tbuckley/cabot-search huggingface dataset:
Heterogeneity within and between physician-diagnosed asthma and/or COPD: NOVELTY cohort
Authors: Helen K. Reddel, Jørgen Vestbo, Alvar Agustí, Gary P. Anderson, Aruna T. Bansal, Richard Beasley, Elisabeth H. Bel, Christer Janson, Barry Make, Ian D. Pavord, David Price, Eleni Rapsomaniki, Niklas Karlsson, Donna K. Finch, Javier Nuevo, Alex de Giorgio-Miller, Marianna Alacqua, Rod Hughes, Hana Müllerová, Maria Gerhardsson de Verdier
Journal: European Respiratory Journal (2021)

Studies of asthma and chronic obstructive pulmonary disease (COPD) typically focus on these diagnoses separately, limiting understanding of disease mechanisms and treatment options. NOVELTY is a global, 3-year, prospective observational study of patients with asthma and/or COPD from real-world clinical practice. We investigated heterogeneity and overlap by diagnosis and severity in this cohort.Patients with physician-assigned asthma, COPD or both (asthma+COPD) were enrolled, and stratified by diagnosis and severity. Baseline characteristics were reported descriptively by physician-assigned diagnosis and/or severity. Factors associated with physician-assessed severity were evaluated using ordinal logistic regression analysis.Of 11 243 patients, 5940 (52.8%) had physician-assigned asthma, 1396 (12.4%) had asthma+COPD and 3907 (34.8%) had COPD; almost half were from primary care. Symptoms, health-related quality of life and spirometry showed substantial heterogeneity and overlap between asthma, asthma+COPD and COPD, with 23%, 62% and 64% of patients, respectively, having a ratio of post-bronchodilator forced expiratory volume in 1 s to forced vital capacity below the lower limit of normal. Symptoms and exacerbations increased with greater physician-assessed severity and were higher in asthma+COPD. However, 24.3% with mild asthma and 20.4% with mild COPD had experienced ≥1 exacerbation in the past 12 months. Medication records suggested both under-treatment and over-treatment relative to severity. Blood eosinophil counts varied little across diagnosis and severity groups, but blood neutrophil counts increased with severity across all diagnoses.This analysis demonstrates marked heterogeneity within, and overlap between, physician-assigned diagnosis and severity groups in patients with asthma and/or COPD. Current diagnostic and severity classifications in clinical practice poorly differentiate between clinical phenotypes that may have specific risks and treatment implications.
Assessment of the Association of Leadership Behaviors of Supervising Physicians With Personal-Organizational Values Alignment Among Staff Physicians
Authors: Tait D. Shanafelt, Hanhan Wang, Mary Leonard, Mary Hawn, Quinn McKenna, Rick Majzun, Lloyd Minor, Mickey Trockel
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Although misalignment of values between physicians and their organization is associated with increased risk of burnout, actionable organizational factors that contribute to perceived values alignment are poorly understood. <h3>Objective</h3> To evaluate the association between the leadership behaviors of immediate supervisors and physicians’ perception of personal-organizational values alignment. <h3>Design, Setting, and Participants</h3> This survey study of faculty physicians and physician leaders at Stanford University School of Medicine was conducted from April 1 to May 13, 2019. The survey included assessments of perceived personal-organizational values alignment, professional fulfillment, and burnout. Physicians also evaluated the leadership behaviors of their immediate supervisor (eg, division chief) using a standardized assessment. Data analysis was performed from May to December 2020. <h3>Main Outcomes and Measures</h3> Association between mean leadership behavior score (range, 0-10) of each supervisor and the mean personal-organizational values alignment scores (range, 0-12) for the physicians in their work unit. <h3>Results</h3> Of 1924 physicians eligible to participate, 1285 (67%) returned surveys. Among these, 651 (51%) were women and 729 (57%) were aged 40 years or older. Among the 117 physician leaders evaluated, 66 (56%) had their leadership behavior independently evaluated by at least 5 physicians and were included in analyses. The mean (SD) personal-organizational values alignment score on the 0 to 12 scale was 6.19 (3.21). As the proportion of work effort devoted to clinical care increased, values alignment scores decreased. Personal-organizational values alignment scores demonstrated an inverse correlation with burnout (<i>r</i> = −0.39;<i>P</i> &lt; .001) and a positive correlation with professional fulfillment (<i>r</i> = 0.52;<i>P</i> &lt; .001). The aggregate leader behavior score of the 66 leaders evaluated correlated with the mean values alignment score for physicians in their work unit (<i>r</i> = 0.53;<i>P</i> &lt; .001). Aggregate leader behavior score was associated with 21.6% of the variation in personal-organizational values alignment scores between work units. After adjusting for age, gender, academic rank, work hours, physician-leader gender concordance, and time devoted to clinical care, each 1-point increase in leadership score of immediate supervisor was associated with a 0.56-point (95% CI, 0.46-0.66;<i>P</i> &lt; .001) increase in personal-organizational values alignment score. <h3>Conclusions and Relevance</h3> This survey study’s results suggest that physicians experience their organization through the prism of their work unit leader. Organizational efforts to improve values alignment should attend to the development of first-line physician leaders.
Lipopolysaccharide Binding Protein and CD14, Cofactors of Toll‐like Receptors, Are Essential for Low‐Grade Inflammation–Induced Exacerbation of Cartilage Damage in Mouse Models of Posttraumatic Osteoarthritis
Authors: Yoonkyung Won, Jeong‐In Yang, Seulki Park, Jang‐Soo Chun
Journal: Arthritis & Rheumatology (2021)

