tbuckley/cabot-search huggingface dataset:
Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy
Authors: Devesh C. Pant, Imen Dorboz, Agatha Schluter, Stéphane Fourcade, Nathalie Launay, Javier Joya, Sergio Aguilera-Albesa, Maria Eugenia Yoldi, Carlos Casasnovas, Mary J. Willis, Montserrat Ruiz, Dorothée Ville, Gaetan Lesca, Karine Siquier-Pernet, Isabelle Desguerre, Huifang Yan, Jingmin Wang, Margit Burmeister, Lauren Brady, Mark Tarnopolsky, Carles Cornet, Davide Rubbini, Javier Terriente, Kiely N. James, Damir Musaev, Maha S. Zaki, Marc C. Patterson, Brendan C. Lanpher, Eric W. Klee, Filippo Pinto e Vairo, Elizabeth Wohler, Nara Lygia de M. Sobreira, Julie S. Cohen, Reza Maroofian, Hamid Galehdari, Neda Mazaheri, Gholamreza Shariati, Laurence Colleaux, Diana Rodriguez, Joseph G. Gleeson, Cristina Pujades, Ali Fatemi, Odile Boespflug-Tanguy, Aurora Pujol
Journal: Journal of Clinical Investigation (2019)

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.
Abstract 12238: Comprehensive Genotyping for Scn5a and Related Genes in the Chinese Han Population With Sunds
Authors: Jianding Cheng, Chao Liu, Yiding Hou, Wen Wang
Journal: Circulation (2013)

Background: Reported for nearly 100 years, sudden unexplained nocturnal death syndrome (SUNDS) remains an enigma to both forensic pathologists and physicians. Previous epidemiological, clinical, an...
AB0373 Sarcopenia could not predict falls in patients with rheumatoid arthritis from the chikara study
Authors: M. Tada, Y. Yamada, K. Mandai, N. Hidaka
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The falls ratio is higher among patients with sarcopenia than among healthy individuals. We reported that the prevalence of sarcopenia was 28% and locomotive syndrome (locomo) was 52% in patients with rheumatoid arthritis (RA)<sup>1</sup>. Whether patients with RA complicated by sarcopenia show a higher ratio of falls compared to those without sarcopenia remains unclear. <h3>Objectives</h3> We investigated events of falls and fractures, and predictors of those events in patients with RA. <h3>Methods</h3> We used data from a prospective observational study (CHIKARA study, UMIN000023744) started in 2016. Sarcopenia was diagnosed using the criteria of the Asia Working Group on Sarcopenia<sup>2</sup>. We counted the number of patients and events of falls and fractures they had per year[A1], and investigated correlations between those events and disease activity, body composition and sarcopenia. Predictors at baseline influencing those events were analysed by uni- and multivariate analysis. <h3>Results</h3> Participants comprised 100 patients with RA (females, 78%; mean age, 66.1 years). Falls occurred in 21 patients (19 women), as 33 events (mean, 2 times/patient). Fractures occurred in 4 patients (4 women), as 5 events. Table 1 shows predictors for falls, with positive correlations for bone mass index, obesity level, fat percentage, and locomo, and negative correlations for height, trunk muscle mass, and grip strength. No relationships were seen between falls and CRP, DAS28ESR, skeletal muscle mass, and sarcopenia. Height (odds ratio, 0.912; p=0.003) and obesity level (odds ratio, 1.04; p=0.006) were independent predictors by multivariate analysis (table 1). In terms of fracture events, falls was the only predictor (r=0.469, p=0.001). <h3>Conclusions</h3> Falls have been reported as significantly more frequent with sarcopenia. However, no relationship was seen between fall events and sarcopenia in this study. We may need to evaluate not only skeletal muscle mass, but also muscle function to predict falls. <h3>References</h3> [1] Tada M, Yamada Y, Mandai K, et al. Relationship of matrix metalloprotease 3 titer and sarcopenia in patients with rheumatoid arthritis: data from the CHIKARA study. Eular2017:abstract THU0157. [2] Chen LK, Liu LK, Assantachai P, et al. Sarcopenia in Asia: consensus report of the Asian Working Group for Sarcopenia. J Am Med Dir Assoc2014;15:95–101. <h3>Disclosure of Interest</h3> None declared
Argon Mitigates Impaired Wound Healing Process and Enhances Wound Healing <i>In Vitro</i> and <i>In Vivo</i>
