bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity
Authors: Mahadevan Navin R. , Knelson Erik H. , Wolff Jacquelyn O. , Vajdi Amir , Saigí Maria , Campisi Marco , Hong Deli , Thai Tran C. , Piel Brandon , Han Saemi , Reinhold Bruce B. , Duke-Cohan Jonathan S. , Poitras Michael J. , Taus Luke J. , Lizotte Patrick H. , Portell Andrew , Quadros Victor , Santucci Alison D. , Murayama Takahiko , Cañadas Israel , Kitajima Shunsuke , Akitsu Aoi , Fridrikh Maya , Watanabe Hideo , Reardon Brendan , Gokhale Prafulla C. , Paweletz Cloud P. , Awad Mark M. , Van Allen Eliezer M. , Lako Ana , Wang Xi-Tao , Chen Benjamin , Hong Fangxin , Sholl Lynette M. , Tolstorukov Michael Y. , Pfaff Kathleen , Jänne Pasi A. , Gjini Evisa , Edwards Robin , Rodig Scott , Reinherz Ellis L. , Oser Matthew G. , Barbie David A.
Published: March 2021

Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity.

Significance:

SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC Ihi subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection.

This article is highlighted in the In This Issue feature, p. 1861
3D Bioprinted Cardiac Tissues and Devices for Tissue Maturation
Authors: Sedlakova Veronika , McTiernan Christopher , Cortes David , Suuronen Erik J. , Alarcon Emilio I.
Published: March 2021

Cardiovascular diseases are the leading cause of mortality worldwide. Given the limited endogenous regenerative capabilities of cardiac tissue, patient-specific anatomy, challenges in treatment options, and shortage of donor tissues for transplantation, there is an urgent need for novel approaches in cardiac tissue repair. 3D bioprinting is a technology based on additive manufacturing which allows for the design of precisely controlled and spatially organized structures, which could possibly lead to solutions in cardiac tissue repair. In this review, we describe the basic morphological and physiological specifics of the heart and cardiac tissues and introduce the readers to the fundamental principles underlying 3D printing technology and some of the materials/approaches which have been used to date for cardiac repair. By summarizing recent progress in 3D printing of cardiac tissue and valves with respect to the key features of cardiovascular tissue (such as contractility, conductivity, and vascularization), we highlight how 3D printing can facilitate surgical planning and provide custom-fit implants and properties that match those from the native heart. Finally, we also discuss the suitability of this technology in the design and fabrication of custom-made devices intended for the maturation of the cardiac tissue, a process that has been shown to increase the viability of implants. Altogether this review shows that 3D printing and bioprinting are versatile and highly modulative technologies with wide applications in cardiac regeneration and beyond.
Perfume de mulher: a adaptação teatral brasileira a partir das obras cinematográficas de Dino Risi e Martin Brest
Authors: Alves Filho Paulo Edson , Hass Juliana
Published: March 2021

Perfume de Mulher, comédia dramática baseada nos filmes Profumo di Donna, de Dino Risi (1974) – protagonizado por Vittorio Gassman – e Scent of a Woman, de Martin Brest (1992) – pelo qual Al Pacino recebeu o Oscar de melhor ator, teve a versão teatral brasileira escrita por Silvio Guindane, Pedro Brício e Walter Lima Jr. Neste trabalho analisaremos os elementos da adaptação brasileira à luz das teorias dos Estudos da Adaptação como as de Linda Hutcheon (2006), Julie Sanders (2006), e outros estudiosos do assunto. Discorreremos sobre o diálogo entre cinema e teatro, buscando destacar as características específicas de cada mídia e o ponto de vista de seus respectivos autores, por meio dos recursos utilizados nas linguagens literária, cinematográfica e teatral.
O Papel das Didascálias no Trabalho de Tradução de Les Cenci, de Artaud
Authors: Ielpo Rodrigo
Published: March 2021

Ao propor uma análise comparativa entre “Teatro oriental e teatro ocidental” em O teatro e seu duplo (1993), Artaud expõe sua conhecida crítica em relação à submissão do espetáculo ao texto dramático. Segundo Artaud, a tradição ocidental faria do teatro um “simples reflexo material do texto”, tornando problemática a própria separação do “teatro da ideia de texto realizado.” Condicionada por esse tipo de afirmação é que Les Cenci (2011), escrita por Artaud e encenada pela primeira vez em 1935 sob sua direção, causaria certo incômodo entre parte dos seus admiradores. Para estes, haveria uma contradição entre as posições teóricas do autor e a proposta cênica de um espetáculo que, no final das contas, orbitaria em torno de um texto. Problematizando esse tipo de recepção, num prefácio escrito para a peça, Michel Corvin (2011) chama atenção para a relevância que as indicações cênicas teriam na obra, subvertendo a importância das didascálias em relação ao conjunto de réplicas. Funcionando como uma partitura visando abrir o texto para sua dimensão propriamente teatral, essas informações acabariam por deslocá-lo de sua pretensa centralidade. O objetivo dessa comunicação é refletir sobre o papel dessas rubricas no trabalho de tradução de Les Cenci, procurando entender em que medida elas permitiriam operar uma prática tradutória que levasse em consideração as especificidades da teatralidade que já estaria presente no próprio suporte escrito da peça.
Left Main Trifurcation and Its Percutaneous Treatment
Authors: Kovacevic Mila , Burzotta Francesco , Elharty Sameh , Besis George , Aurigemma Cristina , Romagnoli Enrico , Trani Carlo
Published: March 2021

