tbuckley/cabot-search huggingface dataset:
Circulating Selenium and Prostate Cancer Risk: A Mendelian Randomization Analysis
Authors: James Yarmolinsky, Carolina Bonilla, Philip C Haycock, Ryan J Q Langdon, Luca A Lotta, Claudia Langenberg, Caroline L Relton, Sarah J Lewis, David M Evans, George Davey Smith, Richard M Martin
Journal: JNCI Journal of the National Cancer Institute (2018)

In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), selenium supplementation (causing a median 114 μg/L increase in circulating selenium) did not lower overall prostate cancer risk, but increased risk of high-grade prostate cancer and type 2 diabetes. Mendelian randomization analysis uses genetic variants to proxy modifiable risk factors and can strengthen causal inference in observational studies. We constructed a genetic instrument comprising 11 single nucleotide polymorphisms robustly (P < 5 × 10-8) associated with circulating selenium in genome-wide association studies. In a Mendelian randomization analysis of 72 729 men in the PRACTICAL Consortium (44 825 case subjects, 27 904 control subjects), 114 μg/L higher genetically elevated circulating selenium was not associated with prostate cancer (odds ratio [OR] = 1.01, 95% confidence interval [CI] = 0.89 to 1.13). In concordance with findings from SELECT, selenium was weakly associated with advanced (including high-grade) prostate cancer (OR = 1.21, 95% CI = 0.98 to 1.49) and type 2 diabetes (OR = 1.18, 95% CI = 0.97 to 1.43; in a type 2 diabetes genome-wide association study meta-analysis with up to 49 266 case subjects and 249 906 control subjects). Our Mendelian randomization analyses do not support a role for selenium supplementation in prostate cancer prevention and suggest that supplementation could have adverse effects on risks of advanced prostate cancer and type 2 diabetes.
The prognostic potential of alternative transcript isoforms across human tumors
Authors: Juan L. Trincado, E. Sebestyén, A. Pagés, E. Eyras
Journal: Genome Medicine (2016)

Phenotypic changes during cancer progression are associated with alterations in gene expression, which can be exploited to build molecular signatures for tumor stage identification and prognosis. However, it is not yet known whether the relative abundance of transcript isoforms may be informative for clinical stage and survival. Using information theory and machine learning methods, we integrated RNA sequencing and clinical data from The Cancer Genome Atlas project to perform the first systematic analysis of the prognostic potential of transcript isoforms in 12 solid tumors to build new signatures for stage and prognosis. This study was also performed in breast tumors according to estrogen receptor (ER) status and melanoma tumors with proliferative and invasive phenotypes. Transcript isoform signatures accurately separate early from late-stage groups and metastatic from non-metastatic tumors, and are predictive of the survival of patients with undetermined lymph node invasion or metastatic status. These signatures show similar, and sometimes better, accuracies compared with known gene expression signatures in retrospective data and are largely independent of gene expression changes. Furthermore, we show frequent transcript isoform changes in breast tumors according to ER status, and in melanoma tumors according to the invasive or proliferative phenotype, and derive accurate predictive models of stage and survival within each patient subgroup. Our analyses reveal new signatures based on transcript isoform abundances that characterize tumor phenotypes and their progression independently of gene expression. Transcript isoform signatures appear especially relevant to determine lymph node invasion and metastasis and may potentially contribute towards current strategies of precision cancer medicine.
Initiating tocilizumab, with or without methotrexate, compared with starting methotrexate with prednisone within step-up treatment strategies in early rheumatoid arthritis: an indirect comparison of effectiveness and safety of the U-Act-Early and CAMERA-II treat-to-target trials
Authors: Maxime MA Verhoeven, Marjolein JH de Hair, Janneke Tekstra, Johannes WJ Bijlsma, Jacob M van Laar, Attila Pethoe-Schramm, Michelle EA Borm, Evert-Jan ter Borg, Suzanne P Linn-Rasker, Xavier M Teitsma, Floris PJG Lafeber, Johannes WG Jacobs, Paco MJ Welsing
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Methotrexate (MTX), often combined with low moderately dosed prednisone, is still the cornerstone of initial treatment for early rheumatoid arthritis (RA). It is not known how this strategy compares with initial treatment with a biological. We therefore compared the effectiveness of tocilizumab (TCZ), or TCZ plus MTX (TCZ+MTX) with MTX plus 10 mg prednisone (MTX+pred), all initiated within a treat-to-target treatment strategy in early RA. Methods Using individual patient data of two trials, we indirectly compared tight-controlled treat-to-target strategies initiating TCZ (n=103), TCZ+MTX (n=106) or MTX+pred (n=117), using initiation of MTX (n=227) as reference. Primary outcome was Disease Activity Score assessing 28 joints (DAS28) over 24 months. To assess the influence of acute phase reactants (APRs), a disease activity composite outcome score without APR (ie, modification of the Clinical Disease Activity Index (m-CDAI)) was analysed. Secondary outcomes were remission (several definitions), physical function and radiographic progression. Multilevel models were used to account for clustering within trials and patients over time, correcting for relevant confounders. Results DAS28 over 24 months was lower for TCZ+MTX than for MTX+Pred (mean difference: −0.62 (95% CI −1.14 to −0.10)). Remission was more often achieved in TCZ+MTX and in TCZ versus MTX+pred (p=0.02/0.05, respectively). Excluding APRs from the disease activity outcome score, TCZ-based strategies showed a slightly higher m-CDAI compared with MTX+pred, but this was not statistically significant. Other outcomes were also not statistically significantly different between the strategies. Conclusions In patients with early RA, although TCZ-based strategies resulted in better DAS28 and remission rates compared with MTX+pred, at least part of these effects may be due to a specific effect of TCZ on APRs.
