tbuckley/cabot-search huggingface dataset:
Abstract MP216: Identification Of Novel Phosphoprotein Signaling Pathways In Human Dilated Cardiomyopathy By Integrative Proteomic And Phosphoproteomic Analysis
Authors: Cristine J Reitz, Marjan Tavassoli, Da Hye Kim, Sina Hadipour-Lakmehsari, Saumya Shah, Shin-Haw Lee, Allen C Teng, Andrew Emili, Gavin Y Oudit, Uros Kuzmanov, Anthony O Gramolini
Journal: Circulation Research (2021)

Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure, yet the majority of the underlying signaling mechanisms remain poorly characterized. Protein phosphorylation is a key regulatory element with profound effects on the activity and function of signaling networks; however, there is a lack of comprehensive phosphoproteomic studies in human DCM patients. We assessed the hypothesis that an integrative phosphoproteomics analysis of human DCM would reveal novel phosphoprotein candidates involved in disease pathophysiology. Combined proteomic and phosphoproteomic analysis of explanted left ventricular tissue samples from DCM patients ( n =4) and non-failing controls ( n =4) identified 5,570 unique proteins with 13,624 corresponding phosphorylation sites. From these analyses, we identified αT-catenin as a unique candidate protein with a cluster of 4 significantly hyperphosphorylated sites in DCM hearts ( P &lt;0.0001), with no change in total αT-catenin expression at the protein level. Bioinformatics analyses of human datasets and confocal imaging of human and mouse cardiac tissue show highly cardiac-enriched expression of αT-catenin, localized to the cardiomyocyte intercalated disc. High resolution 3-dimensional reconstruction shows elongated intercalated disc morphology in DCM hearts (10.07±0.76 μm in controls vs. 17.20±1.87 μm in DCM, P &lt;0.05, n =3/group), with significantly increased colocalization of αT-catenin with the intercalated disc membrane protein N-cadherin (Pearson’s coefficient 0.55±0.04 in controls vs. 0.71±0.02 in DCM, P &lt;0.05, n =3/group). To investigate the functional role of cardiac αT-catenin phosphorylation, we overexpressed WT protein vs. non-phosphorylatable forms based on the loci identified in DCM hearts, in adult mouse cardiomyocytes using lentiviral transduction. Confocal imaging revealed significant internalization of the phospho-null form, as compared to the prominent intercalated disc staining of the WT protein (17.78±0.79% of WT vs. 9.25±0.49% of 4A mutant, P &lt;0.0001, n =50 cells/group). Together, these findings suggest a critical role for αT-catenin phosphorylation in maintaining cardiac intercalated disc organization in human DCM.
Durability of High-Frequency 10-kHz Spinal Cord Stimulation for Patients With Painful Diabetic Neuropathy Refractory to Conventional Treatments: 12-Month Results From a Randomized Controlled Trial
Authors: Erika A. Petersen, Thomas G. Stauss, James A. Scowcroft, Elizabeth S. Brooks, Judith L. White, Shawn M. Sills, Kasra Amirdelfan, Maged N. Guirguis, Jijun Xu, Cong Yu, Ali Nairizi, Denis G. Patterson, Kostandinos C. Tsoulfas, Michael J. Creamer, Vincent Galan, Richard H. Bundschu, Neel D. Mehta, Dawood Sayed, Shivanand P. Lad, David J. DiBenedetto, Khalid A. Sethi, Johnathan H. Goree, Matthew T. Bennett, Nathan J. Harrison, Atef F. Israel, Paul Chang, Paul W. Wu, Charles E. Argoff, Christian E. Nasr, Rod S. Taylor, David L. Caraway, Nagy A. Mekhail
Journal: Diabetes Care (2021)
Abstract 10059: In-Hospital Outcomes of Percutaneous Coronary Intervention versus Coronary Artery Bypass Surgery in Patients with STEMI Due to Unprotected Left Main Disease- A National Propensity Matched Analysis
Authors: Salman Zahid, Waqas Ullah, Muhammmad Khan, AAMER UBAID, Muhammad Atif Khan, Mian Tanveer Ud Din, Hamza Zahid Ullah Muhammadzai, Abid Nawaz Khan Adil, Devesh Rai, David L Fischman, Mahboob Alam, Chadi Alraies, bipul baibhav, Mohan Rao, Jeremiah Depta, Sudarshan balla
Journal: Circulation (2021)

