tbuckley/cabot-search huggingface dataset:
Can Macrolide Antibiotics Prevent Hospital Readmissions?
Authors: Jadwiga A. Wedzicha, Andrew I. Ritchie, Fernando J. Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

stress.The same goes for the observations of corticosteroiddysregulated genes.Of note, ADRB2 gene activity is positively regulated by glucocorticoids.It is difficult to study how these two drug classes impact mechanisms, because both are central to asthma management.Therefore, other ways, including the use of mouse and cell culture models and clinical studies applying different doses of corticosteroids, need to be considered to determine how different doses influence gene expression.The challenge is to decide how best to take these findings forward.Now in its third funding period, SARP continues to show the enormous value and cost-effectiveness of large collaborative research studies to address questions in ways that could never be done by individual academic institutions or pharmaceutical companies.U-BIOPRED has been similarly productive.The findings from both consortia need to be validated, and cross-interrogation of the respective datasets would be of enormous value.We are now well into the era of asthma biologics, and a set of approved monoclonal antibodies that target different pathways is available.To understand how these drugs work on mechanisms, we need to use omics methods like the ones applied in this study.
THU0308 ASSESSMENT OF SEXUAL AND PSYCHOLOGICAL STATES OF BEHÇET’S DISEASE MALE PATIENTS
Authors: Alaa A A Mohamed, Manal Hassanien, Amr Abou Faddan, Arwa Aljohi, Safaa A Mahran
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Behçet's disease (BD) is a chronic multisystem autoimmune disease characterized by orogenital ulceration, uveitis, skin lesions and vascular involvement of different organs in the body. The sexual and psychological aspects of the disease are still not fully recognized. <h3>Objectives:</h3> We aimed to evaluate the sexual and psychological status of BD male patients and to assess the relationship between the sexual function and depression in this cohort. <h3>Methods:</h3> The patients, fulfilling the International Criteria for Behçet's disease (ICBD), and healthy controls, of a comparable age, were evaluated in the Rheumatology and Urology Clinics. The demographic and clinical data was collected. Disease activity of the patients was assessed using Behçet's Syndrome Activity Score (BSAS). For both groups, the sexual function and the psychological status were evaluated using the International Index of Erectile Functions (IIEF- 5) and the Beck Depression Inventory (BDI), respectively. Spearman's rho, Chi-Square and Mann-Whitney U tests were used as appropriated. <h3>Results:</h3> The number of BD patients was 26 and that of the controls was 27. The mean age of the patients was 36±7.4 and that of controls was 40.9±5.2. Though BD patients were younger in age they exhibited significantly lower scores in sexual function, and scored higher in depression as illustrated in <b>Table 1</b>. There were no associations between the disease duration, smoking status or different clinical phenotypes and the sexual or psychological functions. However, there was an inverse relationship between BSAS and the sexual function (rho= -.443, p=.024). The duration of corticosteroids intake was negatively correlating with the sexual function (rho= -.604, p= .001) as well. The depression scores correlated significantly with the presence of inflammatory back pain (rho= .413, p=.036). There was no association between the severity of sexual dysfunction and that of depression. The patients showed different degrees of depression, and there was a tendency towards increased rates of erectile dysfunction in all groups as shown in <b>Table 2</b>. ED; erectile dysfunction. <h3>Conclusion:</h3> BD has a negative impact on men's psychological state and sexual function. Severe disease states, evident in the long duration of corticosteroids use and the high activity scores, are linked to sexual dysfunction. <h3>Disclosure of Interests:</h3> None declared
TCT-661 Impact of Pre-Procedural Blood Pressure on Long-term Outcomes Following Percutaneous Coronary Intervention
Authors: Josephine Warren, Shane Nanayakkara, Nick Andrianopoulos, Angela Brennan, Laura Selkrig, Anthony Dart, David Clark, Chin Hiew, Melanie Freeman, Bronwyn Kingwell, Stephen Duffy
Journal: Journal of the American College of Cardiology (2017)
PF542 MITOCHONDRIAL GENOMIC ANALYSIS IN PATIENTS WITH MYELOID MALIGNANCIES
Authors: S.Y. Kim, M. Koo, Y. Park, G.C. Kwon, S.H. Koo