Authors: Jiaolin Ning, Hailin Zhao, Bin Chen, Emma Zheling Mi, Zhen Yang, Wenhan Qing, Kwok Wing Joyce Lam, Bin Yi, Qian Chen, Jianteng Gu, Thomas Ichim, Vladimir Bogin, Kaizhi Lu, Daqing Ma
Journal: Theranostics (2019)

Diabetic foot ulcers are associated with significant morbidity and mortality, and current treatments are far from optimal. Chronic wounds in diabetes are characterised by impaired angiogenesis, leukocyte function, fibroblast proliferation, and keratinocyte migration and proliferation. Methods: We tested the effect of exposure to argon gas on endothelial cell, fibroblast, macrophage and keratinocyte cell cultures in vitro and in vivo of a streptozotocin-induced diabetic mouse model. Results: Exposure to normobaric argon gas promotes multiple steps of the wound healing process. Argon accelerated angiogenesis, associated with upregulation of pro-angiogenic Angiopoietin-1 and vascular endothelial growth factor (VEGF) signalling in vitro and in vivo. Treatment with argon enhanced expression of transforming growth factor (TGF)-β, early recruitment of macrophages and keratinocyte proliferation. Argon had a pro-survival effect, inducing expression of cytoprotective mediators B-cell lymphoma 2 and heme oxygenase 1. Argon was able to accelerate wound closure in a diabetic mouse model. Conclusion: Together these findings indicate that argon gas may be a promising candidate for clinical use in treatment of diabetic ulcers.
WNT/β-catenin Pathway Activation Correlates with Immune Exclusion across Human Cancers
Authors: Jason J. Luke, Riyue Bao, Randy F. Sweis, Stefani Spranger, Thomas F. Gajewski
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The T-cell-inflamed phenotype correlates with efficacy of immune-checkpoint blockade, whereas non-T-cell-inflamed tumors infrequently benefit. Tumor-intrinsic WNT/β-catenin signaling mediates immune exclusion in melanoma, but association with the non-T-cell-inflamed tumor microenvironment in other tumor types is not well understood. Experimental Design: Using The Cancer Genome Atlas (TCGA), a T-cell-inflamed gene expression signature segregated samples within tumor types. Activation of WNT/β-catenin signaling was inferred using three approaches: somatic mutations or somatic copy number alterations (SCNA) in β-catenin signaling elements including CTNNB1, APC, APC2, AXIN1, and AXIN2; pathway prediction from RNA-sequencing gene expression; and inverse correlation of β-catenin protein levels with the T-cell-inflamed gene expression signature. Results: Across TCGA, 3,137/9,244 (33.9%) tumors were non-T-cell-inflamed, whereas 3,161/9,244 (34.2%) were T-cell-inflamed. Non-T-cell-inflamed tumors demonstrated significantly lower expression of T-cell inflammation genes relative to matched normal tissue, arguing for loss of a natural immune phenotype. Mutations of β-catenin signaling molecules in non-T-cell-inflamed tumors were enriched three-fold relative to T-cell-inflamed tumors. Across 31 tumors, 28 (90%) demonstrated activated β-catenin signaling in the non-T-cell-inflamed subset by at least one method. This included target molecule expression from somatic mutations and/or SCNAs of β-catenin signaling elements (19 tumors, 61%), pathway analysis (14 tumors, 45%), and increased β-catenin protein levels (20 tumors, 65%). Conclusions: Activation of tumor-intrinsic WNT/β-catenin signaling is enriched in non-T-cell-inflamed tumors. These data provide a strong rationale for development of pharmacologic inhibitors of this pathway with the aim of restoring immune cell infiltration and augmenting immunotherapy. See related commentary by Dangaj et al., p. 2943
Determination of Escherichia coli phylogroups in elderly patients with urinary tract infection or asymptomatic bacteriuria
Authors: R. Amarsy, D. Guéret, H. Benmansour, R. Flicoteaux, B. Berçot, F. Meunier, F. Mougari, H. Jacquier, G. Pean de Ponfilly, O. Clermont, E. Denamur, A. Teixeira, E. Cambau
Journal: Clinical Microbiology and Infection (2019)
SP0100 Neuropsychiatric lupus or not?
