bluuebunny/crossref_metadata_2025 huggingface dataset:
Neonatal Screening for Congenital Adrenal Hyperplasia in Denmark: 10 Years of Experience
Authors: Lind-Holst Marie , Bækvad-Hansen Marie , Berglund Agnethe , Cohen Arieh S. , Melgaard Lars , Skogstrand Kristin , Duno Morten , Main Katharina M. , Hougaard David Michael , Gravholt Claus Højbjerg , Hansen Dorte
Published: February 2022

Introduction: Early detection of salt-wasting congenital adrenal hyperplasia (SW-CAH) is important to reduce CAH-related morbidity. However, neonatal screening has shown to have a low positive predictive value (PPV), especially among preterm newborns. Here, the Danish CAH screening is evaluated by comparing incidence and morbidity of SW-CAH 10 years before and after introduction of screening. Furthermore, sensitivity, specificity, and PPV are determined. Methods: All newborns in Denmark born during 1999–2018 and diagnosed with SW-CAH were identified in the Danish National Patient Registry and/or at the Department of Clinical Genetics, Rigshospitalet. Newborns with a positive neonatal CAH screening were identified at Statens Serum Institut. Correct diagnosis was evaluated by medical record review. Results: A total of 65 newborns with SW-CAH were identified. The incidence of SW-CAH was 5:100,000 both before and after introduction of screening. Performance of sensitivity and specificity of the screening were 97% and 100%, respectively, and the PPV was 55% for the given period. Stratified according to gestational age, the PPV was 33% and 61% for pre -and fullterm newborns, respectively. Though not significant, the proportion of newborns presenting with SW-crisis decreased after introduction of screening from 29% versus 10% (p = 0.07). Discussion and Conclusion: Neonatal screening for SW-CAH has not led to an increase in the incidence of newborns diagnosed with SW-CAH. The screening algorithm has effectively identified newborns with SW-CAH. After 2009, there was a tendency toward a lower proportion of newborns with SW-crisis at diagnosis. Finally, the study emphasizes the benefits of using second-tier screening as well as repeated screening of premature newborns.
Response-Guided Omission of Anthracycline in Patients with HER2-Positive Early Breast Cancer Treated with Neoadjuvant Taxane and Trastuzumab: 5-Year Follow-Up of Prognostic Study Using Propensity Score Matching
Authors: Fujita Noriko , Fujita Koichi , Kim Seung Jin , Iguchi Chikage , Nomura Takashi , Aono Toyokazu , Yanagisawa Tetsu , Enomoto Yukie , Inakami Keiko , Miyagawa Yoshimasa , Tomoike Riki , Kasugai Tsutomu , Shiba Eiichi
Published: February 2022

Background: De-escalation therapy omitting anthracycline has been generally adopted for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the adjuvant setting, but not in the neoadjuvant chemotherapy (NAC) setting. We investigated whether anthracycline can be omitted in HER2-positive early breast cancer patients receiving neoadjuvant taxane plus trastuzumab with clinical response. Methods: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and July 2018 at Osaka Breast Clinic. The primary outcome was disease-free survival (DFS). The secondary outcome was overall survival (OS). We investigated survival with or without ﬂuorouracil, epirubicin, and cyclophosphamide (FEC) using the log-rank test and propensity score matching (PSM). Results: In total, 142 patients were retrospectively included and median follow-up was 61 months. There was no significant difference in DFS (p = 0.93) and OS (p = 0.46) between the FEC-omitted group and the FEC-added group. The 5-year DFS was 91% and 88% and OS was 100% and 100%, respectively. After PSM, the FEC-omitted group and the FEC-added group had no significant differences in DFS (p = 0.459) and there were no death events in either group. The 5-year DFS was 90% and 88% and OS was 100% and 100%, respectively. Conclusions: Using PSM, the 5-year DFS of HER2-positive early breast cancer was not different with or without anthracycline. Response-guided omission of anthracycline may be an option for HER2-positive early breast cancer patients receiving neoadjuvant taxane and trastuzumab with good response in order to avoid overtreatment.
How Single-Cell Technologies Have Provided New Insights Into Atherosclerosis
Authors: Eberhardt Natalia , Giannarelli Chiara
Published: February 2022

The development of innovative single-cell technologies has allowed the high-dimensional transcriptomic and proteomic profiling of individual blood and tissue cells. Recent single-cell studies revealed a new cellular heterogeneity of atherosclerotic plaque tissue and allowed a better understanding of distinct immune functional states in the context of atherosclerosis. In this brief review, we describe how single-cell technologies have shed a new light on the cellular composition of atherosclerotic plaques, and their response to diet perturbations or genetic manipulation in mouse models of atherosclerosis. We discuss how single-cell RNA sequencing, cellular indexing of transcriptomes and epitopes by sequencing, transposase-accessible chromatin with high-throughput sequencing, and cytometry by time-of-flight platforms have empowered the identification of discrete immune, endothelial, and smooth muscle cell alterations in atherosclerosis progression and regression. Finally, we review how single-cell approaches have allowed mapping the cellular and molecular composition of human atherosclerotic plaques and the discovery of new immune alterations in plaques from patients with stroke.
Abstract 1: Vagus Nerve Stimulation Paired With Rehabilitation For Upper Limb Motor Function After Ischaemic Stroke: Sub-group Analysis Of The Randomised, Blinded, Pivotal, Vns-Rehab Device Trial.
Authors: Dawson Jesse , Liu Charles , Francisco Gerard E , Cramer Steven C , Wolf Steven L , Dixit Anand , Alexander Jen , Ali Rushna , Brown Benjamin , Feng Wuwei , DeMark Lou , Kautz Steven , Majid Arshad , O'Dell Michael W , Pierce David , Prudente Cecilia , Redgrave Jessica , Turner Duncan , Tarver Brent , Engineer Navzer , Kimberley Teresa J
Published: February 2022

Background:
Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomised, blinded, sham-controlled trial. Here we report post-hoc sub-group analyses from the VNS Rehab trial. We aimed to determine whether treatment effects were consistent across subgroups.

