tbuckley/cabot-search huggingface dataset:
AB0900 Descriptive study of psoriatic arthritis in a historical cohort of 383 patients at a university hospital
Authors: A. Prior Español, L. Mateo, M. Mihaylov, J. Roca, Y. García Mira, J. Camins, I. Casafont, L. Gifre, A. Riveros, S. Holgado, M. Martínez-Morillo, M. Aparicio, A. Olivé
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> There are few recent large cohort epidemiological studies that analyse the clinical profile of patients with psoriatic arthritis (PsA) who require biological treatment, as well as pharmacological survival and reasons for the suspension of these treatments. <h3>Objectives</h3> To describe the clinical, demographic, epidemiological and radiographic characteristics of patients with PsA in our centre, as well as pharmacological survival and reasons for the suspension of different biological treatments. <h3>Methods</h3> Retrospective analysis of patients with PsA treated between 1985 and 2015 at a University Hospital with a referral area of 8 50 000 inhabitants. Demographic, clinical, laboratory and imaging data, as well as patients' clinical and medical treatment records. <h3>Results</h3> The main characteristics of the cohort are summarised in table 1: Approximately one third of patients with PsA (32.3%) required treatment with a biological drug during the course of their disease. The most frequently prescribed first-line drugs (89.5%) were tumour necrosis factor-α inhibitors (TNFi). During the course of their disease, 27 (21.9%) patients who started biological treatment received a biological drug other than TNFi. Of the 124 patients who started treatment with a biological DMARD, more than half (65, 52.8%) required a change to a second drug, and of these, 27 (41.5%) changed to a third, with up to 7 different biological drugs required in one case. The mean survival time for the first bDMARD was 42.8±42.3 months, with secondary failure the most frequent cause of treatment change (37.8%), followed by adverse effects (27.1%) and primary failure (18.9%). The adverse effects registered were: 20% infections, 20% appearance of neoplasms, 5% allergic reactions and 55% other causes. <h3>Conclusions</h3> PsA presents a similar distribution by sex and is usually diagnosed at around the age of 50, having been preceded by cutaneous involvement. PsA is an entity of considerable severity and up to a third of patients will require biological treatments during its evolution. More than half of them will receive a second biological treatment. The retention rate of each drug varies but tends to decrease with each drug change. <h3>Disclosure of Interest</h3> None declared
CD33 recruitment inhibits IgE-mediated anaphylaxis and desensitizes mast cells to allergen
Authors: Shiteng Duan, Cynthia J. Koziol-White, William F. Jester, Corwin M. Nycholat, Matthew S. Macauley, Reynold A. Panettieri, James C. Paulson
Journal: Journal of Clinical Investigation (2019)

Allergen immunotherapy for patients with allergies begins with weekly escalating doses of allergen under medical supervision to monitor and treat IgE mast cell–mediated anaphylaxis. There is currently no treatment to safely desensitize mast cells to enable robust allergen immunotherapy with therapeutic levels of allergen. Here, we demonstrated that liposomal nanoparticles bearing an allergen and a high-affinity glycan ligand of the inhibitory receptor CD33 profoundly suppressed IgE-mediated activation of mast cells, prevented anaphylaxis in Tg mice with mast cells expressing human CD33, and desensitized mice to subsequent allergen challenge for several days. We showed that high levels of CD33 were consistently expressed on human skin mast cells and that the antigenic liposomes with CD33 ligand prevented IgE-mediated bronchoconstriction in slices of human lung. The results demonstrated the potential of exploiting CD33 to desensitize mast cells to provide a therapeutic window for administering allergen immunotherapy without triggering anaphylaxis.