Authors: A. Fanouriakis
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> A 30 year old woman with a 10 year history of SLE was admitted in the Emergency Department with severe headache, drowsiness and vertigo. Brain magnetic resonance imaging revealed an extensive ischaemic stroke in the cerebellum. During the month prior to the episode, the patient had not been feeling well, complaining for arthralgias, fatigue, hair-loss, low grade-fever and the progressively deteriorating headache. Should this patient's ischaemic stroke be attributed to lupus? Moreover, if yes, does it represent a thrombotic or an inflammatory process? The second patient, a 38 year old woman of Asian descent, was referred to our Unit due to refractory seizures and status epilepticus for the past two years. On initial presentation, she had fever, mild leukopenia, low C3 and C4 levels and positive ANA (titer 1:320). She had been previously treated by different neurologists, with a combination of antiepileptic drugs, with no success. Brain magnetic resonance imaging was repeatedly unremarkable and electroencephalogram revealed mild epileptiform changes. Does this patient represent a case of <i>bona fide</i> neuropsychiatric lupus? <h3>Disclosure of Interest</h3> None declared
FRI0551 Comparison of physical activity (PA) between patients with different stages of osteoarthritis(OA) and the general population: a cross-sectional study
Authors: T. Pelle, A. Claassen, J. Meessen, W. Peter, T. Vliet Vlieland, K. Bevers, J. van der Palen, F. van den Hoogen, C. van den Ende
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The benefit of Physical Activity (PA) in different stages of osteoarthritis (OA) is unambiguous considering the positive effects on pain and physical functioning. However, insight in the characteristics of PA (i.e. duration and intensity) between patients in different stages of OA is scarce. Also, comparisons with the general population are understudied. <h3>Objectives</h3> To compare the amount (i.e. duration and intensity) of PA in patients in different stages of OA (i.e. patients in primary and secondary care, and post Total Joint Arthroplasty (TJA)) and the general population. <h3>Methods</h3> This study is based on secondary analyses of baseline data from four studies:<sup>1</sup> an effectiveness study of an educational program for OA patients in primary care,<sup>2</sup> a study on effectiveness of a multidisciplinary self-management program for generalised OA in secondary care,<sup>3</sup> a study among patients whom underwent TJA for end-stage OA in preceding 7–22 months, and<sup>4</sup> a nationwide study among the general population in the Netherlands (n=14,000) on general health.<sup>1</sup> In the current study only patients aged ≥40 years were included. The SQUASH questionnaire was used to assess PA in all 4 studies and to calculate adherence to PA recommendations, duration (hrs/wk) and intensity (MET.hrs/wk). To compare the amount (hrs/wk) and intensity (MET.hrs/wk) between different stages of OA and the general population, we applied multiple linear regression analysis, adjusted for age, gender and Body Mass Index (BMI). <h3>Results</h3> Demographic characteristics and adherence to PA recommendations are illustrated in table 1. Mean duration and intensity of PA in the general population were 41.3 hrs/week and 145.7 MET.hrs/week, respectively. Patients after TJA showed higher PA levels (both in terms of duration and intensity) than patients in secondary care and the general population (table 2). <h3>Conclusions</h3> The results of this study show small non-significant differences in PA levels between primary care patients and the general population. Patients after TJA are more physically active than secondary care patients and the general population. However, low adherence rates to PA recommendations indicate the necessity to promote PA in a substantial group of OA patients. <h3>Reference</h3> [1] Centraal Bureau voor de Statistiek (CBS). Gezondheidsenquête 2012. DANS. 2014. https://doi.org/10.17026/dans-zcc-5stc <h3>Disclosure of Interest</h3> None declared
SP0039 I graduated! education for children and adolescents with rmds
