tbuckley/cabot-search huggingface dataset:
Abstract 13089: Reperfusion Injury is Reduced by Antagonism of NLRP3's Caspase-1
Authors: Michael V Cohen, Xi-Ming Yang, Amanda N Tuckey, Jonathon Audia, James M Downey
Journal: Circulation (2021)

VX-765, inhibitor of caspases-1, 3 and 4, at reperfusion reduces infarction in isolated rat hearts by 50% after ischemia/reperfusion (I/R). It was assumed cardioprotection by this pharmaceutical-grade drug was the result of inhibition of caspase-1 (cas-1) activation by the NLRP3 inflammasome which would trigger lethal pyroptosis. However, there has been no direct proof of that hypothesis. To test which, if any, caspase was responsible for protection, we measured infarct size after 50-min global ischemia/2-h reperfusion in isolated wild type (WT) mouse hearts and hearts from mice in which cas-1 had been genetically deleted (offspring of breeders from Jackson Labs genotyped to confirm mutation). Infarct size was measured objectively by Image J analysis of tetrazolium-stained heart slices using the same threshold settings for all hearts. No gender difference in infarct size was found in WT hearts (see figure) so genders were mixed, especially in the in the knockout (KO) groups. Because Krebs perfusate lacks blood-borne esterases required to convert pro-drug VX-765 to its active metabolite, VRT-043198 (VRT), we employed VRT in our model. Infarct size in hearts reperfused with buffer containing 180 nM VRT was halved to 43.7±4.8% of ventricular mass (p&lt;0.001 vs either cohort of WT hearts). Infarct size in cas-1 KO mice averaged 42.2±5.1% (pNS vs VRT). To eliminate possibility of a protected phenotype unrelated to cas-1, cas-1 KO mice were treated with 180 nM VRT. There was no further change in infarct size (44.0±4.3%) confirming cas-1 is VRT’s only target. NLRC4 also activates cas-1, but NLRC4 KO mice exposed to I/R were not protected (89.2±1.2% infarction), whereas inhibition of NLRP3 with MCC950 resulted in modest protection (65.5±5.3% infarction). These results strongly support NLRP3 as the source of the lethal cas-1. VX-765 at reperfusion is a promising adjunct intervention to decrease infarct size in patients treated for ST-segment elevation myocardial infarction.
Abstract 9467: Prevalence of Chest Pain in Diabetics with Inflammatory Heart Disease
Authors: Deni Drenic, Sathwika Thodeti, Rohith Raghavendran, Michael Yim, J Ronald Mikolich
Journal: Circulation (2021)

Introduction: The deleterious effects of chronic or poorly controlled diabetes mellitus (DM) on the cardiovascular system are well documented, but the prevalence of chest pain associated with inflammatory heart disease (IHD) has not been determined. This study was designed to assess and compare the prevalence of chest pain associated with IHD in diabetic (DM) and non-diabetic (ND) populations. Hypothesis: Diabetic patients may have decreased prevalence of chest pain due to IHD. Methods: A pooled cohort cardiac MRI (CMR) database was queried for all patients who had complete records pertaining to diabetes mellitus, inflammation on CMR, and concurrent chest pain. IHD was defined as myocarditis and/or pericarditis on CMR using using the Modified Lake Louise Criteria published in 2018 using not only T2 STIR and delayed gadolinium imaging, but also T1 and T2 relaxation mapping. Two of these 4 pulse sequences had to be abnormal for a IHD diagnosis. Patients were divided into disease (DM) and control (ND) groups, which were then stratified by IHD-associated chest pain. A two-tailed, two proportion Z-test with a significance value cutoff of p ≤ 0.05 was used for statistical analysis of populations. Results: A total of 951 DM patients and 3134 ND patients were identified. The DM group had 157 patients with CMR-confirmed IHD, of which 94 reported chest pain at 59.87% prevalence. The ND group had 699 patients with IHD, with 495 reporting chest pain at 70.81% prevalence. There was a statistically significant differences between groups related to prevalence of chest pain in cases of confirmed IHD (p&lt;0.0001). There was also a statistically significant difference (p=0.0354) between groups in population prevalence of IHD-associated chest pain in DM (9.88%, 94/951) and ND (14.79%, 494/3134). Conclusions: The ND group demonstrated a 10.94% higher prevalence of chest pain among CMR-confirmed cases of IHD, and a 5.91% higher population prevalence of chest pain associated with IHD. This data suggests that diabetes confers a greater risk of asymptomatic IHD that may go undetected. The lower prevalence of chest pain in DM patients may possibly be explained by diabetic neuropathy induced attenuation of cardiac nociceptive pain response.
Real-World Patterns of Utilization and Outcome of Market Approved Lenalidomide-Based Triplet Combinations in First Relapsed Multiple Myeloma Patients: Evidence from a Propensity Score Matched Analysis
Authors: Silvia Mangiacavalli, Monica Galli, Sara Pezzatti, Angelo Belotti, Francesca Fazio, Magda Marcatti, Anna Maria Cafro, Roberto Mina, Renato Zambello, Laura Paris, Claudio Salvatore Cartia, Gregorio Barilà, Cecilia Olivares, Alessandra Pompa, Rita Mazza, Francesca Farina, Martina Soldarini, Pietro Benvenuti, Marica Lecci, Virginia Valeria Ferretti, Maria Teresa Petrucci
Journal: Blood (2021)
Cytopenias in CAR-T Cell Therapy and Use of Transfusion Resources in Adult Patients with Lymphoproliferative Disorders
Authors: Lucía Mezquita, Maria Eva Mingot, Patricia Alcalde, Paula Sánchez-Llorca, Javier Camuña-Correa, Juan Luis Reguera, Nuria Martínez-Cibrian, Cristina Blazquez-Goñi, Virginia Escamilla Gomez, Laura Pérez-Ortega, Dolores Serrano, Jose A. Perez-Simon
Journal: Blood (2021)
Blockchain for increased trust in observational studies
Authors: Mehdi Benchoufi, Philippe Ravaud, Jordan Tarlet
Journal: The Lancet Digital Health (2021)

