Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 32965792 | Nuclear factor-κB in rheumatoid arthritis. | 2020 Dec | NF-κB (nuclear factor kappa light chain enhancer of activated B cells) signaling pathway is involved in the occurrence and development of various kinds of inflammation, including rheumatoid arthritis (RA). In this paper, the relationship between the activation or inhibition of NF-κB and the pathogenesis of RA is discussed. It is found that activated NF-κB operates a dual-aspect effect which can either promote or suppress inflammation. When NF-κB is inhibited, the symptoms of RA are significantly improved. The specific role of NF-κB is closely related to its upstream stimulator and downstream activator. Therefore, we review the research on NF-κB in RA over the past 20 years in order to have a clearer understanding of its mechanism. | |
| 32512739 | Anti-Citrullinated Protein Antibodies in Patients with Rheumatoid Arthritis: Biological Ef | 2020 Jun 4 | Individuals with high anti-citrullinated protein antibody (ACPA) titers have an increased risk of developing rheumatoid arthritis (RA). Although our knowledge of the generation and production of ACPAs has continuously advanced during the past decade, our understanding on the pathogenic mechanisms of how ACPAs interact with immune cells to trigger articular inflammation is relatively limited. Citrullination disorders drive the generation and maintenance of ACPAs, with profound clinical significance in patients with RA. The loss of tolerance to citrullinated proteins, however, is essential for ACPAs to exert their pathogenicity. N-linked glycosylation, cross-reactivity and the structural interactions of ACPAs with their citrullinated antigens further direct their biological functions. Although questions remain in the pathogenicity of ACPAs acting as agonists for a receptor-mediated response, immune complex (IC) formation, complement system activation, crystallizable fragment gamma receptor (FcγR) activation, cross-reactivity to joint cartilage and neutrophil extracellular trap (NET)-related mechanisms have all been suggested recently. This paper presents a critical review of the characteristics and possible biological effects and mechanisms of the immunopathogenesis of ACPAs in patients with RA. | |
| 32358156 | Ocular Manifestations in Rheumatoid Arthritis, Connective Tissue Disease, and Vasculitis: | 2021 Jan 1 | OBJECTIVE: Rheumatoid arthritis (RA) and other rheumatic diseases may present with ocular manifestations.The purpose of our work was to determine the prevalence and type of eye involvement in RA and other connective tissue diseases through a metaanalysis and literature review. METHODS: A systematic review of the literature was performed using Medline, Web of Science, and the Cochrane Library from their inceptions until January 7, 2019. Conjunctivitis, keratoconjunctivitis sicca, xeropthalmia, uveitis, eye hemorrhage, optic neuritis, papilledema, orbital disease, retinal artery/vein occlusion, macular edema, retinitis, chorioretinitis, scleritis, iridocyclitits, choroid hemorrhage, blindness, and amaurosis fugax were searched for prevalence in patients with RA, systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), dermatomyositis, polymyositis, systemic sclerosis, Sjögren syndrome (SS), undifferentiated connective tissue disease, giant cell arteritis, granulomatosis polyangiitis (GPA; formerly Wegener granulomatosis), systemic vasculitis, and sarcoidosis. RESULTS: There were 3394 studies identified and 65 included. The prevalence of eye involvement was 18% in RA, 26% in GPA, 27% in giant cell arteritis, 27% in sarcoidosis, 31% in SLE, and 35% in APS. The most common manifestation was dry eye syndrome ("dry eye"; keratoconjunctivitis sicca) in most diseases analyzed, with an especially high frequency of 89% in SS. Anterior and posterior uveitis were the most common ocular complications in sarcoidosis, occurring in 16% (95% CI 3-28) and 6% (95% CI 3-9) of patients, respectively. CONCLUSION: Eye involvement is present in approximately one-fifth of patients with RA, and a one-quarter to one-third of patients with connective tissue diseases (other than SS at 89%) and vasculitis. | |
