tbuckley/cabot-search huggingface dataset:
Abstract 13929: Methadone Lengthens Both Early and Late Ventricular Repolarization in Patients Undergoing Maintenance Therapy in an Urban Narcotic Treatment Center
Authors: James E Tisdale, Elena Tomaselli Muensterman, Erika Titus-Lay, Heather Jaynes, Todd Walroth, Gabriela Williams, Paul Moe, Michelle Wilbrandt, Carol Ott
Journal: Circulation (2020)

Introduction: Methadone, a racemic mixture of S - and R -enantiomers, prolongs the QT interval and causes torsades de pointes. Methadone has been shown to lengthen late ventricular repolarization, represented by the T peak-Tend interval, which is modulated primarily by I Kr and I Ks . However, it is unknown whether methadone prolongs early ventricular repolarization, represented by the heart rate-corrected J-T peak (J-T peak c) interval, which is regulated primarily by L-type calcium and late sodium currents. In addition, the relationship between stereospecific serum methadone and metabolite concentrations and effects on J-T peak c and T peak -T end intervals are unknown. Hypothesis: 1) Methadone lengthens both J-T peak c and T peak -T end , and 2) Methadone effects on J-T peak c and T peak -T end correlate with serum S - and R -methadone and S - and R -metabolite [ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)] concentrations. Methods: Patients (n=81) on steady state maintenance methadone therapy at an urban narcotic treatment center who had undergone a pre-methadone 12-lead ECG within the previous 6 months were identified and asked to return for a followup ECG during steady-state methadone therapy. In a subset (n=41), blood was obtained to determine serum S - and R -methadone and S - and R -EDDP concentrations. Results: Compared to baseline, methadone lengthened mean ± SD J-T peak c (225 ± 26 vs 232 ± 28 ms, p=0.02) as well as T peak - T end (80 ±14 vs 90 ± 16 ms, p&lt;0.00001). Serum concentrations of S -methadone correlated with J-T peak c [R 2 = 0.41 (95% CI 0.11-0.65), p=0.007]. Serum R -methadone concentrations also correlated with J-T peak c [R 2 = 0.47 (0.17-0.68), p=0.002]. In addition, serum concentrations of S - and R -EDDP correlated with J-T peak c [R 2 = 0.39 (0.09-0.63), p=0.01] and [R 2 = 0.38 (0.07-0.62), p=0.02], respectively. There were no significant correlations between serum S - and R -methadone or S- and R-EDDP concentrations with T peak - T end intervals. Conclusions: Methadone lengthens both early and late ventricular repolarization, suggesting that methadone’s ion channel effects may extend beyond inhibition of I Kr . Serum S - and R -methadone and S -and R -EDDP concentrations are associated with effects on J-T peak c intervals.
Abstract 15709: Older and Younger Patients’ Perceptions, Evaluations, and Responses to Worsening Heart Failure Symptoms
Authors: Chin-Yen Lin, Muna Hammash, Gia Mudd-martin, Martha J Biddle, Debra K Moser
Journal: Circulation (2020)

Background: Adequate self-care abilities, such as early recognition of and appropriate responses to worsening heart failure (HF) symptoms, are important to prevent further deterioration and avoid unnecessary hospitalization. Patients with HF have difficulty recognizing and responding to worsening symptoms promptly and this problem seems to be worse in older compared to younger patients. Objective: The aims of this study were (1) to compare perceptions, evaluations, and responses to worsening HF symptoms before a hospital admission between older and younger patients, and (2) to compare older and younger patients’ responses when they perceived higher symptom distress. Methods: Data on patients’ perceptions, evaluations, and responses to worsening HF symptoms were collected using HF Somatic Awareness Scale and Modified Response to Symptoms Questionnaire from 185 patients hospitalized with HF (mean age 62 ± 13 years; 51% male; 66% New York Heart Association class III/IV). We compared data between younger and older patients using a cutoff at age 65. Independent t -test, chi-square, and two-way ANOVA were performed. Results: Compared with younger patients, older patients were more likely to attribute their symptoms to aging ( p = 0.003) and to have lower somatic awareness ( p = 0.014); however, there were no significant differences between older and younger patients in their responses to worsening HF symptoms. In response to higher perceived symptom distress, regardless of age grouping, patients at first did nothing and hoped their symptoms would go away ( p = 0.004), ignored symptoms and continued doing what was doing ( p = 0.002), or laid down and tried to relax ( p &lt; 0.001). No other strategies such as self-medicated, contacted doctors, and went to hospital were significantly associated with higher symptom distress. Conclusions: Regardless of age, patients with HF do not respond appropriately to worsening HF symptoms. Older patients have lower somatic awareness, which may partially explain their lack of appropriate response, but younger patients with better somatic awareness do not respond any more appropriately. Interventions should be tested that target better symptom appraisal and promote appropriate symptom responses in patients with HF across all ages.
Abstract 16717: Features of the Candidate Genes Polymorphisms Accumulation in Population of Hypertensive Patients of Different Age Groups
Authors: Vadym Bondar, Kateryna Chernyshova, Halyna Chernyshova, Kateryna Bondar, Viktor Klochko, Sergei Kolomiets, Iegor Maznichenko, Dmitrii Oliynyk
Journal: Circulation (2020)

