tbuckley/cabot-search huggingface dataset:
Abstract 12858: Outcomes And Healthcare Utilization Among Patients Admitted With Heart Failure On Medicaid Versus Private Insurance
Authors: Abdul Wahab Arif, Shweta Gupta, Arooj Mian, Syed A Mehdi, Aviral Vij
Journal: Circulation (2021)

Background: Heart Failure is the most common diagnosis for cardiovascular admissions across the US. We undertook this study to assess differences in outcomes and healthcare utilization in patients less than 65 years old, who were admitted for HF, on Medicaid (HF-M) versus Private Insurance (HF-P) using a national sample. Methods: The National Inpatient Sample (NIS) was queried to identify all Medicaid and Private-Insurance admissions in adults &lt;65 years old with a principal admission diagnosis of HF between 2016-2018. We studied socio-demographic differences, medical comorbidities, mortality, length of stay (LOS), total hospital charges (THC). Secondary outcomes included arrythmia, cardiogenic shock, cardiac arrest, respiratory failure, sepsis, septic shock, and acute kidney injury. Statistics were performed using the t-test, linear regression, univariate and multinomial logistic regression using Stata 16 software. Results: We identified 329,755 Medicaid and 247,685 Private-insurance admissions with HF. Compared to HF-P, HF-M patients were significantly younger, more likely to be women, Black or Hispanic, more likely to hail from zip-codes with lowest income quartiles. HF-M patients were also significantly more likely to be treated at large sized and urban teaching hospitals. Rates of diabetes, dyslipidemia, CAD and obesity were higher in HF-P patients while COPD, CKD, dialysis and VTE were higher in HF-M patients. Rates of hypertension, smoking and old stroke were similar between groups. More patients died in HF-P group (1.6% vs 1.2%, p&lt;0.0001) and when adjusted for socio-demographics and medical comorbidities, the aOR for death was 0.75 (95%CI 0.67-0.83, p&lt;0.001) in favor of HF-M group. All secondary outcomes were significantly higher in HF-P group except cardiac arrest. HF-P patients also reported higher mean LOS (5.7 vs 5.5 days, p&lt;0.0001) and higher THC ($72,966 vs $59,384, p&lt;0.0001). Conclusion: Our study shows that HF-M patients perform better as compared to HF-P patients, in terms of mortality and healthcare utilization when admitted to the hospital with a principal diagnosis of HF. In current times, when a healthcare reform is urgently needed, this study adds support if the country explores designing a single payor healthcare system.
BIOM-16. NTRK (NEUROTROPHIC TYROSINE RECEPTOR KINASE) FUSIONS IN GLIOMA PATIENTS: A PROMISING MOLECULAR TARGET?
Authors: Anastasia Vernadou, Theodoros Argyrakos, Eirini Papadopoulou, Georgios Rigakos, Konstantinos Tsoukalas, Stefanos Labropoulos, Maria Avgoustidou, Evangelia Razis
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND NTRK gene fusions are rare in gliomas (less than 2%). The use of TRK inhibitors in NTRK-fused solid tumors has generated significant clinical interest. It is likely that the unmet need for effective therapies in glioma will lead to routine testing for NTRK fusions. METHODS We performed a retrospective review of 22 patients with malignant gliomas accrued between 2007 and 2021. We collected tumor samples from those patients and NTRK fusions were tested using either immunohistochemistry or FISH or NGS. We then evaluated their association with clinical characteristics, histology and other markers (IDH1/2 mutation, MGMT methylation, BRAF mutation, EGFR expression, ATRX expression, TERT mutation). RESULTS Median age at diagnosis was 50 years. NTRK1 translocation was detected in 3 out of 22 patient tumors, while NTRK1 duplication was present in 1 patient (probably related to a translocation, but not proven). All NTRK1 translocations were not found in glioblastomas and their median survival was 15.8 months. On the other hand, median survival of gliomas without NTRK translocations was 11 months. In one NTRK1-translocated patient a TRK inhibitor (entrectinib) was used (for a few days), but we cannot evaluate its efficacy as the patient deteriorated and died. As far as the other biomarkers are concerned, 2 out of 3 NTRK1-translocated gliomas were MGMT methylated. CONCLUSION NTRK fusions are rare in gliomas, as confirmed in our small sample analysis. Although adult NTRK-fused gliomas are considered to predominantly involve high-grade histology, in our study all patients had initially lower grade gliomas. NTRK alterations can be detected by different laboratory assays, but each of these approaches has specific advantages and limitations and more data are needed in order to identify the best method. For glioblastomas, NTRK fusions and TRK inhibitors are potentially a new targeted therapeutic strategy but more data are needed.
