Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial

National Institute for Health Research Health Technology Assessment (NIHR HTA) programme (project No 06/303/84)

Practitioners' Perceptions of the Soccer Extra-Time Period: Implications for Future Research

Qualitative research investigating soccer practitioners’ perceptions can allow researchers to create practical research investigations. The extra-time period of soccer is understudied compared to other areas of soccer research. Using an open-ended online survey containing eleven main and nine sub questions, we gathered the perceptions of extra-time from 46 soccer practitioners, all working for different professional soccer clubs. Questions related to current practices, views on extra-time regulations, and ideas for future research. Using inductive content analysis, the following general dimensions were identified: ‘importance of extra-time’, ‘rule changes’, ‘efficacy of extra-time hydro-nutritional provision’, ‘nutritional timing’, ‘future research directions’, ‘preparatory modulations’ and ‘recovery’. The majority of practitioners (63%) either agreed or strongly agreed that extra-time is an important period for determining success in knockout football match-play. When asked if a fourth substitution should be permitted in extra-time, 67% agreed. The use of hydro-nutritional strategies prior to extra-time was predominately considered important or very important. However; only 41% of practitioners felt that it was the most important time point for the use of nutritional products. A similar number of practitioners account (50%) and do not (50%) account for the potential of extra-time when training and preparing players and 89% of practitioners stated that extra-time influences recovery practices following matches. In the five minute break prior to extra-time, the following practices (in order of priority) were advocated to players: hydration, energy provision, massage, and tactical preparations. Additionally, 87% of practitioners advocate a particular nutritional supplementation strategy prior to extra-time. In order of importance, practitioners see the following as future research areas: nutritional interventions, fatigue responses, acute injury risk, recovery modalities, training paradigms, injury epidemiology, and environmental considerations. This study presents novel insight into the practitioner perceptions of extra-time and provides information to readers about current applied practices and potential future research opportunities

High sensitivity organic inorganic hybrid X-ray detectors with direct transduction and broadband response

X-ray detectors are critical to healthcare diagnostics, cancer therapy and homeland security, with many potential uses limited by system cost and/or detector dimensions. Current X-ray detector sensitivities are limited by the bulk X-ray attenuation of the materials and consequently necessitate thick crystals (~1 mm-1 cm), resulting in rigid structures, high operational voltages and high cost. Here we present a disruptive, flexible, low cost, broadband, and high sensitivity direct X-ray transduction technology produced by embedding high atomic number bismuth oxide nanoparticles in an organic bulk heterojunction. These hybrid detectors demonstrate sensitivities of 1712 µC mGy-1 cm-3 for "soft" X-rays and ~30 and 58 µC mGy-1 cm-3 under 6 and 15 MV "hard" X-rays generated from a medical linear accelerator; strongly competing with the current solid state detectors, all achieved at low bias voltages (-10 V) and low power, enabling detector operation powered by coin cell batteries

Half-Time Strategies to Enhance Second-Half Performance in Team-Sports Players: A Review and Recommendations

The competitive demands of numerous intermittent team sports require that two consecutive periods of play are separated by a half-time break. Typically, half-time allows players to: return to the changing rooms, temporarily relax from the cognitive demands of the first half of match-play, rehydrate, re-fuel, attend to injury or equipment concerns, and to receive tactical instruction and coach feedback in preparation for the second half. These passive practices have been associated with physiological changes which impair physical and cognitive performance in the initial stages of the second half. An increased risk of injury has also been observed following half-time. On the day of competition, modification of half-time practices may therefore provide Sports Scientists and Strength and Conditioning Coaches with an opportunity to optimise second half performance. An overview of strategies that may benefit team sports athletes is presented; specifically, the efficacy of: heat maintenance strategies (including passive and active methods), hormonal priming (through video feedback), post-activation potentiation, and modified hydro-nutritional practices are discussed. A theoretical model of applying these strategies in a manner that compliments current practice is also presented

Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases

Agents which increase intracellular cyclic adenosine monophosphate (cAMP) may have an antagonistic effect on pro-inflammatory molecule production so that inhibitors of the cAMP degrading phosphodiesterases have been identified as promising drugs in chronic inflammatory disorders. Although many such inhibitors have been developed, their introduction in the clinic has been hampered by their narrow therapeutic window with side effects such as nausea and emesis occurring at sub-therapeutic levels. The latest generation of inhibitors selective for phosphodiesterase 4 (PDE4), such as apremilast and roflumilast, seems to have an improved therapeutic index. While roflumilast has been approved for the treatment of exacerbated chronic obstructive pulmonary disease (COPD), apremilast shows promising activity in dermatological and rheumatological conditions. Studies in psoriasis and psoriatic arthritis have demonstrated clinical activity of apremilast. Efficacy in psoriasis is probably equivalent to methotrexate but less than that of monoclonal antibody inhibitors of tumour necrosis factor (TNFi). Similarly, in psoriatic arthritis efficacy is less than that of TNF inhibitors. PDE4 inhibitors hold the promise to broaden the portfolio of anti-inflammatory therapeutic approaches in a range of chronic inflammatory diseases which may include granulomatous skin diseases, some subtypes of chronic eczema and probably cutaneous lupus erythematosus. In this review, the authors highlight the mode of action of PDE4 inhibitors on skin and joint inflammatory responses and discuss their future role in clinical practice. Current developments in the field including the development of topical applications and the development of PDE4 inhibitors which specifically target the subform PDE4B will be discussed

