tbuckley/cabot-search huggingface dataset:
Abstract 16760: Comparing Major Complications Between Radiofrequency and Cryoballoon Ablation: A Systematic Review and Meta-Analysis
Authors: Awa Drame, Daniel Rodriguez, Nicholas Kotch, Dennis Cassidy, David Wilson, Yuanyuan Lu, Bengt Herweg, Sanders H Chae
Journal: Circulation (2020)

Introduction: Catheter ablation has become the cornerstone for the treatment of drug-refractory paroxysmal atrial fibrillation. Two main forms of energy are used: cryoablation (CB) and radiofrequency (RF). Multiple studies have compared the effectiveness/safety curve between these two; among which is the FIRE AND ICE and the FREEZE AF trials which showed non-inferiority between these two technologies. Despite the remarkable success achieved at controlling arrythmias, complications as high as 16.3% have been reported in both technologies. Objectives: The main purpose of this meta-analysis is to compare the incidence of esophageal and myocardial injuries among patients undergoing radiofrequency ablation vs cryoablation for the treatment of atrial fibrillation or atrial flutter (AF). Methods/Results: We searched Pubmed/Embase, Medline and Cochrane from inception to April 2020 for studies that met our predetermined inclusion and exclusion criteria. All studies comparing RFA to CBA and reporting the incidence of life-threatening complications (esophageal injuries and perforation/tamponade) were included in our analysis. To limit confounding variables and significant heterogeneity between studies, we selected only randomized-control trials and propensity-matched observational studies. A total of 2748 patients were identified. Overall analyses show that RFA has significantly higher life-threatening complications than CBA (OR = 2.79, 95% CI: 1.41-5.52; p=0.003). Conclusion: The present systematic review and meta-analysis demonstrates that RFA has 3 times more life-threatening complications than CBA. As previous studies have already shown similar degree of freedom from AF between these two ablation technologies, CBA appears to be more advantageous overall.
Abstract 15338: Comparison of Treatment Strategies for Neonates With Tetralogy of Fallot and Pulmonary Atresia: A Report From the Congenital Catheterization Research Collaborative
Authors: Holly Bauser Heaton, Bryan H Goldstein, Christopher Petit, Athar M Qureshi, Courtney McCracken, Michael Kelleman, George Nicholson, Mark A Law, Jeffrey Zampi, Shabana Shahanavaz, Christopher Mascio, Paul Chai, Jennifer Romano, Sarosh P Batlivala, Shiraz A Maskatia, Ivor Asztalos, Justin Smith, Lindsay Eilers, Alicia Kamsheh, Steven J Healan, Joelle Pettus, Allen Ligon, andrew dailey-schwartz, James E Raulston, Amy Pajk, Andrew C Glatz, Jeffery J Meadows
Journal: Circulation (2020)

Introduction: Neonates with tetralogy of Fallot and pulmonary atresia (TOF/PA) with pulmonary blood flow supplied by the ductus arteriosus require early intervention. This may be accomplished by: initial palliation (IP) followed by complete repair (CR) or initial primary repair (PR). The optimal approach for patients with TOF/PA has not been established. Methods: Neonates with TOF/PA who underwent IP or PR from 2005-17 were retrospectively reviewed from the Congenital Catheterization Research Collaborative. The primary outcome was mortality. Outcomes were compared as IP vs PR and IP+CR vs PR. Secondary outcomes included hospital and procedural complications and are listed in table 1. Propensity scoring was used to adjust for baseline differences between strategies. Results: Of 282 neonates with TOF/PA, 106 underwent PR and 176 underwent IP (144 surgical, 32 transcatheter). Prior to initial intervention, IP patients had higher rates of mechanical ventilation (83.9% vs 72.2%, p=0.023) and DiGeorge syndrome (14.77% vs 4.72%, p=0.009). Mortality was greater in the IP cohort (HR 2.7, 95% CI 1.02 - 7.1, p = 0.046), with no mortality in the PR cohort after 6 months post-repair. After adjustment, differences in survival were no longer significant (HR 1.4, 95% CI 0.7 - 3.1, p=0.39). Both cohorts had similar mechanical ventilation duration and inotrope use as well as procedural and hospital complications. Intensive care and hospital length of stay, cardiac bypass (CPB) and anesthesia time favored PR when compared to IP+CR (p=&lt;0.001). Early reintervention was more common in patients undergoing IP (rate ratio 1.42, p 0.003), but post-complete repair rates were similar (p=0.837). Conclusions: In neonates with TOF/PA, the IP approach is more often utilized in higher-risk patients. Accounting for this difference, IP and PR strategies have similar adjusted survival rates. Perioperative morbidities and lower risk for reintervention generally favor PR.
Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer
Authors: Rawand Masoud, Gabriela Reyes-Castellanos, Sophie Lac, Julie Garcia, Samir Dou, Laetitia Shintu, Nadine Abdel Hadi, Tristan Gicquel, Abdessamad El Kaoutari, Binta Diémé, Fabrice Tranchida, Laurie Cormareche, Laurence Borge, Odile Gayet, Eddy Pasquier, Nelson Dusetti, Juan Iovanna, Alice Carrier
Journal: Cell Reports Medicine (2020)

