tbuckley/cabot-search huggingface dataset:
Reporting guidelines for clinical trial reports for interventions involving artificial intelligence: the CONSORT-AI Extension
Authors: Xiaoxuan Liu, Samantha Cruz Rivera, David Moher, Melanie J Calvert, Alastair K Denniston
Journal: BMJ (2020)

Abstract The CONSORT 2010 (Consolidated Standards of Reporting Trials) statement provides minimum guidelines for reporting randomised trials. Its widespread use has been instrumental in ensuring transparency when evaluating new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate impact on health outcomes. The CONSORT-AI extension is a new reporting guideline for clinical trials evaluating interventions with an AI component. It was developed in parallel with its companion statement for clinical trial protocols: SPIRIT-AI. Both guidelines were developed through a staged consensus process, involving a literature review and expert consultation to generate 29 candidate items, which were assessed by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed on in a two-day consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The CONSORT-AI extension includes 14 new items, which were considered sufficiently important for AI interventions, that they should be routinely reported in addition to the core CONSORT 2010 items. CONSORT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention is integrated, the handling of inputs and outputs of the AI intervention, the human-AI interaction and providing analysis of error cases. CONSORT-AI will help promote transparency and completeness in reporting clinical trials for AI interventions. It will assist editors and peer-reviewers, as well as the general readership, to understand, interpret and critically appraise the quality of clinical trial design and risk of bias in the reported outcomes.
Current Evidence and Recommendations for Coronary CTA First in Evaluation of Stable Coronary Artery Disease
Authors: Michael Poon, John R. Lesser, Cathleen Biga, Ron Blankstein, Christopher M. Kramer, James K. Min, Pamela S. Noack, Christina Farrow, Udo Hoffman, Jaime Murillo, Koen Nieman, Leslee J. Shaw
Journal: Journal of the American College of Cardiology (2020)
Representation of Older Adults in Cardiovascular Disease Trials Since the Inclusion Across the Lifespan Policy
Authors: Michael G. Nanna, Sean T. Chen, Adam J. Nelson, Ann Marie Navar, Eric D. Peterson
Journal: JAMA Internal Medicine (2020)

This review compares representation of older adults in interventional cardiovascular disease studies in the US before and after implementation of the National Institutes of Health's Inclusion Across the Lifespan Policy.
Abstract 14807: Activation of the Growth Hormone-Releasing Hormone Receptor Prevents the Development of Heart Failure With Preserved Ejection Fraction in CD1 Mice
Authors: Raul A Dulce, Rosemeire M Kanashiro-Takeuchi, Lauro M Takeuchi, Alessandro Salerno, Wayne Balkan, Shathiyah Kulandavelu, Renzhi Cai, Andrew V Schally, Joshua M Hare
Journal: Circulation (2019)

Introduction: Heart failure with preserved ejection fraction (HFpEF) represents ~50% of heart failure cases and is characterized by impaired relaxation, ventricular stiffening and fibrosis. Growth ...
Angiotensin-Neprilysin Inhibition in Black Americans
Authors: Cecilia Berardi, Eugene Braunwald, David A. Morrow, Hillary S. Mulder, Carol I. Duffy, Terrence X. O’Brien, Andrew P. Ambrosy, Hrishikesh Chakraborty, Eric J. Velazquez, Adam D. DeVore
Journal: JACC Heart Failure (2020)

This study compared the efficacy and safety of sacubitril/valsartan to enalapril in Black and non-Black Americans with acute decompensated heart failure (ADHF). Black patients have a different response to treatment with angiotensin-converting enzyme inhibitors compared with other racial and ethnic groups. How Black patients with ADHF respond to sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, is unclear. PIONEER-HF was a double-blind randomized clinical trial of sacubitril/valsartan versus enalapril in hospitalized patients with ADHF following hemodynamic stabilization. In a pre-specified subgroup analysis, we examined changes in N-terminal pro–B-type natriuretic peptide, clinical outcomes, and safety according to race. The study population, all enrolled in the United States, included 316 (36%) Black participants, 515 (58%) White participants, and 50 (5.7%) participants of other racial groups. The reduction in N-terminal pro–B-type natriuretic peptide concentration at weeks 4 and 8 was significantly greater with sacubitril/valsartan than enalapril in both Black (ratio of change with sacubitril/valsartan vs. enalapril: 0.71; 95% confidence interval [CI]: 0.58 to 0.88) and non-Black patients (ratio of change: 0.71; 95% CI: 0.61 to 0.83; interaction p = 1.00). Compared with enalapril, sacubitril/valsartan also reduced the pre-specified exploratory composite of cardiovascular death or HF rehospitalization in both Black (hazard ratio: 0.47; 95% CI: 0.24 to 0.93) and non-Black patients (hazard ratio: 0.65; 95% CI: 0.40 to 1.06; interaction p = 0.44). Among Black patients admitted with ADHF in the United States, the in-hospital initiation of sacubitril/valsartan was more effective than enalapril in reducing natriuretic peptide levels and the composite of cardiovascular death or HF rehospitalization. The effect of sacubitril/valsartan did not differ by race. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890)
NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents
Authors: J. Laskin, S.V. Liu, K. Tolba, C. Heining, R.F. Schlenk, P. Cheema, J. Cadranel, M.R. Jones, A. Drilon, A. Cseh, S. Gyorffy, F. Solca, M. Duruisseaux
Journal: Annals of Oncology (2020)