Introduction: Comparative outcomes for percutaneous coronary intervention versus CABG surgery for left main coronary artery disease remains limited from a large national database. Methods: We studied comparative outcomes of PCI versus CABG using the US national inpatient sample database from 2015 to 2018 for left main disease presenting as STEMI. Results: A total of 930 and 535 patients with STEMI underwent PCI and CABG respectively. The patients undergoing PCI were older (67.5 years [Interquartile range (IQR),59-77]vs 67 [59-74]). Adjusted mortality was much higher in CABG (18.80%) as compared to PCI (7.6%). Higher percentage of patients were discharged to home after PCI as compared to CABG (49.70% vs 27.60%). Conversely, as compared to PCI a higher number of patients undergoing CABG were discharged to long-term care facility (71.90% VS 50.20%). Cost of care ($ 48703[IQR, 36803-71262] vs $ 30376 [19161-52207]) was considerably higher with CABG. The odds of in-hospital mortality and adverse events for CABG compared to PCI are depicted in figure 1. Conclusions: PCI may be associated with lower in-hospital mortality and adverse events when compared to CABG for unprotected left main disease.
TMOD-13. IDENTIFYING DRIVERS IN THE CONVERGING SYNTENIC REGIONS OF SPONTANEOUS CANINE AND PEDIATRIC HIGH-GRADE GLIOMA USING IMAGING BASED CRISPR-CAS9 ARRAY SCREEN
Authors: Samirkumar Amin, Wonyeong Kang, Amit Gujar, Leigh Maher, Elise Courtois, Paul Robson, Peter Dickinson, Rebecca Packer, Charles Lee, Roel Verhaak
Journal: Neuro-Oncology (2021)

Abstract Gliomas occur in companion dogs at rates comparable to humans, with short-snouted breeds such as boxers being more susceptible than others. The natural progression of cancer in the immuno-competent host allows companion dogs diagnosed with sporadic glioma as an optimal model for preclinical testing of therapeutic approaches with human relevance, including immunotherapies. We have recently performed comprehensive genomic and epigenetic characterization of glioma in dogs to their human counterparts and found strong convergent evolution – shared somatic mutations and aneuploidies - among syntenic regions, including those of known pediatric glioma drivers, e.g., PDGFRA, MYC, PIK3CA. Here, using arrayed CRISPR-Cas9 imaging based phenotypic screen, we will probe potential oncogenic drivers and tumor suppressor genes within syntenic aneuploidies and thus outline functional versus non-functional heterogeneity of cancer aneuploidy. Specifically, we are conducting arrayed knockout screen (one gene per well) of 400+ genes within syntenic aneuploidies across canine (n=2) and pediatric (n=2) high-grade glioma cell lines. We will first capture images by high-speed confocal imaging system at three time points post-transduction of single guide RNAs (2 per gene) targeting each of 400+ genes in their separate wells. Then, using high-throughput image analysis and semi-supervised machine learning methods, we will measure well-based phenotypic features (viability, growth, and morphology) from these images. Genes will be ranked per cross-validated predicted probability in yielding either proliferating or slow-growing cell type based on learned phenotypic features using image data of knockout cells from and across wells. The top ranked genes will then be linked to oncogenes and tumor suppressors based on pathway and ontology analysis. We expect that we will see convergence of the most impactful molecular abnormalities (based on their knockout phenotypes) on mechanisms or candidate signaling pathways for the development of new drugs and repurposing of existing drugs for kids and dogs with high-grade glioma.
Abstract 14411: Predictors of Delirium Among Hospitalized Older Adults With Cardiovascular Disease
Authors: Kevin Lin, Rishtina Bhetuwal, Miguel Bonilla Moreno, Jorge Irizarry-Caro, Zachary Cerra, Siddharth Chauhan, Chen Jeffrey, Cigarroa Natasha, Saumil Datar, Puja Gandhi, Jeffrey Hollander, Monika Keiser, Kristine McAndrews, Yawen Ren, Salman A Arain, Abhijeet Dhoble, Min Ji Kwak
Journal: Circulation (2021)