Objective Osteoarthritis (OA) is initiated by pathogenic factors produced by multiple stimuli, including mechanical stress, metabolic stress, and/or inflammaging. This study was undertaken to identify novel low‐grade inflammation–associated pathogenic mediators of OA. Methods Candidate pathogenic molecules were screened using microarray data obtained from chondrocytes exposed to OA‐associated catabolic factors. In mice with OA generated by destabilization of the medial meniscus (DMM), low‐grade inflammation was induced by a high‐fat diet or endotoxemia. Functions of candidate molecules in OA pathogenesis were examined using primary‐culture chondrocytes from mice with DMM‐induced OA, following intraarticular injection of adenovirus expressing the candidate gene. Specific functions of candidate genes were evaluated using whole‐body gene‐knockout mice. Results Bioinformatics analysis identified multiple candidate pathogenic factors that were associated with low‐grade inflammation, including components of the Toll‐like receptor (TLR) signaling pathways (e.g., TLR‐2, TLR‐4, lipopolysaccharide binding protein [LBP], and CD14). Overexpression of the individual TLR signaling components in mouse joint tissue did not alter cartilage homeostasis. However, the low‐grade inflammation induced by a high‐fat diet or endotoxemia markedly enhanced posttraumatic OA cartilage destruction in mice, and this exacerbation of cartilage destruction was significantly abrogated in LBP −/− and CD14 −/− mice. Additionally, LBP and CD14 were found to be necessary for the expression of matrix‐degrading enzymes in mouse chondrocytes treated with proinflammatory cytokines. Conclusion LBP and CD14, which are accessory molecules of TLRs, are necessary for the exacerbation of posttraumatic OA cartilage destruction resulting from low‐grade inflammation, such as that triggered by a high‐fat diet or endotoxemia.
Financing of US Graduate Medical Education
Authors: Trevor J. Royce
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
The Genomes of Two Billfishes Provide Insights into the Evolution of Endothermy in Teleosts
Authors: Baosheng Wu, Chenguang Feng, Chenglong Zhu, Wenjie Xu, Yuan Yuan, Mingliang Hu, Ke Yuan, Yongxin Li, Yandong Ren, Yang Zhou, Haifeng Jiang, Qiang Qiu, Wen Wang, Shunping He, Kun Wang
Journal: Molecular Biology and Evolution (2021)

Abstract Endothermy is a typical convergent phenomenon which has evolved independently at least eight times in vertebrates, and is of significant advantage to organisms in extending their niches. However, how vertebrates other than mammals or birds, especially teleosts, achieve endothermy has not previously been fully understood. In this study, we sequenced the genomes of two billfishes (swordfish and sailfish), members of a representative lineage of endothermic teleosts. Convergent amino acid replacements were observed in proteins related to heat production and the visual system in two endothermic teleost lineages, billfishes and tunas. The billfish-specific genetic innovations were found to be associated with heat exchange, thermoregulation, and the specialized morphology, including elongated bill, enlarged dorsal fin in sailfish and loss of the pelvic fin in swordfish.
Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis
Authors: Andrew Blauvelt, Steven Kempers, Edward Lain, Todd Schlesinger, Stephen Tyring, Seth Forman, Glynis Ablon, George Martin, Hui Wang, David L. Cutler, Jane Fang, Min-Fun R. Kwan
Journal: New England Journal of Medicine (2021)

