tbuckley/cabot-search huggingface dataset:
Adjusting for Nonadherence or Stopping Treatments in Randomized Clinical Trials
Authors: Amanda I. Adler, Nicholas R. Latimer
Journal: JAMA (2021)

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Epigenetic analysis of patients with T-ALL identifies poor outcomes and a hypomethylating agent-responsive subgroup
Authors: Aurore Touzart, Anand Mayakonda, Charlotte Smith, Joschka Hey, Reka Toth, Agata Cieslak, Guillaume P. Andrieu, Christine Tran Quang, Mehdi Latiri, Jacques Ghysdael, Salvatore Spicuglia, Hervé Dombret, Norbert Ifrah, Elizabeth Macintyre, Pavlo Lutsik, Nicolas Boissel, Christoph Plass, Vahid Asnafi
Journal: Science Translational Medicine (2021)

Characterization of adult T-ALL methylomes identifies a clinically aggressive hypermethylated subgroup sensitive to 5-azacytidine.
Increased Incidence of Pediatric Type 1 Diabetes With Novel Association With Coxsackievirus A Species in Young Children but Declined Incidence in Adolescents in Taiwan
Authors: Wei-Liang Shih, Yi-Ching Tung, Luan-Yin Chang, Chi-Tai Fang, Wen-Yu Tsai
Journal: Diabetes Care (2021)

OBJECTIVE Type 1 diabetes (T1D) has been linked to enterovirus infection in small population-based epidemiological studies. We investigated the secular relationship of T1D incidence with enterovirus infection and enterovirus species using nationwide population-based analysis. RESEARCH DESIGN AND METHODS We accessed the National Health Insurance Research Database of Taiwan to identify T1D and enterovirus infection cases from 2001 to 2015. Enterovirus serotype isolation rates were obtained from the nationwide laboratory surveillance systems. Negative binomial regression models assessed the incidence trend, and extended Cox proportional hazards models analyzed the association of enterovirus infection with T1D incidence. Spearman correlation coefficients evaluated the correlation between T1D incidence and circulating enterovirus species. RESULTS T1D incidence rates in youth younger than 20 years were 6.30 and 5.02 per 100,000 person-years in 2001 and 2015 (P = 0.287), respectively. T1D incidence increased significantly in children aged 0–6 years (P &amp;lt; 0.001) but decreased in adolescents aged 13–19 years (P = 0.011). The T1D risk in children aged 0–6 years with enterovirus infection was significantly higher than that in noninfected subjects (hazard ratio 1.46; 95% CI 1.35–1.58; P &amp;lt; 0.001). Additionally, TID incidence in children aged 0–6 years was significantly correlated with the isolation rates of coxsackievirus A species (r = 0.60; P = 0.017), but no association was found beyond the age of 7. CONCLUSIONS We demonstrated that T1D incidence increased in children aged 0–6 years but decreased in adolescents aged 13–19 years in Taiwan. Enterovirus-infected subjects younger than 7 years had a higher risk of T1D than noninfected subjects.
The healing myocardium mobilizes a distinct B-cell subset through a CXCL13-CXCR5-dependent mechanism
Authors: Margarete Heinrichs, DiyaaElDin Ashour, Johanna Siegel, Lotte Büchner, Georg Wedekind, Katrin G Heinze, Panagiota Arampatzi, Antoine-Emmanuel Saliba, Clement Cochain, Ulrich Hofmann, Stefan Frantz, Gustavo Campos Ramos
Journal: Cardiovascular Research (2021)