Introduction: Delirium is an acute confusional state typically seen in patients admitted to the hospital that can affect mentation, cause agitation, and complicate inpatient stays. The number of older adults with cardiovascular diseases is rapidly increasing. When admitted to the hospital, the elderly are at increased risk of developing delirium. Hypothesis: We hypothesized that there will be predictors that are associated with delirium among older adults who were hospitalized in acute care units with cardiovascular disease. Methods: A retrospective chart review was conducted on patients initially admitted to the coronary care unit (CCU) and cardiac intermediate care unit (CIMU) of a major metropolitan hospital between January 2019 and December 2019. Patients under the age of 65 were excluded. The remaining patients were analyzed with logistic multivariable regression and odds ratios were calculated for factors associated with developing delirium, adjusting for patient characteristics including Charlson’s Comorbidity Index (CCI) and admission reasons. Results: A total of 327 patients with a mean age of 75.6 years were analyzed. Of those patients, 227 (69.4%) had a CCI score of 4 or less. There were no significant associations with development of delirium at any CCI score compared to a score of 0; however, certain admission reasons were significantly associated with delirium, including needing a coronary artery bypass graft and minimally invasive valve repair (Table 1). Conclusions: Several different admission diagnoses were significantly associated with increased odds of delirium. Although CCI scores were not significantly associated with the development of delirium during the hospitalization, other risk factors such as age, reason for admission, and procedures performed may have stronger associations. The current study will be a foundation to develop a more patient-centered strategy to prevent and manage delirium in the growing elderly population.
Abstract 10348: Incidence and Characterization of Inpatient Complications Occurring More Than 48 Hours Post Stemi
Authors: Krina Patel, Dhruva T Tangellamudi, Bruce W Andrus, James T Devries, Nathaniel Niles
Journal: Circulation (2021)

Background: With continued reductions in ST-elevation myocardial infarction (STEMI) mortality and an interest in reducing length of stay (LOS), the question of which patients require extended inpatient monitoring remains uncertain. Methods: We present a single center retrospective study of consecutive patients admitted with STEMI undergoing emergent percutaneous intervention (PCI) from 2009-2018 (n=500). We identified subjects using the catheterization lab database and then reviewed the medical record for the following events occurring 48 hours or more following PCI: acute kidney injury (AKI), stent thrombosis, acute bleeding, falls with injury, use of mechanical support, use of vasopressors, cardiogenic shock, arrhythmias, ventricular rupture, papillary muscle rupture, pericarditis, heart failure requiring intravenous diuresis, re-admission within 48 hours of admission, and death. We hypothesized that elderly patients with multiple comorbidities would be at increased risk of late inpatient complications. Results: The average length of stay was 3.9 days and 384/500 patients stayed longer than 48 hours. Predictors of LOS beyond 48 hours included a left-anterior descending (LAD) culprit lesion (p= 0.04) and chronic kidney disease (CKD) (p=0.03). Risk factors for complications occurring beyond 48 hours included PCI of the LAD (increased risk of heart failure, p=0.003), older age (increased risk of cardiogenic shock, p=0.02), male sex (increased risk of requiring intravenous diuresis, p=0.01) and an initial Thrombolysis in Myocardial Infarction (TIMI) flow of 0 (increased risk of requiring vasopressors, p=0.005). Conclusion: In our sample, STEMI involving the LAD and CKD were associated with a prolonged hospital stay. Patients undergoing PCI of the LAD, and those with initial TIMI 0 flow, older age, and male sex should be strongly considered for extended inpatient monitoring.
Abstract 12347: Investigating Correlates of Hypertension Among Primarily Hispanic Women
Authors: Elizabeth Lorenzo, Rebecca E. E Lee
Journal: Circulation (2021)

Introduction: Under-recognized risk factors (social, economic, cultural, psychological) may contribute to the development of HTN among Hispanic women that warrant investigation. The purpose of this study was to explore the unique contribution of education, food insecurity, household size, Hispanic ethnicity, marital status, neighborhood crime, BMI, waist circumference (WC), and subjective physical activity on HTN, SBP, and DBP on a sample of primarily Hispanic women. Methods: Female guardians ( N = 227, 69.6% Hispanic, 32.7±8.3 years) of preschoolers completed sociodemographic and health history and behavior questionnaires. BMI, WC, SBP, and DBP were objectively measured per protocol. Participants with SBP ≥130 and/or DBP ≥80, on medication for HTN, or diagnosed with HTN were categorized with HTN. Unadjusted bivariate associations, and multivariate linear regression and logistic regression, adjusted for age, were conducted. Results: A total of 33.2% of women had HTN and 38.9% were food insecure. Mean BMI was 31.2±7.3 kg/m 2 , WC 99.2±17.2 in., SBP 112.1±12.7 mmHg, and DBP 75.0±10.6 mmHg. HTN was significantly associated with food insecurity (χ 2 (1, n = 180) = 4.50, p = .046). Women with HTN had significantly higher BMI (32.8±6.9 vs 30.4±7.5, t (226) = -2.30, p = .023) and WC (103.0±15.3 vs 97.2±17.8, t (228) = -2.41, p = .017) than those without. In adjusted linear regression models, food insecure women had significantly lower SBP ( B =-4.44, p =.028). Single women had higher SBP ( B =4.20, p =.087), but it did not reach significance, and significantly higher DBP ( B =4.90, p =.022) than married women. As WC increased, SBP increased ( B =.228, p =.077), which trended towards significance, and DBP significantly increased ( B =.229, p =.04). In adjusted logistic regression model, women with food insecurity were less likely to have HTN (OR = .35, p =.021) and single women were more likely [OR = 4.19, p =.008] to have HTN than married women. There were no other significant associations ( p s&gt;.05). Conclusion: This sample of primarily Hispanic women with food insecurity had lower risks for HTN, an unexpected finding. Single women had a higher risk for HTN than married women suggesting the need for further exploration surrounding psychosocial impacts of marital status on HTN.
Abstract 13291: Assessing Organ Procurement Organization Performance Across the Different Routes to Deceased Organ Donation
Authors: Nishma G Valikodath, Andrea N Lambert, Alison Butler, Daniel J Lebovitz, Gretchen Chapman, Seth Karp, Justin Godown
Journal: Circulation (2021)

