tbuckley/cabot-search huggingface dataset:
Deep Neural Networks Can Predict New-Onset Atrial Fibrillation From the 12-Lead ECG and Help Identify Those at Risk of Atrial Fibrillation–Related Stroke
Authors: Sushravya Raghunath, John M. Pfeifer, Alvaro E. Ulloa-Cerna, Arun Nemani, Tanner Carbonati, Linyuan Jing, David P. vanMaanen, Dustin N. Hartzel, Jeffery A. Ruhl, Braxton F. Lagerman, Daniel B. Rocha, Nathan J. Stoudt, Gargi Schneider, Kipp W. Johnson, Noah Zimmerman, Joseph B. Leader, H. Lester Kirchner, Christoph J. Griessenauer, Ashraf Hafez, Christopher W. Good, Brandon K. Fornwalt, Christopher M. Haggerty
Journal: Circulation (2021)

Background: Atrial fibrillation (AF) is associated with substantial morbidity, especially when it goes undetected. If new-onset AF could be predicted, targeted screening could be used to find it early. We hypothesized that a deep neural network could predict new-onset AF from the resting 12-lead ECG and that this prediction may help identify those at risk of AF-related stroke. Methods: We used 1.6 M resting 12-lead digital ECG traces from 430 000 patients collected from 1984 to 2019. Deep neural networks were trained to predict new-onset AF (within 1 year) in patients without a history of AF. Performance was evaluated using areas under the receiver operating characteristic curve and precision-recall curve. We performed an incidence-free survival analysis for a period of 30 years following the ECG stratified by model predictions. To simulate real-world deployment, we trained a separate model using all ECGs before 2010 and evaluated model performance on a test set of ECGs from 2010 through 2014 that were linked to our stroke registry. We identified the patients at risk for AF-related stroke among those predicted to be high risk for AF by the model at different prediction thresholds. Results: The area under the receiver operating characteristic curve and area under the precision-recall curve were 0.85 and 0.22, respectively, for predicting new-onset AF within 1 year of an ECG. The hazard ratio for the predicted high- versus low-risk groups over a 30-year span was 7.2 (95% CI, 6.9–7.6). In a simulated deployment scenario, the model predicted new-onset AF at 1 year with a sensitivity of 69% and specificity of 81%. The number needed to screen to find 1 new case of AF was 9. This model predicted patients at high risk for new-onset AF in 62% of all patients who experienced an AF-related stroke within 3 years of the index ECG. Conclusions: Deep learning can predict new-onset AF from the 12-lead ECG in patients with no previous history of AF. This prediction may help identify patients at risk for AF-related strokes.
Parallel Genomic Changes Drive Repeated Evolution of Placentas in Live-Bearing Fish
Authors: Henri van Kruistum, Reindert Nijland, David N Reznick, Martien A M Groenen, Hendrik-Jan Megens, Bart J A Pollux
Journal: Molecular Biology and Evolution (2021)

The evolutionary origin of complex organs challenges empirical study because most organs evolved hundreds of millions of years ago. The placenta of live-bearing fish in the family Poeciliidae represents a unique opportunity to study the evolutionary origin of complex organs, because in this family a placenta evolved at least nine times independently. It is currently unknown whether this repeated evolution is accompanied by similar, repeated, genomic changes in placental species. Here, we compare whole genomes of 26 poeciliid species representing six out of nine independent origins of placentation. Evolutionary rate analysis revealed that the evolution of the placenta coincides with convergent shifts in the evolutionary rate of 78 protein-coding genes, mainly observed in transporter- and vesicle-located genes. Furthermore, differences in sequence conservation showed that placental evolution coincided with similar changes in 76 noncoding regulatory elements, occurring primarily around genes that regulate development. The unexpected high occurrence of GATA simple repeats in the regulatory elements suggests an important function for GATA repeats in developmental gene regulation. The distinction in molecular evolution observed, with protein-coding parallel changes more often found in metabolic and structural pathways, compared with regulatory change more frequently found in developmental pathways, offers a compelling model for complex trait evolution in general: changing the regulation of otherwise highly conserved developmental genes may allow for the evolution of complex traits.
Endobronchial Valve Lung Volume Reduction and Small Airway Function
Authors: Justin L. Garner, Martyn F. Biddiscombe, Sally Meah, Adam Lewis, Sara C. Buttery, Nicholas S. Hopkinson, Samuel V. Kemp, Omar S. Usmani, Pallav L. Shah, Sylvia Verbanck
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Endobronchial Valve Lung Volume Reduction and Small Airway Function." American Journal of Respiratory and Critical Care Medicine, 203(12), pp. 1576–1579
Abstract 17562: GPCR Gβγ Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure Mice
Authors: Fadia A Kamal, Joshua G Travers, Allison E Schafer, Qing Ma, Prasad Devarajan, Burns C Blaxall
Journal: Circulation (2015)

