The colonic metabolites dihydrocaffeic acid and dihydroferulic acid are more effective inhibitors of in vitro platelet activation than their phenolic precursors

This work was funded by the Spanish Ministry of Economy and Competitivity (projects AGL2010- 18269 and AGL 2015-69986-R). G.B. is a FPI fellow (BES-2011-047476) granted with a bursary for short stays from MINECO (EEBB-I-14-08802). The Rowett Institute of Nutrition and Health receives funding from the Scottish Government Rural and Environment Science and Analytical Services (RESAS). The funding bodies had no involvement in the design and execution of the study.Peer reviewedPostprin

Characterizing the Neurobiological Mechanisms of Action of Exercise and Cognitive–Behavioral Interventions for Rheumatoid Arthritis Fatigue : a magnetic resonance imaging brain study

Open Access via the Wiley/JISC agreement Acknowledgements We would like to thank all the investigators from the original LIFT study, including Kathryn Martin, Lorna Aucott, Neeraj Dhaun, Emma Dures, Stuart R. Gray, Elizabeth Kidd, Vinod Kumar, Karina Lovell, Graeme MacLennan, Paul McNamee, John Norrie, Lorna Paul, Jon Packham, Stefan Siebert, Alison Wearden, and Gary Macfarlane, without whose work this research would not be possible. Furthermore, we thank all the participants who generously supported the LIFT trial. We also acknowledge the contribution of the Trial Steering Committee and Data Monitoring Committee, and Brian Taylor and Mark Forrest (Centre for Healthcare Randomised Trials [CHaRT], University of Aberdeen, Aberdeen, UK) for their technical assistance Funding This study was funded by the Chief Scientist Office (TCS/17/14) and Versus Arthritis (22092).Peer reviewe

Therapists’ experiences of remotely delivering cognitive-behavioural or graded-exercise interventions for fatigue: a qualitative evaluation

Objectives: Fatigue is a challenging feature of all inflammatory rheumatic diseases. LIFT (Lessening the Impact of Fatigue in inflammatory rheumatic diseases: a randomised Trial) included remotely delivered personalised exercise programme (PEP) or cognitive-behavioural approach (CBA) interventions. The aim of this nested qualitative evaluation was to understand rheumatology health professionals (therapists’) perspectives of delivering the interventions in the LIFT trial. Methods: A subgroup of therapists who had delivered the PEP and CBA interventions took part in semi-structured telephone interviews. Results: Seventeen therapists (13 women, 4 men) who delivered PEP (n = 8) or CBA (n = 9) interventions participated. Five themes were identified: In ‘The benefits of informative, structured training’, therapists described how they were able to practice their skills, and the convenience of having the LIFT manual to refer to. When ‘Getting into the swing of it’, supporting patients gave therapists the confidence to tailor the content of the manual to each patient. Clinical supervision supported therapists to gain feedback and request assistance when required. In ‘Delivering the intervention’ therapists reported that patients valued the opportunity to address their fatigue and challenge their own beliefs. ‘Challenges in delivering the LIFT intervention’ therapists struggled to work collaboratively with patients who lacked motivation or stopped engaging. Finally, ‘Lift developing clinical skills’ therapists gained confidence and professional satisfaction seeing patients’ fatigue improve. Conclusion: Findings support the value of skills training for rheumatology health professionals to deliver a remote fatigue management intervention tested in the LIFT trial. These insights can inform service provision and clinical practice Lay summary What does this mean for patients ? Fatigue can be a challenge in inflammatory rheumatic diseases (IRDs). The LIFT study (Lessening the Impact of Fatigue in inflammatory rheumatic diseases: a randomized Trial) explored interventions to support people with fatigue. These were: a cognitive-behavioural approach (CBA), a personalized exercise programme (PEP), or usual care. People with IRDs were chosen randomly to take part in seven sessions of CBA, seven sessions of PEP or usual care. All sessions (aside from the first PEP session) were delivered over the phone. The aim of this study was to explore therapists' experiences of delivering the intervention. Seventeen therapists (13 women and 4 men) took part; eight had delivered the PEP intervention, and 9 delivered the CBA intervention. Therapists who delivered LIFT told us they enjoyed the chance to practice their skills, and that the LIFT manual gave them the confidence to tailor the intervention to each patient. Clinical supervision was valued. Therapists also shared that LIFT improved their skills and they were happy to see patients' fatigue improve over time. These new results can inform clinical practice, and how services are provided

Characterising the neurobiological mechanisms of action of exercise and cognitive behavioural interventions for rheumatoid arthritis fatigue: an MRI brain study

Objective: Chronic fatigue is a major clinical unmet need among patients with rheumatoid arthritis (RA). Current therapies are limited to nonpharmacological interventions, such as personalized exercise programs (PEPs) and cognitive–behavioral approaches (CBAs); however, most patients still continue to report severe fatigue. To inform more effective therapies, we conducted a magnetic resonance imaging (MRI) brain study of PEPs and CBAs, nested within a randomized controlled trial (RCT), to identify their neurobiological mechanisms of fatigue reduction in RA. Methods: A subgroup of patients with RA (n = 90), participating in an RCT of PEPs and CBAs for fatigue, undertook a multimodal MRI brain scan following randomization to either usual care (UC) alone or in addition to PEPs and CBAs and again after the intervention (six months). Brain regional volumetric, functional, and structural connectivity indices were curated and then computed employing a causal analysis framework. The primary outcome was fatigue improvement (Chalder fatigue scale). Results: Several structural and functional connections were identified as mediators of fatigue improvement in both PEPs and CBAs compared to UC. PEPs had a more pronounced effect on functional connectivity than CBAs; however, structural connectivity between the left isthmus cingulate cortex (L-ICC) and left paracentral lobule (L-PCL) was shared, and the size of mediation effect ranked highly for both PEPs and CBAs (ßAverage = −0.46, SD 0.61; ßAverage = −0.32, SD 0.47, respectively). Conclusion: The structural connection between the L-ICC and L-PCL appears to be a dominant mechanism for how both PEPs and CBAs reduce fatigue among patients with RA. This supports its potential as a substrate of fatigue neurobiology and a putative candidate for future targeting