Introduction: Organ procurement organizations (OPOs) are responsible for organ donor recruitment which can occur via donor registries or next-of-kin consent. Donor conversion rate is a metric used to assess OPO performance, reflecting the number of donors per eligible death. However, OPOs are not directly responsible for the success of donor registration. This study aims to describe the trends in donor recruitment via registries and next-of-kin consent, report the relationship between consent mechanisms, and assess the variability across OPOs. Methods: The SRTR database was queried for all eligible deaths (2008-2019), stratified by consent mechanism (Fig A). Trends were assessed over time. Multivariable logistic regression models adjusted for population demographic differences. Linear regression assessed the association between donor registration and next-of-kin consent at the OPO level. The probability of next-of-kin consent was assessed across OPOs after adjusting for population differences. Results: Donor registration has increased over time with a concurrent decrease in next-of-kin consent (Fig B &amp; C). At the OPO level, an increase in donor registration is associated with lower next-of-kin consent rates. However, there are OPOs that demonstrate a high probability of next-of-kin consent in the face of highly successful donor registration (Fig D). The success of next-of-kin consent is highly variable across OPOs, even after adjusting for population demographic differences (Fig E). Conclusions: Utilization of registries for donor recruitment has increased over time while next-of-kin consent has declined. Donor conversion rate provides an incomplete assessment of OPO performance and may artificially favor OPOs in regions with highly successful donor registration practices. There is significant variability across OPOs in next-of-kin consent. Knowledge of detailed donor recruitment data may allow OPOs to better target areas for improvement.
Abstract MP203: Decoding The Cardiac Regulatory Long Noncoding RNAs In Male And Female Mice Using Integrative Multiomics Analysis
Authors: Marlin Touma, Yang Cao, Calvin Pan, Aldons J Lusis
Journal: Circulation Research (2021)

Background: Long non-coding RNAs (lncRNAs) are increasingly recognized as important regulators of mammalian heart development and potential contributors to human cardiovascular diseases by regulating RNA transcription, translation and processing. However, the genetic regulation lncRNAs and their interactions with mRNAs are poorly understood. Methods: Deep RNA sequencing was performed following Illumina HiSeqTM 4000 sequencer protocol. SNP Array was used for mice genotyping. For differential gene expression analysis (DGE), DE Seq was used. Weighted gene co-expression network analysis (WGCNA) was performed using R. FaST-LMM was used for expression quantitative trait locus (eQTL) analysis. Results: To elucidate lncRNA-mediated transcriptional regulation in heart, we performed integrated multiomics analysis of RNA-seq derived transcriptome and SNP genotype data from the hybrid mouse diversity panel (HMDP) of adult male and female mice hearts across 100 strains. We observed significant variability in cardiac lncRNAs expression across the 100 strains. Using a 5% FDR P value threshold, genome-wide eQTL detected total of408513 and 404661 locally associated (within 1 Mb of genomic distance up- or down-stream of a given gene)SNP-lncRNA pairs in female vs male heart, respectively, which corresponded to 2687 unique lncRNAs in female and 2684 unique lncRNAs in males after excluding those with distal eQTLs (at P &lt;4.1e-6). Genome-wide correlation analysis revealed 2794 local and 1233 distal uniquely co-regulated lncRNA-mRNA pairs ( P&lt; 1e-8).Global WGNCA and module-trait correlation analysis identified 14 female and 5 male lncRNA-mRNA networks(Bicor&gt;0.3) that exhibited significant correlation with heart weight, body fat, or insulin resistance. By applying eQTL analysis to the module eigengenes, we identified 11 unique module eigengenes with eQTLs (FDR&lt;0.05). Conclusions: This study represents the first effort to investigate lncRNA-mediated regulation of gene expression in male and female mouse heart across 100 different strains. The results reveal novel associations of lncRNAs with complex clinical traits and provide resources to facilitate mechanistic exploration of the lncRNAs function in cardiovascular disease models.
INNV-33. THE IMPACT OF COVID-19 ON NEURO-ONCOLOGY CLINICAL TRIALS DURING WAVE 1 AND WAVE 2 AT A FRONTLINE DETROIT HEALTH CARE SYSTEM
Authors: Joshua Alton, Carmen Griffin, Amanda Wigand, Kenneth Winters, Emily Krozek, Lisa Scarpace, Tobias Walbert, James Snyder
Journal: Neuro-Oncology (2021)

