tbuckley/cabot-search huggingface dataset:
A nationwide cohort study with propensity score matching
Authors: Lucien Roulet
Journal: Gut (2020)

Lee and colleagues recently published the first large-scale study to investigate the association between proton pump inhibitor (PPI) use and the infectious disease caused by COVID-19.1 Using a nationwide cohort sample with propensity score matching, they concluded that short-term current—but neither long-term current nor past—PPI usage was associated with worse outcomes of COVID-19. These results deserve some comments.

By decreasing the barrier effect of gastric acidity and thus promoting the survival of ingested pathogens, PPIs are a known risk factor for some enteric bacterial and virus infections.2 3 Based on the evidence for a fecal–oral transmission in COVID-19, the authors made the hypothesis that PPI use might influence the susceptibility to COVID-19. Nevertheless, criteria other than biological plausibility should be taken into account when considering retrospective observational studies, in which information is not collected with …
Prevalence and risk factors for back pain in sports: a systematic review with meta-analysis
Authors: Fiona Wilson, Clare L Ardern, Jan Hartvigsen, Kathryn Dane, Katharina Trompeter, Larissa Trease, Anders Vinther, Conor Gissane, Sarah-Jane McDonnell, JP Caneiro, Craig Newlands, Kellie Wilkie, David Mockler, Jane S Thornton
Journal: British Journal of Sports Medicine (2020)

Objectives We aimed to determine the prevalence of low back pain (LBP) in sport, and what risk factors were associated with LBP in athletes. Design Systematic review with meta-analysis. Data sources Literature searches from database inception to June 2019 in Medline, Embase, Cumulated Index to Nursing and Allied Health Literature (CINAHL), Web of Science and Scopus, supplemented by grey literature searching. Eligibility criteria Studies evaluating prevalence of LBP in adult athletes across all sports. Results Eighty-six studies were included (30 732, range 20–5958, participants), of which 45 were of ‘high’ quality. Definitions of LBP varied widely, and in 17 studies, no definition was provided. High-quality studies were pooled and the mean point prevalence across six studies was 42%; range 18%–80% (95% CI 27% to 58%, I 2 =97%). Lifetime prevalence across 13 studies was 63%; range 36%–88% (95% CI 51% to 74%, I 2 =99%). Twelve-month LBP prevalence from 22 studies was 51%; range 12%–94% (95% CI 41% to 61%, I 2 =98%). Comparison across sports was limited by participant numbers, study quality and methodologies, and varying LBP definitions. Risk factors for LBP included history of a previous episode with a pooled OR of 3.5; range 1.6–4.0 (95% CI 1.9 to 6.4). Statistically significant associations were reported for high training volume, periods of load increase and years of exposure to the sport. Conclusion LBP in sport is common but estimates vary. Current evidence is insufficient to identify which sports are at highest risk. A previous episode of LBP, high training volume, periods of load increase and years of exposure are common risk factors.
AB0062 Patients? willingness to accept immediate risk of death in the treatment of ra with high dose chemotherapy
Authors: RJ Verburg, SD Mahabali, JK Sont, AM Stiggelbout, JM Van Laar
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Patients with intractable rheumatoid arthritis (RA) may benefit from treatment with high dose chemotherapy (HDC) followed by rescue with autologous peripheral blood stem cells (SCT). The aim of this study was to establish whether the risks of this approach are acceptable to patients with RA and whether risk taking was associated with disease associated, socio-economic parameters and/or personality. <h3>Objectives</h3> <h3>Methods</h3> 45 RA patients with active RA enrolled. Patients received information about the potential benefit of HDC (2/3 of patients good clinical response, 1/3 not), observed toxicities (alopecia, infections and bleedings) and duration of hospitalisation. Cure was assumed not te be a realistic perspective. Patients were asked what the minimal duration of benefit should be, given a transplant related mortality (TRM) of 0.01% and 2%. Furthermore maximal accepted TRM was asked given a duration of benefit of 2 years. Analysis of predictive factors of patients? willingness to accept risk of death by the Mann-Whitney U-test was performed with parameters of disease activity (Swollen Joint Count, Tender Joint Count, VAS, ESR and HAQ), socio-economic parameters, RAQoL and the Life Orientation Test. <h3>Results</h3> Of the 45 patients, 5 patients were willing to accept TRM in the treatment of RA, 40 patients were not. Of these 5 patients the mean duration of benefit given a TRM of 0.01% was 45 months (range 2‑96). For a TRM of 2% the mean duration was 52 months (range 6‑120). VAS disease activity (P = 0.006), VAS pain (P = 0.021) and HAQ (P = 0.05) were signicantly higher in these patients. Religiosity (P = 0.093) and a higher Ritchie articular index (P = 0.1) showed a trend towards risk taking. <h3>Conclusion</h3> We considered an approach to investigate risk taking in patients with RA based on a realistic perspective in which the trade off between short term risks and possible long term gain of HDC was investigated. It was found that patient with a chronic disease such as RA in which prevention of morbidity instead of mortality is the major
Tetracycline Antibiotics Induce Host-Dependent Disease Tolerance to Infection
Authors: Henrique G. Colaço, André Barros, Ana Neves-Costa, Elsa Seixas, Dora Pedroso, Tiago Velho, Katharina L. Willmann, Pedro Faisca, Gerlinde Grabmann, Hyon-Seung Yi, Minho Shong, Vladimir Benes, Sebastian Weis, Thomas Köcher, Luís F. Moita
Journal: Immunity (2020)