Assessing the effectiveness of synthetic and biologic disease-modifying antirheumatic drugs in psoriatic arthritis – a systematic review

Gabrielle H Kingsley, David L Scott Rheumatology Unit, Kings College London, London, UK Background: Psoriatic arthritis is an inflammatory arthritis the primary manifestations of which are locomotor and skin disease. Although a number of guidelines have been published citing strategies for reducing disease progression, the evidence base for disease-modifying agents is unclear. This forms the focus of this systematic review. Methods: The systematic review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 checklist. We selected randomized controlled trials (RCTs) that looked at the impact of interventions with disease-modifying agents, either synthetic drugs or biologics on musculoskeletal outcomes, notably American College of Rheumatology 20 percent responders. Results were analyzed using Review Manager 5.1.6 (Cochrane Collaboration, Oxford, UK). Whilst our primary focus was on published trials, we also looked at new trials presented in abstract form in 2013–2014 that were not yet published to avoid omitting important and up-to-date information on developing treatments. Results: Our in-depth analysis included 28 trials overall enrolling 5,177 patients published between the 1980s and now as well as limited analysis of some studies in abstract form as described earlier. The most frequently available locomotor outcome measure was the American College of Rheumatology 20 percent responders. The risk ratio for achieving an American College of Rheumatology 20 percent responders response was positive in favor of treatment (risk ratio 2.30; 95% confidence interval 1.78–2.96); however, there was evidence of considerable heterogeneity between trials. Overall randomized controlled trials of established synthetic disease-modifying agents were largely negative (methotrexate, ciclosporin and sulfasalazine) though leflunomide showed a small positive effect. A new synthetic agent, apremilast, did show a positive benefit. For biologics, TNF inhibitors already licensed for use were effective and similar benefits were seen with newer agents including ustekinumab, secukinumab, brodalumab, and abatacept, although the latter did not impact on skin problems. Important limitations of the systematic review included, first, the fact that for many agents there were little data and, second, much of the recent data for newer biologics were only available in abstract form. Conclusion: Conventional disease-modifying agents, with the possible exception of leflunomide, do not show clear evidence of disease-modifying effects in psoriatic arthritis, though a newer synthetic disease-modifying agents, apremilast, appears more effective. Biologic agents appear more beneficial, although more evidence is required for newer agents. This review suggests that it may be necessary to review existing national and international management guidelines for psoriatic arthritis. Keywords: psoriatic arthritis, disease-modifying antirheumatic drugs, biologic

Current concepts and new developments in the treatment of psoriatic arthritis

OBJECTIVES: Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis with psoriasis. Many agents have been proposed for the treatment of PsA, but their use is based more on clinical experience than on sound scientific evidence. METHODS: We reviewed MedLine up to November 2002, searching for 'psoriatic arthritis', 'drug therapy, 'controlled trials' and 'outcomes' and all possible acronyms for these terms. All relevant papers were then examined in detail. RESULTS: PsA is a condition that runs a variable clinical course. Mild forms can usually be controlled by non-steroidal anti-inflammatory drugs (NSAIDs). Intra-articular glucocorticoid injections are indicated in patients with persistent mono- or oligoarthritis. Patients with severe and progressive articular disease not responsive to NSAIDs should be treated with disease-modifying anti-rheumatic drugs (DMARDs) to prevent joint damage and disability. Currently, methotrexate and sulphasalazine are considered the DMARDs of choice, but the evidence for the use of methotrexate in PsA is still largely empirical, while the clinical benefit induced by sulphasalazine appears to be modest. Other DMARDs proposed for the treatment of PsA include cyclosporin, gold salts and, more recently, leflunomide. However, none of the DMARDs available to date are effective in the treatment of psoriatic pelvispondylitis; in addition, a number of patients with severe peripheral arthritis fail to respond to standard DMARDs. Recently, tumour necrosis factor alpha inhibitors have proved effective in many PsA patients with pelvispondylitis or recalcitrant peripheral synovitis. CONCLUSIONS: None of the current treatments for PsA is curative, but significant clinical amelioration can be achieved in the vast majority of patients. Identification and prompt treatment of patients with severe articular disease is crucial for the achievement of a satisfactory clinical response and the improvement of the long-term outcome