•NRG1 fusions result in ErbB-mediated pathway activation and present a rational therapeutic target.•ErbB-targeted treatments, such as afatinib, can be effective therapeutic options in tumors harboring NRG1 fusions.•The incidence of NRG1 fusion-driven tumors is low, occurring in <1% of cancers, but is highest (≈10-30%) in invasive mucinous adenocarcinoma. Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents ≈2%–10% of lung adenocarcinomas and has a reported incidence of ≈10%–30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions. Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents ≈2%–10% of lung adenocarcinomas and has a reported incidence of ≈10%–30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions.
Young versus aged microbiota transplants to germ-free mice: increased short-chain fatty acids and improved cognitive performance
Authors: Juneyoung Lee, Venugopal R. Venna, David J. Durgan, Huanan Shi, Jacob Hudobenko, Nagireddy Putluri, Joseph Petrosino, Louise D. McCullough, Robert M. Bryan
Journal: Gut Microbes (2020)

Aging is associated with cognitive decline and decreased concentrations of short-chain fatty acids (SCFAs) in the gut. SCFAs are significant in that they are protective to the gut and other organs. We tested the hypothesis that the aged gut microbiome alone is sufficient to decrease SCFAs in the host and produce cognitive decline. Fecal transplant gavages (FTGs) from aged (18-20 months) or young (2-3 months) male C57BL/6 mice into germ-free male C57BL/6 mice (N = 11 per group) were initiated at ~3 months of age. Fecal samples were collected and behavioral testing was performed over the study period. Bacterial community structures and relative abundances were measured in fecal samples by sequencing the bacterial 16S ribosomal RNA gene. Mice with aged and young microbiomes showed clear differences in bacterial β diversity at 30, 60, and 90 d (P = .001 for each) after FTGs. The fecal SCFAs, acetate, propionate, and butyrate (microbiome effect, P < .01 for each) were decreased in mice with an aged microbiome. Mice with an aged microbiome demonstrated depressive-like behavior, impaired short-term memory, and impaired spatial memory over the 3 months following the initial FTG as assessed by the tail suspension (P = .008), the novel object recognition (P < .001), and the Barnes Maze (P = .030) tests, respectively. We conclude that an aged microbiome alone is sufficient to decrease SCFAs in the host and to produce cognitive decline.
Platypnoea orthodeoxia after hepatic surgery.
Authors: Muhammad Asrar ul Haq, Vivek Mutha, Ahmed Al-Kaisey, William J van Gaal
Journal: BMJ (2014)

Platypnoea orthodeoxia is a rare clinical syndrome characterised by dyspnoea and deoxygenation exhibited in upright position with improvement in supine posture. Previously described aetiologies include cardiac (pericardial effusion or constrictive pericarditis), pulmonary (pneumonectomy, emphysema or amiodarone toxicity), abdominal (cirrhosis or ileus) or vascular (abdominal aortic aneurysm) causes. We report an unusual case of platypnoea orthodeoxia associated with patent foramen ovale and partial hepatic resection.
A Deep Learning Framework Identifies Pathogenic Noncoding Somatic Mutations from Personal Prostate Cancer Genomes
Authors: Cheng Wang, Jingjing Li
Journal: Cancer Research (2020)

