bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 149: Elevated mir-9 in Cerebrospinal Fluid is Associated With Poor Functional Outcome After Subarachnoid Hemorrhage
Authors: Bache Søren , Rasmussen Rune , Wolcott Zoe , Rossing Maria , Møgelvang Rasmus , Tolnai Daniel , Hassager Christian , Forman Julie Lyng , Køber Lars , Nielsen Finn Cilius , Kimberly W. Taylor , Moller Kirsten
Published: January 2019

Introduction:
Aneurysmal subarachnoid hemorrhage (SAH) has a lower incidence than ischemic stroke but affects younger individuals with a high mortality and a high frequency of complications in survivors. The underlying pathways that contribute to poor functional outcome are poorly understood.

Hypothesis:
MicroRNA (miRNA) changes in cerebrospinal fluid (CSF) are associated with the occurrence of delayed cerebral ischemia and poor functional outcome after SAH.

Methods:
Using real-time polymerase quantification chain reaction (RT-qPCR), 43 selected miRNAs were measured in daily CSF samples from a discovery cohort of SAH patients admitted to Rigshospitalet, Copenhagen, Denmark, and compared to neurologically healthy patients. Findings were validated in CSF from a replication cohort of SAH patients admitted to Massachusetts General Hospital, Boston, Massachusetts. Outcome measures were delayed cerebral ischemia (DCI), as well as functional outcome three months after ictus measured by the modified Rankin Scale score.

Results:
MiRNAs were quantified and passed RT-qPCR quality control in 427 CSF samples from 63 SAH patients in the discovery cohort, in 104 CSF samples from 63 SAH patients in the replication cohort and in 11 CSF samples from 11 neurologically healthy patients. Elevated miR-9-3p was associated with a poor functional outcome in both the discovery cohort (p < 0.0001) after correction for multiple testing (q < 0.01) and in the replication cohort (p < 0.01). Furthermore, elevated miR-9-5p was associated with a poor functional outcome in the discovery cohort (p < 0.01) after correction for multiple testing (q < 0.05). No miRNA was associated with DCI in both cohorts.

Conclusions:
Mir-9-3p is elevated in the CSF following SAH and this elevation is associated with a poor functional outcome.
Abstract 155: Vagus Nerve Stimulation Activates the Critical Brain Nuclei Involved in Ischemic Neuroprotection
Authors: Ay Ilknur , Chen Yin-Ching , Kwong Kenneth , Ay Hakan
Published: January 2019

Objectives:
Stimulation of the vagus nerve in the neck provides up to 50% reduction in infarct volume after middle cerebral artery occlusion (MCAO) in rats. The mechanism of neuroprotection by vagus nerve stimulation (VNS) is not known. We sought to investigate the brain circuitry underlying ischemic protection activated by VNS using functional MRI (fMRI).

Methods:
We performed right vagus nerve stimulation using a pair of implantible electrodes in healthy (n=6) and MCAO (n=8) male and female rats. We used ultrahigh-field fMRI (9.4T) to assess fMRI response to VNS at the nucleus tractus solitarius (NTS) and the cerebellar fastigial nucleus (FN) using 30sec ON (0.5ms, 0.5mA), 270sec OFF block-design (TR=1s, TE=20ms, field of view=2.5cm). We assessed optimal frequency to maximize NTS activation by delivering stimuli that ranged between 1Hz and 50Hz.

Results:
VNS induced increased BOLD signal in both NTS and FN (Figure). The intensity of activation was dependent on stimulation frequency: 1Hz stimulation failed to produce activation in NTS whereas 25Hz induced the maximum BOLD response. Functional connectivity analysis in healthy rats revealed that VNS provoked broader functional connectivity across the brain. In MCAO rats, basal functional connectivity was enhanced in the intact hemisphere but reduced in the ischemic hemisphere. After VNS, the previously enhanced connectivity in the intact hemisphere was reduced while the functional connectivity in the ischemic hemisphere was enhanced.

Conclusion:
This study shows that VNS activates NTS and FN, the two key structures that are linked to neurogenic neuroprotection, via a stimulation frequency-dependent effect. Our findings also indicate that VNS restores reduced functional connectivity in the ischemic hemisphere after MCAO.
Abstract 157: Peptidase Neurolysin Functions to Preserve the Brain After Ischemic Stroke in Mice
Authors: Jayaraman Srinidhi , Rashid Mamoon , Wangler Naomi J , Villalba Heidi , German Nadezhda , Arumugam Thiruma V , Abbruscato Thomas J , Karamyan Vardan T
Published: January 2019