FRI0543 Health resource use and cost-of-illness of symptomatic knee and/or hip osteoarthritis : data from khoala cohort
Authors: J.H. Salmon, A.C. Rat, H. Achit, W. Ngueyon Sime, C. Gard, F. Guillemin, D. Jolly, B. Fautrel
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Hip and knee Osteoarthritis are a major public health problem. Data on the economic impact are scarce. <h3>Objectives</h3> The purpose of our study was to estimate the annual direct costs of patients followed for hip and/or knee osteoarthritis from the KHOALA cohort. <h3>Methods</h3> The KHOALA cohort is a French population-based multicenter cohort of 878 patients with symptomatic knee and/or hip OA, aged between 40 and 75 years old recruited between 2007 and 2009. Direct costs were collected annually for 5 years. Costs were annualised and expressed in euros per patient. <h3>Results</h3> Over the 5 years, the average total direct costs were € 2575 (sd 8085) per patient per year and median € 1015 (IQR 430–2500) (figure 1). Drugs represented the main health expenditure item (&gt;50% of total costs). However, the proportion attributable to osteoarthritis drugs accounted for less than 5% of total costs. The second item of expenditure was hospitalizations (hip and/or knee arthroplasty represents 7% of total average costs). Medical consultations were the third item of health expenditure (2.5% to 4% of total average costs). Physiotherapy represented 1% to 2% of total average costs. Costs increased with older age, female sex, retirement, a high BMI, a high Charlson index and poor health status. <h3>Conclusions</h3> These data are important results to describe the cost of care consumption of a sample of patients with symptomatic osteoarthritis of the hip and/or knee recruited to the general population in France. However, the specific cost attributable to osteoarthritis needs to be studied. <h3>Reference</h3> [1] Guillemin F, Rat AC, Mazieres B, Pouchot J, Fautrel B, Euller-Ziegler L, et al. Prevalence of symptomatic hip and knee osteoarthritis: a two-phase population-based survey.Osteoarthr Cartil OARS Osteoarthr Res Soc. Nov 2011;19(11):1314–22. <h3>Disclosure of Interest</h3> None declared
A Review of 1000 Molecular Investigations of Rare Inherited Anaemia and Related Conditions with the Red Cell Gene Panel
Authors: Rachel Mayhew, Frances Smith, Laura Steedman, Nicholas Parkin, Eva Moldes Beiro, Peter Rushton, Alison Bybee, David Brawand, Judith Marsh, Austin G. Kulasekararaj, Shreyans Ghandi, Sahar Mansour, Ghulam Mufti, Antonio Pagliuca, Subarna Chakravorty, David C Rees, Barnaby Clark
Journal: Blood (2018)
Reduced Right Ventricular Output Reserve in Patients With Systemic Sclerosis and Mildly Elevated Pulmonary Artery Pressure
Authors: Christian Nagel, Alberto M. Marra, Nicola Benjamin, Norbert Blank, Antonio Cittadini, Gerry Coghlan, Oliver Distler, Christopher P. Denton, Benjamin Egenlauf, Christoph Fiehn, Christine Fischer, Satenik Harutyunova, Marius M. Hoeper, Hanns‐Martin Lorenz, Panagiota Xanthouli, Eduardo Bossone, Ekkehard Grünig
Journal: Arthritis & Rheumatology (2019)

This prospective study was undertaken to evaluate right ventricular function and pulmonary arterial compliance (PAC; ratio of stroke volume to pulse pressure) at rest and during exercise in patients with systemic sclerosis (SSc) with normal mean pulmonary artery pressure (PAP), patients with SSc with mildly elevated mean PAP, and patients with SSc with manifest pulmonary hypertension (PH).Patients with SSc (n = 112) underwent clinical assessment and right-sided heart catheterization at rest and during exercise and were divided into 3 groups according to their resting mean PAP values: normal mean PAP (≤20 mm Hg), mildly elevated mean PAP (21-24 mm Hg), and PH (mean PAP ≥25 mm Hg). Results were compared between groups by analysis of variance followed by post hoc Student's t-test.Compared to patients with normal mean PAP, patients with mildly elevated mean PAP had a lower 6-minute walking distance (P = 0.008), lower cardiac index (P = 0.027) and higher pulmonary vascular resistance (P = 0.0002) during exercise, and lower PAC at rest (P = 0.016) and different stages of exercise (P = 0.033 for 25W and P = 0.024 for 75W).The results of this study suggest that impaired 6-minute walking distance in SSc patients with mildly elevated mean PAP might be caused by reduced PAC during exercise and reduced right ventricular output reserve, presumably due to impaired coupling between the right ventricle and the pulmonary vasculature. These findings provide further evidence of the clinical relevance of mildly elevated mean PAP in patients with SSc.