Background: Cardiorenal syndrome type 2 (CRS2), the development of chronic kidney disease (CKD) secondary to chronic heart failure (CHF), is clinically associated with increased incidence of organ failure and reduced survival. Heart and kidney damage in CRS2 is greatly caused by chronic stimulation of the adrenergic and endothelin receptors as a result of elevated neurohormonal signaling of the sympathetic nervous system (SNS) and its downstream endothelin (ET) system, respectively. These receptors belong to the superfamily of G protein-coupled receptors (GPCRs). While chronic GPCR stimulation and its associated upregulated interaction between the G-protein βγ subunit (Gβγ), the GPCR-kinase 2 (GRK2) and β-arrestin are known to be central to various cardiovascular diseases, their role in kidney diseases are by far unknown and beg investigation. Objective: CRS2 animal studies utilize combine ischemic cardiac injury and renal injury, which is of poor clinical relevance. Our study investigates: (1) the development of chronic kidney disease (CKD) in a model of non-ischemic CHF without inducing surgical kidney injury, aiming to establish a more clinically relevant CRS2 model. (2) The possible salutary effect of renal GPCR-Gβγ inhibition in CKD developed in the established CRS2 model. Methods and results: We utilized transverse aortic constriction (TAC) as a non-ischemic hypertrophic murine CHF model. Twelve weeks after TAC, mice developed CKD secondary to CHF suggesting a CRS2 model. This was associated with elevated renal GPCR-Gβγ signaling and ET system expression. Importantly, systemic pharmacologic Gβγ inhibition by gallein attenuated these renal pathological changes in parallel with alleviated CHF. A direct effect of gallein on the kidney was subsequently confirmed in a bilateral ischemia reperfusion acute kidney injury (AKI) mouse model where it attenuated renal dysfunction, tissue damage and ET system activation, indicating a direct role for GPCR-Gβγ signaling in AKI. Further, in vitro studies in mouse embryonic fibroblasts showed a key role for ET receptor-Gβγ signaling in fibroblast activation. Conclusion: Our data suggest TAC as a clinically relevant CRS2 model and GPCR-Gβγ inhibition as a novel therapeutic approach for CRS2 and AKI.
Real-world survival of men with metastatic hormone-sensitive prostate cancer (mHSPC) treated with abiraterone acetate (Abi) or docetaxel (Doc) and comparison with clinical trial outcomes.
Authors: Daniel M. Geynisman, Andres F Correa, Chethan Ramamurthy, J Robert Beck, Elizabeth A. Handorf
Journal: Journal of Clinical Oncology (2021)