The aim of this study was to assess the functional role of peptidase neurolysin (Nln) in the brain after ischemic stroke. Nln is known to inactivate bradykinin, substance P, neurotensin, and angiotensin II, which are cerebrotoxic in the ischemic brain, and to generate angiotensin-(1-7) and Met/Leu-enkephalins, which are cerebroprotective/restorative peptides. To study the functional significance of Nln upregulation in the post-stroke brain we utilized a specific inhibitor of Nln, Agaricoglyceride A (AgaA), in a mouse MCAO model of stroke. Administration of AgaA (10 and 50 mg/kg, i.p.) to mice 1 h after reperfusion (1 h occlusion) aggravated stroke injury measured by increased infarct and edema volume (p < 0.01) and neurological deficit (p < 0.01), in a dose-dependent manner at 24 h after stroke. In this setting, AgaA resulted in a dose-dependent inhibition of Nln in the ischemic but not in the contralateral hemisphere, which, based on preliminary experiments, was also accompanied by increased levels of Nln substrate neuropeptides. In a reverse approach, we developed an adeno-associated virus serotype 2/5 vector encoding mouse Nln driven by cytomegalovirus enhancer/chicken β-actin hybrid (CAG) promoter (AAV2/5-CAG-Nln) to overexpress Nln in the mouse brain prior to stroke. Applicability of AAV2/5-CAG-Nln to transduce catalytically active Nln was confirmed in mouse primary cortical neurons and in mice. In the later experiment, overexpression of Nln in the mouse brain was also accompanied by decreased levels of Nln substrate neuropeptides. Two weeks after
in vivo
transduction using the AAV5-CAG-Nln, or a control AAV5-CAG-eGFP vector (intrastriatal administration; 1.5 x 10
11
genome copies) mice were subjected to MCAO (1 h occlusion followed by 72 h reperfusion). The results of these experiments revealed that abundance of Nln in the brain protects animals from stroke injury measured by reduced infarct and edema volume (p < 0.01 and 0.05, respectively), and improved neurological deficit (p < 0.05). Based on these observations and the knowledge about endogenous substrates of Nln, we view this peptidase as one of brain’s self-protective mechanisms directed towards preservation and recovery of brain after stroke.
Abstract 164: Early Infarct Growth Correlates With Both Collateral Status and Clinical Outcomes After Thrombecomy
Authors: Sarraj Amrou , Savitz Sean , Sitton Clark , Hassan Ameer , Cai Chunyan , Pujara Deep , Grotta James , Imam Bita , Chen Peng R , Cutter Gary , Reddy Sujan , Kamal Haris , Abraham Michael , McCullough Louise , Lansberg Maarten , Gupta Rishi , Albers Gregory
Published: January 2019

Background:
We assessed the correlation between early infarct growth rate (EIGR), collaterals and clinical outcomes following endovascular thrombectomy (EVT).

Methods:
In a prospective multicenter cohort study of imaging selection for EVT (SELECT), consecutive patients with large vessel occlusion (ICA, M1, M2) presenting up to 24 hr from last known well (LKW) were enrolled at 9 centers. CT perfusion was obtained prior to EVT. EIGR was defined as CTP ischemic core volume (rCBF<30%) divided by the time from LKW to baseline CTP. The optimal EIGR cutoff was identified by maximizing the sum of the sensitivity and specificity to predict favorable outcome (90 day mRS 0-2). Slow progressors were defined as having an EIGR below the cutoff. Good collaterals were defined on CTP as a hypoperfusion intensity ratio (HIR) <0.4 and on CTA as collateral score
>
2.

Results:
Of 445 enrolled, 284 received EVT. The optimal EIGR was <10 ml/hr; 199 were slow and 85 fast progressors. Fast progressors had higher median NIHSS (19 vs. 15, P< 0.001), earlier median LKW to puncture 180 vs. 266 min, P< 0.001,. Slow progressors had better collaterals on both CTP and CTAs: HIR aOR 4.97 (2.3-10.7), p<0.001; CTA collaterals 3.02 (1.6-5.7), p=0.001. EIGR was an independent predictor of good outcome after adjusting for age NIHSS, LKW to puncture, mTICI and tPA aOR 0.73 (95% CI 0.61-0.89, p=0.001). Slow progressors were 3.5 times more likely to achieve mRS 0-2 after EVT aOR 3.51 (95% CI 1.8-6.7, p<0.001). Fast progressors had substantially worse clinical outcomes both in early and late time window (Table 1). The odds of good outcome decreased by 14% for each 5 ml/hour increase in EIGR, OR:0.87(0.80-0.94), p<0.001 and the probability of good outcome declined more rapidly in fast progressors (Figure 1).

Conclusion:
The early infarct growth strongly correlates with both collateral status and clinical outcomes after EVT. Fast progressors have a much more rapid decline in favorable outcomes at late treatment times.
Abstract 17: Apolipoprotein E and Intracerebral Hemorrhage: A Trans-Ethnic Meta-Analysis
Authors: Marini Sandro , Morotti Andrea , Pezzini Alessandro , Moomaw Charles J , Flaherty Matthew L , Montaner Joan , Jimenez-Conde Jordi , Cuadrado-Godia Elisa , Slowik Agnieszka , Pichler Alexander , Tirschwell David L , Selim Magdy , Brown Devin L , Silliman Scott L , Worrall Bradford B , Meschia James F , Kidwell Chelsea S , Testai Fernando D , Kittner Steven J , Deary Ian J , Al-Shahi Salman Rustam , Sudlow Catherine L , Klijn Catharina J , Fernandez-Cadenas Israel , Lindgren Arne , Goldstein Joshua N , Viswanathan Anand , Greenberg Steven M , Falcone Guido J , Langefeld Carl D , Woo Daniel , Rosand Jonathan , Anderson Christopher D ,   on behalf of the International Stroke Genetics Consortium
Published: January 2019

Introduction:
Risk of lobar and non-lobar intracerebral hemorrhage (ICH) varies among blacks, whites and Hispanics. We sought to determine whether these differences could be due to variability in the effects of Apolipoprotein E (APOE) epsilon (ε) alleles, the most potent genetic risk factor for ICH.

Methods:
Primary ICH cases and controls were collected from US and European sites contributing to the International Stroke Genetic Consortium (ISGC). We meta-analyzed the effects of APOE allele status on ICH risk applying a two-stage clustering approach based on race/ethnicity and the contributing study. Models were adjusted for age, sex, history of hypertension, hypercholesterolemia, warfarin, statin and antiplatelet use, smoking and alcohol use. A propensity score analysis was used to model the influence of APOE against the burden of hypertension across races/ethnicities.

Results:
13,124 subjects (54.5% male, median age 66 years) were included. In whites, APOE ε2 (odds ratio (OR)=1.85, 95% confidence interval (CI)=1.27-2.69, p<0.001) and APOE ε4 (OR=1.94, 95% CI=1.58-2.38, p<0.001) were independently associated with lobar ICH risk, however within self-identified Hispanics and blacks, no associations were found (Figure). After propensity score-matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among whites (OR=1.12, 95% CI=1.08-1.17) and Hispanics (OR=1.07, 95% CI=1.01-1.15, p=0.01), but not blacks (OR=1.02 95% CI=0.98-1.07, p=0.251). APOE ε2 and ε4 did not show an effect on non-lobar ICH risk in any race/ethnicity.