A blockchain is a decentralised database allowing different stakeholders to obtain local copies of data and to be involved in how each data item is integrated into the database. Stakeholders can manipulate data in a privacy-preserving environment and the database should be immutable. Within this environment, data are time-stamped and added sequentially (by block), thus potentially guaranteeing their traceability and chronology (time-ordering). Furthermore, executable code that runs on top of the blockchain (called a smart contract) enables automation of some routine processes and allows comparison of timestamps that constitutes time-ordering.
Abstract 12487: Antiarrhythmic Medication Discontinuation After Ablation of Atrial Fibrillation
Authors: Winston Guo, David J Slotwiner, Meghan Reading Turchioe
Journal: Circulation (2021)

Introduction: Antiarrhythmic medications are often needed after atrial fibrillation (AF) ablation but may induce side effects (e.g., nausea, fatigue) or new arrhythmias. Knowing the length of time antiarrhythmics may be needed post-ablation is important for patients evaluating benefits and risks of ablation. The purpose of this study was to evaluate the prevalence of antiarrhythmic discontinuation following AF ablation and analyze associations between demographic variables and discontinuation. Methods: We extracted institutional electronic health record (EHR) data for patients who underwent ablation 2010-2019, identified with billing codes. Using medication administration data, we assessed documentation of five common oral antiarrhythmics: amiodarone, flecainide, dronedarone, propafenone, and dofetilide at baseline (within 2 weeks before and after ablation) 2-24 weeks post-ablation, and &gt;24 weeks post-ablation. We calculated standard descriptive statistics and examined differences by age, gender, and race using Chi-square tests. Results: Patients (n=1180) had an average age of 64.9 (±12.1) years; 33% were female, and 74% were White. Most (61.2%) had antiarrhythmics documented at baseline; of these patients, 41.8% did not have antiarrhythmics documented at all post-ablation, 21.3% had them documented 2-24 weeks post-ablation but not after, and 19.4% had them documented at both 2-24 and &gt;24 weeks. Documentation of antiarrhythmics beyond 2 weeks post-ablation was more likely among younger patients (&lt;65) versus older (63.3% vs. 54.2%; p=0.017) and trended towards significant for White versus non-White patients (61.4% vs. 54.5%; p=0.07). There was no significant difference by gender. Conclusion: More than half of patients had antiarrhythmics documented following AF ablation, especially younger patients.
Therapeutic implications of cancer gene amplifications without mRNA overexpression: silence may not be golden
Authors: Amélie Boichard, Scott M. Lippman, Razelle Kurzrock
Journal: Journal of Hematology & Oncology (2021)

Abstract Amplifications of oncogenic genes are often considered actionable. However, not all patients respond. Questions have therefore arisen regarding the degree to which amplifications, especially non-focal ones, mediate overexpression. We found that a subset of high-level gene amplifications (≥ 6 copies) (from The Cancer Genome Atlas database) was not over-expressed at the RNA level. Unexpectedly, focal amplifications were more frequently silenced than non-focal amplifications. Most non-focal amplifications were not silenced; therefore, non-focal amplifications, if over-expressed, may be therapeutically tractable. Furthermore, specific silencing of high-level focal or non-focal gene amplifications may explain resistance to drugs that target the relevant gene product.
Abstract 10331: Caring for Heart Failure with Confidence: Better Preparation and Training Determine Home Health Aide Self-Efficacy
Authors: Michael A Stawnychy, joanna Ringel, Barbara Riegel, Madeline R Sterling
Journal: Circulation (2021)

