tbuckley/cabot-search huggingface dataset:
Development of a new risk stratification system for patients with newly diagnosed multiple myeloma using R-ISS and 18F-FDG PET/CT
Authors: Hee Jeong Cho, Sung-Hoon Jung, Jae-Cheol Jo, Yoo Jin Lee, Sang Eun Yoon, Sung-Soo Park, Do Young Kim, Ho-Jin Shin, Yeung-Chul Mun, Jun Ho Yi, Hyo Jung Kim, Da Jung Kim, Ho Sup Lee, Sung Hwa Bae, Chae Moon Hong, Shin Young Jeong, Jung-Joon Min, Sang Kyun Sohn, Chang-Ki Min, Kihyun Kim, Je-Jung Lee, Joon Ho Moon, Hee Jeong Cho, Sung-Hoon Jung, Jae-Cheol Jo, Yoo Jin Lee, Sang Eun Yoon, Sung-Soo Park, Do Young Kim, Ho-Jin Shin, Yeung-Chul Mun, Jun Ho Yi, Hyo Jung Kim, Da Jung Kim, Ho Sup Lee, Sung Hwa Bae, Chae Moon Hong, Shin Young Jeong, Jung-Joon Min, Sang Kyun Sohn, Chang-Ki Min, Kihyun Kim, Je-Jung Lee, Joon Ho Moon
Journal: Blood Cancer Journal (2021)

Abstract In multiple myeloma (MM), a high number of focal lesions (FL) detected using positron emission tomography/computed tomography (PET/CT) was found to be associated with adverse prognosis. To design a new risk stratification system that combines the Revised International Staging System (R-ISS) with FL, we analyzed the data of 380 patients with newly diagnosed MM (NDMM) who underwent 18 F-fluorodeoxyglucose ( 18 F-FDG) PET/CT upon diagnosis. The K-adaptive partitioning algorithm was adopted to define subgroups with homogeneous survival. The combined R-ISS with PET/CT classified NDMM patients into four groups: R-ISS/PET stage I ( n = 31; R-ISS I with FL ≤ 3), stage II ( n = 156; R-ISS I with FL &gt; 3 and R-ISS II with FL ≤ 3), stage III ( n = 162; R-ISS II with FL &gt; 3 and R-ISS III with FL ≤ 3), and stage IV ( n = 31; R-ISS III with FL &gt; 3). The 2-year overall survival rates for stages I, II, III, and IV were 96.7%, 89.8%, 74.7%, and 50.3%. The 2-year progression-free survival rates were 84.1%, 64.7%, 40.8%, and 17.1%, respectively. The new R-ISS/PET was successfully validated in an external cohort. This new system had a remarkable prognostic power for estimating the survival outcomes of patients with NDMM. This system helps discriminate patients with a good prognosis from those with a poor prognosis more precisely.
Abstract 9716: Association Between Baseline Health-Related Quality of Life and Subsequent Clinical Outcomes in Patients with Atrial Fibrillation
Authors: Nobuhiro Ikemura, John Spertus, Takehiro Kimura, Yoshinori Katsumata, Taishi Fujisawa, Ikuko Ueda, Kojiro Tanimoto, masahiro suzuki, Keiichi Fukuda, Seiji Takatsuki, Shun Kohsaka
Journal: Circulation (2021)