Methods:
VNS Rehab included 108 participants with moderate to severe arm /hand weakness, at least nine months after ischaemic stroke. They were randomised to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). The primary outcome was the change in iFugl-Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of in-clinic therapy. The trial was registered on
ClinicalTrials.gov
(NCT03131960). We explored the effect of VNS treatment by sex (n=70 males; n=38 females), age (≤ 65 or >65 years)), time from stroke (median time, 2 years) and baseline FMA-UE score (<=33 severe, >33 moderate). We assessed whether there was any interaction with treatment. No hypotheses were specified prior to this analysis and no formal adjustment was made for multiplicity.

Findings:
On the first day after completion of in-clinic therapy, the mean (±SD) FMA-UE score increased by 5.0 points (SD 4.4) in the VNS group and by 2.4 points (SD 3.8) in the Control group (p=0.001, between group difference 2.6, 95% CI 1.03 to 4.2). The between group difference was similar across all subgroups (figure). No significant treatment interactions were observed with baseline characteristics.

Interpretation:
Participants with moderate to severe arm and hand impairment after ischaemic stroke showed clinically meaningful improvements in motor impairment and function with rehabilitation paired with VNS compared to rehabilitation with sham VNS. The response appeared similar across pre-defined subgroups of interest.
Abstract 105: Polygenic Burden Of Hypertension-related Alleles Leads To Non-traumatic Subarachnoid Hemorrhage At Younger Ages
Authors: Vanent Kevin N , Acosta Julian N , Both Cameron , Leasure Audrey C , Noche Rommell B , Levitt Michael R , Matouk Charles C , Gunel Murat , Sheth Kevin N , Falcone Guido J
Published: February 2022

Introduction:
Non-traumatic subarachnoid hemorrhage (SAH) is strongly linked to hypertension, a condition highly influenced by common genetic variants. For complex diseases influenced by genetic and environmental factors, genetic predisposition plays a key role in earlier onset. We tested the hypothesis that persons with a higher polygenic burden of hypertension-related alleles have SAH at younger ages.

Methods:
We analyzed data from the UK Biobank, a large cohort study that enrolled over 500,000 Britons aged 40-69. We included participants of European descent. We constructed two polygenic risk scores (PRS) using 807 independent genetic variants known to associate with higher systolic and diastolic blood pressure (BP). We fitted linear regression to assess the relationship between these PRS and the age-of-onset of SAH, using product terms to test for interaction with sex. We subsequently implemented Mendelian Randomization analyses using the inverse variance weighted and weighted median methods to evaluate causality.

Results:
We evaluated a total of 1,178 SAH cases (mean age, 58; female sex, 722 [61.3%]). When evaluating all participants jointly, there was no association between the systolic BP PRS and age-of-onset for SAH (p=0.130). There was a significant interaction between the PRS and sex (p=0.002): each additional standard deviation of the systolic BP PRS was associated with an earlier onset of SAH in females (beta, -1.45; 95% CI, -2.31 to -0.58; p=0.001), but not in males (adjusted beta, 0.83; 95% CI, -0.37 to 2.02; p=0.176). In MR analyses, a 10mmHg increase in genetically determined systolic BP was associated with a 5-year earlier onset of SAH in female participants using both the inverse variance weighted (beta, -4.72; 95% CI, -7.34 to -2.10; p<0.001) and weighted median approaches (beta, -5.05; 95% CI, -9.19 to -0.90; p=0.017). Analyses with the diastolic BP SNPs yielded comparable results (all p<0.05).

Conclusions:
Genetically determined hypertension is associated with earlier onset of non-traumatic SAH in women. These results indicate that genetic predisposition may play a more important causal role in younger patients and point to genetic information as possible tools for early identification of high-risk individuals.
Abstract 106: Twenty Year Trends In US Stroke Mortality In Younger Vs Older Adults
Authors: de Havenon Adam H , Majersik Jennifer J , Leasure Audrey C , Delic Alen , Tirschwell David L , Sheth Kevin N
Published: February 2022

Introduction:
After decades of consistent declines, stroke mortality started to level off beginning in 2013, with increases seen in younger stroke patients.

Methods:
We performed a post hoc analysis of county-level stroke death rate per 100,000 adults, for ischemic and hemorrhagic stroke, from 1999-2018 using CDC estimates. We stratified by age 35-64 (young) and ≥65 (old), and by county-level geographic factors and unemployment rate.

Results:
We included data from over 3,000 counties. Figure 1 shows stroke mortality began to increase for younger patients in 2013-14, but continued to decline for older patients. The second row shows that the disparity in stroke death rate for younger rural patients was no longer significant from 2005-13 (overlapping 95% CIs), but from 2014-18, younger rural patients had a significantly higher rate of stroke death compared to urban/suburban patients. Younger patients in counties with more unemployment (vs. less) or in the South (vs. other Census regions) had higher rates of stroke death. Figure 2 shows county-level changes by 5-year periods (e.g. 1999-2003 vs. 2004-08), which highlight the spread over time of increased stroke death rate in all regions of the contiguous United States for younger patients.

Conclusions:
The trend of consistently decreasing stroke death rate stabilized in 2013, with subsequent increase seen for younger adults aged 35-64, particularly in rural, Southern, and high unemployment counties.
Abstract 111: Establishment Of Non-invasive Imaging Of Vascular Malformations And Intracerebral Hemorrhage In Oncogenic KRAS-induced Sporadic Brain Arteriovenous Malformations
Authors: Park Eunsu , Huang Shuning , Aronowski Jaroslaw A , Chen Peng R , Kim Eunhee
Published: February 2022

Introduction:
Brain arteriovenous malformations (bAVMs) is a high risk factor for intracerebral hemorrhage (ICH). We recently confirmed that KRAS
G12V
mutation is sufficient to induce sporadic bAVMs that recapitulate the characteristics of human bAVMs including a tangled vasculature and ICH. However, the bAVMs form in random location in the mouse brain. Therefore, it will be important to establish non-invasive methods to detect bAVMs and bAVM-associated ICH for further studies identifying pathophysiology of bAVMs and testing drug efficacy on bAVM pathology.

