 10 years of experience treating pediatric stroke (SD 6.8). Fourteen (33%) had never recommended/performed ET, 10 (24%) had treated 1-2 patients, and 17 (40%) had treated 3-10 patients. All but one respondent would consider ET in a child. The mean minimum age for consideration of ET was 3 years (range 2-12 years), however most (n=27) had no set minimum age. Most used a time-window of 6 (33%) or 8 (24%) hours for anterior circulation stroke, though 38% had no set time window. Only 7 respondents reported a minimum NIHSS (median NIHSS 6, range 4-15), with the remainder reporting that deficits needed to be significant or the decision would dependent on the clinical scenario. The institutional analyses included only the responses of the 25 IPSS principal investigators to ensure just one response per institution. Fifty-six percent reported that ET would be performed at a children’s hospitals, 36% at an adjacent hospital, and 4% reported that ET would be performed off-site, with 67% responding that patients would need to travel > 10 miles. Only 3 reported working with interventional neuroradiologists who primarily or exclusively treated children, however 22 (88%) worked with adult interventional neuroradiologists comfortable treating children. Twenty (80%) reported having institutional ET guidelines in place or in development.

Conclusions:
Pediatric stroke neurologists were largely willing to consider ET, though many had limited experience. With varied clinician expertise and hospital settings, consensus-based guidelines would need to include minimum requirements for institutions to perform ET.
Abstract 20: Prevalence of Atherosclerotic Risk Factors Among Young Patients With Arterial Ischemic Stroke
Authors: Poisson Sharon N , Hills Nancy K , Sidney Stephen , Fullerton Heather J
Published: October 2018

Background:
Recent studies have suggested that arterial ischemic stroke (AIS) has increased over the last two decades in young populations, even while declining in older adults. This may be due in part to epidemic obesity in the US, since obesity can contribute to the development of atherosclerotic risk factors associated with stroke. The aim of this study was to determine the earliest age at which AIS can be linked to such risk factors.

Methods:
In the population of Kaiser Permanente Northern California, we retrospectively identified children and young adults (29 days-49 years) with possible AIS from 2000-2014 by searching stroke-related ICD-9 codes and text strings in radiology reports. Two stroke neurologists independently confirmed AIS by chart review using imaging and clinical criteria; medical records analysts abstracted data on atherosclerotic risk factors: hypertension, diabetes, hyperlipidemia, obesity and smoking. We calculated the prevalence of these risk factors among stroke cases stratified by age (decades).

Results:
We confirmed AIS in 128 children and 233 young adults. We found little documentation of atherosclerotic risk factors among stroke patients < 30 years old with the exception of smoking, which was reported in 13% of those in their twenties (Figure 1). Prevalence of risk factors increased between the ages of 30-39 and again from 40-49, by which time nearly half of those with stroke were hypertensive, 31% were reported to have hyperlipidemia, 28% and 30% were obese or smokers, respectively, and 25% had diabetes mellitus.

Conclusions:
These findings suggest that while atherosclerotic risk factors do not play a major role in AIS pathogenesis in the first three decades of life, their cumulative effects begin to contribute to stroke risk beyond this age. Earlier screening for poorly controlled risk factors that begin in childhood could lessen their impact on ischemic strokes in the 4
th
decade of life.
Abstract 25: Late Functional Recovery After Lacunar Stroke: a Population-Based Prospective Cohort Study
Authors: Ganesh Aravind , Wharton Rose M , Gutnikov Sergei A , Rothwell Peter M ,   Oxford Vascular Study
Published: October 2018

Background:
Non-acute interventions to enhance late stroke recovery are often tested initially in uncontrolled studies in patients with lacunar stroke owing to their low mortality and isolated motor deficits. It is often assumed that neurological recovery is near complete by 3 months after the stroke, but there have been few studies of the capacity for late recovery beyond 3 months.

Methods:
In 3-month ischaemic stroke survivors of the Oxford Vascular Study (OXVASC; 2002-2014), we examined changes in functional status (modified Rankin Scale [mRS], Rivermead Mobility Index [RMI], Barthel Index [BI]) in lacunar versus non-lacunar strokes from 3-60 months post-stroke, stratifying by age. We used logistic regression adjusted for age/sex/baseline disability to compare recovery (≥1 mRS grades, ≥1 RMI points and/or ≥2 BI points), particularly from 3-12 months.

Results:
Among 1,425 3-month survivors, the 234 lacunar stroke patients did not differ from others for outcome at 3 months (aOR for 3-month mRS>2 adjusted for age, sex, NIHSS, pre-stroke disability: 1.14, 95%CI 0.75-1.74, p=0.55). However, they were much more likely to demonstrate further recovery between 3 months and 1 year (aOR for mRS recovery adjusted for age, sex, and 3-month mRS: 1.64, 1.17-2.31, p=0.004). Results were similar on restricting the analysis to patients with 3-month mRS 2-4 (the range commonly recruited into recovery studies) and on excluding recurrent events (aOR for 1-year mRS recovery adjusted for age, sex, and 3-month-mRS: 2.28, 1.34-3.86, p=0.002). Similar results were seen with the BI and RMI (e.g. aOR for 1-year RMI recovery adjusted for age, sex, 3-month-RMI: 1.78, 1.20-2.64, p=0.004). There was no difference between lacunar and non-lacunar strokes in utilization of thrombolysis or hospital-based or further community-based rehabilitation services (NIHSS-adjusted OR: 0.97, 0.63-1.49, p=0.88).

