tbuckley/cabot-search huggingface dataset:
Refining Prediction of Atrial Fibrillation–Related Stroke Using the P <sub>2</sub> -CHA <sub>2</sub> DS <sub>2</sub> -VASc Score
Authors: Ankit Maheshwari, Faye L. Norby, Nicholas S. Roetker, Elsayed Z. Soliman, Ryan J. Koene, Mary R. Rooney, Wesley T. O’Neal, Amil M. Shah, Brian L. Claggett, Scott D. Solomon, Alvaro Alonso, Rebecca F. Gottesman, Susan R. Heckbert, Lin Y. Chen
Journal: Circulation (2019)

Background: In people with atrial fibrillation (AF), periods of sinus rhythm present an opportunity to detect prothrombotic atrial remodeling through measurement of P-wave indices (PWIs)—prolonged P-wave duration, abnormal P-wave axis, advanced interatrial block, and abnormal P-wave terminal force in lead V1. We hypothesized that the addition of PWIs to the CHA 2 DS 2 -VASc score would improve its ability to predict AF-related ischemic stroke. Methods: We included 2229 participants from the ARIC study (Atherosclerosis Risk in Communities) and 700 participants from MESA (Multi-Ethnic Study of Atherosclerosis) with incident AF who were not on anticoagulants within 1 year of AF diagnosis. PWIs were obtained from study visit ECGs before development of AF. AF was ascertained using study visit ECGs and hospital records. Ischemic stroke cases were based on physician adjudication of hospital records. We used Cox proportional hazards models to estimate hazard ratios and 95% CIs of PWIs for ischemic stroke. Improvement in 1-year stroke prediction was assessed by C-statistic, categorical net reclassification improvement, and relative integrated discrimination improvement. Results: Abnormal P-wave axis was the only PWI associated with increased ischemic stroke risk (hazard ratio, 1.84; 95% CI, 1.33–2.55) independent of CHA 2 DS 2 -VASc variables, and that resulted in meaningful improvement in stroke prediction. The β estimate was approximately twice that of the CHA 2 DS 2 -VASc variables, and thus abnormal P-wave axis was assigned 2 points to create the P 2 -CHA 2 DS 2 -VASc score. This improved the C-statistic (95% CI) from 0.60 (0.51–0.69) to 0.67 (0.60–0.75) in ARIC and 0.68 (0.52–0.84) to 0.75 (0.60–0.91) in MESA (validation cohort). In ARIC and MESA, the categorical net reclassification improvements (95% CI) were 0.25 (0.13–0.39) and 0.51 (0.18–0.86), respectively, and the relative integrated discrimination improvement (95% CI) were 1.19 (0.96–1.44) and 0.82 (0.36–1.39), respectively. Conclusions: Abnormal P-wave axis—an ECG correlate of left atrial abnormality— improves ischemic stroke prediction in AF. Compared with CHA 2 DS 2 -VASc, the P 2 -CHA 2 DS 2 -VASc is a better prediction tool for AF-related ischemic stroke.