Abstract 12183: Multi-Center Evaluation of Inter-Site Variability in SPECT Myocardial Blood Flow Measurement
Authors: R Glenn Wells, Frank M Bengel, LUCA CAMONI, Elisabetta Cerudelli, Sarah G Cuddy-Walsh, Lewis Han, Naoto Kawaguchi, Felix Keng, Masao Miyagawa, Hagit Ratner, Jonathan Romsa, Terrence D Ruddy
Journal: Circulation (2021)

Introduction: Myocardial blood flow (MBF) imaging with SPECT is possible using cardiac-specific cameras. Single-center studies have shown that SPECT MBF is accurate compared with PET MBF and angiography. Clinical implementation requires consistency of SPECT MBF measurements across multiple sites. This study is the first multi-center evaluation of the inter-site processing variability of SPECT MBF. Objective: To compare SPECT MBF obtained locally to MBF calculated at the core lab in Ottawa, Canada. Methods: Six sites (2 in Canada and one each from Japan, Singapore, Italy, and Germany) each acquired 25 rest/stress MBF studies using Tc99m-tetrofosmin (377 MBq at rest; 1060 MBq at stress) on a pinhole-collimated cadmium-zinc-telluride(CZT)-based cardiac SPECT camera. Patients had intermediate to high pre-test probability of coronary artery disease. MBF was analyzed locally and at a core lab using commercially available software. The time that a room was occupied for a MBF study was compared to that for a standard rest/stress myocardial perfusion study. Results: Preliminary results from 4 sites showed a correlation in MBF between the core lab and the local site of an average of 0.96 (range 0.95 to 0.97) at rest and 0.89 (range 0.77 to 0.96) at stress. From Bland-Altman analysis, the mean bias from zero in global MBF between local and core-lab analysis was 3.3% +/- 13.4% at rest and 3.0 % +/- 18.6% at stress. Between the 4 sites, the bias ranged from -4.1% to 9.9% at rest and from -6.3% to 12.8% at stress; the standard deviation (SD) ranged from 10.5% to 14.0% at rest and from 12.0% to 24.5% at stress. There was no significant difference between sites in the SD. The SD of the local-to-core-lab MBF differences is less than the SD of the test-retest difference of 30%, measured in a previous single-center study. The average additional time to perform a MBF study acquisition varied between sites from 45 to 76 min. This additional time includes the time needed to pharmacologically stress the patient which is normally done outside the camera room. Conclusions: This multi-center evaluation supports the feasibility of consistently measuring MBF using CZT-based cardiac SPECT cameras, as has been suggested from previous single-center studies.