| 32141950 | Skeletal muscle disease in rheumatoid arthritis: the center of cardiometabolic comorbiditi | 2020 May | PURPOSE OF REVIEW: Despite its critical roles in body movement, structure, and metabolism, skeletal muscle remains underappreciated in the context of rheumatoid arthritis. In rheumatoid arthritis, chronic inflammation, physical inactivity, and medication toxicities impair skeletal muscle. These skeletal muscle alterations contribute to continued rheumatoid arthritis disparities in physical function and cardiometabolic health. RECENT FINDINGS: In the prebiologic disease-modifying antirheumatic drug era, rheumatoid arthritis skeletal muscle atrophy was the central feature of 'rheumatoid cachexia,' a hypermetabolic state driven by chronic systemic inflammation and muscle protein degradation. In the current era, rheumatoid arthritis muscle deficits are less visible, yet persist as a key component of 'sarcopenic obesity.' In rheumatoid arthritis sarcopenic obesity, chronic inflammation, physical inactivity, and medication toxicities contribute to muscle contractile deficits, inflammation, altered metabolism, and intramuscular adiposity, a key predictor of rheumatoid arthritis disability and insulin resistance. SUMMARY: Rheumatoid arthritis skeletal muscle disease in the current era is defined by impaired contractile function (poor strength and endurance) and sarcopenic obesity (decreased muscle mass, increased fat mass, and intramuscular adiposity). These muscle impairments contribute to disability and cardiometabolic disease in rheumatoid arthritis. Management should focus on monitoring of rheumatoid arthritis muscle function and body composition, limiting potentially myotoxic drugs, and prescription of exercise training. | |
| 30963978 | Visfatin and Rheumatoid Arthritis: Pathogenetic Implications and Clinical Utility. | 2020 | OBJECTIVE: Analysis and generalization of data related to visfatin involvement in the pathogenesis of inflammation at various stages of rheumatoid arthritis. DATA SYNTHESIS: Visfatin is an adipocytokine which has also been identified in non-adipose tissues. It influences directly on the maturation of B cells, which are involved in autoantibody production and T cell activation. Visfatin can promote inflammation via regulation of pro-inflammatory cytokines including TNF, IL-1β and IL-6. The concentration of circulating visfatin in rheumatoid arthritis patients is higher compared to healthy individuals. Several studies suggest that visfatin level is associated with rheumatoid arthritis activity, and its elevation may precede clinical signs of the relapse. In murine collagen-induced arthritis, visfatin levels were also found to be elevated both in inflamed synovial cells and in joint vasculature. Visfatin blockers have been shown to confer fast and long-term attenuation of pathological processes; however, most of their effects are transient. Other factors responsible for hyperactivation of the immune system can participate in this process at a later stage. Treatment of rheumatoid arthritis with a combination of these blockers and inhibitors of other mediators of inflammation can potentially improve treatment outcomes compared to current therapeutic strategies. Recent advances in the treatment of experimental arthritis in mice as well as the application of emerging treatment strategies obtained from oncology for rheumatoid arthritis management could be a source of novel adipokine-mediated anti-rheumatic drugs. CONCLUSION: The ongoing surge of interest in anticytokine therapy makes further study of visfatin highly relevant as it may serve as a base for innovational RA treatment. | |
| 33244621 | Self-Management of Rheumatoid Arthritis: Mobile Applications. | 2020 Nov 26 | PURPOSE OF REVIEW: To review the self-management of rheumatoid arthritis (RA) using mobile applications. RECENT FINDINGS: Recent research supports that self-management not only can be an empowering behavior for an individual but also has been shown to improve health outcomes in RA. Mobile health applications are growing in popularity and adoption. Emerging evidence supports that using a mobile application for RA self-management may reduce disease activity and improve health outcomes. This review discusses mobile applications designed to improve self-management of RA as well as applications not specific to RA that also may be useful for self-management in this population. Future research should focus on the efficacy of mobile apps for health outcomes and ways to improve the adoption of and adherence to mobile apps in individuals with RA. | |
| 33346109 | Risk of venous thromboembolism in rheumatoid arthritis. | 2021 May | Rheumatoid arthritis (RA) is a chronic autoimmune joint disease with persistent systemic inflammation. Patients with RA suffer from joint pain and physical disability, but have their prognosis mostly driven by cardiovascular events, including venous thromboembolism (VTE). The risk of VTE is more than double in patients with RA compared with the general population. The incidence rate in patients with RA is estimated around 4 cases per 1000 person-years. The etiology of thrombotic tendency in RA is linked to various mechanisms and causal factors (antiphsolpholid antibodies, hyperhomocyteinemia, inflammation…): vascular injury, hypercoagulation, and venous stasis, the three components of the Virchow's