tbuckley/cabot-search huggingface dataset:
Investigating changes in disease activity as a mediator of cardiovascular risk reduction with methotrexate use in rheumatoid arthritis
Authors: Tate M Johnson, Harlan R Sayles, Joshua F Baker, Michael D George, Punyasha Roul, Cheng Zheng, Brian Sauer, Katherine P Liao, Daniel R Anderson, Ted R Mikuls, Bryant R England
Journal: Annals of the Rheumatic Diseases (2021)

Objective Examine the association of methotrexate (MTX) use with cardiovascular disease (CVD) in rheumatoid arthritis (RA) using marginal structural models (MSM) and determine if CVD risk is mediated through modification of disease activity. Methods We identified incident CVD events (coronary artery disease (CAD), stroke, heart failure (HF) hospitalisation, CVD death) within a multicentre, prospective cohort of US Veterans with RA. A 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) was collected at regular visits and medication exposures were determined by linking to pharmacy dispensing data. MSMs were used to estimate the treatment effect of MTX on risk of incident CVD, accounting for time-varying confounders between receiving MTX and CVD events. A mediation analysis was performed to estimate the indirect effects of methotrexate on CVD risk through modification of RA disease activity. Results Among 2044 RA patients (90% male, mean age 63.9 years, baseline DAS28-CRP 3.6), there were 378 incident CVD events. Using MSM, MTX use was associated with a 24% reduced risk of composite CVD events (HR 0.76, 95% CI 0.58 to 0.99) including a 57% reduction in HF hospitalisations (HR 0.43, 95% CI 0.24 to 0.77). Individual associations with CAD, stroke and CVD death were not statistically significant. In mediation analyses, there was no evidence of indirect effects of MTX on CVD risk through disease activity modification (HR 1.03, 95% CI 0.80 to 1.32). Conclusions MTX use in RA was associated with a reduced risk of CVD events, particularly HF-related hospitalisations. These associations were not mediated through reductions in RA disease activity, suggesting alternative MTX-related mechanisms may modify CVD risk in this population.
Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial
Authors: Shun Lu, Jie Wang, Yan Yu, Xinmin Yu, Yanping Hu, Xinghao Ai, Zhiyong Ma, Xingya Li, Wu Zhuang, Yunpeng Liu, Weidong Li, Jiuwei Cui, Dong Wang, Wangjun Liao, Jianying Zhou, Zhehai Wang, Yuping Sun, Xiusong Qiu, Jie Gao, Yuanyuan Bao, Liang Liang, Mengzhao Wang
Journal: Journal of Thoracic Oncology (2021)

Tislelizumab, an anti-programmed cell death protein-1 antibody, was specifically engineered to minimize FcɣR macrophage binding to abrogate antibody-dependent phagocytosis. Compared with chemotherapy alone, tislelizumab plus chemotherapy may improve clinical outcomes in patients with advanced nonsquamous NSCLC (nsq-NSCLC). In this open-label phase 3 trial (RATIONALE 304; NCT03663205), patients with histologically confirmed stage IIIB or IV nsq-NSCLC were randomized (2:1) to receive either arm A: tislelizumab plus platinum (carboplatin or cisplatin) and pemetrexed every 3 weeks (Q3Ws) or arm B: platinum and pemetrexed alone Q3W during induction treatment, followed by intravenous maintenance pemetrexed Q3W. The primary end point was progression-free survival (PFS) assessed by an independent review committee; clinical response and safety and tolerability were secondary end points. Overall, 332 patients (n = 222 [A]; n = 110 [B]) received treatment. With a median study follow-up of 9.8 months, PFS was significantly longer with tislelizumab plus chemotherapy compared with chemotherapy alone (median PFS: 9.7 versus 7.6 mo; hazard ratio = 0.645 [95% confidence interval: 0.462-0.902], p = 0.0044). In addition, response rates were higher and response duration was longer with combination therapy versus chemotherapy alone. Hematologic adverse events (AEs) were common in both treatment arms; the most reported AEs were grades 1 to 2 in severity. The most common grade greater than or equal to 3 AEs were associated with chemotherapy and included neutropenia (44.6% [A]; 35.5% [B]) and leukopenia (21.6% [A]; 14.5% [B]). Addition of tislelizumab to chemotherapy resulted in significantly prolonged PFS, higher response rates, and longer response duration compared with chemotherapy alone, identifying a new potential option for first-line treatment of advanced nsq-NSCLC irrespective of disease stage.
COVID-19 pneumothorax in the UK: a prospective observational study using the ISARIC WHO clinical characterisation protocol
Authors: Stefan J. Marciniak, James Farrell, Anthony Rostron, Ian Smith, Peter J.M. Openshaw, J. Kenneth Baillie, Annemarie Docherty, Malcolm G. Semple
Journal: European Respiratory Journal (2021)