Methods:
We induced bAVMs in mice by adeno-associated virus (AAV)-BR1 carrying KRAS
G12V
. Magnetic resonance angiography (MRA) and T2*-weighted MR imaging (MRI) were performed to assess bAVM and ICH. The bAVM and ICH were graded by the volume (e.g., for bAVMs, grade 1<1mm
3
, 1mm
3
<grade 2<2mm
3
...grade 9>9mm
3
; for ICH, grade 1<0.5mm
3
, 0.5mm
3
<grade 2<1mm
3
...grade 9>4.5mm
3
). The ICHs smaller than 0.5 mm
3
and round shape were considered as microbleeding (ITK-SNAP and ImageJ). The MRI/MRA-visualized bAVM and ICHs were confirmed by histological analyses (latex casting and H&E and Ter-119 immunostaining).

Results:
By MRA, bAVMs were first detected at 7 weeks after AAV-BR1-KRAS
G12V
injection and showed robust growth between 7 to 8 weeks. Various size of bAVMs were detected at 9 weeks after the AAV injection. The grade 1 of microbleeding preceded bAVM formation and was detected 2-3 weeks after AAV-BR1-KRAS
G12V
injection. We confirmed that the locations of bAVM/ICH detected by MRI/MRA imaging overlapped with the ones detected by vascular casting and histological analysis.

Conclusions:
We successfully established the non-invasive protocol for detecting bAVM growth and ICH in our sporadic bAVM mice model using MRI/MRA technique. With further improvement of the imaging resolution to detect smaller and earlier bAVMs, our non-invasive bAVM/ICH imaging methods will be a useful tool for bAVM study.
Abstract 127: Anatomical Predictors Of Malignant Cerebral Edema Using Voxel-based Lesion Symptom Mapping
Authors: Topiwala Karan K , McCullough-Hicks Margy E , Christensen Soren , Albers Gregory W
Published: February 2022

Introduction:
Prior publications indicate an increased risk of developing malignant cerebral edema in acute ischemic stroke patients with temporal lobe involvement. We examined on a voxel-by-voxel basis whether topographic locations of baseline diffusion and perfusion weighted MRI lesions could predict subsequent need for treatment of malignant cerebral edema with either decompressive hemicraniectomy (DHC) or hyperosmolar therapy (HT).

Methods:
We used a registry of 898 patients evaluated for acute treatment for suspected large vessel occlusion (LVO) stroke. Fifty-nine cases, receiving either DHC and/or HT and having sufficient data for evaluation, were manually matched with 59 controls for age, lesion size, and Thrombolysis in Cerebral Infarction (TICI) score. Binary masks of ADC + Tmax >6s lesions generated from automated RAPID software output were created. Lesions were co-registered to standard MNI atlas space. Voxel-based lesion symptom mapping (Version 2.55) was used to generate statistical maps of lesion contribution to malignant cerebral edema formation. Maps were thresholded to P<0.01 on basis of cluster size and permutation method. Hemispheres were combined to increase statistical power.

Results and Conclusions:
118 patients were analyzed. After controlling for age, TICI score, and lesion volume, only punctate regions of the parieto-occipital lobe were found to be mildly predictive of the need for either DHC or HT (T-scores 2.5-3, p<0.01). There does not appear to be any significant topographic region of the brain involved on baseline diffusion-perfusion MRI that predicts subsequent need for treatment of malignant cerebral edema in patients with LVO stroke.
Abstract 13: 3D-Map Analysis Of Symptomatic Intracranial Atherosclerotic Plaques
Authors: Sanchez Sebastian , Raghuram Ashrita , Leira Enrique C. C , Samaniego Edgar A
Published: February 2022

Background:
The study of plaque enhancement using high resolution vessel wall imaging can provide useful prognostic data. However, this analysis is hindered by plaque sampling and methodological constrains. We developed a new method to quantify plaque enhancement with 3D map analysis.

Methods:
Ultra-high resolution (7 Tesla) vessel wall imaging was performed on 41 patients with history of symptomatic atherosclerotic disease. Culprit and non-culprit plaques were analyzed. 3D reconstructions of culprit (N=41) and non-culprit plaques (N=14) was performed on T1 and T1+Gd images. Using an in-house code, orthogonal probes were extended from the lumen of the vessel into the arterial wall (Figure). In this way, the entire wall was sampled with multiple spokes. These values were then normalized to the corpus callosum (CC) to obtain a signal intensity ratio (SI
ratio
). Dynamic contrast uptake was quantified as the change in mean SI of the plaque after contrast administration.

Results:
Forty one culprit and 14 non-culprit plaques (N=55) were analyzed. Culprit plaques enhanced with gadolinium (Gd) more significantly (SI
plaque
= 0.76 ± 0.28) than non-culprit plaques (SI
plaque
=0.58 ± 0.14) (p=0.05). In addition, culprit plaques displayed more contrast uptake (ΔSI
plaque
=0.33±0.25) than non-culprit plaques (ΔSI
plaque
=0.19 ± 0.08,p=0.01).