FRI0006 Association between interleukin-10 polymorphisms and juvenile idiopathic arthritis: a meta-analysis
Authors: J.H. Jung, J.-H. Kim, G.G. Song, S.J. Choi
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Juvenile idiopathic arthritis (JIA) is the most common chronic arthritis in children. JIA is a heterogeneous group of complex diseases and the result of a combination of genetic and environmental factors. Multiple genes contribute to the risk of developing JIA. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is associated with inflammatory diseases. IL-10 is considered a candidate gene for JIA based on its chromosomal location and functional relevance. <h3>Objectives</h3> IL-10 genetic polymorphisms associated with JIA were previously identified, especially in haplotypes studies. However, results from different studies have been inconsistent. Thus, we investigated whether IL-10 polymorphisms were associated with susceptibility to JIA. <h3>Methods</h3> A meta-analysis was conducted of the associations between the IL-10–1082G/A, −819 C/T, and −592 C/A polymorphisms and JIA. A total of eight studies involving 1495 patients and 1670 controls were considered in the meta-analysis. This meta-analysis was conducted based on the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines. <h3>Results</h3> There was no association between the IL-10–1082G/A, −819 C/T, and −592 C/A polymorphisms and JIA in allele contrast and any of the genetic models (allele contrast: OR=0.90, 95% CI=0.79–1.02, p=0.09; OR=0.97, 95% CI=0.83–1.13, p=0.68; OR=0.92, 95% CI=0.81–1.06, p=0.24, respectively). Subgroup analyses revealed a significant association between the IL-10–1082 G allele and systemic JIA (OR=0.80, 95% CI=0.67–0.96, p=0.02). Meta-analysis of the IL-10 haplotype revealed no association between GCC, ACC, and ATA haplotypes and JIA. <h3>Conclusions</h3> This meta-analysis indicated lack of associations between IL-10 polymorphisms and susceptibility to JIA. However, there was a significant association between IL-10–1082 G allele and systemic JIA. <h3>References</h3> [1] Harsini S, et al. Interleukin 10 and transforming growth factor beta 1 gene polymorphisms in juvenile idiopathic arthritis. Bratisl Lek Listy2016;117:258–262. [2] Cinek O, et al. Association of single nucleotide polymorphisms within cytokine genes with juvenile idiopathic arthritis in the Czech population. J Rheumatol2004;31:1206–1210. [3] Fathy MM, et al. Association of IL-10 gene polymorphisms and susceptibility to juvenile idiopathic arthritis in Egyptian children and adolescents: a case-control study. Ital J Pediatr2017;43:9. <h3>Acknowledgements</h3> No grants or other support were received for the conduction of this study. <h3>Disclosure of Interest</h3> None declared
Autophagy Inhibition to Augment mTOR Inhibition: a Phase I/II Trial of Everolimus and Hydroxychloroquine in Patients with Previously Treated Renal Cell Carcinoma
Authors: Naomi B. Haas, Leonard J. Appleman, Mark Stein, Maryann Redlinger, Melissa Wilks, Xiaowei Xu, Angelique Onorati, Anusha Kalavacharla, Taehyong Kim, Chao Jie Zhen, Sabah Kadri, Jeremy P. Segal, Phyllis A. Gimotty, Lisa E. Davis, Ravi K. Amaravadi
Journal: Clinical Cancer Research (2019)

Everolimus inhibits the mTOR, activating cytoprotective autophagy. Hydroxychloroquine inhibits autophagy. On the basis of preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and hydroxychloroquine, to determine its safety and activity in patients with clear-cell renal cell carcinoma (ccRCC).Three centers conducted a phase I/II trial of everolimus 10 mg daily and hydroxychloroquine in patients with advanced ccRCC. The objectives were to determine the MTD of hydroxychloroquine with daily everolimus, and to estimate the rate of 6-month progression-free survival (PFS) in patients with ccRCC receiving everolimus/hydroxychloroquine after 1-3 prior treatment regimens. Correlative studies to identify patient subpopulations that achieved the most benefit included population pharmacokinetics, measurement of autophagosomes by electron microscopy, and next-generation tumor sequencing.No dose-limiting toxicity was observed in the phase I trial. The recommended phase II dose of hydroxychloroquine 600 mg twice daily with everolimus was identified. Disease control [stable disease + partial response (PR)] occurred in 22 of 33 (67%) evaluable patients. PR was observed in 2 of 33 patients (6%). PFS ≥ 6 months was achieved in 15 of 33 (45%) of patients who achieved disease control.Combined hydroxychloroquine 600 mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6-month PFS rate was met. Hydroxychloroquine is a tolerable autophagy inhibitor in future RCC or other trials.
