tbuckley/cabot-search huggingface dataset:
Abstract 11511: Long-Term Outcomes of Transcatheter Aortic Valvuloplasty in Infants: A Study from the Pediatric Cardiac Care Consortium
Authors: Ryan T Greene, Kristi Weinmeister, J’Neka Claxton, Lazaros Kochilas, Gurumurthy Hiremath
Journal: Circulation (2021)

Introduction: Long-term outcomes of aortic stenosis (AS) after balloon aortic valvuloplasty (BAV) in infancy are scarce. Here, we report the 25-year outcomes after the first BAV in infants enrolled in the Pediatric Cardiac Care Consortium (PCCC), a US-based registry of pediatric cardiac interventions. Methods: We queried the PCCC for patients undergoing BAV in infancy between 1982 and 2003. Outcomes were tracked through 2019 in the PCCC and by linkage with the National Death Index and the Organ Procurement and Transplantation Network. Cases dependent on ductus arteriosus at the time of BAV were deemed critical and procedural outcomes were defined as optimal if residual valve gradient was &amp;lt30mmHg and no more than mild insufficiency reported. Reinterventions were tracked in PCCC through 2011. Transplant-free survival (TFS) post initial BAV is described by Kaplan-Meier plots . Results: The cohort included 316 patients: males 75.3%, median age 0.6 months (IQR: 0.1 - 2) at the time of the BAV. Of them, 95 had critical AS and 187 had optimal procedural outcome. A total of 289 (91.5%) survived to hospital discharge. Over a median follow-up time of 21.7 years (IQR: 18.9, 24.6), 3 patients underwent transplantation and 17 died, with a 25-year TFS of 92.4% (95%CI: 89.0-96.0%). Presence of critical AS and procedural outcome did not affect long-term outcomes (Figure 1). One hundred thirteen patients underwent at least one transcatheter or surgical reintervention through 2011: 48 (42%) had critical AS and 59 (52%) had suboptimal outcome after the first BAV (relative risk of reintervention 1.26 (95%CI: 0.94, 1.69) and 1.98 (95%CI: 1.48, 2.64) respectively). Conclusions: Infants undergoing BAV have favorable 25-year survival independent of the critical nature of the AS and the lack of optimal outcome at discharge. Patients with suboptimal result were more likely to require reintervention.
Abstract 11894: Leisure-Time Physical Activity in Late-Life is Associated With Risk of Heart Failure With Preserved and Reduced Ejection Fraction - The Atherosclerosis Risk in Communities Study
Authors: Sheila M Hegde, Andy Kim, Brian Claggett, Kelly R Evenson, Aaron R Folsom, Pamela L Lutsey, Roberta Florido, Chiadi E Ndumele, Dalane W Kitzman, Thomas Mosley, Patricia Chang, Amil M Shah
Journal: Circulation (2021)

Introduction: Leisure-time physical activity (LTPA) is associated with lower heart failure (HF) risk. However, reported associations with incident HF with preserved (HFpEF) and reduced ejection fraction (HFrEF) differ and whether these associations persist into-late life is unclear. Methods: We evaluated 5017 participants in the Atherosclerosis Risk in Communities study who attended visit 5 (2011-2013) and did not have prior HF or significant valvular heart disease. LTPA was assessed by the Baecke questionnaire, summarized in metabolic equivalent (MET)-minutes/week, and related to incident HFpEF (EF ≥ 50%) and HFrEF (EF &lt; 50%) using multivariable Cox regression and restricted cubic splines. All models were adjusted for age, sex, race, center, and smoking status. Results: The mean age was 75.5 ± 5.0 years, 41% were male, 21% Black, and median LTPA was 624 [IQR 0-1270] MET-min/wk. Over a median follow-up of 7.2 years, 435 participants developed HF (208 HFpEF, 166 HFrEF, 61 unknown EF). Compared to those with low LTPA levels (1 st tertile; &lt;139 MET-min/wk), higher levels of LTPA (3 rd tertile; &gt;1053 MET-min/wk) were significantly associated with lower HF risk (HR 0.48 [95% CI 0.37-0.62]) after adjusting for age, sex, race, center, and smoking status. The 2 nd and 3 rd tertile remained associated with lower HFpEF risk (2 nd tertile: HR 0.69 [0.50-0.96]; 3 rd tertile: 0.43 [0.29-0.62]), and lower HFrEF risk (2 nd tertlle: HR 0.55 [0.37-0.81]; 3 rd tertile: 0.57 [0.39-0.85]) in the adjusted model. Restricted cubic splines demonstrated a graded response between higher levels of LTPA and incident HFpEF and HFrEF (Figure). With further adjustment for HF risk factors that may be considered mediators, the association of higher LTPA with lower risk of HFpEF was preserved while the association with HFrEF risk was attenuated. Conclusions: In older adults, higher levels of LTPA are associated with a lower risk of both incident HFpEF and HFrEF.
Abstract 10299: One Acute Exposure to E-Cigarette Smoke Using Various Heating Elements and Power Levels Induces Pulmonary Inflammation
Authors: Jianru Shi, Wangde Dai, Jesus N Chavez, Juan Carreno, Lifu Zhao, Michael T Kleinman, Rebecca J Arechavala, Irene Hasen, Amanda Ting, Bishop Bliss, Jessica E Monterrosa Mena, Robert A Kloner
Journal: Circulation (2021)