Introduction: Nowdays the analysis of gene candidates polymorphisms and formation of genetic risk scores are actively being used in diagnostic and preventive management in arterial hypertension (AH). Hypothesis: The purpose of the research was to analyze and compare the proportion of modified candidate genes (CG) of AH in different age groups by calculating the gene modification index (GMI) for confirmation of the hypothesis of modified genes accumulation through generations. Methods: 182 patients with AH were examined, mean age 44,3 [18-75], m/f=95/87, (ESC/ISH 2018). Patients were divided into 3 groups depending on age: 1st group - from 18 to 30 y.o. (n=48, m/f=27/21); 2nd group - from 31 to 55 y.o. (n=74, m/f=34/40); 3rd group - from 56 to 75 y.o. (n=60, m/f=28/32). Patients were analysed on the the following CG by PCR: ADD1: 1378, AGT: 704, AGT: 521, AGTR1: 1166, AGTR2: 1675, CYP11B2: - 344, GNB3: 825, NOS3: -786 , NOS3: 894. The GMI which represents the percentage of "pathological" genotypes. The GMI from 0 to 20% was considered as low genetic risk (GR), from 21 to 40 % - moderate GR, from 41 to 70% - high GR, from 71 to 100% - very high GR. Results: In 1 group the average GMI was 64,7% [CI 95%, 29-74], with low GR in 2 (4,2%), moderate GR - in 10 (20,8%), high GR - in 22 (45,8%), very high GR - in 14 (29,2%) patients. In 2 group the average GMI was 56,2% [CI 95%, 18-72], 12 (16,2%) patients had low GR, moderate GR was in 20 (27,1%), high GR - in 26 (35,1%), very high GR - in 16 (21,6%) patients. In 3 group the average GMI was 42,4% [CI 95%, 16-71], low GR was in 16 (26,7%), moderate GR - in 22 (36,7%), high GR - in 14 (23,3%), very high GR - in 8 (13,3%) patients. Analyzing data between the groups, a strong significant difference in GMI was between 1 and 3 groups (64,7% vs 42,4%, p=0,002), high significant differences were also between the 1 and 3 groups, especially in the proportion of patients with high GR (45,8% vs 23,3%, p=0,001) and very high GR (29,2% vs 13,3%, p=0,008) in the group of young patients. Conclusions: It was revealed in the research the accumulation of pathological genetic polymorphisms in the population of hypertensive patients through generations. It was found the strong significant difference in the proportion of "pathological" GP between young and older patients.
Abstract 14595: The Clinical Impact of Portal Vein Pulsatility on the Prognosis of Hospitalized Acute Heart Failure Patients
Authors: Naoya Kuwahara, Tomoyuki Honjo, Kenji Kaihotsu, Kohei Kamemura, Kazuhiko Nakayama, Hiroyuki Onishi, Junichi Imanishi, Akane Kajiura, Tomoyuki Nagano, Naohiko Sone, Masanori Iwahashi
Journal: Circulation (2020)