Influence of Donor Type (sibling vs matched-unrelated donor vs haplo-identical donor vs cord blood) on Outcomes after Clofarabine-Based Reduced-Intensity Conditioning Allograft for Myeloid Malignancies
Authors: Louise Bouard, Thierry Guillaume, Pierre Peterlin, Alice Garnier, Amandine Le Bourgeois, Alix Duquesne, Beatrice Mahe, Viviane Dubruille, Nicolas Blin, Cyrille Touzeau, Thomas Gastinne, Anne Lok, Antoine Bonnet, Steven LE Gouill, Philippe Moreau, Marie C Bene, Patrice Chevallier
Journal: Blood (2018)
REFOCUS-PULSAR recovery-oriented practice training in specialist mental health care: a stepped-wedge cluster randomised controlled trial
Authors: Graham Meadows, Lisa Brophy, Frances Shawyer, Joanne C Enticott, Ellie Fossey, Christine D Thornton, Penelope J Weller, Elisabeth Wilson-Evered, Vrinda Edan, Mike Slade
Journal: The Lancet Psychiatry (2019)
SAT0021 Innate lymphoid cells are not a main source of il-17a in the inflamed spondyloarthritis joint
Authors: N. Yeremenko, I.C.J. Blijdorp, L.J.J. Van Mens, S. Menegatti, S. Chen, H.S. Hreggvidsdottir, T. Noordenbos, T.E. Latuhihin, J.H. Bernink, L. Rogge, H. Spits, D.L.P. Baeten
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Clinical trials of the anti-IL-17A antibody secukinumab demonstrated the crucial role of IL-17A cytokine in the pathogenesis of spondyloarthritis (SpA), however, its cellular source in this condition remains controversial. Group 3 innate lymphoid cells (ILC3s) have been recently identified in a number of different tissues as potent producers of proinflamatory cytokines, including IL-17A and IL-22. <h3>Objectives</h3> In this study we set out to characterise the presence and composition of ILCs and investigate whether these cells are the important source of IL-17A in the synovial tissue of patients with SpA. <h3>Methods</h3> Matched synovial tissue (ST), synovial fluid (SF) and peripheral blood (PB) were obtained from SpA and rheumatoid arthritis (RA) patients with actively inflamed knee joints. ILCs subsets were characterised by flow cytometry. Gene expression analysis at the single-cell level was performed directly <i>ex vivo</i> and after stimulation with PMA ionomycin. IL-17A ELISPOT assay was used to detect IL-17A-secreting cells. <h3>Results</h3> Analysis revealed that ILCs, and particularly NKp44-positive ILC3s, are expanded in the inflamed arthritic joint. Single cell expression analysis revealed that ST ILCs are clearly distinguishable from ST T cells and from their PB counterparts. We detected expression of Th17 signature transcripts <i>RORC, AHR</i> and <i>IL-23R</i> in the notable fraction of ST ILC3s. Furthermore these cells were capable to induce <i>IL-22</i>, but not <i>IL-17A</i> expression in response to. <i>in vitro</i> re-stimulation <h3>Conclusions</h3> We demonstrate in this study that ILC3s are absolutely and relatively enriched in the synovial joint of patients with SpA, however these cells are not a significant source of IL-17A cytokine in this pathology. <h3>Disclosure of Interest</h3> None declared
Bacteriophage interactions with mammalian tissue: Therapeutic applications
Authors: Haein Huh, Shirley Wong, Jesse St. Jean, Roderick Slavcev
Journal: Advanced Drug Delivery Reviews (2019)

The human body is a large reservoir for bacterial viruses known as bacteriophages (phages), which participate in dynamic interactions with their bacterial and human hosts that ultimately affect human health. The current growing interest in human resident phages is paralleled by new uses of phages, including the design of engineered phages for therapeutic applications. Despite the increasing number of clinical trials being conducted, the understanding of the interaction of phages and mammalian cells and tissues is still largely unknown. The presence of phages in compartments within the body previously considered purely sterile, suggests that phages possess a unique capability of bypassing anatomical and physiological barriers characterized by varying degrees of selectivity and permeability. This review will discuss the direct evidence of the accumulation of bacteriophages in various tissues, focusing on the unique capability of phages to traverse relatively impermeable barriers in mammals and its relevance to its current applications in therapy.
