tbuckley/cabot-search huggingface dataset:
Expert Perspective: Management of Refractory Inflammatory Myopathy
Authors: Ingrid E. Lundberg
Journal: Arthritis & Rheumatology (2021)

The idiopathic inflammatory myopathies (IIMs) are chronic disorders characterized by inflammation in skeletal muscle but also in other organs such as the skin, lungs, joints, gastrointestinal tract, and heart. The effect of immunosuppressive treatment varies between individual patients and between organ manifestations within the same individual. Many patients respond poorly to first‐line treatment with glucocorticoids and other immunosuppressive agents such as methotrexate or azathioprine, with symptoms persisting in the muscles, skin, and lungs, leading to refractory disease. Management of refractory IIM is a clinical challenge, and a systematic approach is proposed to better understand the lack of treatment response, in order to guide disease management. The first step in the management of refractory IIM is to recognize whether remaining symptoms are caused by persistent inflammation in the affected tissue or whether the symptoms may be attributable to damage preceding inflammation. Thus, a second diagnostic examination is recommended. Second, in particular for patients with remaining muscle weakness, it is important to ascertain whether the diagnosis of myositis is correct or whether another underlying muscle disorder could explain the symptoms. Third, with confirmation of remaining inflammation in the tissues, a strategy to change treatment needs to be undertaken. Few controlled trials are available to guide our treatment strategies. Furthermore, different subgroups of patients may benefit from different therapies, and different organ manifestations may respond to different therapies. In this context, subgrouping of patients with IIM based on autoantibody profile may be helpful, as there are emerging data from open studies and case series to support the notion of a varying treatment response in different autoantibody‐defined subgroups of IIM patients.
Multimodal investigation of rat hepatitis E virus antigenicity: Implications for infection, diagnostics, and vaccine efficacy
Authors: Siddharth Sridhar, Jianwen Situ, Jian-Piao Cai, Cyril Chik-Yan Yip, Shusheng Wu, Anna Jin-Xia Zhang, Lei Wen, Nicholas Foo-Siong Chew, Wan-Mui Chan, Rosana Wing-Shan Poon, Jasper Fuk-Woo Chan, Dominic Ngai-Chong Tsang, Honglin Chen, Ning-Shao Xia, Kwok-Yung Yuen
Journal: Journal of Hepatology (2021)
Is Comprehensive Geriatric Assessment Admission Avoidance Hospital at Home an Alternative to Hospital Admission for Older Persons?
Authors: Sasha Shepperd, Chris Butler, Andrea Cradduck-Bamford, Graham Ellis, Alastair Gray, Anthony Hemsley, Pradeep Khanna, Peter Langhorne, Sam Mort, Scott Ramsay, Rebekah Schiff, David J. Stott, Angela Wilkinson, Ly-Mee Yu, John Young
Journal: Annals of Internal Medicine (2021)

Background: Delivering hospital-level care with comprehensive geriatric assessment (CGA) in the home is one approach to deal with the increased demand for bed-based hospital care, but clinical effectiveness is uncertain. Objective: To assess the clinical effectiveness of admission avoidance hospital at home (HAH) with CGA for older persons. Design: Multisite randomized trial. (ISRCTN registry number: ISRCTN60477865) Setting: 9 hospital and community sites in the United Kingdom. Patients: 1055 older persons who were medically unwell, were physiologically stable, and were referred for a hospital admission. Intervention: Admission avoidance HAH with CGA versus hospital admission with CGA when available using 2:1 randomization. Measurements: The primary outcome of living at home was measured at 6 months. Secondary outcomes were new admission to long-term residential care, death, health status, delirium, and patient satisfaction. Results: Participants had a mean age of 83.3 years (SD, 7.0). At 6-month follow-up, 528 of 672 (78.6%) participants in the CGA HAH group versus 247 of 328 (75.3%) participants in the hospital group were living at home (relative risk [RR], 1.05 [95% CI, 0.95 to 1.15]; P = 0.36); 114 of 673 (16.9%) versus 58 of 328 (17.7%) had died (RR, 0.98 [CI, 0.65 to 1.47]; P = 0.92); and 37 of 646 (5.7%) versus 27 of 311 (8.7%) were in long-term residential care (RR, 0.58 [CI, 0.45 to 0.76]; P < 0.001). Limitation: The findings are most applicable to older persons referred from a hospital short-stay acute medical assessment unit; episodes of delirium may have been undetected. Conclusion: Admission avoidance HAH with CGA led to similar outcomes as hospital admission in the proportion of older persons living at home as well as a decrease in admissions to long-term residential care at 6 months. This type of service can provide an alternative to hospitalization for selected older persons. Primary Funding Source: The National Institute for Health Research Health Services and Delivery Research Programme (12/209/66).
E-Cigarettes and the Multiple Responsibilities of the FDA
Authors: Larisa Svirsky, Dana Howard, Micah L. Berman
Journal: The American Journal of Bioethics (2021)