Several classes of antibiotics have long been known to have beneficial effects that cannot be explained strictly on the basis of their capacity to control the infectious agent. Here, we report that tetracycline antibiotics, which target the mitoribosome, protected against sepsis without affecting the pathogen load. Mechanistically, we found that mitochondrial inhibition of protein synthesis perturbed the electron transport chain (ETC) decreasing tissue damage in the lung and increasing fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a liver-specific partial and acute deletion of Crif1, a critical mitoribosomal component for protein synthesis, we found that mice were protected against sepsis, an observation that was phenocopied by the transient inhibition of complex I of the ETC by phenformin. Together, we demonstrate that mitoribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a mechanism for the induction of disease tolerance.
The Use of Anti-Thymocyte Globulin Is Associated with Decreased Risk of Chronic Graft-Versus-Host Disease without Impact on Survival after Allogeneic Peripheral Blood Stem Cell Transplantation for Adults with Philadelphia-Positive Acute Lymphoblastic Leukemia: An Analysis By the Acute Leukemia Working Party of the EBMT
Authors: Sebastian Giebel, Myriam Labopin, Mohammad Jahani, Didier Blaise, Péter Reményi, Gerard Socie, Nathalie Fegueux, Jakob R. Passweg, Xavier Poire, Charles Craddock, Kroger Nicolaus, Boris Afanasiev, Michael Potter, Jan J Cornelissen, Patrice Chevallier, Dietrich W Beelen, Renate Arnold, Jordi Esteve, Mohamad Mohty, Arnon Nagler
Journal: Blood (2017)
Implications of metabolism-driven myeloid dysfunctions in cancer therapy
Authors: Laura Strauss, Valentina Guarneri, Alessandra Gennari, Antonio Sica
Journal: Cellular and Molecular Immunology (2020)

Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses. In chronic inflammatory states, including cancer, this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils, macrophages, and dendritic cells (DCs), thus giving rise to a decline in the antitumor effector lymphoid response. Cancer-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors, resulting in unresolved and chronic inflammation. This pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool, which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor site. Therefore, persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer, as well as to the severity of a broad range of diseases, including metabolic syndrome and autoimmune and infectious diseases. The aims of this review are to (1) define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients, (2) discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes, and (3) explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor immunity. We propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects (irAEs) for current therapeutic strategies, including immune checkpoint inhibitor (ICI) therapy.
COVID-19 in patients with cancer: managing a pandemic within a pandemic
Authors: Leora Horn, Marina Garassino
Journal: Nature Reviews Clinical Oncology (2020)

The coronavirus disease 2019 (COVID-19) pandemic has disrupted health care worldwide. Patients with cancer seem to be particularly susceptible to morbidities and mortality from this novel disease. No COVID-19-specific therapy currently seems to offer a survival benefit to this unique patient population. Furthermore, the global effects on routine cancer care will likely be felt for decades to come.
Application of CRISPR-Cas9-Mediated Genome Editing for the Treatment of Myotonic Dystrophy Type 1
Authors: Seren Marsh, Britt Hanson, Matthew J.A. Wood, Miguel A. Varela, Thomas C. Roberts
Journal: Molecular Therapy (2020)