Conclusion:
APOE ε4 and ε2 alleles affect lobar ICH risk variably by race and ethnicity. Associations are confirmed in whites but can be shown in Hispanics only when the excess burden of hypertension is propensity score-matched. Further studies are needed to explore interactions between APOE alleles and environmental exposures that vary by race and ethnicity in representative populations at risk for ICH.
Abstract 29: Low Socioeconomic Status and Longer Home-to-Hospital Distances Are Associated With Less Timely Treatment of Ischemic Stroke
Authors: Ader Jeremy , Wu Jingjing , Fonarow Gregg C , Smith Eric E , Shah Shreyansh , Xian Ying , Bhatt Deepak L , Schwamm Lee H , Reeves Mathew J , Matsouaka Roland A , Sheth Kevin N
Published: January 2019

Introduction:
Many patients with ischemic stroke do not receive tissue plasminogen activator (tPA) due to late arrival to the hospital. We assessed whether socioeconomic status (SES) and home-to-hospital driving-times impact tPA administration and timeliness of treatment, and evaluated the interaction between SES and driving time.

Methods:
We conducted a retrospective observational study using data collected from Get With The Guidelines-Stroke between January 2015 to March 2017. The study included 118,683 ischemic stroke patients age ≥18 from 1,489 US hospitals across the US. All patients arrived via EMS from a non-healthcare facility within 24 hours of symptom onset. We estimated patient SES using zip code median household income, and calculated the driving time between each patient’s home zip code and the hospital where they were treated, using the Google Maps Directions Application Programing Interface. The primary outcomes were tPA administration and onset-to-arrival time (OTA), analyzed using hierarchical multivariable logistic regression models with random intercepts to account for clustering at the hospital level.

Results:
Patients had a median OTA of 155 minutes (64-484) and 26.5% were treated with tPA. Zip code median income quintiles were $46,400, $52,136, $57,895 and $70,150. Driving time quartiles were 13.5, 20.7 and 32.1 minutes. SES was not significantly associated with tPA administration (p=0.47) or OTA (p=0.31). However, lower SES was associated with longer symptom onset to treatment time (p=0.02) and higher in-hospital mortality (p=0.004). Longer driving time (comparing top to bottom quartile) was associated with a lower rate of tPA administration (OR 0.83, 0.79-0.88, p <0.001), and longer OTA (OR 1.30, 1.24-1.35, p<0.001). Lower SES was associated with slightly longer driving times (r = -0.04, p=0.004), but there was no interaction between SES and driving time for either OTA (p=0.11) or rate of tPA administration (p=0.61).

Conclusions:
Longer home-to-hospital driving times were associated with lower rates of tPA and longer OTA, however SES did not modify these associations.
Abstract 30: Safety and Feasibility of the “Flying Intervention Team” Model for Endovascular Thrombectomy in Rural Areas: Pilot Phase
Authors: Kraus Frank , Hubert Gordian , Friedrich Benjamin , Maegerlein Christian , Hohenbichler Katharina , Hubert Nikolai , Zietemann Vera , Degenhart Christoph , Platen Sabine , Bath Philip M , Audebert Heinrich , Haberl Roman L
Published: January 2019

Introduction:
Thrombectomy is an established therapy for large vessel occlusion (LVO) usually performed in comprehensive stroke centers (CSC). Patients from remote primary stroke centers (PSC) have to be transported to the CSC either by ambulance or by helicopter (drip-and-ship-model, DSM). In TEMPiS, a large hub-and-spoke telestroke network in Germany, long transfer times delay start of treatment by 180 min. We therefore developed the “Flying Intervention Team” (FIT) model with the interventionalist sent by helicopter to remote PSCs to perform thrombectomy on site. We calculated that FIT-thrombectomy might save 100 min decision-to-groin-time as compared to DSM. This three-step trial is focusing on i) feasibility and safety, ii) time benefit, iii) clinical benefit. Here we report the first results from the pilot phase.

Methods:
Between February and March 2018 patients at 11 TEMPiS PSCs with large vessel occlusion on CTA and decision for thrombectomy were included. The FIT Team was available alternate weeks between 08.00-22.00. Patients were either treated according to FIT or DSM. Costs were covered by German health insurance companies.

Results:

Conclusion:
Thrombectomy was performed approx. 100 min earlier with FIT as compared to DSM. Further time benefits, clinical outcome and safety analyses with this model remain investigation.
Abstract 34: Outcomes of Thrombolysis on Mobile Stroke Unit
Authors: Shimbo Daisuke , Sheikhi Lila , Maselli Kerri , Thompson Nicolas , Reimer Andrew P , Hussain Muhammad S , Uchino Ken , Russman Andrew N
Published: January 2019

Introduction:
Mobile stroke Units (MSU) can shorten the time to intravenous thrombolytic therapy (IVT) in patients with acute ischemic stroke. We aimed to demonstrate the effects of pre-hospital IVT on clinical outcomes.

Methods:
We reviewed patients received IVT from July 2014 to December 2017, and compared patients with pre-hospital IVT on MSU with patients brought to the ED via a conventional ambulance. The primary outcome was the modified Rankin scale score (mRS) of 1 or better at 90 days. Binary logistic regression model of 90-day mRS for 0-1 vs 2-6 was adjusted for age, initial National Institutes of Health Stroke Scale (NIHSS) score, and pre-morbid mRS.

