tbuckley/cabot-search huggingface dataset:
Selective STAT3 Degraders Dissect Peripheral T-Cell Lymphomas Vulnerabilities Empowering Personalized Regimens
Authors: Giuseppina Astone, Luca Vincenzo Cappelli, William Chiu, Clarisse Kayembe, Rui Wang, Bin Yang, Kirti Sharma, Joyoti Dey, Rahul Karnik, Lara Brambilla, David Levy, Liron Yoffe, Francesco Boccalatte, Javier Rodriguez Hernaez, Aristotelis Tsirigos, Paul Zumbo, Doron Betel, Akanksha Verma, Olivier Elemento, Michela Cumerlato, Roberto Piva, Steven M. Horwitz, Zachary D. Epstein-Peterson, Jared Gollob, Chris DeSavi, Phillip CC Liu, Giorgio Inghirami
Journal: Blood (2021)
Abstract 11663: Evaluation of Health Disparities Based on Gender, Race, and Socioeconomic Status in Patients Presenting With Aortic Dissection
Authors: Muhammad A Shakir, Akanksha Bhardwaj, Stephen Q Meng
Journal: Circulation (2021)

Introduction: Aortic dissection can be a catastrophic illness with a high mortality risk. Hypertension is a key predisposing factor, the management of which requires close medical follow up. Access to healthcare and the ability to maintain follow up is an important source of health disparity. In this study, we aimed to investigate disparities in the care of patients presenting with aortic dissection with a focus on gender, race, and socioeconomic status. Methods: From 7/2016 to 8/2020, 152 patients were admitted to our hospital with aortic dissection, 65 Stanford type A and 87 type B. Out of 152 patients, 75% had admission BP &gt;130/80 and 70% had no medical contact in the year prior to admission. Among those with no medical contact, we investigated whether disparities existed based on gender, race, or socioeconomic status. For socioeconomic status, we used publicly available median household income data based on zip code. Outcomes are expressed as percentages and compared using a Chi-square test of independence with significance set at 0.05 level. Results: Among those with no medical contact, there was no significant difference based on gender. 74% of female and 66% of male patients had no medical contact in the year prior to admission (p&gt;0.05). Similarly, there was no significant difference based on race as 71% of white and 65% of black patients had no medical contact in the year prior to admission (p&gt;0.05). Notably, 66% of admitted patients had a median household income below the US national average of 68,703 USD (2019). Those with a median income &lt;60,000 USD were more likely (58%) to have had no medical contact in the year prior to admission than those with a median income &gt;80,000 (13%). (p &lt;0.05). Further, those with a median income of &lt;60,000 USD were more likely to be admitted with aortic dissection (57%) than those with a median income of &gt;80,000 (14%) (p&lt;0.05). Conclusion: Our study showed that most patients presenting with aortic dissection lacked healthcare access in the year leading to the admission. When evaluating for disparities, socioeconomic status was the most significant social determinant of health. Patients with household income less than US national average were more likely to both present with dissection and lack medical contact in the year prior to dissection.
Common Gene Expression Signature of B-Cells of <i>Waldenström</i> Macroglobulinemia (WM) and IgM Monoclonal Gammopathies of Undetermined Significance (<i>IgM MGUS</i>) Compared to Healthy Subjects
Authors: Alessandra Trojani, Barbara Di Camillo, Luca Emanuele Bossi, Antonino Greco, Livia Leuzzi, Alessandra Tedeschi, Anna Maria Frustaci, Marina Deodato, Giulia Zamprogna, Agostina Melluso, Alessia Panzeri, Marco Montillo, Alessandro Beghini, Roberto Cairoli
Journal: Blood (2021)
Abstract 11174: Effect of APOCIII-LRxon Lipoprotein Size and Particle Numbers Measured by NMR in Patients with Hypertriglyceridemia: Results of the AKCEA-APOCIII-LRx Trial
Authors: Ewa Karwatowska-Prokopczuk, Jean-Claude Tardif, Daniel Gaudet, Christie M Ballantyne, Michael D Shapiro, Patrick M Moriarty, Seth J Baum, Eric St Amour, Vickie Alexander, Shuting Xia, James D Otvos, Joseph L Witztum, Sotirios Tsimikas
Journal: Circulation (2021)