In humans, the most common anatomic variation of the left main (LM) stem is represented by its distal division in 3 branches (LM trifurcation) instead of 2. LM trifurcation disease accounts for ≈10% to 15% of all LM diseases and is often managed by cardiac surgery. Over the last decades, due to the improvement of interventional material and techniques, percutaneous coronary intervention started gaining acceptance to treat patients with LM disease including those with trifurcated anatomy. Yet, LM trifurcation stenosis with its intrinsic anatomic complexity (3 branches, at least 4 angles, wide variability in branch size and disease) is recognized as a challenging lesion subset for percutaneous coronary intervention. In this review, we summarize available data about LM trifurcation anatomy, its influence on percutaneous coronary intervention feasibility, and the evidence collected regarding the different technical options (including trissing balloon inflation).
MIR503HG Loss Promotes Endothelial-to-Mesenchymal Transition in Vascular Disease
Authors: Monteiro João P. , Rodor Julie , Caudrillier Axelle , Scanlon Jessica P. , Spiroski Ana-Mishel , Dudnakova Tatiana , Pflüger-Müller Beatrice , Shmakova Alena , von Kriegsheim Alex , Deng Lin , Taylor Richard S. , Wilson-Kanamori John R. , Chen Shiau-Haln , Stewart Kevin , Thomson Adrian , Mitić Tijana , McClure John D. , Iynikkel Jean , Hadoke Patrick W.F. , Denby Laura , Bradshaw Angela C. , Caruso Paola , Morrell Nicholas W. , Kovacic Jason C. , Ulitsky Igor , Henderson Neil C. , Caporali Andrea , Leisegang Matthias S. , Brandes Ralf P. , Baker Andrew H.
Published: March 2021

Rationale:

Endothelial-to-mesenchymal transition (EndMT) is a dynamic biological process involved in pathological vascular remodeling. However, the molecular mechanisms that govern this transition remain largely unknown, including the contribution of long noncoding RNAs (lncRNAs).

Objectives:

To investigate the role of lncRNAs in EndMT and their relevance to vascular remodeling.

Methods and Results:

To study EndMT in vitro, primary endothelial cells were treated with transforming growth factor-β2 and interleukin-1β. Single-cell and bulk RNA-seq (RNA-sequencing) were performed to investigate the transcriptional architecture of EndMT and identify regulated lncRNAs. The functional contribution of seven lncRNAs during EndMT was investigated based on a DsiRNA (dicer-substrate short interfering RNAs) screening assay. The loss of lncRNA MIR503HG was identified as a common signature across multiple human endothelial cell types undergoing EndMT in vitro. MIR503HG depletion induced a spontaneous EndMT phenotype, while its overexpression repressed hallmark EndMT changes, regulating 29% of its transcriptome signature. Importantly, the phenotypic changes induced by MIR503HG were independent of miR-424 and miR-503, which overlap the lncRNA locus. The pathological relevance of MIR503HG downregulation was confirmed in vivo using sugen/hypoxia–induced pulmonary hypertension in mice, as well as in human clinical samples, in lung sections and blood outgrowth endothelial cells from pulmonary arterial hypertension patients. Overexpression of human MIR503HG in sugen/hypoxia mice led to reduced mesenchymal marker expression, suggesting MIR503HG therapeutic potential. We also revealed that MIR503HG interacts with the PTBP1 (polypyrimidine tract binding protein 1) and regulates its protein level. PTBP1 regulation of EndMT markers suggests that the role of MIR503HG in EndMT might be mediated in part by PTBP1.

Conclusions:

This study reports a novel lncRNA transcriptional profile associated with EndMT and reveals the crucial role of the loss of MIR503HG in EndMT and its relevance to pulmonary hypertension.
Abstract 23: Intracerebral Transplantation of Autologous Bone Marrow Stem Cell (BMSC) for Subacute Ischemic Stroke, Phase 1 Clinical Trial (RAINBOW Trial)
Authors: Kawabori Masahito , Shichinohe Hideo , Kuroda Satoshi , Houkin Kiyohiro
Published: March 2021

Background:
Recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. We investigated the safety and feasibility of intracerebral transplantation of autologous BMSC in the subacute phase of stroke (RAINBOW trial). Several new aspects including cell labeling and tracking, socioecomonic analysis using QALY, and the use of human platelet lysate instead of fetal bovine serum were adopted. (UNIN ID: UMIN000026130)

Methods/Design:
This is a phase 1, open-label, uncontrolled, dose-response study enrolling adults with severe motor deficits (mRS>3) 14 days after stroke. Approximately 50 mL of the bone marrow is extracted from the iliac bone of each patient 15 days or later from the onset, and BMSCs are cultured with allogeneic human platelet lysate (PL) and are labeled with superparamagnetic iron oxide for cell tracking using MRI. BMSCs are stereotactically administered around the area of infarction approximately 2 months from the ischemic stroke. Each patient will be administered a dose of 20 or 50 million cells. Neurological scoring, MRI for cell tracking,
18
F-fuorodeoxyglucose positron emission tomography, and
123
I-Iomazenil single photon emission computed tomography will be performed throughout 1 year after the administration.

Results:
All 7 patients have been successfully finished transplantation, and there was no severe adverse event in any of the patient regarding the surgical procedure nor cell quality. Favorable motor recoveries (change in mRS
>
1) are seen in 5 of 7 patients, and cell engraftment and migration to ischemic site was also observed.

