tbuckley/cabot-search huggingface dataset:
SAT0075 FACTORS ASSOCIATED TO DEVELOPING CVD AND STROKE IN PATIENTS WITH ESTABLISHED RHEUMATOID ARTHRITIS- A BARFOT COHORT STUDY
Authors: Ioana Filip, Stefan Bergman, Maria Andersson
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Patients with rheumatoid arthritis (RA) have a higher risk of cardiovascular diseases (CVD) and stroke. More knowledge about associated factors is needed since it could have implications on different treatment strategies <h3>Objectives</h3> To study factors associated to CVD and stroke development in patients with established RA. <h3>Methods</h3> A questionnaire was sent twice to patients with established RA in the BARFOT cohort, in 2010 (n=1525) and in 2017 (n=1046) with a response rate of 73% and 68% respectively. 950 patients responded to both questionnaires. All patients fulfilled the ACR criteria for classification of RA and had a disease duration at inclusion (1992 to 2006) of ≤12 months. The patients reported body mass index, smoking habits, tender (TJC) and swollen joint count (SJC, 28-joints), pain intensity (NRS) and physical function (HAQ), health related QoL (EQ5D), and medical treatment (DMARD, corticosteroids and NSAID). Possible factors associated with developing CVD or stroke at the questionnaire in 2017 or not (dependent variable) was studied by using a logistic regression analysis. <h3>Results</h3> Twenty-two patients (3%) developed CVD and 55 (6%) patients stroke over the seven years between the two questionnaires. Patients that developed CVD were older and to a higher rate men. They also more often, 40% vs. 11%, p=0.001, reported treatment with corticosteroids at both questionnaires. In a multivariate regression analysis age, OR (95% CI) 1.071 (1.015-1.129), male gender 7.459 (2.664-20.883) and reporting treatment with corticosteroids at both questionnaires 4.473 (1.525-13.117) were associated to CVD. Patients that developed stroke were older and more often not treated with any DMARD, 30% vs. 18%, p=0.069. There were no other significant differences between the groups. In a multivariate regression analysis age, OR (95% CI) 1.081 (1.047-1.117) and reporting treatment with conventional DMARD 0.510 (0.259-1.004) were associated to stroke at the second questionnaire. There were no associations between reported use of NSAIDs and development of CVD or stroke in this study. <h3>Conclusion</h3> Knowledge about factors associated to cardiovascular disease is important when treating patients with established RA. Long-term treatment with corticosteroids seems to increase the risk to develop CVD. Treatment with DMARDs, especially conventional DMARDs, seems to decrease the risk to develop stroke. There were no association between developing CVD or stroke and NSAIDs in this study. <h3>Disclosure of Interests</h3> None declared
THU0648 WORK DISABILITY IN A PERUVIAN COHORT OF SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS
Authors: Cristina Reategui Sokolova, Claudia Elera-Fitzcarrald, Rocío Violeta Gamboa Cárdenas, Mariela Medina, Francisco Zevallos Miranda, Paola Alejandra Zeña Huancas, Victor Pimentel Quiroz, Jorge-M Cucho-V, Cesar Pastor Asurza, Zoila Rodriguez Bellido, Risto Perich Campos, Graciela S Alarcon, Manuel F. Ugarte-Gil
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Work disability in patients with systemic lupus erythematosus (SLE) is common but the factors associated with it in Low and Middle Income Countries have been scarcely evaluated(1). <h3>Objectives:</h3> To determine the prevalence of and the factors associated with work disability in SLE patients. <h3>Methods:</h3> We studied 239 consecutive (1997 American College of Rheumatology (ACR) criteria) patients from a Peruvian SLE cohort from October 2017 to December 2018. Work disability was measured from a single self-report questionnaire. Data were collected and included sociodemographic information, clinical lupus features including disease activity [Systemic Lupus Erythematosus Disease Activity Index 2000 update (SLEDAI-2K)], damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)], as well as Health-Related Quality of Life (LupusQoL), and medication use. Work disability was defined by patients' self-report of not being able to work because of SLE. Univariable analysis comparing