Background: Over 3 million home health and personal care aides (HHA) provide essential support for adults with chronic illness, including the complex self-care needs of adults with HF. Self-efficacy has been shown to mediate HHAs’ preparedness for caregiving and contribution to HF self-care. The determinants of HHA self-efficacy are unknown. Aim: Identify the determinants of HHAs’ self-efficacy in contributing to HF self-care. Methods: Secondary analysis of a cross-sectional survey (n=328) that examined the influence of HHA characteristics on contributions to HF self-care. Self-efficacy in contributing to patient HF self-care was assessed using the 10-item Caregiver Self-Efficacy in Contributing to Self-Care Scale. Standardized scores range 0-100; scores ≥ 70 pts indicate adequate self-efficacy. Preparedness was assessed with the 8-item Caregiver Preparedness scale. Additional predictors included job satisfaction, HHA experience, prior HF training, and agency size. Participants were divided into two groups based on a self-efficacy cutoff score of 70 points: low self-efficacy (&lt; 70 pts) vs adequate self-efficacy (≥ 70 pts). Poisson regression with robust standard errors, adjusted for sociodemographic variables, was used to estimate prevalence ratios with 95% confidence intervals (PR [95% CI]) to identify determinants of adequate self-efficacy. Results: HHAs with adequate self-efficacy came from smaller and medium sized agencies (92% vs 84%, p =.049), and cared for either fewer than 6 (78% vs 68%, p=.002 ) or &gt; 10 HF patients (11% vs 8%, p=.002 ). They had at least some prior HF training (55% vs 17%, p &lt;.001), felt better prepared for caregiving (4.55±0.50 vs 3.39±0.85, p &lt;.001), and were more satisfied with their jobs (90% vs 77%, p =.003). In a fully adjusted model, significant determinants for adequate self-efficacy were length of employment (1.02 [1.00-1.03], p =.027), better preparation for caregiving (3.10 [2.42-3.96], p &lt;.001), and more HF training (1.48 [1.20-1.84], p &lt;.001). Conclusion: Preparation for caregiving and HF training were the strongest determinants of HHAs’ caregiving self-efficacy. Home care agencies and policy-makers can target these modifiable determinants to improve this workforces’ ability to care for HF patients.
Non–Small Cell Lung Cancer: Recommendations for Biomarker Testing and Treatment
Authors: Dara L. Aisner, Gregory J. Riely
Journal: Journal of the National Comprehensive Cancer Network (2021)

Updates to the NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) for 2021 include recommendations for biomarker testing in all appropriate patients with newly diagnosed advanced lung cancer, including squamous cell lung cancer. When a targetable genetic alteration is detected, the NCCN Guidelines recommend treatment with a first-line therapy targeted to that alteration. The guidelines contain new information on use of adjuvant treatment with osimertinib for resected early-stage EGFR -mutated NSCLC. New targeted agents are now recommended for the treatment of ALK rearrangements, RET alterations, MET exon 14 skipping mutations in patients with advanced NSCLC; and new immunotherapy agents are recommended for advanced NSCLC without a driver oncogene.
Abstract 13121: Isolation and Primary Culture of Murine Aortic Cells for Atherosclerosis Research
Authors: Jingshu Chen, Rulin Zhuang, Carmel Assa, Henry Cheng, Mark W Feinberg
Journal: Circulation (2021)