Discussion:
This is a first-in-human trial to use labelled BMSC to the patients with subacute ischemic stroke. Intracerebral transplantation of autologous BMSC is safe and well tolerated. Cell migration to the ischemic boundary can clarify the therapeutic mechanisms.
Abstract 33: Qualitative Description of Ischemic Stroke Appearance on Low-Field, Point-Of-Care Magnetic Resonance Imaging
Authors: Yuen Matthew , Mazurek Mercy , Cahn Bradley , Prabhat Anjali , By Samantha , Hu Houchun Harry , Welch Edward B , Sacolick Laura , O’Halloran Rafael , Ward Adrienne , Timario Nona , Falcone Guido J , Gilmore Emily J , Hwang David Y , Kim Jennifer , Kaddouh Firas , Sharma Richa , Amin Hardik , Schindler Joseph L , Matouk Charles , Hebert Ryan , Wira Charles R , Sze Gordon , Rosen Matthew , Kimberly William T , Sheth Kevin N
Published: March 2021

Background and Aims:
Advances in low-field MRI have enabled image acquisition at the point-of-care (POC). We aim to characterize ischemic lesions in low-field, POC MRI and assess its relationship with stroke severity in ischemic stroke patients.

Methods:
We performed POC MRI exams on ischemic stroke patients. T2-weighted (T2W), fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI) exams were acquired with a 64mT, portable bedside MRI system. Three raters computed signal intensity ratios (SIR) for each sequence. For every slice showing an infarct, an SIR was generated by dividing the mean signal intensity of the lesion by the mean signal intensity of the contralateral hemisphere. Infarct volumes were obtained by multiplying the lesion area of each slice by the slice thickness (5mm) and summing the cross-sectional areas. Volumes were correlated with National Institutes of Health Stroke Scale (NIHSS) scores at the time of scan.

Results:
We studied 18 ischemic stroke patients (50% women; ages 30-95 years). Two patients were studied at two and three serial timepoints, respectively. POC exams were obtained 2.7 ± 2.2 days after symptom onset. A total of 18 T2W, 17 FLAIR, and 18 DWI exams were obtained. Three exams (1 T2W; 1 FLAIR; 1 DWI) were excluded due to motion degradation. High field MRI exams (19 ± 16 hours from POC exams) demonstrated ischemic infarcts in 15 of the 18 patients. All POC T2W and FLAIR exams revealed infarcts in these patients, and 14 of the 17 DWI exams showed infarcts. Ischemic infarcts were seen as hyperintense lesions (SIR: T2W = 1.19 ± 0.10, FLAIR = 1.15 ± 0.08, DWI = 1.36 ± 0.17). Infarct volume significantly correlated with NIHSS scores (T2W: r = 0.71, p < 0.01; FLAIR: r = 0.65, p < 0.05; DWI: r = 0.65, p < 0.05).

Conclusions:
These preliminary data suggest that low-field, POC MRI may be useful in the clinical evaluation of ischemic stroke. Further work in larger cohorts is needed to elucidate the appearance of infarction on low-field imaging.
Abstract 36: The Boston Criteria V2.0 for Cerebral Amyloid Angiopathy: Updated Criteria and Multicenter MRI-Neuropathology Validation
Authors: Charidimou Andreas , Boulouis Gregoire , Frosch Matthew , Baron Jean-Claude , Pasi Marco , van Buchem Mark A , Gurol Edip M , Viswanathan Anand , Al-Shahi Salman Rustam , Smith Eric E , Werring David J , GREENBERG Steven M ,   International CAA Association Boston Criteria Study Group
Published: March 2021

Introduction:
The Boston criteria are used worldwide for
in vivo
diagnosis of cerebral amyloid angiopathy (CAA). Given substantial advances in CAA research, we aimed to update the Boston criteria and externally validate their diagnostic accuracy across the spectrum of CAA-related presentations and across international sites.

Methods:
As part of an International CAA Association multicenter study, we identified patients age 50 or older with potential CAA-related clinical presentations (spontaneous intracerebral hemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathologic assessment for the diagnosis of CAA. We derived Boston criteria v2.0 by selecting MRI features to optimize diagnostic specificity and sensitivity in a pre-specified derivation sample (Boston cases 1994 to 2012, n=159), then externally validated in pre-specified temporal (Boston cases 2012-2018, n=59) and geographical (non-Boston cases 2004-2018; n=123) validation samples and compared their diagnostic accuracy to the currently used modified Boston criteria.

Results:
Based on exploratory analyses in the derivation sample, we derived provisional criteria for probable CAA requiring presence of at least 2 strictly lobar hemorrhagic lesions (intracerebral hemorrhage, cerebral microbleed, or cortical superficial siderosis focus) or at least 1 strictly lobar hemorrhagic lesion and 1 white matter characteristic (severe degree of visible perivascular spaces in centrum semiovale or white matter hyperintensities multispot pattern). Sensitivity/specificity of the criteria were 74.8/84.6% in the derivation sample, 92.5/89.5% in the temporal validation sample, 80.2/81.5% in the geographic validation sample, and 74.5/95.0% in cases across all samples with autopsy as the diagnostic gold standard. The v2.0 criteria for probable CAA had superior accuracy to the currently modified Boston criteria (p<0.005) in the autopsied cases.

Conclusion:
The Boston criteria v.2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their high specificity. Validation of the criteria across independent patient settings firmly supports their adoption into clinical practice and research.
Abstract MP41: Acute Ischemic Stroke and Coronavirus Disease 2019: An Analysis of 27,676 Patients
Authors: Qureshi Adnan I , Baskett William , Huang Wei , Shyu Daniel , Myers Danny , Raju Murugesan , Lobanova Iryna , Suri Fareed K , Naqvi Hasan , French Brandi R , Siddiq Farhan , Gomez Camilo r , Shyu Chi-Ren
Published: March 2021

Background and Purpose:
Acute ischemic stroke may occur in patients with Coronavirus disease 2019 but risk factors, in hospital events, and outcomes are not well studied in large cohorts. We identified risk factors, co-morbidities, and outcomes in patients with Coronavirus disease 2019 with or without acute ischemic stroke and compared with patients without Coronavirus disease 2019 and acute ischemic stroke.

