tbuckley/cabot-search huggingface dataset:
Abstract 9869: Validation of a Claims-Based Prediction Rule for In-Hospital Pulmonary Embolism Mortality
Authors: Christine G Kohn, W F Peacock, Gregory J Fermann, Thomas J Bunz, Concetta Crivera, Jeffrey R Schein, Craig I Coleman
Journal: Circulation (2015)

Background: Guidelines suggest that a low risk cohort of patients with pulmonary embolism (PE) may be managed as outpatients or with an abbreviated hospital stay. There is need for a claims-based prediction rule that payers and hospitals can use to efficiently risk stratify PE patients. The authors recently derived a rule found to have high sensitivity and moderate specificity for predicting in-hospital mortality. Objective: To validate the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) prediction rule using admission claims data. Methods: This analysis was performed using Humana admission claims data from January 2007-March 2014, and included adult patients admitted for their first PE (International Classification of Diseases, ninth edition, Clinical Modification code of 415.1x in in the primary position or secondary position when accompanied by a primary code for a PE complication). The IMPACT rule, consists of age + 11 weighted comorbidities (myocardial infarction, chronic lung disease, stroke, prior major bleeding, atrial fibrillation, cognitive impairment, heart failure, renal failure, liver disease, coagulopathy, cancer), and was used to estimate patients’ risk of in-hospital mortality. Low risk was defined as in-hospital mortality ≤1.5%. IMPACT results are presented as prognostic test characteristic values and 95% confidence intervals (CIs). Results: A total of 23,858 patients (47% male, 77% ≥65 years of age) hospitalized for PE were included and 3.3% died in-hospital. The IMPACT prediction rule classified 2,371 (9.9%) as low-risk (0.8% died); with a sensitivity of 97.6% (95%CI=96.1-98.5), specificity of 10.2% (95%CI=9.8-10.6), and C-statistic of 0.70 (95%CI=0.0.68-0.72), for in-hospital mortality. IMPACT classified 42.7% of patients &lt;65 years old as low-risk; with a sensitivity, specificity and C-statistic of 85.0% (95%CI=77.4-90.5), 43.3% (95%CI=42.0-44.7) and 0.74 (95%CI=0.0.69-0.78), respectively. Conclusion: The IMPACT prediction rule was valid when implemented in a database consisting largely of Medicare claims. The rule has high sensitivity for predicting in-hospital mortality, and may be valuable for identifying PE patients that are candidates for an abbreviated hospital admission.
PB2145 POMALIDOMIDE AND DEXAMETHASONE IN RELAPSING POEMS SYNDROME: A FRENCH REPORT OF 5 CASES
Authors: C. Golfier, S. Chaubard, D. Sciortino, G. Salles, S. Viel, L. Garnier, A. Lazareth, L. Karlin, A. Jaccard
Journal: HemaSphere (2019)

Background: Significant improvements have been made in the management of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammapathy and skin changes) syndrome, but patients (pts) still experience relapses or refractoriness. Immunomodulatory drugs are effective agents in the treatment of plasma cells dyscrasias. Lenalidomide has shown interesting activity in POEMS syndrome, but no data on pomalidomide have been published so far. Aims: We report the use of pomalidomide and dexamethasone in five patients with relapsing POEMS syndrome after lenalidomide regimen. Methods Demographics: 5 patients (3 men), median age 74 years old (range, 67–77), median of 2,6 previous lines received (range, 2–4). All patients had received lenalidomide as previous therapy. Results: Hematological overall response rate (ORR) was 3/5 (60%): all 3‐responding patients experienced complete response (CR) according to local evaluation based on IMWG criteria, leading to clinical improvement of neuropathy in all of them, endocrinopathy and peripheral edema (2 of 2 pts). Other clinical responses concerned resolution of papilledema (2 of 2 pts) and improvement of pulmonary hypertension (1 of 1 pt). Noteworthy, serum Vascular Endothelial Growth Factor (sVEGF) level normalized after only one cycle of treatment in those 3‐responding patients (figure 1). No emergent toxicity was observed. As expected, adverse events were mainly hematological but of mild intensity and easily manageable. At this time, the 3‐responding patients are alive, including 2 without relapse after 11 months of follow‐up for both of them. The 2 other patients died, one of them from rapidly progressing disease, the other from heart disease not related to POEMS. Summary/Conclusion: In conclusion, pomalidomide and dexamethasone appears to be a safe and effective option in relapsing POEMS syndrome after lenalidomide regimen, demonstrating rapid and durable responses. image
The Impact of Protein Architecture on Adaptive Evolution
Authors: Ana Filipa Moutinho, Fernanda Fontes Trancoso, Julien Yann Dutheil
Journal: Molecular Biology and Evolution (2019)

Abstract Adaptive mutations play an important role in molecular evolution. However, the frequency and nature of these mutations at the intramolecular level are poorly understood. To address this, we analyzed the impact of protein architecture on the rate of adaptive substitutions, aiming to understand how protein biophysics influences fitness and adaptation. Using Drosophila melanogaster and Arabidopsis thaliana population genomics data, we fitted models of distribution of fitness effects and estimated the rate of adaptive amino-acid substitutions both at the protein and amino-acid residue level. We performed a comprehensive analysis covering genome, gene, and protein structure, by exploring a multitude of factors with a plausible impact on the rate of adaptive evolution, such as intron number, protein length, secondary structure, relative solvent accessibility, intrinsic protein disorder, chaperone affinity, gene expression, protein function, and protein–protein interactions. We found that the relative solvent accessibility is a major determinant of adaptive evolution, with most adaptive mutations occurring at the surface of proteins. Moreover, we observe that the rate of adaptive substitutions differs between protein functional classes, with genes encoding for protein biosynthesis and degradation signaling exhibiting the fastest rates of protein adaptation. Overall, our results suggest that adaptive evolution in proteins is mainly driven by intermolecular interactions, with host–pathogen coevolution likely playing a major role.
PF262 COMPREHENSIVE DIAGNOSTICS OF ACUTE MYELOID LEUKEMIA BY WHOLE TRANSCRIPTOME RNA SEQUENCING
Authors: M. Griffioen, W. Arindrarto, D.M. Borràs, I.J. Locher, S.A. van Diessen, R. van der Holst, E.D. van der Meijden, M.W. Honders, R.H. de Leeuw, I. Jedema, W.G. Kroes, J. Knijnenburg, J.S. Vermaat, P.J. Valk, B. Janssen, P. de Knijff, C.A. van Bergen, E.B. van den Akker, P.A. ’t Hoen, S.M. Kiełbasa, J.F. Laros, H. Veelken
Journal: HemaSphere (2019)

Background: Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of malignant myeloid precursor cells in the bone marrow. Genetic aberrations play an important role in pathogenesis as well as in classification of AML, which is relevant for accurate diagnosis, risk assessment and personalized treatment of AML. Genetic aberrations in AML are structurally diverse and currently measured by different diagnostic tests. Aims: The aim of the study is to establish whole transcriptome messenger RNA sequencing (RNAseq) as single and flexible diagnostic platform for AML classification, prognostication, and choice of targeted agents. Methods: Whole transcriptome RNA sequencing was performed on 100 AML cases and the bioinformatics pipeline HAMLET ( H uman AML E xpedited T ranscriptomics) was developed for simultaneous detection of fusion genes, small variants, long tandem duplications and gene expression. HAMLET results were validated by reference assays and targeted resequencing. Results: HAMLET accurately detected all fusion genes and overexpression of EVI1 irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and internal tandem duplications in FLT3 ( FLT3 ‐ITD) and partial tandem duplications in KMT2A ( KMT2A ‐PTD) were detected by a novel algorithm based on soft clipped reads with 100% sensitivity and 97.1% specificity. Summary/Conclusion: HAMLET accurately provides comprehensive diagnostic information relevant for AML classification, risk assessment and personalized therapy on a single technology platform. Instead of current AML diagnostics based on various assays that target selected aberrations, RNAseq‐HAMLET represents a new diagnostic paradigm according to a “measure all – analyse relevant” approach, which can be adapted to advances in sequencing technology and novel insights in AML pathogenesis, and allows individual retrospective reassessment.
Abstract 14079: Impact of Left Ventricular Deformational Parameters on Ejection Fraction in Hypertension and Hypertensive Heart Failure: A Study Using One-beat Three-dimensional Speckle Tracking Echocardiography
Authors: Shingo Minatoguchi, Masanori Kawasaki, Takashi Yoshizane, Ryuhei Tanaka, Takatomo Watanabe, Makoto Iwama, Maki Nagaya, Koji Ono, Toshiyuki Noda, Sachiro Watanabe, Shinya Minatoguchi
Journal: Circulation (2017)

