Validation of a questionnaire for Central nervous system Aspects of joint Pain: the CAP questionnaire.

BACKGROUND AND AIMS: Neuropathic-like pain, fatigue, cognitive difficulty, catastrophising, anxiety, sleep disturbance, depression, and widespread pain associate with a single factor in people with knee pain. We report the Central Aspects of Pain questionnaire (CAP) to characterise this across painful musculoskeletal conditions. METHODS: CAP was derived from the 8 item CAP-Knee questionnaire, and completed by participants with joint pain in the Investigating Musculoskeletal Health and Wellbeing survey. Subgroups had osteoarthritis, back pain or fibromyalgia. Acceptability was evaluated by feedback and data missingness. Correlation coefficients informed widespread pain scoring threshold in relation to the other items, and evaluated associations with pain. Factor analysis assessed CAP structure. Intraclass Correlation Coefficient (ICC) between paper and electronic administration assessed reliability. Friedman test assessed score stability over 4 years in people reporting knee osteoarthritis. RESULTS: Data were from 3579 participants (58% female, median age; 71 years), including subgroups with osteoarthritis (n = 1158), back pain (n = 1292) or fibromyalgia (n = 177). Across the 3 subgroups, ≥10/26 painful sites on the manikin scored widespread pain. Reliability was high (ICC= 0.89 (95% CI: 0.84-0.92)) and CAP scores fit to 1 and 2 factor model, with a total CAP score that was associated with pain severity and quality (r = 0.50-0.72). In people with knee pain, CAP scores were stable over 4 years at the group level, but displayed significant temporal heterogeneity within individual participants. CONCLUSIONS: Central Aspects of Pain is reliably measured by the CAP questionnaire across a range of painful musculoskeletal conditions, and is a changeable state.

Feasibility of conducting a cohort randomised controlled trial assessing the effectiveness of a nurse-led package of care for knee pain.

OBJECTIVE: To evaluate the feasibility of conducting a cohort randomised-controlled trial (RCT) of a nurse-led package of care for knee pain and determine treatment sequence for use in a future trial. METHODS: Open label, three-arm, single-centre, mixed-methods, feasibility cohort RCT. Adults aged ≥40 years with moderate-to-severe knee pain for ≥3 months were eligible. Participants were randomised into groups A (non-pharmacological treatment first), B (pharmacological treatment first), or group C (usual care). The intervention was delivered over 26-weeks. Outcomes were dropout rate, recruitment rate, intervention fidelity, ability to collect outcome data and treatment acceptability. RESULTS: Seventeen participants were randomised and enrolled into each of groups A and B (5.2% recruitment rate), and 174 randomised to group C. Participant characteristics at randomisation were comparable across the three arms. COVID-19 paused the study from March-November-2020. Participants enrolled in groups A and B before March-2020 were withdrawn at restart. Of the 20 participants enrolled after restart, 18 completed the study (10% dropout). The nurse reported delivering most aspects of the intervention with high fidelity. Participants viewed the package of care as structured, supportive and holistic, they learnt about self-managing knee pain, and could engage with and follow the non-pharmacological treatment. Most found the non-pharmacological treatment more useful than the pharmacological treatment, preferring to receive it before or alongside analgesia. Many self-reported questionnaires were not fully completed. CONCLUSIONS: The nurse-led package of care for knee pain was acceptable with low dropout, although the cohort RCT design may not be feasible for a definitive trial. TRIAL REGISTRATION: clinicaltrials.gov; NCT03670706.

The bidirectional relationship between chronic joint pain and frailty: data from the Investigating Musculoskeletal Health and Wellbeing cohort.