AB0494 Usability of a pre-filled pen for self-administration of subcutaneous methotrexate
Authors: M. Hattesohl, M. Tribanek, K. Gescher
Journal: Annals of the Rheumatic Diseases (2018)

Results: To detect the most effective JAKi in blocking the inflammatory response induced by IL1-b, RA-FLS were first pretreated with different JAKi for 2 hour with concentrations of 1 mM and 10 mM and then additionally stimulated with IL1-b (20 ng/ml) for 18 hour.Even at the highest concentration of 10 mM Tofacitinib and Baricitinib did not change the IL-6 levels, whereas Peficitinib and Filgotinib reduced the IL-6 release at 10 mM.Tofacitinib and Baricitinib reduced the cytokine release if the RA-FLS were stimulated with OSM, a factor directly inducing the JAK-dependent IL-6-pathway (n=3).To obtain a dose-response curve for the clinically relevant range of concentrations between 0.01 mM and 5 mM, RA-FLS were pretreated with Filgotinib and Peficitinib for 2 hour and then stimulated with IL1-b (10 ng/ml) for 17 hour.In contrast to Filgotinib, Peficitinib at 5 mM caused a reduction of IL-6 levels of 66% compared to control with IL1-b (p<0.01,n=5).The MMP-3 release was decreased by both substances at 5 mM: In comparison to the control with IL1-b, Peficitinib caused a reduction of 92% (p<0.0001,n=5) whereas Filgotinib only reduced the levels by 43% (p<0.05,n=3).Furthermore, Peficitinib at 1 mM decreased the MMP-3 release by 46% (p<0.01).The treatment with Peficitinib did not affect the viability, cytotoxicity or apoptosis of RA-FLS (n=3).Therefore, the effects of Peficitinib on the inflammatory response were not caused by cell death.Conclusions: Peficitinib reduced the release of proinflammatory cytokines and of matrix metalloproteinases after activation of RA-FLS with IL1-b and appeared to be superior to Tofacitinib and Baricitinib in targeting the pro-inflammatory and matrix destructive properties of RA-FLS.
Pyoderma gangrenosum and systemic treatment
Authors: A.C.R. Partridge, J.W. Bai, C.F. Rosen, S.R. Walsh, W.P. Gulliver, P. Fleming
Journal: British Journal of Dermatology (2018)

Pyoderma gangrenosum (PG) is a rare disease where a person's own immune system causes painful skin ulcers, due to a complex and poorly understood mechanism. PG is extremely rare, affecting 3–10 people per million people per year globally; however, when it does occur it bears significant impact on quality of life and increases the risk of death. Current treatment includes a combination of systemic steroids (systemic meaning taken inside the body rather than applied to the skin), immune suppressing drugs, and topical (applied to the skin) treatments, but after decades of research we still do not know the best (or “gold‐standard”) treatment regimen. In this study, authors from Canada aimed to systematically review all of the available research evidence on systemic treatments for PG in order to determine the best treatment regimen. After critically reviewing 3326 research studies, 41 studies were deemed relevant to this research question. What they found was that systemic corticosteroids, cyclosporine, and biologic agents were most commonly studied and were most effective at treating PG. Often, these were combined with topically applied drugs such as steroid cream. Nonetheless, amongst included studies, there was a low cure rate of 15–50% after months of treatment; while cure was sometimes achieved after two to four months, there was a high rate of recurrence of ulcers. Furthermore, the authors found that most studies on PG therapies are of poor quality and thus call for higher quality research in this field.