This paper considers the responsibilities of the FDA with regard to disseminating information about the benefits and harms of e-cigarettes. Tobacco harm reduction advocates claim that the FDA has been overcautious and has violated ethical obligations by failing to clearly communicate to the public that e-cigarettes are far less harmful than cigarettes. We argue, by contrast, that the FDA's obligations in this arena are more complex than they may appear at first blush. Though the FDA is accountable for informing the public about the health risks and benefits of products it regulates, it also has other roles (and attendant responsibilities) that inform when and how it should disseminate information. In addition to being a knowledge purveyor, it is also a knowledge producer, an advisor to the public, and a practical agent shaping the material conditions in which people make health-related choices. In our view, those other roles call for caution in the way the FDA interprets and communicates the available evidence.
バイオ3D印刷システムを用いたヒト細胞の層状,Trachea様,足場フリー構造によるラット気管の置換【JST・京大機械翻訳】
Authors: Machino Ryusuke, Matsumoto Keitaro, Taniguchi Daisuke, Tsuchiya Tomoshi, Takeoka Yosuke, Taura Yasuaki, Moriyama Masaaki, Tetsuo Tomoyuki, Oyama Shosaburo, Takagi Katsunori, Miyazaki Takuro, Hatachi Go, Doi Ryoichiro, Shimoyama Koichiro, Matsuo Naoto, Yamasaki Naoya, Nakayama Koichi, Nagayasu Takeshi
Journal: Advanced Healthcare Materials (2019)
A genome-wide atlas of co-essential modules assigns function to uncharacterized genes
Authors: Michael Wainberg, Roarke A. Kamber, Akshay Balsubramani, Robin M. Meyers, Nasa Sinnott-Armstrong, Daniel Hornburg, Lihua Jiang, Joanne Chan, Ruiqi Jian, Mingxin Gu, Anna Shcherbina, Michael M. Dubreuil, Kaitlyn Spees, Wouter Meuleman, Michael P. Snyder, Michael C. Bassik, Anshul Kundaje
Journal: Nature Genetics (2021)
Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury
Authors: Alison W Ha, Tao Bai, David L Ebenezer, Tanvi Sethi, Tara Sudhadevi, Lizar Ace Mangio, Steven Garzon, Gloria S Pryhuber, Viswanathan Natarajan, Anantha Harijith
Journal: Thorax (2021)