Myotonic dystrophy type 1 (DM1) is a debilitating multisystemic disorder, caused by expansion of a CTG microsatellite repeat in the 3' untranslated region of the DMPK (dystrophia myotonica protein kinase) gene. To date, novel therapeutic approaches have focused on transient suppression of the mutant, repeat-expanded RNA. However, recent developments in the field of genome editing have raised the exciting possibility of inducing permanent correction of the DM1 genetic defect. Specifically, repurposing of the prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) system has enabled programmable, site-specific, and multiplex genome editing. CRISPR-based strategies for the treatment of DM1 can be applied either directly to patients, or indirectly through the ex vivo modification of patient-derived cells, and they include excision of the repeat expansion, insertion of synthetic polyadenylation signals upstream of the repeat, steric interference with RNA polymerase II procession through the repeat leading to transcriptional downregulation of DMPK, and direct RNA targeting of the mutant RNA species. Potential obstacles to such therapies are discussed, including the major challenge of Cas9 and guide RNA transgene/ribonuclear protein delivery, off-target gene editing, vector genome insertion at cut sites, on-target unintended mutagenesis (e.g., repeat inversion), pre-existing immunity to Cas9 or AAV antigens, immunogenicity, and Cas9 persistence.
RNA-Binding RING E3-Ligase DZIP3/hRUL138 Stabilizes Cyclin D1 to Drive Cell-Cycle and Cancer Progression
Authors: Srinivasa P. Kolapalli, Rinku Sahu, Nishant R. Chauhan, Kautilya K. Jena, Subhash Mehto, Saroj K. Das, Ashish Jain, Manaswini Rout, Rupesh Dash, Rajeeb K. Swain, David Y. Lee, Tor Erik Rusten, Santosh Chauhan, Swati Chauhan
Journal: Cancer Research (2020)

Abstract DZIP3/hRUL138 is a poorly characterized RNA-binding RING E3-ubiquitin ligase with functions in embryonic development. Here we demonstrate that DZIP3 is a crucial driver of cancer cell growth, migration, and invasion. In mice and zebrafish cancer models, DZIP3 promoted tumor growth and metastasis. In line with these results, DZIP3 was frequently overexpressed in several cancer types. Depletion of DZIP3 from cells resulted in reduced expression of Cyclin D1 and a subsequent G1 arrest and defect in cell growth. Mechanistically, DZIP3 utilized its two different domains to interact and stabilize Cyclin D1 both at mRNA and protein levels. Using an RNA-binding lysine-rich region, DZIP3 interacted with the AU-rich region in 3′ untranslated region of Cyclin D1 mRNA and stabilized it. Using a RING E3-ligase domain, DZIP3 interacted and increased K63-linked ubiquitination of Cyclin D1 protein to stabilize it. Remarkably, DZIP3 interacted with, ubiquitinated, and stabilized Cyclin D1 predominantly in the G1 phase of the cell cycle, where it is needed for cell-cycle progression. In agreement with this, a strong positive correlation of mRNA expression between DZIP3 and Cyclin D1 in different cancer types was observed. Additionally, DZIP3 regulated several cell cycle proteins by modulating the Cyclin D1–E2F axes. Taken together, this study demonstrates for the first time that DZIP3 uses a unique two-pronged mechanism in its stabilization of Cyclin D1 to drive cell-cycle and cancer progression. Significance: These findings show that DZIP3 is a novel driver of cell-cycle and cancer progression via its control of Cyclin D1 mRNA and protein stability in a cell-cycle phase-dependent manner.
MT-Associated Protein Dysfunction May Lead to Impaired Ppf of Megakaryocytes in Corticosteroid-Resistant/Relapse Immune Thrombocytopenia Patients
Authors: Chen-Cong Wang, Ya-Nan Wang, Qi Chen, Xiao Liu, Jia-Min Zhang, Jing Xue, Hai-Xia Fu, Xiaosu Zhao, Xiang-Yu Zhao, Yuan Kong, Ying-Jun Chang, Kai-Yan Liu, Xiao-Jun Huang, Xiaohui Zhang
Journal: Blood (2017)
Equity Is the Foundation of Adolescent-Friendly Health Care
Authors: Angela Diaz, Jeffrey W. Hutchinson
Journal: JAMA Pediatrics (2020)