Machine Learning in Clinical Medicine Still Finding Its Way
Authors: Dickson S. Cheung, Joseph A. Grubenhoff
Journal: JAMA Network Open (2019)

Tadahiro Goto, MD, MPH; Carlos A. Camargo Jr, MD, DrPH; Mohammad Kamal Faridi, MPH; Robert J. Freishtat, MD, MPH; Kohei Hasegawa, MD, MPH
Abstract 1252: A Mouse Model of a Familial Dilated Cardiomyopathy Mutation in Titin Recapitulates the Human Phenotype
Authors: Michael Gramlich, Beate Michely, Brenda Gerull, Christian Krohne, Ingo Morano, Siegfried Labeit, Ludwig Thierfelder
Journal: Circulation (2007)

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial diseases and the third most common cause of heart failure. Familial occurrence, mostly as an autosomal dominant trait, is responsible for 20 –30% of all DCM cases. We have previously shown that mutations in the giant muscle filament titin ( TTN ) cause dilated cardiomyopathy. In a large DCM kindred (A1) with autosomal dominant inherited DCM, we could identify a 2 bp insertion mutation in exon 326 of TTN . This heterozygous nonsense mutation leads to a framshift generating a premature stop codon after the addition of 4 novel amino acid residues. We have recently evaluated a cardiac biopsy sample from an affected family member of kindred A1 showing that no truncated protein is observed in a western blot analysis. To further investigate the functional consequences of the identified human TTN mutation, we now generated a mouse model that includes the 2bp insertion at the corresponding site in the mouse genome. Heterozygous mice are viable and fertile. As in the human situation, the truncated titin is not detectable in western blot analysis of cardiac tissue indicating haploinsufficiency. The ventricles of the heterozygous animals show a decrease in ventricular stiffness as seen in isolated working heart pressure measurements and transmitral Doppler echocardiography (E:A 1.34 vs. 1.075, p&lt;0.01; IVRT 13.57ms vs. 17.01ms, p&lt;0.05). When exposed to angiotensin II (1.4 mg/kg/d for 14d) as a cardiac stressor, heterozygous animals develop dilatation of the left ventricles (4.45mm vs. 3.77 mm, p&lt;0.05) with impaired fractional shortening (25.12% vs. 32.86%, p&lt;0.01) and a diffuse myocardial fibrosis. Homozygous mice die in utero before E8.0. Whether a defect in the formation of sarcomeres or, alternatively, a defect in yet unknown non-muscle functions of titin account for this early embryonic lethality remains to be determined. Conclusion: Our mouse model shows that a mutation in TTN leads to impaired biomechanical properties of the heart, resulting in left ventricular dilatation and decreased systolic function, thereby recapitulating the human phenotype.
Managing the Cost of Medicare Part B Drugs
Authors: Francis J. Crosson, Jon B. Christianson
Journal: JAMA Internal Medicine (2019)

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Genetic Modulation of Adenosine-to-Inosine RNA Editing Selectively Disrupts Inflammasome and Extracellular Matrix Genes in Multiple Myeloma
Authors: Leslie A Crews, Phoebe Mondala, Elisa Lazzari, Gabriel Pineda, Christina Wu, Caitlin L. Costello, Catriona Jamieson
Journal: Blood (2018)
Exosomes from Nischarin-Expressing Cells Reduce Breast Cancer Cell Motility and Tumor Growth
Authors: Mazvita Maziveyi, Shengli Dong, Somesh Baranwal, Ali Mehrnezhad, Rajamani Rathinam, Thomas M. Huckaba, Donald E. Mercante, Kidong Park, Suresh K. Alahari
Journal: Cancer Research (2019)

Exosomes are small extracellular microvesicles that are secreted by cells when intracellular multivesicular bodies fuse with the plasma membrane. We have previously demonstrated that Nischarin inhibits focal adhesion formation, cell migration, and invasion, leading to reduced activation of focal adhesion kinase. In this study, we propose that the tumor suppressor Nischarin regulates the release of exosomes. When cocultured on exosomes from Nischarin-positive cells, breast cancer cells exhibited reduced survival, migration, adhesion, and spreading. The same cocultures formed xenograft tumors of significantly reduced volume following injection into mice. Exosomes secreted by Nischarin-expressing tumors inhibited tumor growth. Expression of only one allele of Nischarin increased secretion of exosomes, and Rab14 activity modulated exosome secretions and cell growth. Taken together, this study reveals a novel role for Nischarin in preventing cancer cell motility, which contributes to our understanding of exosome biology. SIGNIFICANCE: Regulation of Nischarin-mediated exosome secretion by Rab14 seems to play an important role in controlling tumor growth and migration.See related commentary by McAndrews and Kalluri, p. 2099.