Introduction Neonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD. Method The enzyme expression of SPHK1 and LOX were assessed in lung tissues of human BPD using immunohistochemistry and quantified (Halo). In vivo studies were based on Sphk1 −/− and matched wild type (WT) neonatal mice exposed to HO while treated with PF543, an inhibitor of SPHK1. In vitro mechanistic studies used human lung microvascular endothelial cells (HLMVECs). Results Both SPHK1 and LOX expressions were increased in lungs of patients with BPD. Tracheal aspirates from patients with BPD had increased LOX, correlating with sphingosine-1-phosphate (S1P) levels. HO-induced increase of LOX in lungs were attenuated in both Sphk1 −/− and PF543-treated WT mice, accompanied by reduced collagen staining (sirius red). PF543 reduced LOX activity in both bronchoalveolar lavage fluid and supernatant of HLMVECs following HO. In silico analysis revealed STAT3 as a potential transcriptional regulator of LOX. In HLMVECs, following HO, ChIP assay confirmed increased STAT3 binding to LOX promoter. SPHK1 inhibition reduced phosphorylation of STAT3. Antibody to S1P and siRNA against SPNS2, S1P receptor 1 (S1P 1 ) and STAT3 reduced LOX expression. Conclusion HO-induced SPHK1/S1P signalling axis plays a critical role in transcriptional regulation of LOX expression via SPNS2, S1P 1 and STAT3 in lung endothelium.
Bone Marrow Mesenchymal Stromal Cells Can Render Multiple Myeloma Cells Resistant to Cytotoxic Machinery of CAR T Cells through Inhibition of Apoptosis
Authors: Lisa C. Holthof, Jort J. van der Schans, Afroditi Katsarou, Renée Poels, Anne T. Gelderloos, Esther Drent, Susan E. van Hal-van Veen, Fengzhi Li, Sonja Zweegman, Niels W.C.J. van de Donk, Maria Themeli, Richard W.J. Groen, Tuna Mutis
Journal: Clinical Cancer Research (2021)

Abstract Purpose: The microenvironment of multiple myeloma (MM) can critically impair therapy outcome, including immunotherapies. In this context, we have earlier demonstrated that bone marrow mesenchymal stromal cells (BMMSC) protect MM cells against the lytic machinery of MM-reactive cytotoxic T cells (CTL) and daratumumab-redirected natural killer (NK) cells through the upregulation of antiapoptotic proteins Survivin and Mcl-1 in MM cells. Here, we investigated the significance of this mode of immune escape on T cells engineered to express chimeric antigen receptors (CAR T cells). Experimental Design: We tested the cytolytic ability of a panel of 10 BCMA-, CD38-, and CD138-specific CAR T cells with different affinities against a model MM cell line and against patient-derived MM cells in the presence versus absence of BMMSCs. Results: Although BMMSCs hardly protected MM cells from lysis by high-affinity, strongly lytic BCMA- and CD38-CAR T cells, they significantly protected against lower affinity, moderately lytic BCMA-, CD38-, and CD138-specific CAR T cells in a cell–cell contact-dependent manner. Overall, there was a remarkable inverse correlation between the protective ability of BMMSCs and the lytic activity of all CAR T cells, which was dependent on CAR affinity and type of costimulation. Furthermore, BMMSC-mediated resistance against CAR T cells was effectively modulated by FL118, an inhibitor of antiapoptotic proteins Survivin, Mcl-1, and XIAP. Conclusions: These results extend our findings on the negative impact of the microenvironment against immunotherapies and suggest that outcome of CAR T cell or conventional CTL therapies could benefit from inhibition of antiapoptotic proteins upregulated in MM cells through BMMSC interactions.
Incorporating HIV Screening With COVID-19 Testing in an Urban Emergency Department During the Pandemic
Authors: Kimberly A. Stanford, Moira C. McNulty, Jessica R. Schmitt, Dylan S. Eller, Jessica P. Ridgway, Kathleen V. Beavis, David L. Pitrak
Journal: JAMA Internal Medicine (2021)

The Table shows the distribution of observed vs predicted risk based on the COVID-GRAM score by quintile of predicted risk.The COVID-GRAM predictions were similar to the observed outcomes among patients in the first 4 quintiles of risk for critical illness, but it overestimated the predicted risk of events in the highest quintile by almost 2-fold.The accuracy of the COVID-GRAM in the cohort was moderate, with an AUC of 0.72 (95% CI, 0.64-0.80)compared with an AUC of 0.88 (95% CI, 0.84-0.93) in the Chinese validation cohort. 1 A score of 89 or higher showed a sensitivity of 97.7% and a specificity of 32.7% for development of critical illness.Discussion | We were unable to fully validate the COVID-GRAM tool for predicting critical illness among patients hospitalized with COVID-19 in Europe because, although the tool showed good predictive ability for critical illness in lowerrisk patients, it overestimated risk in the highest-risk patients.The study may have been limited by differences in patient age and comorbidities, disease severity, and other variations between the cohorts in China and Spain.
A three-dimensional dietary index (nutritional quality, environment, and price) and reduced mortality: a prospective study in the Seguimiento Universidad de Navarra cohort
Authors: Ujué Fresán, Miguel A Martínez-González, Gina Segovia-Siapco, Joan Sabaté, Maira Bes-Rastrollo
Journal: The Lancet Planetary Health (2021)

