tbuckley/cabot-search huggingface dataset:
Abstract 15353: Apixaban Failure in Prevention of Ischemic Cerebrovascular Accidents in Non-valvular Atrial Fibrillation Patients
Authors: Mohammad Zmaili, Jafar Alzubi, Mohamed Gad, Ahmed Abu-Haniyeh, Walid I Saliba, Oussama M Wazni, Ayman Hussein
Journal: Circulation (2020)

Introduction: Apixaban has been increasingly used over the past decade for the prevention of ischemic strokes in atrial fibrillation (AF) patients. Nonetheless, some patients may experience ischemic strokes despite apixaban therapy. There is scarce information about factors underlying apixaban failure in AF patients. Methods: A system wide search was employed at the Cleveland Clinic Health System using electronic records. All patients 18 years of age or older, who were diagnosed with AF, and developed an ischemic stroke while being treated with apixaban (January 2013 through May 2019) were included. A matched controls series (no stroke on apixaban) was included accounting for antiplatelet and statin therapy, and carotid artery disease. Multivariable analyses were performed to assess for associations between clinical characteristics and stroke on apixaban. Results: A total of 137 patients with stroke while on apixaban were identified and matched to 137 controls. Cases and controls were comparable in a large number of clinical characteristics. There was an association between apixaban dosing and risk of stroke. About 40% of the lower (2.5 mg BID) dose of apixaban was prescribed for patients who would have qualified for full dose. Being on inappropriately low dose of apixaban was associated with a higher risk of ischemic strokes compared to appropriately prescribed doses with an adjusted OR 3.37 [1.37-8.32]. Among appropriately prescribed doses, the 5 mg BID dose showed a statistically nonsignificant lower risk of ischemic stroke compared to the 2.5 mg BID dose, adjusted OR 0.55 [0.21-1.41]. Compared to the inappropriate use of the 2.5 mg dose, the appropriate prescription of the 2.5 mg dose was associated with a lower risk of stroke adjusted OR 0.34 [0.07-1.64]. Conclusion: In this series, there was a statistically significant association between being on an inappropriately low dose of apixaban and the odds of stroke while on apixaban therapy.
Abstract 16457: Racial/Ethnic Differences in Cardiac Surveillance Evaluation for Cancer Patients Treated With Anthracycline-based Chemotherapy: The Oneflorida Clinical Research Consortium
Authors: Nam K Nguyen, Michael G Fradley, Yiqing Chen, David DeRemer, Nida Waheed, Taimour Y Langaee, Faraz S Ahmad, Rhonda M Cooper-dehoff, Carl J Pepine, Yan Gong
Journal: Circulation (2020)