Authors: T.C. Wilhelmer
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> Communication is the key to success in practically every situation. Without communicating to your counterpart, how should they understand your own situation? When it comes to studying with a chronic illness we need to know how the illness affects our ability. We need to communicate what we are able to do and where we need support. When I started my Master Degree I have been honest from the very beginning. I never kept my rheumatic disease and the disability that comes with it a secret. Being open from the very beginning gives yourself and your university, school or even workspace the opportunity to adapt to your abilities. Hiding your disability will make it hard for yourself to keep up with your class. Your fellow students and teachers not knowing what your limitations are will most certainly lead to misunderstandings. Many pupils and students do not know that there are laws and regulations that could help them to get through school easier. For example you are allowed to have longer writing times in exams, or use your computer for typing texts instead of having to write by hand. This helps to prevent pain in your joints. There are even more ways in which your university or school can help you to get through your day than you would think of in the first place. Without asking for help, you will never find out what is actually possible. Through communicating with a disability-spokesperson you will most likely get even greater support. In my lecture I will talk about my own story and how I managed to finish my Bachelor Degree whilst falling chronically ill with Adult Onset Still's Disease. I will give examples on how to handle a life with chronic illness. There will be some tips on what to do when your counterpart is not as understanding as he or she should be. I will explain what I do to get me through lectures and exams. <h3>Disclosure of Interest</h3> None declared
SP0135 The eular/efort recommendations for patients with recent fracture
Authors: W.F. Lems
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> The European League Against Rheumatism (EULAR) and the European Federation of National Associations of Orthopaedics and Traumatology (EFORT) have recognised the importance of optimal acute care for the patient 50 years and over with a recent fragility fracture and the prevention of subsequent fractures in high risk patients, which can be facilitated by close collaboration between orthopaedic surgeons and rheumatologists or other metabolic bone experts. Therefore, the aim was to establish for the first time collaborative recommendations for these patients. According to the EULAR standard operating procedures for the elaboration and implementation of evidence-based recommendations, 8 rheumatologists from 8 countries and 10 orthopaedic surgeons from 10 countries met twice under the leadership of 2 conveners, a senior advisor, a clinical epidemiologist and 3 research fellows. After defining the content and procedures of the task force, 10 research questions were formulated, a comprehensive and systematic literature search was performed, and the results were presented to the entire committee. Subsequently, 10 recommendations were formulated based on evidence from the literature and after discussion and consensus building in the group. The 10 recommendations will be discussed at the meeting; they included appropriate medical and surgical peri-operative care which requires, especially in the elderly, a multidisciplinary approach including orthogeriatric care. A coordinator should build up an organisation with systematic investigations for future fracture risk in all elderly patients with a recent fracture. High-risk patients should have appropriate non-pharmacological and pharmacological treatment to decrease the risk of subsequent fracture. <h3>Reference</h3> [1] EULAR/EFORT recommendations for management of patients older than 50 years with a fragility fracture and prevention of subsequent fractures. Ann Rheum Dis. 2017May;76(5):802–810. <h3>Disclosure of Interest</h3> W. F. Lems Consultant for: Amgen, Eli Lilly, Merck, Speakers bureau: Amgen, Eli Lilly, Merck