THU0224 THE HEPATITIS VIRUS PRES1 PROTEIN RETARDS THE ONSET OF LUPUS-LIKE GLOMERULONEPHRITIS IN NZB/W F1 MICE
Authors: Roberto Luisetto, Anna Ghirardello, Gianmarco Villano, Anna Scanu, Mariele Gatto, Felipe Leite de Oliveira, Patrizia Pontisso, Andrea Doria
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Infection can trigger autoimmunity but the nature of the pathogen could enhance or inhibit the onset of the disease. In this study we tested the tolerogenic effect of the surface Hepatitis B Virus capside protein preS1 in a lupus mouse model. <h3>Objectives:</h3> To evaluate the effect of administration of Hepatitis B virus preS1 subunit to NZB/WF1 mice <h3>Methods:</h3> Mice (10 each group) were injected with a total volume of 200μl of 32.5 μg PreS1 in 200μl PBS (group 1), 200μl PBS (group 2), 3 times at 11<sup>th</sup>, 14<sup>th</sup> and 17<sup>th</sup> weeks of age. Urine samples were collected weekly to evaluate proteinuria by reactive strips. Blood samples were collected before every injection, at 22<sup>th</sup> and 28<sup>th</sup> weeks, and at death to evaluate levels of anti-C1q and anti-dsDNA by home-made ELISA tests. Tissues were harvested for histological analyses. Proteinuria free and survival rates were analyzed by Kaplan-Meier method using Mantel-Cox test for comparisons. Neurocognitive functions were evaluated with Staircase, Y-Maze and Forced Swim Test. <h3>Results:</h3> Anti-dsDNA and Anti-C1q levels (OD±SD) were significantly higher in PBS than in preS1 treated mice (Figure 1). Mean proteinuria levels (mg/dl±SD) were higher in PBS than in preS1 treated mice. Proteinuria free survival rate<b> (</b>&lt;300 mg/dl) was lower in group 2 than group 1 (p=0.016; Figure 2). Also survival rate was significantly lower in PBS than in preS1 injected mice (p=0.033). Memory deficits (p&lt;0.01) and anxiety-like behavior was pronounced in PBS treated mice. Severe segmental and focal glomerulonephritis in both groups with large proliferation of mesangial and endothelial cells and Russell bodies were found by histological analysis. Mice treated with preS1 had more chronic inflammation in the kidneys and extramedullary hematopoiesis in the spleen and liver. Notably, in salivary glands, severe acute inflammation was observed in group 1 and chronic inflammation in group 2. <h3>Conclusion:</h3> HBV capsid protein preS1 causes a delay in the onset of lupus-like glomerulonephrits and ameliorates behavioral disorders in NZW/BF1 mice. This peptide seems to induce a tolerizing rather than a pathogenic effect in these autoimmune prone mice models. <h3>References:</h3> [1] F. McKinneyet al; T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature523, 612–616 (2015). [2] T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature523, 612–616 (2015). [3] D. R. Gettset al, Virus infection, antiviral immunity, and autoimmunity. Immunol. Rev. 255, 197–209 (2013) <h3>Disclosure of Interests:</h3> None declared
AB0324 PAIN IMPROVEMENT IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH BARICITINIB: RESULTS OF A PROSPECTIVE STUDY
Authors: Ricardo Juan Gil Velez, Clara Aguilera Cros, Alberto Ruiz Roman, Lara Mendez Diaz, Elena Alonso Morales, Esteban Rubio Romero, Juan Povedano Gomez
