tbuckley/cabot-search huggingface dataset:
Abstract 13549: GP130 Signaling Promotes Right Ventricular Dysfunction in Pulmonary Arterial Hypertension via Microtubules
Authors: Sasha Z Prisco, Lynn Hartweck, Lauren Rose, Thenappan Thenappan, Kurt W Prins
Journal: Circulation (2020)

Introduction: Pulmonary arterial hypertension (PAH) is a lethal pulmonary arterial vasculopathy that results in right ventricle dysfunction (RVD). We showed that microtubule-mediated junctophilin-2 (MT-JPH2 pathway) downregulation promotes t-tubule disruption and RVD; however, the upstream regulators of this pathway are unknown. GP130 signaling via its downstream mediator, STAT3 promotes microtubule remodeling in neonatal cardiomyocytes. However, the relationship between GP130 signaling and the MT-JPH2 pathway in RVD are unknown. Methods: Immunoblots of RV extracts were probed for the GP130 and the MT-JPH2 pathways in MCT rats treated with a GP130 antagonist (2 weeks after MCT injection). Quantitative mass spectrometry analyzed the microtubule associated protein (MAP) fraction of RV extracts. Echocardiography and invasive closed-chest right heart catheterization quantified RV function and pulmonary vascular disease. Pulmonary vasculature remodeling was assessed by H&amp;E histology. Finally, the relationship between the GP130 agonist, interleukin (IL)-6, and RVD in PAH patients was examined. Results: GP130 antagonist treatment blunted RV STAT3 activation, normalized the MT-JPH2 pathway, and restored t-tubule architecture. Hierarchical cluster analysis and principal component analysis of 2842 proteins identified using mass spectrometry revealed normalization of the MAP-fraction with GP130 antagonist treatment. These molecular changes manifested as improved RV function, improved RV-pulmonary artery coupling, blunted RV hypertrophy, and improved survival despite no differences in pulmonary vascular disease severity. In PAH patients, higher IL-6 levels were associated with higher N-terminal pro-brain natriuretic peptide and lower RV fractional area change despite no differences in pulmonary vascular disease burden. Conclusions: Small molecular inhibition of GP130 enhances RV function, and improves survival in MCT PAH via modulation of the MT-JPH2 pathway.
Abstract 122: Effects of Early Administration of Argatroban on CPR Quality in Porcine Model of Prolonged Out-of-Hospital Cardiac Arrest
Authors: Jensyn J VanZalen, Annie G Phillips, Stephen L Harvey, Joseph E Hill, Olivia L Pak, Alyssa J Enciso, Megan A Mitchell, Joshua H Jung, Pavel Hala, Emre Gok, Robert H Bartlett, Alvaro Rojas-Peña, Robert W Neumar
Journal: Circulation (2020)