Abstract Our understanding of noncoding mutations in cancer genomes has been derived primarily from mutational recurrence analysis by aggregating clinical samples on a large scale. These cohort-based approaches cannot directly identify individual pathogenic noncoding mutations from personal cancer genomes. Therefore, although most somatic mutations are localized in the noncoding cancer genome, their effects on driving tumorigenesis and progression have not been systematically explored and noncoding somatic alleles have not been leveraged in current clinical practice to guide personalized screening, diagnosis, and treatment. Here, we present a deep learning framework to capture pathogenic noncoding mutations in personal cancer genomes, which perturb gene regulation by altering chromatin architecture. We deployed the system specifically for localized prostate cancer by integrating large-scale prostate cancer genomes and the prostate-specific epigenome. We exhaustively evaluated somatic mutations in each patient's genome and agnostically identified thousands of somatic alleles altering the prostate epigenome. Functional genomic analyses subsequently demonstrated that affected genes displayed differential expression in prostate tumor samples, were vulnerable to expression alterations, and were convergent onto androgen receptor–mediated signaling pathways. Accumulation of pathogenic regulatory mutations in these affected genes was predictive of clinical observations, suggesting potential clinical utility of this approach. Overall, the deep learning framework has significantly expanded our view of somatic mutations in the vast noncoding genome, uncovered novel genes in localized prostate cancer, and will foster the development of personalized screening and therapeutic strategies for prostate cancer. Significance: This study's characterization of the noncoding genome in prostate cancer reveals mutational signatures predictive of clinical observations, which may serve as a powerful prognostic tool in this disease.
Human model of <i>IRX5</i> mutations reveals key role for this transcription factor in ventricular conduction
Authors: Zeina R Al Sayed, Robin Canac, Bastien Cimarosti, Carine Bonnard, Jean-Baptiste Gourraud, Hanan Hamamy, Hulya Kayserili, Aurore Girardeau, Mariam Jouni, Nicolas Jacob, Anne Gaignerie, Caroline Chariau, Laurent David, Virginie Forest, Céline Marionneau, Flavien Charpentier, Gildas Loussouarn, Guillaume Lamirault, Bruno Reversade, Kazem Zibara, Patricia Lemarchand, Nathalie Gaborit
Journal: Cardiovascular Research (2020)

Abstract Aims Several inherited arrhythmic diseases have been linked to single gene mutations in cardiac ion channels and interacting proteins. However, the mechanisms underlying most arrhythmias, are thought to involve altered regulation of the expression of multiple effectors. In this study, we aimed to examine the role of a transcription factor (TF) belonging to the Iroquois homeobox family, IRX5, in cardiac electrical function. Methods and results Using human cardiac tissues, transcriptomic correlative analyses between IRX5 and genes involved in cardiac electrical activity showed that in human ventricular compartment, IRX5 expression strongly correlated to the expression of major actors of cardiac conduction, including the sodium channel, Nav1.5, and Connexin 40 (Cx40). We then generated human-induced pluripotent stem cells (hiPSCs) derived from two Hamamy syndrome-affected patients carrying distinct homozygous loss-of-function mutations in IRX5 gene. Cardiomyocytes derived from these hiPSCs showed impaired cardiac gene expression programme, including misregulation in the control of Nav1.5 and Cx40 expression. In accordance with the prolonged QRS interval observed in Hamamy syndrome patients, a slower ventricular action potential depolarization due to sodium current reduction was observed on electrophysiological analyses performed on patient-derived cardiomyocytes, confirming the functional role of IRX5 in electrical conduction. Finally, a cardiac TF complex was newly identified, composed by IRX5 and GATA4, in which IRX5 potentiated GATA4-induction of SCN5A expression. Conclusion Altogether, this work unveils a key role for IRX5 in the regulation of human ventricular depolarization and cardiac electrical conduction, providing therefore new insights into our understanding of cardiac diseases.
Radiologist-like artificial intelligence for grade group prediction of radical prostatectomy for reducing upgrading and downgrading from biopsy
Authors: Lizhi Shao, Ye Yan, Zhenyu Liu, Xiongjun Ye, Haizhui Xia, Xuehua Zhu, Yuting Zhang, Zhiying Zhang, Huiying Chen, Wei He, Cheng Liu, Min Lu, Yi Huang, Lulin Ma, Kai Sun, Xuezhi Zhou, Guanyu Yang, Jian Lu, Jie Tian
Journal: Theranostics (2020)

To reduce upgrading and downgrading between needle biopsy (NB) and radical prostatectomy (RP) by predicting patient-level Gleason grade groups (GGs) of RP to avoid over- and under-treatment.
Genome Duplication Increases Meiotic Recombination Frequency: A <i>Saccharomyces cerevisiae</i> Model
Authors: Ou Fang, Lin Wang, Yuxin Zhang, Jixuan Yang, Qin Tao, Fengjun Zhang, Zewei Luo
Journal: Molecular Biology and Evolution (2020)