Journal: Annals of the Rheumatic Diseases (2019)

<h3><sup>1</sup>Seville, Seville, Spain</h3> <h3>Background</h3> Assessment of pain improvement during treatment for Rheumatoid Arthritis (RA) may be useful to clinical decision between providers and their patients (pts). Baricitinib (BARI) once daily, an oral, selective Janus Kinase (JAK)1/JAK2 inhibitor, reduced disease activity levels in Rheumatoid Arthritis (RA) patients (pts) with an inadequate response (IR) to methotrexate (MTX). <h3>Objectives</h3> To Evaluate the likelihood of achieving different levels of pain control with BARI 2 mg or 4 mg in patients with RA with inadequate response to traditional DMARDs or biological DMARDs. <h3>Methods</h3> Prospective observational registry of pts with RA who start treatment with BARI, in a third level Spanish Hospital (October 2017- June 2018). BARI 2 mg is started in patients with inadequate response to traditional DMARDs and BARI 4 mg in patients with inadequate response to biological DMARDs. The pts were assessment of pain was assessed with 0-100 mm visual analog scale (VAS) at each study visit. The likelihood of achieving &gt;=25%, &gt;=50% and &gt;=70% pain VAS improvement through week 12 and analyze if there are significant differences between the group of patients with BARI 2 mg and BARI 4 mg (Mann-Whitney test). The statistical study was carried out with the SPSS15 computer package. <h3>Results</h3> We included 38 pts (28 women), mean age 52 ± 12 years. Pain VAS improvement for all patients, baseline pain and weeks 12. The frequency is the percentage of improvement with respect to the baseline. In BARI 2 mg group, 58% of pts (p75) have experienced a decrease greater than pain VAS improvement than baseline and in BARI 4 mg group, 55% of pts (p75) have experienced a decrease greater than pain VAS improvement than baseline. No statistically significant differences were found in the two treatment groups (BARI 2 mg and BARI 4 mg) (p 0.847). <h3>Conclusion</h3> Our results, in general, agree with what is published in the literature (RA treated with BARI reported greater improvements in pain control when compared to adalimumab or placebo, a post-hoc analysis of the Phase 3 RA-BEAM study). BARI treated pts reported significantly greater and more rapid reductions in pain severity as measured by the pain VAS, improvements were sustained 12 weeks, without finding differences in pts receiving BARI 2 mg or BARI 4 mg. <h3>Disclosure of Interests</h3> None declared
Prognostic Value of Global Longitudinal Strain and Etiology After Surgery for Primary Mitral Regurgitation
Authors: Yasmine L. Hiemstra, Anton Tomsic, Suzanne E. van Wijngaarden, Meindert Palmen, Robert J.M. Klautz, Jeroen J. Bax, Victoria Delgado, Nina Ajmone Marsan
Journal: JACC. Cardiovascular imaging (2019)
Robotic Renal Artery Aneurysm Repair
Authors: Andre Luis Abreu, Luis G. Medina, Sameer Chopra, Karanvir Gill, Giovanni E. Cacciamani, Raed A. Azhar, Akbar Ashrafi, Matthew Winter, Carlos Fay, Fred Weaver, Vinay Duddalwar, Mihir Desai, Rene Sotelo, Inderbir S. Gill
Journal: European Urology (2019)
Physical activity participation and functional limitations in geriatric cancer survivors.