Journal: HemaSphere (2019)

Background: Mitochondrial DNA (mtDNA) somatic mutation frequently occur in neoplasms. Because of heteroplasmy of mDNA, it is difficult to determine whether genetic variations in mtDNA occur as germline variants or truly somatic variant. Genetic abnormalities in nuclear DNA in myelodysplastic syndrome (MDS) and other myeloid malignancies are massively investigated. However, the molecular abnormalities in mtDNA in MDS and other myeloid malignancies have not been poorly revealed. In this study, we analyzed full sequence of mtDNA using next generation sequencing (NGS) technique in patients with MDS or other myeloid malignancies to investigate possible variants in mtDNA in these patients. Aims: The aim of this study is to find mtDNA variants and to select possible somatic mtDNA variants and investigate possible association with disease characteristics. Methods: We collected total DNA from bone marrow or peripheral blood samples with malignant cells in 35 patients with various myeloid malignancies [15 MDS, 7 acute myeloid leukemia (AML) without recurrent genetic abnormalities, 6 primrary myelofibrosis (PMF), 4 myelomomocytic leukemia (CMML), and 2 atypical chronic myeloid leukemia (aCML)]. In addition, 49 patients with non-hematologic diseases are included as controls. Whole mitochondrial genomic sequencing was amplified, and NGS was performed by HiSeq 2000 (illumine). In addition, targeted sequencing using genomic DNA for 138 genes including well-known genes in MDS was also performed. Results: We selected candidate mtDNA single nucleotide variants (mt-SNVs) according to the heteroplasmy levels of variants and filtering from reference database and control patients’ results. We discarded small insertion or deletions from our analysis. When same selection criteria were applied in control samples, no candidate mt-SNVs were found except 1 known mutation in MELAS patients. We finally selected 53 candidate mt-SNVs in 26 patients (74.3%). The 40/53 (75.5%) of mt-SNVs were found in protein coding genes, 10/53 (18.9%) were found in rRNA genes, and 3/53 (5.7%) were found in tRNA genes. The mt-SNVs were most frequently found in CYTB and CO3, and ND3, ND4, ND4, RNR1, and RNR2 in descending order. mt-SNVs in CO3 were most frequently found in MPN patients, and variants in ND3 and ND4 were most frequently found in AML patients. Most of patients with ND3 variants had ASXL1 mutations. Summary/Conclusion: Our results suggested that somatic mtDNA may present different distributions among disease subtypes of myeloid malignancies, which may give new insight on the pathogenesis of myeloid malignancies.
Hypomethylation of <i>STAT1</i> and <i>HLA-DRB1</i> is associated with type-I interferon-dependent <i>HLA-DRB1</i> expression in lupus CD8+ T cells
Authors: Shaylynn Miller, Pei-Suen Tsou, Patrick Coit, Elizabeth Gensterblum-Miller, Paul Renauer, Dallas M Rohraff, Nathan C Kilian, Mark Schonfeld, Amr H Sawalha
Journal: Annals of the Rheumatic Diseases (2019)

Objective We examined genome-wide DNA methylation changes in CD8+ T cells from patients with lupus and controls and investigated the functional relevance of some of these changes in lupus. Methods Genome-wide DNA methylation of lupus and age, sex and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR. Inhibiting STAT1 and CIITA was performed using fludarabine and CIITA siRNA, respectively. Results Lupus CD8+ T cells had 188 hypomethylated CpG sites compared with healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1 . Genes involved in the type-I interferon response, including STAT1 , were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. CIITA knockdown and STAT1 inhibition experiments revealed that HLA-DRB1 expression in lupus CD8+ T cells is dependent on CIITA and STAT1 signalling. Coincubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69 and cytokine production, in patients with lupus but not in healthy controls. This can be blocked by neutralising antibodies targeting HLA-DR. Conclusions Lupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in patients with lupus. A possible pathogenic role for CD8+ T cells in lupus that is dependent on a high type-I interferon environment and epigenetic priming warrants further characterisation.
Hypertrophic Cardiomyopathy—Need for Gene-Specific Treatment?
Authors: Beau van Driel, Jolanda van der Velden
Journal: JAMA Cardiology (2019)

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PB1996 PROGNOSTICATION OF HODGKIN'S LYMPHOMA BY IPET AND IPS: UPDATE DATA OF 8 HEMATOLOGICAL UKRAINIAN CENTERS.
