tbuckley/cabot-search huggingface dataset:
Abstract 10302: A Case for Ending Rifampicin Use in Endocarditis
Authors: Jose P Sousa, Carolina N Lourenco, Rogerio Teixeira, Lino M Goncalves
Journal: Circulation (2021)

Background: Rifampicin has been employed in various endocarditis antibiotic regimens, particularly in prosthetic, staphylococcus aureus (SA) and culture-negative cases. However, this practice is not without controversy. Purpose: To perform a meta-analysis aimed at ascertaining the efficacy and safety of adjunctive rifampicin use in endocarditis. Methods: We systematically searched MEDLINE, Embase, Web of Science, Cochrane Library and Google Scholar, from inception to June 1st, 2021, for studies comparing rifampicin-containing antibiotic regimens with those comprising no rifamycin derivatives, in the setting of endocarditis. The primary endpoint was all-cause death, while relapse, bail-out valvular surgery, microbiological failure (lasting positivity of blood cultures) and hepatotoxicity (fivefold or higher increase in transaminase levels) were secondary outcomes. SA infections were investigated separately, with respect to the primary endpoint. Mantel-Haenszel odds ratios (ORs) were pooled using traditional meta-analytic techniques, under a random-effects model. Results: 2 randomized, 1 non-randomized prospective and 6 retrospective studies, featuring 886 patients (of whom 322 allocated to rifampicin), were included. While 8 studies addressed staphylococcal endocarditis (with 3 of them dealing exclusively with SA infections), prosthetic and culture-negative cases were only focused on 1 study each. There were 96 deaths (from 7 studies), 32 relapses (from 6 studies), 35 bail-out valvular surgeries (from 4 studies), 14 microbiological failures (from 2 studies) and 32 hepatotoxicity cases (from 5 studies). Rifampicin use was associated with a tendency towards higher all-cause mortality (OR 1.63, 95% CI 0.85-3.12, P 0.14, i 2 12%), which held true for SA infections (OR 1.63, 95% CI 0.67-3.92, P 0.28, i 2 20%), and bail-out valve surgery (OR 2.03, 95% CI 0.65-6.34, P 0.22, i 2 5%). Relapse and microbiological failures rates were similar between groups (OR 1.25, 95% CI 0.59-2.65, P 0.56, i 2 0% and OR 1.3, 95% CI 0.24-6.90, P 0.76, i 2 41%, respectively). Hepatotoxicity odds were greater in the rifampicin arm (OR 3.24, 95% CI 1.35-7.77, P 0.008, i 2 0%). Conclusion: Currently available evidence does not support rifampicin use in endocarditis.
Corrigendum to ‘Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up’
Authors: M.A. Dimopoulos, P. Moreau, E. Terpos, M.V. Mateos, S. Zweegman, G. Cook, M. Delforge, R. Hájek, F. Schjesvold, M. Cavo, H. Goldschmidt, T. Facon, H. Einsele, M. Boccadoro, J. San-Miguel, P. Sonneveld, U. Mey
Journal: Annals of Oncology (2021)
Abstract 11704: NF-κβ Signaling Regulates Vasopressin Receptor 2 Promoter Activity
Authors: Luke S Dingwell, Talat Afroze, Abdul Momen, Annie Zhou, M. Ahsan Siraj, Areeb R Jafrani, Mansoor Husain
Journal: Circulation (2021)

Background: Arginine vasopressin, through vasopressin receptor 2 (AVP-V2R), regulates water reabsorption via aquaporin-2 and sodium reabsorption via several mechanisms. We recently implicated V2R, and its transcriptional downregulation, in a model of B-cell deficiency with increased sodium- and water-excretion and reduced blood pressure (BP). Here, we identify mechanisms underlying the immunoregulation of V2R transcription and evaluate the importance of V2R in BP regulation. Methods &amp; Results: Using an Avpr2 promoter-luciferase reporter in an immortalized mouse inner medullary collecting duct cell line [mIMCD-3], we found that IL-6 (100ng/mL), a stimulator of NF-κβ signaling, increased promoter-reporter activity (10.4±3.2 vs 4.0±0.5 RLU; N=2-3/group); while PDTC (60μM), an inhibitor of NF-κβ signaling, reduced promoter-reporter activity (2.2 vs 4.0±0.5 RLU; N=1-3/group). Importantly, single point mutations in two putative NF-κβ binding sites in the proximal Avpr2 promoter also reduced promoter activity (2.3±0.6 vs 4.0±0.5 RLU; N=2-3/group), and blocked the stimulatory effect of IL-6 (2.4 vs 2.3±0.6 RLU; N=1-2/group). An anti-IL-6 receptor antibody (10μg/mL vs isotype, 10μg/mL) also abolished the stimulatory effect of IL-6 on promoter activity (3.2 vs 9.1 RLU; N=1/group). To determine the role of V2R in BP regulation, wild-type C57BL/6J mice (male and female; aged 10-wk) were randomized to (i) Tolvaptan (TOL), a selective V2R-antagonist or (ii) DMSO/glycerol control (50/50) via osmotic mini-pump (0.0375mg/d). Invasive hemodynamics 12-d post-implant revealed reduced mean arterial pressure (MAP) in TOL-treated mice (76±3 vs 86±3 mmHg; N=4-5/group; P&lt;0.05), while metabolic cage studies 8-11-d post-implant showed higher 24-h urine volume/body weight (UV/BW; 0.07±0.00 vs 0.05±0.00 mL/g; N=4-5/group; P&lt;0.05) and 24-h sodium excretion/BW (0.25±0.01 vs 0.17±0.01 mg/d/g; N=4-5/group; P&lt;0.01). Correlation analyses revealed inverse relationships between MAP and 24-h UV/BW (r=-0.65; N=9 pairs; P&lt;0.05) and 24-h sodium excretion/BW (r=-0.64; N=9 pairs; P&lt;0.05). Conclusion: These studies suggest that the V2R promoter is responsive to NF-κβ signaling, and that V2R serves a role in BP homeostasis through sodium- and water-handling.
Abstract MP252: Genetic Architecture Of Heart Mitochondrial Proteome Influencing Cardiac Hypertrophy
Authors: Karthickeyan Chella Krishnan, Elie-Julien El Hachem, Christine Light, Varun Shravah, Diana Anum, Marcus M Seldin, Chi Fung Lee, Benjamin L Parker, David E James, Aldons J Lusis
Journal: Circulation Research (2021)

Our lab studies how natural genetic variations affect common diseases using a mouse population called hybrid mouse diversity panel (HMDP). In this study, we have explored the genetic regulation of mitochondrial pathways and their contribution to heart function using an integrative proteomics approach. We first performed a whole heart proteomic analysis in the HMDP (72 strains, n=2-3 mice) and surveyed mitochondrial localization using MitoCarta2.0. We retrieved 840 of these proteins (quantified in ≥50 strains) and performed high-resolution association mapping on their respective abundance levels to the HMDP genotypes. Our analyses identified three genetic loci, located on chromosome (chr) 7, chr13 and chr17, that control distinct classes of mitochondrial proteins as well as heart hypertrophy. Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively. All three are associated with heart mass in two independent heart stress models, namely, isoproterenol (ISO)-induced heart failure and diet-induced obesity (DIO) models. Next, to identify the aspects of mitochondrial metabolism regulated by these loci, we constructed co-expression protein networks using weighted gene co-expression network analysis (WGCNA) and identified five modules. Eigengenes, representing the first principal component of two of these modules (Brown and Green), mapped to the same regions as the chr13 and chr17 loci, respectively. DAVID enrichment analyses revealed that the Brown module (72 proteins, 96% overlap with chr13) was highly enriched for complex-I proteins (35 proteins, P = 8.8E-74) and the Green module (44 proteins, 73% overlap with chr17) for mitochondrial ribosomal proteins (25 proteins, P = 1.3E-53). The proteins in the chr7 locus were found primarily in the Turquoise module (393 proteins, 81% overlap) but this module was not enriched for any single mitochondrial protein complex. In summary, we now report the identification of three genetic loci that control distinct classes of mitochondrial proteins as well as heart hypertrophy. Our results provide strong support for a role of the mitochondrial proteome in heart pathophysiology.