BACKGROUND: Pain and frailty are associated, but this relationship is insufficiently understood. We aimed to test whether there is a unidirectional or bidirectional relationship between joint pain and frailty. METHODS: Data were from Investigating Musculoskeletal Health and Wellbeing, a UK-based cohort. Average joint pain severity over the previous month was assessed using an 11-point numerical rating scale (NRS). Frailty was classified as present/absent using the FRAIL questionnaire. Multivariable regression assessed the association between joint pain and frailty, adjusted for age, sex, and BMI class. Two-wave cross-lagged path modelling permitted simultaneous exploration of plausible causal pathways between pain intensity and frailty at baseline and 1-year. Transitions were assessed using t-tests. RESULTS: One thousand one hundred seventy-nine participants were studied, 53% female, with a median age of 73 (range 60 to 95) years. FRAIL classified 176 (15%) participants as frail at baseline. Mean (SD) baseline pain score was 5.2 (2.5). Pain NRS ≥ 4 was observed in 172 (99%) of frail participants. Pain severity was associated with frailty at baseline (aOR 1.72 (95%CI 1.56 to 1.92)). In cross-lagged path analysis, higher baseline pain predicted 1-year frailty [ß = 0.25, (95%CI 0.14 to 0.36), p < 0.001] and baseline frailty predicted higher 1-year pain [ß = 0.06, (95%CI 0.003 to 0.11), p = 0.040]. Participants transitioning to frailty over one year had higher mean pain scores (6.4 (95%CI 5.8 to 7.1)) at baseline than those who remained non-frail (4.7 (95%CI 4.5 to 4.8)), p < 0.001. CONCLUSIONS: The bidirectional relationship between pain and frailty could lead to a vicious cycle in which each accelerates the other's progression. This justifies attempts to prevent frailty by addressing pain and to include pain measures as an outcome in frailty studies.

Investigating musculoskeletal health and wellbeing; a cohort study protocol.

BACKGROUND: In an ageing population, pain, frailty and disability frequently coexist across a wide range of musculoskeletal diagnoses, but their associations remain incompletely understood. The Investigating Musculoskeletal Health and Wellbeing (IMH&W) study aims to measure and characterise the development and progression of pain, frailty and disability, and to identify discrete subgroups and their associations. The survey will form a longitudinal context for nested research, permitting targeted recruitment of participants for qualitative, observational and interventional studies; helping to understand recruitment bias in clinical studies; and providing a source cohort for cohort randomised controlled trials. METHODS: IMH&W will comprise a prospective cohort of 10,000 adults recruited through primary and secondary care, and through non-clinical settings. Data collection will be at baseline, and then through annual follow-ups for 4 years. Questionnaires will address demographic characteristics, pain severity (0-10 Numerical Rating Scale), pain distribution (reported on a body Manikin), pain quality (McGill Pain Questionnaire), central aspects of pain (CAP-Knee), frailty and disability (based on Fried criteria and the FRAIL questionnaire), and fracture risk. Baseline characteristics, progression and associations of frailty, pain and disability will be determined. Discrete subgroups and trajectories will be sought by latent class analysis. Recruitment bias will be explored by comparing participants in nested studies with the eligible IMH&W population. DISCUSSION: IMH&W will elucidate associations and progression of pain, frailty and disability. It will enable identification of people at risk of poor musculoskeletal health and wellbeing outcomes who might be suitable for specific interventions, and facilitate generalisation and comparison of research outcomes between target populations. The study will benefit from a large sample size and will recruit from diverse regions across the UK. Purposive recruitment will enrich the cohort with people with MSK problems with high representation of elderly and unwell people. TRIAL REGISTRATION: Clinicaltrials.gov NCT03696134. Date of Registration: 04 October 2018.

Recruiting ENT and Audiology patients into pharmaceutical trials: evaluating the multi-centre experience in the UK and USA.

OBJECTIVE: Recruiting into clinical trials on time and on target is a major challenge and yet often goes unreported. This study evaluated the adjustment to procedures, recruitment and screening methods in two multi-centre pharmaceutical randomised controlled trials (RCTs) for hearing-related problems in adults. DESIGN: Recruitment monitoring and subsequent adjustment of various study procedures (e.g. eligibility criteria, increasing recruiting sites and recruitment methods) are reported. Participants were recruited through eight overarching methods: trial registration, posters/flyers, print publications, Internet, social media, radio, databases and referrals. The efficiency of the recruitment was measured by determining the number of people: (1) eligible for screening as a percentage of those who underwent telephone pre-screening and (2) randomised as a percentage of those screened. STUDY SAMPLE: A total of 584 participants completed the pre-screening steps, 491 screened and 169 participants were randomised. RESULTS: Both RCTs completed adjustments to the participant eligibility, added new study sites and additional recruitment methods. No single recruitment method was efficient enough to serve as the only route to enrolment. CONCLUSION: A diverse portfolio of methods, continuous monitoring, mitigation strategy and adequate resourcing were essential for achieving our recruitment goals.

Reproducible microbiome composition signatures of anxiety and depressive symptoms.