Introduction: Atherosclerosis is a chronic inflammatory disease of the vascular wall characterized by abnormal lipid deposition, immune cell infiltration, and plaque formation. Isolation of the cellular constituents of the mouse aorta is commonly used for expression or functional analyses in experimental atherosclerosis. Endothelial cell, smooth muscle cell, leukocyte, and fibroblast are four major contributors to the progression of atherosclerosis. However, the isolation and culture of the primary aortic cells is considered difficult, often resulting in low yields. Current procedures are either only focused on isolation of one cell type or required long time for isolation and culture. Objective: To address the gap in experimental atherosclerosis research, we provide a fast and efficient protocol to isolate and culture a diverse range of cell types from the mouse aorta using immunomagnetic cell sorting. Methods and Results: Aortic cells were obtained using an enzymatic solution and different cell types were isolated using magnetic beads conjugated to antibodies targeting endothelial cell (CD31+), leukocyte (CD45+), and fibroblast cell (CD90.2+). Aortic smooth muscle cells were isolated by negatively selection after positive removal of the other cell types. Our protocol allows the isolation of relatively large numbers of cells (approximately 10,000 cells per mouse aorta) in a predictable manner, and the purity of the magnetic beads-selected cells was over 90% which was verified by detection of cell-marker genes expression, immunofluorescence staining, and flow cytometry. We also provide a quick and simple method to collect aortic intima-enriched RNA utilizing an intima peeling approach with Trizol. Conclusion: This protocol provides an effective means for magnetic beads-based isolation of different cell types from the mouse aortic wall, and the isolated cells can be utilized for functional and mechanistic vascular studies including atherosclerosis.
Abstract 12387: Porous Tip Radiofrequency Ablation Catheter Reduced Heart Failure Related Complications and Healthcare Utilization in Paroxysmal Atrial Fibrillation Patients
Authors: ALEXANDRU I COSTEA, Bereket Haile, Adam Barone, Maddie Schenthal, Kathrine Romanowicz, Kamal Joshi, James N Muth, Srinivas Rajsheker, Larry Gache, Lee Ming Boo, Tina D Hunter
Journal: Circulation (2021)

Introduction: Efforts to improve the safety of catheter ablation procedures have led to continuous improvements in catheter design. A 56-hole porous tip contact force (CF) catheter was developed to provide more uniform cooling with less fluid delivery than a prior 6-hole irrigated design, a change intended to reduce fluid overload and associated complications related to congestive heart failure (CHF). Hypothesis: We hypothesized that ablations using a 56-hole porous tip CF catheter would lead to reductions in CHF-related complications and healthcare utilization, compared to the prior 6-hole design. Methods: Consecutive de novo paroxysmal atrial fibrillation (PAF) ablations were performed between 2/14 - 3/19 by six operators at a single academic center. The 6-hole design was used through 12/16 with the 56-hole porous tip adopted in 10/16. Patient characteristics, procedural detail, and CHF-related complications or symptomatic presentation through 30 days were collected from electronic health records, as defined in table. Results: The population included 174 patients, age 61.1 ± 10.8 years, 67.8% male, with 25.3% having a history of CHF. Compared to the 6-hole design, the 56-hole catheter significantly reduced composite CHF-related complications within 7 days and CHF-related healthcare utilization within 30 days. In contrast to CHF reductions, non-CHF complications within 7 days were not different. Conclusion: In a real-world setting, a 56-hole porous tip irrigated CF catheter significantly reduced CHF-related complications and healthcare utilization in PAF patients when compared to the prior 6-hole design. This reduction may be related to the significant reduction in fluid delivery during the procedure. See table on next page.
Abstract 11407: E-Cigarettes Induce Dysregulation of Autophagy Leading to Endothelial Dysfunction in an Ipsc Model of Pulmonary Arterial Hypertension
Authors: Chen-wei Liu, Hoai Le, Philip Denaro, Sang-Ging Ong, Won Hee Lee
Journal: Circulation (2021)

Introduction: Given the increasing popularity of electronic-cigarettes (e-cigs), it is imperative to evaluate the potential health risks of e-cigs especially in users with pre-existing health concerns. Although we have recently demonstrated that acute exposure to e-cig exacerbates endothelial dysfunction, a prominent feature of pulmonary arterial hypertension (PAH), it is currently unknown whether the use of e-cig represents an even higher risk factor in PAH patients. The aim of the present study is to assess if differential susceptibility exists between healthy and PAH patients following e-cig exposure and mechanisms contributing to it. Methods and Results: Using patient-specific induced pluripotent stem cells (iPSCs) derived from both PAH patients and healthy controls, we showed that PAH iPSC-derived endothelial cells (iPSC-ECs) exhibited increased susceptibility against e-cig exposure compared to healthy iPSC-ECs leading to significantly decreased cell viability, increased reactive oxygen species generation and apoptosis, and reduced tube formation and migration. Transcriptomic analyses revealed that differential expression of AKT3 may be responsible for triggering enhanced autophagic flux impairment in PAH iPSC-ECs compared to healthy iPSC-ECs which underlies increased susceptibility upon e-cig exposure. Consistent with sequencing data, western blot confirmed that AKT3 level was decreased in PAH iPSC-ECs following e-cig exposure and AKT3 proteasomal degradation was mediated by K48-linked ubiquitination. Moreover, knockdown of AKT3 in healthy iPSC-ECs significantly induced autophagic flux impairment and increased endothelial dysfunction and these vascular toxicities were further increased when exposed to e-cig, thus mimicking the PAH cell phenotype after e-cig exposure. Finally, rapamycin treatment reversed e-cig-induced decreased AKT3 level, endothelial dysfunction, and autophagy impairment in PAH iPSC-ECs. Conclusions: Taken together, these data suggest a potential link between autophagy and Akt3-mediated increased susceptibility to e-cig in PAH.
Equitable modelling of brain imaging by counterfactual augmentation with morphologically constrained 3D deep generative models
Authors: Guilherme Pombo, Robert Gray, M Jorge Cardoso, Sebastien Ourselin, Geraint Rees, John Ashburner, Parashkev Nachev
Journal: Medical Image Analysis (2022)