THU0671 Standardised mortality rates for systemic lupus erythematosus in western australia from 1980 to 2015
Authors: W.D. Raymond, D. Preen, H. Keen, C. Inderjeeth, J. Nossent
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Patients with Systemic Lupus Erythematosus (SLE) are at increased risk of premature mortality. However, population-level mortality rates for SLE have not yet been reported in Australia. <h3>Objectives</h3> Calculate the standardised mortality rates (SMR) for SLE patients in Western Australia (WA) from 1980 to 2015, overall and by age and gender. <h3>Methods</h3> Utilising whole-population linked hospital admission, cancer registration and death data for WA from 1980 to 2015, we compared characteristics and calculated SMRs (95% CI) for patients with SLE (ICD-9-CM 695.4, 710.0, ICD-10-AM L93.0, M32.0) against controls (5:1) free of rheumatic disease after matching for age, gender, Aboriginality and year of first SLE event. <h3>Results</h3> SLE patients (n=2,868) and controls (n=12,785) recorded 1335 and 4400 deaths with crude mortality rates of 56.3/1,000 vs 37.1/1,000 person-years, respectively. SLE patients were approximately 10 years younger (71 vs 81 years) and 2.2-times more likely hospitalised at death (p&lt;0.001). The age-adjusted SMR (per 1,000) for SLE patients was 4.4 (95%CI 3.0, 5.8), and higher in females 5.4 (95%CI 3.5, 7.4) than in males 3.4 (95%CI 1.5, 5.4). Five-year period SMRs were 8.6 (95%CI 5.0, 12.2) between 1990–1994, 9.3 (95%CI 4.4, 14.2) between 1995–1999, 7.6 (95%CI 3.1, 12.1) between 2000–2004, 4.5 (95%CI 0.2, 8.7) between 2005–2009, and 4.9 (95%CI 1.32, 8.5) between 2010–2015. <h3>Conclusions</h3> SLE patients in WA experienced a decline in SMRs over time, but remain at increased risk of premature mortality. Within the limitations of administrative linked data, SLE in WA associates with an average reduction in life span of 10 years. <h3>Acknowledgements</h3> The authors wish to thank the staff at the Western Australian Data Linkage Branch and Emergency Department Data Collection, Hospital Morbidity Data Collection, WA Cancer Registry and Death Registrations. The Rheumatology Group of UWA (JN) was supported by an unrestricted grant from the Arthritis and Osteoporosis Foundation of Western Australia (AOWA). The AOWA provided WR with a PhD Scholarship in Memory of Johan Donald Stewart. This research was also supported by an unrestricted Australian Project Grant from Arthritis Australia. <h3>Disclosure of Interest</h3> None declared
Abstract 417: BET Bromodomain Inhibition Blunts Heart Failure Progression and Fibrosis in Genetic Cardiomyopathy
Authors: Michael A Burke, Hiroko Wakimoto, Joshua M Gorham, David A Conner, Jonathan G Seidman, James E Bradner, Saptarsi M Haldar, Jonathan D Brown, Christine E Seidman
Journal: Circulation Research (2016)

Pathologic gene network activation is a hallmark of DCM and HF. We have used a chemical genetic strategy to study the role of the bromodomain and extraterminal (BET) family of epigenetic reader proteins in the regulation of gene expression in DCM. Transgenic mice carrying a human DCM mutation in phospholamban (PLN R9C ) develop profound fibrosis and DCM that progresses to symptomatic HF and early death. Temporal RNA-seq and pathway analysis identified pro-fibrotic gene expression as a key early driver of DCM progression. PLN R9C and age-matched wild type (WT) mice were treated daily with the potent and specific BET inhibitor JQ1 or vehicle from 8-weeks-of-age (preDCM) to 20-weeks-of-age. Vehicle-treated PLN R9C mice developed DCM with severely reduced LV function and negative cardiac remodeling. JQ1-treated PLN R9C mice had substantially better fractional shortening (27% vs. 15%, p=7x10 -10 ) and less negative remodeling (LV end diastolic diameter 3.9mm vs. 4.5mm, p=1x10 -5 ; LV wall thickness 0.69mm vs. 0.62mm, p=6x10 -6 ) compared to PLN R9C vehicle-treated mice at 20-weeks (n=15). Myocardial fibrosis was also significantly reduced by JQ1 (5.8% PLN R9C -JQ1 vs. 18.4% PLN R9C -vehicle, p=3x10 -5 ; n=3). RNA-seq in preDCM mice treated with JQ1 for 2 weeks demonstrated a decrease in pathologic gene activation. JQ1-treated PLN R9C mice versus vehicle treated mice had reduced expression of natriuretic peptides ( Nppa -31%, Nppb -29%; p&lt;0.001), less myosin heavy chain and actin isoform switching (ratio Myh6 / Myh7 PLN R9C -JQ1=12.2; PLN R9C -vehicle=8.8; ratio Actc1 / Acta1 PLN R9C -JQ1=39.3; PLN R9C -vehicle=12.1; p&lt;0.001), and lower pro-inflammatory gene expression ( Tgfb2 -48%, Tgfb3 -41%, Ctgf -21%, Gdf15 -56%; p&lt;0.001). At 20-weeks-of-age, continued treatment with JQ1 resulted in sustained suppression of cytokine expression with 2-fold lower levels of Tgfb2 and Tgfb3 compared to vehicle-treated PLN R9C mice. These data suggest that early induction of pro-fibrotic signaling is a key driver of pathologic remodeling in PLN R9C DCM. This study also identifies epigenetic control of pathologic gene activation by BET bromodomain proteins as a critical mechanism for cardiomyopathy progression and supports BET inhibition as a possible novel therapeutic strategy for HF.
Abstract MP01: NMR Metabolomic Insulin Resistance Multimarkers Are Associated With Incident Diabetes: The CARDIA Study
Authors: Amena Keshawarz, David R Jacobs, James D Otvos, Daniel A Duprez, Jamal S Rana, Janet K Snell-Bergeon
Journal: Circulation (2018)

Introduction: Standard lipid panel measures (e.g., low HDL cholesterol and high triglyceride levels) are associated with developing diabetes. Lipoprotein and metabolomics profiles measured by nuclear magnetic resonance (NMR) carry additional information and may add to knowledge of future diabetes risk. Hypothesis: We assessed the hypothesis that two multimarkers of insulin resistance derived from NMR LipoProfile ® analysis, LP-IR (lipoprotein insulin resistance index) and IRDRF (insulin resistance diabetes risk factor index), are associated with incident diabetes independent of traditional risk factors in non-diabetic, apparently healthy subjects. Methods: LP-IR and IRDRF were measured at LipoScience/LabCorp for 3,564 non-diabetic participants (mean age 32±4 years, 46% [n=1,646] male) in the Coronary Artery Risk Development in Young Adults (CARDIA) study. LP-IR was calculated from 6 lipoprotein subclass and size parameters. IRDRF was calculated by combining LP-IR with levels of branched-chain amino acids, the inflammatory marker GlycA, and 2 additional lipoprotein subclasses. Diabetes status was ascertained by fasting glucose levels, hemoglobin A1c, and diabetes medications. We used Cox proportional hazards to model the relationship between LP-IR and IRDRF with incident diabetes. Participants were followed for a mean time of 21±5 years. We considered 4 models that examined LP-IR and IRDRF both as continuous and categorical variables and adjusted for various traditional predictors of diabetes. Results: Model 3, which adjusted for components of metabolic syndrome, had the best model fit in all cases ( Table 1 ). LP-IR and IRDRF had a significant linear relationship with incident diabetes. Participants who had LP-IR and IRDRF scores in Q4 were significantly more likely to develop diabetes than those with scores in Q1. Conclusions: In conclusion, LP-IR and IRDRF can be derived from a clinically-available NMR LipoProfile test, and both were associated with incident diabetes independent of traditional predictors.