Background: Left ventricular (LV) longitudinal strain is reported to be reduced in heart failure with preserved ejection fraction (HFpEF). However, the role and mechanism of LV deformational parame...
Abstract 15913: Statin And Ezetimibe in Silent Ambulatory Myocardial Ischemia (SESAMI Trial)
Authors: Waleed Kadro, Maya Turkmani, Hussam Rahim, Oussama Beshir, Oussama Khatib, Najeeb Jaha, Ashraf Younis, Kishan Pakkal
Journal: Circulation (2015)

Introduction: Cholesterol lowering is associated with a reduction in cardiovascular morbidity and mortality. Statins are the main drugs for cholesterol lowering. Ezetimibe when added to statins gives further reduction in cholesterol but its long-term effect on cardiovascular morbidity and mortality and ischemic events is not known. This study sought to determine whether further cholesterol lowering with ezitimibe will also results in a reduction of myocardial ischemia during daily life. Hypothesis: Further cholestrol with ezetimibe lowering may reduce silent ischemia. Methods: We enrolled 50 patients with proven stable coronary artery disease (CAD) and at least one episode of ST-segment depression on ambulatory ECG monitoring. All of them were receiving optimal therapy for CAD including statin therapy for cholesterol reduction. 25 patients were randomized to continue their statin therapy (Statin only group) and 25 to recieve statin plus Ezitimibe 10mg/day (ezitimibe group). Serum cholesterol and LDL cholesterol levels and ambulatory monitoring were repeated after 4 to 6 months of therapy. The two groups were comparable with respect to baseline characteristics, number of episodes of ST-segment depression, and baseline serum cholesterol levels. Holters were read by a blinded cardiologist. Results: The ezitimibe group had lower mean total and LDL cholesterol levels at study end and experienced a significant reduction in the number of episodes of ST-segment depression compared with the statin only group. ST-segment depression was completely resolved in 13 of 25 patients (52%) in the ezitimibe group versus 3 of 25 (12%) in the statin only group. The ezitimibe group exhibited a highly significant reduction in ambulatory ischemia (P&lt;.001). By logistic regression, treatment with ezitimibe was an independent predictor of ischemia resolution. Conclusions: Further cholesterol lowering with ezitimibe can result in reduction or resolution of myocardial ischemia recorded as episodes of ST-segment depression in ambulatory monitoring of the ECG. A larger study is required to confirm this results. This may be translated into long term mortality reduction for CAD by adding ezetimibe.
The many faces of myocardial ischaemia and angina
Authors: Bernard I Levy, Gerd Heusch, Paolo G Camici
Journal: Cardiovascular Research (2019)

Obstructive disease of the epicardial coronary arteries is the main cause of angina. However, a number of patients with anginal symptoms have normal coronaries or non-obstructive coronary artery disease (CAD) despite electrocardiographic evidence of ischaemia during stress testing. In addition to limited microvascular vasodilator capacity, the coronary microcirculation of these patients is particularly sensitive to vasoconstrictor stimuli, in a condition known as microvascular angina. This review briefly summarizes the determinants and control of coronary blood flow (CBF) and myocardial perfusion. It subsequently analyses the mechanisms responsible for transient myocardial ischaemia: obstructive CAD, coronary spasm and coronary microvascular dysfunction in the absence of epicardial coronary lesions, and variable combinations of structural anomalies, impaired endothelium-dependent and/or -independent vasodilation, and enhanced perception of pain. Lastly, we exemplify mechanism of angina during tachycardia. Distal to a coronary stenosis, coronary dilator reserve is already recruited and can be nearly exhausted at rest distal to a severe stenosis. Increased heart rate reduces the duration of diastole and thus CBF when metabolic vasodilation is no longer able to increase CBF. The increase in myocardial oxygen consumption and resulting metabolic vasodilation in adjacent myocardium without stenotic coronary arteries further acts to divert blood flow away from the post-stenotic coronary vascular bed through collaterals.
The Incompleteness of the Social Security Death Master File
Authors: Charles Maynard
Journal: JAMA Cardiology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines
Authors: Rajarshi Ghosh, Ninad Oak, Sharon E. Plon
Journal: Genome biology (2017)