Conclusions:
Lacunar strokes have greater potential for late functional recovery from 3-12 months post-stroke, supporting the focus of studies of restorative therapies on this group. However, such studies cannot assume that improvements after 3 months are treatment-related, and should therefore be randomized and controlled.
Abstract 32: Targeting Toxic Effects of Blood in Intracranial Hemorrhage Models With a Novel Nano-antioxidant/Chelator: A Ferroptosis Specific Treatment?
Authors: Derry Paul J , Dharmalingam Prakash , Mitra Joy , Hegde Muralidhar L , Nilewski Lizanne G , Mendoza Kimberly , Sikkema William K , Tour James M , Kent Thomas A
Published: October 2018

Introduction:
An attractive treatment target following intracerebral hemorrhage (ICH) are reactive oxidative stress (ROS) reactions occurring after contact with blood breakdown products, such as hemin and iron. Recent work suggests the ferroptosis cell death pathway predominates after ICH, likely secondary to ROS and free iron consuming key protection pathways. While studies directed at iron with deferoxamine (DEF) are underway, DEF suffers from poor cellular uptake, short shelf life and toxicity. We report a new version of our well tolerated poly(ethylene glycol)-ated carbon nanodrug, PEG-HCCs, previously demonstrated to have enormous antioxidant capacity and beneficial effects in trauma and ischemia (Samuel et al, PNAS 2015), tested here in ICH models.

Methods:
PEG-NH
2
and DEF have a terminal amine that can be covalently attached via an amide linkage to the HCC (Fig 1a) to achieve a loading of 25 DEF molecules per DEF-HCC-PEG. We tested the effectiveness of DEF-HCC-PEG against the consequences of hemin (5 μM) and iron (50 μM) in differentiated cultured SHSY-5Y cells and after SQ injection in mice following intracerebral hemolyzed blood. Doses used were based on prior work with PEG-HCCs.

Results:
DEF-HCC-PEG enhanced DEF stability for at least 2 weeks, presumably benefiting from the antioxidant HCC parent. Immunofluorescence demonstrated rapid and robust cellular uptake. When treated .5-1 hour after hemin or iron, DEF-HCC-PEG showed excellent effects against double stranded (ds) DNA damage (p53BP1 and yH2A.X expression) and cell death. Mitochondrial action potential was restored at 24 hours (Fig 1b, c, d). Similar beneficial effects were seen in-vivo. For example, dsDNA damage was significantly reduced (Fig 1e).

Conclusions:
We developed a novel nanodrug that addresses both key mechanisms of ferroptosis, ROS and excessive iron, while overcoming stability and uptake shortcomings of DEF alone. Studies assessing effect on functional outcome are underway.
Abstract 36: Secular Increases in Spontaneous Subarachnoid Hemorrhage during Pregnancy
Authors: LIMAYE KAUSTUBH , Patel Achint , Lahoti Sourabh , Kenmuir Cynthia , Torner James , Samaniego Edgar , Gutierrez Santiago Ortega , Hasan David , Jadhav Ashutosh , Derdeyn Colin P , Jovin Tudor , Adams Harold P , Leira Enrique
Published: October 2018

Introduction:
Our understanding of the epidemiology, outcomes and management of spontaneous subarachnoid hemorrhage (sSAH) in pregnancy is limited by small, single center series, which suggest a slightly higher morbidity and mortality. Larger population studies are needed to accurately estimate the risk of sSAH during pregnancy, and the associated morbidity and mortality.

Methods:
A retrospective analysis was performed utilizing the Nationwide Inpatient Sample (NIS) and Healthcare Cost and Utilization Project for the years 2002–2014. NIS is one of the largest administrative database and is designed to produce nationally weighted estimates. Female patients age 15-49 with spontaneous subarachnoid hemorrhage were identified with International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code 430.Pregnancy and maternal diagnosis were identified using pregnancy related ICD codes validated by previous studies. Cochran-Armitage trend test and parametric tests were utilized to analyze temporal trends and group comparisons.

Results:
There were 73,692 admissions for sSAH occurred in women age group of 15-49 years from 2002-14, of which 3,978 (5.4%) were in pregnant women. Over the 12 years of study period, proportion of sSAH during pregnancy increased from 4.16 % to 6.33% {p-trend <0.001} whereas in non-pregnant women has slightly reduced. In the study cohort, African American women had higher proportion of sSAH during pregnancy (8.19%) followed by Hispanic (7.11%) as compare to Caucasian (3.83%) women. Proportion of sSAH during pregnancy was highest in age group 20-29 years (20.07%) as compared to age 15-19 years (11.39 %), 30-39 years (10.01%) and age 40-49 (0.69%). sSAH during pregnancy had less in-hospital mortality as compare to non-pregnant women with sSAH (7.7% vs 17.4%; p:<0.001) in age controlled cohort and had higher discharge to home as compare to non-pregnant women with sSAH (69.87% vs 53.85% %; p:<0.001).

Conclusion:
There is an upward trend in the pregnancy related spontaneous SAH from 2002 to 2014. African American race and 20-29 years’ age group have higher preponderance of pregnancy related spontaneous SAH. Clinical outcomes of spontaneous SAH in pregnant women were better than in non-pregnant women.
Abstract 4: Safety of Intravenous Thrombolysis Among Patients Taking Direct Oral Anticoagulants: A Systematic Review and Meta-analysis
Authors: Shahjouei Shima , Tsivgoulis Georgios , Goyal Nitin , Alexandrov Andrei V. , Zand Ramin
Published: October 2018

Introduction:
Direct oral anticoagulants (DOACs) are increasingly being administered for atrial fibrillation and stroke prevention. The risk of symptomatic hemorrhagic transformation (sHT) following intravenous thrombolysis (IVT) among stroke patients who take DOACs is not clear.

Methods:
We conducted a systematic review of literature through six different resources—PubMed, Scopus, Embase, Clinicaltrial.gov, ICTRP and Cochrane library. The control groups included patients who took warfarin with INR<1.7 and patients without prior anticoagulation use. The heterogeneity between studies was assessed by χ2 test for heterogeneity. Meta-analysis was conducted by assuming the random-effect models.

