tbuckley/cabot-search huggingface dataset:
Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19
Authors: Gundula Povysil, Guillaume Butler-Laporte, Ning Shang, Chen Wang, Atlas Khan, Manal Alaamery, Tomoko Nakanishi, Sirui Zhou, Vincenzo Forgetta, Robert J.M. Eveleigh, Mathieu Bourgey, Naveed Aziz, Steven J.M. Jones, Bartha Knoppers, Stephen W. Scherer, Lisa J. Strug, Pierre Lepage, Jiannis Ragoussis, Guillaume Bourque, Jahad Alghamdi, Nora Aljawini, Nour Albes, Hani M. Al-Afghani, Bader Alghamdi, Mansour S. Almutairi, Ebrahim Sabri Mahmoud, Leen Abu-Safieh, Hadeel El Bardisy, Fawz S. Al Harthi, Abdulraheem Alshareef, Bandar Ali Suliman, Saleh A. Alqahtani, Abdulaziz Almalik, May M. Alrashed, Salam Massadeh, Vincent Mooser, Mark Lathrop, Mohamed Fawzy, Yaseen M. Arabi, Hamdi Mbarek, Chadi Saad, Wadha Al-Muftah, Junghyun Jung, Serghei Mangul, Radja Badji, Asma Al Thani, Said I. Ismail, Ali G. Gharavi, Malak S. Abedalthagafi, J. Brent Richards, David B. Goldstein, Krzysztof Kiryluk
Journal: Journal of Clinical Investigation (2021)

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.
A novel function of Shugoshin-1 (Sgo1) in maintaining spindle pole integrity
Authors: Xiaoxing Wang, Yali Yang, Wei Dai
Journal: Cancer Research (2008)

LB-260  Errors occurred in mitosis can result in aneuploidy, a hallmark of human cancer. Mitotic fidelity is ensured by the spindle checkpoint which monitors proper attachment of mitotic spindles to condensed chromosomes. Defective coordination between the kinetochores and the spindle pole, two important mitotic apparatuses, during mitosis can impair chromosome segregation. Efforts have been made to discover molecular entities that coordinate the action of kinetochores and spindle poles during mitosis. Shugoshin-1 (Sgo1) is an evolutionarily conserved protein, functioning to timely release centromeric cohesin under the surveillance of the spindle checkpoint in early mitosis. Truncated Sgo1 (probably defective) was found overexpressed in multiple forms of cancers. Here we demonstrate a novel function of human sSgo1, a major splice isoform of Sgo1, at the spindle poles. sSgo1 localizes to the centrosome during interphase and to the spindle poles in mitosis. Sgo1 depletion via RNA interference (RNAi) induces the formation of multiple centrosome-like structures in early mitosis that primarily result from the separation of paired centrioles (referred as centrosome splitting). Murine embryonic fibroblasts (MEFs) derived from Sgo1 heterozygous (Sgo1+/-) mice also display split centrosomes despite of relatively normal mitotic progression. Ectopic expression of an sSgo1 construct efficiently suppresses centrosome splitting in Sgo1 siRNA-transfected cells and Sgo1+/- MEF. Combined, our studies strongly suggest a bifurcate function of Sgo1 at centromeres and spindle poles. Sgo1 deficiency results in both chromosomal and centrosomal instabilities. Given the importance of sSgo1 in regulating the spindle pole integrity, it is necessary to further investigate whether defective sSgo1 during mitosis has any pathological consequences.
POS1249 MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN DURING THE COVID-19 PANDEMIC IN TURKEY: FIRST REPORT FROM THE EASTERN MEDITERRANEAN
Authors: Y. Ozsurekci, S. Gürlevik, S. Kesici, U. Kaya Akca, P. D. Oygar, K. Aykac, D. Karacanoglu, O. Saritas Nakip, S. Ilbay, B. Katlan, A. B. Cengiz, Ö. Basaran, B. C. Cura Yayla, J. Karakaya, Y. Bilginer, B. Bayrakci, M. Ceyhan, S. Özen
Journal: Annals of the Rheumatic Diseases (2021)

