Prevention of Shoulder Problems trial (PROSPER) : Physiotherapist Manual [intervention manual and related materials]

This Physiotherapist Manual contains the relevant information to prepare physiotherapists for delivering the PROSPER exercise programme. The main concepts from each chapter will be covered in detail during your PROSPER training. This is your own reference manual with the relevant background information about trial processes and procedures. The trial is run by the Warwick Clinical Trials Unit based at the University of Warwick and is funded by the National Institute for Health Research (NIHR) under the Health Technology Assessment (HTA) funding stream. The purpose of the trial is to investigate whether postoperative exercise can improve function and quality of life in women at high risk of developing shoulder problems after breast cancer treatment. Some physiotherapists will have considerable experience of treating women with breast cancer or treating patients with musculoskeletal shoulder problems. However, not everyone will have the same skill and experience level, therefore this manual has been written to account for differences in background training, skill and clinical expertise. The aims of this Physiotherapist Manual are: - To explain the trial design; - To describe common side effects from breast cancer treatment; - To provide the research evidence for the PROSPER exercise intervention; - To describe procedures for the assessment and treatment of PROSPER study participants; - To describe trial documentation and reporting procedures. This manual has been produced to ‘standardise’ treatment and to reduce the risk of differences between physiotherapists and centres providing care. For all trial participants referred to your service, we ask that you adhere to the manual. This does not affect the care of non-trial participants, please treat your other patients in your usual way. You may even decide to use some of the approaches within the manual for non-trial patients. Thank you again for taking part in PROSPER. We hope you enjoy reading the manual and we very much look forward to working with you

Exercise to prevent shoulder problems after breast cancer surgery : the PROSPER RCT

Background: Upper limb problems are common after breast cancer treatment. Objectives: To investigate the clinical effectiveness and cost-effectiveness of a structured exercise programme compared with usual care on upper limb function, health-related outcomes and costs in women undergoing breast cancer surgery. Design: This was a two-arm, pragmatic, randomised controlled trial with embedded qualitative research, process evaluation and parallel economic analysis; the unit of randomisation was the individual (allocated ratio 1 : 1). Setting: Breast cancer centres, secondary care. Participants: Women aged ≥ 18 years who had been diagnosed with breast cancer and were at higher risk of developing shoulder problems. Women were screened to identify their risk status. Interventions: All participants received usual-care information leaflets. Those randomised to exercise were referred to physiotherapy for an early, structured exercise programme (three to six face-to-face appointments that included strengthening, physical activity and behavioural change strategies). Main outcome measures: The primary outcome was upper limb function at 12 months as assessed using the Disabilities of Arm, Hand and Shoulder questionnaire. Secondary outcomes were function (Disabilities of Arm, Hand and Shoulder questionnaire subscales), pain, complications (e.g. wound- related complications, lymphoedema), health-related quality of life (e.g. EuroQol-5 Dimensions, five-level version; Short Form questionnaire-12 items), physical activity and health service resource use. The economic evaluation was expressed in terms of incremental cost per quality-adjusted life-year and incremental net monetary benefit gained from an NHS and Personal Social Services perspective. Participants and physiotherapists were not blinded to group assignment, but data collectors were blinded. Results: Between 2016 and 2017, we randomised 392 participants from 17 breast cancer centres across England: 196 (50%) to the usual-care group and 196 (50%) to the exercise group. Ten participants (10/392; 3%) were withdrawn at randomisation and 32 (8%) did not provide complete baseline data. A total of 175 participants (89%) from each treatment group provided baseline data. Participants’ mean age was 58.1 years (standard deviation 12.1 years; range 28–88 years). Most participants had undergone axillary node clearance surgery (327/392; 83%) and 317 (81%) had received radiotherapy. Uptake of the exercise treatment was high, with 181 out of 196 (92%) participants attending at least one physiotherapy appointment. Compliance with exercise was good: 143 out of 196 (73%) participants completed three or more physiotherapy sessions. At 12 months, 274 out of 392 (70%) participants returned questionnaires. Improvement in arm function was greater in the exercise group [mean Disabilities of Arm, Hand and Shoulder questionnaire score of 16.3 (standard deviation 17.6)] than in the usual-care group [mean Disabilities of Arm, Hand and Shoulder questionnaire score of 23.7 (standard deviation 22.9)] at 12 months for intention-to-treat (adjusted mean difference Disabilities of Arm, Hand and Shoulder questionnaire score of –7.81, 95% confidence interval –12.44 to –3.17; p = 0.001) and complier-average causal effect analyses (adjusted mean difference –8.74, 95% confidence interval –13.71 to –3.77; p ≤ 0.001). At 12 months, pain scores were lower and physical health-related quality of life was higher in the exercise group than in the usual-care group (Short Form questionnaire-12 items, mean difference 4.39, 95% confidence interval 1.74 to 7.04; p = 0.001). We found no differences in the rate of adverse events or lymphoedema over 12 months. The qualitative findings suggested that women found the exercise programme beneficial and enjoyable. Exercise accrued lower costs (–£387, 95% CI –£2491 to £1718) and generated more quality-adjusted life years (0.029, 95% CI 0.001 to 0.056) than usual care over 12 months. The cost-effectiveness analysis indicated that exercise was more cost-effective and that the results were robust to sensitivity analyses. Exercise was relatively cheap to implement (£129 per participant) and associated with lower health-care costs than usual care and improved health-related quality of life. Benefits may accrue beyond the end of the trial. Limitations: Postal follow-up was lower than estimated; however, the study was adequately powered. No serious adverse events directly related to the intervention were reported. Conclusions: This trial provided robust evidence that referral for early, supported exercise after breast cancer surgery improved shoulder function in those at risk of shoulder problems and was associated with lower health-care costs than usual care and improved health-related quality of life. Future work: Future work should focus on the implementation of exercise programmes in clinical practice for those at highest risk of shoulder problems. Trial registration: This trial is registered as ISRCTN35358984. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 15. See the NIHR Journals Library website for further project information

