6,487 research outputs found
Nash Equilibrium Strategies in Discrete-Time Finite-Horizon Dynamic Games with Risk-and Effort-Averse Players
No full textThe objective of this paper is to re-examine the risk-and effort attitude in the context of strategic dynamic interactions stated as a discrete-time finite-horizon Nash game. The analysis is based on the assumption that players are endogenously risk-and effort-averse. Each player is characterized by distinct risk-and effort-aversion types that are unknown to his opponent. The goal of the game is the optimal risk-and effort-sharing between the players. It generally depends on the individual strategies adopted and, implicitly, on the the players' types or characteristics.Dynamic Nash game, optimal path, closed-loop control, endogenous risk-and effort-aversion, adaptive risk-and effort management, optimal risk-and effort-sharing.
2019 update: EULAR RA management recommendations, efficacy and safety systematic literature reviews
No full textThis issue of the journal contains the latest update of the European League Against Rheumatism, Rheumatoid Arthrits (EULAR RA) management recommendations as well as the efficacy and safety systematic literature reviews representing an enormous amount of work by a dedicated team. As we enter a new decade, it is timely to consider the utility and worth of this extensive endeavour.No Full Tex
Comorbidities in RA: bringing them to the limelight
No full textIt is invigorating, to say the least, witnessing rheumatology live through an unprecedented era of ground-breaking innovations, bringing new hope to people living with chronic and often debilitating rheumatic and musculoskeletal diseases (RMDs). The importance of accurate and early diagnosis and treatment is now well-recognised across the community and core to new and more effective treatment approaches including treat-to-target strategies, as first described in rheumatoid arthritis (RA) [1].No Full Tex
What have we learnt from the inhibition of IL-6 in RA and what are the clinical opportunities for patient outcomes?
No full textRheumatoid arthritis (RA) is an autoimmune disease characterised by persistent inflammation of the synovial joints as well as other tissues and organs. Left untreated, it can lead to joint damage, disability and even increased mortality. The disease is driven by inflammatory cytokines that contribute to the chronic inflammation seen in RA. Interleukin-6 (IL-6) is a key pathological cytokine and a target for treatments aiming to alleviate local and systemic inflammation. Despite advances in understanding RA and the introduction of new treatments, achieving sustained remission remains challenging. This review explores the role of IL-6 in RA pathogenesis, its potential as a treatment target and the significance of personalised medicine in RA management. IL-6 has a dual signalling mechanism, classical and trans-signalling, which influences various intracellular pathways. While several targeted therapies have emerged, no single mechanism-based therapy is universally effective due to the diversity and complexity of the disease. Different approaches to targeting IL-6 have been tested, including biologic blockade of receptors or ligands, and inhibition of IL-6 signalling. IL-6 receptor inhibitors have been validated as RA therapeutics, either alone or in combination with other treatments. Tocilizumab, the first approved IL-6 inhibitor, blocks both soluble and membrane-bound IL-6 receptors, reducing the inflammatory cascade. Clinical trials confirm the efficacy and safety of tocilizumab and its role as a treatment option for patients unresponsive to conventional therapies. The benefits of IL-6 inhibition extend beyond reduced joint inflammation to the amelioration of comorbidities like anaemia, cardiovascular disease, depression and osteoporosis. Tailoring treatment to patients’ profiles and comorbidities is essential for optimal outcomes. A ‘treat-to-profile’ approach, focusing on a holistic view of the patient, could improve personalised medicine strategies. Biosimilars – lower-cost alternatives to biologics – further enhance the accessibility and cost-effectiveness of treatment. IL-6 inhibitors present a valuable treatment option for RA management, particularly for patients with specific comorbidities.Full Tex
Rayleigh number dependence of the Archimedes number dependent large-scale flow structure formation in mixed convection