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Burden of respiratory syncytial virus infection in community-dwelling older adults in Europe (RESCEU): an international prospective cohort study
Authors: Koos Korsten, Niels Adriaenssens, Samuel Coenen, Christopher Butler, Behnaz Ravanfar, Heather Rutter, Julie Allen, Ann Falsey, Jean-Yves Pirçon, Olivier Gruselle, Vincent Pavot, Charlotte Vernhes, Sunita Balla-Jhagjhoorsingh, Deniz Öner, Gabriela Ispas, Jeroen Aerssens, Vivek Shinde, Theo Verheij, Louis Bont, Joanne Wildenbeest
Journal: European Respiratory Journal (2020)

Background Respiratory syncytial virus (RSV) infection in older adults is recognised as an important health issue. We aimed to assess the community burden of RSV in Europe in older adults aged ≥60 years. Methods This international, prospective, observational cohort study is part of work by the REspiratory Syncytial virus Consortium in EUrope (RESCEU). Participants were recruited through general practitioners' (GPs) offices before two independent RSV seasons. Participants reported weekly about symptoms of acute respiratory tract infection (ARTI) during one RSV season. ARTI patients were tested for RSV during home visits and completed a daily symptom diary. RSV illness included PCR-confirmed ARTI and those showing seroconversion over the season. RSV ARTI was based on PCR alone ( ClinicalTrials.gov , NCT03621930 ). Results We recruited 1040 participants (527 in season 2017–2018 and 513 in season 2018–2019) with a median age of 75 years (range 60–100 years). Of these, 1023 (99%) lived independently at home at baseline. RSV illness incidence was 22 out of 527 (4.2%) and 37 out of 513 (7.2%) in the respective seasons. RSV illness did not affect frailty or cardiopulmonary status during the course of the study. No patients were hospitalised or died from RSV illness. In the 36 patients with PCR confirmed RSV ARTI, symptom duration averaged 19 days, while a doctor's visit took place in 11 out of 36 cases (31%). RSV ARTI could not be differentiated clinically from all other ARTIs based on symptoms. Conclusion This European study showed that RSV is prevalent in community-dwelling older adults and rarely causes severe disease. This suggests that watchful waiting, using a continuity of care approach to identify those who do need more intensive care, is often justified when RSV is suspected in family practice.
JAK2V617F myeloproliferative neoplasm eradication by a novel interferon/arsenic therapy involves PML
Authors: Tracy Dagher, Nabih Maslah, Valérie Edmond, Bruno Cassinat, William Vainchenker, Stéphane Giraudier, Florence Pasquier, Emmanuelle Verger, Michiko Niwa-Kawakita, Valérie Lallemand-Breitenbach, Isabelle Plo, Jean-Jacques Kiladjian, Jean-Luc Villeval, Hugues de Thé
Journal: The Journal of Experimental Medicine (2020)

Interferon α (IFNα) is used to treat JAK2V617F-driven myeloproliferative neoplasms (MPNs) but rarely clears the disease. We investigated the IFNα mechanism of action focusing on PML, an interferon target and key senescence gene whose targeting by arsenic trioxide (ATO) drives eradication of acute promyelocytic leukemia. ATO sharply potentiated IFNα-induced growth suppression of JAK2V617F patient or mouse hematopoietic progenitors, which required PML and was associated with features of senescence. In a mouse MPN model, combining ATO with IFNα enhanced and accelerated responses, eradicating MPN in most mice by targeting disease-initiating cells. These results predict potent clinical efficacy of the IFNα+ATO combination in patients and identify PML as a major effector of therapy, even in malignancies with an intact PML gene.
What is the risk of recurrent concussion in children and adolescents aged 5–18 years? A systematic review and meta-analysis
Authors: Jacqueline van Ierssel, Martin Osmond, Jemila Hamid, Margaret Sampson, Roger Zemek
Journal: British Journal of Sports Medicine (2020)

