tbuckley/cabot-search huggingface dataset:
Increased Cancer Prevalence in Peripartum Cardiomyopathy
Authors: Tobias J. Pfeffer, Stella Schlothauer, Stefan Pietzsch, Maria Schaufelberger, Bernd Auber, Melanie Ricke-Hoch, Manuel List, Dominik Berliner, Valeska Abou Moulig, Tobias König, Zolt Arany, Karen Sliwa, Johann Bauersachs, Denise Hilfiker-Kleiner
Journal: JACC CardioOncology (2019)

This study was designed to analyze the prevalence and potential genetic basis of cancer and heart failure in peripartum cardiomyopathy (PPCM).PPCM manifests as heart failure late in pregnancy or postpartum in women without previous heart disease.Clinical history and cancer prevalence were evaluated in a cohort of 236 PPCM patients from Germany and Sweden. Exome sequencing assessed variants in 133 genes associated with cancer predisposition syndromes (CPS) and in 115 genes associated with dilated/hypertrophic cardiomyopathy (DCM/HCM) in 14 PPCM patients with a history of cancer, and in 6 PPCM patients without a history of cancer.The prevalence of cancer was 16-fold higher (8.9%, 21 of 236 patients) in PPCM patients compared to age-matched women (German cancer registry, Robert-Koch-Institute: 0.59%; p < 0.001). Cancer before PPCM occurred in 12 of 21 patients of whom 11 obtained cardiotoxic cancer therapies. Of those, 17% fully recovered cardiac function by 7 ± 2 months of follow-up compared to 55% of PPCM patients without cancer (p = 0.015). Cancer occurred after PPCM in 10 of 21 patients; 80% had left ventricular ejection fraction of ≥50% after cancer therapy. Whole-exome sequencing in 14 PPCM patients with cancer revealed that 43% (6 of 14 patients) carried likely pathogenic (Class IV) or pathogenic (Class V) gene variants associated with DCM/HCM in CPT2, DSP, MYH7, TTN, and/or with CPS in ATM, ERCC5, NBN, RECQL4, and SLX4. All CPS variants affected DNA damage response genes.Cardiotoxic cancer therapy before PPCM is associated with delayed full recovery. The high cancer prevalence in PPCM is linked to likely pathogenic/pathogenic gene variants associated with DCM/HCM and/or CPS/DNA damage response-related cancer risk. This may warrant genetic testing and screening for heart failure in pregnant women with a cancer history and screening for cancer in PPCM patients.
Detection of PLA2R Autoantibodies before the Diagnosis of Membranous Nephropathy
Authors: Peter D. Burbelo, Megha Joshi, Adrija Chaturvedi, Dustin J. Little, John S. Thurlow, Meryl Waldman, Stephen W. Olson
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Primary membranous nephropathy (MN) is an autoimmune glomerular disease associated with nephrotic syndrome and poor kidney prognosis. Autoantibodies against the M-type phospholipase A2 receptor (PLA2R-AB) are present at diagnosis in about 70% of cases. However, when PLA2R-AB first appear and their trajectory are unknown. The authors used the Department of Defense Serum Repository to describe the prediagnostic evolution of PLA2R-AB over time. In most patients who tested positive for the antibodies, PLA2R-AB appeared and rose rapidly before biopsy-proven MN and before the earliest preclinical evidence of disease, including non-nephrotic range proteinuria and hypoalbuminemia. Our data provides the strongest evidence to date of direct PLA2R-AB pathogenicity in humans and suggests that earlier screening of patients with unexplained NNRP may be warranted. Background Circulating serum autoantibodies against the M-type phospholipase A2 receptor (PLA2R-AB) are a key biomarker in the diagnosis and monitoring of primary membranous nephropathy (MN). However, little is known about the appearance and trajectory of PLA2R-AB before the clinical diagnosis of MN. Methods Using the Department of Defense Serum Repository, we analyzed PLA2R-AB in multiple, 1054 longitudinal serum samples collected before diagnosis of MN from 134 individuals with primary MN, 35 individuals with secondary MN, and 134 healthy volunteers. We evaluated the presence and timing of non-nephrotic range proteinuria (NNRP) and serum albumin measurements in relation to PLA2R-AB status. Results Analysis of PLA2R-AB in longitudinal serum samples revealed seropositivity in 44% (59 out of 134) of primary MN cases, 3% (one out of 35) of secondary MN cases, and in 0% of healthy controls. Among patients with MN, PLA2R-AB were detectable at a median of 274 days before renal biopsy diagnosis (interquartile range, 71–821 days). Approximately one third of the participants became seropositive within 3 months of MN diagnosis. Of the 21 individuals with documented prediagnostic NNRP, 43% (nine out of 21) were seropositive before NNRP was first documented and 28.5% (six out of 21) were seropositive at the same time as NNRP; 66% (39 out of 59) of those seropositive for PLA2R-AB had hypoalbuminemia present at the time antibody was initially detected. Twelve participants (20%) were seropositive before hypoalbuminemia became apparent, and eight participants (14%) were seropositive after hypoalbuminemia became apparent. Conclusions Circulating PLA2R-AB are detectable months to years before documented NNRP and biopsy-proven diagnosis in patients with MN.
Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells
Authors: Ryusaku Matsumoto, Hidetaka Suga, Takashi Aoi, Hironori Bando, Hidenori Fukuoka, Genzo Iguchi, Satoshi Narumi, Tomonobu Hasegawa, Keiko Muguruma, Wataru Ogawa, Yutaka Takahashi
Journal: Journal of Clinical Investigation (2019)