Introduction: Heart failure (HF) especially right-heart failure causes hepatic portal system congestion. The Portal vein (PV) pulsatility can be influenced by right atrial pressure (RAP). However, the association between PV pulsatility and the condition of HF remains unclear. Hypothesis: In this study, we aim to evaluate usefulness of PV pulsatility as a prognostic marker as well as a therapeutic indicator for hospitalized acute HF patients. Methods: We enrolled 54 patients with acute HF and 17 patients without HF served as controls. PV flow velocity was measured by ultrasonography at admission and discharge phase. PV pulsatility ratio (PVPR) was calculated by dividing minimal velocity by peak velocity. The primary endpoint for prognostic analysis was cardiac death and unexpected re-hospitalization for recurrent HF. The observation period was one year from first hospitalization for HF. Results: On admission, PVPR was significantly higher in controls compared to acute HF patients (0.91±0.08 vs. 0.71±0.04, p&amp;lt0.01).PVPR did not change during the hospitalization in controls (admission 0.91±0.08 vs discharge 0.93±0.06, p=0.31). However, in acute HF patients, PVPR was significantly elevated after the improvement of HF (admission 0.71±0.04 vs discharge 0.82±0.02, p&amp;lt0.05) due to the increase in minimal velocity (admission 12.6±4.5 cm/s vs. discharge 14.6±4.6 cm/sec, p&amp;lt0.05), indicating the decrease in RAP. To elucidate the association between PVPR and primary endpoint, the patients were divided into three groups according to the tertile of PVPR at discharge (PVPR-Q1:0.92&amp;ltPVPR&amp;lt1, PVPR-Q2: 0.73&amp;ltPVPR&amp;lt0.92, PVPR-Q3:PVPR&amp;lt0.73). Kaplan-Meier analysis found that the patients with higher PV pulsatility at discharge had significantly higher event rate among the groups (Figure). Conclusions: PVPR at discharge would reflect the condition of HF. It also can be a novel prognostic marker for hospitalized acute HF patients.
Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status
Authors: Stefan D Anker, Javed Butler, Gerasimos Filippatos, Muhammad Shahzeb Khan, Nikolaus Marx, Carolyn S.P. Lam, Sven Schnaidt, Anne Pernille Ofstad, Martina Brueckmann, Waheed Jamal, Edimar Bocchi, Piotr Ponikowski, Sergio V Perrone, James L. Januzzi, Subodh Verma, Michael Böhm, Joao Pedro Ferreira, Stuart J Pocock, Faiez Zannad, Milton Packer
Journal: Circulation (2020)

Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events.Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes.Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P-interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia.In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.
Clump material within drainage chest tubes contains diagnostic information: a proof-of-concept case series
Authors: Amber Louw, Calvin Sidhu, Deirdre B. Fitzgerald, Jenette Creaney, Siaw Ming Chai, Y.C. Gary Lee
Journal: European Respiratory Journal (2020)

Pleural effusion is a common diagnostic and therapeutic challenge [1, 2]. Malignant pleural effusion (MPE), in particular, often necessitates fluid drainage with chest tubes for symptom control [3, 4] and its diagnosis requires cyto-histological assessment of pleural fluid or tissue biopsies [2]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Louw has nothing to disclose. Conflict of interest: Dr. Sidhu has nothing to disclose. Conflict of interest: Dr. Fitzgerald has nothing to disclose. Conflict of interest: Dr. Creaney reports grants from National Health and Medical Research Council, grants from Insurance Commission of Western Australia, during the conduct of the study. Conflict of interest: Dr. Chai has nothing to disclose. Conflict of interest: Dr. Lee has nothing to disclose.
Response to ‘Correspondence on ‘Impact of the COVID-19 pandemic on the disease course of patients with inflammatory rheumatic diseases: results from the Swiss Clinical Quality Management cohort’ by Ruyssen-Witrand<i>et al</i>
Authors: Adrian Ciurea, Axel Finckh
Journal: Annals of the Rheumatic Diseases (2020)

We would like to thank Ruyssen-Witrand et al for their interest in our study1 and their data from French patients with rheumatoid arthritis collected during the first wave of the COVID-19 pandemic through an online survey.2 Despite the fact that up to 70% of medical consultations could not be performed as planned …
E1 Enzymes as Therapeutic Targets in Cancer
Authors: Samir H. Barghout, Aaron D. Schimmer
Journal: Pharmacological Reviews (2020)