Introduction: Anthracyclines remain a key treatment for many malignancies but can increase the risk of heart failure or cardiomyopathy. Different guidelines recommend echocardiography (echo) and BNP or NT-proBNP evaluation before and 6-12 months after treatment. It is unknown however if racial/ethnic disparities exist in the cardiac surveillance of cancer survivors exposed to anthracyclines. Hypothesis: Racial/ethnic disparities are present in the adoption rates of cardiac surveillance guidelines among survivors treated with anthracyclines. Methods: Adult patients in the OneFlorida Consortium without prior cardiovascular disease who received at least 2 cycles of anthracyclines were included in the analysis. Multivariable logistic regression was performed to estimate the odds ratios (OR) and 95% confidence intervals (CI) for receiving echo, BNP or NT-proBNP at 6 months prior (baseline), 6 months after (6M), and 12 months after (12M) treatment among different racial/ethnic groups. Results: A total of 2758 patients were identified, with mean age of 54 ± 16 years and 60% were women. Among the entire cohort, 43% had a baseline echo, with 18% receiving an echo at 6M and 21% at 12M. BNP or NT-proBNP were lower: 5.3% at baseline, 6.5% at 6M and 8.7% at 12M. The prevalence of baseline cardiovascular risk factors ranged from 13% for hyperlipidemia and diabetes to 19% for obesity and 29% for hypertension. Compared to Whites, Blacks (OR: 0.56, 95% CI: 0.45-0.70) and Hispanics (0.52, 0.43-0.64) were less likely to receive echo surveillance at baseline. These differences were also observed at 6M and 12M in Hispanics (Figure). Conclusions: Significant racial/ethnic differences in cardiac surveillance among cancer survivors were present before and after anthracycline-based treatment as Hispanics are least likely to receive cardiac surveillance. This points to the need for improved education and outreach to ensure all cancer survivors receive appropriate and equitable care.
Abstract 11349: Impact of Concomitant Treatment of Non-Chronic Total Occlusion Lesions at the Time of Chronic Total Occlusion Intervention: Insights From the Progress-CTO Registry
Authors: Iosif Xenogiannis, Dimitri Karmpaliotis, Khaldoon Alaswad, Farouc Jaffer, Robert Yeh, Mitul Patel, Ehtisham Mahmud, James Choi, Nicholas Burke, Anthony Doing, Phil Dattilo, Catalin Toma, A.J. Conrad Smith, Barry Uretsky, Oleg Krestyaninov, Dmitrii Khelimskii, Elizabeth Holper, R. Michael Wyman, David Kandzari, Santiago Garcia, Michalis Koutouzis, Ioannis Tsiafoutis, Wissam Jaber, Habib Samady, Jeffrey Moses, Nicholas Lembo, Manish Parikh, Ajay Kirtane, Ziad Ali, Darshan Doshi, Imre Ungi, Peter Tajti, Bavana Rangan, Subhash Banerjee, Emmanouil S Brilakis
Journal: Circulation (2018)

Background: Occasionally during chronic total occlusion (CTO) percutaneous coronary intervention (PCI) non-CTO lesions are also treated. We sought to examine the impact of non-CTO PCI when performe...
Response by Sex in Patient-Centered Outcomes With Baroreflex Activation Therapy in Systolic Heart Failure
Authors: JoAnn Lindenfeld, Richa Gupta, Luanda Grazette, Jean Marie Ruddy, Lana Tsao, Elizabeth Galle, Tyson Rogers, Samuel Sears, Faiez Zannad
Journal: JACC Heart Failure (2021)

The aim of this study was to assess sex differences in the efficacy and safety of baroreflex activation therapy (BAT) in the BeAT-HF (Baroreflex Activation Therapy for Heart Failure) trial.Patients were randomized 1:1 to receive guideline-directed medical therapy (GDMT) alone (control group) or BAT plus GDMT.Pre-specified subgroup analyses including change from baseline to 6 months in 6-min walk distance (6MWD), quality of life (QoL) assessed using the Minnesota Living With Heart Failure Questionnaire (MLWHQ), New York Heart Association (NYHA) functional class, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were conducted in men versus women.Fifty-three women and 211 men were evaluated. Women had similar baseline NT-proBNP levels, 6MWDs, and percentage of subjects with NYHA functional class III symptoms but poorer MLWHQ scores (mean 62 ± 22 vs. 50 ± 24; p = 0.01) compared with men. Women experienced significant improvement from baseline to 6 months with BAT plus GDMT relative to GDMT alone in MLWHQ score (-34 ± 27 vs. -9 ± 23, respectively; p < 0.01), 6MWD (44 ± 45 m vs. -32 ± 118 m; p < 0.01), and improvement in NYHA functional class (70% vs. 27%; p < 0.01), similar to the responses seen in men, with no significant difference in safety. Women receiving BAT plus GDMT had a significant decrease in NT-proBNP (-43% vs. 7% with GDMT alone; difference -48%; p < 0.01), while in men this decrease was -15% versus 2%, respectively (difference -17%; p = 0.08), with an interaction p value of 0.05.Women in BeAT-HF had poorer baseline QoL than men but demonstrated similar improvements with BAT in 6MWD, QoL, and NYHA functional class. Women had a significant improvement in NT-proBNP, whereas men did not. (Baroreflex Activation Therapy for Heart Failure [BeAT-HF]; NCT02627196).
101P E-cadherin inactivation by Trop-2 drives EMT-less metastatic relapse in triple-negative breast cancer
Authors: S. Alberti, E. Guerra, R. Lattanzio, M. Ceci, K. Boujnah, V. Relli, V. Garbo, A. Moschella, D. Altomare, R. Depalo, M. Trerotola
Journal: Annals of Oncology (2021)
The CRTAC1 Protein in Plasma Is Associated With Osteoarthritis and Predicts Progression to Joint Replacement: A Large‐Scale Proteomics Scan in Iceland
Authors: Unnur Styrkarsdottir, Sigrun H. Lund, Saedis Saevarsdottir, Magnus I. Magnusson, Kristbjorg Gunnarsdottir, Gudmundur L. Norddahl, Michael L. Frigge, Erna V. Ivarsdottir, Gyda Bjornsdottir, Hilma Holm, Gudmundur Thorgeirsson, Thorunn Rafnar, Ingileif Jonsdottir, Thorvaldur Ingvarsson, Helgi Jonsson, Patrick Sulem, Unnur Thorsteinsdottir, Daniel Gudbjartsson, Kari Stefansson
Journal: Arthritis & Rheumatology (2021)