Background: The effectiveness of CPR declines over time during prolonged cardiac arrest (CA). Intravascular thrombosis may be a contributing factor. As part of a larger study examining antithrombotic therapy in a porcine model of prolonged CA, the impact of early administration of argatroban on CPR hemodynamics is reported. Hypothesis: Early administration of argatroban during CPR improves the quality of goal-directed CPR (gdCPR). Methods: In a blinded and randomized study, 48 swine (40±5kg) underwent an 8min untreated period of ventricular fibrillation CA followed by a gdCPR protocol for 30min (total arrest time 38min). Manual and mechanical chest compressions with the use of an impedance threshold device (ITD) were introduced to maintain end-tidal CO 2 (Et-CO 2 ) &gt;20mmHg. Argatroban (350mg/kg) or placebo (20mL NSS) were administered to respective groups (n=24 per group) 12mins after initiation of CA. Et-CO 2 , coronary perfusion pressure (CPP), end-diastolic pressure (EDP), and intracranial pressure (ICP) were monitored continuously. Averages were taken over the course of gdCPR for hemodynamic parameters. Arterial blood gases (ABGs) were obtained at the end of gdCPR. Analysis between groups was performed using an unpaired t-test (significance = p &lt;0.05). Results: Average hemodynamic parameters were not statistically different between argatroban vs. placebo groups (Et-CO 2 22.6±6.7 vs. 21.5±5.9 mmHg; EDP 25.6±10.7 vs. 23.7±9.6 mmHg; ICP 25.7±2.0 vs.20.9±2.7 cmH 2 O; CPP 8.7±11.2 vs. 7.0±11.2 mmHg). Final ABG values were also not statistically different between argatroban vs. placebo groups (pH 7.23±0.1 vs. 7.23±0.2; PaO 2 187.4±146.3 vs. 132.2±187.4 mmHg; PaCO 2 38.8±16.6 vs. 43.0±26.1 mmHg; lactate 8.5±1.7 vs. 8.8±1.4 mmol/L). Conclusion: These results demonstrate that early administration of argatroban during CPR did not have a significant effect on gdCPR quality in a porcine model of prolonged CA.
Ultra-short-course and intermittent TB47-containing oral regimens produce stable cure against Buruli ulcer in a murine model and prevent the emergence of resistance for Mycobacterium ulcerans
Authors: Yamin Gao, H.M. Adnan Hameed, Yang Liu, Lingmin Guo, Cuiting Fang, Xirong Tian, Zhiyong Liu, Shuai Wang, Zhili Lu, Md Mahmudul Islam, Tianyu Zhang
Journal: Acta Pharmaceutica Sinica B (2020)

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with rifampin–streptomycin or rifampin–clarithromycin daily for 8 weeks recommended by World Health Organization (WHO). These options are lengthy with severe side effects. A new anti-tuberculosis drug, TB47, targeting QcrB in cytochrome bc1:aa3 complex is being developed in China. TB47-containing regimens were evaluated in a well-established murine model using an autoluminescent M. ulcerans strain. High-level TB47-resistant spontaneous M. ulcerans mutants were selected and their qcrB genes were sequenced. The in vivo activities of TB47 against both low-level and high-level TB47-resistant mutants were tested in BU murine model. Here, we show that TB47-containing oral 3-drug regimens can completely cure BU in ≤2 weeks for daily use or in ≤3 weeks given twice per week (6 doses in total). All high-level TB47-resistant mutants could only be selected using the low-level mutants which were still sensitive to TB47 in mice. This is the first report of double mutations in QcrB in mycobacteria. In summary, TB47-containing regimens have promise to cure BU highly effectively and prevent the emergence of drug resistance. Novel QcrB mutations found here may guide the potential clinical molecular diagnosis of resistance and the discovery of new drugs against the high-level resistant mutants.
SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells
Authors: Sladjana Zagorac, Alex de Giorgio, Aleksandra Dabrowska, Mark Kalisz, Nuria Casas-Vila, Paul Cathcart, Angela Yiu, Silvia Ottaviani, Neta Degani, Ylenia Lombardo, Alistair Tweedie, Tracy Nissan, Keith W. Vance, Igor Ulitsky, Justin Stebbing, Leandro Castellano
Journal: Cancer Research (2020)

In many tumors, cells transition reversibly between slow-proliferating tumor-initiating cells (TIC) and their differentiated, faster-growing progeny. Yet, how transcriptional regulation of cell-cycle and self-renewal genes is orchestrated during these conversions remains unclear. In this study, we show that as breast TIC form, a decrease in cell-cycle gene expression and increase in self-renewal gene expression are coregulated by SOX2 and EZH2, which colocalize at CpG islands. This pattern was negatively controlled by a novel long noncoding RNA (lncRNA) that we named Stem Cell Inhibitory RNA Transcript (SCIRT), which was markedly upregulated in tumorspheres but colocalized with and counteracted EZH2 and SOX2 during cell-cycle and self-renewal regulation to restrain tumorigenesis. SCIRT specifically interacted with EZH2 to increase EZH2 affinity to FOXM1 without binding the latter. In this manner, SCIRT induced transcription at cell-cycle gene promoters by recruiting FOXM1 through EZH2 to antagonize EZH2-mediated effects at target genes. Conversely, on stemness genes, FOXM1 was absent and SCIRT antagonized EZH2 and SOX2 activity, balancing toward repression. These data suggest that the interaction of an lncRNA with EZH2 can alter the affinity of EZH2 for its protein-binding partners to regulate cancer cell state transitions. SIGNIFICANCE: These findings show that a novel lncRNA SCIRT counteracts breast tumorigenesis by opposing transcriptional networks associated with cell cycle and self-renewal.See related commentary by Pardini and Dragomir, p. 535.
Abstract 16723: A Machine Learning Approach to Acute Heart Failure Risk Stratification
Authors: Sina Ghandian, Samson Mataraso, Emily Pellegrini, Anna Lynn-Palevsky, Gina Barnes, Abigail Green Saxena, Jana Hoffman, Jacob Calvert, Ritankar Das
Journal: Circulation (2020)

Introduction: Acute heart failure (AHF) syndromes are associated with significant morbidity, mortality, and hemodynamic complications. Patients at risk of AHF are likely to experience rehospitalization or death post-discharge. AHF patient risk stratification remains an unmet need. Hypothesis: Gradient boosted machine learning can be used to predict likelihood of AHF diagnosis, enabling identification of at-risk patients. Methods: A gradient boosted machine learning algorithm was developed on retrospective data from 236,275 total emergency department patients, 807 of whom experienced AHF and were prescribed a vasodilator during their stay. A model was developed using age, sex, and six vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, peripheral oxygen saturation, and temperature). A second model used these demographics, vitals, and laboratory data (troponin, bicarbonate, and O2 saturation) as available to predict AHF diagnosis, as defined by ICD code and prescription of beta-blocker and angiotensin converting enzyme (ACE) inhibitor vasodilators. Model performance was assessed with regard to area under the receiver operating characteristic (AUROC). Results: The algorithm obtained AUROCs of 0.860 and 0.767 for prediction of AHF diagnosis and prescription of vasodilator at discharge with and without laboratory data, respectively (Figure 1). Predictions from the vitals only model were made an average of 38.5 hours prior to AHF diagnosis. Predictions from the model which included labs were made an average of 34 hours prior to AHF diagnosis. Conclusion: Machine learning is a useful method for predicting AHF diagnosis. Patient risk stratification enabled by the tool may serve to reduce duration of hospital stay for patients at low risk of developing AHF. Identification of high risk patient populations may also allow for earlier diagnosis and treatment, preventing development of chronic heart failure and other sequelae of AHF.
Abstract 16281: Non-calcified Coronary Plaque Burden is Related to Epicardial Adipose Tissue and Peri-coronary Adipose Tissue Attenuation in Heart Failure With Preserved Ejection Fraction
Authors: Haider Aldiwani, Janet Wei, Panteha Rezaeian, Alan C Kwan, Varun Pattisapu, Galen Cook-Wiens, Jenna Maughan, Chrisandra Shufelt, louise e thomson, balaji tamarappoo, Daniel Berman, Damini Dey, C. Noel Bairey Merz
Journal: Circulation (2020)

Introduction: Coronary inflammation may be a factor in developing heart failure with preserved ejection fraction (HFpEF). Epicardial fat volume (EFV) measured using non-contrast computed tomography (CT) and pericoronary adipose tissue (PCAT) attenuation on coronary CT angiography (CCTA) are considered to be inflammatory mediators, which play an important role in the development of coronary plaque. Hypothesis: We hypothesize that there is an interrelationship between these measures in HFpEF and no obstructive coronary artery disease (CAD). Methods: 28 subjects with HFpEF (European Society of Cardiology criteria), with coronary CCTA-documented absence of obstructive CAD. Non-calcified plaque (NCP), low-density non-calcified plaque (LDNCP), PCAT attenuation were quantified using semi-automated software and EFV was quantified using QFAT software. PCAT attenuation in Hounsfield Units (HU) was measured in a standardized 40 mm segment around the proximal right coronary artery. Statistical analysis was performed using Spearman correlation and multivariable regression models adjusted for age, BMI, EFV, and PCAT tested relations to NCP burden. Results: Overall, the mean age of 64.8±12 years, 74% women, BMI 29.3±4, total cholesterol 162±41mg/dl, LDL 85±29 mg/dl, HDL 55±14 mg/dl, systolic BP 132±22mmHg, diastolic BP 77±12mmHg, EFV 139±73 cm 3 and, PCAT attenuation -78±8 HU. Mean total NCP burden 34±13%, total LDNCP burden 3±1.8 %, and coronary calcium score (CCS) 414±920. EFV and PCAT attenuation correlated with the coronary risk markers including CCS and NCP burden variables (Table). In multivariable analysis, age and PCAT (β±SE=0.43±0.2, p=0.04, 0.64±0.3, p=0.03 per 1%-change in NCP burden respectively) were related to NCP burden. Conclusions: EFV and PCAT attenuation are associated with non-calcified plaque burden and may play an important role in the pathophysiological process of HFpEF. Further studies are needed to further understand these findings.
Abstract 12869: Association of Statin Therapy and Progression of Arterial Stiffness in the Multi-ethnic Study of Atherosclerosis
Authors: Anatoliy Nechyporenko, Yacob G Tedla, Claudia E Korcarz, Matthew C Tattersall, Philip Greenland, Adam D Gepner
Journal: Circulation (2020)

Background: Statin therapy may alter arterial stiffness by decreasing the low density lipoprotein cholesterol (LDL-C) content within blood vessel walls and reducing inflammation. Progression of arterial stiffness with prolonged statin treatment is not clear. Methods: The subset of MESA participants (n=1,225) with comprehensive data on statin use who underwent B-mode carotid ultrasound at baseline (visit 1) and after (mean ± SD) 9.3±0.7 years (visit 5) was analyzed. Arterial stiffness was measured using carotid distensibility coefficient (DC) and Young’s elastic modulus (YEM) at MESA exam 1 and 5. Linear regression models evaluated associations of ten-year change in DC and YEM with statin treatment duration and intensity during visits 1-4. Models were adjusted for age, sex, ethnicity, systolic blood pressure (SBP), diabetes status, alcohol use, smoking, and lipid profiles. Results: At baseline, participants were 66.5±8.1 years of age, 41% female, 36% Caucasian, 30% African American, 13.7% Asian American, and 20.0% Hispanic, with LDL-C of 149.5±14.5 mg/dL; DC was 2.88×10-3±1.28×10-3 mmHg-1, YEM was 1659±1056 mmHg. Participants not on statin therapy at any visit had greater baseline arterial stiffness measures compared to participants who were treated at all visits (YEM: 1,724 ±993 mmHg vs 1,457 ±776 mmHg; p=0.0003; DC: 2.72 ±1.22×10-3 mmHg-1 vs 3.22 ±1.33×10-3 mmHg-1; p&lt;0.0001). In unadjusted models, neither duration nor intensity of statin therapy was associated with changes in arterial stiffness measures over 10 years. Fully adjusted multivariable linear regression models showed associations with age and SBP but demonstrated no significant associations between DC and YEM and treatment duration or any statin intensity (table). Conclusions: Statin therapy was not associated with progression of carotid artery distensibility and elasticity over nearly a decade of follow up regardless of treatment duration or dose intensity.
Generating high-fidelity synthetic patient data for assessing machine learning healthcare software
Authors: Allan Tucker, Zhenchen Wang, Ylenia Rotalinti, Puja Myles
Journal: npj Digital Medicine (2020)