<b>Population level data from 131 679 patients show that COVID-19 pneumothorax occurs in 0.97% of admitted patients, especially males and smokers, and is associated with increased mortality</b>https://bit.ly/3oB27ez
AB0038 CIRCULATING MICRORNAS IN HAND OSTEOARTHRITIS
Authors: A. Pekacova, J. Baloun, O. Sleglova, O. Růžičková, J. Vencovský, K. Pavelka, L. Šenolt
Journal: Annals of the Rheumatic Diseases (2021)

Background: microRNAs (miRNAs) are small non-coding RNAs that can ignite the degradation of mRNAs or inhibit the protein translation and are therefore essential for several physiological and pathological functions. miRNAs can regulate up to 60 % of human mRNA, including genes related to cartilage development, homeostasis, and OA pathology. For example, miR-9 inhibits matrix metalloproteinase 13 or miR-140 expression level correlates with the disease progression of knee OA (Zhang et al.; Chao et al.). Under certain circumstances, miRNAs can be released into the body fluids and easily be detected in the blood samples. Therefore, miRNAs are hot candidates as biomarkers for early diagnosis or structural progression of OA. Objectives: The aim of this study was to evaluate circulating miRNAs in patients with hand osteoarthritis (HOA) and healthy individuals. Simultaneously, we studied specific miRNAs in order to differentiate between erosive and non-erosive subsets of the disease. Methods: Eight patients with HOA (erosive: n=4, 3 females, mean age=63.7±7 yrs; non-erosive: n=4, 3 females, mean age= 62.4±6 yrs) and 4 healthy controls (3 females, mean age=63.5±7 yrs) were included in this study. Firstly, Advance TaqMan low-density assay (TLDA) was performed for the purpose of miRNA high-throughput screening. Differently expressed miRNAs were further verified by real-time qPCR on the validation cohort in 31 patients with hand OA (19 females, mean age=66.2±7 yrs, erosive: n=9, non-erosive: n=10, healthy controls: n=12). Results: TLDA profiling displayed 346 circulating miRNAs in plasma of patients with HOA and healthy controls. We demonstrated 40 differently expressed circulating miRNAs in patients with HOA compared with healthy controls. Using a real-time qPCR, we verified increased expression levels of 10 circulating miRNAs in patients with HOA compared with healthy controls, e.g. miR-191-5p (3.4 fold), miR-151a-3p (3.4 fold) or miR-222-3p (2.4 fold). We did not find any specific miRNA, which could distinct erosive from a non-erosive subset of the disease. Conclusion: Extensive profiling of circulating miRNAs revealed several miRNAs that can be associated with HOA and can help to better understand OA pathogenesis. References: [1]Chao, Yu, et al. “Expression of MiR-140 and MiR-199 in Synovia and Its Correlation with the Progression of Knee Osteoarthritis.” Medical Science Monitor , vol. 26, 2020, pp. 1–6, doi:10.12659/MSM.918174. [2]Zhang, Hongxin, et al. “Downregulation of MicroRNA-9 Increases Matrix Metalloproteinase-13 Expression Levels and Facilitates Osteoarthritis Onset.” Molecular Medicine Reports , vol. 17, no. 3, 2018, pp. 3708–14, doi:10.3892/mmr.2017.8340. Acknowledgements: Supported by AZV NV18-01-00542, MHCR No. 023728 Disclosure of Interests: None declared
HYAL4-V1/Chondroitinase (Chase) Drives Gemcitabine Resistance and Predicts Chemotherapy Failure in Patients with Bladder Cancer
Authors: Sarrah L. Hasanali, Daley S. Morera, Ronny R. Racine, Martin Hennig, Santu Ghosh, Luis E. Lopez, Marie C. Hupe, Diogo O. Escudero, Jiaojiao Wang, Huabin Zhu, Semih Sarcan, Ijeoma Azih, Michael Zhou, Andre R. Jordan, Martha K. Terris, Markus A. Kuczyk, Axel S. Merseburger, Vinata B. Lokeshwar
Journal: Clinical Cancer Research (2021)