Authors: Lisa Sprod, Supriya Gupta Mohile, Lin Fan, Michelle Christine Janelsins, Luke Joseph Peppone, Kavita Dayal Chandwani, Gary R. Morrow, Karen Michelle Mustian
Journal: Journal of Clinical Oncology (2012)

9009 Background: Functional limitations (FL) increase with age, as does cancer incidence. Treatments for cancer may exacerbate age-related FL. Physical activity (PA) reduces the risk of recurrence of some cancers and may improve survival. FL may reduce PA participation in geriatric cancer survivors (&gt;65 yrs.) which could increase the risk of recurrence and reduce survival. This investigation describes and compares patterns of PA and FL in geriatric cancer survivors versus those without a cancer history. Methods: Using a national sample of community-dwelling elders (&gt; 65 yrs.) from the 2003 Medicare Current Beneficiary Survey (N=14,887), we characterized the differences between cancer survivors and those without a cancer history in FL, current amount of PA, and current amount of PA compared to PA one year prior. Respondents rated FL on a 1-5 scale (1=no difficulty, 5=can’t do): stooping, crouching, or kneeling (stoop), carrying objects up to 10 lbs (lift), extending arms above shoulder level (reach), grasping small objects (grasp), and walking ¼ of a mile (walk). Frequency of walking for a least 10 minutes (1-5 rating scale; 1=daily, 5=never), weekly participation in PA, exercise, or sports (yes/no), and time spent doing moderate or vigorous PA (hrs/wk) were reported. Multivariate logistic regression was used to determine associations. Results: Of the 14,887 participants, 2,603 (6%) reported a history of cancer. Compared to those without a cancer history, a greater proportion of cancer survivors reported having difficulty or being unable to stoop, lift, reach, grasp or walk (all p&lt;0.01). Cancer survivors who had more FL were less likely to engage in PA (all p&lt;0.01). Cancer survivors reported a lower frequency of walking at least 10 minutes at a time (p&lt;0.01). Cancer survivors were more likely to decrease PA from the previous year (p&lt;0.01) and spent less time doing moderate (p=0.01) or vigorous activity (p&lt;0.01) than those without a cancer history. Conclusions: Older cancer survivors engage in less PA and are at greater risk of FL than those without a history of cancer. This may lead to reduced independence, a greater risk of cancer recurrence, and reduced survival. Therefore, PA interventions are important in this population.
Abstract 17897: Derangement of Cerebral Circulation Due to Carotid Arterial Stiffening is Associated With Distal Aortic Stiffness Rather Than Proximal Aortic Stiffness
Authors: Hirofumi Saiki, Seiko Kuwata, Satoshi Masutani, Hideaki Senzaki
Journal: Circulation (2017)

Introduction: Impaired cerebral blood flow (CBF) due to heart failure(HF) provokes neurodevelopmental deficit. While HF ultimately activates fibrosis and cardiovascular stiffening, predisposing gen...
THU0589 FREQUENCY, CHARACTERISTICS AND CLINICAL DETERMINANTS OF “PRODROME” IN FAMILIAL MEDITERRANEAN FEVER PATIENTS
Authors: Hakan Babaoglu, Nuh Atas, Ozkan Varan, Hasan Satış, Reyhan Bilici Salman, Aslıhan Avanoglu Güler, Hazan Karadeniz, Berna Goker, Seminur Haznedaroglu, Mehmet Akif Ozturk, abdurrahman tufan
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Prodrome was defined by the presence of manifestations that precede an FMF attack and predict its emergence. This period might be turned to a window of the opportunity for the prompt treatment of impending attacks with fast-acting IL-1 inhibitors. <h3>Objectives:</h3> We aimed to determine the frequency, characteristics and clinical determinants of prodrome in patients with FMF <h3>Methods:</h3> 401 FMF patients were enrolled in this cross-sectional study. We applied a questionnaire to the FMF patients about attack types, pre-attack manifestations and latent time. Four hours was accepted as the cutoff point for prodrome as based on the literature, which is compatible with the pharmacokinetics of anakinra. <h3>Results:</h3> The mean age was 37.7 (±11.0) years, and the disease duration was 20 years (3-58). 248 of the patients (61.8%) were female. MEFV gene mutations were achieved in 364 (90.8%) patients, of these 121 (30.2%) patients harbored homozygous exon 10 mutations. Patients with a latent time over four hours considered as prodrome positive (PP) patients (n=141). Male gender, homozygous MEFV mutations, peritonitis, pleuritis, arthritis and ELE were more pronounced in PP group. 25.9% of patients with peritonitis, 14.7% of patients with pleuritis, 13.2% with arthritis and 5.5% with ELE had prodrome with variable latent time durations (median, 6.7(4-72), 6 (4-48), 6 (4-72), and 7.7 (4-30) hours, respectively). Prodrome was found to be more common in those with peritonitis. Male gender, having peritonitis or arthritis were found to be the independent clinical determinants of having prodrome (RR 1.72 (1.07-2.76), P=0.02, 4.27 (1.80-10.1), P=0.001, 1.77 (1.04-3.04), P=0.04, respectively). Age, MEFV mutations, pleuritis and ELE were not found as clinical determinants of prodrome. <h3>Conclusion:</h3> Especially male patients with peritonitis or arthritis tend to have prodrome more than other patients, and should be questioned. Prodrome positive patients are candidates for prevention of the impending attacks with on-demand treatments. <h3>Acknowledgement:</h3> none <h3>Disclosure of Interests:</h3> None declared