Background: A new form of lung injury was described in electronic cigarette users beginning July 2019 with patients presenting with respiratory distress. The condition is known as E-cigarette (eC) or vaping product use associated lung injury or EVALI and was thought to be related to Vit E oils used to dilute cannabis. Whether a single acute exposure of eC smoke can induce lung injury has not been reported. The purpose of this study was to determine if such an acute exposure with eC smoke heated with different heating elements and power levels induced inflammatory changes in the lungs and heart. Methods: Rats were exposed to pure air or received a single, 4-hour exposure to eC vapor (50% propylene glycol, 50% vegetable glycerin; tobacco flavoring, n=16 in each group). The devices used either a stainless steel (SS) or nichrome (NC) heating element randomized to a low or high atomization power (45 versus 70 Watts). Rats were euthanized within 48 hours of exposure and hematoxylin and eosin stained lung and cardiac histology sections were assessed. Inflammatory cells were counted from 12 random areas per section at 10 х magnification. Results: The lung alveoli appeared normal in the air group (Figure, panel A); the eC groups using the SS or NC heating element with high or low power showed accumulation of inflammatory cells (mainly macrophages) in bronchial lumen (B), near the pleura (C), and within the alveolar spaces (D). The numbers of inflammatory cells per field in the lung parenchyma were significantly greater in the rats exposed to eC using SS or NC heating element compared to the air control group (P &lt; 0.05, One way ANOVA, Tukey multiple comparison test; panel E). Cardiac tissue appeared normal with no evidence of inflammation. Conclusion: One 4-hour exposure to eC vapor, in the absence of vitamin E oil or nicotine, significantly increased the number of inflammatory cells in the lung. Effects were seen after exposures to vapor generated using SS and NC heating elements at either high or low power.
A metabolomics approach identified toxins associated with uremic symptoms in advanced chronic kidney disease
Authors: Jiun-Ruey Hu, Leslie Myint, Andrew S. Levey, Josef Coresh, Lesley A. Inker, Morgan E. Grams, Eliseo Guallar, Kasper D. Hansen, Eugene P. Rhee, Tariq Shafi
Journal: Kidney International (2021)
CTNI-40. EVALUATING FEASIBILITY AND EFFICIENCY OF PHASE II ADAPTIVE PLATFORM TRIAL DESIGNS BASED ON THE INDIVIDUALIZED SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGhT) EXPERIENCE
Authors: Rifaquat Rahman, Lorenzo Trippa, Eudocia Quant Lee, Isabel Arrillaga-Romany, Mehdi Touat, Geffrey Fell, Christine McCluskey, Jennifer Bruno, Sarah Gaffey, Jan Drappatz, Andrew Lassman, Evanthia Galanis, Manmeet Ahluwalia, Howard Colman, L Burt Nabors, Jaroslaw Hepel, Heinrich Elinzano, David Schiff, Ugonma Chukwueke, Rameen Beroukhim, Tracy Batchelor, Lakshmi Nayak, J Ricardo McFaline-Figueroa, Mikael Rinne, Thomas Kaley, Christine Lu-Emerson, Wenya Linda Bi, Omar Arnaout, Daphne Haas-Kogan, Shyam Tanguturi, Daniel Cagney, Ayal Aizer, Mary Welch, Lisa Doherty, Maria Lavallee, Brittany Fisher-Longden, Shanna Dowling, William Pisano, Emily Lapinskas, David Meredith, E Antonio Chiocca, David Reardon, Keith Ligon, Brian Alexander, Patrick Wen
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial with Bayesian adaptive randomization and deep genomic profiling to more efficiently test experimental agents in newly diagnosed glioblastoma and to prioritize therapies for late-stage testing. METHODS In the ongoing INSIGhT trial, patients with newly diagnosed MGMT-unmethylated glioblastoma are randomized to the control arm or one of three experimental therapy arms (CC-115, abemaciclib, and neratinib). The control arm therapy is radiotherapy with concomitant and adjuvant temozolomide, and primary endpoint is overall survival. Randomization has been adapted based on Bayesian estimation of biomarker-specific probability of treatment impact on progression-free survival (PFS). All tumors undergo detailed molecular sequencing, and this is facilitated with the companion ALLELE protocol. To evaluate feasibility of this approach, we assessed the status of this ongoing trial. RESULTS Since INSIGhT was activated 4.3 years ago, it has expanded to include 12 sites across the United States. A total of 247 patients have been enrolled. Randomization probabilities have been repeatedly adjusted over time based upon early PFS results to alter the randomization ratio from standard 1:1:1:1 randomization. All three arms have completed accrual and efficacy estimates are available based upon comparison to the common control arm in context of relevant biomarkers. There are 87 patients alive and in follow-up, and there are ongoing plans to add additional arms to evaluate further treatments in the future. CONCLUSION The INSIGhT trial demonstrates that a multi-center Bayesian adaptive platform trial is a feasible and effective approach to help prioritize therapies and biomarkers for newly diagnosed GBM. The trial has maintained robust accrual, and the simultaneous testing of multiple agents, sharing a common control arm and adaptive randomization serve as features to increase trial efficiency relative to traditional clinical trial designs.
Abstract MP225: Macrophage-specificα5 Integrin Signaling Protects The Infarcted Heart From Adverse Remodeling By Stimulating The Angiogenic Response
Authors: Ruoshui Li, Bijun Chen, Anis Hanna, Claudio Humeres, Linda Alex, Nikolaos G Frangogiannis
Journal: Circulation Research (2021)