Gemcitabine-based chemotherapy regimens are first-line for several advanced cancers. Because of better tolerability, gemcitabine + cisplatin is a preferred neoadjuvant, adjuvant, and/or palliative chemotherapy regimen for advanced bladder cancer. Nevertheless, predicting treatment failure and overcoming resistance remain unmet clinical needs. We discovered that splice variant (V1) of HYAL-4 is a first-in-class eukaryotic chondroitinase (Chase), and CD44 is its major substrate. V1 is upregulated in bladder cancer and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance.V1 expression was measured in muscle-invasive bladder cancer (MIBC) specimens by qRT-PCR and IHC. HYAL-4 wild-type (Wt) and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for chemoresistance and associated mechanism in preclinical models.V1 levels in MIBC specimens of patients who developed metastasis, predicted response to gemcitabine + cisplatin adjuvant/salvage treatment and disease-specific mortality. V1-expressing bladder cells were resistant to gemcitabine but not to cisplatin. V1 expression neither affected gemcitabine influx nor the drug-efflux transporters. Instead, V1 increased gemcitabine metabolism and subsequent efflux of difluorodeoxyuridine, by upregulating cytidine deaminase (CDA) expression through increased CD44-JAK2/STAT3 signaling. CDA inhibitor tetrahydrouridine resensitized V1-expressing cells to gemcitabine. While gemcitabine (25-50 mg/kg) inhibited bladder cancer xenograft growth, V1-expressing tumors were resistant. Low-dose combination of gemcitabine and tetrahydrouridine abrogated the growth of V1 tumors with minimal toxicity.V1/Chase drives gemcitabine resistance and potentially predicts gemcitabine + cisplatin failure. CDA inhibition resensitizes V1-expressing tumors to gemcitabine. Because several chemotherapy regimens include gemcitabine, our study could have broad significance.
Emergence of transferable ceftazidime–avibactam resistance in KPC-producing Klebsiella pneumoniae due to a novel CMY AmpC β-lactamase in China
Authors: Min Xu, Jun Zhao, Li Xu, Qing Yang, Hao Xu, Haishen Kong, Jianying Zhou, Yiqi Fu
Journal: Clinical Microbiology and Infection (2021)
AB0311 INCREASED LEVELS OF SERUM WISTERIA FLORIBUNDA AGGLUTININPOSITIVE MAC-2 BINDING PROTEIN IN RHEUMATIC DISEASES INCLUDING SLE
Authors: T. Yoshikawa, K. Azuma, T. Furukawa, M. Tamura, T. Hashimoto, M. Morimoto, N. Azuma, K. Matsui
Journal: Annals of the Rheumatic Diseases (2021)

