Tritiated ethylketocyclazocine binding in rat brain: Differential distribution of binding sites across brain regions

In rat brain, 3H-EKC shows a relative regional distribution of binding which parallels that of 3H-morphine. Dynorphin(1-13) has a pattern similar to morphine and dissimilar to EKC in displacing the three labels. Dynorphin(1-13) is more potent against 3H-morphine than against 3H-EKC across brain regions while [beta]-endorphin competes better against 3H-EKC.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23889/1/0000128.pd

Reducing arthritis fatigue impact: Two-year randomised controlled trial of cognitive behavioural approaches by rheumatology teams (RAFT)

© Author(s) (or their employer(s)) 2019. Objectives To see if a group course delivered by rheumatology teams using cognitive-behavioural approaches, plus usual care, reduced RA fatigue impact more than usual care alone. Methods Multicentre, 2-year randomised controlled trial in RA adults (fatigue severity>6/10, no recent major medication changes). RAFT (Reducing Arthritis Fatigue: Clinical Teams using CB approaches) comprises seven sessions, codelivered by pairs of trained rheumatology occupational therapists/nurses. Usual care was Arthritis Research UK fatigue booklet. Primary 26-week outcome fatigue impact (Bristol RA Fatigue Effect Numerical Rating Scale, BRAF-NRS 0-10). Intention-to-treat regression analysis adjusted for baseline scores and centre. Results 308/333 randomised patients completed 26 week data (156/175 RAFT, 152/158 Control). Mean baseline variables were similar. At 26 weeks, the adjusted difference between arms for fatigue impact change favoured RAFT (BRAF-NRS Effect-0.59, 95% CI -1.11 to -0.06), BRAF Multidimensional Questionnaire (MDQ) Total-3.42 (95% CI -6.44 to -0.39), Living with Fatigue-1.19 (95% CI -2.17 to -0.21), Emotional Fatigue-0.91 (95% CI -1.58 to -0.23); RA Self-Efficacy (RASE, +3.05, 95% CI 0.43 to 5.66) (14 secondary outcomes unchanged). Effects persisted at 2 years: BRAF-NRS Effect-0.49 (95% CI-0.83 to -0.14), BRAF MDQ Total-2.98 (95% CI-5.39 to -0.57), Living with Fatigue-0.93 (95% CI-1.75 to -0.10), Emotional Fatigue-0.90 (95% CI-1.44, to -0.37); BRAF-NRS Coping +0.42 (95% CI 0.08 to 0.77) (relevance of fatigue impact improvement uncertain). RAFT satisfaction: 89% scored ≥ 8/10 vs 54% controls rating usual care booklet (

Group cognitive–behavioural programme to reduce the impact of rheumatoid arthritis fatigue: The RAFT RCT with economic and qualitative evaluations

BACKGROUND: Fatigue is a major problem in rheumatoid arthritis (RA). There is evidence for the clinical effectiveness of cognitive-behavioural therapy (CBT) delivered by clinical psychologists, but few rheumatology units have psychologists. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of a group CBT programme for RA fatigue [named RAFT, i.e. Reducing Arthritis Fatigue by clinical Teams using cognitive-behavioural (CB) approaches], delivered by the rheumatology team in addition to usual care (intervention), with usual care alone (control); and to evaluate tutors' experiences of the RAFT programme. DESIGN: A randomised controlled trial. Central trials unit computerised randomisation in four consecutive cohorts within each of the seven centres. A nested qualitative evaluation was undertaken. SETTING: Seven hospital rheumatology units in England and Wales. PARTICIPANTS: Adults with RA and fatigue severity of ≥ 6 [out of 10, as measured by the Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scale (BRAF-NRS)] who had no recent changes in major RA medication/glucocorticoids. INTERVENTIONS: RAFT - group CBT programme delivered by rheumatology tutor pairs (nurses/occupational therapists). Usual care - brief discussion of a RA fatigue self-management booklet with the research nurse. MAIN OUTCOME MEASURES: Primary - fatigue impact (as measured by the BRAF-NRS) at 26 weeks. Secondary - fatigue severity/coping (as measured by the BRAF-NRS); broader fatigue impact [as measured by the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ)]; self-reported clinical status; quality of life; mood; self-efficacy; and satisfaction. All data were collected at weeks 0, 6, 26, 52, 78 and 104. In addition, fatigue data were collected at weeks 10 and 18. The intention-to-treat analysis conducted was blind to treatment allocation, and adjusted for baseline scores and centre. Cost-effectiveness was explored through the intervention and RA-related health and social care costs, allowing the calculation of quality-adjusted life-years (QALYs) with the EuroQol-5 Dimensions, five-level version (EQ-5D-5L). Tutor and focus group interviews were analysed using inductive thematic analysis. RESULTS: A total of 308 out of 333 patients completed 26 weeks (RAFT, n/N = 156/175; control, n/N = 152/158). At 26 weeks, the mean BRAF-NRS impact was reduced for the RAFT programme (-1.36 units; p

