tbuckley/cabot-search huggingface dataset:
Navigating immunosuppression in a pandemic: A guide for the dermatologist from the COVID Task Force of the Medical Dermatology Society and Society of Dermatology Hospitalists
Authors: Omid Zahedi Niaki, Milan J. Anadkat, Steven T. Chen, Lindy P. Fox, Joanna Harp, Robert G. Micheletti, Vinod E. Nambudiri, Helena B. Pasieka, Michi M. Shinohara, Misha Rosenbach, Joseph F. Merola
Journal: Journal of the American Academy of Dermatology (2020)

Dermatologists treating immune-mediated skin disease must now contend with the uncertainties associated with immunosuppressive use in the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Although the risk of infection with many commonly used immunosuppressive agents remains low, direct data evaluating the safety of such agents in coronavirus disease 2019 (COVID-19) are scarce. This article reviews and offers guidance based on currently available safety data and the most recent COVID-19 outcome data in patients with immune-mediated dermatologic disease. The interdisciplinary panel of experts emphasizes a stepwise, shared decision-making approach in the management of immunosuppressive therapy. The goal of this article is to help providers minimize the risk of disease flares while simultaneously minimizing the risk of iatrogenic harm during an evolving pandemic.
A nomogram for predicting overall survival in patients with low‐grade endometrial stromal sarcoma: A population‐based analysis
Authors: Jie Wu, Huibo Zhang, Lan Li, Mengxue Hu, Liang Chen, Bin Xu, Qibin Song
Journal: Cancer Communications (2020)

Low-grade endometrial stromal sarcoma (LG-ESS) is a rare tumor that lacks a prognostic prediction model. Our study aimed to develop a nomogram to predict overall survival of LG-ESS patients.A total of 1172 patients confirmed to have LG-ESS between 1988 and 2015 were selected from the Surveillance, Epidemiology and End Results (SEER) database. They were further divided into a training cohort and a validation cohort. The Akaike information criterion was used to select variables for the nomogram. The discrimination and calibration of the nomogram were evaluated using concordance index (C-index), area under time-dependent receiver operating characteristic curve (time-dependent AUC), and calibration plots. The net benefits of the nomogram at different threshold probabilities were quantified and compared with those of the International Federation of Gynecology and Obstetrics (FIGO) criteria-based tumor staging using decision curve analysis (DCA). Net reclassification index (NRI) and integrated discrimination improvement (IDI) were also used to compare the nomogram's clinical utility with that of the FIGO criteria-based tumor staging. The risk stratifications of the nomogram and the FIGO criteria-based tumor staging were compared.Seven variables were selected to establish the nomogram for LG-ESS. The C-index (0.814 for the training cohort and 0.837 for the validation cohort) and the time-dependent AUC (> 0.7) indicated satisfactory discriminative ability of the nomogram. The calibration plots showed favorable consistency between the prediction of the nomogram and actual observations in both the training and validation cohorts. The NRI values (training cohort: 0.271 for 5-year and 0.433 for 10-year OS prediction; validation cohort: 0.310 for 5-year and 0.383 for 10-year OS prediction) and IDI (training cohort: 0.146 for 5-year and 0.185 for 10-year OS prediction; validation cohort: 0.177 for 5-year and 0.191 for 10-year OS prediction) indicated that the established nomogram performed significantly better than the FIGO criteria-based tumor staging alone (P < 0.05). Furthermore, DCA showed that the nomogram was clinically useful and had better discriminative ability to recognize patients at high risk than the FIGO criteria-based tumor staging.A prognostic nomogram was developed and validated to assist clinicians in evaluating prognosis of LG-ESS patients.
Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo
Authors: Lars Pache, Matthew D. Marsden, Peter Teriete, Alex J. Portillo, Dominik Heimann, Jocelyn T. Kim, Mohamed S.A. Soliman, Melanie Dimapasoc, Camille Carmona, Maria Celeridad, Adam M. Spivak, Vicente Planelles, Nicholas D.P. Cosford, Jerome A. Zack, Sumit K. Chanda
Journal: Cell Reports Medicine (2020)