Objective Biomarkers for diagnosis and progression of osteoarthritis (OA) are lacking. This study was undertaken to identify circulating biomarkers for OA that could predict disease occurrence and/or progression to joint replacement. Methods Using the SomaScan platform, we measured 4,792 proteins in plasma from 37,278 individuals, of whom 12,178 individuals had OA and 2,524 had undergone joint replacement. We performed a case–control study for identification of potential protein biomarkers for hip, knee, and/or hand OA, and a prospective study for identification of biomarkers for joint replacement. Results Among the large panel of plasma proteins assessed, cartilage acidic protein 1 (CRTAC1) was the most strongly associated with both OA diagnosis (odds ratio 1.46 [95% confidence interval 1.41–1.52] for knee OA, odds ratio 1.36 [95% confidence interval 1.29–1.43] for hip OA, and odds ratio 1.33 [95% confidence interval 1.26–1.40] for hand OA) and progression to joint replacement (hazard ratio 1.40 [95% confidence interval 1.30–1.51] for knee replacement and hazard ratio 1.31 [95% confidence interval 1.19–1.45] for hip replacement). Patients with OA who were in the highest quintile of risk of joint replacement, based on known risk factors (i.e., age, sex, and body mass index) and plasma CRTAC1 level, were 16 times more likely to undergo knee replacement within 5 years of plasma sample collection than those in the lowest quintile, and 6.5 times more likely to undergo hip replacement. CRTAC1 was not associated with other types of inflammatory arthritis. A specific protein profile was identified in those patients who had undergone joint replacement prior to plasma sample collection. Conclusion Through a hypothesis‐free approach, we identified CRTAC1 in plasma as a novel promising candidate biomarker for OA that is both associated with occurrence of OA and predictive of progression to joint replacement. This biomarker might also be useful in the selection of suitable patients for clinical trial enrollment.
Abstract 15651: The Burden of Nontreatment or Undertreatment Among Non-valvular Atrial Fibrillation Patients With Elevated Stroke Risk: A Systematic Literature Review of Real-world Evidence
Authors: Manuela Di Fusco, Matthew Sussman, Geoffrey Barnes, Charles Tao, John A Gillespie, Mauricio Ferri, Nicholas Adair, Matthew Cato, Ilnaz Shirkhorshidian, Jennifer Guo
Journal: Circulation (2020)