triad, are activated in patients with RA. In clinical practice, situations that put patients for VTE should be identified (e.g., surgery, first year after RA diagnosis, hospitalization for acute illness…). Patients with RA are exposed to reversible risk factors, such as major surgery (knee or hip surgery) or hospitalization with immobilization. Similarly, uncontrolled RA, which is defined by the necessity to switch a biological disease-modifying anti-rheumatic drugs (DMARD), increases the incidence of VTE in observational studies. Moreover, DMARDs may impact the risk of VTE, especially in the time window after first prescription. Several biological DMARDs like tofacitinib have been associated with an increased risk of VTE. Therefore, patients with RA may require specific measures in terms of VTE diagnosis and management. In this review, we provide current insights into the pathophysiology, epidemiology, clinical considerations, and treatment strategies of VTE highlighting gaps in evidence and perspectives in patients with RA. | |
| 33036382 | Clinical Aspects of Janus Kinase (JAK) Inhibitors in the Cardiovascular System in Patients | 2020 Oct 7 | Janus kinase (JAK) inhibitors, a novel class of targeted synthetic disease-modifying antirheumatic drugs (DMARDs), have shown their safety and efficacy in rheumatoid arthritis (RA) and are being intensively tested in other autoimmune and inflammatory disorders. Targeting several cytokines with a single small compound leads to blocking the physiological response of hundreds of genes, thereby providing the background to stabilize the immune response. Unfortunately, blocking many cytokines with a single drug may also bring some negative consequences. In this review, we focused on the activity of JAK inhibitors in the cardiovascular system of patients with RA. Special emphasis was put on the modification of heart performance, progression of atherosclerosis, lipid profile disturbance, and risk of thromboembolic complications. We also discussed potential pathophysiological mechanisms that may be responsible for such JAK inhibitor-associated side effects. | |
| 31722515 | Roles of mast cells in rheumatoid arthritis. | 2020 Jan | Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory arthritis, and the complex interaction and activation of innate and adaptive immune cells are involved in RA pathogenesis. Mast cells (MCs) are one of the tissue-resident innate immune cells, and they contribute to RA pathogenesis. In the present review, the evidence of the pathologic role of MC in RA is discussed based on human and animal data. In addition, the potential role of MC in RA pathogenesis and the research area that should be focused on in the future are suggested. | |
| 30259381 | Atherosclerosis in Rheumatoid Arthritis: Promoters and Opponents. | 2020 Feb | Substantial epidemiological data identified cardiovascular (CV) diseases as a main cause of mortality in patients with rheumatoid arthritis (RA). In light of this, RA patients may benefit from additional CV risk screening and more intensive prevention strategies. Nevertheless, current algorithms for CV risk stratification still remain tailored on general population and are burdened by a significant underestimation of CV risk in RA patients. Acute CV events in patients with RA are largely related to an accelerated atherosclerosis. As pathophysiological features of atherosclerosis overlap those occurring in the inflamed RA synovium, the understanding of those common pathways represents an urgent need and a leading challenge for CV prevention in patients with RA. Genetic background, metabolic status, gut microbiome, and systemic inflammation have been also suggested as additional key pro-atherosclerotic factors. The aim of this narrative review is to update the current knowledge about pathophysiology of atherogenesis in RA patients and potential anti-atherosclerotic effects of disease-modifying anti-rheumatic drugs. | |
| 31144208 | Toll-Like Receptors, Infections, and Rheumatoid Arthritis. | 2020 Apr | Toll-like receptors (TLR) that belong to the group of protein recognition receptor (PPR) provide an innate immune response following the sensing of conserved pathogen-associated microbial patterns (PAMPs) and changes in danger-associated molecular patterns (DAMPs) that are generated as a consequence of cellular injury. Analysis of the TLR pathway has moreover offered new insights into the pathogenesis of rheumatoid arthritis (RA). Indeed, a dysfunctional TLR-mediated response characterizes RA patients and participates in establishment of a chronic inflammatory state. Such an inappropriate TLR response has been attributed (i) to the report of important alterations in the microbiota and abnormal responses to infectious agents as part of RA; (ii) to the abnormal presence of TLR-ligands in the serum and synovial fluid of RA patients; (iii) to the overexpression of TLR molecules; (iv) to the production of a large panel of pro-inflammatory cytokines downstream of the TLR pathway; and (v) to genetic variants and epigenetic factors in susceptible RA patients promoting a hyper TLR response. As a consequence, the development of promising therapeutic strategies targeting TLRs for the treatment and prevention of RA is emerging. | |