Pituitary develops from oral ectoderm in contact with adjacent ventral hypothalamus. Impairment in this process results in congenital pituitary hypoplasia (CPH); however, there have been no human disease models for CPH thus far, prohibiting the elucidation of the underlying mechanisms. In this study, we established a disease model of CPH using patient-derived induced pluripotent stem cells (iPSCs) and 3D organoid technique, in which oral ectoderm and hypothalamus develop simultaneously. Interestingly, patient iPSCs with a heterozygous mutation in the orthodenticle homeobox 2 (OTX2) gene showed increased apoptosis in the pituitary progenitor cells, and the differentiation into pituitary hormone-producing cells was severely impaired. As an underlying mechanism, OTX2 in hypothalamus, not in oral ectoderm, was essential for progenitor cell maintenance by regulating LHX3 expression in oral ectoderm via FGF10 expression in the hypothalamus. Convincingly, the phenotype was reversed by the correction of the mutation, and the haploinsufficiency of OTX2 in control iPSCs revealed a similar phenotype, demonstrating that this mutation was responsible. Thus, we established an iPSC-based congenital pituitary disease model, which recapitulated interaction between hypothalamus and oral ectoderm and demonstrated the essential role of hypothalamic OTX2.
Older Adults in the Cardiac Intensive Care Unit: Factoring Geriatric Syndromes in the Management, Prognosis, and Process of Care: A Scientific Statement From the American Heart Association
Authors: Abdulla A. Damluji, Daniel E. Forman, Sean van Diepen, Karen P. Alexander, Robert L. Page, Scott L. Hummel, Venu Menon, Jason N. Katz, Nancy M. Albert, Jonathan Afilalo, Mauricio G. Cohen
Journal: Circulation (2019)

Longevity is increasing, and more adults are living to the stage of life when age-related biological factors determine a higher likelihood of cardiovascular disease in a distinctive context of concurrent geriatric conditions. Older adults with cardiovascular disease are frequently admitted to cardiac intensive care units (CICUs), where care is commensurate with high age-related cardiovascular disease risks but where the associated geriatric conditions (including multimorbidity, polypharmacy, cognitive decline and delirium, and frailty) may be inadvertently exacerbated and destabilized. The CICU environment of procedures, new medications, sensory overload, sleep deprivation, prolonged bed rest, malnourishment, and sleep is usually inherently disruptive to older patients regardless of the excellence of cardiovascular disease care. Given these fundamental and broad challenges of patient aging, CICU management priorities and associated decision-making are particularly complex and in need of enhancements. In this American Heart Association statement, we examine age-related risks and describe some of the distinctive dynamics pertinent to older adults and emerging opportunities to enhance CICU care. Relevant assessment tools are discussed, as well as the need for additional clinical research to best advance CICU care for the already dominating and still expanding population of older adults.
Tracheomalacia and bronchomalacia in children: response to the ERS statement
Authors: Suzanne Crowley, Kai-Håkon Carlsen
Journal: European Respiratory Journal (2019)