those patients with work disability and those who remained working were performed with the Mann Whitney U test for continuous variables and the Chi-square test for dichotomous variables. For the multivariable analyses, binary logistic regression with backward elimination was used to determine which factors remained associated with work disability. <h3>Results:</h3> Of 239 patients, 194 patients were working at least for at least some time since diagnosis, 181 (93.0%) were female, they had a mean age at diagnosis of 34.5 (12.3) years, and a mean disease duration of 11.5 (7.4) years, their mean SLEDAI was 2.53 (3.7) and their mean SDI was 1.2 (1.5). Twenty-eight patients changed their activities at work due to SLE and 51 (26.6%) stopped working after their diagnosis; 21 of them (41.1%) stopped working because of SLE. One hundred and forty-three were working at the time of the evaluation. In the multivariate analyses, those work- disabled due to SLE were more likely to have higher SDI: OR=1.650 (CI95%: 1.134-2.403) p=0.009, and lower HRQoL in two domains, planning: OR=0.975 (CI 95%: 0.954-0.996) p=0.020 and body image OR=0.977 (CI95%: 0.956, 0.998), p=0.032. <h3>Conclusion:</h3> Work disability due to SLE is associated with higher damage accrual and a poorer HRQoL. <h3>References:</h3> [1] Mak A. The economic burden of systemic lupus erythematosus in Asia: the current state. Sing Lau C, editor. Lupus. 2010Oct14;19(12):1442–6. <h3>Disclosure of Interests:</h3> None declared
PS1126 JNK1: AN EMERGING THERAPEUTIC TARGET IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) DOWNSTREAM OF THE B‐CELL RECEPTOR, WHICH OVERCOMES IBRUTINIB RESISTANCE
Authors: S. Decker, S. Khaja Saleem, S. Kissel, J. Duyster, C. Dierks
Journal: HemaSphere (2019)

Background: B‐cell receptor (BCR) inhibitors like ibrutinib are highly effective in the treatment of CLL, but frequent occurrence of resistance mutations limits treatment duration and causes relapses in many patients. The C‐Jun NH2‐terminal protein kinases 1 (JNK 1) belongs to the family of serine/threonine kinases, is involved in cell proliferation, survival and differentiation, and is located downstream of the BCR in CLL. Aims: Therefore, we aimed to validate JNK1 as crucial mediator of BCR signaling in CLL. Further, we wanted to validate JNK1 as a therapeutic target in ibrutinib‐resistant CLL. Methods: Patient derived xenograft mice from CLL patients and ibrutinib‐resistant CLL patients, and Eμ‐TCL1 tg mice were daily treated with the JNK1 inhibitor SP600125 using oral gavage. After 2 and 3 weeks of treatment, mice were sacrificed, and spleen and bone marrow cells were harvested and stained for CLL cells (BD). Results: In this study, we found that JNK1 is overexpressed and highly activated especially in IgVH unmutated B‐CLL lymphocytes with adverse prognosis, and overactive BCR signaling. JNK inhibition with the kinase inhibitors SP600125 and CC‐930, the substrate binding inhibitor protein L‐JNKi or siRNA mediated silencing all lead to apoptosis induction in IgVH unmutated primary human CLL samples. JNK1 inhibition was effective even in the presence of protective stroma cells, and resulted in down‐regulation of the anti‐apoptotic proteins BCL2 and MCL1, and the oncogenic transcription factor c‐JUN. By performing knockdown experiments and kinase inhibition of essential upstream BCR‐signaling mediators in CLL like SYK, BTK and PI3K, we identified JNK1 as a crucial downstream kinase in the BCR signaling pathway. In vivo treatment studies in patient derived xenograft mouse models and the Eμ‐TCL1 tg mouse model with the JNK1 inhibitor SP600125 confirmed our results and strongly reduced CLL cell numbers in the peripheral blood and spleen of both mouse models. JNK1 inhibition was even effective in a CLL xenograft model of a patient being resistant to ibrutinib treatment. In addition to direct effects on CLL cells, we found that JNK1 inhibitors in vivo also improve T‐cell responses, and reduce the frequency of immunosuppressive Tregs, while increasing the activity of CD4+ and CD8+ T‐cells. Summary/Conclusion: In conclusion, our studies revealed JNK1 as a promising novel therapeutic target in CLL downstream of the BCR, which can overcome ibrutinib resistance, and additionally improve immune responses against CLL cells.