The American College of Medical Genetics and American College of Pathologists (ACMG/AMP) variant classification guidelines for clinical reporting are widely used in diagnostic laboratories for variant interpretation. The ACMG/AMP guidelines recommend complete concordance of predictions among all in silico algorithms used without specifying the number or types of algorithms. The subjective nature of this recommendation contributes to discordance of variant classification among clinical laboratories and prevents definitive classification of variants.Using 14,819 benign or pathogenic missense variants from the ClinVar database, we compared performance of 25 algorithms across datasets differing in distinct biological and technical variables. There was wide variability in concordance among different combinations of algorithms with particularly low concordance for benign variants. We also identify a previously unreported source of error in variant interpretation (false concordance) where concordant in silico predictions are opposite to the evidence provided by other sources. We identified recently developed algorithms with high predictive power and robust to variables such as disease mechanism, gene constraint, and mode of inheritance, although poorer performing algorithms are more frequently used based on review of the clinical genetics literature (2011-2017).Our analyses identify algorithms with high performance characteristics independent of underlying disease mechanisms. We describe combinations of algorithms with increased concordance that should improve in silico algorithm usage during assessment of clinically relevant variants using the ACMG/AMP guidelines.
Abstract 21: Effect of Hypoxic Preconditioning on Cortical Bone Stem Cells (CBSCs)
Authors: Giulia Borghetti, Danielle M Trappanese, Sadia Mohsin, Constantine Troupes, Polina Gross, Steven R Houser
Journal: Circulation Research (2016)