Mitochondrial respiration (oxidative phosphorylation, OXPHOS) is an emerging target in currently refractory cancers such as pancreatic ductal adenocarcinoma (PDAC). However, the variability of energetic metabolic adaptations between PDAC patients has not been assessed in functional investigations. In this work, we demonstrate that OXPHOS rates are highly heterogeneous between patient tumors, and that high OXPHOS tumors are enriched in mitochondrial respiratory complex I at protein and mRNA levels. Therefore, we treated PDAC cells with phenformin (complex I inhibitor) in combination with standard chemotherapy (gemcitabine), showing that this treatment is synergistic specifically in high OXPHOS cells. Furthermore, phenformin cooperates with gemcitabine in high OXPHOS tumors in two orthotopic mouse models (xenografts and syngeneic allografts). In conclusion, this work proposes a strategy to identify PDAC patients likely to respond to the targeting of mitochondrial energetic metabolism in combination with chemotherapy, and that phenformin should be clinically tested in appropriate PDAC patient subpopulations.
Abstract 14673: Cardiomyocyte Specific Overexpression of Pellino 1 Reverses Sepsis Induced Cardiac Dysfunction in a Murine Model by Reducing Inflammatory Response and Cardiac Cell Death
Authors: Santosh Swaminathan, Seetur R. Pradeep, Rickesha I Wilson, Jacob Campbell, Mahesh Thirunavukkarasu, Diego Accorsi, J. Alexander Palesty, Nilanjana Maulik
Journal: Circulation (2020)

Introduction: Sepsis remains a significant cause of mortality in the intensive care unit till today. Recent research suggests nearly one in four deaths in people with heart failure is caused by sepsis. Overexpression of mammalian Pellino-1 (Peli1), a E3 ubiquitin ligase, causes inhibition of apoptosis, oxidative stress, and preservation of cardiac function in a myocardial infarction model. Therefore, in the present study, we explored the possibility to overcome sepsis mediated heart failure by overexpressing Peli1 (AMPEL1Tg/+) in a mouse model of severe sepsis. Methods: C57BL/6J (WT) and AMPEL1 Tg/+ mice were divided into Wild-type sham (WTS), Wild-type Cecal Ligation and Puncture (WTCLP), AMPEL1 Tg/+ sham (AMPEL1 Tg/+ S) and AMPEL1 Tg/+ CLP. Cardiac function (LVEF, FS) by two-dimensional echocardiography was assessed pre-procedure, at 6, and 24 hours post-surgery. Serum IL-6 and TNF-alpha (ELISA) at 6 hours and cardiac apoptosis (TUNEL assay) at 24 hours were measured. Results are expressed as mean ± SEM. Results: Analysis of echocardiographic parameters (EF, FS) preoperatively and among the sham groups were similar however there was significant preservation of post-procedure LVEF (%) in the AMPEL1 Tg/+ CLP at the 6 hour (AMPEL1 Tg/+ :52.7 ± 3.71 vs WT:40.7 ±2.46, p=0.013, n=10-11) and 24-hour time point (AMPEL1 Tg/+ :63.1 ± 1.63 vs WT:49.3 ± 4.41, p=0.002, n=9-11) compared to WT. Similar trend was observed in estimation of FS (%) at 6 hours (AMPEL1 Tg/+ :26.3 ± 2.22 vs WT:19.3 ±1.37, p=0.014, n=10-11) and 24 hours (AMPEL1 Tg/+ :32.4 ± 1.89 vs WT:24.4 ± 2.67, p=0.031, n=9-11). A marked decrease in serum IL-6 (AMPEL1 Tg/+ :259.7 ± 18.70 vs WT:483.2 ± 24.01, p&lt;0.0001, n=6, pg/mL) and TNF-alpha (AMPEL1 Tg/+ :86.89 ± 14.36 vs WT:161.8 ± 20, p=0.012, n=6, pg/mL) was observed in the AMPEL1 Tg/+ CLP at 6 hours. The preserved cardiac function in CLP was further supported by a noticeable decrease in cardiac apoptosis (% TUNEL positive cells) at 24 hours in the AMPEL1 Tg/+ CLP group (4.7 ± 0.94 vs 11.7 ± 2.82, p=0.040, n=6,) compared to WTCLP. Conclusions: Thus, Peli1 overexpression is a novel approach that preserved cardiac function, reduced inflammatory markers, and apoptosis following severe sepsis in a murine genetic model.
Abstract 14382: Notch Ligand Delta-like Ligand 1 Promotes Macrophage Activation and Arteriosclerosis
Authors: Jun-ichiro Koga, Shunsuke Katsuki, Tetsuya Matoba, Hiroyuki Tsutsui
Journal: Circulation (2020)