Results:
Seventy eight patients were treated in the MSU and 153 patients were received IVT in the ED. There were no significant differences in gender, age, pre-morbid mRS, initial NIHSS score, and risk factors between the MSU group and the ED group. The MSU patients received thrombolysis 38 minutes earlier from onset than the ED patients (median 79 minutes compared to117 minutes, p<0.001). In an unadjusted analysis, the difference in primary outcome between MSU group and ED group was not significant (41% with MSU vs 29% with ED, p=0.061, Figure). After adjustment for age, initial NIHSS score, and pre-morbid mRS, the odds ratio for mRS of 0-1 at 90 days with IVT on MSU compared to ED for was 2.09 (95% confidence interval (CI), 1.02-4.28, p = 0.044). Further adjustment for the time from onset to thrombolytic treatment, the effect of MSU on 90-day mRS was attenuated and no longer significant (odds ratio 1.65, 95% CI, 0.77-3.55, p=0.196).

Conclusion:
Pre-hospital IVT on MSU compared to conventional care shortened the time to thrombolytic treatment and was associated with improved functional outcomes in patients with acute ischemic stroke.
Abstract 36: Direct Oral Anticoagulant Underdosing Increases Rates of Stroke and Myocardial Infarction With No Reduction in Bleeding Rate
Authors: Arbel Ronen , Hammerman Ariel , Sergeinko Ruslan , Batat Erez , Greenberg-Dotan Sari , Avnery Orly , Ellis Martin H
Published: January 2019

Introduction:
Direct oral anticoagulants (DOACs) reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) patients. The off-label prescription of lower dose DOACs is very common and usually represents an attempt to mitigate bleeding risk. Data regarding the effects of off-label DOAC lower dose on patient outcomes is limited. We evaluated the effectiveness and safety of off-label lower dose DOAC therapy in NVAF patients treated in routine clinical practice.

Hypothesis:
Off-label lower dose DOAC use is associated with higher risk of mortality, stroke and myocardial infarction (MI) and is not associated with a reduced bleeding rate.

Methods:
We identified all newly diagnosed NVAF patients initiating DOAC therapy in Clalit Health Services from 2011 to 2016. Effectiveness was defined as a composite of all-cause mortality, stroke and MI and safety was defined as bleeding requiring hospitalization. Patients were followed until May 15,2017 or until occurrence of an outcome event. The DOAC dose was determined based on electronic drug dispensing records. We compared the outcomes in patients treated with DOACs at per-label standard dose with those treated with off-label lower dose. Hazard ratios (HR) were adjusted for 21 variables, including socio-economic factors, co-morbidities and concomitant medications using multivariate regression.

Results:
During the study period 3,395 patients were treated with DOACs at per-label standard dose and 2,438 patients were treated with an off-label lower dose. Adjusted HR for the composite of mortality, stroke and MI in patients treated with off-label lower dose was 1.38 (95% CI: 1.13- 1.69, P=0.001), and for bleeding 1.34 (95% CI: 0.92-1.95, P=NS).

Conclusions:
In this cohort of NVAF patients treated in routine clinical practice, off-label lower dose of DOACs was associated with a higher risk of mortality, stroke and myocardial infarction and was not associated with a reduced bleeding rate. Our findings provide further support for encouraging adherence to the per-label dosage of DOAC therapy.
Abstract 5: Improved Quality of Life With Endovascular Therapy in the DEFUSE 3 Trial
Authors: Polding Laura C , Tate William J , Mlynash Michael , Marks Michael P , Heit Jeremy J , Kemp Stephanie , Albers Gregory W , Lansberg Maarten G
Published: January 2019

Background:
Little is known about the effect of endovascular therapy on patients’ quality of life. Using data from the randomized DEFUSE 3 trial, we aimed to assess if thrombectomy performed in the late (6-16 hour) time window leads to improved quality of life.

Methods:
Neuro-QoL is a measurement tool designed to assess quality of life (QoL) outcomes in adults with neurologic disorders. In DEFUSE 3, Neuro-QoL short forms were administered at day 90 to assess quality of life in four domains: mobility, ability to participate in social roles and activities, cognitive function, and depression. Raw scores were transformed to T-scores, which calibrates the scores to the distribution in the US general adult population with a mean score of 50 and SD of 10. For consistency among domains, the distribution of depression T-scores was inverted across the mean such that higher scores reflect better outcomes. Quality of life scores were compared between groups using the Wilcoxon rank-sum test (unadjusted) and linear regression (adjusted).

Results:
In DEFUSE 3, 146 patients were alive at day 90. Of these, 128 completed all four QoL forms, 10 did not complete any of the forms, and 8 completed a subset of the forms. Endovascular therapy compared to medical alone was associated with superior quality of life outcomes in all domains: mobility (p<0.001), social participation (p<0.001), cognition (p=0.013), and depression (p=0.003) (figure). Higher NIHSS at baseline was associated with worse outcomes in mobility, social participation and cognition, older age with worse mobility and depression, and female gender with worse mobility, cognition and depression (multivariable p<0.05). The benefit of endovascular therapy in each quality of life domain remained significant after adjusting for these variables.

Conclusion:
In addition to improved functional outcomes, endovascular therapy 6 to 16 hours after onset preserves mental health and social capabilities critical to patients’ quality of life.
Abstract 53: Reorganization of Functional Language Networks Following Neonatal Arterial Ischemic Stroke
Authors: Emami Zahra , Dunkley Benjamin T , Robertson Amanda , Hess Maggie , Westmacott Robyn , Krishnan Pradeep , Pang Elizabeth W , Dlamini Nomazulu
Published: January 2019

Introduction:
Neonatal arterial ischemic stroke (NAIS) is the most common form of childhood stroke. Unlike adults with stroke, children with left middle cerebral artery (MCA) NAIS seldom become aphasic, although adolescence often reveals the emergence of higher-order language deficits. Functional language networks may be predictive of later-emerging language outcomes, and can aid to identify at-risk children with NAIS.