Methods:
We analyzed the data from 54 healthcare facilities using the Cerner de-identified Coronavirus disease 2019 dataset. The dataset included patients with an emergency department or inpatient encounter with a discharge diagnoses codes that could be associated to suspicion of or exposure to Coronavirus disease 2019, or confirmed Coronavirus disease 2019.

Results:
A total of 103 (1.3%) patients developed acute ischemic stroke among 8,163 patients with Coronavirus disease 2019. Among all Coronavirus disease 2019 patients, the proportion of patients with hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation and congestive heart failure was significantly higher among those with acute ischemic stroke. Acute ischemic stroke was associated with discharge to destination other than home or death (relative risk 2.1, 95% confidence interval 1.7-2.4, p<.0001) after adjusting for potential confounders. A total of 199 (1.0%) patients developed acute ischemic stroke among 19,513 patents without Coronavirus disease 2019. Among all ischemic stroke patients, Coronavirus disease 2019 was associated with discharge to destination other than home or death (relative risk 1.2, 95% confidence interval 1.0-1.3, p=.03) after adjusting for potential confounders.

Conclusions:
Acute ischemic stroke was infrequent in patients with Coronavirus disease 2019 and usually occurs in presence of other cardiovascular risk factors. The risk of discharge to destination other than home or death increased two folds with occurrence of acute ischemic stroke in patients with Coronavirus disease 2019.
Abstract P126: Regional Changes in Patterns of Stroke Presentation During the Covid-19 Pandemic
Authors: ETHERTON Mark R , Zachrison Kori S , Yan Zhiyu , Sveikata Lukas , Bretzner Martin , Estrada Juan , Viswanathan Anand , Singhal Aneesh B , Schwamm Lee H
Published: March 2021

Introduction:
Patterns of hospital presentation have changed during the COVID-19 pandemic. In stroke, delayed or avoided care may translate to substantial morbidity. We sought to determine the effect of the pandemic on patterns of stroke patient presentation and quality of care.

Methods:
We analyzed data from 25 New England hospitals: one urban, academic comprehensive stroke center (CSC) and telestroke hub, and 24 spoke hospitals in the telestroke network. We included all telestroke consultations from the 24 spokes and stroke admissions to the CSC from 11/1/2019 through 4/30/2020. We examined trends in stroke presentation including large vessel occlusion (LVO), alteplase use, and endovascular thrombectomy among eligible subjects. We compared proportions and bivariate comparisons to examine for changes pre- vs. post-3/1/2020, and used linear regression to examine trends over time.

Results:
Among 1248 patient presentations, telestroke consultations (0.4 fewer consults per week, p=0.005) and ischemic stroke patient admissions (decrease of 0.2 patients per week, p=0.04) decreased among the spokes and hub. Age and stroke severity were unchanged over the study period. We found no change in alteplase administration at telestroke spoke hospitals, but did note a decrease in both alteplase use (1.5 per week prior to March 1
st
and 1 per week after, p=0.05) and thrombectomy at our CSC (0.1 fewer cases per week, p=0.02). Time metrics for patient presentation and care delivery were unchanged, however, rates of adherence for several quality measures were reduced during the pandemic (Table 1).

Conclusions:
In this regional analysis, we found decreasing telestroke consultations and ischemic stroke admissions, and reduced performance on stroke quality of care measures during the COVID-19 pandemic. Contrary to prior reports, we did not find an increase in thrombectomy nor decrease in clinical severity that might be expected if patients with milder symptoms avoided hospitalization.
Abstract P192: National Institute of Neurological Disorders and Stroke Common Data Elements: Stroke Version 2.0 Recommendations
Authors: Gay Katelyn , Collie Damon , Sheikh Muniza , Saver Jeffrey L , Warach Steven J , Wright Clinton B , Mendoza-Puccini Maria Carolina , Janis Lawrence S ,   Stroke V2.0 CDE Working Group
Published: March 2021

Introduction:
The National Institute of Neurological Disorders and Stroke (NINDS) Common Data Element (CDE) project provides standardized data collection formats for neuroscience clinical research. Goals are to increase harmonization, efficiency, and data quality in studies, and facilitate collaboration through data sharing and analysis. Stroke-specific CDEs were developed in 2010. The Stroke Oversight Committee (OC) reviewed Core CDEs in 2015. Subarachnoid hemorrhage and unruptured cerebral aneurysms (SAH)-specific CDEs were developed in 2017. In 2018, the Stroke OC recommended that Stroke CDEs be updated to Version 2.0.

Methods:
NINDS in August 2018, convened the Stroke V2.0 Working Group (WG) consisting of over 50 international subject matter experts. Each domain-specific subgroup: Biospecimens, Biomarkers, and Laboratory Tests; Hospital Course and Acute Therapies; Imaging; Long Term Therapies; Medical History and Prior Health Status; Outcomes and Endpoints; Stroke Presentation and Vital Signs; and Stroke Types and Subtypes, reviewed Stroke V1.0 and SAH CDEs relevant to their purview. Subgroups met regularly to discuss updates to existing Stroke CDEs, addition of new instruments and case report forms (CRFs), and harmonization with SAH CDEs. Draft V2.0 recommendations were posted for public review from February 26 to April 8, 2020. The WG considered public feedback before V2.0 was finalized.