Introduction: Macrophage-mediated inflammation promotes various vascular diseases, but how macrophage functions are regulated has not been fully understood. Notch signaling is a fundamental pathway regulating cell differentiation in developmental stages, but its role in adult vascular diseases are largely unknown. Aim: The aim of this study is to explore the role of Notch ligands in macrophage activation and subsequent arteriosclerosis. Methods: 1) To screen the Notch ligands, blocking antibodies of each Notch ligands (Jagged-1, Jagged-2, Dll1, and Dll4) were prepared. After pre-treatment with these antibodies, mouse peritoneal macrophages were stimulated with 10 ng/mL LPS + 10 ng/mL IFN-γ or 10 ng/mL IL-4 for 24 hours. mRNA expressions were quantified by real-time PCR. 2) C57BL/6J mice were subjected to femoral arterial wire injury and blocking antibodies (250 μg/injection) were intraperitoneally injected twice a week for 4 weeks, 3) Apolipoprotein E-deficient mice ( Apoe -/- ) at 8 weeks of age were fed a high-fat diet and blocking antibodies (250 μg/injection) were intraperitoneally injected twice a week for 12 weeks. Results: Blockade of Jagged 2, Dll1 and Dll4 decreased expression of iNOS and IL-1β in macrophages treated with LPS and IFN-γ. In contrast, blockade of Dll1 increased arginase-1 and Ym1 in IL-4 treated macrophages. Immobilized recombinant Dll1 increased prototypical Notch-target gene Hes-1 and induced subsequent IL-1β expression. Therefore, we have tested Dll1 blocking antibodies in in vivo models. After femoral arterial injury, administration of Dll1 blocking antibodies attenuated intimal hyperplasia, perivascular fibrosis, and negative remodeling of injured arteries. In Apoe -/- mice, a high-fat diet feeding increased Dll1 expression in atherosclerotic plaques, especially in Mac-3 positive macrophages. Blockade of Dll1 decreased atherosclerotic plaque area and lipid content determined by oil red O staining. In addition, blockade of Dll1 decreased accumulation of Mac-3 positive macrophages to the plaque. Conclusions: These results indicate that Dll1 promotes macrophage activation and arteriosclerosis. Dll1 may be a potential therapeutic target for vascular diseases promoted by macrophage-mediated inflammation.
Abstract 14992: Should Patients With Heart Failure With Reduced Ejection Fraction (HFrEF) be Discharged on Sacubitril/Valsartan or ACEi/ARB: A Decision Analysis Approach
Authors: Lauren Gilstrap, Ronnie J Zipkin, J Aaron Barnes, Anna Tosteson
Journal: Circulation (2020)

