tbuckley/cabot-search huggingface dataset:
Making Health Research Matter: A Call to Increase Attention to External Validity
Authors: Amy G. Huebschmann, Ian M. Leavitt, Russell E. Glasgow
Journal: Annual Review of Public Health (2019)

Most of the clinical research conducted with the goal of improving health is not generalizable to nonresearch settings. In addition, scientists often fail to replicate each other's findings due, in part, to lack of attention to contextual factors accounting for their relative effectiveness or failure. To address these problems, we review the literature on assessment of external validity and summarize approaches to designing for generalizability. When investigators conduct systematic reviews, a critical need is often unmet: to evaluate the pragmatism and context of interventions, as well as their effectiveness. Researchers, editors, and grant reviewers can implement key changes in how they consider and report on external validity issues. For example, the recently published expanded CONSORT figure may aid scientists and potential program adopters in summarizing participation in and representativeness of a program across different settings, staff, and patients. Greater attention to external validity is needed to increase reporting transparency, improve program dissemination, and reduce failures to replicate research.
SAT0499 Association between systemic sclerosis and other systemic auto-immune diseases: study in two university hospitals cohorts
Authors: M. Scherlinger, J. Lutz, J. Sibilia, E. Chatelus, M.-E. Truchetet
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Association between systemic sclerosis (SSc) and another auto-immune systemic disease (AISD) in the same patient seems to be more frequent than each disease's prevalence would explain. <h3>Objectives</h3> The aim of our work was to describe patients presenting an overlap syndrome from 2 french cohorts and to compare their characteristics with patients presenting SSc alone. <h3>Methods</h3> This was a retrospective observational study conducted in two french auto-immune diseases reference centre (Strasbourg and Bordeaux). Patients responding to the 2013 ACR-EULAR scleroderma classification criteria for SSc were screened for concomitant AISD. Patients satisfying 2010 ACR-EULAR diagnostic criteria for rheumatoid arthritis (RA) and/or 2016 ACR-EULAR classification criteria for Gougerot-Sjögren syndrome (GSS) and/or 2012 SLICC systemic lupus erythematosus (SLE) classification criteria were included in our study. Patient, disease, and treatment characteristics were retrospectively retrieved from medical records and were compared to a SSc control cohort for Bordeaux University Hospital. <h3>Results</h3> A population of 534 SSc patients was studied. Thirty-four (6.4%) patients were identified as having overlap syndrome. There was 21 (62%, prevalence 3.9%) patients with RA, 14 (41%, prevalence 2.6%) with GSS and 4 (12%, prevalence 0.7%) with SLE (5 patients had 2 AISD). There were 24 (71%) patients with limited cutaneous SSc. Median Rodnan was 6 (extreme 0–42), 13 (38%) patients had interstitial pneumonia and 9 (26%) presented lung fibrosis. Three patients had pulmonary arterial hypertension (PAH) confirmed with catheterism. Seventeen patients (50%) had anti-centromere Ab, 11 (32%) had anti-Scl70 Ab whereas none had anti-RNA-polymerase III Ab (investigated in 24 patients). Concerning RA patients, 17 (81%) were ACPA-positive and 17 (81%) had erosive disease. Only 6 (29%) were in remission according to Boolean criteria and 13 (62%) had a DAS28-CRP≤3.2 suggesting difficult-to-treat RA. Patients with GSS all presented sicca syndrome, 8 (57%) had a Chisholm grade ≥3 on accessory salivary gland biopsy and 12 (86%) had positive anti-SSA Ab. In patients with SLE, 3 (75%) had positive anti-DNA Ab and one had a grade IV kidney disease. Three (75%) patients with SLE had a SLICC organ-damage score ≥5 suggesting severe SLE. Compared with our control cohort, patients with overlap syndrome had higher frequency of corticosteroid, immunosuppresive and biologic therapy use (85.3% vs 45%; 70.6% vs 31.3%; 52.9 vs 3.8%; p&lt;0.0001 for all comparisons). <h3>Conclusions</h3> Association of SSc and another auto-immune systemic disease is present in more than 6% of patients. These patients might have a more severe disease than usual SSc patients requiring prompt diagnosis and adequate treatment. <h3>Disclosure of Interest</h3> None declared