FRI0594 COMPARISON OF CLINICAL FEATURES BETWEEN HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS COMPLICATED WITH RHEUMATIC DISEASES OR TUMOR
Authors: Zetao Liao, Yutong Jiang, LV Qing, Mingcan Yang, Yanli Zhang, Xinghua Guo, Jieruo Gu
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Hemophagocytic lymphohistiocytosis (HLH) covers a wide spectrum of related life-threatening conditions featuring ineffective immunity characterized by an uncontrolled hyperinflammatory response, which including autosomal recessive familial HLH (FHL), familial erythrophagocytic lymphohistiocytosis, viral-associated hemophagocytic syndrome, and autoimmune-associated macrophage activation syndrome (MAS). <h3>Objectives</h3> Our study was to compare the difference between HLH related with rheumatic diseases or tumor. <h3>Methods</h3> We retrospectively reviewed the patient data with definite bone marrow hemophagocytosis in the inpatient department of the Third Affiliated Hospital of Sun Yat-sen University between 01/11/2011 to 31/05/2018. The clinical manifestations, laboratory exam and prognosis were compared between patients related with tumor and rheumatic diseases. <h3>Results</h3> 7 patients with rheumatic diseases and 5 patients with tumor were enrolled. In patients with rheumatic diseases, 6 with adult-onset Still's disease and 1 with SLE. In patients with tumor, 4 with lymphoma and 1 with undefined tumor. The clinical features were compared between the two types of patients as below. <h3>Conclusion</h3> Clinical features of HLH patients complicated with tumor or rheumatic diseases were comparable in many aspects. Yet patients with tumor have more hypofibrinogenemia and lung involvement, and tend to be treated with VP-16 and Chemical therapy, and have much worse prognosis. <h3>References</h3> <h3>Disclosure of Interests</h3> None declared
Response to Comment on “An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness”
Authors: Dhiren F. Patel, Amit Gaggar, J. Edwin Blalock, Lisa G. Gregory, Clare M. Lloyd, Robert J. Snelgrove
Journal: Science Translational Medicine (2019)

We provide further evidence to support our assertion that PGP is a potent regulator of epithelial remodeling.