Introduction: Recent clinical practice guidelines emphasized the need to quantify patients’ symptoms, and health-related quality of life (HR-QoL) for patients with atrial fibrillation (AF). However, little is known about the associations between patients’ HR-QoL and subsequent clinical outcomes. Methods: We extracted data from a registry-based cohort study (KiCS-AF) designed to enroll consecutive AF patients referred to tertiary hospitals in Japan. Patients completed the Atrial Fibrillation Effects on QualiTy-of-Life (AFEQT) at referral. We investigated the association between the AFEQT-overall summary (AFEQT-OS; range 0-100, higher score indicates better HR-QoL) score and cumulative incidence of the composite of all-cause death, stroke, new-onset heart failure hospitalization, and acute coronary syndrome after 2 years of follow-up. Results: Among 3,313 AF patients (men 68.4%; age 67.8±11.6 years; 60.1% diagnosed ≤1 year before enrollment to the registry), 3,296 patients (99.4%) completed the AFEQT questionnaire at the time of registration. The mean AFEQT-OS score was 77.1±17.6, and 46.8% had AFEQT-OS &lt;80, which indicated impaired HR-QoL. Female sex, education level, higher heart rate, paroxysmal AF, history of congestive heart failure were independently associated with impaired HR-QoL at registration. After a 2-year follow-up (mean 675±143 days), the patients with impaired HR-QoL were more likely to experience the composite outcomes than those without (8.5% vs 5.8%, adjusted OR 1.32 [95%CI 1.01-1.74] P=0.040), and the differences were mainly driven by the incidence of new-onset heart failure hospitalization. Conclusion: In a Japanese, contemporary clinical practice cohort of unselected AF patients with newly diagnosis, almost half of the patients had impaired HR-QoL with worse clinical outcomes after 2-year. Factors associated with patients’ HR-QoL were multifocal and further investigations were needed to clarify the underlying mechanism.
Abstract 10301: Polygenic Risk Scores for Prediction of Atrial Fibrillation and Other Adverse Outcomes After Coronary Revascularization
Authors: Jenni Aittokallio, Anni Kauko, Felix Vaura, Veikko Salomaa, Tuomas Kiviniemi, Renate Schnabel, Teemu Niiranen
Journal: Circulation (2021)

Introduction: Both coronary heart disease and coronary procedures predispose patients to adverse events. To improve our understanding of the genetic factors underlying postoperative prognosis, we studied the association between polygenic risk scores (PRSs) and postprocedural complications in coronary revascularization patients. Hypothesis: We hypothesized that PRSs could improve risk prediction of postprocedural complications. Methods: The study sample comprised 8296, 6132, and 13082 participants of the FinnGen study who underwent percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or any revascularization, respectively. We genotyped the participants and identified adverse events during follow up of up to 30 years by record linkage with nationwide healthcare registers. We computed PRSs for each postoperative adverse outcome (atrial fibrillation [AF], myocardial infarction, stroke and bleeding complications) for all participants based on UK Biobank study GWAS summary statistics. We used multivariable-adjusted Cox proportional hazards models and c-statistics to examine the association between PRSs and outcomes. Results: A 1-SD increase in AF-PRS was associated with greater risk of postoperative AF with HRs of 1.22 (95% CI, 1.16-1.28), 1.15 (95% CI, 1.10-1.20) and 1.18 (95% CI, 1.14-1.22) after PCI, CABG, and any revascularization, respectively (Figure). In contrast, the association of the PRSs with other postoperative complications was non-existent to marginal. Inclusion of the AF-PRS in a model with a clinical risk score resulted in significant model fit improvement (increase in model c-statistic 0.0059-0.0098, depending on procedure type; P&lt;0.0002 for all). Conclusions: The AF-PRS could be potentially used to improve AF prevention and clinical outcomes in revascularization patients.
Abstract 11018: Prognosis Difference of Disproportional Mr According to Disease Etiology
Authors: Minjung Bak, Jihoon KIM, Sung-ji Park
Journal: Circulation (2021)