AB0017 Vitamin d level and mirna 22 and 125b gene expression in behÇet’s disease patients
Authors: R.M. Erfan, Y.H. Nasser, G.N. Morcos, O.G. Shaker, T.A. Gheita
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> To investigate serum levels of vitamin D and its effect on microRNA 22 and 125b gene expression in Behçet's disease (BD) patients and to evaluate their relation to clinical characteristics and disease activity. <h3>Methods</h3> Fifty-one BD patients and 45 matching controls were studied. Disease activity was assessed using BD Current Activity Form (BDCAF). Serum vitamin D3 was measured by ELISA. MicroRNAs were assayed by reverse transcription- quantitative polymerized chain reaction (RT-qPCR). <h3>Results</h3> Patients mean age was 34.3±8.6 years and disease duration 65.3±52.4 months. The BDCAF was 2.4±1.3. Vitamin D level was significantly lower (29.7±14.4 ng/ml) in patients than in control (40.1±17.8 ng/ml)(p&lt;0.001) especially males (25.8±7.5 ng/ml) compared to females (48±23.7 ng/ml)(p&lt;0.001). There was no relation between 25(OH)D levels and disease activity or with the presence of clinical manifestations. There was a 3.8±1.5 fold increase in miRNA125b while miR-22 showed no significant difference (0.38±0.46) but was significantly reduced in those receiving steroids (0.21±0.27) compared to those not (0.66±0.58)(p=0.003). There was no significant difference in the frequency of miR-22 or miR-125 expression according to the presence of clinical manifestations, medications received or disease activity. The fold change in miR-125b significantly correlated with vitamin D (r=0.54,p&lt;0.001) but not with BDCAF (p=0.64). <h3>Conclusions</h3> Vitamin D level is decreased in BD patients and significantly correlated with the fold change of miR-125b especially in males thus representing a possible therapeutic target. The miR-22 expression did not change but was notably downregulated by steroids. Further longitudinal studies on a larger sample are recommended to validate the present results. <h3>Disclosure of Interest</h3> None declared
Ponatinib-induced cardiotoxicity: delineating the signalling mechanisms and potential rescue strategies
Authors: Anand P Singh, Michael S Glennon, Prachi Umbarkar, Manisha Gupte, Cristi L Galindo, Qinkun Zhang, Thomas Force, Jason R Becker, Hind Lal
Journal: Cardiovascular Research (2019)

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myelogenous leukaemia (CML). However, cardiotoxicity of these agents remains a serious concern. The underlying mechanism of these adverse cardiac effects is largely unknown. Delineation of the underlying mechanisms of TKIs associated cardiac dysfunction could guide potential prevention strategies, rescue approaches, and future drug design. This study aimed to determine the cardiotoxic potential of approved CML TKIs, define the associated signalling mechanism and identify potential alternatives.In this study, we employed a zebrafish transgenic BNP reporter line that expresses luciferase under control of the nppb promoter (nppb:F-Luciferase) to assess the cardiotoxicity of all approved CML TKIs. Our in vivo screen identified ponatinib as the most cardiotoxic agent among the approved CML TKIs. Then using a combination of zebrafish and isolated neonatal rat cardiomyocytes, we delineated the signalling mechanism of ponatinib-induced cardiotoxicity by demonstrating that ponatinib inhibits cardiac prosurvival signalling pathways AKT and extra-cellular-signal-regulated kinase (ERK), and induces cardiomyocyte apoptosis. As a proof of concept, we augmented AKT and ERK signalling by administration of Neuregulin-1β (NRG-1β), and this prevented ponatinib-induced cardiomyocyte apoptosis. We also demonstrate that ponatinib-induced cardiotoxicity is not mediated by inhibition of fibroblast growth factor signalling, a well-known target of ponatinib. Finally, our comparative profiling for the cardiotoxic potential of CML approved TKIs, identified asciminib (ABL001) as a potentially much less cardiotoxic treatment option for CML patients with the T315I mutation.Herein, we used a combination of in vivo and in vitro methods to systematically screen CML TKIs for cardiotoxicity, identify novel molecular mechanisms for TKI cardiotoxicity, and identify less cardiotoxic alternatives.