Results:
A total of 12606 search results were retrieved. After reduction of the duplication, screening the title and abstracts and review of the candidate manuscripts, 44877 stroke patients were enrolled in this study—DOACs: 369 patients, warfarin: 1997 patients and 42511 patients without prior anticoagulation use. Pretreatment use of DOACs was not associated with increased risk of sHT compared to those who received warfarin (OR: 0.62; 95% CI: 0.23-1.71; P=0.74) or patients without prior anticoagulation use (OR: 0.89; 95% CI: 0.31- 2.56; P=0.98). Similarly, by restricting the results to last DOACs-IVT interval of 48 hours, DOACs was not associated with increased risk of sICH; neither in comparison with warfarin (OR: 0.63; 95% CI: 0.39- 1.02; P=0.82), nor with patients without prior anticoagulation use (OR: 0.89; 95% CI: 0.53- 1.48; P=0.36).

Conclusion:
Pretreatment use of DOACs appears not to be associated with increased risk of sHT among patients who presented with stroke symptoms and treated with IVT.
Abstract 5: Differences in Stroke Care Among Patients in the REGARDS Study by Admission to a Hospital Participating versus Not Participating in GWTG-Stroke
Authors: Howard George , Schwamm Lee H , Howard Virginia J , Rhodes J. David , Jasne Adam , Smith Eric , Kissela Brett , Fonarow Gregg , Kleindorfer Dawn O , Lackland Daniel T , Judd Suzanne E , Flaherty Matthew L , Cushman Mary , Albright Karen
Published: October 2018

Introduction:
Get With The Guidelines (GWTG)-Stroke is a stroke-care quality-improvement program implemented in 1,656 of 5,564 (30%) US hospitals; however, the assessment of the effectiveness of GWTG is limited by the lack of data from hospitals not participating in the program.

Methods:
The REasons for Geographic And Racial Differences in Stroke (REGARDS) is a national population-based longitudinal cohort study of 30,239 black & white participants aged 45+ years. Participants with an incident stroke were hospitalized in their local hospital. The proportion of patients receiving each of 10 quality-care metrics was calculated among the stroke victims admitted to hospitals with and without GWTG-Stroke. Logistic regression was used to adjust for participant and hospital differences of those seen in GWTG/non-GWTG hospitals.

Results:
Between 2003 and 2015, 207 of the 546 (38%) REGARDS participants suffering an ischemic stroke were treated in a hospital currently participating in the GWTG-Stroke program (the remainder in a non-GWTG hospital). Those hospitalized in a GWTG hospital were of similar age, race, sex, and risk factor profile as those in non-GWTG hospital (data not shown); however, fewer residents of the Stroke Belt were treated in a GWTG hospital (46.9% vs. 60.8%). Among the hospitals where participants were treated, the GWTG hospitals significantly larger (average 425 versus 289 beds) and were more likely to participate in GME resident training (59.9% versus 40.7%). After adjustment for these differences (see table), patients treated in GWTG hospitals were more likely to receive tPA (OR = 3.69), education on stroke risk factors and warning signs (OR = 1.52), swallowing evaluation (OR = 1.26), lipid profile evaluation (OR = 1.17), and evaluation by a neurologist (OR = 1.12).

Conclusions:
The care of stroke patients admitted to hospitals participating in the GWTG-Stroke were more likely to meet important stroke quality care metrics.
Abstract 50: Restarting Therapeutic Anticoagulation in Patients With Intracerebral Hemorrhage and Mechanical Heart Valves
Authors: Kuramatsu Joji B , Investigators RETRACE , Huttner Hagen B
Published: October 2018

Background:
Evidence is lacking regarding anticoagulation management in patients with mechanical heart valves(MHV) after intracerebral hemorrhage(ICH). Aim of the study was to investigate incidence rates of hemorrhagic and thromboembolic complications according to anticoagulation strategies and to define an optimal time-window to restart therapeutic anticoagulation(TA).

Methods:
Pooled individual-data(n=2504) from the German-wide multicenter study (RETRACE-program) were used to identify patients with MHV(n=166) and ICH under oral anticoagulation(OAC). The primary outcome comprised frequencies and incidence rates of new hemorrhagic complications according to treatment (restarted TA vs. no TA). Secondary outcomes consisted of thromboembolic complications, composite outcome (hemorrhagic & thromboembolic), timing of restarted anticoagulation. Incidence rates were compared by conditional maximum likelihood(CML)estimates. Adjusted analyses included ps-matching and multivariable Cox-regressions to identify an optimal timing of TA.

Findings:
Overall, 137 MHV-patients were eligible for outcome analyses and 66 restarted TA compared to 71 without TA during hospital stay. Patients on TA showed a significantly increased rate of hemorrhagic complications (TA=17/66(25·8%)
versus
no-TA=4/71(5·6%);p<0·01). Controlling for treatment crossover by analyzing actual days on treatment provided a significant CML-incidence rate-ratio of 10·31([95%CI:3·67-35·70];p<0·01) in disadvantage of TA. Adjusted analyses of TA-timing provided significant harm until day 14 after ICH(HR=7·06,[95%CI:2·33-21·37];p<0·01). Balancing both complications(hemorrhagic and thromboembolic) showed that TA was significantly associated with an increased rate for this composite outcome until day 6 after ICH(HR=2·51,[95%CI:1·10-5·70];p=0·03).

Interpretation:
In patients with MHV and anticoagulation-associated ICH restarted TA was related to increased hemorrhagic complications until two weeks after ICH. Optimal weighing - between least risks for thromboembolic and hemorrhagic complications - provided an earliest starting point of TA at day 6 which should be reserved for patients at high thromboembolic risk.
Abstract 54: Combined Vessel Wall and Perforator Imaging for Prediction of Stroke Subtype
Authors: Wu Fang , Yang Qi , Ma Qingfeng , Li Debiao , Song Haiqing , Fan Zhaoyang
Published: October 2018

Objective:
The aim of the present study was to evaluate atherosclerotic plaque characteristics and perforating arteries together by high-resolution magnetic resonance imaging (HRMRI) and to establish their relationship with different infarction patterns.