Introduction: In the PARADIGM-HF study, sacubitril/valsartan demonstrated a 16% decrease in all-cause mortality and a 21% decrease in heart failure hospitalization. Cost and concern for a higher risk of side effects especially among older patients may have delayed early diffusion. This study aims to use a decision analysis approach to determine whether discharged on sacubitril/valsartan or ACEi/ARB is optimal after heart failure with reduced rejection fraction (HFrEF) hospitalization and whether this varies by age. Hypothesis: Discharge on sacubitril/valsartan will be associated with lower mortality and readmission rates across all age groups. Methods: We used an absorbing Markov chain simulation model with 1-month cycle length to determine the association between discharge on sacubitril/valsartan vs. ACEi/ARB and survival. We used a random 40% sample of Medicare A, B and D data from 2016-2017 to create a population of HFrEF patients (n=694,149) to determine the probabilities of drug discontinuation and adverse events. We used estimates from the PARADIGM-HF study to define the relative reduction in mortality and readmission rates with sacubitril/valsartan. Results: Among all patients, we found a 3.24 month survival advantage to discharge on sacubitril/valsartan. Among those aged 64-74, there was a 5.85 month survival advantage. Among those aged 74-85, there as a 3.47 month survival and among those aged 85+ there was a 1.38 month survival advantage ( Figure ). Conclusion: Among patients of all ages with HFrEF, there is a survival advantage to discharge on sacubitril/valsartan over ACEi/ARB but the magnitude of this benefit decreases with increasing age.
Targeted genomic analysis of cutaneous T cell lymphomas identifies a subset with aggressive clinicopathological features
Authors: Kimon V. Argyropoulos, Melissa Pulitzer, Francesco Maura, Abhinita Mohanty, Patrizia Mondello, Steven M. Horwitz, Patricia Myskowski, Alison Moskowitz, Ahmet Dogan, Christiane Querfeld, Franck Rapaport, Marina Siakantaris, Peter C. Louis, Natasha Galasso, Marcel R. M. van den Brink, M. Lia Palomba
Journal: Blood Cancer Journal (2020)
Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia
Authors: Ashkan Emadi, Bandish Kapadia, Dominique Bollino, Binny Bhandary, Maria R. Baer, Sandrine Niyongere, Erin T. Strovel, Hannah Kaizer, Elizabeth Chang, Eun Yong Choi, Xinrong Ma, Kayla M. Tighe, Brandon Carter-Cooper, Blake S. Moses, Curt I. Civin, Anup Mahurkar, Amol C. Shetty, Ronald B. Gartenhaus, Farin Kamangar, Rena G. Lapidus
Journal: Leukemia (2020)
Abstract 14150: Long-pulsed Ultrasound Mediated Microbubble Thrombolysis: Is There an Upper Limit?
Authors: Xianghui Chen, Jun Guo
Journal: Circulation (2020)

Introduction: Long-pulsed ultrasound (US) mediated microbubble (MB) has shown successful thrombolystic effects in recent years. Compared to traditional short-pulse US(&lt;5 cycles), long-pulsed US induced more sustained cavitation followed by more complete thrombolysis. It was found more micro-thrombi were dissolved when pulse lengths were increased. However, taking the US safety into consideration, the upper limit of long pulse in vivo remains unknown. Hypothesis: Long-tone-burst US is able to cause successful thrombolysis through microbubble cavitation, and there is an upper limit for the safe long-pulse length in vivo. Methods: Different long- pulse lengths (5,100,500,1000, 5000, 50,000 cycles) were used and their thrombolytic effects in a rat model were observed. About 200μm micro-thrombi were injected into common iliac artery on rats hindlimb to make an embolization model. 1MHz long-pulsed US were delivered at mechanical index 1.8 every 3 seconds (pulse repetition frequency 0.33). The control group was given MBs only without therapeutic US. Contrast echocardiography was performed at three stages: baseline, embolization and 10 minutes post embolization. Peak plateau video intensity ( A ) were obtained for assessment of thrombolytic effects. Finally muscular samples were taken for pathology for assessment of both beneficial and potential detrimental effects from long-tone-burst US. Results: 100 and 500 cycles long-pulsed US showed successful thrombolysis and peak plateau video intensity ( A ) was significantly elevated post US treatment ( P&lt;0.01 vs. baseline ). Pathology revealed 1000 and 5000 cycles groups were the best parameters to induce optimal sonothrombolysis ( P&lt;0.01 vs. other groups), possibly by more sustained cavitation. However, 50,000 cycles showed endothelial injury and tissue bleeding that may be detrimental and hazard. Conclusions: Long-tone-burst US with more than 100 cycles were proved to induce very good micro-thrombi resolution in a rat model of embolization. It seems there is an upper limit for the cycle length to generate beneficial biomechanical effects, and detrimental effect may occur if it was exceeded.
FRI0211 Serum carnitine measurement in primary raynaud’s phenomenon
Authors: L La Civita, G Pugliese, P Fadda, I Olivieri
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Raynaud's phenomenon (RP) is a microcirculatory disorder characterised by deficient endothelial activity. Such endothelial dysfunction should be responsible for reduced release of NO, a potent vasodilatory agent. Since the cell function is dependent on energy production, it is though deficient endothelial activity could be due to the loss of energy production probably secondary to a low availability of Carnitine, an important cell metabolic carrier. <h3>Objectives</h3> To conduct a preliminary evaluation of the serum Carnitine concentrations in primary RP patients (pRP pts.) compared to age- and sex-matched controls. <h3>Methods</h3> After verbal consent, 17 consecutive pRP pts (16 female, mean age 32.1 ± 11.3 yrs) and ten control subjects (9 female, mean age 34 ± 11 yrs) were enrolled for this study. Patients had to have a RP history no longer than 5 years. After acclimatisation, each subject underwent a venous blood drawing from same vessel at baseline and after a 5-minute cold-water test. All blood samples were stored ?20°C. Then, Carnitine was measured in collected sera by enzymatic assay (SIGMA-TAU pharmaceuticals). T-test for paired data was used for statistical analysis. <h3>Results</h3> Table 1 showed the mean values of serum Carnitine concentrations in two studied groups. After test, serum Carnitine concentration increased in 12/17 pRP patients and lowered in the remainders. Contrary, in the control group circulating Carnitine increased significantly after provocative test. <h3>Conclusion</h3> Lower circulating Carnitine titres in our pRP pts could be associated with diminished availability of Carnitine in endothelial cells and consequently with their impaired activity. Although this study is preliminary, our results suggest Carnitine supplementation for promotion of endothelial activity in pRP pts may be worth investigating, particularly in RP subjects unresponsive to conventional treatments.
Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease
Authors: Deepak L. Bhatt, Michael Szarek, Bertram Pitt, Christopher P. Cannon, Lawrence A. Leiter, Darren K. McGuire, Julia B. Lewis, Matthew C. Riddle, Silvio E. Inzucchi, Mikhail N. Kosiborod, David Z.I. Cherney, Jamie P. Dwyer, Benjamin M. Scirica, Clifford J. Bailey, Rafael Díaz, Kausik K. Ray, Jacob A. Udell, Renato D. Lopes, Pablo Lapuerta, P. Gabriel Steg
Journal: New England Journal of Medicine (2020)