BackgroundSeveral healthy diet indices have been associated with mortality risk. However, the ideal diet should not only be healthy but also environmentally friendly and affordable. This study aimed to determine if a new Sustainable Diet Index (SDI), which takes into account the nutritional quality, environmental impacts, and market price of diets, was associated with all-cause and cause-specific mortality.MethodsUsing data from the Seguimiento Universidad de Navarra Project, a prospective cohort study of Spanish university graduates, the study included 15 492 participants (median age 34 years, IQR 27–45) recruited between Dec 1, 1999, and March 31, 2014 who were followed-up for a median of 10 years (IQR 7–14). Cox regression was used to determine the relationship of SDI and its components with all-cause and cause-specific mortality risk, where high values of SDI represent high nutritional quality, low environmental impacts, and low market price. Hazard ratios (HRs) with adjustment for several confounders were calculated. The weights for the foods contributing to the SDI were assessed with multiple regression analyses and variability with nested regression analyses.FindingsThe highest quartile of the SDI scores was associated with a 59% relative reduction in all-cause mortality (HR 0·41, 95% CI 0·23–0·75) and a 79% reduction in cardiovascular mortality (0·21, 0·05–0·85). The nutritional index was itself statistically associated with a reduction in all-cause mortality, but not the environmental impact index and the market price. Nevertheless, a diet only focused on the nutritional quality would be less eco-friendly and more expensive than an overall sustainable diet. SDI was positively correlated with beans and potato consumption but negatively correlated with red meat intake. Red and processed meats, fatty dairy products, and fish consumption accounted for most of the variability in the SDI.InterpretationDietary patterns accounting not only for nutritional quality of the food but also the environmental impact and affordability could still provide health benefits. Such sustainable diets are rich in minimally processed plant-based foods and low in some animal-sourced products.FundingThe Seguimiento Universidad de Navarra Project has received funding from the Spanish Government—Instituto de Salud Carlos III, and the European Regional Development Fund (CIBEROBN, PI17/01795).
Eosinophilic Granulomatosis With Polyangiitis
Authors: Abraham M. Korman, Catherine G. Chung
Journal: JAMA Dermatology (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 Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Safety, Antitumor Activity, and Biomarker Analysis in a Phase I Trial of the Once-daily Wee1 Inhibitor Adavosertib (AZD1775) in Patients with Advanced Solid Tumors
Authors: Naoko Takebe, Abdul Rafeh Naqash, Geraldine O'Sullivan Coyne, Shivaani Kummar, Khanh Do, Ashley Bruns, Lamin Juwara, Jennifer Zlott, Larry Rubinstein, Richard Piekarz, Elad Sharon, Howard Streicher, Arjun Mittra, Sarah B. Miller, Jiuping Ji, Deborah Wilsker, Robert J. Kinders, Ralph E. Parchment, Li Chen, Ting-Chia Chang, Biswajit Das, Ganesh Mugundu, James H. Doroshow, Alice P. Chen
Journal: Clinical Cancer Research (2021)