AB0672 RENAL INVOLVEMENT IN PATIENTS WITH DERMATOMYOSITIS AND POLYMYOSITIS
Authors: Simeon Monov, Daniela Monova, Russka Shumnalieva, Elena Miloshova
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Dermatomyositis (DM) and polymyositis (PM) are characterized by moderate to severe muscle weakness and inflammatory lesions in the muscle. They lead to frequent, and, in some cases, life-threatening extramuscular (lung, cardiac, neurologic, kidney) complications. <h3>Objectives</h3> The aim of this study was to determine the incidence, the severity, the course and outcome of renal diseases in patients with DM or PM. <h3>Methods</h3> We identified 84 patients (68 female, 16 male) with the diagnosis of DM and 23 (14 female, 9 male) with PM. Diagnosis of DM and PM was based on the ENMC classification. The mean follow-up was 5,6 ± 3,8 years. Evaluation of extramuscular involvement was mainly performed in the presence of suggestive clinical signs. Autoantibodies were detected by ELISA. Acute kidney injury (AKI) was defined as an acute doubling of serum creatinine level. Chronic kidney disease (CKD) was defined if an estimated glomerular filtration rate (eGFR) &lt;60 mL/min on at least 2 measurements 3 months apart. <h3>Results</h3> Of the 107 patients, 26 were found to have suffered varying degree of renal involvement. All the 26 patients (22 patients with DM and 4 with PM) had varying degree of proteinuria and haematuria. Renal involvement consisted of aKI in 8 patients and CKD in 18 patients. Among patients with aKI, 6 (75%) progressed to CKD, including 2 patients who reached end-stage renal disease (ESRD). Acute tubular necrosis with renal failure developed in 3 patients with PM and in 4 patients with DM. In descriptive analysis, male sex, cardiovascular risk factors, the severity of muscle injury, heart involvement, and initial proteinuria (&gt;0.3 g/d) were associated with aKI. In multivariate survival analysis, only age at disease onset, male sex, history of cardiovascular events, and a previous episode of aKI were identified as risks factors of CKD. Although the proteinuria and haematuria responded to therapy (except in 2 cases), the creatinine clearance remained decreased during the treatment. Kidney biopsy was performed in 16 patients and showed chronic tubulointerstitial nephritis (7 cases), minimal change disease (2 cases), focal segmental glomerulosclerosis lesions (3 cases), IgA nephropathy (2 cases), membranous nephropathy (1 case), and amyloid deposits (1 case). <h3>Conclusion</h3> Our data clearly indicate that DM and PM are associated with a wide range of renal disorders. Renal damage was noted in 24,3% of all included patients. AKI occurred in 7,48% of cases and CKD developed in 16,82% of the patients. AKI and CKD contribute to an increased morbidity in these patients. AKI and CKD are probably not a direct manifestation of PM or DM, but rather result from drug and myoglobin-induced renal damage. However, aKI and CKD contribute to increased morbidity in these patients <h3>Disclosure of interests</h3> None declared
IL-23–producing IL-10Rα–deficient gut macrophages elicit an IL-22–driven proinflammatory epithelial cell response
Authors: Biana Bernshtein, Caterina Curato, Marianna Ioannou, Christoph A. Thaiss, Mor Gross-Vered, Masha Kolesnikov, Qian Wang, Eyal David, Louise Chappell-Maor, Alon Harmelin, Eran Elinav, Paresh Thakker, Venizelos Papayannopoulos, Steffen Jung
Journal: Science Immunology (2019)

Cytokines maintain intestinal health, but precise intercellular communication networks remain poorly understood. Macrophages are immune sentinels of the intestinal tissue and are critical for gut homeostasis. Here, we show that in a murine inflammatory bowel disease (IBD) model based on macrophage-restricted interleukin-10 (IL-10) receptor deficiency (
Whorlton Hall: Advisers quit government review in protest at CQC’s handling of abuse scandal
Authors: Anthony Harwood
Journal: BMJ (2019)

Four members of the government’s review into the use of restraint, seclusion and segregation of people with learning disabilities and autism have resigned in protest at the Care Quality Commission’s handling of the Whorlton Hall scandal.

England’s health and social care secretary, Matt Hancock, commissioned the review from the CQC in December 2018 in response to concerns about the treatment of patients in secure hospitals. The CQC released an interim report on the review last month, which said that a high proportion of people in segregation had autism and that many staff lacked the necessary training and skills to look after them. The final report is due in March 2020.