| 33146370 | Skeletal muscle redox signaling in rheumatoid arthritis. | 2020 Nov 13 | Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis and the presence of serum autoantibodies. In addition, skeletal muscle weakness is a common comorbidity that contributes to inability to work and reduced quality of life. Loss in muscle mass cannot alone account for the muscle weakness induced by RA, but instead intramuscular dysfunction appears as a critical factor underlying the decreased force generating capacity for patients afflicted by arthritis. Oxidative stress and associated oxidative post-translational modifications have been shown to contribute to RA-induced muscle weakness in animal models of arthritis and patients with RA. However, it is still unclear how and which sources of reactive oxygen and nitrogen species (ROS/RNS) that are involved in the oxidative stress that drives the progression toward decreased muscle function in RA. Nevertheless, mitochondria, NADPH oxidases (NOX), nitric oxide synthases (NOS) and phospholipases (PLA) have all been associated with increased ROS/RNS production in RA-induced muscle weakness. In this review, we aim to cover potential ROS sources and underlying mechanisms of oxidative stress and loss of force production in RA. We also addressed the use of antioxidants and exercise as potential tools to counteract oxidative stress and skeletal muscle weakness. | |
| 32802866 | Comprehensive Bioinformatics Analysis Reveals Hub Genes and Inflammation State of Rheumato | 2020 | Rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis, which has not been thoroughly cured yet, and standardized treatment is helpful for alleviating clinical symptoms. Here, various bioinformatics analysis tools were comprehensively utilized, aiming to identify critical biomarkers and possible pathogenesis of RA. Three gene expression datasets profiled by microarray were obtained from GEO database. Dataset GSE55235 and GSE55457 were merged for subsequent analyses. We identified differentially expressed genes (DEGs) in RStudio with limma package, performing functional enrichment analysis based on GSEA software and clusterProfiler package. Next, protein-protein interaction (PPI) network was set up through STRING database and Cytoscape. Moreover, CIBERSORT website was used to assess the inflammatory state of RA. Finally, we validated the candidate hub genes with dataset GSE77298. As a result, we identified 106 DEGs (72 upregulated and 34 downregulated genes). Through GO, KEGG, and GSEA analysis, we found that DEGs were mainly involved in immune response and inflammatory signaling pathway. With the help of Cytoscape software and MCODE plug-in, the most prominent subnetwork was screened out, containing 14 genes and 45 edges. For ROC curve analysis, eight genes with AUC >0.80 were considered as hub genes of RA. In conclusion, compared with healthy controls, the DEGs and their closely related biological functions were analyzed, and we held that chemokines and immune cells infiltration promote the progression of rheumatoid arthritis. Targeting the eight biomarkers we identified may be useful for the diagnosis and treatment of rheumatoid arthritis. | |
| 32515665 | Evaluating upadacitinib for the treatment of rheumatoid arthritis. | 2020 Sep | INTRODUCTION: The introduction of JAKs inhibitors for the treatment of rheumatoid arthritis represents a promising new era in the management of the disease. New compounds under investigation, like upadacitinib, with greater selectivity for JAK1 inhibition have recently been approved for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drugs. AREAS COVERED: Herein, the authors review the pharmacological data, the therapeutic efficacy, and safety data of upadacitinib before providing the reader with their critical evaluation and future perspectives. EXPERT OPINION: Upadacitinib was able to accomplish all the primary and secondary end points in most of the trials, with a safety profile that is similar to the other JAK inhibitors. It has also demonstrated superiority over a tumor necrosis factor inhibitor and data on new indications is also favorable. Upadacitinib is a promising new drug for the treatment of rheumatoid arthritis. GLOSSARY: Adalimumab: ADA; American College of Rheumatology: ACR; Assessment of Spondylarthritis International Society 40: ASAS40; Ankylosis Spondylitis: AS; Area under the Curve: AUC; Biological Disease-modifying arthritis drugs: bDMARDs; Clinical disease activity index: CDAI; C Reactive Protein: CRP; Conventional Synthetic Disease-modifying arthritis drugs: csDMARDs; Deep Venous Thrombosis: DVT; Disease arthritis score: DAS. | |