Introduction: Global treatment guidelines (e.g., AHA/ACC/HRS, ESC, JCS) recommend treatment with oral anticoagulants (OACs) for patients with non-valvular atrial fibrillation (NVAF) and an elevated stroke risk, defined by CHA 2 DS 2 -VASc score ≥2. However, not all patients with NVAF and an elevated stroke risk receive guideline-recommended therapy. A systematic literature review of observational studies was undertaken based on PRISMA guidelines to identify the body of evidence on untreated and undertreated NVAF among patients with elevated stroke risk, and assess its epidemiological and clinical burden. Methods: An extensive search of MEDLINE, GoogleScholar, the Cochrane Library, relevant conference proceedings, and health technology assessments (HTAs) was conducted for RWE studies. Studies published between 1/2010-4/2020 were included if they evaluated rates of nontreatment or undertreatment in NVAF. Nontreatment was defined as absence of OACs, while undertreatment was defined as treatment with only antiplatelet agents. Studies focusing on valvular AF were excluded. Results: Thirty-nine published studies (13 countries) met inclusion criteria. Rates of nontreatment for patients with elevated stroke risk ranged from 2.0%-51.1% (median: 23.3%), while rates of undertreatment ranged from 10.0%-45.1% (median: 34.6%). Few studies assessed the relationship between nontreatment or undertreatment and clinical outcomes in the evaluated population. Among US outpatients with NVAF and an elevated stroke risk, those undertreated had a higher likelihood of death (HR: 1.22; 95% CI: 1.05-1.41; p=.006) compared to patients treated with OACs. Also, in a separate US study of NVAF patients with varying levels of warfarin exposure, patients with no warfarin exposure had significantly higher rates of ischemic stroke than patients with low adherence (4.41 vs. 1.87 per 100 person-years, p&lt;.001) or high adherence (4.41 vs. 0.72 per 100 person years, p&lt;.001). Conclusion: Rates of nontreatment and undertreatment among NVAF patients with elevated stroke risk remain high and are associated with potentially preventable cardiovascular events and death. Strategies to increase rates of treatment may reduce adverse clinical outcomes.
Abstract 15303: Dimethylarginine Dimethylaminohydrolase-1 is Not Involved in Chronic Hypoxic Pulmonary Hypertension and Right Ventricular Hypertrophy in Mice
Authors: Juliane Hannemann, Antonia Glatzel, Jonas Hillig, Julia Zummack, Rainer H Boeger
Journal: Circulation (2020)

Introduction: Chronic hypoxia causes persistent pulmonary vasoconstriction and leads to pulmonary hypertension and right ventricular hypertrophy. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis; its level increases in hypoxia concomitantly with reduced activity of dimethylarginine dimethylaminohydrolases (DDAH-1 and DDAH-2), the enzymes metabolizing ADMA. DDAH knockout models may therefore help to understand the pathophysiological roles of this enzyme and its substrate, ADMA, in the development of hypoxia-associated pulmonary hypertension. Hypothesis: We hypothesized that DDAH1 knock-out mice have an attenuated hypoxia-induced elevation of ADMA and reduced right ventricular hypertrophy. Methods: DDAH1 knock-out mice (KO) and their wild-type littermates (WT) were subjected to normoxia (NX) or hypoxia (HX) during 21 days. We measured ADMA concentration in plasma, DDAH1 and DDAH2 expression in the lung, right ventricular hypertrophy by the Fulton index, cardiomyocyte hypertrophy by dystrophin staining of heart tissues, and muscularization of pulmonary arterioles by CD31 and α-actin staining of lung sections. Results: DDAH1 KO mice had higher ADMA concentration than WT under NX (2.31±0.33 μmol/l vs. 1.20±0.17 μmol/l; p &lt; 0.05). ADMA significantly increased in WT-HX (to 1.74±0.86 μmol/l; p &lt; 0.05 vs. normoxia), whilst it did not further increase in KO-HX (2.58±0.58 μmol/l; p = n.s.). This was paralleled by a 38±13% reduction in DDAH1 mRNA but not DDAH2 mRNA expression, and reduced DDAH protein expression. We observed right ventricular hypertrophy under hypoxia in both, WT and KO mice, with no significant differences between both genotypes. Further, cardiomyocyte hypertrophy and pulmonary arteriolar muscularization were significantly increased by hypoxia, but not significantly different between WT and KO mice. Conclusions: We conclude that chronic hypoxia causes an elevation of ADMA, which impairs NO production and leads to endothelial dysfunction and vasoconstriction. Downregulation of DDAH expression and activity may be involved in this; however, knockout of DDAH1 does not modify the pathophysiological changes in remodeling of the pulmonary vasculature and the right ventricle.
Collaborative Risk-Adapted Treatment for Pediatric Acute Lymphoblastic Leukemia in Mexico
Authors: Pablo Gonzalez-Montalvo, Hugo Romo, Lourdes Vega-Vega, Fernando Sanchez-Zubieta, Eduardo Altamirano-Alvarez, Rebeca Rivera-Gomez, Maite Echavarria-Valenzuela, Oscar Gonzalez-Ramella, Daniela Covarrubias-Zapata, Mónica Malavar-Guadarrama, Paula Aristizabal, Paola Friedrich, Gaston K Rivera, Carlos Rodriguez-Galindo
Journal: Blood (2017)
Abstract 12964: Complete Revascularization of Stable Patients Presenting With STEMI is Associated With Decreased Cardiovascular Death and Reinfarction If Performed During Index Percutaneous Coronary Intervention, but Not If Complete Revascularization is Staged
Authors: Roberto C Cerrud-Rodriguez, Syed Muhammad Ibrahim Rashid, Ioanna Katsa, Mario J Garcia, Azeem Latib
Journal: Circulation (2020)