Results:
This comprehensive review led to updates across CDEs and additions to therapies, outcomes, and imaging domains including Imaging Acquisition and SAH Surgical/Procedural Interventions CRFs and Fugl-Meyer Assessment and PROMIS-29 outcome measures. Following review of 39 V1.0 Stroke outcome measures, 11 were reclassified. Stroke V2.0 CDE recommendations include revised and new template CRFs, data dictionaries, instrument informational documents and guidance documents. Stroke V2.0 was posted to the NINDS CDE website in summer 2020.

Conclusions:
Updates to the NINDS CDEs based on scientific advancements and user feedback ensure they remain a useful resource. The Stroke v2.0 CDEs provide a current tool for clinical investigators across research domains. NINDS encourages CDE use to standardize research data collection across studies.
Abstract P211: Stroke Recovery Navigator to Improve Post Stroke Recovery
Authors: Rindels Erin , Taylor Anna , Quigley Aurora ,   SRN Steering Committee
Published: March 2021

Social support impacts recovery after stroke. Patient centered navigation programs provide social support and have shown benefit with other patient populations. The purpose of this study is to determine if there is a difference in outcomes for stroke survivors and caregivers who receive navigation services post-discharge. The study used a multi-center quasi-experimental before-after design to examine the impact of a telephone-based stroke navigation. Selected recruitment sites were nine facilities without navigation programs. Facilities provided information to survivors and caregivers about Stroke Recovery Navigator (SRN) prior to discharge and made referrals to the program. Participants were randomized into control and intervention groups using a computer-generated coin flip. Navigators completed telephone assessments within a week of referral. Navigators received the following trainings: Patient Navigation Fundamentals, motivational interviewing, and mental health first aid. The Reintegration to Normal Living (RNLI) scale was completed by all survivors and the Zarit Caregiver Burden scale was completed by all caregivers. The control group completed the initial and final assessments using these tools. In addition to these assessments, the intervention group received an individualized navigation plan and weekly contact by the SRN. The study randomized 301 individuals (82 caregivers, 219 survivors), with completion rate of 32%. Caregiver demographic characteristics and baseline caregiver burden scores were not statistically significant. Caregiver burden in the intervention group were lower compared to the control group, but not statistically significant (p=0.25). Demographic characteristics for survivors were similar between groups. RNLI score for survivors was slightly higher for the intervention group (p<0.10). To achieve statistical significance additional participants were needed.

In conclusion differences in quality of life for survivors and caregivers were not statistically significant between the groups. Additional information on the benefits of an SRN program is needed to support its implementation. However, important lessons were learned to improve such program and its design.
Abstract P248: CSC Implementation of Artificial Intelligence Software Significantly Improves Door-In to Groin Puncture Time Interval and Recanalization Rates
Authors: Hassan Ameer E , Ringheanu Victor M , Preston Laurie , TEKLE WONDWOSSEN
Published: March 2021

Introduction:
Viz.ai artificial intelligence (AI) software utilizes AI powered large vessel occlusion (LVO) detection technology which automatically identifies suspected LVO through CT angiogram (CTA) imaging and alerts on-call stroke teams. We performed this analysis to determine if utilization of this AI software can reduce the door-in to groin puncture time interval within the comprehensive care center (CSC) for patients arriving at the CSC for endovascular treatment.

Methods:
We compared the time interval between door-in to groin puncture for all LVO transfer patients who arrived at our comprehensive care center for approximately two years prior to and after the implementation of the AI software in November of 2018. Using a prospectively collected database at a CSC, demographics, door-in to groin time, modified Rankin Scale at discharge (mRS dc), mortality rate at discharge, length of stay (LOS) in hospital, mass effect, and hemorrhage rates were examined.

Results:
There were a total of 188 patients during the study period (average age 69.26 ± 14.55, 42.0% women). We analyzed 86 patients from the pre-AI (average age 68.53 ± 13.13, 40.7% women) and 102 patients from the post-AI (average age 69.87 ± 15.75, 43.1% women); see Table 1 for comparison of baseline characteristics and outcomes. Following the implementation of the AI software, the mean door-in to groin puncture time interval within the CSC significantly improved by 86.7 minutes (206.6 vs 119.9 minutes; p < 0.0001); significant improvements were also noted in the rate of good recanalization (mTICI 2B-3) for patients in the post-AI population (p=0.0364).

Conclusion:
The incorporation of the AI software was associated with a significant improvement in treatment time within the CSC as well as significantly higher rates of good recanalization for patients treated. More extensive studies are warranted to expand on the ability of AI technology to improve transfer times and outcomes for LVO patients.
Abstract P29: Improving Door to Needle Alteplase Times: Pharmacist Involvement During Code Stroke
Authors: Bayies Aaron L , Kiley Amy , Eng Claire C
Published: March 2021

Introduction:
According to the American Stroke Association’s “Guidelines for Acute Ischemic Stroke (2018),” it is a Class IIb recommendation that hospitals set a goal of achieving Door to Needle (DTN) times within 45 minutes in > 50% of ischemic stroke patients who are treated with IV alteplase (tPA). Furthermore, a new Class I recommendation states that “multidisciplinary teams with access to neurological expertise [be utilized] to safely increase IV thrombolytic treatment.” Review of the literature shows that there is still limited research in this area, and the potential exists to discover more about the utility of the pharmacist role in the acute stroke patient.