The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied.We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m2 of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding.Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo.In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.).
COVID-19, seasonal influenza and measles: potential triple burden and the role of flu and MMR vaccines
Authors: Nazrul Islam, Kamlesh Khunti, Azeem Majeed
Journal: Journal of the Royal Society of Medicine (2020)

While we wait for an effective vaccine against SARS-CoV-2, the influenza and Measles-Mumps-Rubella vaccine with proven safety and efficacy profile can a play critical role in reducing the healthcare burden. First, an increase in the coverage of influenza and Measles-Mumps-Rubella vaccines will decrease the number of cases and the need for hospitalisations for severe illnesses due to these diseases. It will, thereby, reduce the burden on healthcare providers and facilities, which will be particularly crucial in resource-poor settings in making the scarce resources (e.g. hospital beds) allocated to those who need them the most. Second, live attenuated vaccines such as Measles-Mumps-Rubella and Bacillus Calmette-Guerin have been reported to provide non-specific protection against lethal infections including pneumonia and sepsis, especially in low-income settings. Third, infection with measles has been shown to increase children's susceptibility to other infections by reducing the immune system's memory against other pathogens including the influenza virus. Therefore, infection with measles may also increase the susceptibility to SARS-CoV-2 even though it is yet to be empirically tested. Therefore, as we wait for a successful vaccine for COVID-19, we can minimise winter pressures on health systems and societies by maximising the uptake of influenza and Measles-Mumps-Rubella vaccines (and potentially Bacillus Calmette-Guerin vaccines, especially in tuberculosis-endemic areas).
Development and Characterization of the Novel Orally Bioavailable EZH1/2 Dual Inhibitor DS-3201
Authors: Daisuke Honma, Nobuaki Adachi, Osamu Kanno, Jun Watanabe, Makoto Hirasawa, Emi Nosaka, Machiko Shiroishi, Takeshi Takizawa, Isao Yasumatsu, Takao Horiuchi, Akira Nakao, Keisuke Suzuki, Tomonori Yamasaki, Katsuyoshi Nakajima, Miho Hayakawa, Takanori Yamazaki, Kazushi Araki, Kosaku Fujiwara
Journal: Blood (2017)