Post-translational modifications of cellular substrates with ubiquitin and ubiquitin-like proteins (UBLs), including ubiquitin, SUMOs, and neural precursor cell–expressed developmentally downregulated protein 8, play a central role in regulating many aspects of cell biology. The UBL conjugation cascade is initiated by a family of ATP-dependent enzymes termed E1 activating enzymes and executed by the downstream E2-conjugating enzymes and E3 ligases. Despite their druggability and their key position at the apex of the cascade, pharmacologic modulation of E1s with potent and selective drugs has remained elusive until 2009. Among the eight E1 enzymes identified so far, those initiating ubiquitylation (UBA1), SUMOylation (SAE), and neddylation (NAE) are the most characterized and are implicated in various aspects of cancer biology. To date, over 40 inhibitors have been reported to target UBA1, SAE, and NAE, including the NAE inhibitor pevonedistat, evaluated in more than 30 clinical trials. In this Review, we discuss E1 enzymes, the rationale for their therapeutic targeting in cancer, and their different inhibitors, with emphasis on the pharmacologic properties of adenosine sulfamates and their unique mechanism of action, termed substrate-assisted inhibition. Moreover, we highlight other less-characterized E1s—UBA6, UBA7, UBA4, UBA5, and autophagy-related protein 7—and the opportunities for targeting these enzymes in cancer. <h3>Significance Statement</h3> The clinical successes of proteasome inhibitors in cancer therapy and the emerging resistance to these agents have prompted the exploration of other signaling nodes in the ubiquitin-proteasome system including E1 enzymes. Therefore, it is crucial to understand the biology of different E1 enzymes, their roles in cancer, and how to translate this knowledge into novel therapeutic strategies with potential implications in cancer treatment.
Using Machine Learning Algorithms to Predict Immunotherapy Response in Patients with Advanced Melanoma
Authors: Paul Johannet, Nicolas Coudray, Douglas M. Donnelly, George Jour, Irineu Illa-Bochaca, Yuhe Xia, Douglas B. Johnson, Lee Wheless, James R. Patrinely, Sofia Nomikou, David L. Rimm, Anna C. Pavlick, Jeffrey S. Weber, Judy Zhong, Aristotelis Tsirigos, Iman Osman
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Several biomarkers of response to immune checkpoint inhibitors (ICI) show potential but are not yet scalable to the clinic. We developed a pipeline that integrates deep learning on histology specimens with clinical data to predict ICI response in advanced melanoma. Experimental Design: We used a training cohort from New York University (New York, NY) and a validation cohort from Vanderbilt University (Nashville, TN). We built a multivariable classifier that integrates neural network predictions with clinical data. A ROC curve was generated and the optimal threshold was used to stratify patients as high versus low risk for progression. Kaplan–Meier curves compared progression-free survival (PFS) between the groups. The classifier was validated on two slide scanners (Aperio AT2 and Leica SCN400). Results: The multivariable classifier predicted response with AUC 0.800 on images from the Aperio AT2 and AUC 0.805 on images from the Leica SCN400. The classifier accurately stratified patients into high versus low risk for disease progression. Vanderbilt patients classified as high risk for progression had significantly worse PFS than those classified as low risk (P = 0.02 for the Aperio AT2; P = 0.03 for the Leica SCN400). Conclusions: Histology slides and patients' clinicodemographic characteristics are readily available through standard of care and have the potential to predict ICI treatment outcomes. With prospective validation, we believe our approach has potential for integration into clinical practice.
Abstract 13780: Effects of Op2113 on Myocardial Infarct Size and No Reflow in a Rat Myocardial Ischemia/reperfusion Model
Authors: Wangde Dai, Bruno Le Grand, Aurelie Boucard, Juan Carreno, lifu Zhao, Robert A Kloner
Journal: Circulation (2020)