Authors: O. Novosad, T. Skrypets, I. Pastushenko, T. Kadnikova, K. Ulianchenko, A. Gorbach, A. Ashykhmin, Y. Kmetyuk, O. Karpova, L. Mykhalska, O. Kindrakevych, V. Kozlov, N. Novikov, V. Kosinova, E. Oliinichenko, N. Kostiukova, O. Tkachenko, O. Karnabeda, V. Stratienko, I. Kriachok
Journal: HemaSphere (2019)

Background: PET‐CT has completely changed and improved treatment approaches in patients with Hodgkin Lymphoma (HL) for the last years. Recent studies are evaluated predictive role PET for survival rate. The major idea is to identify patients from a high‐risk group who can have early relapse/refractory disease using iPET and IPS to guide the choice of chemotherapy. Aims: To evaluate the prognostic role of iPET in patients with HL. Methods: The cohort consisted of 132 patients of up to 69 years of age with newly diagnosed HL were treated with ABVD or BEACOPP‐14/esc based on their stage and risk group. Metabolic PET‐CT imaging was performed to routine protocols using Deauville criteria for response assessment. Interim PET was performed at 15.5 ± 3 days (range, 5‐26) after 2‐3d and 4th cycles of treatment in 81% and 19% cases, respectively (p &lt; 0.05). The main endpoints of study were to assess the correlation between IPS, iPET findings and clinical outcome (relapse/death). Results: The ORR (CR, PR) in this group of patients was 85.6%. The maximum follow‐up period was 70 months (median 16 months). Under the follow‐up there are still 96.9% (128/132) patients. 81.8% (108/132) and 18.2% (24/132) of patients had 1–3 and 4–5 scores of iPET by Deauville 5‐PS scale, respectively (p &lt; 0.05). In total, disease progression was documented in 20.8% (5/24) iPET‐positive (iPET+) and 13% (14/108) iPET‐negative (iPET‐) patients (p &lt; 0.05). There were two deathss from refractory disease. The 5‐year EFS of iPET+ patients vs iPET‐was 50% and 80%, respectively (p &lt; 0.05). We divided patients by IPS groups: 71(53.8%) with ≤2 and 61(46.2%) with ≥3 risk factors (low and high‐risk group, respectively, p &lt; 0.05).Patients in low‐risk group were associated with significant improvement in 5‐year EFS compared with patients in high‐risk group (80% vsthe 65%, respectively, longrank test, p = 0.01 ).The estimated 5‐year EFS was 80% in iPET‐ vs 65% with iPET+ in low risk group (p &lt; 0.05). The 5‐year EFS was significantly better in high‐risk patients who achieved iPET‐ status compared to iPET+ status (70% vs 55%, p &lt; 0.05). Summary/Conclusion: In our study, we found that IPS correlates with iPET results. Moreover, it could predict treatment outcomes in patients with HL.
PS1585 ELDERLY WITH ANTIPHOSPHOLIPID SYNDROME PRESENT WITH DISTINCT CLINICAL PROFILE: A RETROSPECTIVE SINGLE CENTER STUDY
Authors: S. Bountola, V. Perifanis, A. Kazantzi, C. Keramidioti, E. Hassapopoulou‐Matami, A. Hatzitolios, F. Girtovitis
Journal: HemaSphere (2019)

Background: Antiphospholipid syndrome (APS) is an acquired autoimmune disorder. It is characterized by venous and/or arterial thrombosis and/or pregnancy related morbidity in the presence of persistent antiphospholipid antibodies (aPL). It can occur as primary or as secondary APS in association with an autoimmune disorder (usually SLE). APS mainly affects women who are of child‐bearing age and less often elderly patients. Aims: We aimed to describe the clinical and immunological features of APS in patients diagnosed after the age of 55. Methods: The PSA (Phospholipid Syndrome Aged) study is a retrospective study of patients with suspected APS, who were referred to the Thrombosis and Haemostasis Clinic during the last decade (2009–2018). Clinical and serological data of patients with late onset APS (occurred after the age of 55) were analyzed and compared with patients presenting with early onset APS. The aPL (anticardiolipin (ACA) and anti‐b 2 GP‐I antibodies, IgG and IgM) were measured by ELISA (Euroimmun, Germany). Results: We evaluated 149 patients diagnosed with