53 Background: Multiple phase III trials have proven that Abi and Doc both improve overall survival (OS) in men with mHSPC. No randomized trials have compared the two approaches. Methods: We conducted a retrospective, observational study to compare OS in de novo M1 men, treated with Abi vs. Doc using patient-level data from the Flatiron health EHR-derived de-identified database. We also compared this real-world OS to trial level data using extracted data points along the OS curves from CHAARTED and LATITUDE trials. OS was compared via Kaplan-Meier curves. Analyses were adjusted via propensity score weighting for age, Gleason score, PSA at diagnosis, race, ethnicity, ECOG PS, insurance type and treatment setting. Results: The cohort included 418 Abi pts and 807 Doc pts (Table). Median follow-up was 13.5 mo for Abi and 31.6 mo for Doc. Unadjusted median OS for Abi and Doc were 31.6 mo (95% CI 28.1-NA) and 41.8 mo (95% CI 37.4-46.3) respectively (P=0.09). Twelve mo and 24 mo OS for Abi was 86.3% and 69%; for Doc it was 89.8% and 72.1 %. Median adjusted OS for Abi and Doc were 31.6 mo (95% CI 28.0-undefined) and 38.8 mo (95% CI 33.1-46.3) respectively (P=0.4). Twelve mo and 24 mo adjusted OS for Abi was 86.6% and 69.4%; for Doc it was 87.9% and 69.2%. Based on extracted trial data, in LATITUDE, Abi treated pts had 12 mo and 24 mo OS of 93.5% and 77.0%; in CHAARTED, Doc treated pts had 12 mo and 24 mo OS of 94.3% and 83.6%. Conclusions: Utilizing real-world data, we demonstrate that 12 and 24-months OS are clinically and statistically similar between Abi and Doc in men with mHSPC. Median OS is also similar, although due to limited follow-up, the estimate of median OS for Abi has large variability. In addition, we show that clinical trial pts had superior outcomes to those in a real-world clinic population. Recent meta-analyses of trial data have not found significant differences in OS for Abi vs. Doc; this analysis of real-world data confirms these findings and indicates that they may be generalizable to a broader patient population. Although this observational study is subject to residual confounding and missing data, it provides further evidence to support the use of both Abi and Doc in men with mHSPC. Differentiating costs, side-effects and QOL can thus become more prominent when making decisions about therapy. [Table: see text]
Identification of pathogenic variants in cancer genes using base editing screens with editing efficiency correction
Authors: Changcai Huang, Guangyu Li, Jiayu Wu, Junbo Liang, Xiaoyue Wang
Journal: Genome biology (2021)

Abstract Background Millions of nucleotide variants are identified through cancer genome sequencing and it is clinically important to identify the pathogenic variants among them. By introducing base substitutions at guide RNA target regions in the genome, CRISPR-Cas9-based base editors provide the possibility for evaluating a large number of variants in their genomic context. However, the variability in editing efficiency and the complexity of outcome mapping are two existing problems for assigning guide RNA effects to variants in base editing screens. Results To improve the identification of pathogenic variants, we develop a framework to combine base editing screens with sgRNA efficiency and outcome mapping. We apply the method to evaluate more than 9000 variants across all the exons of BRCA1 and BRCA2 genes. Our efficiency-corrected scoring model identifies 910 loss-of-function variants for BRCA1/2 , including 151 variants in the noncoding part of the genes such as the 5′ untranslated regions. Many of them are identified in cancer patients and are reported as “benign/likely benign” or “variants of uncertain significance” by clinicians. Our data suggest a need to re-evaluate their clinical significance, which may be helpful for risk assessment and treatment of breast and ovarian cancer. Conclusions Our results suggest that base editing screens with efficiency correction is a powerful strategy to identify pathogenic variants in a high-throughput manner. Applying this strategy to assess variants in both coding and noncoding regions of the genome could have a direct impact on the interpretation of cancer variants.
Effect of Emergency Department Care Bundle on Elderly Patients With Acute Heart Failure—Reply
Authors: Yonathan Freund, Judith Gorlicki
Journal: JAMA (2021)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Abstract 11650: Adcy9 Inactivation Improves Cardiac Function After Myocardial Infarction in Absence of Cholesterol Ester Transfer Protein
Authors: Marine Ferron, Nolwenn Merlet, Mélanie Mecteau, Teodora Mihalache-Avram, Geneviève Brand, Marc-Antoine Gillis, Yanfen Shi, Eric Rheaume, Jean Claude Tardif
Journal: Circulation (2019)

Pharmacogenomic studies have shown that polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the effects of dalcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, on cardiov...
Clinical characteristics and outcomes of B-ALL with ZNF384 rearrangements: a retrospective analysis by the Ponte di Legno Childhood ALL Working Group
Authors: Shinsuke Hirabayashi, Ellie R. Butler, Kentaro Ohki, Nobutaka Kiyokawa, Anke K. Bergmann, Anja Möricke, Judith M. Boer, Hélène Cavé, Giovanni Cazzaniga, Allen Eng Juh Yeoh, Masashi Sanada, Toshihiko Imamura, Hiroto Inaba, Charles Mullighan, Mignon L. Loh, Ulrika Norén-Nyström, Agata Pastorczak, Lee-Yung Shih, Marketa Zaliova, Ching-Hon Pui, Oskar A. Haas, Christine J. Harrison, Anthony V. Moorman, Atsushi Manabe
Journal: Leukemia (2021)