Conclusion:
3D analysis of plaque enhancement with ultra-high resolution MRI is a promising technique that may be used as a biomarker of culprit intracranial atherosclerotic plaques. In addition, quantifying the dynamic plaque contrast uptake may provide more insight into the biology of these lesions.Figure. Magnified 7T coronal view of a basilar artery plaque pre (A) and post administration of Gd (B). 3D analysis of the dynamic uptake of Gd in T1 (C) and T1 + Gd (D). This plaque had a of 0.49 = highly enhancing.
Abstract 146: Stroke Misses Are Rare And Elusive In Telestroke Care
Authors: Miao Chris , Edwards Brandon , Musser William S , Graham Glenn , Anderson Jane A , Martini Sharyl , Williams Linda S
Published: February 2022

Background:
Stroke mimic algorithms have been developed for use in telestroke systems of care but less is known about how frequently and what factors are associated with a clinically significant missed telestroke ischemic stroke diagnosis. We sought to examine the frequency and clinical characteristics of missed strokes (MS) in the VA National TeleStroke Program (NTSP)

Methods:
We analyzed NTSP consultations from April 2018 to September 2020. Consults with a telestroke diagnosis of “other” (not stroke/TIA) and a primary inpatient discharge diagnosis of ischemic stroke were chart reviewed. We applied the Oxfordshire stroke localization categories to all MRIs positive for acute ischemic stroke. Clinical outcomes were designated as MS-significant (MS-S) if symptoms of stroke persisted at discharge or rehabilitation was required, otherwise they were MS-not significant (MS-NS). Patient demographics, clinical conditions, last known well (LKW) and NIHSS were compared between the MS-S and MS-NS groups using Chi-square and t-tests.

Results:
Out of 3,163 consultations, 55 (1.7%) were identified as MS; 33 (60%) of these were MS-S, and 22 (40%) were MS-NS. The overall sample had a mean age of 72 years, mean LKW of 219 minutes prior to arrival, and median NIHSS of 3. Of those with MS, 46 (83.6%) had a brain MRI showing acute stroke; 30% partial anterior, 26% lacunar, 24% posterior. MS-S patients did not differ from MS-NS in age, race, LKW, NIHSS, stroke location or clinical diagnoses (Table). The most common diagnosis among MS was stroke recrudescence (25%).

Conclusions:
Clinically significant missed strokes were present in only 1% of more than 3,000 telestroke cases. Demographic and clinical features did not distinguish clinically significant misses from non-significant misses. Posterior circulation strokes represented almost a quarter of all MS. Implementing a rapid brain MRI protocol may be one way to avoid rare misses of acute ischemic stroke diagnosis via telestroke.
Abstract 147: Reducing The Workflow Times For Reperfusion Therapy For Acute Ischemic Stroke By Using A Task Management Mobile Application For Stroke Care
Authors: Matsumoto Shoji , Nakahara Ichiro , Yasuda Ayuko , Okita Shinpei , Aoki Michiru , Ishii Akira , Okawa Masakazu , Nishi Hidehisa , Yamada Kentaro , Kubo Michiya , Ishihara Takuma , KOYAMA Hiroshi , Kira Junichi
Published: February 2022

Background:
Since the effectiveness of reperfusion therapy for acute ischemic stroke (AIS) is highly time-dependent, stroke centers are required to carry out quality management (QM) of AIS care and provide treatment promptly. For many hospitals, however, QM are not easy. We have developed a mobile application named Task Calc. Stroke (TCS) to support the hospital's QM while supporting the staffs task processing. This study aims to evaluate the impact of using TCS on the workflow times of reperfusion therapy and clinical outcomes.

Methods:
We conducted a prospective cohort study at 4 Japanese comprehensive stroke centers for 33 months from June 2018 to December 2020. Patients treated with intravenous tissue plasminogen activator (IV-t PA) / mechanical thrombectomy (MT) were enrolled. The research team visited each facility and trained how to use TCS for AIS care. Each facility begun using TCS after training. We divided the study period into three stages as follows: 1) Pre-intervention stage, 2) Training stage, and 3) Using TCS stage and examined the workflow times such as door-to-needle time (D2N) for IV-tPA and door-to-puncture time (D2P) for MT and clinical outcomes (at discharge modified Rankin Scale score (mRS)).

Results:
During the study period, 333 cases (165 pre-intervention stage, 80 training stage, and 88 using TCS stage) underwent reperfusion therapy, 250 received IV-tPA, and 156 received MT. For D2N, the geometric mean decreased significantly from 57.7 minutes to 51.3 minutes in the training stage compared to the pre-intervention stage (Exp (β) 0.816: 95% CI 0.691-0.963, P=0.016) and further decreased to 49.7 minutes in the using TCS stage (Exp(β) 0.759: 95% CI 0.65-0. 888, P=0.001). For D2P, it slightly increased from 91.1 to 95.8 minutes in the training stage (Exp(β) 0.939: 95%CI 0.75-01.175, P=0.578), and significantly decreased to 84.2 minutes in the using TCS stage (Exp(β) 0.675: 95%CI 0. 524-0.87, P=0.003). The severity of disability tended to decrease across the mRS range (adjusted common odds ratio, 0.49; 95% CI, 0.22-1.11; P = 0.088) in the TCS using stage.

Conclusions:
TCS care support hospital's QM to reduce the workflow times of reperfusion therapy and tends to improve clinical outcomes.
Abstract 150: Safety And Feasibility Of An ED-To-Outpatient Pathway For Transient Ischemic Attack Or Non-Disabling Stroke
Authors: Roy Alexis T , Sreekrishnan Anirudh , Faye Erica Camargo , Silverman Scott , Harriott Andrea , Matiello Marcelo , Nedelcu Simona , Manzano Giovanna S , Singhal Aneesh B
Published: February 2022

Introduction:
The evaluation and risk stratification of patients with TIA/non-disabling ischemic stroke (TIA/NDS) arriving to the Emergency Department (ED) incurs high-cost imaging and increases ED length of stay (EDLOS). We evaluated the safety and feasibility of an ED-to-Outpatient Pathway for TIA/NDS.

Methods:
In April 2020, we developed a risk stratification algorithm for TIA/NDS in the ED using features of the clincal presentation, limited blood tests, telemetry, and head-neck CT/CTA. Patients deemed low risk based on a “safety checklist” were discharged with plans for expedited outpatient testing as warranted (e.g., brain MRI, echocardiogram) followed by rapid outpatient follow-up. To assess safety/feasibility of this pathway, we analyzed data of the first 101 patients prospectively enrolled through October 2020.