The effect of COVID19 public health restrictions on the health of people with musculoskeletal conditions and symptoms : the CONTAIN study

Funding This work was supported by Versus Arthritis [Grant Number: 20748] and the British Society for Rheumatology. The funding for the original studies included were from Versus Arthritis (MAmMOTH) and the British Society for Rheumatology (BSRBR-AS and BSR-PsA). Daniel Whibley is supported by a Versus Arthritis Foundation Fellowship [Grant Number 21742] Acknowledgements We are grateful to help from staff at the National Ankylosing Spondylitis Society and specifically to patient partners Lynne Laidlaw (for help with designing questionnaire) and Susan Davis (for commenting on the manuscript). The authors do not report any conflicts of interest. GJM conceived the idea for the study and all authors were involved in the detailed planning. MH, KK, EM-B and MB were responsible for obtaining ethics and research governance approvals. MB undertook the analysis which was independently verified by GTJ. GJM, with input from MB, drafted the manuscript, and all authors contributed important intellectual content via written comments. We thank Linda Dean for comments on the manuscript. Data Availability Statement The data within the article which relate to the collection of BSR register data are owned by the BSR – access to these data are subject to application being made to the BSR: Registers (rheumatology.org.uk) . For other data in the article, application can be made for access to the data by contacting the corresponding author.Peer reviewedPublisher PD

Remotely delivered cognitive-behavioural and personalised exercise interventions to lessen the impact of fatigue: a qualitative evaluation

Abstract Objectives Fatigue can be a disabling symptom of inflammatory rheumatic diseases (IRD). LIFT (Lessening the Impact of Fatigue in inflammatory rheumatic diseases: a randomised Trial) is a randomised trial of remotely delivered cognitive-behavioural approach (CBA) or personalised exercise programme (PEP) interventions, compared with usual care. The aim of this nested qualitative study was to evaluate participants’ experiences of taking part in the intervention, including their ideas about future service delivery. Methods Semi-structured telephone interviews with a subgroup of LIFT participants to discuss their views and experiences of the interventions. Results Forty-three participants (30 women) from six sites who had participated in CBA (n = 22) or PEP (n = 21) interventions took part. Five themes were identified in the thematic analysis: In ‘Not a miracle cure, but a way to better manage fatigue’, LIFT could not cure fatigue, however, most felt better able to manage after participating. Participants valued ‘Building a therapeutic relationship’ with the same therapist throughout the intervention. In ‘Structure, self-monitoring and being accountable’, participants liked the inclusion of goal setting techniques, and were motivated by reporting back to the therapist. After taking part in the interventions, participants felt ‘Better equipped to cope with fatigue’; more confident and empowered. Lastly, participants shared ideas for ‘A tailored programme delivered remotely’, including follow-up sessions; video calling; and group-based sessions for social support. Conclusion Many participants engaged with the LIFT interventions and reported benefits of taking part. This suggests an important future role for the remote delivery of fatigue self-management. Lay summary What does this research mean for patients? Fatigue can be a disabling symptom in inflammatory rheumatic diseases (IRDs). The LIFT Study (Lessening the Impact of Fatigue in inflammatory rheumatic diseases: a randomised Trial) looked at different interventions; a cognitive-behavioural approach (CBA), Personalised Exercise Programme (PEP), or usual care. CBA sessions addressed unhelpful thoughts and feelings. The PEP sessions supported people with IRDs to gradually increase their exercise levels. People with IRDs were randomly selected to take part in seven sessions of CBA, seven sessions of PEP, or usual care. All sessions except the first PEP session were delivered remotely by phone. The aim of this study was to explore people’s experiences of taking part. Forty-three people with IRDs (30 women, 13 men) were interviewed from six UK locations. Twenty-two took part in the CBA sessions, and twenty-one took part in PEP. People with IRDs who took part in LIFT told us about a range of benefits. These included feeling less fatigue and more confidence. Those in PEP told us they felt stronger. People with IRDs shared that they liked being able to talk about their fatigue with a supportive therapist. These are encouraging results for remotely-delivered research to support people with fatigue

Cost-effectiveness of cognitive behavioural and personalised exercise interventions for reducing fatigue in inflammatory rheumatic diseases

Acknowledgements The authors would like to thank all the participants who supported this trial. We acknowledge the contribution of the Trial Steering Committee and Data Monitoring Committee, and Brian Taylor and Mark Forrest (Centre for Healthcare Randomised Trials [CHaRT], University of Aberdeen, Aberdeen, UK) for their technical assistance. Funding: This work was supported by Versus Arthritis (formerly Arthritis Research UK) grant number 21175.Peer reviewe

SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice

Background: Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus. Results: Mouse global array data identified serpinA3N as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed serpinA3N expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (α1AC), the protein encoded by serpinA3, is localised to neurons and revealed that it is secreted into the media. SerpinA3N expression in N42 neurons is upregulated by palmitic acid and by leptin, together with IL-6 and TNFα, and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of serpinA3 in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of serpinA3N expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout (IL-1R1−/−) mice. Conclusions: These data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio