tbuckley/cabot-search huggingface dataset:
Abstract 16309: Age Specific Baseline Predictors of All-cause Mortality in Systolic Blood Pressure Intervention Trial (SPRINT) Identified by Machine Learning
Authors: Nuha Gani, Anwar Husain, Gauri Dandi, Ian Atkinson, Zyannah Mallick, Avantika Banerjee, Victoria Xin, Scout Hayashi, Natalie Lewis, Nayab Mahmood, Noah Hasan, Khizar Qureshi, Amit Dey, Yves D Rosenberg, Ahmed A Hasan
Journal: Circulation (2020)

Introduction: The NHLBI supported Systolic Blood Pressure (SBP) Intervention Trial (SPRINT) (NCT01206062) aimed to identify an SBP target to reduce incidence of cardiovascular (CV) morbidity and mortality in hypertensive, non-diabetic patients of age ≥ 50 at increased CV risk. It found that intensive treatment (SBP target &lt;120 mmHg) led to fewer major CV events and death but higher rates of adverse events. We reused publicly available patient-level SPRINT data from NHLBI Data Repository (BioLINCC) to perform hypothesis-generating secondary analyses by machine learning (ML) using random survival forest (RSF), to identify age specific baseline (bl) predictors for all-cause mortality (ACM). Methods: RSF was performed on 30 bl variables from 9361 patients in age group specific cohorts (50-59, 60-69, 70-79, 80-90). The identified top 10 predictors from each cohort were included in a multivariate analysis using a Cox proportional hazards model. Results: The top 10 predictors of ACM for age specific subgroups are shown in Figure 1. As expected, cardiovascular disease (CVD) predictors were selected, yet RSF distinctively identified renal biomarkers as important predictors, consistent with our previous analyses. Smoking status and history of CVD ranked as top predictors among age groups 50-59, 60-69, and 70-79. RSF also identified social factors, including race among age groups 60-69 and 80-90 and female gender among age groups 50-59 and 80-90 as important predictors for ACM. Lipid markers and medications used also showed up as top predictors. Specifically, polypharmacy emerged as a top predictor in age groups 60-69, 70-79, and 80-90, notably ranking higher in the 80-90 age group. Conclusions: Using ML, we uncovered in an unbiased fashion, unanticipated age specific top predictors for ACM in SPRINT trial. This highlights the value of ML for analyzing disease and therapeutic intervention outcomes and age specific prognostic factors to advance precision medicine.
Abstract 14968: Geographic Variation in the Early Diffusion and of Sacubitril/Valsartan
Authors: Ashleigh King, Andrea Austin, Stephanie Tomlin, Lauren Gilstrap
Journal: Circulation (2020)

Introduction: In the PARADIGM-HF trial, sacubitril/valsartan demonstrated a 20% reduction in mortality and heart failure (HF) hospitalization compared to enalapril. Despite this success, diffusion has been slower than anticipated. To date, high co-payments have been identified as a key barrier. The aim of this study is to examine the role of geographic prescribing patterns in the early diffusion of sacubitril/valsartan, after controlling for cost. Hypothesis: There will be significant geographic variation in the use of sacubitril/valsartan, after controlling for cost. Methods: We used 100% Medicare Parts A and B and a random 40% sample of Part D to create a cohort of beneficiaries with heart failure with reduced ejection fraction (HFrEF) between 2016 and 2018. We calculated age, sex, race adjusted rates of sacubitril/valsartan use by hospital referral region (HRR) and used multivariable logistic regression to determine the association between geographic region and sacubitril/valsartan use, controlling for cost. Results: Early use rates of sacubitril/valsartan have been low: 1.9% in 2016, 3.3% in 2017 and 4% in 2018. There has been substantial geographic variation with most concentrated in the South and Northeast ( Figure ). After controlling for cost, HFrEF patients in the Northeast were 1.32 times (95% CI 1.26-1.29, p&lt;0.001)) more likely, those in the South were 1.24 times more likely (95% CI 1.20-1.29, p&lt;0.001)) and those in the West were 1.10 times more likely (95% CI 1.05-1.15, p&lt;0.001) to receive sacubitril/valsartan compared to HFrEF patients in the Midwest. Conclusions: There has been substantial variation in the early diffusion of sacubitril/valsartan. In addition to cost, geographic prescribing patterns play a major role in early drug diffusion.
The Impact of Bariatric Surgery on Incident Microvascular Complications in Patients With Type 2 Diabetes: A Matched Controlled Population-Based Retrospective Cohort Study
Authors: Pushpa Singh, Nicola Adderley, Anuradhaa Subramanian, Krishna Gokhale, Rishi Singhal, Konstantinos A. Toulis, Srikanth Bellary, Krishnarajah Nirantharakumar, Abd A. Tahrani
Journal: Diabetes Care (2020)

To assess the impact of bariatric surgery (BS) on incident microvascular complications of diabetes-related foot disease (DFD), sight-threatening diabetic retinopathy (STDR), and chronic kidney disease (CKD) in patients with type 2 diabetes and obesity.
Competition for Active TGFβ Cytokine Allows for Selective Retention of Antigen-Specific Tissue- Resident Memory T Cells in the Epidermal Niche
Authors: Toshiro Hirai, Yi Yang, Yukari Zenke, Haiyue Li, Virendra K. Chaudhri, Jacinto S. De La Cruz Diaz, Paul Yifan Zhou, Breanna Anh-Thu Nguyen, Laurent Bartholin, Creg J. Workman, David W. Griggs, Dario A.A. Vignali, Harinder Singh, David Masopust, Daniel H. Kaplan
Journal: Immunity (2020)
Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization
Authors: Kazuma Oyama, Remo H.M. Furtado, Antonio Fagundes, Thomas A. Zelniker, Minao Tang, Julia Kuder, Sabina A. Murphy, Andrew Hamer, Huei Wang, Anthony C. Keech, Robert P. Giugliano, Marc S. Sabatine, Brian A. Bergmark
Journal: Journal of the American College of Cardiology (2020)
Abstract 292: Detection of Return of Spontaneous Circulation in Pseudo-Pulseless Electrical Activity Using Trans-thoracic and Trans-abdominal Bioimpedance
Authors: William J Hunckler, Alexander L Lindqwister, Ethan K Murphy, Samuel B Klein, Karen L Moodie, Alexandra P Hamlin, Justin E Anderson, Joseph M Minichiello, Norman A Paradis
Journal: Circulation (2020)

Introduction: Pseudo-Pulseless Electrical Activity (p-PEA) is a lifeless form of profound cardiac shock characterized by measurable cardiac mechanical activity without clinically detectable pulses. Patients in pseudo-PEA carry different prognoses than those in true PEA and may require different therapies. Noninvasive technologies capable of detecting return of spontaneous circulation (ROSC) are needed to guide transition therapy from ACLS to critical care. Electrical impedance (EI) measurements across the thorax and abdomen may reflect the state of the cardiovascular system and change with ROSC. Hypothesis: EI measured across the chest wall or abdomen can detect ROSC in p-PEA. Methods: Female swine (N = 14) under intravenous anesthesia were instrumented with aortic and central venous micromanometer catheters. EI was measured with cutaneous belts around the chest and abdomen (Swisstom). p-PEA was induced by ventilation with 6% oxygen in 94% nitrogen and was defined as a systolic aortic pressure &lt; 40 mmHg. Experiments in which ROSC occurred within 20 seconds of starting 100% FiO 2 were studied. EI waveforms were analyzed with fast fourier transforms, and the dominant frequencies of p-PEA and ROSC signals were subtracted to create a difference distribution. Results: With onset of ROSC, there was a characteristic frequency increase in EI measurable across both chest and abdominal bands. Fourier transform analysis demonstrated a significant difference in dominant frequencies between resuscitation and p-PEA. The median difference between resuscitation and p-PEA dominant frequencies were 5.49 in the thorax [95% CI 3.48 - 7.50] and 6.65 in the abdomen [95% CI 3.63 - 9.67]. Conclusions: There appear to be characteristic EI frequency patterns and changes in p-PEA and ROSC. If confirmed clinically, this indicates that EI may be a promising technology for non-invasive monitoring in cardiac arrest.
Abstract 13035: Beta3-Adrenergic-Receptor-Deficient Mice Protected From Diabetic Cardiomyopathy in Type 2 Diabetic Murine Model: Beneficial Effects on Cardiomyocyte Contractile Function, [Ca <sup>2+</sup> ] <sub>i</sub> Regulation and Beta-Adrenergic Modulation
Authors: Xiaoqiang Sun, Jing Cao, Heng-Jie Cheng, Yixi Liu, Zhe Chen, Donald A McClain, Dalane Kitzman, David Zhao, Che Cheng
Journal: Circulation (2020)

Background: Diabetic cardiomyopathy (DCM) is the main cause of increased mortality in Diabetes mellitus (DM). There are no effective therapeutic strategies. Recently, we found that DM is associated with the upregulation of β 3 adrenergic receptor (AR) mediated cardiac inhibitory pathway. This suggests cardiac β 3 -AR activation may contribute to DCM progression and be a therapeutic target. We hypothesize that upregulation of β 3 -AR is maladaptive, and DM-caused progressive decline in cardiac function and β-adrenergic reserve will be prevented in β 3 -AR knockout (β 3 KO) mice. Methods: Studies were conducted in female mice of 2 Vehicle controls groups (n=8/group) of wild-type (CWT) and Cβ 3 KO, and 2 Type 2 DM (T2) of T2WT (n=8) and T2β 3 KO (n=6).T2 was induced by fed high-fat diet (HFD) for 14 weeks (W), but after HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. for 5 days). We compared LV myocyte contractile and [Ca 2+ ] iT responses to β-AR subtype stimulation by random exposure of myocytes to the superfusion of isoproterenol (ISO,10 -8 M) or a selective β 1 -, or β 3 -agonist, Norepinephrine (NE, 10 -7 M), and BRL-37,344 (BRL, 10 -8 M), respectively. Results: Mice received HFD plus STZ developed T2DM with elevated mean blood glucose from 128 mg/dl of control to 388 mg/dl and 382 mg/dl in T2WT and T2β 3 KO, respectively. However only T2WT mice developed DCM followed by significant decreases in myocyte contraction (dL/dt max , T2WT: 74.8 vs CWT:140.1 μm/s), relaxation (dR/dt max , 58.0 vs 117.9 μm/s) and [Ca 2+ ] iT (0.16 vs 0.22). ISO-stimulated increases in dL/dt max (37% vs 58%), dR/dt max (30% vs 53%), and [Ca 2+ ] iT (19% vs 30%) were attenuated accompanied by a diminished NE-caused increase in dL/dt max (28% vs 41%), but enhanced BRL-induced decrease in dL/dt max (29% vs 15%). By contrary, T2β 3 KO showed normal basal dL/dt max (137.6 μm/s), dR/dt max (111.4 μm/s) and [Ca 2+ ] iT (0.22). Importantly, T2β 3 KO myocytes showed preserved ISO-stimulated increases in dL/dt max (60%), dR/dt max (51%) and [Ca 2+ ] iT (32%) and restored normal dL/dt max responses to NE (41%). Conclusions: β 3 KO prevents T2DM-caused contrast changes in β 1 - and β 3 -AR-stimulated cardiac inotropic actions and leading to the preservation of normal myocyte function, [Ca 2+ ] iT , and β-AR responsiveness in DCM.
Intracellular Vitamin A-Binding Proteins
Authors: F Chytil, D E Ong
Journal: Annual Review of Nutrition (1987)

INTRODUCTION   321 CELLULAR RETINOL-BINDING PROTEIN  322 Detection and Quantitation     322 Physiochemical and Spectral Properties   323 Tissue and Cellular Distribution    324 Putative Functions  325 CELLULAR RETINOIC ACID-BINDING PROTEIN  328 Detection and Quantitation     328 Physiochemical and Spectral Properties   328 Tissue and Cellular Distribution    329 Putative Functions  329 CELLULAR RETINOL-BINDING PROTEIN TYPE II  330 Detection and Quantitation ....   ........ . . .     330 Physiochemical and Spectral Properties   330 Tissue and Cellular Distribution  33 I Putative Functions  331 RELATEDNESS OF INTRACELLULAR VITAMIN A-BINDING PROTEINS ........ 332
Abstract PO-052: Determining the role of Apolipoprotein E in pancreatic cancer immune suppression
Authors: Samantha B. Kemp, Nina G. Steele, Fatima Lima, Carlos Espinoza, Yaqing Zhang, Zeribe Nwosu, Eileen S. Carpenter, Meggie Hoffman, Amanda Pacheco, Ashley Velez-Delgado, Stephanie The, Howard C. Crawford, Marina Pasca di Magliano
Journal: Cancer Research (2020)

Pancreatic cancer (PDA) is a lethal malignancy with a 5-year survival rate of about 10%. The poor prognosis is, in part, due to patients most often presenting with already metastatic disease. PDA is characterized by an abundant, fibroinflammatory stroma, that contains abundant cancer-associated fibroblasts and infiltrating immune cells. Myeloid cells such as tumor-associated macrophages (TAMs) are abundant within the stroma and a key driver of immunosuppression. We and others have identified elevated expression of Apolipoprotein E (ApoE) in a subset of TAMs. Further, using single cell sequencing of human tumor samples as well as mouse tumors, we determined that ApoE expression is elevated in tumor macrophages compared to macrophages in the normal pancreas. ApoE has been well studied in various biological processes, but its role in pancreatic cancer has not been determined. In this study, we sought to determine whether ApoE had a functional role within the pancreatic cancer microenvironment. Based on observations in other systems, we hypothesized that it might be a mediator of immune suppression in pancreatic cancer. We thus implanted mouse pancreatic cancer cell lines in syngeneic wild type C57/BL6 mice or in ApoE-/- mice. We did not observe a change in tumor growth in ApoE-/- mice compared to control. However, histological and Mass Cytometry (CyTOF) analysis revealed changes in the tumor microenvironment in ApoE-/- mice. Tumors from ApoE-/- mice had fewer aSMA+ fibroblasts, and subsequently less collagen deposition. In addition, CyTOF analysis revealed an increase in CD8+ T cell and CD4+ T cell infiltration, along with a decrease in regulatory T cells. Tumors harvested from ApoE-/- mice had lower levels of both Tgfb1 and Cxcl1. Further analysis in vitro, revealed ApoE secreted from tumor-associated macrophages regulates tumor-cell derived Tgfb1 and Cxcl1. Cxcl1 in turns inhibits T cell infiltration in tumors. We are currently conducting mechanistic studies to determine the mediators of the cytokine-regulatory effects of ApoE in cancer cells. Further, we are exploring whether ApoE loss sensitizes tumors in vivo to immunoregulatory agents.Citation Format: Samantha B. Kemp, Nina G. Steele, Fatima Lima, Carlos Espinoza, Yaqing Zhang, Zeribe Nwosu, Eileen S. Carpenter, Meggie Hoffman, Amanda Pacheco, Ashley Velez-Delgado, Stephanie The, Howard C. Crawford, Marina Pasca di Magliano. Determining the role of Apolipoprotein E in pancreatic cancer immune suppression [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-052.
Abstract 14578: Transcatheter Aortic Valve Replacement for Symptomatic Severe Aortic Stenosis in Rheumatic Heart Disease: Analysis of the National Inpatient Sample Database (2012-2017)
Authors: Jelani Grant, Bertrand Ebner, Jennifer Maning, Louis Vincent, Amanda Fernandes, neal olarte, Odunayo P Olorunfemi, Rhanderson Cardoso, Rosario A Colombo, Carlos Alfonso
Journal: Circulation (2020)

Introduction: TAVR is widely accepted for the management of symptomatic severe aortic stenosis (AS), but its use in rheumatic heart disease has been limited. We sought to investigate the in-hospital outcomes of patients undergoing TAVR for symptomatic severe rheumatic AS. Methods: This is a retrospective NIS Database search from 2012 to 2017 to identify patients with ICD-9 and10 procedure codes for TAVR and for rheumatic AS. We compared baseline characteristics, procedure characteristics, in-hospital mortality and length of hospitalization based on the presence or absence of rheumatic AS. Results: From a total of 32,273 patients who underwent TAVR, the incidence of non-rheumatic severe AS was 6.54%. Baseline characteristics are displayed in Table 1. All-cause mortality was similar between both groups (2.3% vs. 2.4%, p=0.780) but length of stay (days) was significantly higher in the rheumatic AS group (6.1 ± 7 vs. 5.8 ± 6.4, p&lt;0.001). Rates of Paravalvular Leak (1.1% vs. 0.7%, p&lt;0.05) and post-procedure ischemic stroke (5.3 vs. 2.0%, p&lt;0.001) were higher in patients with non-rheumatic AS. Using a multivariate logistic regression model, this cohort did not reveal increased odds of in hospital mortality based on the presence of severe rheumatic AS after adjusting for confounders (OR-0.97, 95% CI 0.69 to 1.37, p=0.867). Conclusions: This retrospective cohort demonstrated that TAVR may be feasible for rheumatic severe AS. Despite an older population than reported in the literature, mortality rates, complications and hospital length of stay was comparable to patients undergoing TAVR for calcific aortic disease. Further randomized studies are needed to support these findings.
‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19
Authors: Swapna Mandal, Joseph Barnett, Simon E Brill, Jeremy S Brown, Emma K Denneny, Samanjit S Hare, Melissa Heightman, Toby E Hillman, Joseph Jacob, Hannah C Jarvis, Marc C I Lipman, Sindhu B Naidu, Arjun Nair, Joanna C Porter, Gillian S Tomlinson, John R Hurst
Journal: Thorax (2020)

Large numbers of people are being discharged from hospital following COVID-19 without assessment of recovery. In 384 patients (mean age 59.9 years; 62% male) followed a median 54 days post discharge, 53% reported persistent breathlessness, 34% cough and 69% fatigue. 14.6% had depression. In those discharged with elevated biomarkers, 30.1% and 9.5% had persistently elevated d-dimer and C reactive protein, respectively. 38% of chest radiographs remained abnormal with 9% deteriorating. Systematic follow-up after hospitalisation with COVID-19 identifies the trajectory of physical and psychological symptom burden, recovery of blood biomarkers and imaging which could be used to inform the need for rehabilitation and/or further investigation.
Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1-positive pediatric leukemia identifies drug-targetable transcription factor activities
Authors: Juha Mehtonen, Susanna Teppo, Mari Lahnalampi, Aleksi Kokko, Riina Kaukonen, Laura Oksa, Maria Bouvy-Liivrand, Alena Malyukova, Artturi Mäkinen, Saara Laukkanen, Petri I. Mäkinen, Samuli Rounioja, Pekka Ruusuvuori, Olle Sangfelt, Riikka Lund, Tapio Lönnberg, Olli Lohi, Merja Heinäniemi
Journal: Genome Medicine (2020)

Tight regulatory loops orchestrate commitment to B cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention. We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNA-sequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bone marrow lymphoid cell states. We compared these to ALL bone marrow at diagnosis and in vivo during chemotherapy, focusing on leukemias carrying the ETV6-RUNX1 fusion. We show that lymphoid cell transcription factor activities uncovered from bone marrow scRNA-seq have high correspondence with independent ATAC- and ChIP-seq data. Using this comprehensive reference for regulatory factors coordinating B-lineage differentiation, our analysis of ETV6-RUNX1-positive ALL cases revealed elevated activity of multiple ETS-transcription factors in leukemic cells states, including the leukemia genome-wide association study hit ELK3. The accompanying gene expression changes associated with natural killer cell inactivation and depletion in the leukemic immune microenvironment. Moreover, our results suggest that the abundance of G1 cell cycle state at diagnosis and lack of differentiation-associated regulatory network changes during induction chemotherapy represent features of chemoresistance. To target the leukemic regulatory program and thereby overcome treatment resistance, we show that inhibition of ETS-transcription factors reduced cell viability and resolved pathways contributing to this using scRNA-seq. Our data provide a detailed picture of the transcription factor activities characterizing both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia.
SAT0022 Successful treatment of patients with severe undifferentiated spondyloarthropathy with the anti-tnfa antibody infliximab
Authors: J Brandt, H Haibel, J Sieper, J Braun
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Anti-TNFa therapy has been successfully used in patients with active ankylosing spondylitis (AS;A&amp;R June 2000). Whether this treatment is also efficacious in patients with undifferentiated spondyloarthropathies (uSpA), the second most frequent SpA subset, has not been assessed to date. <h3>Objectives</h3> To test the efficacy of the monoclonal anti-TNFa antibody infliximab in patients with severe uSpA. <h3>Methods</h3> Six uSpA patients (4 male, 2 female) with a median age of 36 years (range 19–49) were diagnosed according to the 1991 ESSG criteria. The median disease duration was 6.2 years (1.2–35 years). They had been refractory to other therapies including NSAIDs, steroids and sulfasalazine and were treated with infliximab in an open observational way at week 0, 2 and 6 and followed up for 12 weeks. Three patients received infliximab in a dosage of 3 mg/kg and the other three received 5 mg/kg. The leading clinical symptoms were peripheral arthritis (n = 6), inflammatory back pain (n = 6) and enthesitis of the heels (n = 4). HLA B27 was positive in 5/6 patients. No patient had sacroiliitis &gt; grade II unilateral. The Bath AS disease activity index (BASDAI), the functional index (BASFI), pain on a visual analogue scale (VAS), and the Bath AS Metrology Index (BASMI) were assessed before, during and after therapy. Quality of life was measured using the Short Form (SF) 36 instrument. <h3>Results</h3> All patients improved after 1–3 days. There was a more substantial response in the group treated with 5 mg/kg infliximab then in the 3 mg/kg group. The range of the BASDAI in the 5 mg/kg group was 7.0 -7.6 (3 mg/kg-group: 7.7–8.6) before and 6 weeks after the third infusion 0.7–2.7 (3 mg/kg-group: 1.7–7.8). The functional index also improved in all but one patient: the BASFI values had decreased from 7.0–7.6 in the 5 mg/kg group (3 mg/kg-group: 6.7–8.5) to 0.8–2.7 (3 mg/kg-group: 0.8–8.4). Pain on a VAS improved in the 5 mg/kg group from 7.1–7.7 (3 mg/kg-group: 5.1–9.0) to 0.8–2.6 (3 mg/kg-group: 1.2–8.1). Joints, entheses and spinal symptoms improved equally. CRP levels dropped from &lt;6.0–120 mg/l before therapy to &lt;6.0–15.6 mg/l at week 12. No side effects occurred. There was improvement in all 8 SF-36 concepts assessed at baseline and at week 12; the improvement was significant for the concepts bodily pain and vitality. <h3>Conclusion</h3> These data suggest that anti-TNFa therapy has significant short-term efficacy in severe uSpA. Infusions with 5 mg/kg infliximab might be more effective than 3 mg/kg in SpA patients. Since it is known that 30–50% of uSpA patients develop AS over time it seems worthwhile to study whether this can be prevented by anti-TNFa therapy.