Methods:
Stroke patients with artery-to-artery (A-to-A) embolism or branch atheromatous disease (BAD) in middle cerebral artery territory were prospectively enrolled and whole-brain HRMRI was performed. The characteristics of the intracranial atheroma at the maximal stenosis and the numbers of ipsilateral perforating arteries were analyzed.

Results:
The study involved 59 first-time stroke patients (32 A-to-A embolism and 27 BAD) with 59 culprit plaques. Hyperintensity plaques (HIP) and plaque surface irregularity were more frequently observed in A-to-A embolism group than in the BAD group (
P
< 0.001 and
P
= 0.049, respectively). Patients with A-to-A embolism infarction had more severe stenosis than patients with BAD infarction (
P
< 0.001). Logistic regression analysis showed that HIP was an independent predictive factor for A-to-A embolism, with odds ratio of 6.858 (95% confidence interval 1.780 – 26.421;
P
= 0.005). Moreover, 54 patients (31 A-to-A embolism and 23 BAD) with good-quality images were included in the analysis of perforating arteries. The average number of visualized perforating arteries was significantly lower in patients with BAD compared with A-to-A embolism (
P
= 0.022).

Interpretation:
A-to-A embolism infarction have distinct vascular pathophysiologies in terms of plaque and perforating artery characteristics compared with BAD. Whole brain HRMRI enables the combination of vessel wall and perforating artery imaging which can predict future stroke types.
Abstract 55: The Probability of Ischemic Stroke Endovascular Targets: Extended Treatment Window for Women
Authors: Dula Adrienne N , King Ben T , Luby Marie L , Davis Lisa A , Warach Steven J
Published: October 2018

Introduction:
The decline in the probability of a therapeutic target over time from stroke onset may underlie the declining efficacy of stroke therapies over time. The persistence of a therapeutic target in some patients supports the use of imaging to identify candidates for treatments at later time windows. In light of the known sex differences in stroke subtype, severity and outcomes, we investigated sex differences in the probability of endovascular targets and its relationship of time from stroke onset.

Hypothesis:
The rate of endovascular targets is different in women than men and sex interacts with endovascular target timing.

Methods:
A prospective consecutive cohort of 1,092 ischemic stroke patients, with NIHSS > 3, in whom MRI performed within 24 hours of last known well (LKW), was evaluated for potential endovascular therapeutic (EVT) target: intracranial ICA or MCA-M1 occlusion on MRA. Time from LKW, sex, age and the presence of perfusion-diffusion mismatch were modeled as predictors of EVT target.

Results:
Overall, women had a significantly higher probability of presenting with endovascular targets with an adjusted odds ratio, OR, of 1.450, p=0.013. The probability of target detection decreased over time for both sexes, but the rates of decline differed significantly (p=0.034) in multivariate models, with targets consistently present at later times in women. A multivariate model of endovascular target adjusted for the presence of mismatch and the interaction between sex and mismatch resulted in a sex difference of 230% (odds ratio of 2.32, p=0.010), independent of time from onset.

Conclusions:
Women demonstrated prolonged presence of endovascular targets. In light of recent endovascular trial results, this identification of disparities in imaging biomarkers represents a step toward further refining the imaging selection of patients for acute reperfusion therapy and trials. The results implicate the need to stratify considerations of treatment intervention based on sex due to the potentially extended therapeutic time window for women.
Abstract 56: Frequency, Determinants, and Outcomes of Distal Emboli Related to Mechanical Thrombectomy for Acute Ischemic Stroke
Authors: Wong Gregory J , Yoo Bryan , Jahan Reza , Szeder Viktor , Liebeskind David S , Sharma Latisha , Duckwiler Gary , Tateshima Satoshi , Nour May , Shkirkova Kristina , Lee Jin-Moo , Starkman Sidney , Saver Jeffrey L ,   UCLA Thrombectomy Investigators
Published: October 2018

Introduction:
Clot fragmentation and distal embolization is a feared complication of mechanical thrombectomy treatment for acute ischemic stroke, but the frequency, determinants, and outcomes of distal emboli (DE) with modern endovascular reperfusion techniques is poorly characterized. Gradient refocused echo (GRE) MRI, performed before and after intervention, is a novel technique to directly visualize distal emboli and characterize their causes and consequences.

Methods:
We analyzed consecutive acute ischemic stroke thrombectomy patients who had MR imaging pre- and post-intervention. Distal emboli were defined as new post-procedure susceptibility vessel signs on GRE, within arteries distal to the target occlusion or within new territories.

Results:
Among 50 consecutive patients, age was 70.4 (±15.8), 44% were female, and NIHSS was 15 (IQR 8-19). Thrombectomy techniques include retrievers alone in 42%, aspiration alone in 8%, both retriever and aspiration in 50%, and other (e.g. angioplasty, wire maceration) in 22%. The rate of substantial reperfusion (mTICI 2b-3) was 84%. New distal emboli downstream in the territory of the target occlusion were noted in 22% of patients (single in 91% and multiple in 9%), while no emboli in a new territory were observed. Predictors of distal emboli were: pretreatment with IV tPA (present in 64% of patients with DE vs 26% without, p=0.03); and ICA target occlusion location (64% vs 28%, p=0.04). Nominal differences in the 3-month rate of severely disabled or dead outcome (mRS 5-6) did not reach statistical significance (44% vs 24%, p=0.40).

Conclusions:
In the modern neurothrombectomy era, distal emboli within the territory of the target occlusion occur in more than 1 in 5 patients, but embolization to new territories is very uncommon. Predictors of distal emboli are prior intravenous thrombolytic therapy (increasing clot friability) and ICA occlusion location (requiring manipulation of larger thrombi).
Abstract 61: Endothelium-Targeted Deletion of MicroRNA-15a/16-1 Cluster Promotes Post-Stroke Angiogenesis and Improves Long-Term Neurological Functions
Authors: Sun Ping , Zhang Kai , Hassan Sulaiman H , Tang Xuelian , Pu Hongjian , Liu Kai , Stetler R A , Chen Jun , Yin Ke-Jie
Published: October 2018

Introduction:
Angiogenesis promotes functional recovery and is associated with longer survival time in stroke patients. Accumulating studies have shown important roles for microRNAs (miRs) in regulating angiogenesis. Previously, we have demonstrated that miR-15a/16-1 cluster in endothelium negatively regulates hindlimb ischemia-induced angiogenesis. Here we further investigate its functional significance and molecular mechanism on post-ischemic cerebral angiogenesis.