The gut microbiome is a significant contributor to mental health, with growing evidence linking its composition to anxiety and depressive disorders. Gut microbiome composition is associated with signs of anxiety and depression both in clinically diagnosed mood disorders and subclinically in the general population and may be influenced by dietary fibre intake and the presence of chronic pain. We provide an update of current evidence on the role of gut microbiome composition in depressive and anxiety disorders or symptoms by reviewing available studies. Analysing data from three independent cohorts (osteoarthritis 1 (OA1); n = 46, osteoarthritis 2 (OA2); n = 58, and healthy controls (CON); n = 67), we identified microbial composition signatures of anxiety and depressive symptoms at genus level and cross-validated our findings performing meta-analyses of our results with results from previously published studies. The genera Bifidobacterium (fixed-effect beta (95% CI) = -0.22 (-0.34, -0.10), p = 3.90e-04) and Lachnospiraceae NK4A136 group (fixed-effect beta (95% CI) = -0.09 (-0.13, -0.05), p = 2.53e-06) were found to be the best predictors of anxiety and depressive symptoms, respectively, across our three cohorts and published literature taking into account demographic and lifestyle covariates, such as fibre intake. The association with anxiety was robust in accounting for heterogeneity between cohorts and supports previous observations of the potential prophylactic effect of Bifidobacterium against anxiety symptoms.

Heading Frequency and Risk of Cognitive Impairment in Retired Male Professional Soccer Players.

Importance: Although professional soccer players appear to be at higher risk of neurodegenerative disease, the reason remains unknown. Objective: To examine whether heading frequency is associated with risk of cognitive impairment in retired professional soccer players. Design, Setting, and Participants: A UK nationwide cross-sectional study was conducted between August 15, 2020, and December 31, 2021, in 459 retired male professional soccer players older than 45 years and registered with the Professional Footballers' Association or a League Club Players' Association. Exposure: Data on heading frequency in 3 bands-0 to 5, 6 to 15, and more than 15 times per match or training session and other soccer-specific risk factors, such as player position and concussion-were collected through a self-reported questionnaire. Main Outcomes and Measures: Cognitive impairment was defined using the Telephone Interview for Cognitive Status-modified as scores of less than or equal to 21. Hopkins Verbal Learning Test, verbal fluency, and independent activities of daily living were also assessed. Test Your Memory and physician-diagnosed dementia/Alzheimer disease were self-reported via the questionnaire. Adjusted odds ratios (AORs) with 95% CIs were calculated. Results: Of 468 retired male professional soccer players who completed questionnaires (mean [SD] age, 63.68 [10.48]; body mass index, 27.22 [2.89]), 459 reported heading frequency: 114 headed 0 to 5 times, 185 headed 6 to 15 times, 160 headed more than 15 times per match, and 125 headed 0 to 5 times, 174 headed 6 to 15 times, and 160 headed more than 15 times per training session during their careers. The prevalence of cognitive impairment was 9.78% (0-5 times), 14.78% (6-15 times), and 15.20% (>15 times) per match (P = .51). Compared with players reporting 0 to 5 headers per match, the AORs were 2.71 (95% CI, 0.89-8.25) for players reporting 6 to 15 headers per match and 3.53 (95% CI, 1.13-11.04) for players reporting more than 15 headers per match (P = .03 for trend). Corresponding AORs for heading frequency per training session were 2.38 (95% CI, 0.82-6.95) for those reporting 6 to 15, and 3.40 (95% CI, 1.13-10.23) for those reporting more than 15 in comparison with those who reported 0 to 5 (P = .03 for trend). Concussion involving memory loss was also associated with a greater risk of cognitive impairment (AOR, 3.16; 95% CI, 1.08-9.22). Similar results were observed with other cognitive tests and self-reported physician-diagnosed dementia/Alzheimer disease. Conclusions and Relevance: The findings of this study suggest that repetitive heading during a professional soccer career is associated with an increased risk of cognitive impairment in later life. Further study is needed to establish the upper threshold for heading frequency to mitigate this risk.

Cognitive Impairment and Self-Reported Dementia in UK Retired Professional Soccer Players: A Cross Sectional Comparative Study.