Managing Multiple Myeloma in Older Adults Using Real World Evidence and Clinical Integration of a Geriatric Assessment Tool in Clinical Practice
Authors: Smith Giri, D'Ambra Dent, Kelly N. Godby, Luciano J. Costa, Susan Bal, Gayathri Ravi, Stacey Ingram, William Dudley, Matthew Dudley, Julie M Scott, Debra M Wujcik
Journal: Blood (2021)
NIMG-58. CANONICAL CORRELATION ANALYSIS IN GLIOBLASTOMA REVEALS ASSOCIATIONS BETWEEN EXPRESSION OF RADIOMIC SIGNATURES AND GENOMICS
Authors: Jun Guo, Anahita Fathi Kazerooni, Hamed Akbari, Erik Toorens, Chiharu Sako, Elizabeth Mamourian, Costas Koumenis, Stephen J Bagley, Robert A Lustig, Donald M O’Rourke, Tapan Ganguly, Spyridon Bakas, MacLean Nasrallah, Christos Davatzikos
Journal: Neuro-Oncology (2021)

Abstract PURPOSE Understanding the molecular underpinnings of imaging signatures of glioblastoma can provide insights into the biologic basis of tumor formation and progression as well as in vivo surrogate markers of molecular events driving the tumor’s phenotype. Through machine learning (ML), this study demonstrates that distinct imaging subtypes of glioblastoma are related to specific molecular alterations. METHODS Pre-operative multi-parametric MRI (T1, T2, T1CE, T2-FLAIR, DSC-MRI, DTI-MRI) of 669 IDH-wildtype subjects with glioblastoma were retrospectively collected and radiomic features, including descriptors of morphology, intensity, histogram, and texture, were extracted. Imaging subtypes were identified by a feature selection and clustering approach. Genomic markers, obtained using next generation sequencing (NGS) panel of 27 key glioblastoma genes, were available in 358/669 patients. Canonical correlation analysis (CCA) was conducted within each imaging subtype between the selected imaging features and genetic variables to seek maximum correlations between combinations of variables in imaging and genomic sets, and hence elucidate the molecular drivers of respective subtypes. RESULTS Three distinct imaging subtypes were identified by clustering on 50 selected features, representing characteristics of morphology, tumor neo-angiogenesis (DSC-derived features), and cellular density (DTI-derived features). These subtypes yielded differentiable overall survival based on Kaplan-Meier analysis. The canonical coefficients of each subtype revealed the distinction of the underlying genomic characteristics: one exhibited frequently mutated [ARID2, NTRK1], another subtype showed increased frequency of mutation in [ATRX, EGFR, PIK3R1], while the third was associated with all these genes and [NF1, PIK3CA, RB1], additionally. CONCLUSION We derived three distinct radiomic MRI subtypes for glioblastoma that highly correlate with the patients' survival and molecular genetic characteristics. Investigating the relationship between imaging and genomic information may enable identification of molecularly- and phenotypically-consistent tumor subtypes, which would offer non-invasive approaches for characterizing heterogeneity of glioblastoma, further facilitating patient stratification and treatment planning.
Preclinical Assessment of Alvocidib in Combination with 5-Azacytidine in High-Risk Myelodysplastic Syndromes
Authors: Vladimir Riabov, Qingyu Xu, Nanni Schmitt, Alexander Streuer, Johann-Christoph Jann, Alina Wein, Eva Altrock, Arwin Mehralivand, Verena Nowak, Nadine Weimer, Julia Obländer, Iris Palme, Mohamad Jawhar, Christel Weiss, Georgia Metzgeroth, Jason M Foulks, Wolf-Karsten Hofmann, Daniel Nowak
Journal: Blood (2021)
Abstract 9884: Supranormal Left Ventricular Ejection Fraction and Risk of Major Adverse Cardiovascular Events: Findings from the Multi-Ethnic Study of Atherosclerosis and Dallas Heart Study
Authors: Sonia Shah, Nitin Kondamudi, Matthew W Segar, Colby Ayers, Susan A Matulevicius, Alvin Chandra, Suhny Abbara, MD, Erin Michos, Joao Lima, Ron Peshok, Mark H Drazner, Ambarish Pandey
Journal: Circulation (2021)

Introduction: Left ventricular (LV) systolic dysfunction is associated with a higher risk of adverse cardiovascular (CV) outcomes. However, the prognostic implication of supranormal LV ejection fraction (LVEF), as assessed by cardiac MRI, among adults with no prior CV disease (CVD) is unknown. Methods: Participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and Dallas Heart Study (DHS) who were free of CVD at baseline and underwent cardiac MRI with LVEF above the normal MRI cutoff (≥57%) were included. The association between cohort specific LVEF categories and risk of clinically adjudicated major adverse CV events (MACE) was assessed using adjusted Cox models. The association between continuous measures of LVEF and risk of MACE was assessed in a pooled cohort analysis using cohort-specific Z-scores of LVEF. Results: There were 4,703 participants from MESA (mean age 62, 25% black, 54% women, median follow up 13.1 years) and 2,287 participants from DHS (mean age 44, 46% black, 57% women, median follow up 12 years) with 747 and 151 MACE events, respectively. In both cohorts, participants across increasing LVEF quartiles (MESA Q1 mean LVEF=63% vs. Q4 mean LVEF=78%) were older and had a higher burden of CV risk factors. Among cardiac parameters, across increasing quartiles, LV end-diastolic volume (Q1: 69.9 vs. Q4: 64.6 ml/m2) and LV mass (Q1: 79.1 vs. Q4: 74.9 gm/m2) significantly decreased (p&lt;0.001), while LV stroke volume (Q1: 43.8 vs. Q4: 49.8 ml/m2) increased (p&lt;0.001). In adjusted Cox models, the risk of MACE was highest among individuals in LVEF Q4 (vs. Q1) in both cohorts (Figure A). Similar patterns of association were observed between continuous distribution of LVEF and risk of MACE in the pooled analysis (Figure B). Conclusions: Among community-dwelling adults without CVD, supranormal LVEF is associated with elevated risk of MACE. Future studies are needed to elucidate the mechanisms underlying risk of CVD among individuals with supranormal LVEF.