Hypothesis:
Genetic deletion of miR-15a/16-1 cluster in endothelium increases cerebral angiogenesis and improves long-term neurological functions after ischemic stroke.

Methods:
EC-selective miR-15a/16-1 conditional knockout mice (EC-miR-15a/16-1 cKO) and WT controls were subjected to 1h MCAO followed by 3-28d reperfusion. Neurobehavioral outcomes were determined by the foot fault, rotarod, adhesive tape removal and Morris water maze tests. Brain capillary density and functional vessels were examined by CD31 and tomato-lectin immunofluorescent staining.
In vitro
angiogenesis assays, including capillary tube formation, scratch assay and BrdU cell proliferation were applied to cultured mBMECs with lentiviral loss- or gain-of-miR-15a/16-1 function. Pro-angiogenic factors were determined by 3’-UTR luciferase reporter assay, ELISA and western blotting.

Results:
Brain capillary density and the number of functional vessels in the ischemic penumbra of EC-miR-15a/16-1 cKO mice are higher than those of WT controls. Accordingly, EC-miR-15a/16-1 cKO mice exhibit improved sensorimotor and cognitive outcomes. Moreover, loss- or gain-of-miR-15a/16-1 function in mBMECs significantly increases or reduces tube formation, cell migration and cell proliferation, respectively. Mechanistically, gain-of miR-15a/16-1 function decreases luciferase reporter activity of VEGF, and remarkably reduces VEGF expression in mBMECs.

Conclusions:
Our findings suggest endothelial miR-15a/16-1 cluster is a negative regulator for post-ischemic cerebral angiogenesis and long-term functional recovery. Clinical intervention of miR-15a/16-1 mediated angiogenesis may be helpful for the development of novel neurorestorative therapies after ischemic stroke.
Abstract 67: RNA Expression Differentiates Large Artery And Cardioembolic Stroke: A Pilot Analysis From The BASE Trial
Authors: Jauch Edward C , Barreto Andrew D , Broderick Joseph P , Char Doug M , Cucchiara Brett L , Hicks William J , Jickling Glen C , June Jeffrey G , Liebeskind David S , Miller Joseph B , Morgan Judy , O’Neill John , Schoonover Tim , Sharp Frank , Peacock W. F , Lowenkopf Ted J , Huang David Y
Published: October 2018

Background:
An accurate test to differentiate large artery stroke patients from those with cardioembolic stroke would be of significant utility. Using the Biomarkers of Acute Stroke Etiology (BASE) trial (NCT02014896) dataset, our purpose was to determine if blood gene expression signatures accurately differentiate large artery stroke patients from those with cardioembolic stroke.

Methods:
The BASE trial enrolled suspected stroke patients presenting to 10 hospitals within 8 hours of symptom onset. Gold standard diagnosis was per local neurologist adjudication blinded to RNA testing. The final gold standard diagnosis was determined by an adjudication committee blinded to RNA test results. Whole blood, obtained in PAX tubes, was frozen at -20C within 72 hours and analyzed at a core lab (Ischemia Care, LLC, Blue Ash, OH) using Affymetrix HTA micro arrays. Significantly differentially expressed genes (p<0.005) were identified by calculating an empirical Bayes moderated t-statistic contrasting expression in large artery and cardioembolic stroke patients. Differentially expressed genes were used as input to a multi-layer perceptron neural network to derive a 66-gene diagnostic signature.

Results:
Overall, 32 patients were enrolled, 8 (25%) with large artery stroke and 24 (75%) with cardioembolic stroke; 50% were male, and median (IQR) age was 68.6 (47,88). Median (IQR) time from symptoms to presentation was 102.5 (14, 450) minutes. Coexistent pathology at presentation was atrial fibrillation in 13 (41%), heart failure 7 (22%), prior stroke 7 (22%), and coronary artery disease 8 (25%). The resulting gene signature distinguished large artery stroke from cardioembolic stroke; C-statistic 0.99 (0.94-1.0, 95% CI), sensitivity 0.91 (0.56-1.0, 95% CI), at a fixed specificity of 0.95, as observed in 5-fold cross validation of the training data.

Conclusion:
RNA expression differentiates large artery stroke patients from those with cardioembolic stroke, and may have therapeutic and outcome implications.
Abstract 68: Peripheral Markers of Blood-Brain Barrier Remodeling Predict Intracerebral Hemorrhage Etiology and Outcomes
Authors: Howe Matthew D , Zhu Liang , McCullough Louise D , Edwards Nancy J
Published: October 2018

Introduction:
Intracerebral hemorrhage (ICH) dramatically remodels the blood-brain barrier (BBB). However, BBB remodeling may differ between ICH cases due to location (lobar or deep hemorrhage) as well as etiology (hypertension, trauma or amyloid-β). This study addresses whether serum levels of BBB remodeling proteins, including matrix metalloproteases (MMPs), transforming growth factor-β (TGF-β) and fibronectin (FN), are biomarkers of ICH etiology and outcomes.

Hypothesis:
We hypothesize that serum MMP, TGF-β and FN levels are predictive of ICH etiology, severity and functional outcomes.

Methods:
Patient data (n=37 lobar, n=42 deep ICH patients) were abstracted from prospective ICH databases detailing admission data, radiology, hospital course (ICH score, NIH stroke scale [NIHSS], Glasgow Coma Scale [GCS]), and functional outcomes (modified Rankin Scale [mRS], Euroqol). Serum samples were drawn from admission to 10 days post-injury. Levels of TGF-β isoforms, MMPs and FN were measured by multiplex ELISA (11 cytokines total) and divided into early (<24hrs-5 days) and late (6-10 days) groups for analysis. P-values were obtained by Spearman correlation, Wilcoxon rank sum or Kruskal Wallis tests, with false discovery rate controlled at 0.05.