Results:
Mean age 68 years (range, 33-99); 53% men; median NIHSS score 0 (range 0-3). Symptom duration was classified as <10 min (24%), 10-59 min (23%), >60 min (49%), unclear (4%). Deficits included isolated weakness (16%), isolated aphasia (15%), amaurosis fugax (6%), numbness/combined deficits/other (63%). Median ABCD2 score 3 (range 1-7). Outpatient follow-up included stroke clinic (82%), primary care (4%), not required or patient declined (6%), other hospital (1%); 7% were lost to follow-up; 43% had follow-up within 7 days. Imaging performed in the ED included CT/CTA only (39%), MRI/MRA only (27%), both (33%), or no imaging (1%). EDLOS was significantly less for patients when CT/CTA only was performed, as per pathway (12.8 versus 16.8 hours, p<0.05). The safety checklist was followed in 69% of patients. When the checklist was used properly, there were 0 recurrent strokes or TIAs within 90-days (versus 2 when not used correctly, p<0.05). Return rates to the ED were 8% with use of checklist and 6% without use (p=0.76).

Conclusion:
Our TIA/NDS pathway, implemented shortly after the outbreak of Covid-19 in the USA, significantly decreased EDLOS, and still allowed for TIA/NDS patients to be safely discharged from the ED. Acceptable risk stratification and safety is suggested by the low rates of recurrent events when the pathway was followed properly. More education is needed to ensure consistent and proper use of the pathway.
Abstract 154: Sex-specific Genome Wide Association Study Of Early-onset Ischemic Stroke
Authors: Tomppo Liisa , Rannikmae Kristiina , Stanne Tara M , Putaala Jukka , Strbian Daniel , Jern Christina , de Leeuw Frank-Erik , Cadenas Israel Fernandez , Slowik Agnieszka M , Boncoraglio Giorgio , Lindgren Arne , Conde Jordi J , Schmidt Reinhold , Sharma Pankaj , Lemmens Robin , MELANDER Olle , Rothwell Peter , Levi Christopher , Sudlow Catherine , Debette Stephanie , Metso Tiina , Pare Guillaume , Markus Hugh , Saleheen Danish , Danesh John , Zand Ramin , Worrall Bradford B , Meschia James F , Rundek Tatjana , Woo Daniel , Lee Jin-moo , Irvin Marguerite R , McDonough Caitrin W , Rexrode Kathryn M , Wassertheil-smoller Sylvia W , Rosand Jonathan , Gieger Christian , Muller-Nurasyid Martina , Salomaa Veikko V , Kamatani Yoichiro , Walters Robin , Chen Zhengming , Dichgans Martin , Malik Rainer , Gaynor Brady , Cole John , Xu Huichun , Mitchell Braxton D , Kittner Steven J ,   Early-Onset Stroke Consortium
Published: February 2022

Introduction:
Genetic studies of early-onset disease have been an effective strategy to identify novel pathways and drug targets generalizable also to later-onset disease. Few studies have investigated the sex-specific genetic associations with early-onset ischemic stroke even though several features of ischemic stroke differ between males and females. We hypothesized that stratifying the GWAS by sex would reveal novel stroke loci.

Methods:
We performed a transethnic ischemic stroke GWAS of 3,056 female cases and 4,462 male cases < 60 years-old and 16,192 and 16,048 sex-matched controls, respectively, from the Early Onset Stroke Genetics Consortium.

Results:
We identified a significant association in women with a locus in close proximity to
TMX1
, a transmembrane platelet protein that inhibits platelet function. Additionally, we identified 2 other suggestive (P < 5 x 10
-6
) loci in females (see Table), i.e., at
APOH
, which encodes beta2-glycoprotein I, an established GWAS locus for lipoprotein(a), and
LRFN2
which has been previously reported to associate with obesity-related measures and type II diabetes. We observed suggestive evidence for association in males with
MMP3/MMP12
, a known stroke susceptibility locus.

Conclusions:
Despite a very modest sample size, sex-specific analyses identified suggestive associations at biologically important novel loci in females and a known stroke locus in males. Further studies of sex-specific associations in both early- and later-onset ischemic stroke are needed.
Abstract 155: Hyperglycemia And Hypertension Predict Subsequent Ischemic Stroke In Patients With Minor Stroke Or TIA Treated With Dual Antiplatelet Therapy: A Post-hoc Analysis Of The POINT Trial
Authors: Kvernland Alexandra , de Havenon Adam , Rostanski Sara , Mac Grory Brian , Goldstein Eric , Johnston Claiborne , Easton J. Donald , Kim Anthony , Anadani Mohammad , Henninger Nils , Liberman Ava L , Furie Karen L , Yaghi Shadi
Published: February 2022

Background:
Randomized trials have shown that dual antiplatelet therapy (DAPT) reduces the risk of subsequent ischemic stroke in patients with minor stroke or high-risk TIA (MS-TIA). However, the 90 day risk remains elevated at 5-8%. In this exploratory study, we aimed to identify predictors of subsequent ischemic stroke in patients with MS-TIA treated with DAPT.

Methods:
This is a post-hoc analysis of the POINT trial that randomized patients with MS-TIA to DAPT versus aspirin monotherapy. For this analysis, we included only patients treated with DAPT and performed univariate and adjusted Cox-regression analyses to determine predictors of subsequent ischemic stroke. We also performed receiver operating analysis to determine predictive accuracy. P<0.05 was considered statistically significant.