Methods:
Five neurotypical children (2F; 5 RH; mean 12.7 ± 2.6 years), and five children with unilateral-MCA NAIS (3F; 5 RH; mean 11.3 ± 2.0 years) listened to semantically correct and incorrect sentences while magnetoencephalography (MEG) was recorded. Task-related functional connectivity was calculated using the phase lag index (PLI) across regions of interest. The relationship between the functional brain networks and language skill was examined.

Results:
Neurotypical children showed increased global functional connectivity for semantically correct sentences 1.8 to 2.0 seconds from stimulus onset in the theta band (4-7 Hz;
p
<0.05). The top connections in the theta band and time window of interest involved a significantly greater number of nodes in the left frontal lobe for controls compared to patients (
p
<0.05), while patients recruited a greater number of temporal lobe nodes than controls (
p
<0.05). Furthermore, patient language networks demonstrated a more bilateral distribution than those of typically-developed children (37.5% vs. 30% of top connections). The mean connectivity strength in the language network was positively correlated with vocabulary skill (r=0.84) for patients, and with word reading ability for both patients and neurotypical children (r=0.95, r=0.88, respectively).

Conclusions:
These results suggest reorganization of expected unilateral and frontal language networks towards a bilateral and temporal distribution following stroke, with less reliance on traditional language nodes. Such reorganization may underlie the language ability trajectory of children with neonatal MCA stroke. Reorganization of functional brain networks may be used as a predictive marker for language development following neonatal stroke, which can ultimately guide precision medicine and improve long-term outcomes.
Abstract 54: Utility of Automated Perfusion-diffusion Magnetic Resonance Imaging in Acute Childhood Arterial Ischaemic Stroke
Authors: Doyle Melissa J , Yang Joseph Yuan-Mou , Adamson Chris , Sharma Gagan , Calamante Fernando , Campbell Bruce , Anderson Vicki , Mackay Mark T
Published: January 2019

Background and Objectives:
Recent studies have used automated perfusion imaging software to identify adults most likely to benefit from reperfusion therapies in extended time windows. The time course of penumbral evolution in childhood arterial ischemic stroke (AIS) is poorly characterised. We investigated the utility of automated perfusion imaging software in childhood AIS and explored the relationship between time to imaging and perfusion-diffusion mismatch.

Methods:
Convenience population of children with acute AIS, presenting to the Royal Children’s Hospital Melbourne from 2005-2014, where diffusion and dynamic susceptibility contrast MRI were performed <48 hours of symptom onset. Perfusion-diffusion mismatch was estimated using RAPID (iSchemaView). Core was defined as ADC<620х10
-6
mm2/s and hypoperfusion as Tmax>6s. Favourable mismatch profile was defined as core <70mls, mismatch volume ≥15mls and ratio ≥1.8.

Results:
Twenty-nine children (median age 8, IQR 4.4-14.6) met eligibility criteria (26 unilateral MCA and 3 unilateral cerebellar infarcts). Median PedNIHSS was 4.5. Etiologies included focal cerebral arteriopathy (n=9), cryptogenic (n=12), cardioembolic (n=5), other (n=3). Median time from onset to imaging was 13.7 hours (IQR 7.5-25.3). The visible diffusion lesion was not below ADC<620 threshold in 19 (34% of cases) (median time to imaging 21 hours). Two children with subcortical/cortical lesions, imaged at 3.75 and 11 hours had favourable mismatch profile.

Conclusions:
RAPID failed to segment the ischaemic core in cases with delayed imaging. Favourable mismatch profiles persisted beyond the standard 4.5 hours window for thrombolysis. Further work is required to investigate the effect of time-delay and aetiology on mismatch characteristics in childhood AIS.

Figure: 22-month child with acute left MCA occlusion. Diffusion (left) and Tmax perfusion (right) MRI at 3.75 hours post-onset demonstrating a favourable mismatch profile.
Abstract 62: Disruption of DLL4/Notch Signaling in the Post Stroke Period Results in Enhanced Angiogenesis and Improved Outcome Following Stroke
Authors: Kim Gab Seok , Herman Alexander M , Wythe Joshua D , Marrelli Sean P
Published: January 2019

Delta-like 4 (DLL4) is an endothelial transmembrane ligand for the Notch family receptors.
Dll4
contributes to vascular development and angiogenesis, specifically as a negative regulator of capillary sprouting. We hypothesized endothelial-specific deletion of
Dll4
or inhibition of Notch receptor activity in the post-stroke brain would result in enhanced reparative angiogenesis and improved functional outcome following permanent stroke in young and aged mice.

Methods:
We used the permanent distal middle cerebral artery occlusion (dMCAO) model to induce primary injury in the cortex with delayed secondary injury in the thalamus. DLL4 protein expression (IHC) and Notch receptor activity (
in vivo
biosensor,
CBF::H2B-Venus
) were determined through 2 weeks post-stroke. Tamoxifen-inducible, endothelial-specific
Dll4
KO mice (
Dll4
iecKO
) and
Dll4
fl/fl
(“floxed-only” control) female mice (3 mos) were treated with tamoxifen (n=4 each) at 24 and 48 hrs post-stroke. In a separate cohort, young (3 mos, n=5 each) and aged (20 mos, n=3-4) male mice were treated with DAPT (Y-secretase inhibitor; 100 mg/kg) at 24 hours post-stroke to inhibit Notch activity. Functional angiogenesis was assessed histologically following
in vivo
perfusion of fluorescent lectin. Behavioral tests (foot fault) were conducted at post-stroke days 1, 3, 7, and 14.

Results:
Elevated Dll4 expression and Notch activation were observed in peri-infarct cortex (piCtx) and ipsilateral thalamus (iTh) by 24 hours after dMCAO. Post-stroke endothelial
Dll4
deletion led to increased perfusion-competent microvessels (e.g. vessel area, length, etc.) at 2 weeks post-stroke in piCtx and iTh. Post-stroke DAPT treatment trended toward increased total microvascular length in piCtx (P=0.051 young/P=0.126 aged), but not iTh. Importantly, both treatment methods demonstrated significant improvement in neurological function at 7 and 14 days post-stroke.