"Shock and kill" strategies focus on purging the latent HIV-1 reservoir by treating infected individuals with therapeutics that activate the latent virus and subsequently eliminating infected cells. We have previously reported that induction of non-canonical nuclear factor κB (NF-κB) signaling through a class of small-molecule antagonists known as Smac mimetics can reverse HIV-1 latency. Here, we describe the development of Ciapavir (SBI-0953294), a molecule specifically optimized for HIV-1 latency reversal that was found to be more efficacious as a latency-reversing agent than other Smac mimetics under clinical development for cancer. Critically, this molecule induced activation of HIV-1 reservoirs in vivo in a bone marrow, liver, thymus (BLT) humanized mouse model without mediating systemic T cell activation. This study provides proof of concept for the in vivo efficacy and safety of Ciapavir and indicates that Smac mimetics can constitute a critical component of a safe and efficacious treatment strategy to eliminate the latent HIV-1 reservoir.
Notice of Retraction and Replacement. Pornpattananangkul et al. Association between childhood anhedonia and alterations in large-scale resting-state networks and task-evoked activation. <i>JAMA Psychiatry</i>. 2019;76(6):624-633
Authors: Narun Pornpattananangkul, Ellen Leibenluft, Daniel S. Pine, Argyris Stringaris
Journal: JAMA Psychiatry (2020)

Notice of Retraction and Replacement. Pornpattananangkul et al. Association between childhood anhedonia and alterations in large-scale resting-state networks and task-evoked activation. JAMA Psychiatry. 2019;76(6):624-633
Population-Based Screening for Atrial Fibrillation
Authors: Shaan Khurshid, Jeffrey S. Healey, William F. McIntyre, Steven A. Lubitz
Journal: Circulation Research (2020)

Atrial fibrillation (AF) is a common and morbid arrhythmia. Stroke is a major hazard of AF and may be preventable with oral anticoagulation. Yet since AF is often asymptomatic, many individuals with AF may be unaware and do not receive treatment that could prevent a stroke. Screening for AF has gained substantial attention in recent years as several studies have demonstrated that screening is feasible. Advances in technology have enabled a variety of approaches to facilitate screening for AF using both medical-prescribed devices as well as consumer electronic devices capable of detecting AF. Yet controversy about the utility of AF screening remains owing to concerns about potential harms resulting from screening in the absence of randomized data demonstrating effectiveness of screening on outcomes such as stroke and bleeding. In this review, we summarize current literature, present technology, population-based screening considerations, and consensus guidelines addressing the role of AF screening in practice.
Infographic. Graduated return to play guidance following COVID-19 infection
Authors: Niall Elliott, Rhodri Martin, Neil Heron, Jonathan Elliott, Dan Grimstead, Anita Biswas
Journal: British Journal of Sports Medicine (2020)

With risk of cardiological, renal, respiratory and haematological complications,1–5 it is best practice to follow steady resumption of training, paying attention to physical and psychological factors after COVID-19 infection.

This guidance takes into account public health guidelines in the UK (although we hope its content is relevant more widely) and available expert opinion at time of publication and is for use by healthcare practitioners. It is applicable to performance athletes who have had mild to moderate illness. Those requiring hospital admission merit further assessment.



If an athlete develops an illness with symptoms of COVID-19, they should follow national guidance, speak to their sports medicine doctor, and undertake …
Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency
Authors: Emilia J. Kozyra, Victor B. Pastor, Stylianos Lefkopoulos, Sushree S. Sahoo, Hauke Busch, Rebecca K. Voss, Miriam Erlacher, Dirk Lebrecht, Enikoe A. Szvetnik, Shinsuke Hirabayashi, Ramunė Pasaulienė, Lucia Pedace, Marco Tartaglia, Christian Klemann, Patrick Metzger, Melanie Boerries, Albert Catala, Henrik Hasle, Valerie de Haas, Krisztián Kállay, Riccardo Masetti, Barbara De Moerloose, Michael Dworzak, Markus Schmugge, Owen Smith, Jan Starý, Ester Mejstrikova, Marek Ussowicz, Emma Morris, Preeti Singh, Matthew Collin, Marta Derecka, Gudrun Göhring, Christian Flotho, Brigitte Strahm, Franco Locatelli, Charlotte M. Niemeyer, Eirini Trompouki, Marcin W. Wlodarski
Journal: Leukemia (2020)

Abstract Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2 . In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C&gt;G, p.T117T ( N = 4); c.649C&gt;T, p.L217L; c.981G&gt;A, p.G327G; c.1023C&gt;T, p.A341A; and c.1416G&gt;A, p.P472P ( N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C&gt;G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.
Autocrine IL6-Mediated Activation of the STAT3–DNMT Axis Silences the TNFα–RIP1 Necroptosis Pathway to Sustain Survival and Accumulation of Myeloid-Derived Suppressor Cells
Authors: Alyssa D. Smith, Chunwan Lu, Daniela Payne, Amy V. Paschall, John D. Klement, Priscilla S. Redd, Mohammed L. Ibrahim, Dafeng Yang, Qimei Han, Zhuoqi Liu, Huidong Shi, Thomas J. Hartney, Asha Nayak-Kapoor, Kebin Liu
Journal: Cancer Research (2020)

Although accumulation of myeloid-derived suppressor cells (MDSC) is a hallmark of cancer, the underlying mechanism of this accumulation within the tumor microenvironment remains incompletely understood. We report here that TNFα-RIP1-mediated necroptosis regulates accumulation of MDSCs. In tumor-bearing mice, pharmacologic inhibition of DNMT with the DNA methyltransferease inhibitor decitabine (DAC) decreased MDSC accumulation and increased activation of antigen-specific cytotoxic T lymphocytes. DAC-induced decreases in MDSC accumulation correlated with increased expression of the myeloid cell lineage-specific transcription factor IRF8 in MDSCs. However, DAC also suppressed MDSC-like cell accumulation in IRF8-deficient mice, indicating that DNA methylation may regulate MDSC survival through an IRF8-independent mechanism. Instead, DAC decreased MDSC accumulation by increasing cell death via disrupting DNA methylation of RIP1-dependent targets of necroptosis. Genome-wide DNA bisulfite sequencing revealed that the Tnf promoter was hypermethylated in tumor-induced MDSCs in vivo. DAC treatment dramatically increased TNFα levels in MDSC in vitro, and neutralizing TNFα significantly increased MDSC accumulation and tumor growth in tumor-bearing mice in vivo. Recombinant TNFα induced MDSC cell death in a dose- and RIP1-dependent manner. IL6 was abundantly expressed in MDSCs in tumor-bearing mice and patients with human colorectal cancer. In vitro, IL6 treatment of MDSC-like cells activated STAT3, increased expression of DNMT1 and DNMT3b, and enhanced survival. Overall, our findings reveal that MDSCs establish a STAT3-DNMT epigenetic axis, regulated by autocrine IL6, to silence TNFα expression. This results in decreased TNFα-induced and RIP1-dependent necroptosis to sustain survival and accumulation. SIGNIFICANCE: These findings demonstrate that targeting IL6 expression or function represent potentially effective approaches to suppress MDSC survival and accumulation in the tumor microenvironment.
Combinatorial Single-Cell Analyses of Granulocyte-Monocyte Progenitor Heterogeneity Reveals an Early Uni-potent Neutrophil Progenitor
Authors: Immanuel Kwok, Etienne Becht, Yu Xia, Melissa Ng, Ye Chean Teh, Leonard Tan, Maximilien Evrard, Jackson L.Y. Li, Hoa T.N. Tran, Yingrou Tan, Dehua Liu, Archita Mishra, Ka Hang Liong, Keith Leong, Yuning Zhang, Andre Olsson, Chinmay Kumar Mantri, Pavithra Shyamsunder, Zhaoyuan Liu, Cecile Piot, Charles-Antoine Dutertre, Hui Cheng, Sudipto Bari, Nicholas Ang, Subhra K. Biswas, H. Philip Koeffler, Hong Liang Tey, Anis Larbi, I-Hsin Su, Bernett Lee, Ashley St. John, Jerry K.Y. Chan, William Y.K. Hwang, Jinmiao Chen, Nathan Salomonis, Shu Zhen Chong, H. Leighton Grimes, Bing Liu, Andrés Hidalgo, Evan W. Newell, Tao Cheng, Florent Ginhoux, Lai Guan Ng
Journal: Immunity (2020)
Prone Positioning in Awake, Nonintubated Patients With COVID-19
Authors: Aartik Sarma, Carolyn S. Calfee
Journal: JAMA Internal Medicine (2020)