The tubulin polymerization and Src kinase signaling inhibitor tirbanibulin is being investigated as a topical treatment for actinic keratosis, a precursor of squamous-cell carcinoma.
Deficiency of inactive rhomboid protein 2 (iRhom2) attenuates diet-induced hyperlipidaemia and early atherogenesis
Authors: Carmen Hannemann, Johannes H Schecker, Alica Brettschneider, Jana Grune, Nicole Rösener, Andrea Weller, Verena Stangl, Edward A Fisher, Karl Stangl, Antje Ludwig, Bernd Hewing
Journal: Cardiovascular Research (2021)

Abstract Aims Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall and anti-inflammatory treatment strategies are currently pursued to lower cardiovascular disease burden. Modulation of recently discovered inactive rhomboid protein 2 (iRhom2) attenuates shedding of tumour necrosis factor-alpha (TNF-α) selectively from immune cells. The present study aims at investigating the impact of iRhom2 deficiency on the development of atherosclerosis. Methods and results Low-density lipoprotein receptor (LDLR)-deficient mice with additional deficiency of iRhom2 (LDLR−/−iRhom2−/−) and control (LDLR−/−) mice were fed a Western-type diet (WD) for 8 or 20 weeks to induce early or advanced atherosclerosis. Deficiency of iRhom2 resulted in a significant decrease in the size of early atherosclerotic plaques as determined in aortic root cross-sections. LDLR−/−iRhom2−/− mice exhibited significantly lower serum levels of TNF-α and lower circulating and hepatic levels of cholesterol and triglycerides compared to LDLR−/− mice at 8 weeks of WD. Analyses of hepatic bile acid concentration and gene expression at 8 weeks of WD revealed that iRhom2 deficiency prevented WD-induced repression of hepatic bile acid synthesis in LDLR−/− mice. In contrast, at 20 weeks of WD, plaque size, plaque composition, and serum levels of TNF-α or cholesterol were not different between genotypes. Conclusion Modulation of inflammation by iRhom2 deficiency attenuated diet-induced hyperlipidaemia and early atherogenesis in LDLR−/− mice. iRhom2 deficiency did not affect diet-induced plaque burden and composition in advanced atherosclerosis in LDLR−/− mice.
The knowns and unknowns of latent Mycobacterium tuberculosis infection
Authors: W. Henry Boom, Ulrich E. Schaible, Jacqueline M. Achkar
Journal: Journal of Clinical Investigation (2021)

Humans have been infected with Mycobacterium tuberculosis (Mtb) for thousands of years. While tuberculosis (TB), one of the deadliest infectious diseases, is caused by uncontrolled Mtb infection, over 90% of presumed infected individuals remain asymptomatic and contain Mtb in a latent TB infection (LTBI) without ever developing disease, and some may clear the infection. A small number of heavily Mtb-exposed individuals appear to resist developing traditional LTBI. Because Mtb has mechanisms for intracellular survival and immune evasion, successful control involves all of the arms of the immune system. Here, we focus on immune responses to Mtb in humans and nonhuman primates and discuss new concepts and outline major knowledge gaps in our understanding of LTBI, ranging from the earliest events of exposure and infection to success or failure of Mtb control.
Viral Loads of SARS-CoV-2 in Young Children
Authors: Heather Finlay-Morreale
Journal: JAMA Pediatrics (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 Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals 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 2024 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 Pediatrics journal
Specific Follicular Helper T Cell Signature in Takayasu Arteritis
Authors: A. C. Desbois, P. Régnier, V. Quiniou, A. Lejoncour, A. Maciejewski‐Duval, C. Comarmond, H. Vallet, M. Rosenzwag, G. Darrasse‐Jèze, N. Derian, J. Pouchot, M. Samson, B. Bienvenu, P. Fouret, F. Koskas, M. Garrido, D. Sène, P. Bruneval, P. Cacoub, D. Klatzmann, D. Saadoun
Journal: Arthritis & Rheumatology (2021)