Background: APOCIII-LRx is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of apoC-III and triglyceride-rich lipoproteins (TRLs). We examined the effec...
Abstract 14065: Computational Intelligence: A Novel Way of Uncovering Hidden Information
Authors: Dieter Bender, Ryan W Morgan, Vinay M Nadkarni, Robert A Berg, Todd J Kilbaugh, Robert M Sutton, C Nataraj
Journal: Circulation (2021)

Background: This study describes a novel approach to identify diagnostic properties in an electrocardiogram (ECG) waveform to classify cardiac arrest etiologies in human patients. Through an interdependent optimization algorithm linking machine learning and signal processing, the technique allows extensive electrocardiogram analysis, retrieving physiologically relevant and demonstrative characteristics embedded in the waveforms across a population. Methods: Secondary analysis of electrocardiography data collected from swine models of either primary VF (n=17) or secondary asphyxia-associated VF (7 minutes of asphyxia prior to VF induction; n=13). Carrying out the analysis, we develop a mutually related algorithm utilizing wavelet synchrosqueezed transform (WSST) and Machine Learning Tree-Classifier (ML-TC). The extraction of the waveform characteristics (WSST) and the learning stage of the ML algorithm (ML-TC) are mutually related through a genetic optimization method to extract the most effective signal characteristics (and their attributes) with respect to the classification performance. This method thus focuses the WSST analysis on a particular frequency bandwidth of the ECG waveform and previously unknown time-dependent frequency patterns that were consistent across all subjects. Results: The innovative approach uncovers previously unknown frequency patterns in the ECG waveform. The proposed method achieves an average classification accuracy of 100% when using 35-second ECG segments and 93% while using 5-second ECG segments, this being the best results ever obtained for this specific problem. Conclusion: This kind of analytical research demonstrates the benefits of computational intelligence, such as machine learning and optimization. It presents a novel method of viewing frequently used data in electrocardiography and illustrates how new hidden information can be obtained to assist in patient diagnosis and prognosis.
CDC20 regulates cardiac hypertrophy via targeting LC3-dependent autophagy: Erratum
Authors: Yun-Peng Xie, Song Lai, Qiu-Yue Lin, Xin Xie, Jia-Wei Liao, Hong-Xia Wang, Cui Tian, Hui-Hua Li
Journal: Theranostics (2021)

[This corrects the article DOI: 10.7150/thno.27706.].
Inherited retinal diseases: Linking genes, disease-causing variants, and relevant therapeutic modalities
Authors: Nina Schneider, Yogapriya Sundaresan, Prakadeeswari Gopalakrishnan, Avigail Beryozkin, Mor Hanany, Erez Y. Levanon, Eyal Banin, Shay Ben-Aroya, Dror Sharon
Journal: Progress in Retinal and Eye Research (2021)
Abstract 12279: CD40, a Significant Mediator of Hypertensive Renal Injury, Activates Pro-Apoptotic P53 Signaling in Human Renal Proximal Tubule Cells
Authors: Shungang Zhang, Joshua Breidenbach, Alan Fahoury, Andrew Kleinhenz, Deepak Malhotra, Lance Dworkin, David J Kennedy, Steven Haller
Journal: Circulation (2021)