Background: Mac-2 binding protein is a cell-adhesive glycoprotein of the extracellular matrix secreted as a ligand of galectin-3 (Mac-2). Recently, a Wisteria floribunda agglutinin positive-M2BP (M2BP) assay developed using a lectin-antibody sandwich immunoassay has shown promise as a new fibrotic marker in liver fibrosis and interstitial lung disease (ILD) to detect unique fibrosis-related glycoalteration. Objectives: The aim of this study is to evaluate the utility of serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels in patients with rheumatic diseases (RD). Methods: We retrospectively measured serum M2BPGi levels in 68 patients with RD and 16 healthy controls (HC). There were no patients of cirrhosis and active hepatitis. Serum levels of M2BPGi were measured using HISCL M2BP glycosylation isomer Assay Kit. We examined the relationship between serum M2BPGi levels and clinical parameters in patients with RD. Results: In patients with RD, the median age was 62.0 years and 79.4% of them were female. Serum M2BPGi levels were significantly higher in patients with RD than in HC (median 0.98 cutoff index [COI], 0.32 COI, respectively; P &lt; 0.00001). Patients with SLE tended to have higher serum M2BPGi levels than other rheumatic diseases. In patients with RD, a significant correlation was not found between serum M2BP levels and inflammation markers such as CRP or ferritin. However, serum M2BPGi levels were significantly correlated with B cell activation markers such as immunoglobulin free light chain and IgG (r = 0.588, 0.504) and T cell activation marker such as sIL-2R (r = 0.408). Conclusion: Most of the rheumatic diseases in this study were considered to be type I interferonopathy diseases such as rheumatoid arthritis, Sjogren’s syndrome, inflammatory myositis, scleroderma and SLE. Serum M2BPGi was reported to have a significant correlation with SLE disease activity [SS Ahn et al. Lupus. 2018; 27: 771], and also to have a significant correlation with Gakectin-9, a novel biomarker for IFN signiture [Lucas L van den Hoogen et al. Ann Rheum Dis. 2018; 77: 1810]. So, it was suggested that serum M2BPGi may be a novel biomarker that indirectly indicates how much IFN is activated in rheumatic diseases. Disclosure of Interests: None declared
Impact of PET Staging of Follicular Lymphoma on Treatment Outcomes and Prognosis
Authors: Anna Alperovich, Connie L. Batlevi, Andrew M Intlekofer, Craig H. Moskowitz, Steven M. Horwitz, Andrew D. Zelenetz, Maria Lia Palomba, Alison J. Moskowitz, John Gerecitano, Paul A. Hamlin, Matthew J. Matasar, Craig S. Sauter, Anita Kumar, Ariela Noy, David J. Straus, Carol S. Portlock, Audrey Hamilton, Pamela Drullinsky, Philip Caron, Ai Ni, Venkatraman Seshan, Anas Younes
Journal: Blood (2017)
Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study
Authors: Guillaume Butler-Laporte, Tomoko Nakanishi, Vincent Mooser, David R. Morrison, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk, Annarita Giliberti, Alessandra Renieri, Yiheng Chen, Sirui Zhou, Vincenzo Forgetta, J. Brent Richards
Journal: PLoS Medicine (2021)

Background Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity. Methods and findings Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency. Conclusions In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.
POS1279 ADVERSE DRUG REACTIONS IN TUBERCULOSIS AND MANAGEMENT
Authors: R. Grassa, N. El Amri, S. Lataoui, O. Jomaa, H. Zeglaoui, K. Baccouche, E. Bouajina
Journal: Annals of the Rheumatic Diseases (2021)

Background: Around 10 million people worldwide contract tuberculosis (TB) every year. According to the World Health Organization (WHO), approximately one-quarter of the world’s population is latently infected with Mycobacterium tuberculosis. Its treatment is extremely long and patients may experience a variety of adverse reactions. Objectives: The aim of this study was to assess the different adverse drug reactions (ADR’s) in patients treated with first-line anti-tubercular drugs. Methods: This retrospective study included 45 cases of TB followed in the Rheumatology department of Farhat Hached hospital in Sousse, Tunisia, over a period of 22 years (1998-2020). Results: The mean age was 52.2 ± 17.72 years [14-95 years]. These were 19 men (42.2%) and 26 women (57.8%).The different locations of tuberculosis were as follows: pulmonary for 5 patients (11.1%), spinal for 26 patients (57.8%), articular for one patient (2.2%), urinary for two (4.4%), and multifocal for 8 patients (17.8%). An anti-tuberculosis treatment (based on quadrytherapy: Rifadine(R), Isoniazide(I), Pyrazinamide (Z) and Ethambutol (E)during 2 months, followed by biotherapy based on (R)and (I) was prescribed for an average duration of 10.85 months [6-24 months]. ADR’s were observed in 53.33% of patients. Abdominal pain and nausea were detected in 5 cases (11.1%). Hepatic cytolyse was noticed in 8 cases (17.8%) under (R). Cholestatic hepatitis occurred in 9 cases (20%) under (R). Asymptomatic Hyperuricemia was detected in 15 cases (33.3%) with (E). Two cases of toxiderma were detected: the first under (E) and the second under (E) + (Z). Ethambutol was responsible for a case of DRESS syndrome and a case of drug-induced hepatitis. One case of hemolytic anemia had occurred under (R). A sensorineural hearing loss was noted under streptomycin in one case. No fatal side effects were observed. These ADR’s were reversible in all cases. Conclusion: The treatment of TB can cause a variety of ADRs’. Early recognition by active surveillance and appropriate management of these ADRs’ might improve adherence and treatment success. References: [1]Prasad, R., Singh, A., &amp; Gupta, N. Adverse drug reactions in tuberculosis and management. Indian Journal of Tuberculosis, 66(4), 520–532 (2019). Disclosure of Interests: None declared
Explanatory coherence
Authors: Paul Thagard
Journal: Behavioral and Brain Sciences (1989)