Results:
Among 2,398 MS-TIA patients treated with DAPT, 109 (4.5%) had ischemic stroke during the 90 day follow up interval. In Cox-regression analyses, predictors of subsequent ischemic stroke were admission glucose level per 10 mg/dL increase (adjusted HR 1.04 95% CI 1.03-1.06, p < 0.001), admission blood pressure per 10 mm Hg increase (aHR 1.10 95% CI 1.03-1.17, p = 0.006) and presence of infarct on index imaging (adjusted HR 2.04 95% CI 1.40-2.98, p<0.001). Subsequent stroke risk was particularly increased in patients with serum glucose ≥180 mg/dL (adjusted HR 2.45 95% CI 1.60-3.75, p<0.001) and systolic blood pressure ≥180 mmHg (adjusted HR 1.71 95% CI 1.16-2.52, p = 0.007). The rate of subsequent stroke when both predictors were present was 14.7% and when none was present was 3.3%. Their independent predictive accuracy was modest in receiver operating curves: glucose (AUC = 0.66 95% CI 0.61-0.71) and systolic blood pressure (AUC = 0.60 95% CI 0.54-0.65). Findings were similar in a sensitivity analysis where patients without imaging confirmation of subsequent stroke were excluded.

Conclusion:
Patients with MS-TIA who have hyperglycemia or hypertension on admission are at a relatively high risk of subsequent ischemic stroke despite DAPT. Future studies are needed to validate our findings and explore whether targeted treatment of these factors can affect short term stroke risk.
Abstract 158: Stroke During Pregnancy: Risk Factors, Clinical Outcomes, And Recurrence
Authors: Garg Aayushi , Roeder Hannah , Leira Enrique C. C
Published: February 2022

Background:
There is limited data regarding the clinical course of acute stroke during pregnancy.

Methods:
Pregnancy-related hospitalizations with age>18 years were identified from the Nationwide Readmissions Database 2016-2018. Logistic regression and survival analyses were used to compare the risk factors, outcomes, and readmissions in patients with and without acute strokes.

Results:
There were 11829044 pregnancy-related hospitalizations, of which 3498 had acute stroke and a 5% random sample of the remaining non-stroke hospitalizations (N=628106) were included as controls (mean±SD age: 29.0±5.7 years). Intracranial hemorrhage (ICH) was present in 1952 (55.8%) cases, acute ischemic stroke (AIS) in 1646 (47.1%) cases, and cerebral venous sinus thrombosis in 105 (3.0%) cases. We identified several independent factors associated with acute stroke during index hospitalization (figure 1). Among patients with AIS, 60 (4.0%) received intravenous thrombolysis and 95 (6.3%) underwent mechanical thrombectomy. Among patients with ICH, 420 (23.5%) had catheter angiogram, 177 (9.9%) underwent ventriculostomy, and 14 (0.8%) underwent decompressive craniotomy. Patients with stroke had longer length of stay (mean: 11.7 vs. 2.8 days), higher in-hospital mortality (5.3% vs. 0.0001%) and were less likely to discharge home (70.3% vs. 98.4%). Non-elective readmission within 90 days of discharge occurred in 17% of patients with stroke versus in 3% without stroke [hazards ratio (HR): 5.6, 95% confidence interval (CI): 4.8-6.6]. Readmissions due to cerebrovascular events occurred in 1.8% of patients with stroke versus in 0.00004% of patients without stroke (HR: 438.6, 95% CI: 211.0-911.9) within 1 year of discharge, with mean±SD time to readmission 43.1±60.8 days.

Conclusion:
Stroke during pregnancy is associated with very high morbidity and mortality. Recurrence of stroke occurs in a small proportion of patients and the risk is highest during the first month.
Abstract 160: Age-associated CD11b
High
B Cells Are Recruited To The Brain After Stroke And Regulate Microglial Function
Authors: Korf Janelle , Honarpisheh Pedram , Mohan Eric , Banerjee Anik , Blasco-Conesa Maria P , Ahmad Mian , Ganesh Bhanu P , Hazen Amy , Lee Juneyoung , Kumar Aditya , McCullough Louise , Chauhan Anjali
Published: February 2022

CD11b expression is essential for immunity due to its role in cell motility and phagocytosis. Leukocytes, including monocytes, neutrophils and macrophages, express CD11b. B lymphocytes, which are both adaptive immune cells and antigen presenting cells (APCs), also express CD11b at varying levels. The role of B lymphocytes after stroke is multifaceted, and recent studies have highlighted their deleterious contributions to post-stroke recovery and cognitive decline. CD11b
high
B cells have not been studied in the context of aging and stroke. We hypothesized that CD11b
high
B cells increase in the brain after stroke and regulate microglia function. We used a middle cerebral artery occlusion (MCAO) model of stroke in young (2mo) and aged (18mo) WT male mice to investigate the role of CD11b
high
B cells in post-ischemic immune responses. In the acute phase following stroke, resident immune cells, primarily microglia (MG), are rapidly activated. Thus, we studied the ability of CD11b
high
B cells to influence MG phenotype in young and aged brain. We found that CD11b
high
B cells are a heterogeneous subpopulation of B lymphocytes and predominantly found in aged mice (n=4/gp,
p=0.0089
) and after stroke (n=5/gp,
p=0.0078
). This subset is characterized by their higher expression of CD80 and CD73 (n=8/gp,
p<0.0001, for both
). The frequency of CD11b
high
B cells increases in the brain after stroke in both young and aged mice. These cells are capable of changing MG phenotype sorted from either young or aged brain, as assessed by decreased expression of CD45, CD11b, and MHC-II by MG (n=4/gp,
p=0.0013, p=0.0033, p=0.0310
, respectively). When co-incubated with
ex vivo
sorted MG, CD11b
high
B cells increased phagocytic function MG more than their CD11b
low
B cell counterparts (n=4/gp,
p=0.0486
). Lastly, the regulatory influence of CD11b
high
B cells is likely through production of inflammatory cytokines including TNF-α (n=5/gp,
p<0.0001
). As both APCs and adaptive immune cells with memory function, B lymphocytes are uniquely positioned to regulate both acute and chronic phases of the post-stroke immune response, and their influence is subset-specific. Future studies are warranted to better understand the function of these age-associated CD11b
high
B cells in neuroinflammation.
Abstract 27: Predicting Ischemic Stroke In Emergency Departments: Development And Validation Of Machine Learning Models
Authors: Abedi Vida , Misra Depdipto , Chaudhary Durgesh , Avula Venkatesh , Schirmer Clemens M , Li Jiang , Zand Ramin
Published: February 2022

Background:
Stroke misdiagnosis is estimated to occur in 9% of all stroke patients and is associated with poor outcomes. We hypothesized that machine learning (ML) could be used to detect ischemic stroke at the point of care in emergency departments (ED).