Abstract Aims Recent studies have revealed that B cells and antibodies can influence inflammation and remodelling following a myocardial infarction (MI) and culminating in heart failure—but the mechanisms underlying these observations remain elusive. We therefore conducted in mice a deep phenotyping of the post-MI B-cell responses in infarcted hearts and mediastinal lymph nodes, which drain the myocardium. Thereby, we sought to dissect the mechanisms controlling B-cell mobilization and activity in situ. Methods and results Histological, flow cytometry, and single-cell RNA-sequencing (scRNA-seq) analyses revealed a rapid accumulation of diverse B-cell subsets in infarcted murine hearts, paralleled by mild clonal expansion of germinal centre B cells in the mediastinal lymph nodes. The repertoire of cardiac B cells was largely polyclonal and showed no sign of antigen-driven clonal expansion. Instead, it included a distinct subset exclusively found in the heart, herein termed ‘heart-associated B cells’ (hB) that expressed high levels of Cd69 as an activation marker, C-C-chemokine receptor type 7 (Ccr7), CXC-chemokine receptor type 5 (Cxcr5), and transforming growth factor beta 1 (Tgfb1). This distinct signature was not shared with any other cell population in the healing myocardium. Moreover, we detected a myocardial gradient of CXC-motif chemokine ligand 13 (CXCL13, the ligand of CXCR5) on Days 1 and 5 post-MI. When compared with wild-type controls, mice treated with a neutralizing CXCL13-specific antibody as well as CXCR5-deficient mice showed reduced post-MI infiltration of B cells and reduced local Tgfb1 expression but no differences in contractile function nor myocardial morphology were observed between groups. Conclusion Our study reveals that polyclonal B cells showing no sign of antigen-specificity readily infiltrate the heart after MI via the CXCL13-CXCR5 axis and contribute to local TGF-ß1 production. The local B-cell responses are paralleled by mild antigen-driven germinal centre reactions in the mediastinal lymph nodes that might ultimately lead to the production of specific antibodies.
POS1015 ANTI-TNF DRUGS AND CARDIOVASCULAR EVENTS IN PATIENTS WITH SPONDYLOARTHRITIS
Authors: C. W. S. Chan, P. H. LI, C. S. Lau, H. Y. Chung
Journal: Annals of the Rheumatic Diseases (2021)

Background: Cardiovascular (CVS) diseases are the leading cause of death worldwide and patients with rheumatic diseases have an increased CVS risk including stroke and myocardial infarction (MI) (1-3). CVS risk factors and CVS events are common in SpA (4). Delineating the CVS risk and the association with medications in patients with SpA would be useful. Objectives: The objective of this study was to delineate the CVS risk and the association with medications in patients with SpA. Methods: Patients with SpA and patients with non-specific back pain (NSBP) were identified in rheumatology and orthopedics clinics respectively. Clinical information and CVS events were retrieved. Incidence rates were calculated. Association analysis was performed to determine the CVS risk of SpA and other modifiable risk factors. Results: A total of 5046 patients (SpA 2616 and NSBP 2430) were included from eight centers. Over 56 484 person-years of follow-up, 160 strokes, 84 MI and 262 major adverse cardiovascular events (MACE) were identified. Hypercholesterolemia was more prevalent in SpA (SpA 34.2%, NSBP 28.7%, P&lt;0.01). Crude incidence rates of stroke and MI were higher in SpA patients. SpA was associated with a higher risk of MACE (HR 1.66, 95%CI 1.22-2.27, P&lt;0.01) and cerebrovascular events (HR 1.42, 95%CI 1.01-2.00, p=0.04). The use of anti-tumor necrosis factor (TNF) drugs was associated with a reduced risk of MACE (HR 0.37, 95%CI 0.17-0.80, P=0.01) and cerebrovascular events (HR 0.21, 95%CI 0.06-0.78, P=0.02). Conclusion: SpA is an independent CVS risk factor. Anti-TNF drugs were associated with a reduced CVS risk in these patients. References: [1]Crowson CS, Liao KP, Davis JM, 3rd, Solomon DH, Matteson EL, Knutson KL, et al. Rheumatoid arthritis and cardiovascular disease. Am Heart J. 2013;166(4):622-8 e1. [2]Verhoeven F, Prati C, Demougeot C, Wendling D. Cardiovascular risk in psoriatic arthritis, a narrative review. Joint Bone Spine. 2020;87(5):413-8. [3]Liew JW, Ramiro S, Gensler LS. Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis. Best Pract Res Clin Rheumatol. 2018;32(3):369-89. [4]Molto A, Etcheto A, van der Heijde D, Landewe R, van den Bosch F, Bautista Molano W, et al. Prevalence of comorbidities and evaluation of their screening in spondyloarthritis: results of the international cross-sectional ASAS-COMOSPA study. Ann Rheum Dis. 2016;75(6):1016-23. Disclosure of Interests: None declared.
AB0858 SUCCESSFUL TERM PREGNANCY IN A PATIENT WITH GRANULOMATOSIS WITH POLYANGIITIS AFTER UNDERGOING RITUXIMAB THERAPY - CASE REPORT
Authors: O. Sirenko, O. Kuryata, T. Lysunets, A. Legkobyt, H. Mostova
Journal: Annals of the Rheumatic Diseases (2021)