Introduction: After concept of disproportional MR (mitral regurgitation) is raised, investigators focused on whether disproportional MR could predict prognosis of secondary MR. But subgroup analysis of secondary MR according to etiology is limited until now. Hypothesis: We assessed the hypothesis that prognosis of disproportional MR is different according to etiology. Methods: We collected total 395 patients with severe secondary MR with reduced ejection fraction from January 2000 to October 2020 in one medical center, in South Korea. Only patients with DCMP (dilated cardiomyopathy) or ICMP (ischemic cardiomyopathy) were included. Criteria of disproportional MR was over 0.17 of RV (regurgitant volume)/EDV(end diastolic volume) in this study. We analyzed 1) the prognosis of disproportional MR according to etiologies and compared 2) predictive performance for mortality of disproportional MR with other MR measurements, RV and EROA (effective regurgitant orifice area), in each group. Results: In analysis based on etiology, disproportional group showed significantly higher all death risk (HR 10.08, 95% CI [1.237 - 82.07], p value = 0.031) in only DCMP group. There was no meaningful difference of mortality in ICMP group according to disproportionality (HR 1.265, 95% CI [0.556 - 2.882], p value = 0.575) (figure 1). When compare predictive performance of MR measurements for mortality, RV/EDV has highest value of C index than other methods in DCMP group and not in ICMP (figure 2). Conclusions: In conclusion, prognostic implication of disproportional MR was different according to disease etiology.
Impact of 2020 EUCAST criteria on meropenem prescription for the treatment of Pseudomonas aeruginosa infections: an observational study in a university hospital
Authors: Aline Munting, Jean Regina, José Damas, Loïc Lhopitallier, Antonios Kritikos, Benoît Guery, Laurence Senn, Benjamin Viala
Journal: Clinical Microbiology and Infection (2021)
EXTH-09. TUMOR PHARMACOKINETICS, PHARMACODYNAMICS AND RADIATION SENSITIZATION IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA TREATED WITH THE AURORA KINASE A INHIBITOR LY3295668
Authors: Shwetal Mehta, Artak Tovmasyan, An-Chi Tien, Michael Holter, Barbara Hopkins, Tigran Margaryan, Yu-Wei Chang, Sarah Himes, Mackenna Elliott, Ernesto Luna Melendez, Chelsea Pennington-Krygier, Connor White, Jennifer Molloy, Miao Liu, William Knight, Nader Sanai
Journal: Neuro-Oncology (2021)

Abstract Cell-cycle deregulation is at the crux of all malignancies, including glioblastoma (GBM). Aurora Kinase A (AURKA) plays a central role in G2/M transition and faithful chromosome segregation. In this study, we evaluated the pharmacokinetics, pharmacodynamics, and radiation sensitization properties of LY3295668, a highly specific AURKA inhibitor, in orthotopic patient-derived xenograft (PDX) models of GBM. Mice with intracranial tumors were randomized to 50 mg/kg LY3295668 PO BID x 4 days vs. placebo. LY3295668 levels in plasma and contrast-enhancing tumor tissue were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Unbound fractions were determined by equilibrium dialysis. Immunohistochemistry was performed to assess levels of pAURKA (T288), phospho-Histone H3 (pHH3), and cleaved caspase 3 (CC3). For survival studies, mice with intracranial tumors were randomized to four cohorts – vehicle, radiotherapy, LY3295668 monotherapy, and LY3295668 plus radiotherapy. The median unbound concentration of LY3295668 was 270.88 nmol/L and 22.33 nmol/kg in plasma and tumor tissue, respectively – significantly higher than the biochemical IC50 of LY3295668 for AURKA inhibition (0.8 nM). A decrease in pHH3(+) cells (0.8% vs. 6.4%, p=0.036) indicated drug-induced mitotic arrest and was accompanied by an increase in CC3(+) cells (6.4% vs. 8.0%, p=0.67). Combination of LY3295668 with radiotherapy prolonged survival compared to either therapy alone in orthotopic GBM PDX models. LY3295668 is well tolerated, achieves pharmacologically-relevant unbound concentrations in GBM PDX models, and is associated with significant target modulation. Preclinical combination of LY3295668 with radiation therapy leads to synergistic effects and supports future clinical study of this multimodal strategy in glioblastoma patients.
Third-Generation Chimeric Antigen Receptor (CAR) T Cells in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL) - Results from the Heidelberg Trial 1 (HD-CAR-1 trial)
Authors: Maria-Luisa Schubert, Anita Schmitt, Brigitte Neuber, Angela Hückelhoven-Krauss, Alexander Kunz, Lei Wang, Birgit Michels, Philip Waldhoff, Leopold Sellner, Felix Korell, Susanne Hofmann, Petra Pavel, Anthony D Ho, Carsten Müller-Tidow, Peter Dreger, Michael Schmitt
Journal: Blood (2021)
Novel Cytokine-Mediated Mechanism of Action Identified By Quantitative Seroproteomics in Multiple Myeloma Patients Treated with Tagraxofusp, a Novel CD123-Directed Targeted Therapy
Authors: Arghya Ray, Clifton C. Mo, Ting DU, Arturo Olguin, Janice Chen, Christopher L Brooks, Tariq I. Mughal, Paul G. Richardson, Dharminder Chauhan, Kenneth C. Anderson
Journal: Blood (2021)
Abstract 12552: Juxta-Purkinje Ventricular Myocytes Are the Cellular Trigger of Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Daniel Blackwell, Michela Faggioni, Wleklinski Matthew, Nieves Gomez-Hurtado, Raghav Venkataraman, Franz J Baudenbacher, Shiaoching Gong, Glenn I Fishman, Karl Pfeifer, Bjorn C Knollmann
Journal: Circulation (2021)