But four members of the review’s expert …
National Early Warning Score (NEWS) and Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) Validation in AML Patient during Febrile Neutropenia
Authors: Barbara Nicolino, Umberto Vitolo, Ernesta Audisio, Stefano D'Ardia, Chiara Frairia, Giorgia Iovino, Andrea Evangelista, Giovannino Ciccone, Semra Aydin
Journal: Blood (2017)
Choosing panels of genomics assays using submodular optimization
Authors: Kai Wei, Maxwell W. Libbrecht, Jeffrey A. Bilmes, William Stafford Noble
Journal: Genome biology (2016)

Due to the high cost of sequencing-based genomics assays such as ChIP-seq and DNase-seq, the epigenomic characterization of a cell type is typically carried out using a small panel of assay types. Deciding a priori which assays to perform is, thus, a critical step in many studies. We present the submodular selection of assays (SSA), a method for choosing a diverse panel of genomic assays that leverages methods from submodular optimization. More generally, this application serves as a model for how submodular optimization can be applied to other discrete problems in biology.
AB0469 THE EFFECTS OF ACUPUNCTURE ON XEROSTOMIA, XEROPHTHALMIA AND ANTIBODY MODIFICATION IN PATIENTS WITH SJŐGREN SYNDROME: A META-ANALYSIS
Authors: Tzu-Hao Li, Yen-Ying Kung, Chang-Youh Tsai
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Xerostomia and xerophthalmia are common chief complaints among patients with Sjőgren syndrome (SS) but there has been no satisfying pharmacy to relieve the associated symptoms; hence the effectiveness of other non-pharmacological interventions such as acupuncture should be accessed. <h3>Objectives</h3> To access the therapeutic effects of acupuncture on xerostomia and xerophthalmia in patient with SS. <h3>Methods</h3> We conducted a meta-analysis of randomized clinical trials (RCTs) which evaluated the effectiveness of xerostomia and xerophthalmia in SS. PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chongqing Weipu Database (CQVIP), China Academic Journals Full-text Database, AiritiLibrary, Chinese Electronic Periodicals Service (CEPS), China National Knowledge Infrastructure (CNKI) Database were searches through Oct, 2018 to select studies. Data for evaluation of subjective and objective xerostomia was extracted and was assessed with random-effects meta-analysis. <h3>Results</h3> After searching, a total of 680 references were yielded and five RCTs were included, covering 460 patients dry mouth resulted from SS, among whom 229 patients received acupuncture and 231 patients were control group. Acupuncture group was associated with higher subjective response rate (odds ratio 3.036, 95% confidence interval [CI] 1.828 – 5.042, P &lt; 0.001, Fig. 1) and increased salivary flow rate (weighted mean difference [WMD] 3.066, 95% CI 2.969 – 3.164, P &lt; 0.001, Fig. 2), as an objective marker. Regarding xerophthalmia, acupuncture group revealed less dry eye visual analog scale (VAS, WMD -1.035, 95% CI -1.457 - -1.673, P &lt; 0.001, Fig. 3), better Schirmer test (WMD 2.357, 95% CI 1.021 – 3.692, P = 0.001, Fig. 4) and trend of longer break-up time (WMD 4.927, 95% CI -0.055 – 9.908, P = 0.053, Fig. 5). In addition, two studies examined IgG levels, which were lower in the acupuncture group (WMD -166.857, 95% CI -233.138 - -100.576, P &lt; 0.001, Fig. 6). <h3>Conclusion</h3> In the present meta-analysis, acupuncture improves both subjective and objective markers of xerostomia and xerophthalmia in patients with SS and is considered as an option of non-pharmacological treatment. <h3>References</h3> [1] Vivino FB. Sjogren's syndrome: Clinical aspects. Clin Immunol. 2017;182:48-54. [2] Kuklinski E, Asbell PA. Sjogren's syndrome from the perspective of ophthalmology. Clin Immunol. 2017;182:55-61. <h3>Disclosure of Interests</h3> None declared
THU0673 CARDIOVASCULAR DISEASE AS A RISK FACTOR FOR DEVELOPMENT OF RHEUMATOID ARTHRITIS – A DANISH FOLLOW-UP STUDY
Authors: Asta Linauskas, Annette de Thurah, Martin Berg Johansen, Kristian Stengaard-Pedersen, Kim Overvad