Background: Granulomatosis with polyangiitis (GWP) is a relatively rare disease with the lack of experience in the management of pregnancy currently. Potentially negative factors of pregnancy prognosis are both disease-related and teratogenic effects of specific vasculitis therapy [1]. Objectives: To describe a clinical case of Successful term pregnancy in a patient with Granulomatosis with polyangiitis after undergoing rituximab therapy. Methods: 19 years-old woman was admitted to the rheumatology department of Clinical Regional Hospital After Mechnicov in 2013 with the debut of Granulomatosis with polyangiitis. Her disease course included recurrent rhinitis and sinusitis, Granulomatosis of the eye orbits. Positive ANCA titers were present in the disease onset. In the preceding 7 years she had been treated with corticosteroids, cyclophospan (discontinuated in 2017 because of lack of efficiency), than azathioprine. Aseptic necrosis of the both femoral head was estimated on fifth disease year. In 2018 azathioprine therapy had been discontinued owing to the disease progression and biological agents were prescribed – rituximab with positive effect. The disease remission was achived by rituximab therapy, the patient was warned about the need for contraception. The last dose of rituximab was introduced in February 2020. However, in March 2020, the patient reported pregnancy and therapy was discontinued. At the onset of pregnancy she was treated with 6 mg oral methylprednisolone. Daily and this dose was stable till all pregnancy period. Fetal growth assessment, congenital abnormalities screening test, and laboratory tests for gestational diabetes and preeclampsia were unremarkable during all gestational trimesters. The ANCA titers remained negative and renal function was normal and there was no flare during all pregnancy period. Results: At 38 weeks’ gestation a spontataneous labor started without induction. A 3270-g healthy boy delivered with APGAR score of 9 at 1 minute and 5 minutes. Postpartum the disease remained in remission, and the patient was maintained on corticosteroids. The infant was healthy, with normal development. Conclusion: Thus, the use of biological agents therapy in patients with GWP shows possible ways to safe reproductive potential with disease remission achievement. References: [1]Daher A, Sauvetre G, Girszyn N, Verspyck E, Levesque H, Le Besnerais M. Granulomatosis with polyangiitis and pregnancy: A case report and review of the literature. Obstetric Medicine . 2020;13(2):76-82. doi: 10.1177/1753495X18822581 Disclosure of Interests: None declared
AB0627 THE EFFECT OF BIOLOGICALLY ACTIVE FOOD SUPPLEMENT WITH CALCIUM AND VITAMIN D3 ADMINISTRATION ON CALCIUM HOMEOSTASIS AND FALLS INCIDENCE IN PATIENTS WITH HIGH FRACTURE RISK UNDERGOING MEDICAL REHABILITATION
Authors: L. Marchenkova, V. Vasileva
Journal: Annals of the Rheumatic Diseases (2021)