We describe CounterSynth, a conditional generative model of diffeomorphic deformations that induce label-driven, biologically plausible changes in volumetric brain images. The model is intended to synthesise counterfactual training data augmentations for downstream discriminative modelling tasks where fidelity is limited by data imbalance, distributional instability, confounding, or underspecification, and exhibits inequitable performance across distinct subpopulations. Focusing on demographic attributes, we evaluate the quality of synthesised counterfactuals with voxel-based morphometry, classification and regression of the conditioning attributes, and the Fréchet inception distance. Examining downstream discriminative performance in the context of engineered demographic imbalance and confounding, we use UK Biobank and OASIS magnetic resonance imaging data to benchmark CounterSynth augmentation against current solutions to these problems. We achieve state-of-the-art improvements, both in overall fidelity and equity. The source code for CounterSynth is available at https://github.com/guilherme-pombo/CounterSynth.
Abstract 9691: Lipoprotein Subclasses Are Associated With Hepatic Steatosis: Insights from the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) Clinical Trial
Authors: Maros Ferencik, Robert W McGarrah, Maggie Nguyen, Ann M Navar, Nandini Meyersohn, Stephanie Giamberardino, Michael Lu, Pedro Staziaki, Stefan B Puchner, Daniel Bittner, Borek Foldyna, Neha J Pagidipati, William E Kraus, Geoffrey S Ginsburg, Pamela S Douglas, Udo Hoffmann
Journal: Circulation (2021)

Introduction: Hepatic steatosis (HS) is associated with coronary artery disease (CAD) and cardiovascular (CV) events. Previously, we have demonstrated that granular measures of lipids (lipoprotein particle number/size) are associated with CAD and CV events and incremental to traditional lipid measures. Hypothesis: Granular measures of lipids are associated with HS detected by cardiac computed tomography (CT) and with HS detected by histopathology. Methods: We included 1524 subjects from the PROMISE trial. HS was defined as CT attenuation of the liver &lt;40HU or liver&lt;spleen HU on CT. Plasma lipoprotein particle parameters were measured by NMR. Principal components analysis was used for dimensionality reduction and logistic regression was used to test the association of lipoprotein factors and individual lipoproteins with HS cases and controls in uni/multivariable models. The association of lipoproteins with HS was validated in an independent cohort of 58 subjects (Laval U) with and without HS defined by histopathology on liver biopsy. Results: Subjects with HS (n=413) were slightly younger (59±8 vs 61±8 yrs) and more likely men (53 vs 44%) as compared to controls (n=1111). Three lipoprotein factors were associated with HS: LDL/LDL particle size (OR 1.36, 95%CI 1.21-1.53, p&lt;0.001); HDL/HDL size (OR 1.75, 95%CI, 1.53-2.02, p&lt;0.001), and TG-rich-lipoprotein particles (OR 0.74, 95% CI 0.65-0.84, p&lt;0.002). Individual lipoproteins heavily loaded in these factors were also significant in multivariable analysis (Figure). These lipoproteins were also associated with HS in the validation cohort: small LDL (OR 6.36, p&lt;0.05), large HDL (OR 0.29, p&lt;0.05), and large TG particles (OR 13.83, p&lt;0.05). Conclusions: We found association of small LDL, large HDL and large TG particles, previously associated with CV event risk, with HS phenotyped by CT and histopathology. These results suggest that use of lipoprotein subclasses may improve CV risk assessment in patients with HS.
Vaccination strategy and challenges for consolidating successful containment of covid-19 with population immunity in China
Authors: Zhijie An, Fuzhen Wang, An Pan, Zundong Yin, Lance Rodewald, Zijian Feng
Journal: BMJ (2021)

<b>Zijian Feng and colleagues</b> argue that sustained elimination of SARS-CoV-2 in China offers flexibility in covid-19 vaccination policy and discuss the anticipated challenges and systematic monitoring necessary to keep the immunisation component of the response on track