Rationale: Cortical Bone Stem Cells (CBSCs) improve cardiac performance when delivered in an infarcted heart, in part, through secretion of paracrine factors. However transplanted cells can die due to hypoxia or other hostile fators within the infarcted heart. Hypoxia is known to also influence several biological process including migration, proliferation and secretory activity. Objective: the aim of this study is to define the effects of hypoxia on biological properties of CBSCs. Methods and Results: CBSCs were isolated from C57Bl/6 mouse, expanded in vitro and characterized. CBSCs were subjected to hypoxia (1% O 2 ) or normoxia (21% O 2 ) condition and then several biological properties were analysed. Hypoxia resulted in upregulation of CAIX and GLUT1 expression, two HIF1α downstream targets (3.2 and 5.1 fold increase of GLUT1; 6.7 and 65 fold increase of CAIX after 6 and 24 hours respectively). This indicates an effective hypoxic response activation in our experimental conditions. Cell proliferation was assessed by CyQuant assay: no significant difference between normoxic and hypoxic cells were found after 1 and 2 days. Growth curves were determined to evaluate hypoxia effects at longer time points. Hypoxic cells had the same growing rate as cells in normoxia in the first days, but their number increased at longer time points, indicating different kinetics with respect to normoxic when cells were grown in a challenging condition like an exhausted media. CBSCs migration and chemotaxis decreased when cells were cultured at 1%O 2 . Hypoxia preconditioning increased the paracrine activity of CBSCs. VEGF expression was increased after 6 hours (3 fold), and this effect remain stable after 24 hours and 3 days of 1% O 2 . Hypoxia resulted in 2.2 and 1.9 fold increase of SDF1 after 24 hours and 3 days respectively and a 1.8 fold increase of IGF1 after 1 day. The expression of bFGF, Angiopoietin and SCF was not affected. Conclusion: CBSCs can survive hypoxia and their paracrine activity increases without adversely affecting their proliferative capacity. In vivo experiments are needed to investigate if hypoxic preconditioning will enhance the ability of CBSCs to improve the structure and function of the injured heart.
TRPC6 Binds to and Activates Calpain, Independent of Its Channel Activity, and Regulates Podocyte Cytoskeleton, Cell Adhesion, and Motility
Authors: Louise K. Farmer, Ruth Rollason, Daniel J. Whitcomb, Lan Ni, Alexander Goodliff, Abigail C. Lay, Lutz Birnbaumer, Kate J. Heesom, Shang-Zhong Xu, Moin A. Saleem, Gavin I. Welsh
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Mutations in the transient receptor potential channel 6 ( TRPC6 ) gene are associated with an inherited form of FSGS. Emerging evidence has linked TRPC6 activity with calpain activation and podocyte injury. In this study, the authors generated a TRPC6 knockout podocyte cell line from TRPC6 knockout mice, engineering these cells to express wild-type and various mutations of TRPC6. They show that TRPC6 binds to both ERK 1/2 and calpain, and is important for the localization of calpain to the cell membrane, independent of TRPC6 calcium influx. This interaction is vital for cell motility and detachment and demonstrates a scaffolding role of TRPC6. These findings suggest that calpain activation and trafficking may be novel therapeutic targets in the treatment of FSGS. Background Mutations in the transient receptor potential channel 6 ( TRPC6 ) gene are associated with an inherited form of FSGS. Despite widespread expression, patients with TRPC6 mutations do not present with any other pathologic phenotype, suggesting that this protein has a unique yet unidentified role within the target cell for FSGS, the kidney podocyte. Methods We generated a stable TRPC6 knockout podocyte cell line from TRPC6 knockout mice. These cells were engineered to express wild-type TRPC6 , a dominant negative TRPC6 mutation, or either of two disease-causing mutations of TRPC6 , G109S or K874*. We extensively characterized these cells using motility, detachment, and calpain activity assays; immunofluorescence; confocal or total internal reflection fluorescence microscopy; and western blotting. Results Compared with wild-type cells, TRPC6−/− podocytes are less motile and more adhesive, with an altered actin cytoskeleton. We found that TRPC6 binds to ERK1/2 and the actin regulatory proteins, caldesmon (a calmodulin- and actin-binding protein) and calpain 1 and 2 (calcium-dependent cysteine proteases that control the podocyte cytoskeleton, cell adhesion, and motility via cleavage of paxillin, focal adhesion kinase, and talin). Knockdown or expression of the truncated K874* mutation (but not expression of the gain-of-function G019S mutation or dominant negative mutant of TRPC6 ) results in the mislocalization of calpain 1 and 2 and significant downregulation of calpain activity; this leads to altered podocyte cytoskeleton, motility, and adhesion—characteristics of TRPC6 −/− podocytes. Conclusions Our data demonstrate that independent of TRPC6 channel activity, the physical interaction between TRPC6 and calpain in the podocyte is important for cell motility and detachment and demonstrates a scaffolding role of the TRPC6 protein in disease.
Clinical and Pathological Characterization of Lynch-Like Syndrome
Authors: María Dolores Picó, Adela Castillejo, Óscar Murcia, Mar Giner-Calabuig, Miren Alustiza, Ariadna Sánchez, Leticia Moreira, María Pellise, Antoni Castells, Marta Carrillo-Palau, Teresa Ramon y Cajal, Alexandra Gisbert-Beamud, Gemma Llort, Carmen Yagüe, Adriá López-Fernández, Cristina Alvarez-Urturi, Joaquin Cubiella, Laura Rivas, Daniel Rodríguez-Alcalde, Maite Herraiz, Catalina Garau, Carlos Dolz, Luis Bujanda, Lucia Cid, Carmen Povés, Marta Garzon, Inmaculada Salces, Marta Ponce, Luís Hernández-Villalba, Cristina Alenda, Francesc Balaguer, Jose-Luis Soto, Rodrigo Jover
Journal: Clinical Gastroenterology and Hepatology (2019)
SP0075 CASE PRESENTER: CHILDHOOD ONSET OF NEUROLUPUS
Authors: Eve Smith
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> In the series of talks 'How to manage and treat childhood onset lupus? A multidisciplinary point of view" the first talk focuses on achievement of the initial diagnosis of Lupus within the childhood period, including some potential pitfalls and how these can be avoided. Initial and ongoing treatment within the childhood period, alongside paediatric specific therapeutic considerations will be discussed. The role of the multidisciplinary team of doctors, nurses, physiotherapists, occupational therapists, psychologists and sub-specialists will be highlighted. The impact of the diagnosis on the child, family, education and social activities will also be described. This talk will be followed by a subsequent talks following the patient through transition and into adulthood. <h3>Disclosure of Interests:</h3> None declared