Background: Despite advances in early reperfusion therapy for acute ST elevation myocardial infarction (MI), mortality rates and prevention of heart failure after the MI are not optimal. There have been many attempts to further reduce the size of acute MI and to limit the no reflow phenomenon after reperfusion, with mixed results. One promising approach may be to target the mitochondria. The purpose of the present study was to determine whether OP2113 and its active principle ATT (Anethol-TriThione, named also 5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione; CAS 532-11-6 ), a pharmaceutical that has been shown to decrease mitochondrial reactive species production from complex I of the mitochondrial respiratory chain, could limit MI size and the no reflow phenomenon in a standardized rat model of 30 minutes of proximal coronary artery occlusion and reperfusion. Methods and Results: Anesthetized rats were exposed to MI and received OP2113 as an intravenous infusion starting either 5 minutes prior to coronary artery occlusion (preventive), or 5 minutes prior to reperfusion (curative), or received vehicle starting 5 minutes prior to coronary artery occlusion. Infusions continued until the end of the study (3 hours of reperfusion). MI size ( triphenyl tetrazolium chloride staining technique) , expressed as a percentage of the ischemic risk zone ( blue dye technique) was significantly lower in the OP2113 treated preventive group at 44.5 ± 2.9% versus 57.0 ± 3.6% ( p&lt;0.05) in the vehicle group, with a nonsignificant trend toward a smaller infarct size in the curative group ( 50.8 ± 3.9%). Area of no reflow ( thioflavin S technique) as a percentage of the risk zone was significantly smaller in both the OP2113 treated preventive (28.8 ± 2.4%; p =0.026 vs vehicle) and curative groups ( 30.1 ± 2.3%; p=0.04 vs vehicle) compared to the vehicle group ( 38.9 ± 3.1%). OP2113 was not associated with any hemodynamic changes. Conclusions: These results suggest that OP2113 is a promising agent to reduce no-reflow as well as to reduce MI size, especially if it is on board early in the course of the MI. It appears to have benefit on no-reflow even when administered relatively late in the course of ischemia.
Abstract 13484: Acute Coronary Syndrome: A Unique Presentation of Libman Sacks Endocarditis
Authors: Sheraz Hussain, Ambar A Afshar, Anjali Joshi, Muhammad A Khan, Antone Tatooles, Patroklos Pappas
Journal: Circulation (2020)

Introduction: Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease with multiorgan involvement. Cardiac involvement can range from endocarditis to cardiomyopathy. We present a case of SLE complicated by Libman Sacks Endocarditis (LSE) presenting as an acute coronary syndrome (ACS). Case Presentation: A 34 year old male with a history of SLE, DVT/PE, RCA thrombus status post thrombectomy, noncompliance and drug abuse presented to the hospital with complaints of central chest pain associated with right neck, jaw, mouth and arm pain. Vitals were stable. Troponin increased from 0.8 to 13. EKG demonstrated inferior Q waves and ST elevation. CT angiogram was negative for pulmonary embolism but revealed a mobile aortic mass involving the right coronary cusp at the origin of right coronary artery. Transthoracic echocardiogram confirmed this finding. He was started on an infusion of heparin. Surgical evaluation was obtained for emergent thrombectomy and coronary artery bypass grafting. Due to the aortic root thrombus, coronary angiogram was not performed. Lower extremity venous and arterial doppler revealed chronic bilateral DVTs as well as a thrombus in the right common femoral artery. A right heart catheterization demonstrated normal cardiac output and intracardiac filling pressures.Rheumatology was consulted and the patient’s presentation was deemed secondary to Libman sacks endocarditis in the setting of untreated SLE. The pro-coagulant state was chronic and exacerbated secondary to medical noncompliance. Patient was started on hydroxychloroquine with plans for long term anti-coagulation with warfarin in addition to daily aspirin. His symptoms subsided and was discharged home with plans for outpatient follow up. Discussion: Libman sacks endocarditis is a form of noninfectious endocarditis in SLE patients with deposition of thrombi on heart valves. In literature it has been reported to cause valvular dysfunction and cerebrovascular thromboembolism. Our case was unique as it represents a rare manifestation of LSE with an embolic event to a coronary vessel causing ACS. The patient was known to have had prior LSE and due to the complexity of his case and history of medical noncompliance, he was deemed a poor surgical candidate.