Conclusions:
Deletion of endothelial
Dll4
at 24 hours post-stroke leads to increased angiogenesis and improved functional recovery. Notch inhibition demonstrated improved outcome (young and aged), but increased angiogenesis was only suggestive in the cortex. DAPT treatment appears to have translational value as a delayed treatment option.
Abstract 64: Novel and Known Genes Elucidated in Cerebral Cavernous Malformation Through Comparative Transcriptomic Analysis of Multiple Model Species and Human Microdissected Lesional Endothelial Cells
Authors: Koskimäki Janne , Girard Romuald , Li Yan , Zeineddine Hussein , Lightle Rhonda , Moore Thomas , Lyne Séan , Shenkar Robert , Saadat Laleh , Cao Ying , Polster Sean P , Zhang Dongdong , Carrion-Penagos Julian , Lopez-Ramirez Miguel A , Chapman Eric , Tang Alan T , Akers Amy , Faber Pieter , Andrade Jorge , Ginsberg Mark , Derry Brent , Kahn Mark L , Marchuk Douglas A , Awad Issam A
Published: January 2019

Cerebral cavernous malformations (CCMs) are vascular brain lesions predisposing 0.5% of the population to a lifetime risk of hemorrhagic stroke and seizures. The disease is associated to a mutation in one of the three CCM genes (
CCM1, CCM2
and
CCM3
). CCM pathogenesis has been shown to be endothelial autonomous, linked to angiogenic, adhesion, and inflammatory processes.

Using RNA-Seq, we profiled the transcriptomes of lesional endothelial cells (ECs) extracted from 5 human CCMs. We also profiled the more common
Ccm1,
and the exceptionally aggressive
Ccm3
genotypes in mouse brain microvascular endothelial cells (BMECs) and
C. elegans
. We first identified differently expressed genes (DEGs), gene ontology (GO) functions, and gene networks for each model separately. We then cross-compared the models and genotypes to identify the important and conserved genes likely contributing to pathogenesis of CCM disease.

Nine hundred-fifteen DEGs in human microdissected lesional ECs, 1932 in

Ccm1
ECKO

and 524 in

Ccm3
ECKO

BMECs, as well as 1643 in
ccm1
C. elegans
and 1581 in
ccm3 C. elegans
were identified (p<0.05, FDR corrected, fold change≥1.2).
FAT1
was commonly identified in the 5 models, while 7 other DEGs were common between human lesional ECs, mouse BMEC Ccm1
ECKO
and
ccm1
C. elegans:
GNAO1
,
SPARCL1
,
PLXDC2
,
PLCD3
,
PDGFRA
,
FAXC
, and
UNC13A
. Seventy-one DEGs were only identified in
Ccm1
models, these genes were related to DNA repair, angiogenesis, microtubule functions and magnesium ion binding. Eleven DEGs were only found in
Ccm3
models, and were related to rRNA processing, ribosome biogenesis and structural constituent, protein targeting to endoplasmic reticulum, protein intracellular targeting, and vesicle transportation to a cell membrane.

We provide a comprehensive transcriptome library of CCM disease across species and genotypes. The results will be useful for validating putative mechanistic targets and biomarkers in this disease. For the first time, we also report fundamental transcriptomic differences between
Ccm1
and
Ccm3
genotypes, potentially explaining differences in CCM disease severity. Our results confirm several previously reported mechanisms, and suggest multiple novel gene candidates to be investigated in CCM pathogenesis.
Abstract 65: Risk of Intracerebral Hemorrhage Associated With Pregnancy in Women With Cerebral Arteriovenous Malformations: A Large-Scale Controlled Cohort Study
Authors: Medhus Annika , Bambhroliya Arvind , Chen Peng R , Blackburn Spiros , Savitz Sean , Vahidy Farhaan , McCullough Louise D , Sheth Sunil A
Published: January 2019

Introduction:
Prior single-center reports have suggested an increased incidence of intracerebral hemorrhage (ICH) from cerebral arteriovenous malformation (AVM) rupture during pregnancy. Unfortunately, data on this topic are limited due to small sample size as well as the aggregation of all patients with AVMs, failing to account for the well-described variability in ICH risk based on AVM size, location and morphology.

Methods:
Using administrative data on all discharges from hospitals in New York (2005-2014) and Florida (2005-2015), we identified patients with first time pregnancy and delivery. The primary endpoint was first time ICH. We used a case-crossover design in which each woman and her unique AVM served as her own control, by matching the pregnancy period with an equal duration of time 1 year prior. Women were excluded for any treatment (embolization, surgery or radiosurgery) for AVM or first time ICH prior to the control period. Results are presented as OR [95% CI] or median [IQR].

Results:
Among 6,273,562 women with first time pregnancy, median age was 28 [23 – 33], 49% were white, 19% were black, and 19% were Hispanic. Of these patients, 1,024 (0.02%) had an AVM and 79 were excluded for ICH or treatment prior to the control period. Women with AVMs were more likely to undergo Caesarian section than those without (58% vs. 36%, p<0.001). There were no major differences in vascular risk factors between the women without an AVM versus those with AVM. In unmatched analysis, the incidence of first time ICH in women with AVMs was greater than those without in the control (0.8% vs. 0.001%, p<0.0001), pregnancy/delivery (5.1% vs. 0.01%, p<0.0001), and 12-week post-partum (1.2% vs 0.01%, p<0.0001) periods. In matched case-crossover analysis in women with AVMs, pregnancy was associated with an increased risk (OR 3.4 [1.4 – 8.6]) relative to the control non-pregnant period.