Results:
Early FN levels were lower in lobar than deep hemorrhages (
p=0.007
). Levels of early MMP-8, -9 and -10, as well as levels of TGF-β1, TGF-β2 and TGF–β3 positively correlated with initial neurological deficits (NIHSS,
p=0.005-0.039
). Additionally, late MMP-8 levels negatively correlated with edema (
p=0.018
). Furthermore, early MMP-1, TGF-β1 and TGF-β3 levels positively correlated with persistent neurologic deficits (mRS) at discharge and 90-days post-injury (
p=0.003-0.041
). Finally, females had lower early levels of MMP-8, -9 and -10 than males (
p=0.019, 0.019, 0.019
).

Conclusion:
BBB remodeling markers change with ICH location and patient sex, and are predictive of functional deficits and recovery. Specifically, these markers correlate with
(1)
the type and severity of initial injury,
(2)
the induction of secondary injury and
(3)
long-term functional recovery. This research improves our understanding of BBB responses to ICH, and may lead to novel biomarkers for ICH diagnosis and treatment.
Abstract 72: The Innate Immunity Receptor CD36 Contributes to Ischemic Brain Injury by Regulating Post-ischemic Caspase-1 Activity and Interleukin-1b Production in Microglia
Authors: Garcia-Bonilla Lidia , Janakiraman Mathangi , Shahanoor Ziasmin , Racchumi Gianfranco , Zhou Ping , Anrather Josef , Iadecola Costantino
Published: October 2018

CD36, an innate immunity receptor enriched in microglia, and IL-1β, a cytokine produced by the inflammasome, play a key role in ischemic brain injury by mediating the inflammatory component of the damage (J Neurosci, 35:4674, 2015; Nat Rev Immunol, 5:629, 2005). However, a link between post-ischemic CD36 activation and IL-1β has not been established. Microglial CD36 could contribute to ischemic brain injury by increasing the post-ischemic production of IL-1β. To test this hypothesis, male wild type (WT) and CD36
–/–
mice were subjected to transient middle cerebral artery occlusion (tMCAO), and infarct volume was assessed in cresyl violet-stained brain sections 72 hrs later. At 18 hrs after tMCAO, the expression of IL-1β mRNA in microglia, isolated by cell sorting, increased equally in WT (3.4±0.9) and CD36
–/–
mice (3.6±0.8, fold increase; p>0.05; N=3 pools, 3 mice/pool). However, the levels of mature IL-1β protein, measured by cytometric bead arrays in the ischemic hemisphere, were higher in WT mice (104±30 pg/g) than in CD36
–/–
mice (59±14 pg/g; p<0.05 from WT; n=5/group). Since caspase-1 regulates active IL-1β levels by cleaving the mature form from its pro-peptide, we next analyzed microglial caspase-1 activity using a flow cytometry-based assay. The percentage of active caspase-1 was greater in WT (4.0±0.2%) than in CD36
–/–
microglia (2±0.2 %; p= 0.001; n=5/group). Therefore, the reduction in infarct volume in CD36
–/–
mice could be due to reduced caspase-1 and attendant IL1β signaling. Consistent with this hypothesis, pretreatment with recombinant IL-1β receptor antagonist (2 μg into the cerebral ventricles) decreased infarct volume in WT (47±5 vs. 32±5 mm
3
; p<0.5; n=8-5), but not in CD36
–/–
mice (23±6 vs. 21±5 mm
3
; p> 0.5; n=5). We conclude that CD36 localized to microglia is a key determinant of post-ischemic IL-1β production by regulating caspase-1 activity. Although the CD36 ligand(s) and the molecular mechanisms linking CD36 to caspase-1 activation remain to be established, this study identifies microglial CD36 signaling as a previously unrecognized pathway for inflammasome activation and IL-1β production after cerebral ischemia, and a viable target to mitigate the damaging effects of post-ischemic inflammation.
Abstract 75: Plasma Biomarkers of Inflammation and Angiogenesis Predict Cerebral Cavernous Malformation Symptomatic Hemorrhage or Lesional Growth
Authors: Girard Romuald , Zeineddine Hussein A , Fam Maged D , Cao Ying , Shi Changbin , Moore Thomas , Lightle Rhonda , Stadnik Agnieszka , Shenkar Robert , Polster Sean P , Whitehead Kevin J , Li Dean Y , Awad Issam A
Published: October 2018

Introduction:
The clinical course of cerebral cavernous malformations (CCMs) is highly unpredictable, with a limited number of cross sectional studies correlating pro-inflammatory genotypes and plasma biomarkers with prior disease severity. We hereby hypothesize that a panel of plasma biomarkers, with reported role in the physiopathology of CCM, may predict subsequent clinically relevant disease activity.

Methods:
This was a single-site prospective observational cohort study, without planned intervention. Non-fasting peripheral venous blood samples from 55 patients (25 with sporadic and 30 with familial CCM) were collected. Twenty-four plasma biomarkers were quantified and analyzed regarding their predictive association with the occurrence of a symptomatic hemorrhage or lesional growth within a year following the blood sample. We generated the receiver operating characteristic (ROC) curves and area under curves (AUC) for each biomarker individually and for each weighted linear combination of relevant biomarkers. The best model to predict lesional activity was selected as that minimizing the Akaike Information Criterion (AIC), representing parsimonious model offering the best fit to the data with the fewest number of predictors.