Abstract Genetic recombination characterized by reciprocal exchange of genes on paired homologous chromosomes is the most prominent event in meiosis of almost all sexually reproductive organisms. It contributes to genome stability by ensuring the balanced segregation of paired homologs in meiosis, and it is also the major driving factor in generating genetic variation for natural and artificial selection. Meiotic recombination is subjected to the control of a highly stringent and complex regulating process and meiotic recombination frequency (MRF) may be affected by biological and abiotic factors such as sex, gene density, nucleotide content, and chemical/temperature treatments, having motivated tremendous researches for artificially manipulating MRF. Whether genome polyploidization would lead to a significant change in MRF has attracted both historical and recent research interests; however, tackling this fundamental question is methodologically challenging due to the lack of appropriate methods for tetrasomic genetic analysis, thus has led to controversial conclusions in the literature. This article presents a comprehensive and rigorous survey of genome duplication-mediated change in MRF using Saccharomyces cerevisiae as a eukaryotic model. It demonstrates that genome duplication can lead to consistently significant increase in MRF and rate of crossovers across all 16 chromosomes of S. cerevisiae, including both cold and hot spots of MRF. This ploidy-driven change in MRF is associated with weakened recombination interference, enhanced double-strand break density, and loosened chromatin histone occupation. The study illuminates a significant evolutionary feature of genome duplication and opens an opportunity to accelerate response to artificial and natural selection through polyploidization.
Clinical Outcomes in Young US Adults Hospitalized With COVID-19
Authors: Jonathan W. Cunningham, Muthiah Vaduganathan, Brian L. Claggett, Karola S. Jering, Ankeet S. Bhatt, Ning Rosenthal, Scott D. Solomon
Journal: JAMA Internal Medicine (2020)

Clinical Outcomes in Young US Adults Hospitalized With COVID-19Coronavirus disease 2019 (COVID-19) is increasing rapidly among young adults in the US. 1 Often described as a disease affecting older adults, to our knowledge, few studies have included younger patients to better understand their anticipated clinical trajectory.We investigated the clinical profile and outcomes of 3222 young adults (defined by the US Census as age 18-34 years) who required hospitalization for COVID-19 in the US.Methods | Young adults age 18 to 34 years with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) code U07.1 (COVID-19, virus identified) discharged between April 1 and June 30, 2020, were identified in the Premier Healthcare Database, a hospitalbased, all-payer database including 1030 US hospitals and health care systems and more than 8 million annual inpatient admissions. 2,3Pregnant young adults (n = 1644) were excluded because many were admitted for childbirth and not for COVID-19 infection.Only a patient's first hospitalization for COVID-19 was considered.Comorbidities and outcomes during COVID-19 hospitalization were defined using diagnosis, procedure, or billing ICD-10 codes.Intensive care utilization was defined by a billing code for intensive care unit room or daily ventilator management.Independent factors associated with the composite outcome of mechanical ventilation or death were identified by multivariable logistic regression.Race and ethnicity were reported by participating hospitals.
YAP and AP-1 Cooperate to Initiate Pancreatic Cancer Development from Ductal Cells in Mice
Authors: Jaeoh Park, David Eisenbarth, Wonyoung Choi, Hail Kim, Chan Choi, Dahye Lee, Dae-Sik Lim
Journal: Cancer Research (2020)

The development of pancreatic cancer is heavily dependent upon the aberrant activation of KRAS signaling. Among the downstream targets of KRAS, the effectors of the Hippo pathway YAP and TAZ (YAP/TAZ) are crucial during cancer initiation and progression. However, little is known about the cell type-specific effects of YAP/TAZ on the development of pancreatic cancer. Here we clarify the unique consequences of YAP/TAZ activation in the ductal cell population of the pancreas by generating mice with pancreatic duct cell-specific, inducible knockouts of Lats1 and Lats2, the main kinases upstream of YAP/TAZ. Oncogenic activation of YAP by deletion of Lats1/2 in ductal cells led to the rapid transformation of the pancreas, which was accompanied by a robust increase in the expression of YAP and AP-1 target genes. Pharmacologic inhibition of AP-1 activity induced death in Lats1/2 knockout organoids and attenuated YAP-dependent transformation of the pancreas in vivo. Both YAP and AP-1 were activated during the development of KRAS-dependent cancer in mice and human patients with pancreatic ductal adenocarcinoma, suggesting that this signaling hub represents an important mediator of pancreatic cancer development and progression. Collectively, these data define a YAP-dependent mechanism of pancreatic cancer cell development and suggest that inhibition of AP-1 can suppress this development. SIGNIFICANCE: A pancreatic ductal cell-specific knockout mouse model featuring constitutively active YAP allows for the study of YAP-dependent transformation of the pancreas and for screening pharmacologically active inhibitors.
Primo: integration of multiple GWAS and omics QTL summary statistics for elucidation of molecular mechanisms of trait-associated SNPs and detection of pleiotropy in complex traits
Authors: Kevin J. Gleason, Fan Yang, Brandon L. Pierce, Xin He, Lin S. Chen
Journal: Genome biology (2020)

To provide a comprehensive mechanistic interpretation of how known trait-associated SNPs affect complex traits, we propose a method, Primo, for integrative analysis of GWAS summary statistics with multiple sets of omics QTL summary statistics from different cellular conditions or studies. Primo examines association patterns of SNPs to complex and omics traits. In gene regions harboring known susceptibility loci, Primo performs conditional association analysis to account for linkage disequilibrium. Primo allows for unknown study heterogeneity and sample correlations. We show two applications using Primo to examine the molecular mechanisms of known susceptibility loci and to detect and interpret pleiotropic effects.