Maintaining musculoskeletal health using a behavioural therapy approach : a population-based randomised controlled trial (the MAmMOTH Study)

Acknowledgements: The study was funded by Arthritis Research UK (now Versus Arthritis) grant number: 20748. Costs for delivery of the intervention were provided by NHS Grampian, NHS Greater Glasgow and Clyde, and NHS Highland. The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. We acknowledge the contribution of the trial steering committee to the successful conduct of the study. The members were Professor Ernest Choy (Cardiff University), Professor Tamar Pincus (Royal Holloway, University of London) and Gordon Taylor (Bath University). We thank Brian Taylor and Mark Forrest from the Centre for Healthcare Randomised Trials (CHaRT) at the University of Aberdeen for their technical assistance and Professor Graeme MacLennan, Director of CHaRT, for methodological input. Professor John Norrie (originally University of Aberdeen now University of Edinburgh) and Dr. Majid Artus (originally Keele University, now the Osmaston surgery, Derbyshire) were study investigators at the time of grant award but subsequently left the study. We thank Kathy Longley (a representative of Fibromyalgia Action UK) for her input to the grant application and the project as well as from members of the public on the University of Aberdeen College of Life Sciences and Medicine Research Interest Group. The prioritisation of “Prevention of chronic pain” arose from a 2012 meeting of the Arthritis Research UK Clinical Study Group in Pain to which patients contributed.Peer reviewedPostprintsupplementary_datasupplementary_dat

Receiving Preferred Treatment not Associated with Positive Outcome in a Randomized Trial

Background: In a randomized trial of treatments for chronic widespread pain (CWP), participants were asked their treatment preference just prior to randomisation (baseline). This analysis examined whether treatment preference was associated with baseline factors and whether receiving a preferred treatment affected outcomes. Methods: The MUSICIAN trial was a 2 × 2 randomized trial of cognitive behavioural therapy (CBT) or exercise for people with CWP. Participants were randomly allocated to one of three active treatments [CBT (n = 112), exercise (n = 109), both exercise and CBT (n = 112)] or usual care (n = 109). Before allocation participants were asked, if they had a choice, which active treatment they would choose. A positive outcome was self-reported improvement in health of much or very much better 6, 9 and 30 months after entering the study. Associations between preference and baseline characteristics were examined, including age, gender, chronic pain grade (CPG), passive and active coping, fatigue, psychological distress, sleep problems and kinesiophobia. Differences in gender and CPG between preferences were tested by chi-square tests. For continuous variables, comparison was by analysis of variance and, where a difference was observed, Tukey’s honest significant difference was used to identify which preferences differed and then the standardized mean difference (d) with 95% CIs were calculated. Among those allocated to active treatments, logistic regression was used to calculate odds ratios, adjusted for factors associated with preference, with 95% CIs of positive outcome in those receiving their preferred treatment and not receiving preferred treatment as the referent group. Results: Of 442 participants, 144 (33%) expressed preference for exercise, 20 (5%) for CBT, 199 (45%) for combined exercise and CBT and 79 (18%) expressed no preference. Compared with females, males were more likely to prefer exercise only (44 vs 28%) and less likely to prefer combined treatment (35 vs 50%). Those preferring CBT, compared with those preferring exercise, were higher in passive coping [d = 0.9 (95% CI 0.41, 1.37)], fatigue [0.8 (0.34, 1.31)], psychological distress [0.7 (0.26, 1.21)], sleep problems [0.7 (0.18, 1.12)] and kinesiophobia [0.6 (0.17, 1.12)]. Those preferring CBT also had greater scores on passive coping than those preferring combined treatment [0.6 (95% CI 0.11, 1.03)] or no preference [0.5 (−0.01, 0.98)] and greater kinesiophobia than those with no preference [0.5 (−0.05, 0.95)]. Of participants allocated to CBT, exercise or combined treatment, 7, 39 and 50%, respectively, had a preference for their allocated treatment. There was no clear association between achieving a positive outcome and whether or not someone received their preferred treatment (see Table 1). Conclusion: Exercise and exercise combined with CBT were the most preferred treatments. Participants with specific preferences differed from each other with respect to factors which might influence outcome. However, receiving preferred treatment did not appear to influence treatment response. Disclosure statement: M.B. has received funding for the MUSICIAN Study from Arthritis Research UK. G.J.M. has received funding for the MUSICIAN Study from Arthritis Research UK. All other authors have declared no conflicts of interest