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmia syndrome caused by mutations that render intracellular calcium release channels hyperactive during adrenergic stress. Hyperactive calcium release has also been identified as a cause of ventricular arrhythmia in acquired heart diseases such as heart failure. What remains unknown is the cellular source of ventricular arrhythmia triggered by inappropriate calcium release – Purkinje cells in the cardiac conduction system or ventricular cardiomyocytes in the working myocardium. Methods: To investigate the cellular origin, we used a genetic approach in mice to knock out cardiac calsequestrin (Casq2) either in Purkinje cells or in ventricular cardiomyocytes (Panel A). Total loss of calsequestrin in the heart causes a severe CPVT phenotype in mice and humans. Immunostaining and western blotting were used to examine protein expression and arrhythmias were induced by administration of isoprenaline. Results: Loss of Casq2 only in ventricular myocytes produced a full-blown CPVT phenotype, whereas mice with loss of Casq2 only in Purkinje cells were comparable to wild-type mice (Panel B). Subendocardial chemical ablation or restoration of Casq2 expression in subendocardial cardiomyocytes neighboring Purkinje cells was sufficient to protect against catecholamine-induced arrhythmias (Panels C, D). Conclusion: Our data indicate that subendocardial ventricular myocytes juxtaposed to Purkinje fibers are the source of ventricular arrhythmias triggered by intracellular calcium release and hence identify a novel cellular target for arrhythmia prevention.
Role of asymptomatic and pre-symptomatic infections in covid-19 pandemic
Authors: Wenjing Gao, Jun Lv, Yuanjie Pang, Li-Ming Li
Journal: BMJ (2021)

Pre-symptomatic infection Pre-symptomatic cases are those in which infection is detected before the person develops symptoms.Pre-symptomatic transmission is defined as transmission that occurs during the pre-symptomatic phase of the viral incubation period. 3
Abstract 13605: Kidney Function, Body Mass Index and Bleeding Complications in Patients Undergoing Percutaneous Coronary Intervention: Obesity Paradox Redux?
Authors: Tia Bimal, Md Bhuiyan, Puneet Gandotra, Joanna Fishbein, Samy Selim, Lawrence Ong, Luis Gruberg
Journal: Circulation (2021)

Background: Low body mass index (BMI) patients (pts) undergoing percutaneous coronary intervention (PCI) are at the highest risk for in-hospital complications and cardiac death when compared to overweight or obese pts (“obesity paradox”). Likewise, chronic kidney disease (CKD) (eGFR &lt;60 mL/min/1.73m 2 ) pts are at a higher risk of adverse events following PCI. Aim: To assess the impact of BMI on bleeding complications in pts with and without CKD undergoing PCI. Methods: Between 12/2010 and 03/2018 a total of 4,400 CKD pts (eGFR &lt;60 mL/min) and 13,197 pts without CKD underwent PCI. Pts were divided into three groups: BMI &lt;24.9 (normal), BMI 25 to 29.9 (overweight), and BMI &gt;30 (obese). Bleeding complications were classified by the Bleeding Academic Research Consortium (BARC). BARC Type 4 (CABG-related) and Type 5 (fatal) bleeding events were excluded. Multiple logistic regression was utilized with p&lt;0.05 significance level. Results: Pts were 72% male, mean age 67 and 43% were diabetic. Both BMI category and CKD status were significantly associated with BARC score ≥3 in a multiple logistic regression model (p=0.004, and p&lt;0.0001, respectively). There was no evidence of an interaction between CKD status and BMI and the effect on BARC score (p= 0.08). Among those with CKD, BMI category failed to associate with BARC≥3 status (p=0.1), but among those without CKD, BMI category was significantly associated with BARC ≥3 status (p= 0.003), as shown in Figure. Multivariate logistic regression analysis will be presented. Conclusion: In pts undergoing PCI: 1) BMI and CKD status are associated with severe bleeding (BARC≥3) complications; 2) normal BMI, non-CKD patients had a significantly higher rate of severe bleeding complications when compared to overweight or obese patients; and 3) obese CKD patients had a lower rate of severe bleeding complications compared to normal BMI or overweight patients but did not achieve statistical significance.
Health-Service Systems in the United States and Other Countries — Critical Comparisons
Authors: Odin W. Anderson
Journal: New England Journal of Medicine (1963)