Background: We have shown clinical evidence that circulating levels of the proinflammatory receptor CD40 contribute to the progression of hypertensive renal disease and that the ligand for CD40 (sCD40L) is significantly elevated in these patients. Experimentally, we developed a CD40 knockout (CD40KO) rat model on the Dahl-S background that is prone to hypertensive renal injury, and demonstrated significantly reduced renal inflammation and proteinuria following high salt diet in the CD40KO vs Dahl-S controls. On this background we used HK-2 cells and created a stable CD40 knockout cell line (HK-2CD40KO) and performed the following experiments. Hypothesis: Renal proximal tubule-specific CD40 signaling significantly contributes to the development of renal injury. Methods: HK2 cells and HK2-CD40KO cells were stimulated with 100 ng/ml of soluble CD40 ligand (sCD40L) for 24hrs. RNA from duplicate samples was isolated for RNA sequencing followed by bioinformatic pathway analysis (R program). Additionally, one-week high salt diet (2% NaCl) was administered to seven-week old Dahl S wild-type and Dahl S CD40KO male rats (n=8 per group) and kidney cell apoptosis was evaluated by TUNEL staining. Results: Bioinformatic analysis identified 1231 differentially expressed genes when comparing sCD40L-stimulated HK2 vs HK2-CD40KO cells. KEGG pathway analysis demonstrated p53 signaling as one of the most significantly altered pathways. The pro-apoptotic gene PMAIP1 was found to be among the most highly upregulated in sCD40L treated HK2 cells vs HK2 control (2.6-fold change), which was confirmed by qPCR and Western blot. Furthermore, CD40KO rats demonstrated significantly reduced renal cell death (3-fold decrease vs. S rat, p&lt;0.01) compared to wild-type Dahl S rats following high salt diet. Conclusion: RNA sequence analysis demonstrates that disruption of CD40 in renal proximal tubule epithelial cells significantly alters p53 signaling pathways and the pro-apoptotic gene PMAIP1 is upregulated upon sCD40L treatment. Disruption of CD40 significantly attenuates kidney cell death following high salt diet induced renal injury. Our data indicates that PMAIP1 contributes to CD40-mediated renal injury.
Abstract 13740: QT Interval-Prolonging Drugs May Influence Risk for Sudden Cardiac Death in Patients With Chronic Obstructive Pulmonary Disease
Authors: Oliver Leitner, Nanki Chugh, Sol Bloomfield, Audrey Uy-Evanado, Sumeet S Chugh, Kyndaron Reinier
Journal: Circulation (2021)

Background: QT-prolonging drugs have been shown to increase risk of sudden cardiac death (SCD). Here we aimed to identify comorbidities that may influence risk for SCD when taking specific types of QT-prolonging drugs. Methods: From the ongoing Oregon Sudden Unexpected Death Study (ORESUDS), we identified individuals with SCD and geographically-matched control subjects (2002 – 2016) with pre-arrest medical history and data on current medication use (at the time of arrest for cases). QT prolonging drugs were categorized according to the four risk categories defined by crediblemeds.com (referred to as A (Known risk), B (Possible risk), C (Conditional risk), and D (Risk of TdP in congenital LQTS). We utilized multivariable logistic regression models with backwards stepwise selection to identify significant comorbidities and QT risk categories or drug types associated with SCD. Models were adjusted for age, sex, history of MI, diabetes, congestive heart failure, hypertension, renal insufficiency, history of epilepsy, chronic obstructive pulmonary disease (COPD), and asthma. We evaluated two-way interactions between QT drugs and comorbidities. Results: A total of 2,813 cases (64% male, mean age 67 years) and 1,547 controls (66% male, mean age 65 years) were included. After variable selection, COPD, among other clinical profile variables, was significantly associated with SCD (OR 3.00, 95% CI 1.99 to 4.64). QT type D drugs were negatively associated with SCD (OR .39, 95% CI .30 to .50), whereas type A drugs were associated with significantly increased risk of SCD (OR 1.48, 95% CI 1.17 to 1.89). Two interactions between COPD and QT drug classes were observed. In one, the negative association of type D drugs with SCD was significantly attenuated in patients with COPD due to a positive interaction (interaction OR 1.90, 95% CI 1.19 to 3.04, p = .007). In the other, a stronger positive association with SCD was observed in patients with COPD taking type A drugs but not type D drugs (interaction OR 2.25, 95% CI .85 to 7.78, p = .14). Conclusion: These findings suggest the need for careful assessment of risk vs. benefit while considering QT-prolonging agents in patients with COPD. Further investigation is needed on the potential contribution of these agents on risk of SCD in COPD.
Abstract 11410: One Drop’s Multicondition Program is Associated with Blood Pressure Reduction in Employees with High Blood Pressure and Maintenance for Employees with Blood Pressure in Range
Authors: Lindsay Sears, Jamillah Hoy-Rosas, Kai Prenger, Alison Printz, Archer Lyle, Rachel Sanchez-Madhur, Harpreet Nagra, Dan Goldner, Jeff Dachis
Journal: Circulation (2021)