Abstract 12253: Fam210a Maintains Cardiac Mitochondrial Homeostasis by Promoting Ca <sup>2+</sup> Efflux
Authors: Peng Yao, Jiangbin Wu, Chinna Venkata, Si Chen, Omar Hedaya, Chen Yan
Journal: Circulation (2021)

Mitochondria play fundamental roles in maintaining cellular metabolism and energetics and supporting normal myocardial function. Disturbed cardiac mitochondrial homeostasis causes m itochondrial dysfunction associated with c ardiomyopathy (MC) in humans and mice. Recent genome-wide association studies discovered that the mutations of FAM210A (family with sequence similarity 210 member A) are associated with sarcopenia. Intriguingly, FAM210A is most highly expressed in the heart, and multi-omics analyses in mouse hearts reveal Fam210a as a hub gene in cardiac hypertrophy and remodeling. However, the physiological and molecular functions of FAM210A in the heart remain elusive. Here, we discover that cardiomyocyte (CM) specific knockout (KO) of Fam210a in adult mice leads to progressive dilated cardiomyopathy and heart failure, ultimately causing mortality at ~10 weeks after Fam210a KO. The Fam210a deficient CMs exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of MC. Furthermore, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in CMs at the early stage prior to contractile dysfunction and heart failure. Transcriptomic, proteomic and metabolomic analyses from Fam210a KO hearts indicate that FAM210A deficiency activates chronic integrated stress response (ISR), resulting in metabolic and translational reprogramming in the heart. Therefore, persistent ISR activation contributes to the pathogenesis in MC and progression of heart failure. Mechanistically, interactome and biochemical analyses show that FAM210A binds to mitochondrial Ca 2+ /H + exchanger LETM1 (leucine zipper and EF-hand containing transmembrane protein 1) and promotes LETM1-mediated mitochondrial Ca 2+ efflux. Our evidence suggests that FAM210A is a novel mitochondrial Ca 2+ efflux regulator required for maintaining cardiac mitochondrial homeostasis and offers new targets for treating mitochondrial disease. This work uncovers important interplay among mitochondrial Ca 2+ signaling, metabolic reprogramming, and translational control in cardiac health and disease.
Abstract 13426: CRISPR Guide RNA Design is Able to Use for Studying Splicing and Circadian Gene Expression
Authors: Saidulu Mattapally, Eric Zhang, Vladimir G Fast, Andrew E Pollard, Chandrakala Mattapally, Jianyi Zhang
Journal: Circulation (2021)

Introduction: CRISPR editing of genomic regulatory elements with the intention of direct exon/intron splicing is a hopeful means of everlastingly alleviating genetic diseases. Cas9-induced DNA double-stranded break, non-homologous end-joining repair pathways frequently introduce variable indel mutations at the cut site. Circadian rhythms control cell proliferation and differentiation, however circadian control of Human induced pluripotent stem cells (hiPSCs) remains study at the molecular level. Hypothesis: Elucidation of circadian rhythms in hiPSCs differentiated cardiomyocytes. Methods: In the current investigation, hiPSCs carrying knockout mutations for Per1, Per2, and connexin43 were generated via CRISPR/Cas9 gene-editing technology. hiPSCs were differentiated into cardiomyocytes (CM) and spheroid cultured was performed as previously described. We evaluated different guide RNAs Cas9-induced DNA double-stranded break were analyzed using Sanger sequencing and bioinformatics. Optical mapping was used to measure the electrical properties of individual spheroids and monolayers of WT, connexin 43 KO, and overexpression of connexin 43 (WT, Cx43 KO, and Cx43 OV). We also study in the hiPSCs CMs of monolayer resistivity and reactivity and compared them with rabbit ventricular myocardium. Results: To determine the genomic regulatory elements that control exon splicing we designed several guides Per1, Per2, and Connexin 43. Our sequencing and bioinformatics analysis found untranslated region or coding region designed guide RNA found changes in splicing but protein truncation observed in connexin 43 of the coding region. To further understand the differential expression of Cx43 in hiPSC-CMs optical mapping in monolayers and spheroids were observed decreased conduction velocities. To further understand we also perform impedance measurement in WT, Cx43 KO, and Cx43-OV. We found resistivity and reactivity were significantly changed between groups. We will look these mechanisms has any role in the spheroid treatment is associated with significant changes in arrhythmogenicity of swine studies. Conclusions: Our study established the CRISPR gRNA design can be used study splicing and circadian pattern regulated by connexin 43.