Background: The severity of COVID-19 symptoms can range from mild to severe. Severe COVID-19 cases with excessive hyperinflammation have many overlap features with multisystem inflammatory syndrome in children (MIS-C). Objectives: We aimed to describe the typical clinical and laboratory features and treatment of children diagnosed with MIS-C and to understand the differences as compared to severe/critical pediatric cases with COVID-19 in an eastern Mediterranean country. Methods: Children (aged &lt;18 years) who diagnosed with MIS-C and severe/critical pediatric cases with COVID-19, were admitted to hospital between 26 March and 3 November 2020 were enrolled in the study. Results: A total of 52 patients, 22 patients diagnosed with COVID-19 with severe/critical disease course and 30 patients diagnosed with MIS-C. Although severe COVID-19 cases and cases with MIS-C share many clinical and laboratory features, MIS-C cases had longer fever duration and higher rate of the existence of rash, conjunctival injection, peripheral edema, abdominal pain, altered mental status, and myalgia than in severe cases (p&lt;0.001 for each). Of all, 53.3% of MIS-C cases had the evidence of myocardial involvement as compared to severe cases (27.2%). Additionally, C-reactive protein (CRP) and white blood cell (WBC) are the independent predictors for the diagnosis of MIS-C, particularly in the existence of conjunctival injection and rash. Corticosteroids, intravenous immunoglobulin (IVIG), and biologic immunomodulatory treatments were mainly used in MIS-C cases rather than cases with severe disease course. There were only 3 deaths among 52 patients, one of whom had Burkitt lymphoma and the two cases with severe COVID-19 of late referral. Conclusion: Differences between clinical presentations, acute phase responses, organ involvements, and management strategies indicate that MIS-C might be a distinct immunopathogenic disease as compared to pediatric COVID-19. Conjunctival injection and higher CRP and low WBC count seem good diagnostic parameters for MIS-C cases. Disclosure of Interests: None declared
AB0439 CAPILLAROSCOPIC PATTERNS IN PATIENTS WITH SYSTEMIC SCLEROSIS-POLYMYOSITIS/DERMATOMYOSITIS (SSc-PM/DM) OVERLAP SYNDROME
Authors: O. Desinova, M. Starovoytova, L. P. Ananyeva
Journal: Annals of the Rheumatic Diseases (2021)

Background: Impaired microcirculation is one of the leading factors in local and general pathogenesis of SSc. Widefield nail-fold video-capillaroscopy (NFVC) stands as the most informative and at the same time simple method used for evaluation of capillary circulation. Objectives: To identify characteristic and specific for SSc– PM/DM capillaroscopic features. Methods: Both hand II – V fingers of 68 pts with SSc-PM/DM were subjected to widefield NFC, evaluated using a binocular 20x magnification Olympus microscope and analyzed in view of specific skin lesions discriminating diffuse and limited SSc forms. Results: SSc-specific dilatations of capillary loops were the most common for SSc-PM/DM and were found in all pts; 50% of them had signs of active scleroderma pattern, such as capillary loss or “avascular areas” (50%) and hemorrhages (51.5%), associated with generalized microvascular spasm in early disease and capillary sclerosis in advanced disease. The morphological capillary abnormalities such as varying degrees of capillary loops tortuosity/vascular inhomogeneity were present in 63% of examined nailfolds, branching bushy behavior of capillary loops and mega-capillaries predominated; architectural disorientation/disarrangement of capillary loops with formation of subcutaneous plexus was seen in more than 50% of them. Capillaroscopic changes consistent with active scleroderma pattern were present in 54 % and were associated with lab signs of inflammatory muscle syndrome and immunological disorders: giant capillaries (p&lt;0.02), disorientation of capillary loops (p&lt;0.02) and ramified/bushy capillaries (p&lt;0.04) were significantly more frequent in patients with severe muscle syndrome, increased CPK, ANF -positivity and hemorrhages (p&lt;0.03). Conclusion: Thus, widefield NFVC revealed a “mixed” nature of capillaroscopic changes, combining features specific for SSc (capillary dilation, avascular areas, hemorrhages) and for PM/DM (bushy and giant capillaries, disorientation of capillary loops of the nailfold with formation of subcutaneous plexuses.) Disclosure of Interests: None declared
POS0455 EFFECT OF ANTI-Ro/SSA ANTIBODIES FOR TREATMENT RESPONSE TO METHOTREXATE IN RHEUMATOID ARTHRITIS: A RETROSPECTIVE MULTICENTER OBSERVATIONAL STUDY
Authors: R. Yokochi, H. Tamai, T. Kido, Y. Yagyu, D. Waki, R. Yanai, K. E. Sada
Journal: Annals of the Rheumatic Diseases (2021)