as inappropriate for PCI (13% of all cases).Notably, this figure likely greatly underestimates the number of inappropriate PCIs because the authors were unable to determine if symptomatic patients had first tried and failed optimal medical management before undergoing PCI.Although robust guidelines should be expected to reduce inappropriate PCI, Howard and Desai 3 demonstrate how implementing such criteria depends on accurately reporting case characteristics (eg, the severity of coronary stenosis and symptoms) and highlight egregious examples for which the reporting was not only inaccurate but dishonest.Specifically, they investigated the association of the US False Claims Act, a law that allows whistleblowers to raise concerns of inappropriate care, with PCI volumes for patients without acute MI. 2 Between 2006 and 2016, the authors identified 8 cases of PCI-related US False Claims Act cases that became public.Compared with matched control hospitals, PCI volumes for nonacute MI decreased more from 2006 and 2016 in hospitals subject to claims of dishonest reporting (68.4% vs 81.2%; P< .001).Although the substantial decrease in PCI seen in all hospitals suggests an overall movement to a more evidence-based use of PCI, the differential decrease in hospitals that underwent investigations of false claims suggests that there is a role for the enforcement of accurate reporting of indications for PCI.It is unknown how commonly coronary stenosis is overestimated in centers that have not been targeted by False Claims cases.Despite the effect of these efforts, without quantitative, objective standards for stenosis, it is likely that some overestimation of coronary stenosis will remain. 10 Reports of continued substantial rates of inappropriate PCI provide a compelling illustration of the considerable work that remains to protect patients and the health care system from the harms and costs of unnecessary PCI.As a conservative estimate (ie, not including cases that could be averted with optimal medical management or the costs of adverse outcomes of PCIs), if the approximately 50 000 PCI cases deemed rarely appropriate by Malik et al 2 were averted at a cost of $30 000 per PCI, 11 this would produce a savings of $1.5 billion annually.However, if we extrapolate from prior work showing that greater than 50% of patients undergoing PCIs with stable CAD are not receiving optimal medical therapy, 12 it is likely that at least 150 000 more PCI cases are inappropriate and cost savings are closer to $6 billion annually.The work of these authors shows a promising method of reducing unnecessary PCI by combining robust, unambiguous consensus guidelines with enforcement of accurate reporting of indications for PCI.However, these measures are not a cure-all in a health care system propelled by enthusiasm for technology regardless of net benefits and rewarded with fee-for-service payments not associated with the appropriateness of the procedure.
Covid-19 is threatening the survival of US primary care
Authors: Bob Roehr
Journal: BMJ (2020)

Covid-19 is threatening the survival of US primary care In the US, government imposed lockdowns and public fears have slashed primary care visits-and with it revenue for physicians, Bob Roehr reports Bob Roehr science journalistThis is an especially difficult time to be a GP, internist, paediatrician, or other physician providing primary care in the US."To be honest, independent primary care was struggling long before this pandemic came along," primary care provider (PCP) Leto Quarles wrote on the popular MedPage Today blog KevinMD.But it's recently become much worse.Since the pandemic hit, "revenues are way down and the bills that I can't pay are piling up," Quarles wrote. 1 Quarles's concerns are shared across the country.
Abstract 111: Identification of the agent causing Kawasaki Disease via throat swab cultures
Authors: Stephanie Menikou, Vanessa Sancho-Shimizu, Zoe Levin, Shea M. Hamilton, Paul Langford, Mike Levin
Journal: Circulation (2015)