Methods:
A retrospective, single-center study of patients who received alteplase for acute ischemic stroke in the Emergency Department, based on the initial “Code Stroke” activation, between January 1, 2019 and July 1, 2020 was conducted. The purpose was to investigate the difference in DTN treatment times when a pharmacist is involved compared with times when a pharmacist is not available. The primary outcome was the median DTN administration time, with secondary outcome of achievement of DTN time < 45 minutes.

Results:
The patients who had a pharmacist involved in their care (n=30) showed a median DTN time of 42.5 minutes, compared to 58 minutes in the group without pharmacy involvement (n=22). Patients in the pharmacy group achieved a DTN time of < 45 minutes in 57% of cases, versus 32% of cases in the non-pharmacy group.

Conclusion:
Our current practice in the ED regarding availability of a pharmacist varies, given variable patient volume and limitation of resources in our community-based, Primary Stroke Center. Our data suggests that expanding the number of hours covered by a dedicated pharmacist might help improve DTN times. Though our standard practice is still to provide scheduled, regular training on alteplase to ED nursing staff, the unique expertise and additional benefits provided by a pharmacist may serve to complement and enhance the treatment effectiveness of the entire team.
Abstract P323: Stroke Lesion Pattern-Specific Influence of White Matter Hyperintensities on Stroke Severity in Acute Ischemic Stroke
Authors: Bonkhoff Anna K , Bretzner Martin , Schirmer Markus D , Hong Sungmin , Giese Anne-Katrin , Donahue Katy , Nardin Marco , Dalca Adrian , ETHERTON Mark R , Golland Polina , Wu Ona , Jern Christina , Lindgren Arne , Maguire Jane , Rost Natalia S ,   on behalf of the MRI-GENIE and GISCOME Investigators and International Stroke Genetics Consortium.
Published: March 2021

Introduction:
MRI-detected white matter hyperintensity (WMH) burden is linked to the overall brain health and incident stroke outcomes. However, data are limited as to whether specific acute stroke lesion patterns purport greater stroke severity in patients with extensive pre-existing WMH. In this analysis, we sought to investigate lesion pattern-specific WMH effects on AIS severity.

Methods:
We analyzed clinical and lesion data from 621 AIS patients enrolled in the multi-site MRI-GENIE study. The acute NIHSS was modelled via Bayesian hierarchical regression. Using ten stroke lesion patterns, that served as input variables of main interest, we introduced a hierarchical level differentiating between patients with higher and lower than median WMH volume (WMHv). Lesion pattern posterior distributions for higher and lower WMHv patients were subtracted to infer substantial differences.

Results:
In this AIS cohort [age: 65.3±14.6, 60% male], a higher WMHv was associated with greater stroke severity only when specific left-hemispheric brain regions were infarcted. This
“lesion pattern 3”
was mainly characterized by left middle and inferior frontal gyrus, insular and opercular cortex, pre- and post-central gyrus, and subcortical basal ganglia regions (
Fig
).

Conclusions:
Higher WMH burden appears to enhance the detrimental effect of acute stroke lesions involving left-hemispheric brain regions underlying language and motor functions. This effect might be due to an exacerbated disruption of functional network integrity by the combination of WMH and stroke lesions and could be explored further in functional imaging studies that simultaneously considered information from both lesion types.
Abstract P333: Prediction of Stroke Lesion Growth Rates by Baseline Perfusion Imaging
Authors: Wouters Anke , Robben David , Christensen Soren , Marquering Henk , Roos Yvo , Oostenbrugge Robert Van V , van Zwam Wim , DIPPEL Diederik W , Majoie Charles B , van der Lugt Aad , Lansberg Maarten G , Albers Gregory W , Suetens Paul , Lemmens Robin
Published: March 2021

Objective:
Computed Tomography Perfusion imaging (CTP) allows estimation of tissue status in patients with acute ischemic stroke. We aimed to improve prediction of the final infarct and individual infarct growth rates based on a deep learning approach.

Methods:
We trained a deep neural network to predict the final infarct volume in patients presenting with large vessel occlusions based on the native CTP images, time to reperfusion and reperfusion status in a derivation cohort (MR CLEAN study). The model was internally validated in a five-fold cross-validation and externally in an independent dataset (CRISP study). We calculated the mean absolute difference (MAD) between the predictions of the deep learning model and the final infarct volume versus the MAD between CTP processing by RAPID software and the final infarct volume. Next, we determined infarct growth rates for every patient.

Results:
We included 127 patients from the MR CLEAN (derivation) and 101 patients of the CRISP study (validation). The deep learning model improved final infarct lesion prediction compared to the RAPID software in both the derivation, MAD 34.5 vs 52.4ml, and validation cohort, 41.2 vs 52.4 ml, (p < 0.01). We obtained individual infarct growth rates enabling the estimation of final infarct volume based on time and grade of reperfusion.

Interpretation:
We validated a deep learning-based method which improved final infarct volume estimations compared to classic CTP processing. In addition, the deep learning model predicted individual infarct growth rates which could potentially enable the introduction of tissue clocks during the management of acute stroke.

Figure

A.
Patient with a mean infarct growth of 18.3 ml/h. The final infarct volume was 104 ml. Recanalization was performed 131 min after CT perfusion with a mTICI = 2b.
B
. Patient with a mean infarct growth of 2.3 ml/h. The final infarct volume was 10.8 ml. Recanalization was performed 101 min after CT perfusion with a mTICI = 3.
Abstract P34: Comparing the Burden of Telehealth versus In-Person Speech Rehabilitation Therapy - Perspectives From Patients and Care Partners
Authors: Mehta Sonia , Sico Jason J
Published: March 2021

Introduction:
While speech rehabilitation therapy (SRT) for stroke survivors with residual speech and cognitive impairment is standard of care, SRT delivered in person in the clinic imposes several burdens on stroke survivors and their care partners. This is especially true with more frequent, higher intensity SRT. SRT delivered via telehealth has the potential to mitigate such travel-related financial, physical stress and psychological stress burdens.