Background: Several previous observational studies have suggested that patients with anti-Ro/SSA antibody-positive rheumatoid arthritis (RA) may respond poorly to treatment, including tumor necrosis factor inhibitors 1 . However, its influence on methotrexate (MTX) treatment, which is the anchor drug of treat-to-target strategy in RA treatment, remains unclear. Objectives: We compared the clinical response to MTX in both anti-Ro/SSA antibody-positive and -negative patients with MTX-naiive RA and investigated the reasons for the difference in response. Methods: We recruited 210 consecutive patients with RA who were newly started on MTX in this retrospective cohort study. The effect of the presence of anti-Ro/SSA antibodies on achieving low disease activity (LDA) of DAS28-CRP at six months after initiating MTX was investigated by using logistic regression analysis. CDAI, SDAI, concomitant using DMARDs and painkillers, patient’s and evaluator’s VAS, tender joint counts, and swollen joint counts at six months were also compared between the anti-Ro/SSA-positive patients and -negative patients. Missing data were imputed by using multiple imputations before multivariate analysis. Results: 32 anti-Ro/SSA antibody-positive patients and 178 anti-Ro/SSA antibody-negative patients were included. The rate of achieving DAS28-LDA at six months was significantly lower in the anti-Ro/SSA antibody-positive patients than those in the anti-Ro/SSA antibody-negative patients (56.2% versus 75.8%, P =0.03). in the logistic regression analysis, the presence of anti-Ro/SSA antibodies was an independent negative predictor for achieving DAS-28-LDA at six months (OR:0.431, 95%CI: 0.190-0.978, P =0.044) (Table1). Anti-Ro/SSA antibody-positive patients had significantly higher patient’s VAS at six months (median [IQR]: 22 [15-41] vs 19 [5-30], P =0.038), and prescribed NSAIDs (37.5% vs 18.0%, P =0.018). CDAI and SDAI after six months were not significantly different between the group. Conclusion: The presence of anti-Ro/SSA antibodies might be one of the predictive factors for the insufficient response to treat to target strategy in RA treatment. Residual pain was suspected as one of the mechanisms contributing to the lesser clinical response of MTX in anti-Ro antibody-positive RA. References: [1]Ran Matsudaira wt al. J Rheumatol 2011;38(11):2346-54 Table 1. Logistic regression analysis for the rate of achieving DAS28 low disease activity at six months. Risk factor Odds ratio 95%CI P value Age at onset 0.993 0.968-1.018 0.586 Sex (woman) 0.643 0.300-1.384 0.258 RF-positive 1.962 0.853-4.511 0.112 ACPA-positive 0.552 0.225-1.351 0.192 Anti-Ro/SSA antibody-positive 0.431 0.190-0.978 0.044 Disclosure of Interests: None declared
Single‐Cell Transcriptomic Analysis Reveals a Hepatic Stellate Cell–Activation Roadmap and Myofibroblast Origin During Liver Fibrosis in Mice
Authors: Wu Yang, Hao He, Tongtong Wang, Nan Su, Feng Zhang, Kai Jiang, Jing Zhu, Chonghe Zhang, Kongyan Niu, Luyue Wang, Xiaodong Yuan, Nan Liu, Lingjie Li, Wu Wei, Junhao Hu
Journal: Hepatology (2021)

Background and Aims HSCs and portal fibroblasts (PFs) are the major sources of collagen‐producing myofibroblasts during liver fibrosis, depending on different etiologies. However, the mechanisms by which their dynamic gene expression directs the transition from the quiescent to the activated state—as well as their contributions to fibrotic myofibroblasts—remain unclear. Here, we analyze the activation of HSCs and PFs in CCL 4 ‐induced and bile duct ligation–induced fibrosis mouse models, using single‐cell RNA sequencing and lineage tracing. Approach and Results We demonstrate that HSCs, rather than PFs, undergo dramatic transcriptomic changes, with the sequential activation of inflammatory, migrative, and extracellular matrix–producing programs. The data also reveal that HSCs are the exclusive source of myofibroblasts in CCL 4 ‐treated liver, while PFs are the major source of myofibroblasts in early cholestatic liver fibrosis. Single‐cell and lineage‐tracing analysis also uncovers differential gene‐expression features between HSCs and PFs; for example, nitric oxide receptor soluble guanylate cyclase is exclusively expressed in HSCs, but not in PFs. The soluble guanylate cyclase stimulator Riociguat potently reduced liver fibrosis in CCL 4 ‐treated livers but showed no therapeutic efficacy in bile duct ligation livers. Conclusions This study provides a transcriptional roadmap for the activation of HSCs during liver fibrosis and yields comprehensive evidence that the differential transcriptomic features of HSCs and PFs, along with their relative contributions to liver fibrosis of different etiologies, should be considered in developing effective antifibrotic therapeutic strategies.
AB0718 ASSESSMENT OF SEXUAL DYSFUNCTION IN WOMEN AND MEN WITH FIBROMYALGIA SYNDROME
Authors: G. Mouna, J. Mahbouba, S. Zrour, I. Bejia, M. Touzi, N. Bergaoui
Journal: Annals of the Rheumatic Diseases (2021)