No full textWe report on experimental investigations of large-scale flow structure formation in mixed convection. We characterize the flow field by measuring the velocity fields within a rectangular model room using 2D2C PIV. The control parameters are the Reynolds number Re, the Rayleigh number Ra and the Prandtl number Pr. All parameters are linked through the Archimedes number Ar. In 6.4x10-2 ≤ Ar ≤ 1.39x101, 4.2x103 ≤ Re ≤ 6.35x104 and Ra = 3.1x107, Ra = 1.8x108 and Pr = 0.713 we found flow 3 different flow structures. While keeping Ra and Pr constant and varying Ar through Re variations, we found an Ar dependence of the largescale flow structure formation within 6.4x10-2 ≤ Ar ≤ 1.39x101. Furthermore, we found a Ra dependence of the structure formation, which shifts the transition points between the structures to higher Archimedes numbers and reduces the mean velocities within the investigated domain
Real-world Evidence Needs Careful Interpretation (Editorial)
No full textThe Janus kinase (JAK) inhibitors have proven to be popular across the globe for an increasing variety of autoimmune inflammatory disorders seen in rheumatology, dermatology, and gastroenterology1. In patients with rheumatoid arthritis (RA), market share is on the rise in many countries, with 4 or 5 JAK inhibitors available or under development, and most patient categories are comprehensively studied, such as methotrexate (MTX)-naïve, MTX-inadequate responders, biological disease-modifying antirheumatic drug (bDMARD)–inadequate responders, and monotherapy, in large randomized controlled trials (RCT) that have shown efficacy with a manageable safety profile.No Full Tex
Serum oxidative stress markers and lipidomic profile to detect NASH patients responsive to an antioxidant treatment: a pilot study.
No full textLiver steatosis can evolve to steatohepatitis (NASH) through a series of biochemical steps related to oxidative stress in hepatocytes. Antioxidants, such as silybin, have been proposed as a treatment of patients with nonalcoholic fatty liver disease (NAFLD) and NASH. In this study, we evaluated, in patients with histologically documented NASH, the oxidant/antioxidant status and lipid "fingerprint" in the serum of NASH patients, both in basal conditions and after 12 months of treatment with silybin-based food integrator Realsil (RA). The oxidant/antioxidant status analysis showed the presence of a group of patients with higher basal severity of disease (NAS scores 4.67 ± 2.5) and a second group corresponding to borderline NASH (NAS scores = 3.8 ± 1.5). The chronic treatment with RA changed the NAS score in both groups that reached the statistical significance only in group 2, in which there was also a significant decrease of serum lipid peroxidation. The lipidomic profile showed a lipid composition similar to that of healthy subjects with a restoration of the values of free cholesterol, lysoPC, SM, and PC only in group 2 of patients after treatment with RA. Conclusion. These data suggest that lipidomic and/or oxidative status of serum from patients with NASH could be useful as prognostic markers of response to an antioxidant treatment
How Can We Improve the Use of Established Therapies in PsA?
No full textJust because nobody complains it doesn’t mean all parachutes are perfect. — Benny Hill
While there has been an expansion in therapeutic targets and a renaissance of novel therapies in psoriatic arthritis (PsA)1, the efficacy and safety of tumor necrosis factor inhibitors (TNFi) in PsA have long been established2,3. With an influx of “cheaper” biosimilars attractive to regulators and reimbursers, it behooves rheumatologists spoiled with choice to maximize efficient use of readily accessible agents.
Immunogenicity due to anti-drug antibodies (ADAb) in TNFi therapy has been shown to affect drug levels and subsequently to affect clinical response in rheumatoid arthritis (RA)4 and inflammatory bowel disease5. In turn it affects safety, inducing infusion and injection site reactions (ISR), but the issue has been less well studied in patients with PsA.No Full Tex
CXCR2 inhibition enables NASH-HCC immunotherapy
No full text\ua9 Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. Objective: Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy. Design: Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry. Results: Neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1+ dendritic cell activation and CD8+ T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8+ T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8+ T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs. Conclusion: CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC
Reynolds numbers near the ultimate state of turbulent Rayleigh-Bénard convection
No full textWe report on measurements of the mean-flow Reynolds number ReU and the rms fluctuation Reynolds number ReV in turbulent Rayleigh-Bénard convection as a function of the Rayleigh number Ra for 4 x 1011 < Ra < 2 1014 and Pr ' 0:8. Both can be described by the same power law with an effective exponent = 0:44, in agreement with predictions for ReU but in disagreement with predictions for ReV
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