Important Treatment Outcomes for Patients with Psoriatic Arthritis: A Multisite Qualitative Study

© 2017, The Author(s). Background: Psoriatic arthritis (PsA) is a variable and complex inflammatory condition. Symptoms can compromise physical function, reduce quality of life, and accrue significant health costs. Commonly used patient-reported outcomes largely reflect the professionals’ perspective, however it is not known whether they capture what is important to patients. Objective: The aim of our study was to identify treatment outcomes important to patients with PsA. Methods: Eight focus groups that were audio recorded, transcribed, anonymised and analysed using inductive thematic analysis were conducted at five hospital sites. The full data set was analysed by the lead researcher, and subsets analysed by three team members (including patient partners). Results: Overall, 41 patients sampled for a range of phenotypes and domains of disease activity participated in the study: 20 males; mean age 58years (range 28–75, standard deviation [SD] 11.4); mean disease duration 9years (range 0.5–39, SD 8.3); and mean Health Assessment Questionnaire score of 1 (range 0.0–2.5, SD 0.7). Over 60 outcomes were identified and grouped into four themes: (i) symptom alleviation (e.g. pain, fatigue, itchy skin, swelling, and reducing variability); (ii) reduction of disease impact (e.g. tiredness and pain, mobility and dexterity, deteriorating physical fitness, negative emotional responses, and strained relationships and social interactions); (iii) improved prognosis (e.g. slowing down disease progression, maintaining independence, and enhancing quality of life); and (iv) minimisation of treatment harm and burden (e.g. nausea, long-term effects, and administration and monitoring of treatments). Conclusions: Outcomes from treatments that are important to patients, which relate to impacts from PsA and its treatment that range beyond those outcomes commonly measured, were identified. These patient perspectives need to be considered when evaluating treatments

International patient and physician consensus on a psoriatic arthritis core outcome set for clinical trials

© 2017 Published by the BMJ Publishing Group Limited. Objective To identify a core set of domains (outcomes) to be measured in psoriatic arthritis (PsA) clinical trials that represent both patients' and physicians' priorities. Methods We conducted (1) a systematic literature review (SLR) of domains assessed in PsA; (2) international focus groups to identify domains important to people with PsA; (3) two international surveys with patients and physicians to prioritise domains; (4) an international face-To-face meeting with patients and physicians using the nominal group technique method to agree on the most important domains; and (5) presentation and votes at the Outcome Measures in Rheumatology (OMERACT) conference in May 2016. All phases were performed in collaboration with patient research partners. Results We identified 39 unique domains through the SLR (24 domains) and international focus groups (34 domains). 50 patients and 75 physicians rated domain importance. During the March 2016 consensus meeting, 12 patients and 12 physicians agreed on 10 candidate domains. Then, 49 patients and 71 physicians rated these domains' importance. Five were important to >70% of both groups: musculoskeletal disease activity, skin disease activity, structural damage, pain and physical function. Fatigue and participation were important to >70% of patients. Patient global and systemic inflammation were important to >70% of physicians. The updated PsA core domain set endorsed by 90% of OMERACT 2016 participants includes musculoskeletal disease activity, skin disease activity, pain, patient global, physical function, health-related quality of life, fatigue and systemic inflammation. Conclusions The updated PsA core domain set incorporates patients' and physicians' priorities and evolving PsA research. Next steps include identifying outcome measures that adequately assess these domains