The Maintaining Musculoskeletal Health (MAmMOTH) Study: Protocol for a randomised trial of cognitive behavioural therapy versus usual care for the prevention of chronic widespread pain

Background Cognitive behavioural therapy (CBT) has been shown to improve outcomes for patients with fibromyalgia, and its cardinal feature chronic widespread pain (CWP). Prediction models have now been developed which identify groups who are at high-risk of developing CWP. It would be beneficial to be able to prevent the development of CWP in these people because of the high cost of symptoms and because once established they are difficult to manage. We will test the hypothesis that among patients who are identified as at high-risk, a short course of telephone-delivered CBT (tCBT) reduces the onset of CWP. We will further determine the cost-effectiveness of such a preventative intervention. Methods The study will be a two-arm randomised trial testing a course of tCBT against usual care for prevention of CWP. Eligible participants will be identified from a screening questionnaire sent to patients registered at general practices within three Scottish health boards. Those returning questionnaires indicating they have visited their doctor for regional pain in the last 6 months, and who have two of, sleep problems, maladaptive behaviour response to illness, or high number of somatic symptoms, will be invited to participate. After giving consent, participants will be randomly allocated to either tCBT or usual care. We aim to recruit 473 participants to each treatment arm. Participants in the tCBT group will have an initial assessment with a CBT therapist by telephone, then 6 weekly sessions, and booster sessions 3 and 6 months after treatment start. Those in the usual care group will receive no additional intervention. Follow-up questionnaires measuring the same items as the screening survey questionnaire will be sent 3, 12 and 24 months after start of treatment. The main outcome will be CWP at the 12 month questionnaire. Discussion This will be the first trial of an intervention aimed at preventing fibromyalgia or CWP. The results of the study will help to inform future treatments for the prevention of chronic pain, and aetiological models of its development

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

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission

Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16–20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p

The electroanalytical applications of carbon nanotube-modified electrodes

THESIS 8621In this study, cyclic voltammetry, potential step chronoamperometry, batch amperometry, hydrodynamic voltammetry and electrochemical impedance spectroscopy were used to investigate the physical and chemical properties of glassy carbon macro-electrodes modified using HiPCo? single-walled carbon nanotubes. The latter were themselves characterised using atomic force microscopy, infrared and Raman spectroscopy and thermo-gravimetric analysis. The electrochemistry of redox-active functionalities present on the nanotube surface was probed. The modified electrodes were used to determine ferrocyanide, dopamine, epinephrine, norepinephrine, ascorbic acid, NADH, oxygen and hydrogen peroxide. Comparisons between the electro-catalytic properties of nanotubes and conventional graphite were also performed. The suitability of a number of different solvents for the dispersion and casting of nanotubes was evaluated

Effect of external magnetic fields on electron transfer and ion pairing dynamics at ferrocenyl alkane thiol SAM/solution interfaces

The redox behaviour of ferrocene alkane thiol self assembled monolayer modified electrodes in contact with aqueous perchlorate solutions both in the absence of and in the presence of an external magnetic field is examined using both electrochemical and gravimetric techniques The redox switching process involves an ET reaction involving the ferrocene/ferricinium redox transition coupled with an ion pairing step involving perchlorate ion. The voltammetric response recorded in the latter medium is irreversibly effected by the imposition of a static magnetic field of magnitude 0.5 T applied in a direction parallel to the electrode surface. The magnetic field dependence of the redox behaviour is attributed to structural changes in the monolayer arising from double layer effects involving changes in the spatial distribution of perchlorate counterions at the monolayer/solution interface, brought about by local convective stirring arising from the B field generated magnetohydrodynamic Lorenz body force

The Redox Behaviour of Randomly Dispersed Single Walled Carbon Nanotubes both in the Absence and in the Presence of Adsorbed Glucose Oxidase

The electrochemical behaviour of SWCNTs randomly dispersed on gold and glassy carbon electrode surfaces was characterised via cyclic voltammetry and complex impedance spectroscopy, using the ferri/ferrocyanide couple as a redox active test probe . In subsequent investigations glucose oxidase (GOx) was adsorbed onto the SWCNT ensemble without apparent denaturation of the enzyme. Cyclic voltammetry and potential step chronoamperometry were used to quantify and understand the process of electron transfer between the immobilised protein redox site and the working electrode. The effect of pH on the system was also investigated. In particular, we have shown that, for the calculation of electron transfer rate constants for surface-immobilised redox systems, chronoamperometry is preferable to voltammetry, which has been the technique of choice until now