B-acute lymphoblastic leukemia (B-ALL) comprises a wide variety of subtypes with diverse clinical and biological features and outcomes.Risk-stratified and targeted therapy according to genetic subtype has improved B-ALL outcomes [1].Next generation sequencing (NGS) has identified several novel subtypes, including one with ZNF384 rearrangements involving ZNF384 located at position 12p13.31[2][3][4][5][6][7].Interestingly, patients with this subtype appear to express various leukemic phenotypes, including B-ALL (with or without aberrant expression of myeloid markers) and B/myeloid mixed phenotype acute leukemia (MPAL).In this regard, ~5% of childhood B-ALL, ~10% of adult B-ALL, and 48% of B/Myeloid MPAL cases have been observed to harbor
Association Between Changes in Social Distancing Policies in Ohio and Traffic Volume and Injuries, January Through July 2020
Authors: Li Li, Lucas M. Neuroth, Edward Valachovic, David C. Schwebel, Motao Zhu
Journal: JAMA (2021)

This study compares traffic volume and motor vehicle crash injuries before, during, and after state-of-emergency and stay-at-home orders in the state of Ohio from January to July 2020 vs the same period in 2019.
Crumbs2 Is an Essential Slit Diaphragm Protein of the Renal Filtration Barrier
Authors: Annika Möller-Kerutt, Juan E. Rodriguez-Gatica, Karin Wacker, Rohan Bhatia, Jan-Peter Siebrasse, Nanda Boon, Veerle Van Marck, Peter Boor, Ulrich Kubitscheck, Jan Wijnholds, Hermann Pavenstädt, Thomas Weide
Journal: Journal of the American Society of Nephrology (2021)

Crumbs2 is expressed at embryonic stages as well as in the retina, brain, and glomerular podocytes. Recent studies identified CRB2 mutations as a novel cause of steroid-resistant nephrotic syndrome (SRNS).To study the function of Crb2 at the renal filtration barrier, mice lacking Crb2 exclusively in podocytes were generated. Gene expression and histologic studies as well as transmission and scanning electron microscopy were used to analyze these Crb2podKO knockout mice and their littermate controls. Furthermore, high-resolution expansion microscopy was used to investigate Crb2 distribution in murine glomeruli. For pull-down experiments, live cell imaging, and transcriptome analyses, cell lines were applied that inducibly express fluorescent protein-tagged CRB2 wild type and mutants.Crb2podKO mice developed proteinuria directly after birth that preceded a prominent development of disordered and effaced foot processes, upregulation of renal injury and inflammatory markers, and glomerulosclerosis. Pull-down assays revealed an interaction of CRB2 with Nephrin, mediated by their extracellular domains. Expansion microscopy showed that in mice glomeruli, Crb2 and Nephrin are organized in adjacent clusters. SRNS-associated CRB2 protein variants and a mutant that lacks a putative conserved O-glycosylation site were not transported to the cell surface. Instead, mutants accumulated in the ER, showed altered glycosylation pattern, and triggered an ER stress response.Crb2 is an essential component of the podocyte's slit diaphragm, interacting with Nephrin. Loss of slit diaphragm targeting and increasing ER stress are pivotal factors for onset and progression of CRB2-related SRNS.
Feeding the Controversy: When Pelvic Irradiation Improves Outcomes in High-Risk and Very High-Risk Prostate Cancer
Authors: Imraan Jan, Rahul R. Parikh
Journal: Journal of Clinical Oncology (2021)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
Association between antibiotics and gut microbiome dysbiosis in children: systematic review and meta-analysis
Authors: Lucy McDonnell, Alexander Gilkes, Mark Ashworth, Victoria Rowland, Timothy Hugh Harries, David Armstrong, Patrick White
Journal: Gut Microbes (2021)