We welcome the timely publication of the European Respiratory Society statement on tracheomalacia and bronchomalacia (TBM) in children [1], but are concerned that the definition of malacia used in the statement may contribute to underdiagnosis in those older children with milder degrees of malacia whose main symptom is exercise limitation [2]. Malacia in the statement is defined as an "arbitrary >50% expiratory reduction in the cross-sectional luminal area during quiet respiration" diagnosed with the use of multidetector computed tomography (MDCT); the authors cite seven references in support of their definition. Dynamic expiratory manoeuvres should be used to diagnose mild airway malacia <http://bit.ly/2NBJ3Mn>
Trends in List Prices, Net Prices, and Discounts for Originator Biologics Facing Biosimilar Competition
Authors: Alvaro San-Juan-Rodriguez, Walid F. Gellad, Chester B. Good, Inmaculada Hernandez
Journal: JAMA Network Open (2019)

In this cohort study, pricing data from January 2007 to June 2018 from SSR Health were used to determine how list prices, net prices, and discounts for the originator biologics changed with biosimilar competition.
Abstract 19862: T-cell Specific Overexpression of IL-17A Induces Vascular Dysfunction Per Se Without Increasing Vascular Inflammation and IL-17 Receptor a Knock-out Attenuates Angiotensin-II Induced Vascular Inflammation
Authors: Rebecca Schüler, Susanne Karbach, Katrin Schäfer, Sabine Kossmann, Matthias Oelze, Venkata Garlapati, Jula Huppert, Andrew Croxford, Andreas Daiber, Thomas Münzel, Ari Waisman, Philip Wenzel
Journal: Circulation (2017)

Introduction: Interleukin-17A (IL-17A) plays a major role in the development of vascular dysfunction although there still remain open questions concerning the mechanisms. Hypothesis: We investigate...
Moderate but not severe hypothermia causes pro-arrhythmic changes in cardiac electrophysiology
Authors: Erik S Dietrichs, Karen McGlynn, Andrew Allan, Adam Connolly, Martin Bishop, Francis Burton, Sarah Kettlewell, Rachel Myles, Torkjel Tveita, Godfrey L Smith
Journal: Cardiovascular Research (2020)

Treatment of arrhythmias evoked by hypothermia/rewarming remains challenging, and the underlying mechanisms are unclear. This in vitro experimental study assessed cardiac electrophysiology in isolated rabbit hearts at temperatures occurring in therapeutic and accidental hypothermia.Detailed ECG, surface electrogram, and panoramic optical mapping were performed in isolated rabbit hearts cooled to moderate (31°C) and severe (17°C) hypothermia. Ventricular activation was unchanged at 31°C while action potential duration (APD) was significantly prolonged (176.9 ± 4.2 ms vs. 241.0 ± 2.9 ms, P < 0.05), as was ventricular repolarization. At 17°C, there were proportionally similar delays in both activation and repolarization. These changes were reflected in the QRS and QT intervals of ECG recordings. Ventricular fibrillation threshold was significantly reduced at 31°C (16.3 ± 3.1 vs. 35 ± 3.5 mA, P < 0.05) but increased at 17°C (64.2 ± 9.9, P < 0.05). At 31°C, transverse conduction was relatively unchanged by cooling compared to longitudinal conduction, but at 17°C both transverse and longitudinal conduction were proportionately reduced to a similar extent. The gap junction uncoupler heptanol had a larger relative effect on transverse than longitudinal conduction and was able to restore the transverse/longitudinal conduction ratio, returning ventricular fibrillation threshold to baseline values (16.3 ± 3.1 vs. 36.3 ± 4.3 mA, P < 0.05) at 31°C. Rewarming to 37°C restored the majority of the electrophysiological parameters.Moderate hypothermia does not significantly change ventricular conduction time but prolongs repolarization and is pro-arrhythmic. Further cooling to severe hypothermia causes parallel changes in ventricular activation and repolarization, changes which are anti-arrhythmic. Therefore, relative changes in QRS and QT intervals (QR/QTc) emerge as an ECG-biomarker of pro-arrhythmic activity. Risk for ventricular fibrillation appears to be linked to the relatively low temperature sensitivity of ventricular transmural conduction, a conclusion supported by the anti-arrhythmic effect of heptanol at 31°C.
Trial of Anifrolumab in Active Systemic Lupus Erythematosus
Authors: Eric F. Morand, Richard Furie, Yoshiya Tanaka, Ian N. Bruce, Anca D. Askanase, Christophe Richez, Sang-Cheol Bae, Philip Z. Brohawn, Lilia Pineda, Anna Berglind, Raj Tummala
Journal: New England Journal of Medicine (2019)

Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant effect on the primary end point in a previous phase 3 trial. The current phase 3 trial used a secondary end point from that trial as the primary end point.
Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1
Authors: Tobias Petzold, Manuela Thienel, Lisa Dannenberg, Philipp Mourikis, Carolin Helten, Aysel Ayhan, René M’Pembele, Alina Achilles, Kajetan Trojovky, Daniel Konsek, Zhe Zhang, Ron Regenauer, Joachim Pircher, Andreas Ehrlich, Enzo Lüsebrink, Leo Nicolai, Thomas J. Stocker, Richard Brandl, Franz Röschenthaler, Jan Strecker, Inas Saleh, Michael Spannagl, Christoph H. Mayr, Herbert B. Schiller, Christian Jung, Norbert Gerdes, Till Hoffmann, Bodo Levkau, Thomas Hohlfeld, Tobias Zeus, Christian Schulz, Malte Kelm, Amin Polzin
Journal: Circulation Research (2019)

Rationale: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown. Objective: In this study, we hypothesized that rivaroxaban’s antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis. Methods and Results: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban’s antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban’s anticoagulatory capacity. Conclusions: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.
Safety of oral ivermectin during pregnancy: a systematic review and meta-analysis
Authors: Patricia Nicolas, Marta F Maia, Quique Bassat, Kevin C Kobylinski, Wuelton Monteiro, N Regina Rabinovich, Clara Menéndez, Azucena Bardají, Carlos Chaccour
Journal: The Lancet Global Health (2019)

About 3·7 billion doses of ivermectin have been distributed in mass drug administration (MDA) campaigns globally over the past 30 years. At 10-100 times higher than current human doses, ivermectin is a known teratogen in mammals. During these campaigns with recommended doses, pregnant women might be inadvertently exposed. We therefore aimed to evaluate the existing evidence for serious and non-serious adverse events after ivermectin exposure in pregnant women.For this systematic review and meta-analysis, we searched relevant databases and trial registry platforms on July 15, 2018, for randomised controlled trials (RCTs) and observational studies that reported adverse events in pregnant women. We did not use language or date restrictions. Outcomes of interest were spontaneous abortions, stillbirths, congenital anomalies, and neonatal death (serious adverse events), as well as maternal morbidity, preterm births, and low birthweight (adverse events). The risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias Tool for RCTs. We did the meta-analysis of observational studies and RCTs separately. The quality of evidence was assessed using the GRADE approach. The study protocol is registered with PROSPERO, protocol CRD42016046914.We identified 147 records, of which only five observational studies and one RCT were included for quantitative analysis; these studies were published between 1990 and 2008, and were done in six African countries. 893 women with 899 pregancy outcomes were included, of whom 496 pregnant women (500 pregnancy outcomes) received ivermectin inadvertently during MDA campaigns in the observational studies and 397 pregnant women (399 pregnancy outcomes) purposely received ivermectin as part of the open-label RCT. No study reported neonatal deaths, maternal morbidity, preterm births, or low birthweight. It is unclear whether exposure to ivermectin during pregnancy increases the risk of spontaneous abortions and stillbirths (odds ratio [OR] 1·15 [95% CI 0·75-1·78] with very low certainty of evidence for the four observational studies and 0·62 [0·18-2·14] with very low certainty of evidence for the RCT) or congenital anomalies (OR 1·69 [95% CI 0·83-3·41] with very low certainty of evidence for the five observational studies and 1·10 [0·07-17·65] with very low certainty of evidence for the RCT).There is insufficient evidence to conclude on the safety profile of ivermectin during pregnancy. Treatment campaigns should focus additional efforts on preventing inadvertent treatment of pregnant women.Unitaid.
Transcriptome assembly from long-read RNA-seq alignments with StringTie2
Authors: Sam Kovaka, Aleksey V. Zimin, Geo M. Pertea, Roham Razaghi, Steven L. Salzberg, Mihaela Pertea
Journal: Genome biology (2019)