Background: Fibromyalgia syndrome is a chronic musculoskeletal disease, which compromises physical, mental, and sexual health. Although concerns related to sexuality are commonly reported, the literature on sexual functioning in patient with fibromyalgia is limited to female patients. Objectives: The aim of our study is to identify sexual dysfunction in women and men with fibromyalgia syndrome compared with patients with rheumatoid arthritis. Methods: This is a cross-sectional comparative study: ‘34 patients with fibromyalgia syndrome compared to 100 patients with rheumatoid arthritis’ conducted in the rheumatology department of CHU Fattouma Bourguiba de Monastir over a period from February to November 2017. We used the Female Sexual Function Index (FSFI) and the Sexual Health Inventory for Men (SHIM). Results: Our sample comprised 34 patients with fibromyalgia (31 females and 3 males) and 100 patients with rheumatoid arthritis (58 females and 15 males).Sexual dysfunction was present in 100% of female patients with fibromyalgia syndrome compared to 60% of female patients with rheumatoid arthritis. Female patients with fibromyalgia syndrome had a decreased FSFI score: 10,3±8,74 versus 16,86±8,87 in the rheumatoid arthitis group with p=0.001. While among the male patients, we found no significant difference between the two groups. Conclusion: Fibromyalgia syndrome had negative side effect on the sexual life of female patients. Recognition of this dysfunction and its inclusion in the multidisciplinary management of fibromyalgia must be part of the treatment. References: [1]P. Romero-Alcalá et al. , « Sexuality in male partners of womenwithfibromyalgiasyndrome: A qualitative study », PLoS One , vol. 14, n o 11, nov. 2019, doi: 10.1371/journal.pone.0224990. [2]M. D. H. Besiroglu et M. D. M. Dursun, « The association betweenfibromyalgia and femalesexualdysfunction:asystematicreview and meta-analysis of observationalstudies », Int J ImpotRes , vol. 31, n o 4, p. 288-297, juill. 2019, doi: 10.1038/s41443-018-0098-3. [3]T. M. Matarín Jiménez, C. Fernández-Sola, J. M. Hernández-Padilla, M. Correa Casado, L. H. Antequera Raynal, et J. Granero-Molina, « Perceptions about the sexuality of womenwithfibromyalgiasyndrome:aphenomenologicalstudy », J Adv Nurs , vol. 73, n o 7, p. 1646-1656, juill. 2017, doi: 10.1111/jan.13262. [4]L. Bazzichi et al. , « Fibromyalgia and sexualproblems », Reumatismo , vol. 64, n o 4, p. 261-267, sept. 2012, doi: 10.4081/reumatismo.2012.261. Disclosure of Interests: None declared
Association between Hyperinsulinemia and Hypertension among White, Black, and Mexican American Adults. Results from the Third National Health and Nutrition Examination Survey, 1988-1994.
Authors: David W Brown, Verna Lamar-Welch, Wayne H Giles, Kurt J Greenlund, Janet B Croft
Journal: Circulation (2001)