APS (56,4% males, median age 43,74 ± 13,4 years). Patients with late onset APS were 32 (21,5%) and consisted Group A. The other 117 patients were Group B. Median follow‐up was 62,5 months (13–147). The most common clinical manifestation was stroke (20,5%), followed by deep vein thrombosis of the lower extremities (15,4%) and pulmonary embolism (12,7%). Clinical characteristics of patients are shown in table 1. x 2 test was used to assess statistical significance. All triple positive patients were in group B (10 women and one man). All patients were treated with antithrombotic treatment including antiplatelet agents (26,5%) and/or oral anticoagulants (69%). 14% of the patients received only LMWH (younger women). Male gender, LA positivity and a higher frequency of secondary APS were statistically significant in the older group. Summary/Conclusion: Elderly APS patients should not be disregarded because they represent 21,4% of an APS population. Patients aged &gt;55 who are diagnosed with APS share a distinct disease profile. Clinicians must be aware of this situation in order to identify specific causes, to evaluate the risk of recurrence and to establish a therapeutic approach. image
FRI0211 A LOW AND PROMPTLY TAPERED STEROID REGIMEN CAN ACHIEVE EXCELLENT RESULTS IN LUPUS NEPHRITIS, WITH LESS ADVERSE EVENTS
Authors: Farah Tamirou, Nathalie Demoulin, Selda Aydin, Frederic Houssiau
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The optimal use of glucocorticoids (GC) in lupus nephritis (LN) remains a topic of debate, especially the tapering protocol and the duration of treatment. To date, only one randomized controlled trial, <i>MyLupus</i>, has compared two oral prednisolone (P) regimens in LN (0.5 <i>versus</i> 1mg/kg/d) in addition to mycophenolic acid. Although non-inferiority was not proven, this study demonstrated a similar rate of renal response at 24 weeks, with fewer side-effects in the 0.5mg/kg/d group. <h3>Objectives:</h3> To determine by a retrospective study the efficacy and the toxicity of an even lower P regimen (20mg/d), very promptly tapered to 5mg/d at week 12 and stopped as early as at week 52. <h3>Methods:</h3> Data from the last 30 consecutive proliferative LN patients diagnosed at the Louvain Lupus Clinic (between 2015 and 2018) were reviewed retrospectively. In these patients, the 10 last consecutive patients received a low fixed dose of P (20mg/d) for 4 weeks, rapidly tapered as follows: 15mg/d for 2 weeks, 12.5mg/d for 2 weeks, 10mg/d for 2 weeks, 7.5mg/d from for 2 weeks, 5mg/d for 3 months and 2.5mg/d for 6 months. GC were withdrawn at week 52. The baseline and the follow-up data of these 10 patients were compared to the 20 previous consecutive LN patients followed in the same center but given a standardized P dose of 0.5mg/kg/d. Both groups of patients received 750 mg methylprednisolone IV pulses on 3 consecutive days at baseline. The one-year renal response was defined by achieving a proteinuria target &lt; 0.8g/d. <h3>Results:</h3> Clinical (BMI, gender, age, mean serum creatinine, mean proteinuria, SLEDAI-2K, non-steroid immunosuppressants) and pathological (ISN/RPS class) characteristics did not differ at baseline between the two groups. As illustrated in the Table, the mean uP/C ratios measured at one year were similar, as were the percentages of patients who achieved the proteinuria target. Importantly, <i>Herpes zoster</i> infections were only observed in the higher P dose group, with the difference reaching almost statistical significance. <h3>Conclusion:</h3> In patients suffering from proliferative LN, an induction protocol with a low and rapidly tapered dose of P may be as effective as higher dose regimen to achieve the proteinuria target at one year, with fewer <i>Herpes zoster</i> episodes. These results deserve to be confirmed in a controlled trial. <h3>References:</h3> BMI: body mass index; IV MP: intravenous methylprednisolone; P: prednisolone; uP/C: urine protein to creatinine ratio; <i>P</i> values were calculated by unpaired <i>t</i>-tests and Fisher’s exact tests, as appropriate. <h3>Disclosure of Interests:</h3> None declared