Our aim was to compare transcriptome and phenotype profiles of CD4+ T cells and CD19+ B cells in patients with Takayasu arteritis (TAK), patients with giant cell arteritis (GCA), and healthy donors.Gene expression analyses, flow cytometry immunophenotyping, T cell receptor (TCR) gene sequencing, and functional assessments of cells from peripheral blood and arterial lesions from TAK patients, GCA patients, and healthy donors were performed.Among the most significantly dysregulated genes in CD4+ T cells of TAK patients compared to GCA patients (n = 720 genes) and in CD4+ T cells of TAK patients compared to healthy donors (n = 1,447 genes), we identified a follicular helper T (Tfh) cell signature, which included CXCR5, CCR6, and CCL20 genes, that was transcriptionally up-regulated in TAK patients. Phenotypically, there was an increase in CD4+CXCR5+CCR6+CXCR3- Tfh17 cells in TAK patients that was associated with a significant enrichment of CD19+ B cell activation. Functionally, Tfh cells helped B cells to proliferate, differentiate into memory cells, and secrete IgG antibodies. Maturation of B cells was inhibited by JAK inhibitors. Locally, in areas of arterial inflammation, we found a higher proportion of tertiary lymphoid structures comprised CD4+, CXCR5+, programmed death 1+, and CD20+ cells in TAK patients compared to GCA patients. CD4+CXCR5+ T cells in the aortas of TAK patients had an oligoclonal α/β TCR repertoire.We established the presence of a specific Tfh cell signature in both circulating and aorta-infiltrating CD4+ T cells from TAK patients. The cooperation of Tfh cells and B cells might be critical in the occurrence of vascular inflammation in patients with TAK.
Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease
Authors: Nan Ye, Meg J. Jardine, Megumi Oshima, Carinna Hockham, Hiddo J.L. Heerspink, Rajiv Agarwal, George Bakris, Aletta E. Schutte, Clare Arnott, Tara I. Chang, Jose L. Górriz, Christopher P. Cannon, David M. Charytan, Dick de Zeeuw, Adeera Levin, Kenneth W. Mahaffey, Bruce Neal, Carol Pollock, David C. Wheeler, Gian Luca Di Tanna, Hong Cheng, Vlado Perkovic, Brendon L. Neuen
Journal: Circulation (2021)

Background: People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. Methods: The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. Results: The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, –4.27 to –2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61–0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59–0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. Conclusions: In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02065791.
The Hydroxyquinoline Analogue YUM70 Inhibits GRP78 to Induce ER Stress–Mediated Apoptosis in Pancreatic Cancer
Authors: Soma Samanta, Suhui Yang, Bikash Debnath, Ding Xue, Yuting Kuang, Kavya Ramkumar, Amy S. Lee, Mats Ljungman, Nouri Neamati
Journal: Cancer Research (2021)

Abstract GRP78 (glucose-regulated protein, 78 kDa) is a key regulator of endoplasmic reticulum (ER) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis and folding, which results in significant stress on the ER. To respond to ER stress and maintain cellular homeostasis, cells activate the unfolded protein response (UPR) that promotes either survival or apoptotic death. Cancer cells utilize the UPR to promote survival and growth. In this study, we describe the discovery of a series of novel hydroxyquinoline GRP78 inhibitors. A representative analogue, YUM70, inhibited pancreatic cancer cell growth in vitro and showed in vivo efficacy in a pancreatic cancer xenograft model with no toxicity to normal tissues. YUM70 directly bound GRP78 and inactivated its function, resulting in ER stress–mediated apoptosis. A YUM70 analogue conjugated with BODIPY showed colocalization of the compound with GRP78 in the ER. Moreover, a YUM70-PROTAC (proteolysis targeting chimera) was synthesized to force degradation of GRP78 in pancreatic cancer cells. YUM70 showed a strong synergistic cytotoxicity with topotecan and vorinostat. Together, our study demonstrates that YUM70 is a novel inducer of ER stress, with preclinical efficacy as a monotherapy or in combination with topoisomerase and HDAC inhibitors in pancreatic cancer. Significance: This study identifies a novel ER stress inducer that binds GRP78 and inhibits pancreatic cancer cell growth in vitro and in vivo, demonstrating its potential as a therapeutic agent for pancreatic cancer.
Abstract 11081: Minute Myocardial Injury as Measured By High-sensitive Troponin T Predicts the Response to Intracoronary Infusion of Bone Marrow-derived Mononuclear Cells in Patients With Stable Chronic Post-infarction Heart Failure - Insights From the TOPCARE-CHD Registry
Authors: David M Leistner, Florian H Seeger, Joerg Honold, Brigitte Luu, Stephan Fichtlscherer, Andreas M Zeiher, Birgit Assmus
Journal: Circulation (2012)

Cell based therapies are a promising option in pts with chronic post-infarction heart failure (ICM). However, the responses following intracoronary infusion of autologous bone marrow-derived mononu...