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> It is well-established that patients with rheumatoid arthritis (RA) have higher risk for development of atherosclerotic cardiovascular diseases (CVD) than the general population (1). The evidence shows that a CVD burden is already notable at the onset of RA (2). It is well-known, that atherosclerosis is an inflammatory condition (3). Therefore, we hypothesize that atherosclerotic CVD is positively associated with subsequent development of RA. <h3>Objectives</h3> To examine the risk of developing RA in persons who have had CVD, defined as acute myocardial infarction (AMI) or ischaemic stroke while controlling for established shared risk factors. <h3>Methods</h3> We conducted a population-based cohort study within the Danish Diet, Cancer and Health (DCH) cohort. The cohort was recruited 1993-97 and included individuals aged 50 to 64 years, born in Denmark and living in geographically defined parts of Denmark. Data on lifestyle factors and anthropometric measurements were collected at enrolment into the DCH. Information on incident AMI (ICD-10 code: I21), ischemic stroke (ICD-10 code: I63) and RA (ICD-10 codes: M05, M06 combined with ATC codes for DMARDs) was obtained from nationwide administrative registers. Participants were followed until development of RA, death, loss to follow-up or October 2016, whichever came first. Data were analyzed using Cox's proportional hazards regression models with delayed entry and age as the underlying time scale and cardiovascular disease (CVD) as a time-varying exposure variable, stratifying by gender. Established shared risk factors - smoking, body mass index and waist circumference - were included in the multivariable analyses. <h3>Results</h3> Complete data were available on 53287 subjects (52% female) without a AMI, stroke or RA diagnosis prior to their enrolment into the DCH. Median age at entry into DCH was 56 years. During follow-up (median 21 years), 4,627 participants developed CVD (37% female) and 516 participants developed RA (69% female). The risk for developing RA was 30% higher in women with CVD than in women without CVD (adjusted hazard ratio (HR) 1.30 (95% CI 0.70-2.38)) (Table 1). In men, there was no clear association between CVD and development of RA (adjusted HR 0.73 (95% CI 0.34-1.58)). <h3>Conclusion</h3> The investigation showed tendency towards a higher risk of developing RA in women with previous CVD than women without CVD. Male gender was not associated with subsequent development of RA, possibly related to low sample size. <h3>References</h3> [1] Avina-Zubieta et al. Ann Rheum Dis. 2012;71(9):1524–9. [2] Hannawi et al. Arthritis Res Ther. 2007;9(6):R116. [3] Ross R. N Engl J Med. 1999 Jan 14;340(2):115–26 <h3>Disclosure of Interests</h3> None declared
The Role of Homology and Orthology in the Phylogenomic Analysis of Metazoan Gene Content
Authors: Walker Pett, Marcin Adamski, Maja Adamska, Warren R Francis, Michael Eitel, Davide Pisani, Gert Wörheide
Journal: Molecular Biology and Evolution (2019)

Abstract Resolving the relationships of animals (Metazoa) is crucial to our understanding of the origin of key traits such as muscles, guts, and nerves. However, a broadly accepted metazoan consensus phylogeny has yet to emerge. In part, this is because the genomes of deeply diverging and fast-evolving lineages may undergo significant gene turnover, reducing the number of orthologs shared with related phyla. This can limit the usefulness of traditional phylogenetic methods that rely on alignments of orthologous sequences. Phylogenetic analysis of gene content has the potential to circumvent this orthology requirement, with binary presence/absence of homologous gene families representing a source of phylogenetically informative characters. Applying binary substitution models to the gene content of 26 complete animal genomes, we demonstrate that patterns of gene conservation differ markedly depending on whether gene families are defined by orthology or homology, that is, whether paralogs are excluded or included. We conclude that the placement of some deeply diverging lineages may exceed the limit of resolution afforded by the current methods based on comparisons of orthologous protein sequences, and novel approaches are required to fully capture the evolutionary signal from genes within genomes.