Background: Vitamin D and calcium deficiencies is of particular importance in older patients undergoing medical rehabilitation and having a high risk of fractures. Preventing falls and fractures, including during the course of rehabilitation, is an important challenge that can be addressed in these patients, in particular through improved nutrition and vitamin D and calcium supplementation. Objectives: to evaluate the effect of long-term calcium and vitamin D3 intake on calcium homeostasis and fall’s rate in patients with high fracture risk starting rehabilitation course. Methods: The study enrolled 119 men and women aged 50-80 y.o. with high absolute fracture probability by FRAX who started medical rehabilitation. 41 patients have been receiving antiresorptive therapy already comprised group 1, other patients were randomized into groups 2 (n=39) and 3 (control, n=39). In groups 1 and 2, a food supplement containing calcium citrate 1000 mg and vitamin D3 600 IU was prescribed for 12 months. All patients undergo laboratory examination, food calcium intake and fall assessment at baseline, in 6 and 12 months. Results: Daily calcium intake in the study sample (n=119) was 782.9±243.4 mg. Vitamin D deficiency was detected in 38.4% of the examined. An increase in 25(OH)D level was noted in groups 1 and 2 after 6 and 12 months (p&lt;0.01). Patients in group 1 showed an increase in serum osteocalcin and calcium levels after 6 and 12 months (p&lt;0.05). In group 3, there was an increase of immunoreactive parathyroid hormone levels after 6 (p&lt;0.05) and 12 months (p&lt;0.01), C-terminal telopeptide of type I collagen level and alkaline phosphatase activity after 12 months (p&lt;0.05). In group 1, there was also a decrease in proportion of patients who fell after 6 months (χ2=4.97, p=0.026) and a decrease in the total number of falls after 12 months (χ2=4.89, p=0.027). Group 2 showed a decrease in the number of patients who fell after 6 and 12 months (χ2=48.58, p=0.0034 at both stages of the study) and the number of falls in general after 6 months (χ2=6.02, p=0.0142). Conclusion: The obtained data allow us to recommend prescription of dietary supplements containing calcium and vitamin D3 as a part of complex rehabilitation of patients with high fracture risk. Disclosure of Interests: None declared.
新規4フレンチ冠状動脈アクセッサー”KIWAMI”を使った経皮冠動脈インターベンション
Authors: Takeshita Satoshi, Tanaka Shinji, Miyashita Yusuke, Shiono Takaaki, Takahashi Saeko, Taketani Yoshio, Doumae Hiroshi, Mizuno Shingo, Saito Shigeru
Journal: Circulation (2009)
Medium-Chain Acyl-CoA Dehydrogenase Protects Mitochondria from Lipid Peroxidation in Glioblastoma
Authors: Francesca Puca, Fei Yu, Caterina Bartolacci, Piergiorgio Pettazzoni, Alessandro Carugo, Emmet Huang-Hobbs, Jintan Liu, Ciro Zanca, Federica Carbone, Edoardo Del Poggetto, Joy Gumin, Pushan Dasgupta, Sahil Seth, Sanjana Srinivasan, Frederick F. Lang, Erik P. Sulman, Philip L. Lorenzi, Lin Tan, Mengrou Shan, Zachary P. Tolstyka, Maureen Kachman, Li Zhang, Sisi Gao, Angela K. Deem, Giannicola Genovese, Pier Paolo Scaglioni, Costas A. Lyssiotis, Andrea Viale, Giulio F. Draetta
Journal: Cancer Discovery (2021)

Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes medium-chain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM. SIGNIFICANCE: MCAD exerts a protective role to prevent accumulation of toxic metabolic by-products in glioma cells, actively catabolizing lipid species that would otherwise affect mitochondrial integrity and induce cell death. This work represents a first demonstration of a nonenergetic role for dependence on fatty acid metabolism in cancer.This article is highlighted in the In This Issue feature, p. 2659.
The Development of Living, Rapid Practice Points: Summary of Methods From the Scientific Medical Policy Committee of the American College of Physicians
Authors: Amir Qaseem, Jennifer Yost, Mary Ann Forciea, Janet A. Jokela, Matthew C. Miller, Adam Obley, Linda L. Humphrey
Journal: Annals of Internal Medicine (2021)

In response to the COVID-19 pandemic, the Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) began developing “practice points” to provide clinical advice based on the best available evidence for the public, patients, clinicians, and public health professionals. As one of the first organizations in the United States to develop evidence-based clinical guidelines, ACP continues to lead and advance the science of evidence-based medicine by implementing new methods to rapidly publish practice points and maintain them as living advice that regularly assesses and incorporates new evidence. The overarching aim of practice points is to answer targeted key questions for which there is a timely need to synthesize evidence for decision making. The SMPC believes these methods can potentially be adapted to address various clinical and public health topics beyond the COVID-19 pandemic. This article presents an overview of the SMPC's living, rapid practice points development process, which includes a rapid systematic review, use of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method, use of stringent policies on the disclosure of interests and management of conflicts of interest, incorporating a public (nonclinician) perspective, and maintenance of the documents as living through ongoing surveillance and synthesis of new evidence as it emerges.
Long-term Follow-up of Patients with Relapsed or Refractory Non–Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human Study
Authors: Matthew S. Davids, Andrew W. Roberts, Vaishalee P. Kenkre, William G. Wierda, Abhijeet Kumar, Thomas J. Kipps, Michelle Boyer, Ahmed Hamed Salem, John C. Pesko, Jennifer A. Arzt, Margaret Mantas, Su Y. Kim, John F. Seymour
Journal: Clinical Cancer Research (2021)