Methods of EvaluationIf there were agreed-on measures of efficiency and effectiveness of various health-service systems there would be little difficulty in deciding which one would provide the best service at the least cost to the most people and satisfy three important parties: the recipients of service; the providers of service; and those who must raise and allocate the money. Because hard-and-fast criteria are lacking, debates on public policy then become very opinionated. Differences of opinion are based on philosophic differences regarding the proper role of the government, nebulous concepts of adequate care, unmet need and many others.It seems, . . .
TAMI-13. MODULATION OF REDUCTIVE CARBOXYLATION FLUX OF GLUTAMINE IN GLIOBLASTOMA CELLS BY USING OSCILLATING MAGNETIC FIELD
Authors: Kumar Pichumani, Omkar Ijare, Shashank Hambarde, Martyn Sharpe, Blessy John, David Baskin, Santosh Helekar
Journal: Neuro-Oncology (2021)

Abstract Increased cell proliferation in glioblastoma (GBM) leads to hypoxia in the tumor microenvironment. This is a major concern in GBM patients as it promotes tumor invasion. Glutaminolysis is a hallmark of cancer cells and under hypoxic conditions glutamine metabolism proceeds through reductive carboxylation pathway. Recently, we have shown that oscillating magnetic field (OMF) produces oncolytic effects which can influence cellular metabolism. Here, we have explored the effect of OMF on glutamine metabolism in GBM cells. Patient-derived GBM cells were grown in high glucose (25 mM) DMEM supplemented with 20% fetal bovine serum (FBS), 2.0 mM glutamine and 1.0 mM pyruvate at 37 °C under humidified air and 5% CO2. Cells were divided into 2 groups (Test and Sham; n = 4 each group). When reached confluency (~2.0×106 cells/mL), cells in both groups were treated with 4.0 mM of [U-13C]glutamine in DMEM (supplemented with 20% FBS, and 1.0 mM pyruvate). The “Test” group was subjected to OMF for 3 hours, and the “Sham” group was treated similar to the “Test” group but with non-magnetic rods of the same dimensions as the magnets in the Test group. After 3 h, cells were harvested in 50% methanol analyzed by GC-MS. The 13C-isotopomer analysis showed that glutamine metabolism in GBM cells proceeds through reduction carboxylation, confirmed by the higher levels of M+5 citrate (15.42 ± 1.28 % ) than M+4 citrate (2.05 ± 0.28 %). When GBM cells were treated with OMF, a statistically significant decrease in the citrate M+5 was observed, compared to the “Sham” treated group (15.42 ± 1.28 % vs. 8.89 ± 1.30 %; p = 0.0003). This decrease in M+5 citrate upon OMF treatment clearly indicates that the OMF decreases the reductive carboxylation flux of glutamine in GBM cells which would have therapeutic value in treating GBM patients.
Abstract 13925: Non-Linear Modelling of Social Determinants of Health to Predict Cardiovascular Mortality Risk
Authors: Mauricio E Tano, Javier Valero Elizondo, Miguel Cainzos Achirica, Zulqarnain Javed, Bobak Mortazavi, Safi U Khan, Khurram Nasir
Journal: Circulation (2021)