BACKGROUND: Previous studies based on death certificates have found professional soccer players were more likely to die with neurodegenerative diseases, including dementia. Therefore, this study aimed to investigate whether retired professional male soccer players would perform worse on cognitive tests and be more likely to self-report dementia diagnosis than general population control men. METHODS: A cross-sectional comparative study was conducted between August 2020 and October 2021 in the United Kingdom (UK). Professional soccer players were recruited through different soccer clubs in England, and general population control men were recruited from the East Midlands in the UK. We obtained self-reported postal questionnaire data on dementia and other neurodegenerative diseases, comorbidities and risk factors from 468 soccer players and 619 general population controls. Of these, 326 soccer players and 395 general population controls underwent telephone assessment for cognitive function. RESULTS: Retired soccer players were approximately twice as likely to score below established dementia screening cut-off scores on the Hopkins Verbal Learning Test (OR 2.06, 95%CI 1.11-3.83) and Verbal Fluency (OR 1.78, 95% CI 1.18-2.68), but not the Test Your Memory, modified Telephone Interview for Cognitive Status, and Instrumental Activities of Daily Living. Analyses were adjusted for age, education, hearing loss, body mass index, stroke, circulatory problems in the legs and concussion. While retired soccer players were younger, had fewer cardiovascular diseases and other morbidities and reported healthier lifestyles, 2.8% of retired soccer players reported medically diagnosed dementia and other neurodegenerative disease compared to 0.9% of controls (OR = 3.46, 95% CI 1.25-9.63) after adjustment for age and possible confounders. CONCLUSIONS: UK male retired soccer players had a higher risk of performing below established cut-off scores of dementia screening tests and were more likely to self-report medically diagnosed dementia and neurodegenerative diseases, despite having better overall physical health and fewer dementia risk factors. Further study is needed to determine specific soccer-related risk factors.

Brain connectivity-guided, Optimised theta burst transcranial magnetic stimulation to improve Central Pain Modulation in knee Osteoarthritis Pain (BoostCPM): protocol of a pilot randomised clinical trial in a secondary care setting in the UK.

INTRODUCTION: Chronic pain is a common health problem that is not efficiently managed by standard analgesic treatments. There is evidence that treatment resistance may result from maladaptive brain changes in areas that are fundamental to the perception of pain. Knee osteoarthritis is one of the most prevalent causes of chronic pain and commonly associated with negative affect. Chronic knee osteoarthritis pain is also associated with altered right anterior insula functional connectivity. We posit that reversal of these brain circuit alterations may be critical to alleviate chronic pain and associated negative affect, and that this can be achieved through non-invasive neuromodulation techniques. Despite growing interest in non-invasive neuromodulation for pain relief and proven efficacy in depression, results in chronic pain are mixed with limited high-quality evidence for clinical and mechanistic efficacy. Limitations include patient heterogeneity, imprecision of target selection, uncertain blinding and protocols that may deliver pulses at subclinical efficacy. METHODS AND ANALYSIS: We hence developed an optimised treatment protocol of connectivity-guided intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex with accelerated delivery on four consecutive days (allowing 4 days within the same week as protocol variation) with five daily treatment sessions that will be piloted in a sham-controlled design in 45 participants with chronic knee pain. This pilot study protocol will assess feasibility, tolerability and explore mechanistic efficacy through serial functional/structural magnetic resonance imaging (MRI) and quantitative sensory testing. ETHICS AND DISSEMINATION: This pilot trial has been approved by the Ethics Committee Cornwall and Plymouth.Results of the pilot trial will be submitted to peer-reviewed journals, presented at research conferences and may be shared with participants and PPI/E advisors. TRIAL REGISTRATION NUMBER: ISRCTN15404076.

Fidelity assessment of nurse-led non-pharmacological package of care for knee pain in the package development phase of a feasibility randomised controlled trial based in secondary care: a mixed methods study.

OBJECTIVES: To evaluate fidelity of delivery of a nurse-led non-pharmacological complex intervention for knee pain. SETTING: Secondary care. Single-centre study. STUDY DESIGN: Mixed methods study. PARTICIPANTS: Eighteen adults with chronic knee pain. INCLUSION CRITERIA: Age >40 years, knee pain present for longer than 3 months, knee pain for most days of the previous month, at least moderate pain in two of the five domains of Western Ontario and McMaster Universities Osteoarthritis Index pain scale. INTERVENTIONS: Nurse-led non-pharmacological intervention comprising assessment, education, exercise, use of hot/cold treatments, footwear modification, walking aids and weight-loss advice (if required). OUTCOMES: Primary: fidelity of delivery of intervention, secondary: nurses' experience of delivering intervention. METHODS: Each intervention session with every participant was video recorded and formed part of fidelity assessment. Fidelity checklists were completed by the research nurse after each session and by an independent researcher, after viewing the video-recordings blinded to nurse ratings. Fidelity scores (%), percentage agreement and 95% Confidence Intervals (CI) were calculated. Two semi-structured interviews were conducted with the research nurse. RESULTS: Fourteen participants completed all visits. 62 treatment sessions took place. Nurse self-report and assessor video rating scores for all 62 treatment sessions were included in fidelity assessment. Overall fidelity was higher on nurse self-report (97.7%) than on objective video-rating (84.2%). Percentage agreement between nurse self-report and video-rating was 73.3% (95% CI 71.3 to 75.3). Fidelity was lowest for advice on footwear and walking aids. The nurse reported difficulty advising on thermal treatments, footwear and walking aids, and did not feel confident negotiating achievable and realistic goals with participants. CONCLUSIONS: A trained research nurse can deliver most components of a non-pharmacological intervention for knee pain to a high degree of fidelity. Future research should assess intervention fidelity in a routine clinical setting, and examine its clinical and cost-effectiveness. TRIAL REGISTRATION NUMBER: NCT03670706.