Inhaled Corticosteroid Therapy in Adult Asthma. Time for a New Therapeutic Dose Terminology
Authors: Richard Beasley, James Harper, Grace Bird, Ingrid Maijers, Mark Weatherall, Ian D. Pavord
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Section:ChooseTop of pageAbstract <<Starting DoseModerate to Severe AsthmaVariability in ResponseSystemic Adverse EffectsStep DownICS/LABA TherapyConclusionsSearch Strategy and Selec...The EvidenceKey MessagesReferencesCITING ARTICLES
AB0039 Immunosuppressive effect of mesenchymal stem cells on monocytes derived from patients with rheumatoid arthritis
Authors: G. Vasilev, M.G. Ivanova, E. Ivanova-Todorova, K. Tumangelova–Yuzeir, E. Krassimirova, R. Stoilov, D. Kyurkchiev
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Mesenchymal stem cells (MSCs) are a heterogeneous population of fibroblast-like progenitor cells that may be isolated and expanded from bone marrow, umbilical cordand other tissues. Moreover, MSCs display the capacity to self-renew and differentiate into various mesodermal cell lineages. They also have drawn considerable attention for their regenerative and immunosuppressive effects in a range of autoimmune diseases, which raises the question for their potential use as therapeutic tool in rheumatoid arthritis. <h3>Objectives</h3> In line with aforementioned and taking in mind that monocytes playing pivotal role in orchestrating immunological tolerance, we aimed to study the immunosuppressive effects of adipose tissue derived mesenchymal stem cells (AT-MSC) on monocytes derived from patients with rheumatoid arthritis (RA). <h3>Methods</h3> We enrolled 12 patients matching the ACR/<sup>EULAR 2010</sup> criteria for RA. AT-MSC were isolated and cultured according to well established protocols. ELISA was performed for testing the cytokines produced by AT-MSC (IL-1, IL-10, IL-4, IFN-γ, IL-6, IL-8, CCL-5, RANTES, IL-17). Peripheral blood mononuclear cells (PBMCs) isolated from RA patients' samples were cultured in AT-MSC conditioned media and in control media. Flow cytometry was used for detection of monocytes markers (CD14, CD80, CD86, HLA-DR). <h3>Results</h3> Our results revealed considerable increase in number of cells expressing the myeloid lineage surface marker CD14 (p=0.026) under the influence of AT-MSC medium. We further demonstrated decrease in percentage values of monocytes expressing HLA-DR (p=0.004) and CD80/86 surface molecules (p=0.47). Moreover, significant reduction in mean fluorescent intensity of HLA-DR surface expression (p=0.016) was also demonstrated. <h3>Conclusions</h3> Our study unambiguously points out that under the impact of AT-MSC media monocyte development into dendritic cells was hampered and was also skewed into direction of accumulation of monocytes displaying more tolerogenic phenotype characterised by down regulation of HLA-DR and B7 complex (CD80/86) surface expression. Furthermore, antigen presentation alongside with expression of the co-stimilatory B7 complex and cytokine ambience forms a three-way signalling pathway responsible for T helper activation and proliferation and consequent antibody production by plasma cells. Hence, effects exerted by AT-MSC conditioned media on monocyte lineage development should not be neglected in the context of developing novel therapeutic approaches and strategies for treatment of RA. <h3>Disclosure of Interest</h3> None declared
Abstract 16758: Gut Microbiota Metabolism of L-Carnitine, a Nutrient in Red Meat, and the Atherogenic Metabolites γ–Gammabutyrobetaine and TMAO in Humans
Authors: Robert A Koeth, Zeneng Wang, Rachel Levia, Jose Carlos Garcia-Garcia, W. H. Wilson Tang, Stanley Hazen
Journal: Circulation (2017)

Introduction: L-carnitine potentially contributes to atherosclerosis via gut microbe-dependent formation of trimethylamine N-oxide (TMAO). Microbiota-dependent conversion of L-carnitine to TMAO in ...
FRI0408 Invariant natural killer t cells in systemic sclerosis
Authors: A.-C. Pecher, F. Kettemann, J. Henes, S. Duerr-Stoerzer, C. Schneidawind, L. Kanz, D. Schneidawind
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Systemic sclerosis (SSc) is a rare and heterogeneous immune-mediated disease. Its complex pathogenesis remains incompletely understood. Invariant natural killer T (iNKT) cells have been discussed in several autoimmune diseases<sup>1</sup>. They recognise selected endogenous as well as synthetic glycolipids like α-galactosylceramide by their TCR with high affinity and when activated, they typically release high amounts of pro- and/or anti-inflammatory cytokines<sup>2</sup>. <h3>Objectives</h3> To evaluate numbers and function of invariant natural killer T cells in patients with systemic sclerosis and analyse their correlation with disease parameters. <h3>Methods</h3> Human iNKT cells from 91 patients with SSc and 23 healthy controls were analysed by flow cytometric analysis. Their proliferative capacity and cytokine production was investigated following activation with CD1d