Background: Studies of mobile apps to reduce and manage blood pressure (BP) show mixed results. One Drop’s (OD) multicondition program incorporates a mobile app, health predictions and insights, in-app coaching, connected devices (glucometer, blood pressure cuff, scale) and integration with thousands of apps &amp; devices to support management of pre-diabetes, diabetes and hypertension. This study evaluated BP outcomes for employees in a large healthcare organization. Methods: Participants were employees identified as having hypertension, enrolled and participated in an OD hypertension program for 30+ days and had at least two systolic/diastolic BP measurements (SBP, DBP; via manual entry or Bluetooth cuff). For employees starting with high BP (Stage 1: SBP 130-139 mmHg, Stage 2: SBP 140-179 mmHg), Wilcoxon signed rank and t-tests evaluated BP change, and ANCOVA assessed program engagement level and duration effects. For in range (SBP &lt; 130 mmHg) and high BP groups, McNemar’s test evaluated risk change. Results: Participants (N = 94) tended to be male, in their 40’s, white and non-hispanic. For the high BP group (N = 45), baseline SBP/DBP was 144.6±11.3/87.8±10.7 mmHg. OD yielded significant reduction in SBP (-16.5±13.2 mmHg, p &lt; .01), DBP (-9.3±12.3 mmHg, p &lt;.01), SBP risk category (p = .01) and marginal reduction in DBP risk category (p = .06). The greatest reduction was within Stage 2 (N = 27; SBP -21.4±13.2, p &lt; .01; DBP -12.2±13.8, p &lt; .01). SBP/DBP change did not vary by engagement level (p = .63/.86) or duration (p = .10/.57), suggesting BP outcomes may be achieved for individuals through varied strategies and timelines. For the in range BP group (N = 49), baseline SBP/DBP was 117.6±9.5/77.7±8.5 mmHg. Of those starting in range, 81.6% stayed in SBP range at follow-up (73.2% for DBP). Of those starting with high BP, 57.8% moved in range at follow-up (43.4% for DBP). Conclusions: For employees with high BP, One Drop’s multicondition program is associated with -16.5/-9.3 mmHg SBP/DBP reduction, and -21.4/-12.2 mmHg reduction for those at Stage 2 hypertension. Employees with hypertension and BP in range were 4.4 times more likely to stay in range. Future studies should validate BP reduction results and explore patterns of engagement and outcomes in additional populations.
Abstract 13441: Which Indices of Heart Rate Variability are the Best Predictors of Mortality After Acute Myocardial Infarction? Meta-Analysis of Observational Studies
Authors: Oscar L Rueda-ochoa, Luisa F Osorio-Romero, Lizeth Daniela D Sanchez Mendez
Journal: Circulation (2021)