Introduction: Community-level social determinants of health (SDOH) can facilitate the identification of vulnerable populations with poor health outcomes. Hypothesis: We assess whether machine learning methods utilizing area-level SDOH indicators can identify populations at higher risk for CV mortality. Methods: 144 SDOHs were extracted from the SDOH database compiled, at a county level, by the Agency for Healthcare Research and Quality between 2009-2018. The Person’s correlation coefficient between SDOH with CV mortality was used to select 12 key SDOH (p &lt; 0.05) and linear and nonlinear models were tested to build a predictive model for CVD mortality rates per 100,000 people for each county from SDOH. Datasets were randomly split in 80/20 for training and validation, and the accuracy of the models was compared in terms of mean relative error (MRE). Results: SDOH related to income (median household income), poverty (fraction population with a poverty ratio more than 2.00), and educational attainment (high school, BSc, MSc, doctorate) were the principal factors affecting CV mortality. Factors related to race/ethnicity, living conditions (children living with grandparents), and physical infrastructure (median household value and fraction of mobile homes) were also included in the model. The most performant regression method is the Bayesian optimized artificial neural network (Figure). The performance of linear models (linear elastic-networks, MRE = 17.6%; linear regression, MRE = 38.8%) was inferior to nonlinear models. Among nonlinear models, optimized Bayesian feedforward neural networks OBFNN presented the best performance (MRE = 9.7%). Conclusions: We developed a county-level risk score for cardiovascular mortality using 12 SDOH including demographics, income and poverty, education, and physical infrastructure. Future work should look at extending beyond CVD mortality and combining this SDOH-based score for patient-level cardiovascular risk.
Abstract 9894: Identifying Myocardial Infarction Using Clinical 12-Lead Electrocardiogram and Deep Learning
Authors: Ran Xiao, Fan Yang, Cheng Ding, Jessica K Zegre-hemsey, Xiao Hu
Journal: Circulation (2021)

Introduction: Early identification of myocardial infarction (MI) to activate rapid reperfusion therapies is linked to improved mortality and morbidity. Mounting evidence shows that electrocardiogram (ECG) markers are predictive of MI in the initial evaluation phase. Yet few studies have explored the feasibility of predictive modeling with deep learning, which has achieved promising performance in classifying cardiac arrhythmias. The pilot study aims to establish the baseline performance of deep learning in predicting MI. Methods: The PTB-XL database includes over 20K records of 10s 12-lead ECG and diagnostic annotations. ECGs with labels of normal sinus rhythm (9,528 records) and MI (5,486 records) were entered into the study. The dataset was first divided into development and test sets with an 80%-20% split. The development set was further split into training and validation sets following a five-fold cross-validation setup. The first 2.5s ECGs organized by the standard 12-lead ECG layout were converted into 2D image samples for model training. Two deep learning models, LeNet and a more complex ResNet, were adopted to probe the impact of model complexity on predicting MI. The area under the ROC curve (AUC) was selected to evaluate the model performance. Results: The AUCs were 93.45% ± 0.67% and 96.80% ± 0.50% (mean ± SD) achieved by the LeNet and ResNet models, respectively. Between the two, the ResNet outperformed the LeNet with statistical significance ( p&lt;0.05, Wilcoxon rank-sum test). Discussion: By leveraging an unprecedented large-scale MI database and deep learning, our study demonstrated the feasibility of predicting MI using just 2.5s of standard 12-lead ECG and established the baseline performance. Results further show the more complex model offers additional performance gain. Our next step will be to evaluate the derived model's generalizability on a locally collected ECG dataset towards evaluation in clinical settings.
Phase 1/2 Trial of IL7/IL15-Expanded Bispecific LV20.19 CAR T-Cells for Relapsed, Refractory B-Cell Non-Hodgkin Lymphoma
Authors: Nirav N. Shah, Joanna C. Zurko, Dina Schneider, Sharon Yim, Mehdi Hamadani, Timothy S. Fenske, Bryon Johnson, Parameswaran Hari
Journal: Blood (2021)