Abundant macrophages infiltrate the infarcted heart and play a critical role in repair, remodeling and fibrosis. Macrophages sense changes in the extracellular matrix (ECM) environment through Integrins, thus activating signaling pathways that regulate their function. Analysis of our RNA sequencing data identified integrin α5 (Itgα5) as one of the most upregulated integrin genes in infarct macrophages. Accordingly, we hypothesized that integrin α5 signaling in infarct macrophages transduces ECM-derived signals, regulating responses critical for repair and remodeling of the infarcted heart.In order to study the role of macrophage α5 integrin in the infarcted heart, we generated 2 lines of macrophage-specific α5 integrin KO mice: myeloid cell-specific KOs (Myα5KO, using the lysozyme-M Cre driver) and inducible macrophage-specific α5 KOs (iMaα5KO, using CX3CR1 CreER ). 28 days after infarction, Myα5KO mice had accentuated adverse remodeling, evidenced by increased LVEDV and LVESV, a trend towards reduced ejection fraction. Adverse remodeling in Mya5KO was associated with a marked reduction in microvascular density in the infarct and in the border zone. iMaα5KO mice also exhibited worse remodeling and impaired infarct angiogenesis. A PCR array in infarct macrophages showed that α5 integrin loss was associated with markedly reduced transcription of VEGF-A, and lower levels of the angiogenic CXC chemokines CXCL1 and CXCL2. RNAseq followed by bioinformatic analysis predicted that that Nrf2, Erk5, HIF1a, p38 MAPK, VEGF, RhoA, and PI3K/Akt pathways were inhibited in the absence of α5 signaling in vivo (in infarct macrophages) and in vitro (in bone marrow macrophages undergoing α5 antibody neutralization experiments).In conclusion, α5 integrin promotes an angiogenic VEGF-expressing phenotype in infarct macrophages, protecting the infarcted heart from adverse remodeling. The angiogenic effects of α5 integrin in macrophages may have important therapeutic implications for heart failure patients.
Initial assessment of the COVID-19 vaccination’s impact on case numbers, hospitalisations and deaths in people aged 80 years and older, 15 EU/EEA countries, December 2020 to May 2021
Authors: Nathalie Nicolay, Francesco Innocenti, Julien Beauté, Veronika Učakar, Marta Grgič Vitek, Eero Poukka, Tuula Hannila-Handelberg, Charmaine Gauci, Tanya Melillo, Theano Georgakopoulou, Jiri Jarkovsky, Pavel Slezak, Concepción Delgado-Sanz, Carmen Olmedo-Lucerón, Heleene Suija, Rasa Liausediene, Piaras O’Lorcain, Niamh Murphy, André Peralta-Santos, Pedro Casaca, Ioanna Gregoriou, Nick Bundle, Gianfranco Spiteri, Giovanni Ravasi
Journal: Eurosurveillance (2021)