Designing Next‐Generation Local Drug Delivery Vehicles for Glioblastoma Adjuvant Chemotherapy: Lessons from the Clinic
Authors: Anthony Tabet, Melanie P. Jensen, Christopher C. Parkins, Parag G. Patil, Colin Watts, Oren A. Scherman
Journal: Advanced Healthcare Materials (2019)

Abstract To date, the clinical outcomes and survival rates for patients with glioblastoma (GB) remain poor. A promising approach to disease‐modification involves local delivery of adjuvant chemotherapy into the resection cavity, thus circumventing the restrictions imposed by the blood–brain barrier. The clinical performance of the only FDA‐approved local therapy for GB [carmustine (BCNU)‐loaded polyanhydride wafers], however, has been disappointing. There is an unmet medical need in the local treatment of GB for drug delivery vehicles that provide sustained local release of small molecules and combination drugs over several months. Herein, key quantitative lessons from the use of local and systemic adjuvant chemotherapy for GB in the clinic are outlined, and it is discussed how these can inform the development of next‐generation therapies. Several recent approaches are highlighted, and it is proposed that long‐lasting soft materials can capture the value of stiff BCNU‐loaded wafers while addressing a number of unmet medical needs. Finally, it is suggested that improved communication between materials scientists, biomedical scientists, and clinicians may facilitate translation of these materials into the clinic and ultimately lead to improved clinical outcomes.
AB0823 Patients with connective tissue disease have more anxiety in comparison with patients with other rheumatic diseases
Authors: Y. Jiang, D. Lin, P. Zhang, X. Zhang, Z. Liao, Y. Pan, J. Gu
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Rheumatic diseases often coexists with psychological disorders. Psychological symptoms not only have a substantial negative impact on the quality of life, but also on the course and outcome of the chronic disorders.<sup>1</sup> <h3>Objectives</h3> Our study was to investigate psychological disorders in Chinese patients with rheumatic diseases and to compare the differences of psychological disorders among different diseases. <h3>Methods</h3> Patients with rheumatic diseases were enrolled from July to December in 2017 in rheumatology department of the Third Affiliated Hospital of Sun Yat-sen University. Participants were required to complete a set of questionnaires and examinations, including demographic and clinical information, Zung self-rating anxiety scale (SAS), and Zung self-rating depression scale (SDS). The Statistical Package for Social Sciences (SPSS) software version 21 was used for all data management and analysis. The Mann-Whitney U test and Student's t test were used to compare patients with different rheumatic diseases and psychological disorders. Stepwise linear multiple regression was used to determine the contributors to SAS and SDS. <h3>Results</h3> Of all the 153 patients, 49 (32%) were male patients. 14.4% had only primary education, while 32% received education in university. Numbers of the patients were stated as follows. Lupus, 44; rheumatoid arthritis,11; Sjogren's syndrome, 11; systemic sclerosis, 9; myositis, 7; vasculitis, 6; spondyloarthritis, 9; gout, 10; other diseases 46. Mean age was 37.64±15.23 years. Mean disease duration was 3.78±5.07 years. Mean SAS scores were 43.44±8.51, and mean SDS scores were 46.66±12.43. 35 (22%) of the patients had anxiety, while 6 (3.9%) had moderate anxiety. 50 (32.7%) patients suffered from depression, of which 5 (3.3%) had severe depression, and 13 (8.5%) had moderate depression. Patients with connective tissue diseases had more anxiety (30.5%) than average score (p&lt;0.05), especially in patients with lupus. SDS (B=1.073, p&lt;0.001), educational scale (B=−2.147, p&lt;0.05) contributed to SAS scores. <h3>Conclusions</h3> Psychological disorders could concur with rheumatic diseases, especially in connective tissue diseases. Physicians should be aware of psychological status in these patients. <h3>Reference</h3> [1] Gladis MM, Gosch EA, Dishuk NM, Crits-Christoph P (1999) Quality of life: expanding the scope of clinical significance. J Consult Clin Psychol67:320–331. <h3>Acknowledgements</h3> None. <h3>Disclosure of Interest</h3> Y. Jiang: None declared, D. Lin: None declared, P. Zhang: None declared, X. Zhang: None declared, Z. Liao Grant/research support from: National Natural Sciences Foundation of China [grant number 81201372], Y. Pan: None declared, J. Gu Grant/research support from: the 5010 Subject of Sun Yat-sen University (2007023)
Abstract 20237: Genetic Depletion of Thromboxane A2/Thromboxane-Prostanoid Receptor Signaling Prevents Microvascular Dysfunction in Ischemia/Reperfusion Injury
Authors: Chen-Yen Chien, Chih-Yao Chiang, Wei-Yin Qiou, Christopher Chang, Po-Yuan Chang, Chiang-Ting Chien
Journal: Circulation (2017)

Introduction: Activation of thromboxane A2 synthase (TXAS)/thromboxane A2 (TXA2)/thromboxane-prostanoid receptor (TP) leads to arterial constriction, platelet aggregation and ultimate vascular dama...