Results:
Eleven patients experienced lesional activity events (5 symptomatic bleeds and 10 lesional growths) within a year after the blood draw. These patients had lower levels of CD14 (p=0.05), IL6 (p=0.04), ROBO4 (p=0.03) and VEGF (p=0.0003), along with higher IL1β (p=0.008) plasma levels. Among the 35 weighted linear combinations of these 5 biomarkers, the best model (with the lowest AIC value=25.3), was the combination including CD14, IL1β, VEGF and ROBO4, predicting a symptomatic bleed or lesional growth with a sensitivity of 86% and specificity of 88% (AUC=0.90, p<0.0001).

Conclusion:
This is the first study reporting a predictive association between plasma biomarkers and subsequent CCM disease clinical activity. This may be applied in clinical prognostication, and in the stratification of cases in clinical trials.
Abstract 78: Time to Endovascular Treatment and Outcomes in the DAWN Trial
Authors: Nogueira Raul G , Haussen Diogo C , Jadhav Ashutosh , Liebeskind David S , Budzik Ronald F , Bonafe Alain , Bhuva Parita , Yavagal Dileep R , Hanel Ricardo A , Ribo Marc , Cognard Christophe , Sila Cathy A , Hassan Ameer E , Frankel Michael , Smith Wade S , Saver Jeffrey L , Jovin Tudor G ,   for the DAWN Investigators
Published: October 2018

Introduction:
It is well-established that, within 0-6 hours, the benefit of thrombectomy rapidly decays over time. The DAWN trial demonstrated that, in the presence of clinical-core mismatch (CCM), thrombectomy remains beneficial within 6-24 hours. We aim to assess the effect of time to randomization on outcomes in the DAWN.

Methods:
We used traditional multivariate logistic regression controlling age and NIHSS at baseline adding an interaction between Trevo and Time last seen well and then generated the odds ratio of the interaction of Trevo and time at particular time points.

Results:
Each 1-hour delay to treatment markedly impacted functional independence (OR,0.89 [95% CI 0.75 to 1.03]). Although the odds of functional independence at 90 days (mRS 0-2) with thrombectomy declined with longer time from last seen well (TLSW) to puncture, treatment benefit was observed through 24 hours : cOR at 8 hours, 6.8 (95% CI, 2.1 to 22.0), absolute risk difference (ARD) for mRS 0-2, 24.4%; cOR at 12 hours, 9.4 (95% CI, 4.1 to 21.6), ARD, 35.1%; cOR at 16 hours, 13.0 (95% CI, 4.1 to 41.3), ARD, 37.2%; cOR at 20 hours, 17.8 (95% CI, 2.9 to 110.4), ARD, 36.5%; cOR at 24 hours, 24.6 (95% CI, 1.9 to 322), ARD, 35.5% (Figure). Comparable analysis using time from symptoms first observed (TSFO) yielded similar results.

Conclusion:
In patients selected based on CCM, treatment benefit persists all the way to 24 hours; however, both the chances of good outcome and the overall treatment effect continuously drop over time.
Abstract 82: Endovascular Therapy Eligibility in the Advent of DAWN and DEFUSE-3 Results
Authors: Khatri Pooja , Jovin Tudor , Noqueira Raul , Albers Gregory W , Jadhav Ashutosh , Moomaw Charles , Alwell Kathleen , Khoury Jane , Heldner Mirjam , Urs Fischer , Adeoye Opeolu , Flaherty Matthew , Woo Daniel , Ferioli Simona , Mackey Jason , Martini Sharyl , De Los Rios La Rosa Felipe , Broderick Joseph , Vagal Achala , Kissela Brett , Kleindorfer Dawn
Published: October 2018

Introduction:
We previously estimated that, among 2297 ischemic stroke patients in our 1.3 million metropolitan population in 2010, 159 were potentially IV rtPA (IVT)- and 29 were endovascular (EVT)-eligible based on AHA Class I, Level A guideline criteria; this projected to 31,000 IVT and 5600 EVT-eligible patients in the US annually. Given recent DAWN and DEFUSE 3 results suggesting EVT benefit beyond 6 hours to 24 hours, we aim to estimate the number of additional EVT-eligible patients in our region.

Methods:
We ascertained all hospitalized AIS patients ≥18 years old in 2010 using ICD-9 codes 430-436 within Greater Cincinnati/Northern Kentucky (GCNK) population; all cases were physician-reviewed. GCNK patients were considered potentially DAWN-eligible if ≥18 years, presenting within 5 to 23 hours from onset, and with a baseline NIHSS ≥10, prestroke mRS 0-1, platelets ≥50k, glucose 51-399 mg/dL, INR ≤3.0 and creatinine ≤3.0. Based on single-center (Pittsburgh) data, an eligibility proportion of 22% for both large vessel occlusion (LVO) and clinical-imaging-mismatch (CIM) was then applied. Additional patients eligible by only DEFUSE 3 criteria were identified within the GCNK population by including NIHSS 6-9, prestroke mRS 2, and an upper age of 90 years among patients presenting within 5 to 15 hours. Based on single-center (Bern) data, LVO rates by NIHSS score were applied. Based on DEFUSE 3 screening estimates, a 50% target mismatch (TTM) rate was then applied.

Results:
Among 2297 ischemic stroke patients hospitalized in our region, 34 were potentially DAWN-eligible, including 8 estimated to meet LVO and CIM criteria, and 19 additional patients were DEFUSE 3-eligible, including 4 estimated to meet LVO and TMM criteria.

Conclusion:
The 6-24 hour EVT treatment window may increase EVT eligibility by approximately 40% in the GCNK metropolitan region annually, although this estimate is limited by small sample sizes and inferences. Estimates will be updated as further data become available by the time of presentation of this abstract.
Abstract 83: Successful Recanalization With Intravenous Thrombolysis Preceding Mechanical Thrombectomy in Large Vessel Occlusions: A Systematic Review and Meta-Analysis
Authors: Tsivgoulis Georgios , Katsanos Aristeidis H , Schellinger Peter D , Köhrmann Martin , Varelas Panos , Magoufis Georgios , Paciaroni Mauricio , Caso Valeria , Alexandrov Anne W , Gurol Edip , Alexandrov Andrei V
Published: October 2018

Introduction:
Although current guidelines advocate pretreatment with intravenous thrombolysis (IVT) in all eligible patients with emergent large vessel occlusion (ELVO) prior to mechanical thrombectomy (MT), there are observational data questioning the efficacy of IVT pretreatment in patients with ELVO. One of the main arguments in favour of IVT pretreatment is the potential for tPA-induced successful recanalization (SR) before the onset of endovascular procedure averting the need for MT.