Mining the 99 Lives Cat Genome Sequencing Consortium database implicates genes and variants for the Ticked locus in domestic cats (Felis catus)

Tabby patterns of fur coats are defining characteristics in wild and domestic felids. Historically, three autosomal alleles at one locus (Tabby): Abyssinian (Ta; a.k.a. ticked), mackerel (Tm; a.k.a. striped) and blotched (tb; a.k.a. classic, blotched) were thought to control these patterns in domestic cats and their breeds. Currently, at least three loci influence cat tabby markings, two of which are designated Tabby and Ticked. The Tabby locus is laeverin (LVRN) and affects the mackerel and blotched patterns. The unidentified gene for the Ticked locus on cat chromosome B1 was suggested to control the presence or absence of the ticked pattern (Tabby – Abyssinian (Ta; a.k.a. ticked). The cat reference genome (Cinnamon, the Abyssinian) has the ticked phenotype and the variant dataset and coat phenotypes from the 99 Lives Cat Genome Consortium (195 cats) were used to identify candidate genes and variants associated with the Ticked locus. Two strategies were used to find the Ticked allele(s), one considered Cinnamon with the reference allele or heterozygous (Strategy A) and the other considered Cinnamon as having the variant allele or heterozygous (Strategy B). For Strategy A, two variants in Dickkopf Wnt Signaling Pathway Inhibitor 4 (DKK4), a p.Cys63Tyr (B1:41621481, c.188G>A) and a less common p.Ala18Val (B1:42620835, c.53C>T) variant are suggested as two alleles influencing the Ticked phenotype. Bioinformatic and molecular modeling analysis suggests that these changes disrupt a key disulfide bond in the Dkk4 cysteine‐rich domain 1 or Dkk4 signal peptide cleavage respectively. All coding variants were excluded as Ticked alleles using Strategy B