Abstract 12877: National Trends of Atrial Fibrillation/Atrial Flutter Mortality in the United States From 1999 to 2019: Regional, Racial, and Gender Variations
Authors: Alireza Ghajar, Mohammed Essa, Arshi Parvez, Augustin DeLago, Zahra Aryan, Joseph Shalhoub, Matthew Hammond-Haley, Justin Salciccioli, Kamil Faridi, Binu Philips
Journal: Circulation (2021)

Introduction: There is an emerging need to evaluate Atrial Fibrillation/Atrial Flutter (AF/AFL) mortality trends in different races and genders in different regions across the US. Methods: In an observational study utilizing the CDC WONDER database, age-adjusted mortality rates (AAMR) per 100,000 people for AF/AFL between 1999 and 2019 were investigated. Trends in AAMR were determined by evaluating average annual percentage changes (AAPC)s with Joinpoint regression analysis. Results: In the total US population from 1999 to 2019, AAMR due to AF/AFL has increased from 3.1 to 6.5 per 100,000 population. AF/AFL-related mortality rates have nearly doubled in all racial groups, ranging from an 84% increase in Black males (2.5 to 4.6 per 100,000) to a 123% increase in White males (3.1 to 6.9 per 100,000). AF/AFL-related mortality relative increase was highest in the West (140%) followed by Midwest (124%) and South (103%) while North East (81%) came last. Comparing white race mortality rates in different census regions, West demonstrated the highest increase in AAMR in the white population [170% in males, 138% in females]. Meanwhile, Midwest had the highest increase in the Black/African American population with a 111% increase in Females and 130% increase in Males. The Northeast showed the least increase in AAMR in both blacks and whites. Joinpoint analysis demonstrated that AF/AFL-related mortality rate has plateaued for black females and white males since 2017; the same plateau occurrence can be seen for white females since 2015 (Figure 1). Conclusion: The greatest increases in mortality occurred among white men and women and in Western states. AAMR increase has plateaued recently in white males as well as black and white females. AAPCs demonstrate that the rates of increases in AF mortality are greatest in Caucasians, followed by Asian and Black Americans.
Abstract 11823: Machine Learning-Based Model for Prediction of All-Cause Mortality in Low Ejection Function Patients
Authors: Yuji Sakashita, Ai Kawamura, Noriyuki Kashiyama, Takuji Kawamura, Daisuke Yoshioka, Koichi Toda, Shigeru Miyagawa
Journal: Circulation (2021)

Introduction: It is important to accurately predict heart failure prognosis for quality of life and selection of the treatment. In this article, we developed the prediction model based on machine learning and show how each variable used in the prediction model contributed to the prediction. Methods: We developed the 5-year all-cause mortality prediction model by machine learning. The database contained 1227 cases and 232 variables. We dropped the variables which had over 20% of missing value. We split the database into 80% as training data and 20% as test data. We selected the variables for model development by statistical methods, algorithm-based method, and past findings. The models were developed using selected variables and evaluated the performance with the area under the curve. The best-performing model was analyzed how each variable contributed to the prediction by the SHapley Additive exPlanations (SHAP). Results: We selected 19 variables by statistical methods, algorithm-based method, and past findings for the model development. The best model has used six variables, age, creatinine, body surface area, blood urea nitrogen, diabetes mellitus, and emergency hospitalization from all combinations of variables. The AUC was 0.80 in training data and 0.79 in test data. We showed the contributions of variables to the prediction by SHAP in Figure. The variables listed in higher were more affected to the prediction value. The values positioned in more right were contributed to survival. Conclusions: We successfully developed the prediction model using six variables and with good AUC.