Prioritisation of elderly people in COVID-19 vaccination campaigns aimed at reducing severe outcomes in this group. Using EU/EEA surveillance and vaccination uptake, we estimated the risk ratio of case, hospitalisation and death notifications in people 80 years and older compared with 25-59-year-olds. Highest impact was observed for full vaccination uptake 80% or higher with reductions in notification rates of cases up to 65% (IRR: 0.35; 95% CI: 0.13-0.99), hospitalisations up to 78% (IRR: 0.22; 95% CI: 0.13-0.37) and deaths up to 84% (IRR: 0.16; 95% CI: 0.13-0.20).
Abstract 10254: HDAC Inhibition Regulates Cardiac Function via Myofilament Acetylation
Authors: Deborah M Eaton, Thomas G Martin, Michael Kasa, Natasa Djalinac, Jaslyn P Johnson, Ewald Kolesnik, Senka Ljubojevic-Holzer, Dirk von Lewinski, Maria Poettler, Heinrich Maechler, Andreas Zirlik, Timothy A McKinsey, Jonathan A Kirk, Steven R Houser, Peter P Rainer, Markus Wallner
Journal: Circulation (2021)

Introduction: Heart failure (HF) is a global issue and approximately 50% of patients are classified as having HF with preserved Ejection Fraction (HFpEF), with no FDA approved therapies available. We previously characterized a large animal model that recapitulates key features of HFpEF and tested the effects of suberanilohydroxamic acid (SAHA, pan-HDAC inhibitor), which reversed and prevented the development of cardiopulmonary dysfunction. Parallel studies in cardiac tissue from humans and large mammals were designed to evaluate the effects of SAHA at the cellular level. Hypothesis: SAHA treatment will improve cardiomyocyte function. Methods: Adult feline ventricular cardiomyocytes (AFVM) were isolated from male domestic short hair cats and treated with 2.5μM SAHA or vehicle (DMSO) for 90 minutes, then incubated with a calcium (Ca 2+ ) indicator (Fluo-4AM) and electrically stimulated (0.5Hz) to record Ca 2+ transients and contractions. Human left ventricle (LV) trabeculae isolated from non-failing donor hearts were treated with 10μM SAHA or vehicle for 120 minutes while being electrically stimulated (1Hz) to record developed force and relaxation parameters. Skinned myocytes were isolated from treated AFVM and human trabeculae to assess myofilament Ca 2+ sensitivity and passive stiffness. Mass spectrometry (MS) was performed on AFVM skinned myocytes to identify novel acetylation sites. Results: There was no difference in AFVM peak Ca 2+ transients with SAHA treatment, but calcium removal was increased (tau, time to 30% baseline). There was a significant increase in contractility (fractional shortening) and relaxation kinetics (time to 50% baseline, return velocity). Trabeculae treated with SAHA had decreased diastolic tension and an increase in developed force. Skinned myocytes were isolated from treated AFVMs and trabeculae and both had a significant improvement in myofilament Ca 2+ sensitivity and significant decrease in passive stiffness with SAHA. MS of AFVM skinned myocytes revealed increased acetylation of the myosin regulatory light chain, driven by lysine 115. Conclusions: These findings suggest that SAHA may have an important role in regulating cardiac function via the cardiomyocyte and myofilament in feline and human myocardium.
Abstract 12121: Coronary Disease Association With ADAMTS7 is Due to Protease Activity: Implications for Therapeutic Development
Authors: Taiji Mizoguchi, Bryan T MacDonald, Bidur Bhandary, Nicholas R Popp, Dylan Laprise, Alessandro Arduini, Daniel Lai, Qiuyu M Zhu, Yi Xing, Virendar K Kaushik, Sekar Kathiresan, Patrick T Ellinor
Journal: Circulation (2021)