East Midlands knee pain multiple randomised controlled trial cohort study: cohort establishment and feasibility study protocol.

INTRODUCTION: Knee pain due to osteoarthritis (OA) is a common cause of disability. The UK National Institute for Health and Care Excellence OA guidelines recommend education, exercise and weight loss advice (if overweight) as core interventions before pharmacological adjuncts. However, implementation of these in primary care is often suboptimal. This study aims to develop a complex intervention with non-pharmacological and pharmacological components that can be delivered by nurses. The feasibility and acceptability of the intervention, and feasibility of undertaking a future cohort randomised controlled trial (RCT) will be explored. METHODS AND ANALYSIS: In phase 1, we will develop a training programme for nurses and evaluate the fidelity and acceptability of the non-pharmacological element of the intervention. Fidelity checklists completed by the nurse will be compared with video analysis of the treatment sessions. Patients and nurses will be interviewed to determine the acceptability of the intervention and explore challenges to intervention delivery. The non-pharmacological component will be modified based on the findings. In phase 2, we will assess the feasibility of conducting a cohort RCT comprising both the pharmacological and modified non-pharmacological components. We will compare three groups: group A will receive the non-pharmacological components delivered before pharmacological components; group B will receive pharmacological components followed by the non-pharmacological components; and group C (control arm) will continue to receive usual care. Study outcomes will be collected at three time points: baseline, 13 and 26 weeks after randomisation. Qualitative interviews will be conducted with a sample of participants from each of the two active intervention arms. ETHICS AND DISSEMINATION: This protocol was approved by the East Midlands-Derby Research Ethics Committee (18/EM/0288) and registered at ClinicalTrials.gov (protocol v4.0, 10/02/2020). The study will be reported in accordance with the Consolidated Standards of Reporting Trials guidance and standards. The results will be submitted for publication in peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: NCT03670706.

A balanced randomised placebo controlled blinded phase IIa multi-centre study to investigate the efficacy and safety of AUT00063 versus placebo in subjective tinnitus: The QUIET-1 trial.

AUT00063 is an experimental new medicine that has been demonstrated to suppress spontaneous hyperactivity by modulating the action of voltage-gated potassium-channels in central auditory cortical neurons of a rodent model. This neurobiological property makes it a good candidate for treating the central component of subjective tinnitus but this has not yet been tested in humans. The main purpose of the QUIET-1 (QUest In Eliminating Tinnitus) trial was to examine the effect of AUT00063 on the severity of tinnitus symptoms in people with subjective tinnitus. The trial was a randomised, placebo-controlled, observer, physician and participant blinded multi-centre superiority trial with two parallel groups and a primary endpoint of functional impact on tinnitus 28 days after the first drug dosing day. The trial design overcame the scale and logistical challenges of delivering a scientifically robust, statistically powered multi-centre study for subjective tinnitus within the National Health Service in England. The trial was terminated early for futility. Overall, 212 participants consented across 18 sites with 91 participants randomised to groups using age, gender, tinnitus symptom severity and hearing status as minimisation factors. While the pharmacokinetic markers confirm the uptake of AUT00063 in the body, within the expected therapeutic range, with respect to clinical benefit findings indicated that AUT00063 was not effective in alleviating tinnitus symptoms (1.56 point change in Tinnitus Functional Index). In terms of clinical harms, results indicated that a daily dose of 800 mg capsules of AUT00063 taken for 28 days was safe and well tolerated. These findings provide significant advances in the drug development field for hearing sciences, but raise questions about the predictive validity of certain rodent models of noise-induced hearing loss and tinnitus, as least for the mechanism evaluated in the present study. Trial Registration: (EudraCT) 2014-002179-27; NCT02315508.