Abstract 11534: Persistent Hopelessness is Reduced in Home Exercisers in a Primarily Rural Population of Adults with Ischemic Heart Disease
Authors: Susan L Dunn, Anna Luong, Debbie Bomgaars, Gwenneth A Jensen, Lynn L White, Kristin M Van De Griend, Angela Kroeze Visser, Madison P Goodyke, Melissa Gutierrez-Kapheim, Nathan L Tintle
Journal: Circulation (2021)

Introduction: Hopelessness and rurality are each associated with increased mortality in adults with ischemic heart disease (IHD), yet there is no known research examining hopelessness in rural adults with IHD. Purpose: This pilot study examined state hopelessness in a primarily rural population of adults with IHD living in West-Northcentral United States. Methods: A longitudinal design was used to collect data from 42 participants during their hospitalization with IHD and at a long-term recovery time point. Rural-Urban Commuting Area (RUCA) codes were used to stratify participants by rurality level, with 64% (n=28) categorized as rural. The relationships between changes in hopelessness and other variables were evaluated with both single- and multi-variable linear models. Results: A moderate to severe level of state hopelessness (&gt;1.8 on the State-Trait Hopelessness Scale) was present in 47.6% (n=20) of participants during their hospitalization and persisted over time, with 57.1% (n=24) of participants reporting hopelessness between 200 to 540 days post-hospital discharge (p=0.42). Changes in state hopelessness levels from baseline to follow-up were not significantly associated with demographics, rurality, prior or current exercise, prior depression, depression score (measured by the Patient Health Questionnaire-8), or time to follow-up (p&gt;0.05). However, participation in home-based exercise (measured by the Cardiac Rehabilitation Exercise Participation Tool) was associated with a significant decrease in state hopelessness among those reporting moderate to severe state hopelessness (n=20) at baseline, with an estimated decrease of 0.72 points in hopelessness levels (SE=0.32; p=0.04). There was no association for hospital-based exercise (p=0.91). Conclusions: Hopelessness symptoms were frequent and persistent in a primarily rural sample of adults with IHD, with a decrease in symptoms observed in the moderately to severely hopeless who participated in home-based exercise. Knowledge of hopelessness in rural IHD patients is important for health care professionals in acute care and outpatient settings so at-risk patients can be identified and interventions employed. Future work should replicate these findings in larger samples.
Abstract 13312: Comprehensive Sequencing of Small Non-Coding RNA Reveals Plasma Circulating Biomarkers of Hypertrophic Cardiomyopathy and Dysregulated Signaling Pathways
Authors: Yuichi J Shimada, Kohei Hasegawa, Michael A Fifer
Journal: Circulation (2021)

Background: Hypertrophic cardiomyopathy (HCM) is caused by mutations in the genes essential in normal myocardial contraction. However, it remains unclear through which signaling pathways gene mutations mediate the development of HCM. Growing evidence indicates that small non-coding RNAs (snRNAs) play important roles in post-transcriptional regulation of gene expression. Hypothesis: Comprehensive sequencing of snRNAs in plasma reveals circulating HCM biomarkers and differentially regulated signaling pathways. Methods: We conducted a multicenter case-control study of cases with HCM and age-, sex-, and body mass index-matched controls with hypertensive left ventricular hypertrophy. We carried out RNA-seq of 3293 snRNAs in plasma. We performed a sparse partial least squares discriminant analysis to develop snRNA-based discrimination model using samples retrieved during the first two-thirds of the study period (the training set). We prospectively tested the discriminative ability in independent samples that were collected thereafter (the test set). We also identified signaling pathways associated with snRNAs that were significantly dysregulated in HCM with Bonferroni-adjusted P&lt;0.05. Results: The study included 324 patients (165 cases and 159 controls; n=224 in the training set, n=100 in the test set). Using the transcriptomics-based model derived from the training set, the area under the receiver-operating-characteristic curve in the test set was 0.89 (95%CI 0.81-0.96; Figure ). Pathway analysis revealed that the Ras-MAPK pathway was upregulated in HCM (false discovery rate [FDR]=0.000002). Pathways involved in inflammation and fibrosis - e.g., TNF (FDR=0.000003) and TGF-β (FDR=0.002) - were also upregulated. Conclusions: This study serves as the largest-scale investigation to reveal circulating snRNA biomarkers of HCM and exhibits both novel (e.g., Ras-MAPK) and known (e.g., TNF, TGF-β) pathways that are differentially regulated in HCM.