ligand α-GalCer. <h3>Results</h3> We observed an absolute and relative decrease of iNKT cells in patients with SSc (0.036 iNKT cells/10<sup>6</sup> lymphocytes) compared with healthy controls (0.159 iNKT cells/10<sup>6</sup> lymphocytes, p&lt;0.001). We could also demonstrate that iNKT cells from patients with SSc showed a significantly decreased expansion capacity upon stimulation with α-GalCer. Interestingly, there was no difference concerning the subtype of SSc, disease severity or whether patients received immunosuppressive drugs. <h3>Conclusions</h3> iNKT cells are deficient and functionally impaired in patients with SSc. Therefore, adoptive transfer strategies using culture-expanded iNKT cells or administration of glycosphingolipids such as α-GalCer could be a novel approach to treat SSc patients. <h3>References</h3> [1] Wu L, Van KL. Natural killer T cells and autoimmune disease. Curr Mol Med2009;9:4–14. [2] Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol. 2007;25:297–336. <h3>Acknowledgements</h3> The National Institutes of Health Tetramer Core Facility kindly provided CD1d tetramer reagents. We would like to thank the Flow Cytometry Core Facility Berg of the University Hospital Tübingen for their excellent technical support. <h3>Disclosure of Interest</h3> None declared
Human Double-Negative Regulatory T Cells Modulate Effector Functions of Conventional T Cells By Selectively Blocking mTOR Signaling
Authors: Tabea Haug, Michael Aigner, Heiko Bruns, Moritz Peuser, Dorothea Gebhardt, Jana Berger, Florentine Koppitz, Andreas Mackensen, Simon Voelkl
Journal: Blood (2018)
FRI0385 Clinical characteristic features of brainstem encephalitis in neuropsychiatric systemic lupus erythematosus
Authors: S. Hirohata, Y. Matsueda, Y. Arinuma, H. Kikuchi
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Neuropsychiatric manifestation in systemic lupus erythematosus (NPSLE) is one of the most serious complications of the disease. The American College of Rheumatology (ACR) developed standardised nomenclature and case definitions for neuropsychiatric involvement in SLE (NPSLE) in 1999. Although myelopathy is included in the ACR nomenclature, no space is provided for the brainstem encephalitis. Moreover, it is still unclear whether the brainstem encephalitis is an independent clinical entity in NPSLE. <h3>Objectives</h3> The present study was designed in order to disclose the clinical characteristic features of the brainstem encephalitis in NPSLE. <h3>Methods</h3> We prospectively collected the patients who presented brainstem lesions from 2005 to 2015. The diagnosis of the brainstem encephalitis was made by the elevation of cerebrospinal fluid (CSF) IL-6, Magnetic Resonance Imaging and response to steroid. Serum autoantibodies, including anti-ribosomal P protein antibodies (anti-P), anti-NMDA receptor NR2 antibodies (anti-NR2), anti-Sm antibodies and anti-aquaporin 4 antibodies (anti-AQP4) and anti-cardiolipin antibodies (anti-CL), were measured by ELISA. <h3>Results</h3> Seven patients presented the brainstem encephalitis during the period of 10 years. All the patients showed the elevation of CSF IL-6 (8.3–2716 pg/ml, median 377 pg/ml), whereas CSF cell count was elevated in 6 patients. The most common clinical symptoms were headache (4 patients), vertigo (3patients) and consciousness disturbance (3 patients). All the patients showed high intensity lesions in FLAIR images on MRI. Notably, 5 of the 7 patients also showed the high intensities periventricular regions, including cerebral aqueduct and the 4th ventricle (figure 1). Anti-NR2 and anti-P were positive in 7 patients and 6 patients, respectively. By contrast, anti-CL, anti-Sm and anti-AQP4 were positive in 4 patients, 3 patients and 1 patient, respectively. Six patients recovered after steroid therapy, while 1 patient died due to severe brainstem damages at the onset. <h3>Conclusions</h3> These results indicate that the brainstem encephalitis is an independent clinical entity in NPSLE, characterised by reversible high intensity lesions, especially in periventricular areas. Moreover, the data demonstrate that anti-AQP4-related neuromyelitis optica disorder is a minor population within the brainstem encephalitis. By contrast, it is suggested that anti-NR2 and anti-P might play an important role in the pathogenesis of the brainstem encephalitis. <h3>Reference</h3> [1] ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum1999;42:599–608. <h3>Disclosure of Interest</h3> None declared
AB1244 Quality life in patients with rheumatic disease, non-rheumatic diseases and healthy population
Authors: F.M. Cuervo, A.M. Santos, J.C. Rueda, I. Angarita, E.L. Saldarriaga, R. Giraldo, J. Ballesteros, I. Pelaez, E. Forero, J. Ramirez, C. Toro