Methods:
We performed a systematic review in MEDLINE and SCOPUS databases for randomized clinical trials (RCTs) and observational cohorts providing rates of SR with IVT in patients with ELVO before the initiation of MT. We also performed subgroup analyses according to study type (RCTs or observational) and according to the inclusion per-protocol of patients with tandem (intracranial/extracranial) occlusions.

Results:
We identified 10 eligible studies (7 RCTs & 3 observational cohorts), including 1227 ELVO patients (median NIHSS score: 17). SR following IVT and before MT was documented in 9% (95%CI: 5%-14%; I
2
=85.4%) of ELVO patients, with no significant (p=0.263) differences among RCTs and observational cohorts (Figure). Higher tPA-induced SR rates were identified in studies reporting exclusion of patients with tandem occlusions compared to the rest (15%, 95%CI: 6%-26% vs 5%, 95%CI: 2%-9%; p for subgroup difference=0.052).

Conclusions:
Pretreatment with IVT in ELVO patients eligible for MT results in SR in almost one out of ten cases, negating the need for additional endovascular reperfusion. Tandem occlusions appear to be the least responsive to IVT pretreatment.
Abstract 86: Morphological Evolution of Symptomatic Intracranial Atherosclerotic Plaques: a 10-year Longitudinal Study by 3-Dimensional Rotational Angiography
Authors: Leng Xinyi , Wang Li , Zou Xinying , Soo Yannie O , Chan Anne Y , Ip Vincent H , Fan Florence S , Mok Vincent C , Wong Lawrence K , Yu Simon C , Leung Thomas W
Published: October 2018

Introduction:
Patients with symptomatic high-grade intracranial atherosclerotic disease (ICAD) are at risk of stroke recurrence even under stringent medical therapy. Understanding how the plaque evolves in these patients may help prevent recurrent stroke.

Methods:
In a prospective, multicenter referral, longitudinal study, we recruited 40 patients (mean age = 61.1 years) with symptomatic high-grade ICAD (70-99% stenosis) confirmed by 3-dimensional rotational angiography (3DRA) from July 2007 to Feb 2016. All patients had 3DRA at baseline and 1 year. All patients received contemporary optimal medical treatment. We assessed the morphological features of qualifying ICAD lesions in the paired 3DRA images. A plaque was considered progressive if the plaque surface evolved from being smooth to irregular/ulcerated or from irregular to ulcerated, or the affected artery occluded at 1 year. We explored factors associated with plaque progression.

Results:
The qualifying ICAD lesions were in average 77.7% stenosis at baseline. The point of maximum stenosis was located at the distal end of the plaques in 21 (52.5%) cases, and 38 (95.0%) patients had eccentric plaques at baseline. The mean upstream plaque shoulder angulation was 46.4° at baseline. Eleven (27.5%) ICAD lesions progressed from baseline to 1 year. Longer lesions (p=0.038) with a smaller upstream plaque shoulder angulation (p=0.038) and the maximum stenosis locating at the distal end of the lesion (p=0.056) at baseline were more likely to progress in the plaque morphology over 1 year.

Conclusions:
Under modern medical treatment, although the majority of symptomatic ICAD lesions might regress over 1 year after an index stroke, lesions of a longer length, a smaller upstream angulation, or with the maximum stenosis located at the distal end were more likely to progress in terms of the plaque morphology.
Abstract 87: Population-Level Analysis of the Impact of SAMMPRIS on Intracranial Atherosclerosis Management
Authors: Alenzi Bader , Dialeda Taylor , Vahidy Farhaan S , Chen P. Roc , Liang Conrad W , Sarraj Amrou , Savitz Sean I , Sheth Sunil A
Published: October 2018

Introduction:
Released in 2011, the SAMMPRIS trial found significantly lower rates of stroke or death in patients with symptomatic intracranial atherosclerotic disease (sICAD) treated with medical management (MM) vs. percutaneous angioplasty and stenting (PTAS), 5.8% vs. 14.7%. However, the intensity with which MM was pursued has called into question the generalizability of the study. We report temporal trends in treatment for sICAD and 30-day event rates in a state-wide cohort, spanning the pre- and post-period of the SAMMPRIS trial.

Methods:
Using the Healthcare Cost and Utilization Project database on all discharges from acute care hospitals in Florida (2005-2014), we identified patients admitted for sICAD (defined as ICAD with TIA or stroke), and PTAS or angioplasty alone (AA). Patients were excluded for any diagnosis of ICH, SAH, AVM, aneurysm or trauma.

Results:
Among 8,745 patients with sICAD, 541 (6.2%) were treated with PTAS and 230 (2.6%) with AA. The mean(SD) age was 74±13 years, 52% were female, and 60% were white, 24% black and 13% Hispanic. 22% of patients were smokers, 43% had diabetes, and 86% HTN. All patients carried a diagnosis of dyslipidemia. Over the 10-year period, the number of patients diagnosed with sICAD increased; PTAS and AA treatments increased until 2011 and then decreased (Figure). 30-day rates of stroke, hemorrhage or death were comparable in the PTAS vs. AA groups (15.9% vs. 19.5%, p=0.24), and significantly lower in sICAD patients treated without PTAS or AA (6.0%, p<0.0001 vs. both PTAS and AA).

Conclusion:
Analysis of population-level data demonstrates reduction in the use of PTAS and angioplasty coinciding with the release of SAMMPRIS. Importantly, 30-day event rates for patients with sICAD treated with MM were comparable to the low rates achieved in the trial.