THU0405 PREVALENCE OF FIBROMYALGIA IN INFLAMMATORY BOWEL DISEASE (IBD) PATIENTS: A SINGLE CENTRE OBSERVATIONAL PROSPECTIVE STUDY
Authors: Ilaria Tinazzi, Angela Variola, Andrea Geccherle, Antonio Marchetta, Dennis Mcgonagle
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Joint pain is frequently reported by IBD patients and can be associated to extra-intestinal manifestations of diseases or adverse events associated to anti-TNF or vedolizumab therapy and also associated with other non-SpA-disease related factors including mechanical/degenerative problems. An appropriate rheumatological referral pathway is crucial to drive therapeutic strategy in case of concomitant spondyloarthritis (SpA). Fibromyalgia is a frequent cause of chronic pain that needs to be identified in order to not overestimate the prevalence of SpA in IBD patients <h3>Objectives:</h3> The aim of the study was to assess the prevalence of FM in a cohort of IBD outpatients <h3>Methods:</h3> Consecutive patients of the IBD Unit coming for a routine visit were screened by a rheumatologist in order to identify cases presenting the 2010 ACR criteria for FM or ASAS criteria for SpA (1,2). Patients affected by other rheumatic conditions such as rheumatoid arthritis and crystal arthritis were excluded from the study. The rheumatological assessment included a 66 swollen joint count (SJC) and 68 TJC, MASEI, LEI and the fibromyalgia tender points examination. The patient completed BASDAI and BASFI on the day of clinical evaluation. Imaging exams (MSK ultrasound, MRI) and HLA-B27 determination were requested if needed for diagnostic confirmation <h3>Results:</h3> Between January to May 2018, 210 patients were enrolled in the study and 181 completed the clinical and imaging/laboratory assessment if requested for diagnostic purpose. examination. A total of 44 patients (24.3%) in the IBD cohort met the ACR 2010 criteria for FM. 34 patients (18.8%) presented the criteria for primary FM, and 10 patients (5.5%) presented FM and SpA. Of note FM patients presented LEI; BASDAI and BASFI scores higher than SpA patients <h3>Conclusion:</h3> FM is a common comorbidity in IBD patients and can be associated to SpA. An appropriate rheumatological referral is crucial exclude a concomitant SpA and to manage FM <h3>References:</h3> [1] Wolfe, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care and Research. 2010;62(5):600–610. [2] Rudwaleit M, et al. The Assessment of SpondyloArthritis international Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis 2011;70:25–31 <h3>Disclosure of Interests:</h3> Ilaria Tinazzi: None declared, Angela Variola: None declared, Andrea Geccherle: None declared, Antonio Marchetta: None declared, Dennis McGonagle Consultant for: Lilly, Novartis UCB, Speakers bureau: Lilly, Novartis UCB
PB2249 CAPLACIZUMAB MODEL-BASED DOSING RECOMMENDATIONS IN PEDIATRIC PATIENTS WITH ACQUIRED THROMBOTIC THROMBOCYTOPENIC PURPURA
Authors: L. Sargentini, E. Hansson, M. Bergstrand, F. Callewaert, R. Sousa
Journal: HemaSphere (2019)

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare and life-threatening autoimmune blood clotting disorder, with a much lower incidence in children compared to adults. Caplacizumab has been evaluated in phase 2 and phase 3 randomized clinical trials in adult patients with aTTP. Aims: As no pediatric patients were enrolled in clinical trials with caplacizumab, dosing recommendations were developed using model-based simulations for this population. Methods: A semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) population model has been developed describing the interaction between caplacizumab and von Willebrand factor antigen (vWF:Ag) following intravenous and subcutaneous administration of caplacizumab in different adult populations at various dose levels using non-linear mixed effects modeling. Simulations based on the allometrically scaled PKPD model were performed to establish a suitable dosing regimen in adolescents and children >2 years.Eight age categories including 1000 individuals in each category were defined, and corresponding individual body weights were sampled from the National Health and Nutrition Examination Survey database. The simulated exposure levels of caplacizumab in the different age categories were compared to those predicted in adults. Results: The simulations of exposure indicate that a flat 10 mg daily dosing would result in higher exposure in children with a low body weight, primarily children under 10 years of age. A dose adjustment to 5 mg daily to children with a body weight <40 kg would result in an on average similar exposure across age and weight groups. The body weight adjusted dosing is also predicted to result in highly similar suppression of vWF:Ag across the different age groups. Summary/Conclusion: The recommended dose in adolescents 12-18 years with a body weight ≥40 kg is 10 mg, and 5 mg if <40 kg. Since no differences in vWF:Ag suppression are expected based on differences in age, the same dosing recommendation applies for children 2-12 years, 10 mg if the body weight is ≥40 kg and 5 mg if <40 kg.