P72 Objective: To examine the association between hyperinsulinemia and blood pressure independent of body mass among nondiabetic white non-Hispanic, black non-Hispanic, and Mexican American adults. Methods: We examined this relationship using data from 8004 adults aged ≥20 years from the Third National Health and Nutrition Examination Survey (1988-1994). Univariate differences in body mass index (BMI), waist-to-hip ratio (WHR), glycosylated hemoglobin (HbA 1c ), fasting plasma glucose and C-peptide were examined between normotensives and hypertensives within each racial or ethnic group. Logistic regression was used to obtain the likelihood of being hypertensive across race specific tertiles of C-peptide adjusting for age, sex, education, BMI, and WHR. Results: The prevalence of hypertension was 21.1% among whites, 24.6% among blacks, and 10.9% among Mexican Americans. Hypertensives were older, with higher BMI, WHR, HbA 1c , fasting plasma glucose, and fasting C-peptide levels than normotensives. Also, the prevalence of hypertension increased significantly with C-peptide level for each of the racial or ethnic groups. Persons with a C-peptide in the upper tertile were more likely to be hypertensive than those with a C-peptide level in the lower tertile after adjustment for age, sex, education, and BMI (Mexican Americans OR=3.3, 95% CI=2.2-4.8; whites OR=2.0, 95% CI=1.5-2.7, blacks OR=2.0, 95% CI=1.3-3.0). Adjustment for WHR attenuated the association between C-peptide and hypertension (Mexican Americans OR=3.0, 95% CI=2.0-4.5; whites OR=1.6,95% CI=1.2-2.2; blacks OR=1.7, 95% CI=1.1-2.6). Conclusion: These results suggest that hyperinsulinemia is associated with hypertension independent of BMI and diabetes. Further, WHR was identified as a confounder and should be taken into account in addition to BMI when evaluating the relationship between C-peptide and hypertension.
Fibroblasts positive for meflin have anti-fibrotic properties in pulmonary fibrosis
Authors: Yoshio Nakahara, Naozumi Hashimoto, Koji Sakamoto, Atsushi Enomoto, Taylor S. Adams, Toyoharu Yokoi, Norihito Omote, Sergio Poli, Akira Ando, Keiko Wakahara, Atsushi Suzuki, Masahide Inoue, Akitoshi Hara, Yasuyuki Mizutani, Kazuyoshi Imaizumi, Tsutomu Kawabe, Ivan O. Rosas, Masahide Takahashi, Naftali Kaminski, Yoshinori Hasegawa
Journal: European Respiratory Journal (2021)

The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine the pathogenesis of IPF, identification of functional fibroblasts is warranted. The aim of this study was to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis. We characterised meflin-positive cells in a single-cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis. scRNA-seq combined with in situ RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic properties to prevent pulmonary fibrosis. Although transforming growth factor-β-induced fibrogenesis and cell senescence with the senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution. These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.
AB0918-PARE FAMILY PLANNING AND RMDS: A SURVEY
Authors: U. Viora, P. Grossi, F. Padovani, G. Mussi, S. Severoni, S. Tonolo, A. Verducci
Journal: Annals of the Rheumatic Diseases (2021)

Background: It is well known and universally aknowledged that RMDs are not related to old age, as those who are affected by these illness between 30 and 45 years old are a big number, perhaps the biggest one. Therefore, family planning and pregnancy are topics even more actual and their management is certainly one of the biggest source of distress and troubles in people affected by RMDs and their spouses. Objectives: to define and deeply understand the problem’s dimension, ANMAR made a survey according to the CAPIRE Observatory. Methods: an pposite questionnaire was given to patients waiting for a rheumatological consultation, during 6 months in 2020. Results: Over 300 women with an RMD fulfilled the questionnaire: 7 on 10 women are trying to become pregnant 51% of them did not notice it to their Rheumatologist. 57% of them has been already pregnant. Conclusion: In Italy, women with RMDs are over 3.5 millions and the a lot of them are women of childbearing potential. As therapies actually used are really effective, but may induce side effects on the reproductive system, it is absolutely needed to inform the Rheumatologist about the intent to procreate and to have suggestions about the correct chice of contracception models. Communication between patient and Rheumatologist must be improoved, even in this important topic. Disclosure of Interests: None declared
The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy
Authors: Laura Rodríguez-Pascau, Anna Vilalta, Marc Cerrada, Estefania Traver, Sonja Forss-Petter, Isabelle Weinhofer, Jan Bauer, Stephan Kemp, Guillem Pina, Sílvia Pascual, Uwe Meya, Patricia L. Musolino, Johannes Berger, Marc Martinell, Pilar Pizcueta
Journal: Science Translational Medicine (2021)

Leriglitazone reduces pathologically activated microglia and protects neurons, astrocytes, and oligodendrocytes in experimental models of X-ALD.