Conclusion:
In this large-scale cohort study in which women with AVMs served as their own controls, we account for the variability in ICH risk based on AVM morphology and identify a nearly 350% increased risk of ICH associated with first time pregnancy and delivery. These findings support the need for further work on mechanistic underpinnings as well as a major need for improved methods to abrogate ICH risk.
Abstract 7: Procedural Approaches and Angiographic Signs Predicting First-Pass Recanalization in Patients Treated With Mechanical Thrombectomy for Acute Ischemic Stroke
Authors: Gramegna Laura Ludovica , Ribò Marc , Rosati Santiago , Aixut Sonia , Werner Mariano , Remollo Sebastian , Quintana Manuel , Hernandez David , Dinia Lavinia , Rubiera Marta , Tomasello Alejandro
Published: January 2019

Background:
First pass recanalization via mechanical thrombectomy (MT) has been associated with improved clinical outcome in patients with acute ischemic stroke. However, the optimal approach to achieve First Pass Effect (FPE) remains unclear. No study has evaluated angiographic features associated with the FPE. We aimed to determine the procedural approaches and angiographic signs that may predict FPE.

Methods:
We performed a prospective, multi-center, observational, study in patients with large vessel occlusion of the anterior circulation treated with MT between February and June 2017. MT was performed using different devices, deployment manoeuvres (standard unsheathing versus the “Push and Fluff” technique), Proximal Balloon Guide Catheter (PBGC), Distal Aspiration Catheter (DAC), or both. The Angiographic Clot Protrusion Sign (ACPS) was recorded. The modified Thrombolysis in Cerebral Infarction (mTICI) scale was used to score different levels of revascularization: FPE was defined as mTICI2b-3 and complete FPE (cFPE) as mTICI2c-3 after first pass. Associations were sought between FPE/cFPE and procedural approaches and angiographic signs. Adjusted logistic regression model was used to define independent predictors of succesful recanalization.

Results:
A total of 193 patients were included. FPE was achieved in 97 (50.3%) and cFPE in 74 (38.3%) patients. When the interventionalist decided to combine a PBGB and the Push and Fluff technique, FPE was achieved in 75% vs 47% of other cases (p<0.01) and cFPE in 64% vs 34% respectively (p<0.01). When the combination concurred with APCS, higher incidence of FPE (91% vs 47% p<0.01) and cFPE (82% vs 35% p<0.01) were observed. The use of PBGC (OR 3.81, 95%CI:1.41-10.22, p<0.01), the use of Push and Fluff technique (OR 3.45, 95%CI:1.28-9.29, p=0.01) and the record of ACPS (OR 4.71, 95%CI:1.78-12.44, p<0.01) were independently associated with higher rates of cFPE.

Conclusions:
In our experience, the concurrence of the PBGC, the Push and Fluff technique, and the ACPS was associated with the highest rates of FPE and cFPE. Appropriate selection of the thrombectomy device and deployment technique may lead to better procedural outcomes. ACPS could be used to assess clot integration strategies in future trials.
Abstract 80: The Experimental Neuroprotective Drug Na1 Does Not Interfere With the Fibrinolytic Activities of Alteplase or Tenecteplase
Authors: Sun Xiujun , Garman David , Tymianski Michael
Published: January 2019

Introduction:
Tissue plasminogen activator (Alteplase; tPA) is the most commonly used thrombolytic medication for treatment of acute ischemic stroke, and recent research suggests that Tenecteplase (TNKase) is also effective. NA-1 is a novel neuroprotective drug intended to reduce disability when administered after stroke that is currently being studied in two late stage clinical trials, FRONTIER (NCT02315443) and ESCAPE-NA1 (NCT02930018). Given the overlap in the patient populations and the likelihood that subjects receiving NA-1 could receive thrombolysis, studies were performed to evaluate the effects of NA-1 on the fibrinolytic activity of tPA and TNKase.

Methods:
A spectrophotometric method of measuring clot formation and lysis in citrated human plasma was developed and used to assess the fibrinolytic activity of tPA and of TNKase. Aprotinin, a known protease inhibitor capable of blocking tPA and TNKase activity, was used as a positive control to demonstrate that the assay system was appropriately sensitive to detect inhibition of thrombolytic activity. Varying concentrations of NA-1 were added to the reaction to assess whether NA-1 could affect the rate of clot formation or the rate of clot lysis in the presence of tPA or TNKase.

Results:
The sensitivity of this assay system was demonstrated to enable detection of small changes in the fibrinolytic activity of tPA and TNKase on human plasma in the presence of thrombin. NA-1 did not display any fibrinolytic activity on its own nor did it affect the rate of clot formation in the system. NA-1 also did not affect the rate of clot formation or of fibrinolysis in the presence of tPA or TNKase.

Conclusions:
NA-1 has no intrinsic fibrinolytic activity and does not modulate the fibrinolytic activity of tPA or TNKase. Therefore, NA-1 can be given safely to stroke victims receiving tPA or TNKase without negatively impacting the potential benefit of thrombolysis. This method could also be used to assess other drugs that may have the potential to interact with or be concurrently administered to patients receiving thrombolytic medications.
Abstract 88: Decrease in Stroke Mortality With Increase in Rate of Thrombectomy in Acute Ischemic Stroke in Nationwide Inpatient Sample
Authors: Mir Osman , Ogola Gerald P
Published: January 2019

Background:
Endovascular Thrombectomy was shown to be effective in treatment of Acute Ischemic Stroke (AIS) in series of clinical trials in 2015, prior to that there were neutral trials. We looked at National inpatient sample to see the trends in Thrombectomy and outcomes after the publication of clinical trials.

Methods:
Using the National Inpatient Sample, we evaluated outcomes of patients treated for AIS in the United States from first 9 months of 2013 and compared them to first 9 months of 2015 due to ICD 9 to 10 migration. Patients who had AIS and underwent endovascular clot retrieval were identified. Morbidity and mortality were evaluated as a function of patient age and of concomitant thrombolytic agent administration. We compared the rates of thrombectomy done before the clinical trials were published to the time after the clinical trials were published.