RNA sequencing using the latest single-molecule sequencing instruments produces reads that are thousands of nucleotides long. The ability to assemble these long reads can greatly improve the sensitivity of long-read analyses. Here we present StringTie2, a reference-guided transcriptome assembler that works with both short and long reads. StringTie2 includes new methods to handle the high error rate of long reads and offers the ability to work with full-length super-reads assembled from short reads, which further improves the quality of short-read assemblies. StringTie2 is more accurate and faster and uses less memory than all comparable short-read and long-read analysis tools.
Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes
Authors: Valerie D Heuvelman, Daniël H Van Raalte, Mark M Smits
Journal: Cardiovascular Research (2019)

Type 2 diabetes mellitus (T2DM) is currently one of the most prevalent diseases, with as many as 415 million patients worldwide. T2DM is characterized by elevated blood glucose levels and is often accompanied by several comorbidities, such as cardiovascular disease. Treatment of T2DM is focused on reducing glucose levels by either lifestyle changes or medical treatment. One treatment option for T2DM is based on the gut-derived hormone glucagon-like peptide 1 (GLP-1). GLP-1 reduces blood glucose levels by stimulating insulin secretion, however, it is rapidly degraded, and thereby losing its glycaemic effect. GLP-1 receptor agonists (GLP-1RAs) are immune to degradation, prolonging the glycaemic effect. Lately, GLP-1RAs have spiked the interest of researchers and clinicians due to their beneficial effects on cardiovascular disease. Preclinical and clinical data have demonstrated that GLP-1 receptors are abundantly present in the heart and that stimulation of these receptors by GLP-1 has several effects. In this review, we will discuss the effects of GLP-1RA on heart rate, blood pressure, microvascular function, lipids, and inflammation, as measured in human mechanistic studies, and suggest how these effects may translate into the improved cardiovascular outcomes as demonstrated in several trials.
Safety of Intravenous Arginine Therapy in Children with Sickle Cell Disease Hospitalized for Vaso-Occlusive Pain: A Randomized Placebo-Controlled Trial in Progress
Authors: Claudia R. Morris, Janet Figueroa, Amanda Watt, Kirshma Khemani, Polly Kumari, Morgan Barnett, Nitya Bakshi, Peter A. Lane, Carlton Dampier
Journal: Blood (2019)
Quantitative IFN-γ Release Assay and Tuberculin Skin Test Results to Predict Incident Tuberculosis. A Prospective Cohort Study
Authors: Rishi K. Gupta, Marc Lipman, Charlotte Jackson, Alice J. Sitch, Jo Southern, Francis Drobniewski, Jonathan J. Deeks, Chuen-Yan Tsou, Chris Griffiths, Jennifer Davidson, Colin Campbell, Oliver Stirrup, Mahdad Noursadeghi, Heinke Kunst, Pranab Haldar, Ajit Lalvani, Ibrahim Abubakar
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Development of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority.Objectives: We evaluated whether implementing higher diagnostic thresholds than currently recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB, and the tuberculin skin test (TST) might improve prediction of incident TB.Methods: Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by relinkage to national TB surveillance records (median follow-up 4.7 yr). Incidence rates and rate ratios, sensitivities, specificities, and predictive values for incident TB were calculated according to ordinal strata for quantitative results of QFT-GIT, T-SPOT.TB, and TST (with adjustment for prior bacillus Calmette-Guérin [BCG] vaccination).Measurements and Main Results: For all tests, incidence rates and rate ratios increased with the magnitude of the test result (P < 0.0001). Over 3 years' follow-up, there was a modest increase in positive predictive value with the higher thresholds (3.0% for QFT-GIT ≥0.35 IU/ml vs. 3.6% for ≥4.00 IU/ml; 3.4% for T-SPOT.TB ≥5 spots vs. 5.0% for ≥50 spots; and 3.1% for BCG-adjusted TST ≥5 mm vs. 4.3% for ≥15 mm). As thresholds increased, sensitivity to detect incident TB waned for all tests (61.0% for QFT-GIT ≥0.35 IU/ml vs. 23.2% for ≥4.00 IU/ml; 65.4% for T-SPOT.TB ≥5 spots vs. 27.2% for ≥50 spots; 69.7% for BCG-adjusted TST ≥5 mm vs. 28.1% for ≥15 mm).Conclusions: Implementation of higher thresholds for QFT-GIT, T-SPOT.TB, and TST modestly increases positive predictive value for incident TB, but markedly reduces sensitivity. Novel biomarkers or validated multivariable risk algorithms are required to improve prediction of incident TB.