Kawasaki disease (KD) is a paediatric inflammatory disease and is the most common cause of acquired heart disease in children in developed countries. The cause of KD is unknown but epidemiological data indicate that it is most likely to be an infectious agent. The clinical features of KD are consistent with either bacterial or fungal infection rather than a virus, as KD is associated with an intense inflammatory process. It has been suggested that the oral and respiratory mucosa are the primary site of infection as the initial infection in KD patients is likely to be in the mucosal surfaces of the respiratory track with prominent lymphadenopathy and oral mucous membrane inflammation. This study examines whether the agent causing KD induces disease through production of novel toxins, or inflammation inducing antigens in the supernatants of cultured bacteria isolated from KD patients and healthy controls. Throat swabs were collected from children with KD (n=14), other diseases (n=10) and healthy children (n=8), and were inoculated into growth medium, incubated and then centrifuged. The supernatants were collected and toxicity was measured by microscopic observation as well as by resazurin dye reduction of cells after growth in the presence of the KD or control supernatant. An effect of the toxins in activating inflammation was also tested by the addition of the supernatants to healthy donor peripheral blood mononuclear cells (PBMCs) and measurement of interleukin 6 production by Enzyme linked immune assay (ELISA). There was no significant difference in the reduction of cells after growth between control and KD supernatants. No difference in the production of IL-6 was observed between the three groups. Further analysis and larger sample size are required to establish whether novel toxins are present in cultured supernatants of KD patients.
THU0582 EFFECTIVE MANAGEMENT OF REFRACTORY GOUT: EFFECT OF ONLINE CONTINUING EDUCATION ON RHEUMATOLOGISTS’ KNOWLEDGE
Authors: N. Mehta, S. Fagerlie, J. Maeglin
Journal: Annals of the Rheumatic Diseases (2020)

Background: Gout is a chronic condition with a considerable effect on patient health and quality of life. Despite the availability of multiple pharmacologic treatments and evidence-based management guidelines, treatment targets are often not achieved in patients with gout. Identification and optimal management of patients with severe or refractory gout is specially challenging. Objectives: The objective of this study was to determine if an online, continuing education activity could improve knowledge of rheumatologists regarding strategies to ensure effective and safe use of urate-lowering therapies in the management of patients with refractory gout. Methods: Educational design included an online, 30-minute, video-based discussion among two faculty experts with synchronized slides. Educational effectiveness was assessed with a repeated-pairs pre-/post-assessment study design using 3 knowledge questions and 1 confidence question, in which each individual served as his/her own control. A chi-squared test assessed differences from pre- to post-assessment. P values &lt;.05 are statistically significant. Cramer’s V was used to calculate the effect size (&lt;0.06 modest effect; 0.06-0.15 noticeable effect; 0.16-0.26 considerable effect; &gt;0.26 extensive effect). The activity launched May 1, 2019, with data collected through December 30, 2019. Results: The analysis set consisted of responses from rheumatologists (n=300) who answered all assessment questions during the study period. Analysis of pre- vs post-intervention responses demonstrated a significant improvement in overall knowledge of rheumatologists with considerable educational impact (V = .201, P&lt;.001). Average correct responses increased from 54% pre to 74% post education. Specific areas of improvement in knowledge include: •Optimal strategies for reducing the risk for immunogenicity associated with the use of pegloticase in patients with refractory gout (40% pre, 73% post; P&lt;.001; V = .326) •Serum uric acid targets to optimize management of the patient with severe or refractory gout (45% pre, 57% post; P&lt;.05; V = .120) •Selection of pegloticase for rapid decreases in tophi and serum uric acid in patients with refractory gout (77% pre, 91% post; P&lt;.001; V = .187) Post-education, 32% of rheumatologists were more confident in their ability to manage patients with refractory gout. Conclusion: This study demonstrated the success of online, 30-minute, video-based discussion among two faculty experts with synchronized slides on improving the knowledge of rheumatologists regarding appropriate management of patients with refractory gout. Disclosure of Interests: None declared