Abstract This target article presents a new computational theory of explanatory coherence that applies to the acceptance and rejection of scientific hypotheses as well as to reasoning in everyday life. The theory consists of seven principles that establish relations of local coherence between a hypothesis and other propositions. A hypothesis coheres with propositions that it explains, or that explain it, or that participate with it in explaining other propositions, or that offer analogous explanations. Propositions are incoherent with each other if they are contradictory. Propositions that describe the results of observation have a degree of acceptability on their own. An explanatory hypothesis is accepted if it coheres better overall than its competitors. The power of the seven principles is shown by their implementation in a connectionist program called ECHO, which treats hypothesis evaluation as a constraint satisfaction problem. Inputs about the explanatory relations are used to create a network of units representing propositions, while coherence and incoherence relations are encoded by excitatory and inhibitory links. ECHO provides an algorithm for smoothly integrating theory evaluation based on considerations of explanatory breadth, simplicity, and analogy. It has been applied to such important scientific cases as Lavoisier's argument for oxygen against the phlogiston theory and Darwin's argument for evolution against creationism, and also to cases of legal reasoning. The theory of explanatory coherence has implications for artificial intelligence, psychology, and philosophy.
Annals Graphic Medicine - Dr. Mom: Who Is Watching Your Kids?
Authors: Grace E. Farris
Journal: Annals of Internal Medicine (2021)

Web ExclusivesJune 2021Annals Graphic Medicine - Dr. Mom: Who Is Watching Your Kids?FREEGrace E. Farris, MDGrace E. Farris, MDUniversity of Texas, Austin, Texas (G.E.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G21-0026 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: University of Texas, Austin, Texas (G.E.F.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G21-0024.Author/Illustrator Information: Grace E. Farris, MD, is an assistant professor of medicine at Dell Medical School at the University of Texas in Austin, Texas. You can view her work at her website: www.farrisgrace.com.About Dr. Mom: In Dr. Mom, physician and cartoonist Grace Farris examines work–life balance while mothering and doctoring. Dr. Mom appears monthly in Annals Graphic Medicine at Annals.org.This article was published at Annals.org on 25 May 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics June 2021Volume 174, Issue 6Page: W56-W57 ePublished: 25 May 2021 Issue Published: June 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Mild pulmonary hypertension and premature mortality among 154 956 men and women undergoing routine echocardiography
Authors: Simon Stewart, Yih-Kai Chan, David Playford, Geoffrey A. Strange
Journal: European Respiratory Journal (2021)

<b>Mild pulmonary hypertension (as indicated by estimated right ventricular systolic pressure 30.0–39.9 mmHg) is associated with increased risk of all-cause mortality and a substantial component of premature mortality</b>https://bit.ly/3ytwlEP
Implantable Energy Harvesters: Implantable Cardiac Kirigami‐Inspired Lead‐Based Energy Harvester Fabricated by Enhanced Piezoelectric Composite Film (Adv. Healthcare Mater. 8/2021)
Authors: Zhe Xu, Congran Jin, Andrew Cabe, Danny Escobedo, Aleksandra Gruslova, Scott Jenney, Andrew B. Closson, Lin Dong, Zi Chen, Marc D. Feldman, John X. J. Zhang
Journal: Advanced Healthcare Materials (2021)

Implantable energy harvesters offer a promising solution to overcome the power challenge encountered by most biomedical devices. In article number 2002100 Zi Chen, Marc D. Feldman, John X. J. Zhang, and co-workers, prudently take advantage of both a metamaterial and a piezoelectric composite material, to develop a novel, flexible Kirigamiinspired energy harvester that can convert the pacemaker leads bending energy to electrical power. This technology realizes energy sustainability for implantable biomedical devices.