There is a growing demand for the uptake of modern artificial intelligence technologies within healthcare systems. Many of these technologies exploit historical patient health data to build powerful predictive models that can be used to improve diagnosis and understanding of disease. However, there are many issues concerning patient privacy that need to be accounted for in order to enable this data to be better harnessed by all sectors. One approach that could offer a method of circumventing privacy issues is the creation of realistic synthetic data sets that capture as many of the complexities of the original data set (distributions, non-linear relationships, and noise) but that does not actually include any real patient data. While previous research has explored models for generating synthetic data sets, here we explore the integration of resampling, probabilistic graphical modelling, latent variable identification, and outlier analysis for producing realistic synthetic data based on UK primary care patient data. In particular, we focus on handling missingness, complex interactions between variables, and the resulting sensitivity analysis statistics from machine learning classifiers, while quantifying the risks of patient re-identification from synthetic datapoints. We show that, through our approach of integrating outlier analysis with graphical modelling and resampling, we can achieve synthetic data sets that are not significantly different from original ground truth data in terms of feature distributions, feature dependencies, and sensitivity analysis statistics when inferring machine learning classifiers. What is more, the risk of generating synthetic data that is identical or very similar to real patients is shown to be low.
Abstract 15905: Monocyte Subsets Predict Mortality After Cardiac Arrest
Authors: Konstantin Krychtiuk, Max Lenz, Bernhard Richter, Philipp Hohensinner, Stefan Kastl, Andreas Mangold, Kurt Huber, Christian Hengstenberg, Johann Wojta, Heinz Gottfried, Walter S Speidl
Journal: Circulation (2020)

Background: After successful cardiopulmonary resuscitation (CPR) with return of spontaneous circulation (ROSC), many patients show signs of an overactive immune activation. Monocytes are a heterogeneous cell population that can be distinguished into three subsets. The aim of this prospective, observational study was to analyse whether monocyte subset distribution is associated with mortality at 6 months in patients after cardiac arrest (CA). Methods: We included 53 patients admitted to our medical intensive care unit (ICU) after CA. Blood was taken on admission and after 72 hours and monocyte subset distribution was analysed by flow cytometry and distinguished into classical monocytes (CD14++CD16-), intermediate monocytes (CD14++CD16+CCR2+) and non-classical monocytes (CD14+CD16++CCR2-). Results: Median age was 64.5 (interquartile range (IQR) 49.8-74.3) years and 75.5% were male. Six-month mortality was 50.9% and survival with good neurological outcome was 37.7%. Monocyte subset distribution upon admission to the ICU did not differ according to survival. However, patients who died within 6 months showed a more pronounced increase in the pro-inflammatory subset of intermediate monocytes (8.3% (3.8-14.6)% vs. 4.1% (1.5-8.2)%; p=0.025), and a decrease of classical monocytes (87.5% (79.9-89.0)% vs. 90.8% (85.9-92.7)%; p=0.036) 72 hours after admission. In addition, intermediate monocytes were predictive of outcome independent of time to ROSC and witnessed cardiac arrest, and correlated with the cerebral performance category (CPC)-score at 6 months (R=0.32; p=0.043). Discussion: Monocyte subset distribution is associated with outcome in patients surviving a CA. The activation of the innate immune system may play a significant role in CA patients.
Abstract 13604: Virulence of Staphylococcus Infection in Surgically Treated Patients With Endocarditis - A Multi-center Analysis
Authors: Maximilian Luehr, Carolyn Weber, Martin Misfeld, Artur LICHTENBERG, sems M tugtekin, Mahmoud Diab, Shekhar Saha, Yupeng Li, George Petrov, Klaus Matschke, Torsten Doenst, Michael A Borger, Thorsten Wahlers, Payam Akhyari, Christian Hagl
Journal: Circulation (2020)