| 32920707 | ROS-Dependent Lipid Peroxidation and Reliant Antioxidant Ferroptosis-Suppressor-Protein 1 | 2021 Feb | Rheumatoid arthritis (RA) is a common systemic autoimmune disease with a prevalence of about 1% in which genetic and environmental risk factors both participate in performance of disease. Though several studies contributed in identifying its etiology and pathogenesis, the underlying mechanisms are still unknown. To date, so as palliative for RA, cure strategies are still popular. Hypoxia and oxidative stress are implicated to RA development and subsequent ROS-mediated cell death which is a critical feature for RA progression. As for cell death and lipid peroxidation, ferroptosis is a newly discovered, iron-dependent, and non-apoptotic cell death which draws various attention due to its potential strategies for cancer therapy. Meanwhile, ferroptosis-suppressor-protein 1 (FSP1) is recently identified as a seminal breakthrough owing to its property of versus ferroptosis. By virtue of the complicated research progress on FSP1 with ferroptosis, in this review, we summarize the whole region of relevance between ROS and RA. Taken together, we hypothesize that ROS accompanied with ferroptosis may function as a reciprocal with cell death that interplays with RA; besides, FSP1 might become a potential therapeutic target for RA because of its potential interaction with TNF-α/ROS-positive feedback loop. This review systematically concludes the previous understandings about identification of ROS and FSP1 and, in turn, aims to provide references for further achievements of them and hints on elucidation of its thorough underlying mechanisms. | |
| 33037539 | Cervical spine manifestations of rheumatoid arthritis: a review. | 2021 Aug | Rheumatoid arthritis (RA) is a progressive autoimmune inflammatory disease affecting 1% of the population with three times as many women as men. As many as 86% of patients suffering from RA have cervical spine involvement. Synovial inflammation in the cervical spine causes instability and injuries including atlantoaxial subluxation, retroodontoid pannus formation, cranial settling, and subaxial subluxation. While many patients with cervical spine involvement are asymptomatic, symptomatic patients often present with nonspecific symptoms resulting from inflammation and additional secondary symptoms that are due to compression of the brainstem, cranial nerves, vertebral artery, and spinal cord. Radiographs are the imaging modality used most often, while MRI and CT are used for assessment of neural element involvement and surgical planning. Multiple classification systems exist. Early diagnosis and treatment of cervical spine involvement is critical. Surgical management is indicated when patients experience symptoms from cervical involvement that result in biomechanical instability and, or a neurological deficit. Atlantoaxial instability managed with atlantoaxial fusion, retroodontoid pannus with neural element compression is managed with posterior decompression and atlantoaxial fusion or occipitocervical fusion. Cranial settling is managed can be managed with anterior decompression and posterior fusion or with dorsal only approaches. Subaxial subluxation is managed with circumferential fusion or posterior only decompression and fusion. Patients with atlantoaxial instability have better functional and neurologic outcomes. RA patients have higher complication rates and more frequent need for revision surgery than the general population of spine surgery patients. | |
| 33060323 | The Prevalence of Rheumatoid Arthritis: A Systematic Review of Population-based Studies. | 2021 May | OBJECTIVE: To estimate the prevalence of rheumatoid arthritis (RA) from international population-based studies and investigate the influence of prevalence definition, data sources, classification criteria, and geographical area on RA prevalence. METHODS: A search of ProQuest, MEDLINE, Web of Science, and EMBASE was undertaken to identify population-based studies investigating RA prevalence between 1980 and 2019. Studies were reviewed using the Joanna Briggs Institute approach for the systematic review and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Sixty studies met the inclusion criteria. There was a wide range of point prevalence reported (0.00-2.70%) with a mean of 0.56% (SD 0.51) between 1986 and 2014, and a mean period prevalence of 0.51% (SD 0.35) between 1955 and 2015. RA point and period prevalence was