Results:
In 2013, there were 4,700 (15.6%) reported thrombectomies from 30,160 treated patients, as compared to 8,880 (22.3%) in 2015 from 39,795 treated patients. This increase was statistically significant (p<0.0001) and indicated almost doubling of raw numbers of thrombectomies. Multivariable analysis showed statistically significant decrease in adjusted risk of mortality (aOR, 95%CI = 0.81(0.71-0.92), p=0.002) see figure 1. The comorbidities as measured by Charlson’s Comorbidity index remained unchanged 7.2±2.6 vs 7.3±2.7 (p=0.22). Unadjusted mortality rate significantly decreased from 17.2% in 2013 to 15.2% in 2015 (p<0.002). Complication rates and median length of stay (LOS) were similar in the two time periods 42% vs 41.3% and 7 (4-12) vs 6 (4-11) days, respectively. Chance of having thrombectomy was 50% higher in 2015 vs 2013 (aOR, 95%CI = 1.49 (1.35-1.64), p<0.0001). Rates of IV t-PA administration as a control did not change 3.1 vs 3.2%.

Conclusions:
The OR of having thrombectomy for AIS patient increased by 50% from 2013 to 2015 and led to improved outcomes including lower mortality.
Abstract NS1: Hands-On Curriculum Educates Neuroscience Nurses on Bedside Swallow Screening
Authors: Meletis Stephanie , Bloom Lisa , Malinowski Diane
Published: January 2019

Background:
Swallow screening effectively identifies patients at risk for post-stroke dysphagia. This screening can be effectively performed by nurses at the bedside to aid in early detection. However, many screens lack curricula to adequately establish knowledge and skills.

Purpose:
The purpose of this project was to design and implement a comprehensive, interdisciplinary curriculum to promote a nurse-driven bedside swallow screen across the care continuum in our hospital.

Methods:
An interprofessional team of content experts developed and taught an eight-hour stroke curriculum, which included care of ischemic and hemorrhagic stroke, neurological assessment and diagnostics, stroke rehabilitation, and an introduction to the multidisciplinary care team. An interactive training session on a valid and reliable nurse-driven bedside swallow screen was included, featuring lecture, computer-based modules, and hands-on simulation components. Three validations of the swallow screen were completed by each bedside nurse to ensure competency, performed under the supervision of a speech pathologist or clinical nurse educator. The process included completion of the screen on a stroke patient and documentation on a newly created EMR flowsheet. Nursing knowledge and behavior were assessed by post-tests and on-unit validations of the swallow screen.

Results:
Evaluation based on Kirkpatrick’s Model found that nurses’ initial reaction was positive, describing the curriculum as engaging and empowering. After implementation, the percentage of swallow screens properly performed increased from 73.3% in 2015 to 93.5% in 2017 (p<.001). Screening effectiveness was reinforced with additional education on dysphagia by the neuroscience nursing unit-based councils after the project roll-out. The incidence of aspiration pneumonia and all pneumonia on the neurology unit decreased by over 25% after the implementation of this initiative.

Conclusion:
In conclusion, an innovative, hands-on comprehensive nursing curriculum that employs interprofessional efforts effectively supports learner outcomes and optimizes patient care.
Abstract NS4: Early and Continued Nursing Care Allows a Fast, Intensive, and Maintained BP Reduction in Patients With Acute Intracerebral Hemorrhage
Authors: Pancorbo Olalla , Sanjuan Estela , Santana Katherine , Sala Victoria , García-Tornel Álvaro , Rodríguez Noelia , Juega Jesús , Boned Sandra , Muchada María Ángeles , Pagola Jorge , Rubiera Marta , Ribó Marc , Molina Carlos , Rodríguez-Luna David
Published: January 2019

Background and Purpose:
Recent studies have highlighted the key influence of both time to achieve blood pressure (BP) control and the persistence of BP stable in the potential benefit of intensive BP reduction on attenuating intracerebral hemorrhage (ICH) expansion. We aimed to compare two different BP management protocols in acute ICH to determine the influence of stroke nursing practice in BP control over first 24h.

Methods:
Consecutive patients with spontaneous ICH <6h and systolic BP (SBP) >150 mmHg under an early (antihypertensive IV bolus by nursing attention at CT scan), intensive (SBP target <140 mmHg), and maintained (antihypertensive continuous infusion after IV bolus) BP protocol within a 4-year period (2013-2017) were evaluated (Early-Intensive-Maintained SBP group). They were compared with a 1:1 matched prospectively collected historical control group (2009-2013) under a non-early (IV bolus by nursing attention at Stroke Unit), non-intensive (SBP target <180 mmHg), and no-maintained (no continuous infusion after initial IV bolus) BP protocol. All patients underwent a bedside non-invasive BP monitoring at 15 min intervals over the first 24h. The time from BP lowering treatment initiation to achieve SBP target and the persistence of SBP bellow target at different time points was recorded in both groups.

Results:
One hundred and three Early-Intensive-Maintained SBP patients were matched with 103 controls. Mean age was 71.7±13.3 years, 134 (65%) were men, and median SBP was 177 (162-197) mmHg. Median time to SBP target achievement was lower in Early-Intensive-Maintained SBP patients as compared with control group (45 [30-60] vs. 90 [27-167.50] min,
P=0.045
). Early-Intensive-Maintained SBP patients maintained the SBP below the target more frequently than control group at different time points, including 60 min (40.8% vs. 36.9%,
P
<0.001), 120 min (36.9% vs. 34%,
P
<0.001), 18h (32% vs. 22.3%,
P
<0.001), and 24h (33% vs. 4.9%,
P
<0.001), respectively.

Conclusions:
The stroke nurse plays a key role in the management of BP in acute ICH patients. An early and continued nursing care allows a fast and maintained BP reduction in acute ICH patients under an intensive BP reduction protocol.