Abstract In the wake of the Coronavirus disease outbreak (COVID-19), clinical trial operations were significantly impacted following the shutdown of elective healthcare services and even emergency operations. When the pandemic hit Detroit, Michigan in March 2020, the Hermelin Brain Tumor Center (HBTC) at Henry Ford Health System was consumed in COVID-19 emergency care which affected patient enrollment, conduct of trial activities, therapeutic treatment, deviation from protocol requirements, and sponsor-study site contact. The first Metro-Detroit COVID-19 case was confirmed March 10th 2020. At that time there were 18 active brain tumor clinical trials (phase 1 - phase 3) providing anti-cancer therapies. Trial modifications included decentralized operations to buildings with clinic and radiology access away from inpatient COVID-19 care, utilization of telemedicine for non-essential visits, shipping of investigational products to patient home, and in some cases utilization of local results in place of central histopathological confirmation. By April 2020, trials were ranked based on availability of alternative therapies and subject safety in 4 tiers that correlated with subject benefit and impact on care. Trials were given a prioritization level to commence enrollment with priority given to trials where no standard of care exists. Of the HBTC trials, one was graded Tier 1 and most were graded Tier 2. All patients already enrolled continued on study. As restrictions eased, trials were opened in a sequential manner. Changes that were made during the first wave of the pandemic helped to minimize its effect on clinical trial operation and enrollment during the second wave in Fall 2020. Thus, leading toward a decrease in trial deviations and increased enrollment during the 2nd wave. The changes made during the first wave helped to safely continue enrollment and treatment during the second wave and will have a longstanding impact on how clinical trials will be conducted in the future.
Abstract 13965: Natural Language Processing of Hospitalization Discharge Summary to Predict 1-year Post-Discharge Mortality Among Patients With Acute Heart Failure
Authors: Benjamin Rosand, Dragomir Radev, Harlan M Krumholz, Rohan Khera
Journal: Circulation (2021)

Background: Patients hospitalized with heart failure (HF) have over 20% risk post-discharge 1-year mortality. Current risk models rely on multiple structured clinical data elements including vitals, diagnoses, laboratory tests and medications to predict mortality and have modest performance (AUROC 0.70-0.74). However, clinical notes, which capture the assessment of patients and their prognosis have had a limited role in predictive models, due to challenges with engineering features from the unstructured text. Methods: We identified all primary HF hospitalizations for consecutive patients at Yale, between 2013-2019, and linked to the Connecticut death index to assess 1-year post-discharge deaths. The discharge summaries for these hospitalizations were split into training and validation sets (80% and 10%), and a 10% independent test set. We used the interpretable term frequency-inverse document frequency NLP model to assess the probability of 1-year death, evaluated against observed events, presented as Kaplan-Meier Curves, and interpreted using a word importance plot. Results: There were 6702 discharge summaries for HF hospitalization survivors. Their mean age was 78 (SD 15) years, 50% were women, with a 1-year mortality of 21%. The NLP model on discharge summaries had high discrimination for 1-year death in the independent test set, AUROC 0.78 (Figure A), with high positive and negative predictive role (F1 score, 0.73). Moreover, the model identified prognosis over the course of the post-discharge year (Fig B), reflecting prognostic cues outside of the immediate post-discharge period. Word tokens of chronic, severe, end organ disease, represented most frequent predictors of mortality (Fig C). Conclusions: An NLP model exceeded the performance of the best models based on structured data. Risk-prediction using unstructured clinical notes could reduce the burden of data collection for risk prediction and adjustment while maintaining interpretability.