Hypothesis:
The High-Intensity Tele-speech Therapy for Stroke (HITTS) pilot program will reduce burden for the stroke survivor:care partner dyad compared with in-person visits.

Methods:
We adapted evidence-based aphasia therapies implemented into a telehealth delivery model for four stroke survivor:care partner dyads over a six-week period. Following an initial face-to-face evaluation, skilled SRT was delivered via telehealth for five hours per week. The projected cost of travel between their home and VA medical center (VAMC) was obtained via VA Managerial Accounting System. Appointment preparation and travel time was calculated based on a combination of dyad report and GoogleMaps. All completed a survey at the end of HITTS regarding potential value of HITTS, perceived burden, and open text fields.

Results:
HITTS saved dyads (mean ± SD) both money ($370.96 ± 63.26) and time (16.47 ± 3.55 hours) over the six-week period. Increased burden was commonly reported for in-person appointments but not for telehealth appointments. Patients more commonly reported physical burden of attending in-person appointments whereas care partners more commonly reported psychological burden (Table).

Conclusions:
Dyad burden was not associated with a high intensity STR program, likely attributable to the reduction in resources required to attend in-person visits. HITTS is a promising healthcare delivery model which can also promote social distancing and reduce COVID exposure for high-risk stroke patients and their care partners.
Abstract P375: Cortical Venous Opacification Patterns and Outcome in Patients With Tandem Carotid Occlusion - Results From the ESCAPE NA1-Trial
Authors: Marko Martha , Cimflova Petra , Singh Nishita , Ospel Johanna , Kashani Nima , Mayank Arnuv , Nogueira Raul G , McTaggart Ryan A , Demchuk Andrew M , Poppe Alexandre Y , Hill Michael D , Menon Bijoy K , Goyal Mayank , Almekhlafi Mohammed A ,   on behalf of the ESCAPE NA1-Investigators
Published: March 2021

Background:
The degree of cortical venous opacification could reflect the degree of ischemia in tandem occlusions strokes. We assessed the association between asymmetric cortical vein opacification and outcome among patients with acute ischemic stroke and tandem occlusion.

Methods:
ESCAPE NA1 was a multicenter randomized-controlled trial comparing medical treatments nerinetide vs. placebo in patients with acute ischemic stroke and large vessel occlusion who underwent EVT. Tandem carotid occlusion was defined as complete occlusion of the ICA on catheter angiography. We assessed cortical venous opacification on baseline CTA using the COVES score (Jansen, et al. Radiology 2019, ranging from 0-6 with lower numbers indicating poor cortical venous filling, and dichotomized to 0 vs. 1-6). The influence of cortical venous opacification on functional outcome was analyzed using regression modelling with adjustment for age, baseline NIHSS and ASPECTS, thrombolysis and treatment allocation.

Results:
We assessed 115 patients with tandem occlusion. Median COVES score was 2 (IQR 1-3) with 9 patients (8%) scoring 0 (complete absence of cortical venous filling). Patients with COVES 0 were less likely to have good leptomeningeal collaterals (good collaterals: COVES 0: 0/9 (0%) vs. COVES 1-6: 19/102 (18%), p = 0.007). Patients with COVES 0 were less likely to achieve good outcome (mRS 0-2, COVES 0: 3/9 patients (33%) vs. COVES 1-6: 79/106 (74%), p=0.016). Cortical venous filling was significantly associated with good functional outcome on univariable analysis (OR 5.9, 95%CI 1.4 - 25.0), and after adjustment for baseline variables (OR 8.6, 95%CI 1.4 - 51.0). Cervical carotid angioplasty and/or stenting did not modify functional outcome after adjustment for COVES score.

Conclusion:
Impaired venous drainage is a marker of poor pial collaterals and is associated with poorer outcome in tandem occlusion patients.
Abstract P43: The Importance of Medical Complications in Determining Outcomes After Subarachnoid Hemorrhage
Authors: Neifert Sean , Schupper Alexander , Martini Michael , Chapman Emily , Shuman William , Oermann Eric , Mocco J D , Mayer Stephan A , MacDonald R Loch L ,   SAHIT Collaboration
Published: March 2021

Introduction:
Despite their high prevalence, prospective data on medical complications after aneurysmal subarachnoid hemorrhage (aSAH) and their contribution to functional outcome are sparse. We review rates of such events and correlate them to functional outcomes in three prospective datasets of patients with aSAH.

Methods:
Patients from two clinical trials (NEWTON-2, CONSCIOUS-1) and one clinical registry (Subarachnoid Hemorrhage Outcomes Project) were included. A good functional outcome was defined as a Glasgow Outcomes Scale (GOS) score of 4 or 5. Seventeen medical complications were assessed and their association with functional outcomes was determined with multivariable logistic regression. The variance in outcome explained by medical complications was calculated using difference in Nagelkerke’s R-squared.

Results:
Among the 1,430 patients, the most common complications were fever (564, 39%), anemia (410, 29%), and pneumonia (341, 24%). Patients who suffered any complication (OR: 0.45; 95% CI: 0.36 to 0.57; p<0.001) were less likely to have a good functional outcome in unadjusted analyses. In multivariable analysis, complications independently associated with lower rates of good functional outcome were anemia (OR: 0.60; 95% CI: 0.44 to 0.80; p<0.001), cardiac arrest (OR: 0.14; 95% CI: 0.05 to 0.37; p<0.001), pneumonia (OR: 0.48; 95% CI: 0.35 to 0.66; p<0.001), pulmonary edema (OR: 0.67; 95% CI: 0.45 to 0.99; p=0.047), and acute kidney injury (OR: 0.34; 95% CI: 0.12 to 0.98; p=0.047). A panel of eleven medical complications explained 8% of the variation in functional outcomes.