Abstract Purpose: The Wee1 kinase inhibitor adavosertib abrogates cell-cycle arrest, leading to cell death. Prior testing of twice-daily adavosertib in patients with advanced solid tumors determined the recommended phase II dose (RPh2D). Here, we report results for once-daily adavosertib. Patients and Methods: A 3 + 3 dose-escalation design was used, with adavosertib given once daily on days 1 to 5 and 8 to 12 in 21-day cycles. Molecular biomarkers of Wee1 activity, including tyrosine 15–phosphorylated Cdk1/2 (pY15-Cdk), were assessed in paired tumor biopsies. Whole-exome sequencing and RNA sequencing of remaining tumor tissue identified potential predictive biomarkers. Results: Among the 42 patients enrolled, the most common toxicities were gastrointestinal and hematologic; dose-limiting toxicities were grade 4 hematologic toxicity and grade 3 fatigue. The once-daily RPh2D was 300 mg. Six patients (14%) had confirmed partial responses: four ovarian, two endometrial. Adavosertib plasma exposures were similar to those from twice-daily dosing. On cycle 1 day 8 (pre-dose), tumor pY15-Cdk levels were higher than baseline in four of eight patients, suggesting target rebound during the day 5 to 8 dosing break. One patient who progressed rapidly had a tumor WEE1 mutation and potentially compensatory PKMYT1 overexpression. Baseline CCNE1 overexpression occurred in both of two responding patients, only one of whom had CCNE1 amplification, and in zero of three nonresponding patients. Conclusions: We determined the once-daily adavosertib RPh2D and observed activity in patients with ovarian or endometrial carcinoma, including two with baseline CCNE1 mRNA overexpression. Future studies will determine whether CCNE1 overexpression is a predictive biomarker for adavosertib.
Abstract 996: Growth Differentiation Factor-5 (GDF-5) Dictates Cardiac Remodelling in a Mouse Model of Myocardial Infarction
Authors: Syed Zaidi, Ali M Riazi, Qingling Huang, Md A Momen, Mansoor Husain
Journal: Circulation (2007)

Background: Bone Morphogenetic Proteins (BMPs) regulate diverse cellular functions during foetal development and postnatal life. Growth Differentiation Factor 5 (GDF5 a.k.a. BMP-14) is a BMP, which is expressed in a variety of tissues including heart. We previously showed that cardiac GDF5 mRNA levels are elevated after experimental myocardial infarction (MI) caused by permanent left anterior descending coronary artery (LAD) ligation. However, the significance of this finding was not known. Methods &amp; Results: GDF5 knock-out (KO; n = 18 for MI) and wild-type (WT; n = 18 for MI) littermate controls were subjected to chronic LAD ligation in order to investigate the consequences resulting from the loss of GDF5 signalling following MI. At 28 days post-LAD ligation or sham (n = 12 for KO; n = 10 for WT), invasive hemodynamic parameters of cardiac function were examined just prior to sacrifice. Histopathology was assessed by morphometric analyses of perfusion fixed hearts and subsequent immunostaining. At 28 days post-MI, GDF5-KO mice exhibited decreased left ventricular systolic pressure and peak positive- and negative- dP/dt , and increased heart rate as compared to WT littermates ( P &lt; 0.005 for each parameters). GDF5-KO mice also exhibited a significant increase in the area, length and transmural expansion of the infarct, scar thinning and cardiac dilatation ( P &lt; 0.05 for each parameter). In addition, GDF5-KO mice displayed significantly fewer myocardial vessels in the infarct and peri-infarct regions as compared to WT littermates ( P &lt; 0.05) . To explore mechanisms underlying this phenotype, we assessed gene expression levels of relevant potential downstream targets of GDF5. At 7d post-MI, quantitative RT-PCR revealed a significant reduction (35%) in VEGF mRNA levels in hearts of KO (n = 6) as compared to WT mice (n = 5, P = 0.033). Summary &amp; Conclusion: These data suggest that increased GDF5 expression observed in hearts after MI plays an important role in cardiac remodelling. Absence of GDF5 expression in KO mice confers detrimental effects on healing and repair of myocardial and vascular tissues after MI. Regulated levels of GDF5, a BMP family member, play an important role in the repair process following cardiac injury.
Fractional Flow Reserve Treatment and Major Adverse Cardiac Events in Patients With Coronary Artery Disease—Reply
Authors: Maneesh Sud, Jiming Fang, Dennis T. Ko
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