Introduction: Recent evidence suggests that complete revascularization (CR) of stable patients presenting with STEMI improves outcomes, but the appropriate timing of said CR has not been clearly established (CR during index PCI [iCR] versus staged CR [sCR]). sCR is defined as CR within a mean of 31.5±24.6 days after the STEMI. Objective: To determine the appropriate timing of CR for it to be beneficial (iCR versus sCR). Methods: A systematic review of Medline, Cochrane, and Embase was performed for randomized control trials (RCTs) that reported outcomes of stable patients presenting with STEMI and whose culprit lesion received PCI, who were subsequently randomized into culprit-lesion only and CR cohorts. Only RCTs with at least a 12-month follow-up were included. The timing of CR, for the subdivision of CR cohort into iCR and sCR, had to be stated. Seven RCTs comprising 6647 patients (mean age: 62.9±1.4 years, male sex: 79.4%) met this criteria and were included. Results: After a mean follow-up of 25.1±9.4 months, iCR, when compared to a culprit-lesion only strategy, was associated with a significant cardiovascular mortality benefit (Risk Ratio [RR] 0.48 95% Confidence Interval [CI] 0.26-0.90 p=0.02, Relative Risk Reduction [RRR] 52%) and a significant decrease in reinfarctions (RR 0.42 95% CI 0.25-0.70 p=0.001 RRR: 58%). sCR showed no significant benefit for any of the studied outcomes when compared to a culprit-lesion only strategy. There was no significant difference in all-cause mortality or in the composite safety outcome of contrast-induced nephropathy nor stroke in either the iCR or the sCR groups when compared to the culprit-lesion only group. Conclusion: Complete revascularization during index PCI of stable patients presenting with STEMI, but not staged CR, is associated with a statistically significant decrease in cardiovascular death and non-fatal reinfarctions. There is no difference between groups in all-cause mortality or in the composite safety outcome.
Response to ‘A call to standardize the BCC:SCC ratio’: reply from the authors
Authors: Z. Jiyad, L. Marquart, A.C. Green
Journal: British Journal of Dermatology (2021)

Linked Articles: Ma et al. Br J Dermatol 2021; 185:868–869; Jiyad et al. Br J Dermatol 2021; 184:545.
Abstract 16594: Disruption of Caveolae-Confined Phosphorylation of Ryanodine Receptors Promotes Ca <sup>2+</sup> Handling Abnormalities and Arrhythmogenesis in Mouse Atrial Myocytes
Authors: Roman Medvedev, Di Lang, Alexey Glukhov
Journal: Circulation (2020)