Introduction: Infective endocarditis (IE) caused by Staphylococcus species have been noted to increase and are believed to be associated with higher morbidity and mortality rates. Hypothesis: Staphylococcus species are more virulent compared to other commonly causative bacteria of IE. Methods: The database of the Clinical Multicenter Project for Analysis of Infective Endocarditis in Germany (CAMPAIGN), comprising 4917 consecutive patients (mean age 62.2±14.6 years) undergoing heart valve surgery, was retrospectively analyzed. Uni- and multivariable regression analyses were used for comparison and risk stratification. The Kaplan Meier method was used for long-term survival estimation of the respective groups. Results: Staphylococcus patients (n=1260) were significantly more morbid than the Non-Staphylocccus group (n=3657) with regard to NYHA IV (21.4% vs. 16.7%*), CAD (29.0% vs. 25.7%; p =0.027), arterial hypertension (64.8% vs. 45.8%*), diabetes (29.9% vs. 24.8%*), renal failure (47.5% vs. 35.2%*), COPD (12.8% vs. 9.9%; p =0.007), PAD (11.3% vs. 6.4%*), preoperative stroke (35.1% vs. 18.0%*) and need for mechanical ventilation (18.2% vs. 6.4%*). Overall, Staphylococcus infections were more prevalent on mitral (51.0% vs. 42.0%*) and tricuspid (9.4% vs. 4.4%*) valves and showed higher incidences of large vegetations (87.0% vs. 56.0%*), mitral regurgitation (62.5% vs. 41.5%*) and preoperative septic embolism (51.8% vs. 28.9%*). Postoperatively, need for tracheostomy (13.7% vs. 7.6%*) and dialysis (29.4% vs. 13.6%*) were also significantly increased. The 30-day mortality for Staphylococcus was significantly higher (21.3% vs. 15.9%*) and long-term survival was significantly worse ( Fig. 1 ). Conclusions: Staphylococcus endocarditis is associated with significantly worse outcome compared to IE by other commonly causative bacteria. Early surgery should be considered to avoid preoperative septic embolism, deterioration and death. *= p &lt;0.0001
Abstract 200: Discordance Between Monitor-measured and EMS Documented Respiratory Rates in Major Traumatic Brain Injury: Implications for Injury Scoring Systems
Authors: Bruce J Barnhart, Daniel W Spaite, Eric Helfenbein, Dawn Jorgenson, Saeed Babaeizadeh, Joshua B Gaither, Amber D Rice, Samuel M Keim, Gail Bradley, Chengcheng Hu
Journal: Circulation (2020)

Background: Respiratory rate (RR) is a key component in commonly-used trauma scoring systems [e.g., Revised Trauma Score (RTS), TRISS]. Imprecise documentation of RR introduces misclassification when these tools are used in trauma research. By identifying each waveform, nasal cannula end tidal CO2 (NCCO2) accurately measures RR in non-intubated patients. Objective: Evaluate the relationship between EMS-documented RR measurements in patient care records (PCRs) vs. true RR recorded by non-invasive NCCO2 monitoring in major TBI patients who were never actively ventilated. Methods: Among spontaneously-breathing, major TBI cases (moderate/severe/critical), continuous NCCO2 data (Philips MRx™) were evaluated from the EPIC Prehospital TBI Study (NIH 1R01NS071049). RR classifications for RTS/TRISS were then established for each case using both PCR-documentation and monitor data. Routine monitor data (including RR) were available to EMS providers on the display at all times during care. Results: Included: 158 cases from 7 Arizona EMS agencies [(7/13-7/17; median age 55 (range 18-94); 65% male]. The Table shows RTS/TRISS case classification by PCR and monitor RR. PCR-documented RR frequently failed to correctly classify cases: RR &lt;6 (0/10; 0%); 6-9 (3/21; 14.3%; &gt;29: (11/34, 32.4%), normal (67/93, 72.0%; Table). In total, PCR documentation misclassified 48.7% of cases (77/158). Conclusion: These findings identify a major contributor to inaccurate trauma scoring. Since RTS and TRISS are used widely in research, this has important implications for study enrollment, case ascertainment, confounding, and risk-adjustment in injury studies. Whenever possible, QI and research studies should utilize monitor data to identify and evaluate RR and other vitals rather than relying on PCR documentation. Future development of monitor-based, real-time feedback technology might improve trauma scoring precision and provider identification of RR abnormalities.