SAT0261 CHARACTERISTICS ASSOCIATED TO SCLERODERMAL RENAL CRISIS, AND INCIDENCE VARIATION OVER TIME IN THE RESCLE REGISTRY
Authors: Xavier Pla Salas, Carles Tolosa, Eduardo L. Callejas-Moraga, Alfredo Guillén del Castillo, Jose Antonio Todolí Parra, Luis Trapiella Martínez, Mónica Rodríguez Carballeira, Adela Marín Ballvé, Isabel Perales Fraile, Vicent Fonollosa-Pla, Carmen Pilar Simeón-Aznar
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Scleroderma Renal Crisis (SRC) is a serious complication of Systemic Sclerosis (SSc). Nowadays, it seems that there is a reduction in its prevalence and mortality<sup>1</sup>. <h3>Objectives</h3> To evaluate the characteristics of patients with SRC in a large cohort of SSc pacients. To investigate predictors of SRC, and epidemiologic differences over time. <h3>Methods</h3> 1933 patients were collected in ongoing registry of Spanish SSc pacients – RESCLE. We did descriptive study and epidemiologic analysis. <h3>Results</h3> Out of 1933 SSc, 43 (2.2%) developed SRC. Univariate analysis showed significant differences of SRC vs. non-SRC cases: SSc subtypes: diffuse cutaneous SSc (dcSSc), 72% vs. 19%; limited cutaneous SSc (lcSSc), 26% vs. 61%. Demographics: Female gender, 77% vs. 89%; time from SSc onset to SSc diagnosis, 3.0±8.0 vs. 6.6±9.5 years; arterial hypertension (HT), 56% vs. 32%. 1st manifestation: Raynaud’s phenomenon (RP), 68% vs. 82%. Clinical manifestations: RP, 88% vs. 96%; digital ulcers, 70% vs. 38%; arthritis, 45% vs. 20%; myositis, 30% vs. 13%; joint contractures, 45% vs. 18%; intestinal involvement, 24% vs. 11%; malabsorption, 24% vs. 7%; interstitial lung disease 58% vs. 41%; pulmonary HT, 56% vs. 29%; pericardial effusion, 28% vs. 7.4%; pericarditis, 24% vs. 8.3%; ischemic cardiopathy, 31% vs. 12%; diastolic dysfunction, 67% vs. 34%. Capillaroscopy: active pattern 77% vs. 33%. Immunological data: anti-Topoisomerase I, 39% vs. 20%; anti-centromere, 15% vs. 49%; anti-RNApol III, 45% vs. 11%. Prognosis: Overall mortality, 56% vs. 18%; SSc-related mortality, 83% vs. 49%. Survival at 5, 10, 20, and 30 years was 73% vs. 96%, 56% vs. 92%, 28% vs. 80%, and 28% vs. 67%, respectively. Treatment: ACEI use, 35% vs. 14%, corticoid use, 51% vs. 25%. Multivariate analysis: dsSSc subtype, RR 22.68 (5.81-88.51) p&lt;0.001; intestinal malabsorption, RR 7.35 (2.55-21.18) p&lt;0.001, and active capillaroscopy pattern RR 7.26 (1.61-32.7) p&lt;0.010. Prevalence of SRC (P) in dcSSc subtype 7.8%, and in lcSSc subtype 0.9%. P over decades: P-80’s, 3.8%; P-90’s, 2.7%; P-00’s: 2.3% and P-10’s: 0.9%, achieving statistical significance in the last decade RR: 0.33 (0.13-0.85) p=0.014. <h3>Conclusion</h3> In RESCLE cohort, SRC predominated in dcSSc patients, and it was associated to intestinal malabsorption, and an active pattern by capillaroscopy. SRC showed a very poor prognosis. Finally, we evidenced a decreasing prevalence of SRC over time in our cohort. <h3>Reference</h3> [1] Turk M, et al. The Frequency of Scleroderma Renal Crisis over Time: A Metaanalysis. J Rheumatol 2016; 43: 1350. <h3>Disclosure of Interests</h3> None declared
Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance
Authors: Zinan Zhang, Florian Gothe, Perrine Pennamen, John R. James, David McDonald, Carlos P. Mata, Yorgo Modis, Anas M. Alazami, Meghan Acres, Wolfram Haller, Claire Bowen, Rainer Döffinger, Jan Sinclair, Shannon Brothers, Yu Zhang, Helen F. Matthews, Sophie Naudion, Fanny Pelluard, Huda Alajlan, Yasuhiro Yamazaki, Luigi D. Notarangelo, James E. Thaventhiran, Karin R. Engelhardt, Hamoud Al-Mousa, Sophie Hambleton, Caroline Rooryck, Kenneth G.C. Smith, Michael J. Lenardo
Journal: The Journal of Experimental Medicine (2019)

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.