higher in urban settings (0.69% vs 0.48%) than in rural settings (0.54% vs 0.25%). An RA diagnosis validated by rheumatologists yielded the highest period prevalence of RA and was observed in linked databases (0.80%, SD 0.1). CONCLUSION: The literature reports a wide range of point and period prevalence based on population and method of data collection, but average point and period prevalence of RA were 51 in 10,000 and 56 in 10,000, respectively. Higher urban vs rural prevalence may be biased due to poor case findings in areas with less healthcare or differences in risk environment. The population database studies were more consistent than sampling studies, and linked databases in different continents appeared to provide a consistent estimate of RA period prevalence, confirming the high value of rheumatologist diagnosis as classification criteria. | |
| 33070253 | RANKL as a therapeutic target of rheumatoid arthritis. | 2021 Jan | Rheumatoid arthritis (RA) is an inflammatory disorder characterized by progressive joint destruction. Recent studies have demonstrated that osteoclasts are responsible for bone destruction in RA. Receptor activator of nuclear factor kappa B ligand (RANKL), an osteoclast differentiation factor, belongs to the tumor necrosis factor superfamily and plays a critical role in osteoclast differentiation. RANKL is highly expressed in the synovial tissues in patients with RA and is involved in osteoclast development and thus bone destruction in RA. Denosumab, a specific antibody to human RANKL, efficiently suppressed the progression of bone destruction in patients with RA in a randomized controlled study and is considered a putative therapeutic option for RA. | |
| 32016655 | Obesity and its role in the management of rheumatoid and psoriatic arthritis. | 2020 Apr | In the last decade, interest has been growing in the relationship between obesity and several other clinical conditions, besides the well-established links between body mass index (BMI) and cardiovascular diseases or cancer. A particular focus has been put on the impact of a higher BMI on immune-mediated diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Obesity has been found to be associated with greater arthritis activity and a reduced probability of response to anti-tumor necrosis factor (TNF) agents. On the other hand, weight loss increases the chances of treatment success. Although the direct effect of a higher body mass on drug clearance might in part account for this obesity-related effect, other biological mechanisms could be involved. The evidence of a negative influence of obesity on arthritis treatment is particularly strong as far as anti-TNF inhibition is concerned; on the contrary, the response to biologic agents targeting interleukin-6, cytotoxic T lymphocyte antigen 4, or CD20 seems not to be negatively affected by a higher BMI. In this review, we will consider the main studies investigating the influence of obesity on anti-rheumatic treatment in RA and PsA patients. We will also try to hypothesize about a possible pathogenic explanation of this phenomenon and its role in the choice of an appropriate and personalized therapy. | |
| 33079230 | Gaps between research and recommendations in rheumatoid arthritis. | 2021 Jan | OBJECTIVES: To identify recommendations on the diagnosis and management of rheumatoid arthritis (RA) supported by low recommendation grades, to study the causes of this low grading, and to propose solutions. METHODS: A group of six rheumatologists, with extensive experience in the development of systematic reviews, reviewed national and international RA recommendations and practice guidelines. They identified all recommendations with a low level of evidence or recommendation grade (levels equivalent to 4, 5, or grades C or D of the Oxford Levels of Evidence), classified them by areas (diagnosis, follow-up, treatment, others), and analyzed plausible causes of low graduation. A Delphi was used to select 10 recommendations where it was most important to obtain quality evidence to support them. Subsequently, actions were proposed to improve evidence and recommendation grading. RESULTS: Fourteen documents were analyzed, in which 192 recommendations with low evidence/grade of recommendation were identified, most of which were on treatment. The two most frequent causes of this low level are the absence of studies and the discrepancy between the wording of the recommendation and the evidence used. Finally, the proposed solution to the critical recommendations is a list of unanswered research questions and possible designs to answer them. CONCLUSIONS: We propose to design and promote research that truly supports or rectifies clinical practice and, thus, bridges the gap between existing evidence and critical recommendations. |