Methods:
Clinical data from 13 hospitals of a large health system in Pennsylvania, United States, from September 2003 to May 2019 were used for model development. Data from June 2019 to December 2020 were prospectively collected and divided into pre- and post-COVID cohorts for validation. We simulated three clinical settings by enrollment with different inclusion/exclusion criteria and created two ML pipelines: ML applied to pre-event clinical data, and natural language processing (NLP) with ML applied to clinical notes during triaging. Misdiagnosed stroke in ED was a case study to show the discriminative power.

Results:
We included a total of 49,155 patient encounters (8,900 consecutive ischemic stroke patients and 40,255 controls). The best model, based on the patient’s pre-event information, was XGBoost (AUROC=0.91). Using NLP+ML pipeline, we collected 2,070 notes during the triage process and 9,607 notes (non-stroke) for modeling. For independent validation, we identified 2,989 notes for stroke and 4,303 notes for non-stroke. We identified nine models that reached a balanced performance in terms of AUROC, sensitivity, and specificity. Model performance, in terms of AUROC, ranged from 0.876 to 0.985. Model sensitivity and specificity reached 0.993 and 0.975, respectively. There was no performance difference between models tested on pre- and post-COVID. Three out of four models correctly identified a separate case series of five misdiagnosed strokes.

Conclusion:
Available clinical information can be used to reduce stroke misdiagnosis in real-time. In addition, this study serves as a foundation for prospective trials to establish how pre-event clinical data and triage information can be used to improve care.
Abstract 29: Recurrent Stroke Arrival Time
Authors: Dymm Braydon , Meurer William J , Kwicklis Madeline , Lisabeth Lynda D , Shi Xu
Published: February 2022

Introduction:
All stroke patients and family members should receive stroke education including recognition of stroke symptoms and prompt activation of emergency medical (EMS). The impact of this education is unclear. We aimed to measure the association between EMS use and timing of arrival within first ever and recurrent strokes.

Methodology:
The study analyzed data from validated strokes identified by the Brain Attack Surveillance in Corpus Christi (BASIC) project between 1/1/2000-1/1/2020. We analyzed 5,617 first-ever strokes (FES), 259 instances of recurrent stroke within 1 year of the first (RS1), and 2,044 recurrent strokes over 1 year or unknown duration from the first (RS0). Following imputation, recurrent stroke’s associations with both EMS arrival (available post-2010) and early arrival (< 3hrs) were assessed with logistic models, accounting for clustering with generalized linear models (GEEs).

Results:
Compared to FES, there was significantly higher unadjusted odds of arrival by EMS, but not early arrival, for one of the recurrent stroke groups (Table 1; RS0: OR = 1.29, 95% CI=1.10-1.50; RS1:OR=1.24, CI=0.87-1.75). The association was not significant after adjustment. Increasing stroke severity, married status and EMS use were associated with higher odds of early arrival, while African Americans (AAs) had lower odds than non-Hispanic Whites (NHWs, Table 1). However, AAs did have higher odds of EMS use relative to NHWs. Those who were married and living together had lower odds of EMS use compared to those who were not.

Conclusion:
Our study examines the association of repeat stroke on early arrival and EMS use as a surrogate for adequate stroke education. By examining subsets, we can identify groups that would benefit from targeted education. For example, younger, non-AA patients with smaller strokes would benefit from more education on EMS use and African American patients would benefit from education related to faster recognition or urgency of presentation.
Abstract 35: Unmet Need In Acute Ischemic Stroke Patients Arriving After 4.5 Hours
Authors: Mac Grory Brian , Xian Ying , Solomon Nicole , Matsouaka Roland , Decker-palmer Marquita , Fonarow Gregg C , Smith Eric E , Schwamm Lee H
Published: February 2022

Introduction:
Many patients arrive beyond the guideline-recommended time window for treatment with IV alteplase. For most of these patients, few treatment options exist. There is a need to understand the characteristics, outcomes, and healthcare costs of patients in this population in order to develop new treatments options.

Methods:
We analyzed patients ≥65 years old with a primary diagnosis of AIS arriving within 24 hours of time last known well (LKW) but not treated with IV alteplase at Get With The Guidelines-Stroke Hospitals in the United States (Jan 2016 - Dec 2016). We report clinical characteristics, 90-day and 1-year outcomes including Medicare costs, stratified by time from LKW to arrival (≤4.5 hours, >4.5-6 hours and >6-24 hours).

Results:
Of 39,760 patients (80.0% White, 10.5% Black, 4.1% Hispanic, 2.2% Asian), 20,369 (51.2%) presented from 4.5 - 24 hours of LKW. Compared to patients arriving within ≤4.5 hours, patients arriving within 4.5 - 24 hours of LKW were more likely to be Black, Hispanic, or Asian (≤4.5 hours: 9.4% Black, 3.8% Hispanic, 1.9% Asian; >4.5 - 6 hours: 11.7% Black, 4.1% Hispanic, 2.4% Asian; >6 - 24 hours since LKW: 11.6% Black, 4.4% Hispanic, 2.6% Asian; p < 0.001). The most common discharge location for those arriving within ≤4.5 hours was home; for those arriving >4.5 hours since LKW the most common discharge location was inpatient rehab (IRF) or skilled nursing facility (SNF) (≤4.5 hours: 44.7% home vs 42.3% IRF or SNF; >4.5 - 6 hours: 35.4% home vs 51.7% IRF or SNF; >6 - 24 hours: 35.8% home vs 51.0% IRF or SNF). The 90-day and 1-year mortality rates were 18.9% and 30.0% in those arriving within ≤4.5 hours, 19.0% and 29.8% in those arriving between 4.5 - 6 hours, and 19.1% and 29.1% in those arriving between 6 - 24 hours. Median 90-day inpatient costs were highest among those arriving 6 - 24 hours from LKW (≤4.5 hours: $9,471 [IQR: 5,622-21,356]; >4.5 - 6 hours: $10,884 [IQR: 6,036-25,992]; 6 -24 hours: $11,162 [6,073-26,372]).