Human preferences for sexually dimorphic faces may be evolutionarily novel

A large literature proposes that preferences for exaggerated sex typicality in human faces (masculinity/femininity) reflect a long evolutionary history of sexual and social selection. This proposal implies that dimorphism was important to judgments of attractiveness and personality in ancestral environments. It is difficult to evaluate, however, because most available data come from large-scale, industrialized, urban populations. Here, we report the results for 12 populations with very diverse levels of economic development. Surprisingly, preferences for exaggerated sex-specific traits are only found in the novel, highly developed environments. Similarly, perceptions that masculine males look aggressive increase strongly with development and, specifically, urbanization. These data challenge the hypothesis that facial dimorphism was an important ancestral signal of heritable mate value. One possibility is that highly developed environments provide novel opportunities to discern relationships between facial traits and behavior by exposing individuals to large numbers of unfamiliar faces, revealing patterns too subtle to detect with smaller samples

Oral abstracts 1: SpondyloarthropathiesO1. Detecting axial spondyloarthritis amongst primary care back pain referrals

Background: Inflammatory back pain (IBP) is an early feature of ankylosing spondylitis (AS) and its detection offers the prospect of early diagnosis of AS. However, since back pain is very common but only a very small minority of back pain sufferers have ASpA or AS, screening of back pain sufferers for AS is problematic. In early disease radiographs are often normal so that fulfilment of diagnostic criteria for AS is impossible though a diagnosis of axial SpA can be made if MRI evidence of sacroiliitis is present. This pilot study was designed to indicate whether a cost-effective pick up rate for ASpA/early AS could be achieved by identifying adults with IBP stratified on the basis of age. Methods: Patients aged between 18 and 45 years who were referred to a hospital physiotherapy service with back pain of more than 3 months duration were assessed for IBP. All were asked to complete a questionnaire based on the Berlin IBP criteria. Those who fulfilled IBP criteria were also asked to complete a second short questionnaire enquiring about SpA comorbidities, to have a blood test for HLA-B27 and CRP level and to undergo an MRI scan of the sacroiliac joints. This was a limited scan, using STIR, diffusion-weighted, T1 and T2 sequences of the sacroiliac joints to minimize time in the scanner and cost. The study was funded by a research grant from Abbott Laboratories Ltd. Results: 50 sequential patients agreed to participate in the study and completed the IBP questionnaire. Of these 27 (54%) fulfilled criteria for IBP. Of these, 2 patients reported a history of an SpA comorbidity - 1 psoriasis; 1 ulcerative colitis - and 3 reported a family history of an SpA comorbidity - 2 psoriasis; 1 Crohn's disease. 4 were HLA-B27 positive, though results were not available for 7. Two patients had marginally raised CRP levels (6, 10 -NR ≤ 5). 19 agreed to undergo MRI scanning of the sacroiliac joints and lumbar spine; 4 scans were abnormal, showing evidence of bilateral sacroiliitis on STIR sequences. In all cases the changes met ASAS criteria but were limited. Of these 4 patients 3 were HLA-B27 positive but none gave a personal or family history of an SpA-associated comorbidity and all had normal CRP levels. Conclusions: This was a pilot study yielding only limited conclusions. However, it is clear that: Screening of patients referred for physiotherapy for IBP is straightforward, inexpensive and quick. It appears that IBP is more prevalent in young adults than overall population data suggest so that targeting this population may be efficient. IBP questionnaires could be administered routinely during a physiotherapy assessment. HLA-B27 testing in this group of patients with IBP is a suitable screening tool. The sacroiliac joint changes identified were mild and their prognostic significance is not yet clear so that the value of early screening needs further evaluation. Disclosure statement: C.H. received research funding for this study from Abbott. A.K. received research funding for this study, and speaker and consultancy fees, from Abbott. All other authors have declared no conflicts of interes

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes