tbuckley/cabot-search huggingface dataset:
Abstract 14409: TRPA1 Channels Are a Source of Calcium-driven Cellular Mechano-arrhythmogenicity
Authors: Breanne A Cameron, Matthew R Stoyek, T Alexander Quinn
Journal: Circulation (2020)

Introduction: Pathologic changes in myocardial mechanics and hemodynamic load result in arrhythmias via mechanically-induced changes in electrophysiology or intracellular Ca 2+ (‘mechano-arrhythmogenicity’). While molecular mechanisms driving mechano-arrhythmogenicity are poorly defined, they are associated with disease-related alterations in voltage-Ca 2+ dynamics. Objective: Define mechanisms of mechano-arrhythmogenicity during alterations in voltage-Ca 2+ dynamics in rabbit ventricular myocytes. Methods: Rabbit (♀, NZW) LV myocytes were transiently stretched (8-16% change in sarcomere length, 100ms) during diastole or late repolarisation in control or during K ATP channel activation (pinacidil). Drugs were used to buffer Ca 2+ (BAPTA), stabilise RyR (dantrolene), non-selectively block stretch-activated channels (streptomycin), or specifically block (HC-030031) or activate (AITC) mechano-sensitive TRPA1 channels. Voltage-Ca 2+ dynamics were simultaneously monitored with fluorescent dyes (di-4-ANBDQPQ, Fluo-5F) and a single camera-optical splitter system and diastolic Ca 2+ was measured using Fura Red. Results: Pinacidil caused greater shortening of the AP than Ca 2+ transient (-144±17 vs -74±11ms; n =24 cells, N =7 rabbits; p &lt;0.001) with no change in cell stiffness or contractility. Stretch during pinacidil application caused arrhythmias in both diastole and late repolarisation (8 and 10% of stretches; n =46, N =5), which voltage-Ca 2+ imaging revealed were Ca 2+ -driven. Arrhythmias were reduced with BAPTA (3 and 0% of stretches; p &lt;0.05), streptomycin (4 and 2%; p &lt;0.05), and HC-030031(2 and 1%; p &lt;0.01), while dantrolene had no effect ( n =40, N =5 for each). Stretch in diastole during AITC application also caused arrhythmias (15%; p &lt;0.001), which were blocked by HC-030031 (4%; p &lt;0.001) or BAPTA (3%; p &lt;0.001; n =40, N =5 each). Both AITC and pinacidil caused an increase in diastolic Ca 2+ (112±29 and 78±29% of control; p&lt;0.05), which was reduced by HC-030031 with AITC (26±24%; p &lt;0.05), but not with pinacidil ( n =25, N =5 each). Conclusions: TRPA1 activation increases mechano-arrhythmogenicity via a Ca 2+ -driven mechanism and may represent a novel anti-arrhythmic target in pathologies involving altered cardiac mechanics.
Abstract IA-09: The end of perpetual chemotherapy?
Authors: Kim A Reiss
Journal: Cancer Research (2020)

Abstract The traditional therapeutic model for patients with metastatic pancreatic cancer is perpetual chemotherapy from diagnosis to death. However, subsets of patients who achieve durable responses to cytotoxic chemotherapy may benefit from a switch maintenance approach. Maintenance therapy with the PARP inhibitor olaparib has recently been established for one such subgroup: Patients with germline BRCA mutations. In this talk we will review the available data and the future directions for maintenance therapy including combination treatments and expanding beyond germline BRCA carriers. Citation Format: Kim A Reiss. The end of perpetual chemotherapy? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-09.
Abstract 14316: Diurnal Variation of the Macrophage Expressed Gene-1 Inflammatory Marker in the Timing of Sudden Cardiac Arrest
Authors: Sharma Kattel, Hardik Bhatt, Shirley Xu, Jibran Mirza, Saraswati Pokharel, Umesh C Sharma
Journal: Circulation (2020)

Background: In the last decade, inflammatory biomarkers have been implicated in out of hospital sudden cardiac arrest (OH-SCA). However, the role of diurnal variation in these inflammatory markers in relation to the timing of OH-SCA is unknown. Here we report an increased macrophage-expressed gene-1 (MPEG-1) expression, an evolutionary conserved protein with membrane attack complex domain, in relation to the timing of OH-SCA and survival after resuscitation. Objectives: To examine the relationship between the circulating MPEG-1protein levels and the timing of OH-SCA. Methods: We prospectively enrolled 144 subjects from 4 different tertiary care centers who were successfully resuscitated from OH-SCA. The timing of OH-SCA and other clinical parameters were obtained from medical record review. Serum levels of a novel biomarker, MPEG-1, and other conventional clinical biomarkers including troponin-I and CK-MB were measured in the blood samples obtained within the 6 hours of OH-SCA. Results: Approximately 32% of the sudden cardiac arrest happened in the morning hours ( 5AM- 12PM ). The higher incidence of the OH-SCA occurring in morning hours correlated with elevated serum MPEG-1 levels as shown in figure 1 . In 71% of the OH-SCA, the etiology was of cardiac in nature, of which 32% were from acute myocardial infraction. At the end of the hospital stay, 46% of the patients had died. Conclusions: This study suggests that the diurinal variation in the propensity to develop OH-SCA is associated with elevated serum levels of MPEG-1. Further research examining this novel biomarkers in larger cohorts can form the basis for accurate and timely risk-prediction.
Endoscopic prediction of submucosal invasion in Barrett’s cancer with the use of artificial intelligence: a pilot study
Authors: Alanna Ebigbo, Robert Mendel, Tobias Rückert, Laurin Schuster, Andreas Probst, Johannes Manzeneder, Friederike Prinz, Matthias Mende, Ingo Steinbrück, Siegbert Faiss, David Rauber, Luis A. de Souza, João P. Papa, Pierre H. Deprez, Tsuneo Oyama, Akiko Takahashi, Stefan Seewald, Prateek Sharma, Michael F. Byrne, Christoph Palm, Helmut Messmann
Journal: Endoscopy (2020)

Abstract Background The accurate differentiation between T1a and T1b Barrett’s-related cancer has both therapeutic and prognostic implications but is challenging even for experienced physicians. We trained an artificial intelligence (AI) system on the basis of deep artificial neural networks (deep learning) to differentiate between T1a and T1b Barrett’s cancer on white-light images. Methods Endoscopic images from three tertiary care centers in Germany were collected retrospectively. A deep learning system was trained and tested using the principles of cross validation. A total of 230 white-light endoscopic images (108 T1a and 122 T1b) were evaluated using the AI system. For comparison, the images were also classified by experts specialized in endoscopic diagnosis and treatment of Barrett’s cancer. Results The sensitivity, specificity, F1 score, and accuracy of the AI system in the differentiation between T1a and T1b cancer lesions was 0.77, 0.64, 0.74, and 0.71, respectively. There was no statistically significant difference between the performance of the AI system and that of experts, who showed sensitivity, specificity, F1, and accuracy of 0.63, 0.78, 0.67, and 0.70, respectively. Conclusion This pilot study demonstrates the first multicenter application of an AI-based system in the prediction of submucosal invasion in endoscopic images of Barrett’s cancer. AI scored equally to international experts in the field, but more work is necessary to improve the system and apply it to video sequences and real-life settings. Nevertheless, the correct prediction of submucosal invasion in Barrett’s cancer remains challenging for both experts and AI.
Central Command and the Regulation of Exercise Heart Rate Response in Heart Failure With Preserved Ejection Fraction
Authors: Satyam Sarma, Erin Howden, Justin Lawley, Mitchel Samels, Benjamin D. Levine
Journal: Circulation (2020)

Chronotropic incompetence is common in heart failure with preserved ejection fraction (HFpEF) and is linked to impaired aerobic capacity. Whether upstream autonomic signaling pathways responsible for raising exercise heart rate are impaired in HFpEF is unknown. We investigated the integrity of central command and muscle metaboreceptor function, 2 predominant mechanisms responsible for exertional increases in heart rate, in patients with HFpEF and senior controls.Fourteen healthy senior controls (7 men, 7 women) and 20 carefully screened patients with HFpEF (8 men, 12 women) underwent cardiopulmonary exercise testing (peak Vo2) and static handgrip exercise at 40% of maximal voluntary contraction to fatigue with postexercise circulatory arrest for 2 minutes to assess central command and metaboreceptor function, respectively.Peak Vo2 (13.1±3.4 versus 22.7±4.0 mL/kg/min; P<0.001) and heart rate (122±20 versus 155±14 bpm; P<0.001) were lower in patients with HFpEF than senior controls. There were no significant differences in peak heart rate response during static handgrip between groups (patients with HFpEF versus controls: 90±13 versus 93±10 bpm; P=0.49). Metaboreceptor function, defined as mean arterial blood pressure at the end of postexercise circulatory arrest, was not significantly different between groups.Central command (vagally mediated) and metaboreceptor function (sympathetically mediated) in patients with HFpEF were not different from those in healthy senior controls despite significantly lower peak whole-body exercise heart rates. These results demonstrate key reflex autonomic pathways regulating exercise heart rate responsiveness are intact in HFpEF.
Abstract 13286: Finding the Missing Heritability of Serum Lipids: Leveraging the Relatedness in a Large-scale Biobank
Authors: Hung-hsin Chen, Ryan J Bohlender, Lauren E Petty, Quinn Wells, Chad Huff, Jennifer Below
Journal: Circulation (2020)

Introduction: High prevalence of dyslipidemia in the United States results in elevated risk of cardiovascular disease. Although the high heritability of serum lipids has motivated many genome-wide association studies (GWAS), much of the heritability is still unexplained. Genomic regions shared with identity by descent (IBD) are inherited from the same common ancestor without recombination, and can be observed in both close and distant relatives. IBD segments provide an opportunity to discover genes that harbor low frequency, large effect variants that are undetectable in GWAS due to low power at rare and heterogeneous alleles. Methods: The Vanderbilt biobank (BioVU) comprises over 280,000 DNA samples from participants with linked electronic medical record (EMR). In this study, we extracted 18,337 European dyslipidemia cases, who have either diagnosed dyslipidemia or record of taking lipid-lowering drugs in linked EMR, and 18,337 sex, age, and ancestry-matched controls. The pairwise IBD shared segments were identified by GERMLINE using genotype data. To assess enrichment of IBD, we compared local shared IBD rates in case-case pairs and case-control pairs. Results: The greatest enrichment of IBD sharing was found on chromosome 5 (chr5: 169-171 MB, p-value=3.3х10 -5 ), and another three suggested regions were from chromosome 10, 18 and 22 (chr10: 86-87 MB, p-value=5.5х10 -4 , chr18: 10-11 MB, p-value=5.3х10 -4 , and chr22: 49.3-49.7 MB, p-value=2.1х10 -4 ). To further explore the molecular function, we used PrediXcan to impute the genetically regulated expression of the genes which locate within 1 MB of identified regions. A total of 31 unique genes in these regions exhibit significantly different predicted expression between risk IBD segment carriers and non-carriers, and are also significantly correlated with at least one serum lipids level. For instance, a novel long non-coding RNA, LINC01310, from chr22 associated with total glyceride (p-value=5.3х10 - 3 ) and expressed a lower level in risk people carrying the risk-associated IBD segment (p-value=1.2х10 - 6 ). Conclusions: Our results identity four genomic segments enriched in dyslipidemia cases, and, using GReX, we demonstrate the potential function of novel genes on the regulation of serum lipids.
Discriminating between CPAP success and failure in COVID-19 patients with severe respiratory failure
Authors: Pietro Arina, Beatrice Baso, Valeria Moro, Hemani Patel, Gareth Ambler
Journal: Intensive Care Medicine (2020)

Dear Editor,Continuous positive airways pressure (CPAP) treatment was used increasingly in the UK and elsewhere for coronavirus disease 2019 (COVID-19) to avoid the need for mechanical ventilation [1][2][3].Early identification of patients benefitting from CPAP would assist decision making however we found that intensive care unit (ICU) admission respiratory parameters (rate, PaO 2 /FiO 2 ratio) were poorly discriminatory.Using electronic healthcare records we retrospectively studied COVID-19 patients admitted to the University College London Hospital ICU between 8 March and 5 June 2020 in moderate-to-severe respiratory failure who received initial management with CPAP to see whether better prognosticators could be identified.Comparison of demographic, clinical and biochemical parameters measured on ICU admission was made between patients adjudged CPAP success (hospital survival with CPAP alone) or failure (either death where CPAP was a ceiling of treatment, or need for mechanical ventilation regardless of hospital outcome).Requirement for other organ support was also compared.Patients managed on CPAP in non-ICU wards were excluded as detailed clinical and lab data were often lacking.
Abstract 325: Resuscitation Practices in Pediatric Hospitals: Insights From Get with the Guidelines-Resuscitation
Authors: Jesse L Chan, Yuanyuan Tang, Joan S Roberts, Paul S Chan
Journal: Circulation (2020)

Background: Resuscitation practices for adult in-hospital cardiac arrest (IHCA) vary widely, based on setting and size. Resuscitation practices in pediatric hospitals have not been examined in detail, and whether practices differ between free-standing pediatric hospitals and combined hospitals (which care for adults and children) is unknown. Methods: We conducted a survey of U.S. hospitals that submit data on pediatric IHCA to GWTG-Resuscitation, a large national registry of IHCA, to elicit detailed information on resuscitation practices. Hospitals were categorized as free-standing pediatric hospitals and combined hospitals, and rates of resuscitation practices were compared. Results: A total of 33 hospitals with at least 5 IHCA events between 2015-2019 completed the survey, of which 9 (27.3%) were freestanding pediatric hospitals and 24 (72.7%) were combined hospitals. Overall, 18 (54.5%) hospitals used a device to measure chest compression quality, 2 (6.1%) used a mechanical device to deliver chest compressions, 6 (18.2%) routinely monitored diastolic pressures during resuscitations, 16 (48.5%) had a staff member monitor chest compression quality, 10 (30.3%) used lanyards or hats to designate leaders during a resuscitation, 16 (48.5%) routinely conducted immediate code debriefings, and 7 (21.2%) conducted mock codes at least quarterly and 17 (51.5%) reported no set schedule. Freestanding pediatric hospitals were more likely to employ a device to measure chest compressions (88.9% vs. 41.7%; P=0.016), conduct code debriefing always or frequently after resuscitations (77.8% vs. 37.5%, P=0.044), use lanyards or a hat to designate the code team leader during resuscitations (66.7% vs. 16.7%, P=0.006), and allow nurses to defibrillate using an AED (77.8% vs. 29.2%, P=0.01). There were no differences in simulation frequency or other resuscitation practices between the 2 hospital groups. Conclusions: Across hospitals caring for pediatric patients, substantial variation exists in resuscitation practices. For some resuscitation practices, there were differences between freestanding pediatric hospitals and hospitals which care for both adults and children.
Abstract 14533: Guideline Directed Medical Therapy Optimization Assisted by Telemonitoring for Heart Failure With Reduced Ejection Fraction Patients: Rationale and Design
Authors: Erick Sandro Romero
Journal: Circulation (2020)

Background: Only a small proportion of patients with Heart Failure with Reduced Ejection Fraction (HFrEF) receive optimal Guideline-Directed Medical Therapy (GDMT) despite being eligible based on their clinical profile. The GDMT underuse leads to an important gap in clinical outcomes. In light of this gap, we integrated telemonitoring with a protocol for therapy optimization. We hypothesize that GDMT assisted by telemonitoring can improve the proportion of patients receiving optimal GDMT Objective: The aim of this study is to assess the value of telemonitoring in the optimization of GDMT. Methods: In a randomized controlled trial control patients will receive standard of care for GDMT, whereas the intervention group will receive GDMT assisted by telemonitoring. Patient eligibility includes HFrEF (LVEF≤ 40%), ACC/AHA stage C while receiving ≥ 1 GDMT medication at &lt;50% of target dose. Patients in the intervention group will record daily Patient Generated Health Data (PGHD) including step counts, weight, blood pressure, and heart rate which will be transmitted to their electronic health records. The heart failure team will review the PGHD and clinical profile every two weeks and recommend dose titration according to the ACC/AHA Guidelines. The patient will be contacted through phone calls to evaluate medication tolerance, discuss laboratory test results and provide instructions for medication titration. This workflow is repeated cyclically until patients reach target doses or further adjustments are not tolerated. The estimated sample size is 206 (103 participants in the intervention and control groups, power of 80%). The primary outcome is the optimal target doses of GDMT at 3-6 months. Conclusions: This trial implements and tests the value of GDMT assisted by telemonitoring. Our approach combines telemonitoring in a structured titration program for therapy optimization. Findings may have implications for achieving GDMT adherence in clinical practice.
Automated size-specific dose estimates using deep learning image processing
Authors: Jan Juszczyk, Pawel Badura, Joanna Czajkowska, Agata Wijata, Jacek Andrzejewski, Pawel Bozek, Michal Smolinski, Marta Biesok, Agata Sage, Marcin Rudzki, Wojciech Wieclawek
Journal: Medical Image Analysis (2020)
Abstract 15874: An Ischaemia Time of Greater Than 6 Hours is Associated With Deleterious Outcomes in Pediatric Heart Transplantation
Authors: Adam Arshad, Estela Azeka, Ryan Cantor, Devin Koehl, James Kirklin, Jacob Simmonds, Fawwaz Shaw, Jondavid Menteer, William J Ravekes, Renata Shih, Jean Ballweg
Journal: Circulation (2020)

Introduction: The shortage of available donor organs means we must re-consider our current policies on donor selection. There is a broad variation in practice between centers as to the acceptable limit to ischaemia time (IT) in pediatric cardiac transplantation, with no recommendations in international guidelines. Hypothesis: We hypothesised that a prolonged ischaemia time was not associated with impaired post-transplant outcomes. Methods: Data from the Pediatric Heart Transplantation Society was analysed for all pediatric patients receiving heart transplants (Jan 1993 - June 2019). Transplants were separated into 5 categories depending on the IT (hours): &lt; 2.4, 2.5-3.4, 3.5-4.4, 4.5-6.0, &gt;6. Risk-adjusted outcomes were assessed by multivariable analysis, adjusting for donor, recipient, and peri-operative characteristics. Results: Data for 6,903 transplants were assessed (IT &lt; 2.4 in 980, 2.5-3.4 in 2032, 3.5-4.4 in 2310, 4.5-6.0 in 1162, &gt;6 in 281). In univariate analysis, increasing IT was associated with reduced 1-year survival (90.1%, 87.7% and 84.6%; p&lt;0.001) for the 3.5-4.4, 4.5-6.0 and &gt;6 groups, respectively. Similar findings, of a deleterious association with prolonged IT, were observed for freedom from infection (73.0%, 66.8% and 56.4%; p&lt;0.001), freedom from first rejection (67.4%, 62.6% and 61.0%; p = 0.01) and freedom from haemodynamically compromising rejection (89.1%, 85.4% and 85.3%; p=0.004) at 1-year. No significant differences in the risk of malignancy (p=0.2) and time to first CAV (p=0.08) between the IT groups were noted. We separately analysed the risk of graft failure by multiphase hazards modelling. In adjusted analysis, increasing IT was found to be a risk factor for graft failure (HR: 1.08, 95% CI: 1.00-1.16, p=0.04). Within this model, primary diagnosis was a predictor of the outcome (p&lt;0.001). Exploring this association, an IT of &gt; 6 hours was associated with graft failure in cardiomyopathy (HR: 2.87, 95% CI: 1.34 - 6.15, p=0.007), but not congenital heart disease patients. Conclusions: In this large multi-centre cohort study, we found a deleterious association between prolonged IT and post-transplant outcomes. We recommend that an IT greater than 6 hours should be avoided in pediatric cardiac transplantation.
Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure
Authors: Deepak L. Bhatt, Michael Szarek, P. Gabriel Steg, Christopher P. Cannon, Lawrence A. Leiter, Darren K. McGuire, Julia B. Lewis, Matthew C. Riddle, Adriaan A. Voors, Marco Metra, Lars H. Lund, Michel Komajda, Jeffrey M. Testani, Christopher S. Wilcox, Piotr Ponikowski, Renato D. Lopes, Subodh Verma, Pablo Lapuerta, Bertram Pitt
Journal: New England Journal of Medicine (2020)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure. However, the safety and efficacy of SGLT2 inhibitors when initiated soon after an episode of decompensated heart failure are unknown.We performed a multicenter, double-blind trial in which patients with type 2 diabetes mellitus who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin or placebo. The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). The trial ended early because of loss of funding from the sponsor.A total of 1222 patients underwent randomization (608 to the sotagliflozin group and 614 to the placebo group) and were followed for a median of 9.0 months; the first dose of sotagliflozin or placebo was administered before discharge in 48.8% and a median of 2 days after discharge in 51.2%. Among these patients, 600 primary end-point events occurred (245 in the sotagliflozin group and 355 in the placebo group). The rate (the number of events per 100 patient-years) of primary end-point events was lower in the sotagliflozin group than in the placebo group (51.0 vs. 76.3; hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.85; P<0.001). The rate of death from cardiovascular causes was 10.6 in the sotagliflozin group and 12.5 in the placebo group (hazard ratio, 0.84; 95% CI, 0.58 to 1.22); the rate of death from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (hazard ratio, 0.82; 95% CI, 0.59 to 1.14). Diarrhea was more common with sotagliflozin than with placebo (6.1% vs. 3.4%), as was severe hypoglycemia (1.5% vs. 0.3%). The percentage of patients with hypotension was similar in the sotagliflozin group and the placebo group (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively). The benefits of sotagliflozin were consistent in the prespecified subgroups of patients stratified according to the timing of the first dose.In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo. (Funded by Sanofi and Lexicon Pharmaceuticals; SOLOIST-WHF ClinicalTrials.gov number, NCT03521934.).
Equivocal, explicit and emergent actions of PKC isoforms in cancer
Authors: Peter J. Parker, Sophie J. Brown, Veronique Calleja, Probir Chakravarty, Mathias Cobbaut, Mark Linch, Jacqueline J. T. Marshall, Silvia Martini, Neil Q. McDonald, Tanya Soliman, Lisa Watson
Journal: Nature reviews. Cancer (2020)