Conclusions:
Results show the importance of timely hospital arrival, as well as a need to address racial disparities in arrival times, reduce costs, and develop new treatment options for patients with AIS arriving after 4.5 hours from last known well time.
Abstract 44: Safety Of Tenecteplase And Alteplase In Tandem Lesion Stroke: A Pooled Analysis Of The Extend-IA TNK Trials
Authors: Yogendrakumar Vignan , churilov leonid , Mitchell Peter J , Kleinig Timothy J , Yassi Nawaf , Thijs Vincent , Wu Teddy Y , Shah Darshan , Dewey Helen M , Wijeratne Tissa , Yan Bernard , Sharma Gagan , Desmond Patricia , Parsons Mark , Donnan Geoffrey A , Davis Stephen , Campbell Bruce ,   EXTEND-IA TNK Investigators
Published: February 2022

Introduction:
The efficacy of tenecteplase (TNK) in patients with tandem lesions (TL) in the anterior circulation is unknown. The longer half-life of TNK could potentially lead to increased hemorrhage, especially in patients who require stenting of the extracranial internal carotid artery (eICA) and subsequent antiplatelet therapy. We assessed the efficacy and safety of TNK in a pooled analysis of the EXTEND-IA TNK trials.

Methods:
We compared the treatment effect of TNK (pooled analysis of 0.25 and 0.40mg/kg dosing) with alteplase (tPA), stratifying for TL presence. A TL was defined as a combination of eICA pathology (ipsilateral stenosis >70% or occlusion) and intracranial LVO. Outcomes evaluated include 90-day mRS, intracranial reperfusion at initial angiographic assessment, mortality, ICH (symptomatic [sICH] and parenchymal hematoma [PH]). Treatment effect was adjusted for baseline NIHSS, age, and time from symptom onset to puncture via mixed effects proportional odds and logistic regression models.

Results:
Of 483 patients with an anterior circulation occlusion, 71/483 (15%) patients had a TL and 43/71 (61%) patients required eICA stenting. In TL patients, reperfusion at initial angiographic assessment was observed in 11/56 (20%) of patients treated with TNK vs. 1/15 (7%) patients treated with tPA (aOR:3.71; 95% CI:0.42-32.75). sICH was observed in 4/71(6%) TL vs 7/412 (2%) nonTL patients (p=0.04). Among TL patients, sICH occurred in 4/56 (7%) patients treated with TNK vs 0/15 (0%) tPA treated patients (p=0.57); sICH occurred in 2/40 (5%) of the 0.25mg/kg TNK group and 2/16 (12.5%) of the 0.40mg/kg TNK group. PH was observed in 6/56 (11%) patients treated with TNK vs 0/15 (0%) tPA treated patients (p=0.33). 90-day mRS (TNK median 2 vs. tPA median 4, acOR:1.21; 95% CI:0.42-3.48), mortality (TNK: 5 [9%] vs. tPA: 3 [20%], aOR:0.45; 95% CI:0.08-2.50), and eICA stenting (TNK: 35 [64%] vs. tPA: 8 [57%], p=0.65) rates did not differ between the two treatment groups.

Conclusions:
Although patients with TL in the anterior circulation were at higher risk of hemorrhagic complications, these did not significantly differ between the TNK and tPA groups. A numeric increase in bleeding with TNK was not accompanied by an increase in mortality or worse functional outcome.
Abstract 47: Project TURNIP: Teleproctoring Of Rural Stroke Patients With Advanced Nurse Practitioner
Authors: Vezzetti Alex , Lybrand Megan , Shephard Shanika , Lescantz Janet , Kabetso Amanda , Kodumuri Nishanth , Lowe Forrest , venkatesh yedatore S , kothari Ravish , Sen Souvik
Published: February 2022

Introduction:
Prisma Health Tuomey (PHT) is a rural-based spoke hospital, with advanced Nurse Practitioners (ANP). Prisma Health Richland (PHR) is an urban-based hub hospital with access to vascular neurologists. In this ongoing project we evaluated the effectiveness of Zeriscope, a web-based, HIPAA compliant, teleproctoring platform, for ANP evaluation of etiology of ischemic stroke.

Methods:
PHT uses a web-based, HIPAA compliant, telemedicine platform, Zeriscope, to provide a live interactive video stream to PHR, a certified Comprehensive Stroke Center 45 miles away. Zeriscope uses a mobile exam headset, comprised of a camera attached to a cellphone and an audio headset, to provide two-way audio and visual communication between an APP and a board-certified vascular neurologist (Figure). The care was provided in inpatient setting with full access to neuroimaging, vascular imaging, cardiac imaging, and long-term monitoring. Patients evaluated directly by teleneurology platform in the PHT emergency room for TPA and thrombectomy were transferred to PHR and excluded from the teleproctoring assessment.

Results:
Fifty-two ischemic stroke and TIA patients (age 67.8 ± 12.7, 52 % African American, 69 % Males) were evaluated and treated in 4-month period from April to August 2021. Patients underwent a standardized stroke work-up to determine stroke etiology, which was classified by TOAST criteria (11.8% LAA, 19.6% Cardioembolic, 27.5% Lacunar, 39.2% Cryptogenic and 1.9% Undetermined). All patients received best medical management based on the secondary stroke prevention guidelines. To date, no patients experienced complications or were readmitted or needed transfer to a stroke center.

Conclusion:
Tele-proctoring is a feasible method of delivering stroke care that has not been previously implemented in a rural hospital. The use of Zeriscope was practical and effective in determination of ischemic stroke etiology and implementation of best practice guidelines.