Barriers and Facilitating Factors for Conducting Systematic Evidence Assessments in Academic Clinical Trials
Authors: Stuart McLennan, Barbara Nussbaumer-Streit, Lars G. Hemkens, Matthias Briel
Journal: JAMA Network Open (2021)

<h3>Importance</h3> A systematic assessment of existing research should justify the conduct and inform the design of new clinical research but is often lacking. There is little research on the barriers to and factors facilitating systematic evidence assessments. <h3>Objective</h3> To examine the practices and attitudes of Swiss stakeholders and international funders regarding conducting systematic evidence assessments in academic clinical trials. <h3>Design, Setting, and Participants</h3> In this qualitative study, individual semistructured qualitative interviews were conducted between February and August 2020 with 48 Swiss stakeholder groups (27 primary investigators, 9 funders and sponsors, 6 clinical trial support organizations, and 6 ethics committee members) and between January and March 2021 with 9 international funders of clinical trials from North America and Europe with a reputation for requiring systematic evidence synthesis in applications for academic clinical trials. <h3>Main Outcomes and Measures</h3> The main outcomes were practices and attitudes of Swiss stakeholders and international funders regarding conducting systematic evidence assessments in academic clinical trials. Interviews were analyzed using conventional content analysis. <h3>Results</h3> Of the 57 participants, 40 (70.2%) were male. Participants universally acknowledged that a comprehensive understanding of the previous evidence is important but reported wide variation regarding how this should be achieved. Participants reported that the conduct of formal systematic reviews was currently not expected before most clinical trials, but most international funders reported expecting a systematic search for the existing evidence. Whereas time and resources were reported by all participants as barriers to conducting systematic reviews, the Swiss research ecosystem was reported not to be as supportive of a systematic approach compared with international settings. <h3>Conclusions and Relevance</h3> In this qualitative study, Swiss stakeholders and international funders generally agreed that new clinical trials should be justified by a systematic evidence assessment but that barriers on individual, organizational, and political levels kept them from implementing it. More explicit requirements from funders appear to be needed to clarify the required level of comprehensiveness in summarizing existing evidence for different types of clinical trials.
Abstract 10158: Clinical Features and Outcome-Predictors of Patients with Out-of-Hospital Cardiac Arrest Complicating Acute Myocardial Infarction
Authors: Taketo Sonoda, Hideki Wada, Manabu Ogita, DAIGO TAKAHASHI, ryota nishio, Kentaro Yasuda, Mitsuhiro Takeuchi, Yatsu Shoichiro, Jun Shitara, Tsuboi Shuta, Dohi Tomotaka, Satoru SUWA, Katsumi MIYAUCHI, Tohru Minamino
Journal: Circulation (2021)

Background: Although short-term mortality of acute myocardial infarction (AMI) has decreased dramatically, sudden cardiac arrest is still one of serious complication. We assessed the clinical characteristics and prognosis’ predictors of AMI patients with out-of-hospital cardiac arrest (OHCA). Methods: We retrospectively analyzed consecutive patients with AMI who were treated with emergency percutaneous coronary intervention between 2004 and 2017. Patients with OHCA were compared with those without OHCA. Results: Among 2,101 AMI patients, 95 (4.7%) presented OHCA. Younger age (odds ratio [OR]: 0.95; 95% confidence interval [CI]: 0.93-0.97; p&lt;0.0001), absence of coronary risk factors such as, diabetes mellitus (OR: 0.51; 95% CI: 0.30-0.85; p=0.01) or dyslipidemia (OR: 0.56; 95% CI: 0.36-0.88; p=0.01), left main trunk (LMT) and left anterior descending artery (LAD) as culprit lesion (OR: 3.26; 95% CI: 1.99-5.33; p&lt;0.0001), and renal deficiency (OR: 3.64; 95% CI: 2.27-5.84; p&lt;0.0001) were significantly associated with incidence of OHCA. The 30-day mortality of patients with OHCA was more than 5-hold higher compared with those without OHCA (32.6% vs. 4.5%, p&lt;0.0001). In multivariate logistic regression analysis, LMT or LAD as culprit lesion (OR: 12.18; 95% CI: 2.27-65.41; p=0.04), glucose level (OR: 1.01; 95% CI: 1.00-1.01; p=0.01) and renal deficiency (OR: 3.35; 95% CI: 1.07-10.53; p=0.04) were found as independent predictors of 30-day mortality among AMI patients with OHCA. Conclusions: About 1 of 20 AMI patients presented with OHCA and younger age, absence of coronary risk factors, and anterior wall infarction were associated with OHCA occurrence.