Introduction: Cardiovascular disease is the first cause of death globally with myocardial infarction as the main event. Heart rate variability (HRV) has been associated with an increased risk of mortality post-myocardial infarction. However, which indices of heart rate variability are the best predictors for total and cardiac mortality post-myocardial infarction remains unclear. Predict mortality risk by these indices, is important as HRV is a low-cost, low-invasive, and easy biomarker to interpret. Hypothesis: Indices evaluating heart rate variability are differentially associated with cardiac and total mortality, but to date, there is no evidence about which is the best for these outcomes Methods: PubMed, Google Scholar, Embase, Cochrane databases, and grey literature were searched for studies with HRV as a predictive mortality marker. Two authors independently selected papers and extracted data. Disagreements were solved with a third author. Clinical and statistical heterogeneity was assessed. Forest and funnel plot graphs were made. HRV indices included were SDNN, SDANN, HRV index, Total power, RMSSD, pNN50, LF, HF, ULF, VLF, and LF/HF. Sensitivity analysis, cumulative and regression meta-analysis were performed. Stata 16 was used for statistical analysis. Results: From 338 articles found, 29 were included. Low values of SDNN, HRV index, HF, ULF, and VLF showed statistically significant association with cardiac mortality, but HRV index had the highest association RR: 5.10 (CI95% 3.92 - 6.65, I 2 of 22%). For overall mortality, SDNN, HRV index, LF, VLF y ULF had statistically significant association, but HRV index was the best index, RR:3.60 (CI95% 2.52- 5.15, I 2 0%). Both associations had high consistency in subgroup analysis, with quality of articles, year of publication, and different cut-off points. Conclusions: the best index associated with cardiac and total mortality post-myocardial infarction is low values of HRV index.
Abstract 12640: Automated Pre-Operative Frailty Assessment in CABG: The Electronic Frailty Index
Authors: Eric Crespo, Jared Davis, Rachel Bordelon, Kate Callahan, Nicolas M Pajewski, Maria O Rangel, David X Zhao, Karl Richardson
Journal: Circulation (2021)

Introduction: Frailty results in decreased capacity to respond to physiologic stress, increasing risk of adverse outcomes following surgery. There is no standard tool for quantifying frailty in the pre-operative setting; available screening tools are resource intensive and typically focus on comorbidity. Many patients who undergo Coronary Artery Bypass Grafting (CABG) are medically frail. The electronic Frailty Index (eFI), based on the theory of deficit accumulation, is an automated score embedded in the electronic health record (EHR) at our institution that integrates 54 deficits assessing outpatient vital signs and labs, comorbidity, polypharmacy, and functional status. This study aims to assess the clinical utility of the eFI in preoperative risk stratification among patients who underwent CABG. Methods: Single institution, retrospective cohort study of patients that underwent CABG from January 2017 to July 2020. Exclusion criteria included patients with insufficient pre-operative EHR data for the eFI, INR &gt;1.5, total bilirubin &gt;2, and CABG &gt;5 days after admission. Outcomes included length of stay (LOS) and discharge destination (home vs acute care facility). Patients’ eFI score prior to surgery was classified as fit (0-0.10), pre-frail (&gt;0.10-0.21), or frail (&gt;0.21). Data were analyzed using multivariable linear regression and area under the curve. Results: 414 patients, mean age = 68.7 (SD 7.4) years, underwent CABG, with 49.3% categorized at pre-frail and 30.2% as frail. Both mean LOS (fit 7.0 days, pre-frail 7.3 days, frail 9.7 days) and the likelihood of being discharged to an acute care facility (fit 21.6%, pre-frail 19.6%, frail 34.1%) were increased for patients classified as frail. The eFI was the only variable we considered that was associated with LOS (p=0.006), while both age (p&lt;0.001) and the eFI (p=0.005) were associated with discharge location. Adding the eFI to a classifier based on age and sex improved the AUC from 0.627 to 0.671 for LOS &lt; 6 days vs &gt;6 days, and from 0.675 to 0.695 for discharge destination. Conclusions: The eFI was a strong predictor of LOS and discharge to an acute care facility after CABG. Automated tools such as the eFI should be considered preoperatively when discussing potential revascularization options.
Abstract 11258: Engaging Diverse Patients, Caregivers, and Clinicians as Partners to Identify Disease Management Related Challenges in Atrial Fibrillation: <i>A Qualitative Study Utilizing Human-Centered Design Methodology</i>
Authors: Nino Isakadze, Nancy Molello, David D Spragg, Yumin Gao, Erin Spaulding, Zane MacFarlane, Erin Michos, Joseph E Marine, Ronald D Berger, Hugh G Calkins, Seth S Martin
Journal: Circulation (2021)