Antibiotics in childhood have been linked with diseases including asthma, juvenile arthritis, type 1 diabetes, Crohn's disease and mental illness. The underlying mechanisms are thought related to dysbiosis of the gut microbiome. We conducted a systematic review of the association between antibiotics and disruption of the pediatric gut microbiome. Searches used MEDLINE, EMBASE and Web of Science. Eligible studies: association between antibiotics and gut microbiome dysbiosis; children 0-18 years; molecular techniques of assessment; outcomes of microbiome richness, diversity or composition. Quality assessed by Newcastle-Ottawa Scale or Cochrane Risk of Bias Tool. Meta-analysis where possible. A total of 4,668 publications identified: 12 in final analysis (5 randomized controlled trials (RCTs), 5 cohort studies, 2 cross-sectional studies). Microbiome richness was measured in 3 studies, species diversity in 6, and species composition in 10. Quality of evidence was good or fair. 5 studies found a significant reduction in diversity and 3 a significant reduction in richness. Macrolide exposure was associated with reduced richness for twice as long as penicillin. Significant reductions were seen in Bifidobacteria (5 studies) and Lactobacillus (2 studies), and significant increases in Proteobacteria such as E. coli (4 studies). A meta-analysis of RCTs of the effect of macrolide (azithromycin) exposure on the gut microbiome found a significant reduction in alpha-diversity (Shannon index: mean difference -0.86 (95% CI -1.59, -0.13). Antibiotic exposure was associated with reduced microbiome diversity and richness, and with changes in bacterial abundance. The potential for dysbiosis in the microbiome should be taken into account when prescribing antibiotics for children.Systematic review registration number: CRD42018094188.
Immune checkpoint inhibitors (ICI) in advanced upper tract and lower tract urothelial carcinoma (UC): A comparison of outcomes.
Authors: Stepan M. Esagian, Ali Raza Khaki, Lucia Carril-Ajuria, Joseph J. Park, Mehmet Asim Bilen, Tyler Francis Stewart, Victor Sacristan Santos, Jayanshu Jain, Rafael Morales-Barrera, Michael Edward Devitt, Christopher J. Hoimes, Evan Shreck, Abhishek Tripathi, Roubini Zakopoulou, Alejo Rodriguez-Vida, Alexandra Drakaki, Vivek Kumar, Pavlos Msaouel, Vadim S Koshkin, Petros Grivas
Journal: Journal of Clinical Oncology (2021)

406 Background: Despite anatomical and biological differences, upper and lower tract UC (UTUC; LTUC) are usually managed similarly. Modern era clinical trial data comparing their outcomes with ICI are conflicting. We hypothesized that response and outcomes would be similar in patients (pts) with advanced UTUC and LTUC. Methods: We performed a retrospective cohort study collecting demographic, clinicopathologic, treatment, and outcome data for pts with advanced UC receiving ICI (2013-2020) across 24 centers (US; Europe). We compared objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) between pts with UTUC and LTUC. Uni- / multi- variable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Stratified subgroup analyses were performed according to histology (pure, mixed) and line of treatment (first-line, subsequent). Results: A total of 984 pts were identified, and 707, 717, and 738 were included in ORR, OS, and PFS analyses, respectively. After exclusions, the UTUC group comprised of 130 pts (vs. 616 in LTUC) with median age 71 (40-92) (vs. 70 [32-93]), 62% men (vs. 76%), 41% never smokers (vs. 29%), 62% with history of prior radical surgery for primary tumor (vs. 52%), and 29% with liver metastases (vs. 18%). Table shows results of ORR, OS, and PFS analyses. In the overall population, pts with UTUC and LTUC receiving ICI had comparable ORR, OS, and PFS. Pts with mixed-histology UTUC had significantly lower ORR (adjusted OR 0.20, 95%CI 0.05-0.91) and shorter PFS (adjusted HR 1.66, 95%CI: 1.06-2.59) vs. mixed-histology LTUC. Conclusions: Pts with advanced UTUC and LTUC receiving ICI have similar response and outcomes, except for pts with mixed-histology UTUC vs LTUC. Subset analysis of primary tumor location in ongoing clinical trials can validate our data, while biomarker work is ongoing. [Table: see text]