Abstract 13019: Unique Changes in Electrocardiographic Metrics on Continuous Telemetry Prior to In-Hospital Cardiac Arrests Identified With Automated Algorithms
Authors: Alan Kuo, Duc H Do, Yazdi Daniel, Yong Bai, Quan Ding, David Mortara, Xiao Hu, Noel G Boyle
Journal: Circulation (2016)

Introduction: Despite advances, survival to discharge for in-hospital cardiac arrests (IHCA) remains less than 25%. Patients at risk of IHCA are often on continuous ECG monitoring, but no automated methods exist to leverage this information. Hypothesis: We hypothesize that ECG changes detectable with automated algorithms in the hours preceding IHCA may aid in predicting which patients are at risk of IHCA. Methods: We conducted a retrospective study on 79 IHCA and 1743 age-matched control patients. Telemetry data was processed with SuperECG (Mortara Instruments, Milwaukee, WI) for PR, QRS duration (QRSd), ST, QTc, RR, and QRS amplitude (AMP) metrics. Median, discontinuity, tachyarrhythmia and pacer dependence filters were applied. For cases, we selected the final (C1) and preceding (C2) 3-hour blocks before IHCA. For controls, we randomly selected two consecutive 3-hour blocks (T1, T2). C1 was compared to C2 and to a pooled control group (TP), consisting of T1 and T2, to identify changes unique to the final 3 hours. C2 was compared to TP, and T1 to T2 for internal control. Single and dual metric comparisons were performed. Maximal false positive rate of 5% was used to define thresholds for metric changes. We used chi-square testing and adjusted for multiple comparisons. Results: For C1 vs C2, we found higher percentages of significant QRSd prolongation (19.0% vs 3.8%, P=0.003) and AMP decrease (11.4% vs 1.3%, P=0.009). For C1 vs TP, we found higher percentages of QRSd prolongation (19.0% vs 4.6%, P&lt;0.001), AMP decrease (11.4% vs 4.5%, P=0.004), and ST elevation (11.4% vs 3.0%, P&lt;0.001). For dual metric comparisons, highest sensitivity was found with having both QRSd prolongation and ST elevation (C1 vs C2: 21.5% vs 3.8%, P&lt;0.001 and C1 vs TP: 21.5% vs 4.7%, P&lt;0.001). The sensitivity for meeting any single or dual metric comparison was 44.3% for C1 versus a specificity of 88.6% (P&lt;0.001) for C2 and 86.5% (P&lt;0.001) for TP. T1 vs T2 and C2 vs TP were statistically insignificant for all comparisons above. Conclusions: Significant ECG changes, identified by automated methods, are seen in the hours prior to IHCA. With further refinement and investigation, algorithms to detect ECG changes can be used in conjunction with traditional methods to help identify patients at risk of IHCA.
Silk Protein Bioresorbable, Drug‐Eluting Ear Tubes: Proof‐of‐Concept
Authors: Sarah A. Bradner, Deepa Galaiya, Nikhila Raol, David L. Kaplan, Chistopher J. Hartnick
Journal: Advanced Healthcare Materials (2019)

Abstract Otitis media with effusion (OEM) is a common pediatric pathology treated with topical fluoroquinolones (ear drops) and tympanoplasty tube, also referred to as ear tube, implantation for middle ear drainage. Commercially available ear tubes are fabricated using poly (lactic‐co‐glycolic acid) synthetic materials that are associated with long‐complications due to premature extrusion. Resorbable materials have emerged as desirable alternatives to reduce extrusion‐related complications, but often limited by fast resorption rates. Therefore, resorbable tubes with long‐term functional integrity are required for future clinical translation. In this communication, a proof‐of‐concept study is reported on a bioresorbable and drug‐eluting silk ear tube device. Preliminary in vitro assessments reveal time‐dependent drug elution and antimicrobial properties, while maintaining long‐term functional integrity in vivo. This report provides evidence of a silk ear tube with potential for future clinical translation and OEM treatment.
Phase II of Single-Agent Ibrutinib in Recurrent/Refractory Primary (PCNSL) and Secondary CNS Lymphoma (SCNSL)
Authors: Christian Grommes, Julia Wolfe, Igor Gavrilovic, Thomas Kaley, Jacqueline Stone, Mariza Daras, Craig Nolan, Elena Pentsova, Vaios Hatzoglou, Ingo Mellinghoff, Lisa DeAngelis
Journal: Blood (2018)