Conclusions:
Medical complications contribute to functional outcomes after aSAH, but their individual contributions to outcomes are relatively small. This should be noted when considering trials directed at preventing or treating any one complication and raises the question of studying comprehensive neurointensive care packages in the future.
Abstract P685: Primary Care Utilization for Primary Prevention Continues to Be Lacking in Patients With Stroke
Authors: Senetar Alexander J , Bonnin Daniel A , Branstetter Hannah E , Simpkins Alexis N ,   on behalf of the Univ of Florida CREST Initiative
Published: March 2021

Introduction:
Primary care plays an essential role in stroke prevention. Yet still, for many stroke patients, a relationship with a primary care provider (PCP) is not established until after stroke. Our goal was to determine if lack of PCP and the consequential differences in management affects stroke severity.

Methods:
Data was obtained from our Institutional Review Board approved stroke admission database from 2017 to November 2019 of all stroke subtypes (ischemic stroke, transient ischemic attack, subarachnoid and intracerebral hemorrhages). Non-parametric Mann Whitney t-test and regression analysis was used to identify significant differences in medications, stroke risk factors and stroke severity.

Results:
A total of 559 patients were included, median age 67 (interquartile range (IQR) 58-76), 49% woman, 32% established care with a PCP, 36% on medications for diabetes mellitus (DM), 42% hyperlipidemia, 66% anti-hypertensives, 39% anti-platelet agents, and 10% anticoagulation. More patients with PCP were taking anti-hypertensive medications (80% versus (vs) 60%, p value < 0.0001), DM medications (56% vs 30%, p value < 0.0001), anti-platelet agents (46% vs 35%, p value = 0.0149), and medications for hyperlipidemia (49% vs 39%, p value = 0.0426). Admission NIHSS was lower in patients with a PCP median 6 (IQR 3-11) vs median 9 (IQR 4 -15), p value= 0.0016, and median hemoglobin A1c was higher in patients with a PCP 8 (IQR 5.7- 9.3) vs patients without a PCP prior to their stroke 6 (IQR 5.4 - 8.5), p value= 0.0002. Admitting systolic blood pressure was similar 155 (137-177) vs 152 (134-171). After correcting for age and gender, regression analysis demonstrated a significant association between whether a patient had PCP and antihypertensive medication use (odds ratio (OR) 2.413, 95% confidence interval 1.511 - 3.914) and hemoglobin A1c (OR 1.122, 95% CI 1.037 - 1.215). Also, patients with a PCP were more likely to have a lower NIHSS on admission (OR 0.9679, 95% CI 0.9423 - 0.9930).

Conclusions:
These result show that patients not followed by a PCP prior to stroke are less likely to be on medications for primary prevention of stroke, contributing to an increased stroke severity on admission. More research is needed to identify barriers to patients establishing care with PCP.
Abstract P70: SPAK/OSR1 Signaling as a Novel Target for Post-Stroke Oxidative Stress Brain Injury
Authors: Wang Jun , Fiesler Victoria M , Begum Gulnaz , Bhuiyan Mohammad Iqbal H , Dong Shuying , Li Eric , Kahle Kristopher T , Zhang Jinwei , Deng Xianming , Yin Yan , Sun Dandan
Published: March 2021

Stroke is the second leading cause of death worldwide, and ischemic stroke accounts for the vast majority of stroke cases. Currently, recombinant tissue plasminogen activator and endovascular thrombectomy are the two primary therapy strategies for acute ischemic stroke patients. Reactive oxygen species (ROS)-mediated oxidative stress can cause brain injury during reperfusion. We have shown that the Ste20/SPS1-related proline-alanine-rich protein kinase/oxidative stress-responsive kinase-1 (SPAK/OSR1) are activated in ischemic stroke brains, resulting in worsened outcomes in murine stroke models. SPAK activation induces the production of pro-inflammatory cytokines. Post-stroke administration of a novel SPAK inhibitor ZT-1a attenuates cerebral edema and protects against brain damage in
in vivo
model of ischemic stroke. However, whether ROS mediated oxidative stress directly activate SPAK/OSR1 pathway and induces SPAK pro-inflammatory cytokine production in ischemic brains remains unknown. In our extended study, we examined activation of SPAK/OSR1 and its substrate Na-K-Cl cotransporter (NKCC1) in cultured mouse primary neurons in response to hydrogen peroxide (H
2
O
2
)-mediated oxidative stress. We found that exposure of neurons to H
2
O
2
for 24 hrs triggered upregulation of protein expression and phosphorylation activation of SPAK/OSR1 and NKCC1 (
p
< 0.05), which are accompanied with an increase in intracellular Na
+
concentration and neuronal death (
p
< 0.01). These changes were blocked by an ROS scavenger ebselen. Interestingly, both novel SPAK inhibitor ZT-1a and NKCC1 inhibitor bumetanide are able to block H
2
O
2
-induced neuronal damage. We are in the process to assess effects of SPAK inhibitor ZT-1a in reducing ROS-mediated inflammation and brain injury in
in vivo
model of ischemic stroke. Together, our study suggests that ROS can activate SPAK/OSR1 complex during reperfusion injury and the therapeutic potentials of SPAK inhibitor ZT-1a for ischemic stroke.