Objective We aimed to examine the risk of concussion in children with a previous history of concussion. Design Systematic review and meta-analysis. The primary outcome was number of children with and without a previous lifetime history of concussion who sustained a diagnosed concussion within each study period. Risk of bias was assessed using the Newcastle-Ottawa Scale. A random effects model was used to estimate a pooled risk ratio (RR) with corresponding 95% CIs; results were summarised in forest plots. Data sources Four electronic databases (MEDLINE, Embase, CINAHL, SPORTDiscus) and selected reference lists were searched (PROSPERO registration No CRD42019135462). Eligibility criteria Original English language peer-reviewed publications that compared concussion risk in children aged 5–18 years with and without a previous concussion history in which risk estimates were reported or able to be calculated. Results Of 732 identified studies, 7 studies representing 23 411 children (risk of bias range, 7–9; maximum possible score=9) were included for meta-analysis. Pooled risk of sustaining a concussion was more than three times greater in children with a previous concussion compared with those with no previous concussion (RR=3.64; 95% CI: 2.68 to 4.96; p&lt;0.0001; I 2 =90.55%). Unreported sex-stratified data precluded direct comparison of concussion risk in male versus female athletes. Conclusion Previously concussed children have four times the risk of sustaining a concussion compared with those with no previous concussion history. This should be a consideration for clinicians in return to sport decision-making. Future studies examining subsequent recurrent concussion in youth sports must consider sex differences.
FRI0198 The ultrastructure of the muscle coat of the gastric wall in a case of systemic sclerosis (ssc)
Authors: L Ibba Manneschi, A Del Rosso, A Tani, S Pacini, P Bechi, M Matucci Cerinic
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> In Systemic Sclerosis (SSc) the gastrointestinal (GI) involvement leads to hypomotility and dysphagia at esophageal level and severe constipation of the colon,<sup>1,2</sup> even if other segments of GI are known to be affected in subclinical form. <h3>Objectives</h3> Few studies have assessed the morphological features of the stomach in SSc. A 52 years old female with limited SSc from 1979, suffering from dysphagia, pyrosis, epigastric pain, gastro-esophageal reflux, in 1998, underwent to distal esophagectomy for Barrett?s oesophagus and, in 1999, to total gastrectomy with Roux y esophago-jejunal anastomosis. The stomach appeared very small, shrunken, its wall being stiff and increased in consistence. Samples were taken to study the ultrastructural modifications of the gastric wall and, in particular, the muscle coat. <h3>Methods</h3> Samples of the gastric anterior wall from fundus, corpus and antrum, along the greater curvature, were obtained. The specimens were fixed in 4% glutaraldehyde in 0,1 M phosphate buffer, postfixed in 1% osmium tetroxide in 0,1M phosphate buffer and routinely processed for transmission electron microscopic observation. The ultrathin sections (1 μm) were stained with uranyl acetate and alkaline bismuth subnitrate and observed under Jeol 1010 electron microscope. <h3>Results</h3> Wide focal areas of fibrosis, characterised by collagen fibres depositions, surrounding smooth muscle cells (SMC) were found. Many SMC were hypercontracted and/or showed a severe disarrangement of the myofilaments. Often, the dense bodies and the dense bands were thickened. Some SMC showed cytoplasmic vacuolisation and swollen mithocondria. Nerve bundles containing many axons were close to vessels and SMC. The axoplasms of nerve fibres were oedematous and poor in neurotubules and filaments, but the nerve endings close to SMC showed normal morphology, with the presence of synaptic vescicles, whose number was seldom decreased. Blood vessels were lined by intact endothelial cells, while the basement membrane appeared or thickened and laminated. The lumen was partially or completely occluded by erythrocytes and neutrophils. Inflammatory infiltrate as well, and many mast cells rich in granules or partially degranulated, were close to vessels and SMC. <h3>Conclusion</h3> In the muscle coat of stomach focal fibrosis, severe ultrastructural modification of SCM and mild nerve fibres involvement are evident, without signs of endothelial damage. <h3>References</h3> Russell LM, <i>et al</i>. Ultrastructure of the esophagus in scleroderma. Arthritis Rheum. 1982;25:1117–2 Malandrini A, <i>et al</i>. Autonomic nervous system ansd smooth muscle cell involvement in systemic sclerosis: ultrastructural study of three cases. J Rheumatol. 2000;27:1203–6