Introduction: Despite advances in atrial fibrillation (AF) management, patients with AF continue to experience poor quality of life and adverse outcomes. Engagement of patients, caregivers, and clinicians to identify challenges in AF management can inform strategies to improve quality of life and improve AF related outcomes. Methods: We conducted virtual Human Centered Design (HCD) sessions with a) patients with AF and their caregivers to understand challenges in living with AF, and b) clinicians caring for patients with AF to identify difficulties encountered in AF management. During HCD sessions, we engaged participants to answer open-ended questions. Transcripts of audio recorded sessions were coded and emerging themes were identified. Results: 8 patients (25% African American, 13% Asian), 3 caregivers, and 7 clinicians participated in HCD sessions. Median (interquartile range) patient age was 69 years (58 - 78). Major themes from the patient and caregiver perspective included inadequate education on AF, lack of guidance on AF risk factor modification, lack of support networks, and absence of systems to guide patients when experiencing recurrent AF episodes. Major themes from the clinician perspective were complementary to patient and caregiver input. Themes included inadequate patient education due to limited time clinicians can spend with patients, lack of AF risk factor modification programs, and lack of streamlined services to allow timely communication with patients without increasing the administrative burden for physicians (Figure 1). Conclusions: A diverse group of patients, their caregivers, and clinicians identified lack of adequate education, guidance on AF risk factor modification as well as poorly structured patient-clinician communication as major challenges in AF care. Our findings are informing development of mobile health application addressing identified challenges with a goal to improve quality of life and adverse AF outcomes.
Abstract P464: Cardiac Dysfunction In A Mouse Model For Autosomal Dominant Polycystic Kidney Disease
Authors: William Perez, Troy Hendrickson, Gabriele G Schiattarella, Joseph A Hill, Francisco J Altamirano
Journal: Circulation Research (2021)

Mutations in polycystin-1 (PC1) cause autosomal dominant polycystic kidney disease (ADPKD), a disorder that manifests with cardiac hypertrophy and dysfunction. We recently showed that cardiomyocyte-specific PC1 KO mice exhibit both systolic and diastolic dysfunction without signs of cardiac hypertrophy. The purpose of this study was to determine the effects of ADPKD-causing PC1 mutations on cardiac function using a mouse model for ADPKD harboring a mutation in PC1 R3277C (RC/RC). We used echocardiography to determine cardiac function and Western blot analysis to explore signaling pathways in WT and RC/RC mice (2-4 months of age).We observed a slight but significant decrease in ejection fraction (77.2±0.7 vs 86.2±2.4 %, N=5, 4, P=0.015) without signs of left ventricular hypertrophy (LV mass 78.4±5.5 vs 93.5±4.2 mg, N=5, 4, P&gt;0.05) in RC/RC compared to WT mice. Western blot analysis from total heart lysates (WT and RC/RC; N=5) revealed no changes in protein levels of hypertrophic markers: beta myosin heavy chain (β-MHC) and regulator of calcineurin 1 (RCAN1). In addition, we studied multiple signaling pathways involved in cardiac hypertrophy by analyzing their phosphorylation status by Western blot (phosphorylated/total protein). We observed no changes in mTOR, S6K1 and S6 phosphorylation. However, a decrease in p-4EBP1 and p-eIF4B was observed in RC/RC compared to WT. Moreover, we observed a significant increase in p-ERK and p-CaMKII. Our data suggest that alterations in PC1 signaling promote cardiac dysfunction but do not promote hypertrophy in young mice (2-4 months of age). Published evidence (PMID: 32730856) suggest that RC/RC hearts become hypertrophic at 6 months of age. However, our data suggest there may be dysfunction prior to cardiac hypertrophy. This warrants further investigation into the more primary role of ADPKD-associated co-morbidities. More studies, with a larger animal cohort, are necessary to unveil the effects of mutant PC1 on cardiac function.