Rationale: Chronic atrial fibrillation has been linked to ectopic triggered activity driven by delayed afterdepolarizations in response to sarcoplasmic reticulum Ca 2+ leak from certain areas in atria. These activities were associated with hyperphosphorylated ryanodine receptors (RyRs), while the underlying mechanisms remain uncertain. Here, we hypothesized that mouse atria have areas with lower transversal-axial tubule system (TATS) organization, where phosphorylation of RyRs is mainly confines by caveolae nanodomains and might be firstly disturbed in disease conditions. Methods and results: In wild type (WT) mouse intact atria stained with RH-237, we found that myocytes located in the intercaval region (ICR, between the superior vena cava and atrioventricular junction and between the crista terminalis and interatrial septum) have a significantly less density of TATS than right atrial appendage (RAA) myocytes: 5.7±0.4% in ICR vs. 13.4±0.9% in RAA, P&lt;0.01. Also an elevated frequency of spontaneous Ca 2+ sparks was observed in myocytes isolated from ICR vs. RAA (12.5±2.6 vs. 1.5±0.3 sparks/μm/s, P&lt;0.01). ICR myocytes isolated from mice with a cardiac-specific knockout of the main structural protein of caveolae, caveolin-3, showed significant increase of Ca 2+ sparks frequency as compared to WT (27.3±4.1 sparks/μm/s, P&lt;0.01). Immunofluorescence staining of RyRs, phosphorylated at protein kinase A/ Ca 2+ /calmodulin-dependent protein kinase-II phosphorylation sites: Ser 2808 -RyR and Ser 2814 -RyR, showed predominant subsarcolemmal localization, with a high co-localization with caveolin-3, in ICR and RAA cells. Myocytes isolated from caveolin-3 knockout mice showed extension of both Ser 2808- RyR and Ser 2808- RyR to whole-cell wide striated pattern in ICR, but not RAA. This redistribution was associated with development of delayed afterdepolarizations in ICR but not RAA cells. Conclusions: Our findings demonstrate that in ICR in mouse atria, caveolae form functional, spatially-confined cAMP nanodomains and control localized RyR phosphorylation. Disruption of caveolae structures, seen in various pathologies, may lead to hyperphosphorylation of RyRs promoting Ca 2+ handling abnormalities and arrhythmogenic triggered activity.
HDAC4 degradation during senescence unleashes an epigenetic program driven by AP-1/p300 at selected enhancers and super-enhancers
Authors: Eros Di Giorgio, Harikrishnareddy Paluvai, Emiliano Dalla, Liliana Ranzino, Alessandra Renzini, Viviana Moresi, Martina Minisini, Raffaella Picco, Claudio Brancolini
Journal: Genome biology (2021)

Cellular senescence is a permanent state of replicative arrest defined by a specific pattern of gene expression. The epigenome in senescent cells is sculptured in order to sustain the new transcriptional requirements, particularly at enhancers and super-enhancers. How these distal regulatory elements are dynamically modulated is not completely defined.Enhancer regions are defined by the presence of H3K27 acetylation marks, which can be modulated by class IIa HDACs, as part of multi-protein complexes. Here, we explore the regulation of class IIa HDACs in different models of senescence. We find that HDAC4 is polyubiquitylated and degraded during all types of senescence and it selectively binds and monitors H3K27ac levels at specific enhancers and super-enhancers that supervise the senescent transcriptome. Frequently, these HDAC4-modulated elements are also monitored by AP-1/p300. The deletion of HDAC4 in transformed cells which have bypassed oncogene-induced senescence is coupled to the re-appearance of senescence and the execution of the AP-1/p300 epigenetic program.Overall, our manuscript highlights a role of HDAC4 as an epigenetic reader and controller of enhancers and super-enhancers that supervise the senescence program. More generally, we unveil an epigenetic checkpoint that has important consequences in aging and cancer.
Covid-19: Why we must temper urgency with diligence
Authors: Fiona Godlee
Journal: BMJ (2021)

How should we balance the need for speed with our duty towards care and rigour?In the first days of the pandemic doctors who were faced with patients sick and dying from an unknown disease turned by necessity to existing drugs, those known to work against viral illness or to be potentially beneficial in multiorgan inflammatory disease.The list of these "repurposed" drugs is long, many with honourable records of safety and effectiveness in other conditions.Almost all have fallen under scientific scrutiny.The Recovery trial, so impressively established in the very first days of the pandemic, 1 has given us one remarkable positive finding: that a cheap and widely available drug, dexamethasone, reduces mortality in critically ill patients. 2Apart from this, and some emerging evidence of benefit from monoclonal antibodies, trials have almost all given existing drugs the thumbs down. 3 4