DDRE-23. PRECLINICAL EVALUATION OF BRAIN PENETRATION PROPERTIES OF NEW FIRST-IN-CLASS LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1) INHIBITOR, SP-2577
Authors: Jun Jiang, Barbara Hopkins, Garry Hook, Ernesto Luna Melendez, Artak Tovmasyan, Shwetal Mehta, Jing Li, Nader Sanai
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Lysine specific demethylase 1 (LSD1) is a histone demethylase implicated in the maintenance of pluripotency and proliferation gene programs that give rise to a number of cancers. SP-2577 is a first-in-class selective and reversible inhibitor of LSD1. Here, we evaluated the ability of SP-2577 to cross blood-brain barrier in mouse brain. METHODS Fifteen BALB/c mice were treated with 50 mg/kg SP-2577 twice daily intraperitoneally for 4 days. At 2, 6, and 12 hours after the last treatment dose was delivered, plasma and brain samples were collected for analysis of SP-2577 bound and unbound fractions (5 mice/time point). An LC–MS/MS method was developed to measure the drug levels in mouse plasma and brain. The unbound fractions of SP-2577 in plasma and brain tissue were determined using equilibrium dialysis. RESULTS Total plasma levels of SP-2577 at the 2, 6, and 12-hour time points following the last dose were 1353 nM, 1209 nM, and 560 nM, accordingly. Total drug levels in brain measured at the same time points were 276 nM, 183 nM, and 168 nM. SP-2577 is highly bound to plasma proteins and brain tissue components with an average plasma unbound fraction value of 0.009. Unbound levels of SP-2577 were undetectable in brain tissue, potentially due to instability of the drug in brain homogenates. The total brain-to-plasma ratio (Kp) was determined as 0.032 (range, 0.027–0.046) in mice. CONCLUSION SP-2577 is well tolerated in mice and achieves reasonable total drug levels in mouse brain, yet is highly-bound to plasma proteins and brain components. Taken together, these data indicate that SP-2577 cannot reach pharmacologically-relevant drug concentrations across the mouse blood-brain barrier.
Abstract 11546: Ten-Year Trends in the Nationwide Clinical Outcome After Percutaneous Coronary Intervention
Authors: Jung-Min Choi, Yu Jeong Jang, Seung-Hwa Lee, Jin-Ho Choi
Journal: Circulation (2021)

Introduction: We investigated the 10-year trends in the clinical outcome of percutaneous coronary intervention (PCI) in an unselected all-comer nationwide cohort. Hypothesis: Mortality following PCI is a key quality measurement in clinical practice and should be investigated within the context of the changing clinical comorbidities. Methods: Patients undergoing PCI for the first time between 2006 and 2015 from database of the National Health Insurance Service of Korea were included and followed until death or being censored by December 2016. Results: A total of 437,436 patients was included. Patients were divided into quartile subgroups according to a clinical score that predicting 1-year death risk. Over the decade, the annual number of PCI increased from 32,098 to 51,990 (p&lt;0.001). The proportion of patients with higher risk quartiles increased, whereas lower risk quartiles decreased (p&lt;0.001). The 1-year cumulative incidence rate of death did not change in the population with 1st (0.9% to 0.8%) and 2nd (1.3% to 1.3%) risk score quartiles, whereas it increased in the population with 3rd (3.4% to 5.1%) and 4th (15.5% to 19.4%) risk score quartiles (p&lt;0.001 by restrictive mean survival time). Conclusions: This real-world data analysis showed that the number, proportion, and the risk of high-risk patients increased over the decade in Korea.
Acquired and Inherited Thrombophilia Testing in Patients with Chronic Thromboembolic Pulmonary Hypertension: Value of Testing in an Academic Health Center
Authors: Bharath Ram S, Monisha Harimadhavan, Shilpa Prabhu, Karthick R G, Devi Prasad Shetty, Sharat Damodar
Journal: Blood (2021)
Intrathecal Chemotherapy As a Potential Alternative Treatment for Steroid-Refractory Immune Effector Cell-Associated Neurotoxicity Syndrome
Authors: Urwat Til Vusqa, Palash Asawa, Maitreyee Rai, Yazan Samhouri, Prerna Mewawalla, Anna Koget, Santhosh Sadashiv, Cyrus Kahn, Salman Fazal, John Lister
Journal: Blood (2021)