Abstract Purpose: We previously reported a 44% overall response rate (ORR) with the oral BCL-2 inhibitor venetoclax in a phase I study of relapsed/refractory non–Hodgkin lymphoma (NHL). Complete response (CR) was observed in patients with mantle cell lymphoma [(MCL), 21%, n = 6/28] and follicular lymphoma [(FL), 17%, n = 5/29], and partial response (PR) noted in several patients with Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Here, we report the long-term outcomes of these four cohorts. Patients and Methods: All patients (n = 106) received venetoclax monotherapy in dose cohorts of 200 to 1,200 mg daily until disease progression or unacceptable toxicity. ORR, progression-free survival (PFS), duration of response (DoR), and adverse events (AEs) were evaluated. Results: At a median follow-up of 38.5 months (range, 30.0–46.5), the median PFS for all 106 patients was 5.4 [95% confidence interval (CI), 3.5–8.4] months (FL, 10.8; MCL, 11.3; MZL, 21.2; and WM, 30.4). The median DoR was 14.9 (95% CI, 9.7–27.6) months (FL, 26.6; MCL, 15.7; MZL, 20.1; and WM, 25.3). Achievement of CR versus PR predicted longer DoR in both MCL (31.5 vs. 10.1 months) and FL (37.6 vs. 9.7 months). All grade hematologic AEs were infrequent: neutropenia (19%), anemia (19%), and thrombocytopenia (17%), with no new cytopenias after 2 years on therapy. Nonhematologic AEs included nausea (49%), diarrhea (46%), fatigue (44%), with decreased incidence after 1 year. Conclusions: Venetoclax monotherapy has a manageable safety profile and achieves durable responses in a subset of patients with FL, MCL, WM, and MZL, particularly in those who achieve CR. Further research is warranted on combination strategies to enhance the durability of response to venetoclax.
POS1236 IMPACT OF COVID-19 ON INITIATION AND RENEWAL OF BIOTHERAPIES AND TARGETED SYNTHETIC TREATMENTS
Authors: P. Richette, M. Allez, V. Descamps, L. Perra, S. Pilet, M. Maravic
Journal: Annals of the Rheumatic Diseases (2021)

Background: During the epidemic’s peak of COVID-19, scientific societies published recommendations on biotherapy and targeted synthetic treatment (B/TST) use in patients with chronic articular inflammatory diseases, inflammatory bowel diseases, and psoriasis. Objectives: The objective was to evaluate the impact of COVID-19 in France on initiation and renewal of B/TST. Methods: LRx contains all anonymized medication dispenses prescribed in outpatient care in a representative panel of French retails pharmacies, including data of near 40 million patients. The impact of B/TST initiation and renewal were studied using 2019 as reference and dispense deliveries data of pharmacies with regular flew in order to perform the comparison. B/TST considered were abatacept, anti-TNF, anti-IL6, anti-IL17, anti-IL12/23 or anti-IL23, JAK inhibitors (JAKi) and other classes such as aprelimast, aminosalicylates (AS), hydroxychloroquine (HCQ), and methotrexate (MTX). A treatment initiated was defined as a treatment not delivered in the past 12 months, and conversely for a treatment renewal. Results were presented as raw one and expressed in percentage of patients having at least one B/TST delivery in each therapeutic classes of interest in 2020 compared to 2019 used as reference year (period from week 12 to week 19 considered and corresponding to the lockdown period in France). Results: During the lockdown period, a decrease in initiation was observed for patients treated with: abatacept (405 in 2019 vs 227 in 2020: -44%, p&lt;0.001), anti-TNF (1156 vs 1058, -31%, p&lt;0.001), anti-IL17 (415 vs 206, -50%, p&lt;0.001), anti-IL12-23 (395 vs 339, -12%, p=0.16), JAKi (289 vs 174, -39%, p=0.006), contrasting with an increase for Tociliumab (117 vs 445, +152%, p=0,01). We found a decrease of 7% (2171 vs 2015, p=0,35), 44% (405 vs 227, p&lt;0.001), 30% (3430 vs 2390, p p&lt;0.001) of AS, aprelimast and MTX initiation, respectively, and an increase of 173% (1708 vs 4671, p=0.11) of HCQ initiation. No decrease for the renewal of B/TST was observed Conclusion: During the epidemic’s peak, initiation of AS, MTX, biotherapies (except for tocilizumab), and JAKi dramatically decreased without impacting their renewal. Two treatments were mainly initiated, tocilizumab probably due to a switch from intravenous to subcutaneous injection and HCQ in relation to its presumably effect on COVID-19. Overall, recommendations from scientific societies have been followed. Disclosure of Interests: None declared