SAT0613 Increased serum level of il-36 receptor antagonist is associated with active disease in patients with adult-onset still’s disease
Authors: H. Kim, J. Kang, B. Nam, J.S. Kim, D.-H. Yoo
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Adult onset Still's disease (AOSD) is an inflammatory disorder which was associated with varying level of pro-inflammatory cytokines. However, the role of natural anti-inflammatory molecules has not been evaluated to date. Interleukin (IL) 1 cytokine family is closely related to clinical presentations, disease activity and thus is a target for treatment of AOSD. IL-36 receptor antagonist (Ra) is an anti-inflammatory molecule, but its clinical significance has not been studied in AOSD patients. <h3>Objectives</h3> To figure out the role of IL-36Ra in monitoring disease activity in patients with AOSD. <h3>Methods</h3> The number of 49 AOSD patients meeting Yamaguchi criteria were recruited. Each patient was serially monitored following clinical course of flare and remission, which presented at least 2 points of change in modified Pouchot's score. They were divided into two groups by clinical courses, which were predominant systemic symptoms or arthritis. We compared erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin as disease activity markers between flare and remission. Serum levels of inflammatory cytokines, IL-18, IL-37, and IL-36Ra were measured by enzyme-linked immunosorbent assay (ELISA) in each clinical state of AOSD patients. <h3>Results</h3> Forty-nine patients with AOSD were included in this study; 40 were women (81.6%) and 9 were men (18.3%), with mean age of 49.08±14.17 years old. The mean duration of follow-up was 6.44±3.87 years, and mean difference of modified Pouchot's score was 5.37±1.98 between remission and flare. The number of 33 (67.4%) patients had presented systemic symptoms predominantly, while 16 (32.7%) presented arthritis more frequently in their clinical course. In flare state of AOSD, overall inflammatory markers were elevated, including cytokines of IL-18 and IL-37. The serum level of IL-36Ra was 164.04±169.03 pg/mL in active state, compared to 125.36±452.0 in inactive state of AOSD patients (p<i>&lt;</i>0.001). IL-36Ra presented positive correlation with modified Pouchot's score and inflammatory markers, including CRP (r=0.286, p<i>&lt;</i>0.01), ferritin (r=0.225, p<i>&lt;</i>0.05) and IL-37 (r=0.353, p<i>&lt;</i>0.01), but was not with level of IL-18 and ESR in active AOSD. Distribution of IL-36Ra level was analysed by each clinical course, however, there was no significant difference in level of IL-36Ra by clinical presentations stratified with predominance of arthritis. <h3>Conclusions</h3> Serum IL-36Ra level was significantly increased in active AOSD patients compared to inactive AOSD patients, presenting positive correlation with other inflammatory markers. In patients with AOSD, level of IL-36Ra might be another potential serologic marker to estimate disease activity, especially active state of the disease. <h3>Disclosure of Interest</h3> None declared