Background: Despite contemporary therapy, coronary artery disease (CAD) remains a leading cause of mortality. Genetic variants at ADAMTS7 have been associated with CAD and the loss of ADAMTS7 is protective for atherosclerosis. ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs 7) is a secreted metalloproteinase and complex proteoglycan, yet the mechanism linking ADAMTS7 to CAD risk remains unresolved. Methods and Results: We established a new purification strategy for full-length mouse ADAMTS7 and demonstrated the loss of activity in the catalytic mutant form of ADAMTS7. To test if the enzymatic activity of ADAMTS7 mediates atherosclerosis, we generated a catalytically inactive mutant mouse allele and compared it to the Adamts7 knockout. Using two models of atherosclerosis, we found that reducing either ADAMTS7 dosage or catalytic function decreased the burden of atherosclerosis. We demonstrate impaired vascular smooth muscle migration in both Adamts7 catalytic mutant and null cells using a lateral migration wound healing assay. Expression of the WT allele rescued the migration phenotype in Adamts7 null cells while expression of the catalytic mutant protein did not. We then characterized a human ADAMTS7 coding variant rs3825807 (Ser214Pro) associated with reduced CAD risk. This variant had a hypomorphic effect on ADAMTS7 secretion and migration of vascular smooth muscle cells, findings consistent with our mouse studies. Conclusions: We demonstrated that loss of ADAMTS7 catalytic function protects against atherosclerosis via phenotype switch of VSMCs and that the atherosclerosis protective effects could be mediated by a loss-of-function coding variant associated with CAD risk. In aggregate, we provide compelling evidence that dosage of ADAMTS7 and catalytic function are responsible for the atherosclerotic phenotype, suggesting that the catalytic domain would be an attractive therapeutic target for CAD.
How significant is the Ventavia scandal?
Authors: Roger Fisken
Journal: BMJ (2021)

<h3>ABSTRACT</h3> <h3>Background</h3> There are no standardized reporting systems or assessments specific to residents of retirement homes in North America. As such, little is known about these older adults as a distinct population. We created a new population-level cohort of residents of retirement homes and examined their health service rates relative to other older adult populations. <h3>Methods</h3> We conducted a population-based retrospective cohort study in Ontario, Canada in 2018. The postal codes of all licensed retirement homes (<i>n</i> = 757) were classified and linked to individual-level health system administrative data to derive a cohort of residents of retirement homes. A generalized linear model with a gamma distribution and log link function was used to model rates of emergency department visits, hospitalizations, alternate levels of care (ALC) days, primary care visits, and specialist physician visits. <h3>Results</h3> Residents of retirement homes comprised two percent of the older adult population in Ontario (<i>n</i> = 54,773; 2.3%). After adjustment for relevant characteristics, residents of retirement homes had 10 times the rate of emergency department visits (Relative Rate [RR] 10.02, 95% Confidence Interval [CI] 9.83 to 10.21), 20 times the rate of hospitalizations (RR 20.43, 95% CI 20.08 to 20.78), and 44 times the rate ALC days (RR 43.91, 95% CI 43.28 to 44.54) compared to community-dwelling older adults. <h3>Interpretation</h3> Residents of retirement homes are a distinct older adult population with high rates of hospital-based care. Our findings contribute to policy debates about the provision of health care in privately operated congregate care settings for older adults.
Type I interferon activates MHC class I-dressed CD11b+ conventional dendritic cells to promote protective anti-tumor CD8+ T cell immunity
Authors: Ellen Duong, Tim B. Fessenden, Emi Lutz, Teresa Dinter, Leon Yim, Sarah Blatt, Arjun Bhutkar, Karl Dane Wittrup, Stefani Spranger
Journal: Immunity (2021)
Abstract 13650: Prognostic Significance Of Atrial Arrhythmias In Pulmonary Hypertension: A Meta-analysis
Authors: Joseph Sebastian, Daniel Deneve, Sreya Sebastian, Swara Sarvepalli, Abdel-Rhman Mohamed, Katherine Akers, Ramanjit Kaur, Aiden Abidov
Journal: Circulation (2021)

Background: Atrial arrhythmias (AA: atrial tachycardia, atrial fibrillation, and atrial flutter) are common in patients (pts) with pulmonary hypertension (PH) due to increased right atrial pressure and increased sympathetic tone. AA occurrence in PH may lead to clinical deterioration and affect prognosis. Whether mortality in pts with PH is increased with comorbid AA compared to those without AA is not well established. The aim of this meta-analysis is to investigate published evidence of AA role in predicting outcomes of pts with PH. Methods and Results: We searched available literature across PubMed, EMBASE and Cochrane Library databases, and 11 observational studies with a pooled population of 2763 pts were included in this meta-analysis. Among the pooled population of pts with PH, there were 561 pts with AA (20%). We compared the outcomes of all-cause mortality among PH pts with and without AA. All-cause mortality was significantly higher in PH pts with AA compared to those without AA (odds ratio, OR=1.78; 95% confidence interval, 1.46-2.18; P &lt;0.01). No AA-driven differences were found among WHO groups of PH (p=0.75) or gender (p=0.42). Conclusion: Our results indicate that overall mortality is higher in PH pts presenting with AA as compared to those without AA. Further research needed in evaluating the effect of AA therapy with restoration and maintenance of sinus rhythm on mortality in PH.