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Within public health strategies, the quality of life is a fundamental factor of intervention. The EQ-5D-3L is one of the most used instruments worldwide. <h3>Objectives</h3> To describe the change in quality of life and functional limitation of patients with rheumatic diseases compared to a healthy population and patients with other systemic diseases. <h3>Methods</h3> The EQ-5D-3L survey was used in 6693 people from 6 cities in Colombia. An analytical study was developed. <h3>Results</h3> In general, the healthy population (n=1104) reported not to have problems according to the EQ-5D-3L (median: 98,34). Of the non-rheumatic patients (n=642), 20% showed a moderate compromise because of pain and discomfort, as well as anxiety and depression. Twenty percent of patients with cardiovascular disease (n=53) reported moderate limitation for mobility. Patients with cardiovascular diseases reported moderate difficulties in carrying out daily activities. * The values of each of the dimensions of the instrument are expressed in% ** HBP: high blood pressure, CVD: cardiovascular disease, TB: tuberculosis *** Mental disorders: anxiety, nervousness or depression. Patients with rheumatic diseases (n=2274) manifested different degrees of limitation in mobility and daily activities. Patients with rheumatic diseases and comorbidities had greater compromise in quality of life predominately by pain and physical discomfort (more than 50% of the patients) figure 1. <h3>Conclusions</h3> In comparison with general population, rheumatic patients had a lower quality of life, and it is even worse in patients with rheumatic diseases and comorbidities. Comprehensive care of rheumatic patients should include strategies to improve standards of quality of life such as mobility, to perform daily activities and management of problems such as pain and discomfort. There are specific factors of intervention to reduce long-term disability of patients with rheumatic diseases. <h3>Disclosure of Interest</h3> None declared
Asthma admission rates and patterns of salbutamol and inhaled corticosteroid prescribing in England from 2013 to 2017
Authors: Sherif Gonem, Andrew Cumella, Matthew Richardson
Journal: Thorax (2019)

Asthma exacerbations are a common reason for hospital admission. We sought to identify whether patterns of inhaler prescribing are significantly associated with regional asthma admission rates. Asthma admission rates were obtained for English Clinical Commissioning Group (CCG) regions from 2013/2014 to 2016/2017. Raw prescribing data were obtained from OpenPrescribing.net, based on monthly general practice-level data published by the National Health Service Business Services Authority. Data were analysed using a linear mixed effects model. The ratio of salbutamol to inhaled corticosteroid prescriptions within a CCG was positively associated with asthma admission rates, independently of median age, asthma prevalence and socioeconomic deprivation.
Lipid-Mediated Relation between Tissue Factor Pathway Inhibitor Activity and Cardiovascular Risk Factors and Diseases in a Large Population Sample
Authors: Pauline van Paridon, Marina Panova-Noeva, Rene van Oerle, Andreas Schulz, Jürgen Prochaska, Natalie Arnold, Irene Schmidtmann, Manfred Beutel, Norbert Pfeiffer, Thomas Münzel, Karl J. Lackner, Tilman M. Hackeng, Hugo ten Cate, Philipp Wild, Henri M.H. Spronk
Journal: Blood (2018)
Long-term prognosis of patients with systemic lupus erythematosus-associated pulmonary arterial hypertension: CSTAR-PAH cohort study
Authors: Junyan Qian, Mengtao Li, Xiao Zhang, Qian Wang, Jiuliang Zhao, Zhuang Tian, Wei Wei, Xiaoxia Zuo, Miaojia Zhang, Ping Zhu, Shuang Ye, Wei Zhang, Yi Zheng, Wufang Qi, Yang Li, Zhuoli Zhang, Feng Ding, Jieruo Gu, Yi Liu, Yanhong Wang, Xiaofeng Zeng
Journal: European Respiratory Journal (2019)

This study aimed to identify the long-term clinical outcomes and prognostic factors of patients with systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension (PAH) confirmed by right heart catheterisation.A multicentre prospective cohort of SLE-associated PAH was established. Baseline and follow-up records were collected. The primary end-point was death. The secondary exploratory end-point was treatment goal achievement (TGA), defined as an integrated outcome.In total, 310 patients were enrolled from 14 PAH centres. The 1-, 3- and 5-year survival rates were 92.1%, 84.8% and 72.9%, respectively. The 1-, 3- and 5-year TGA rates were 31.5%, 53.6% and 62.7%, respectively. Baseline serositis, 6-min walking distance >380 m and cardiac index ≥2.5 L·min-1·m-2 were identified as independent prognostic factors of TGA. Patients with baseline serositis were more likely to reach TGA after intensive immunosuppressive therapy. TGA was identified as a positive predictor of survival in patients with SLE-associated PAH.TGA was associated with long-term survival, which supports the treat-to-target strategy in SLE-associated PAH. Baseline heart function predicted both survival and treatment goal achievement in patients with SLE-associated PAH. Patients with serositis at baseline tended to benefit from intensive immunosuppressive therapy and have a better clinical outcome.