Single nucleus and spatial transcriptomic profiling of healthy human hamstring tendon.

The molecular and cellular basis of health in human tendons remains poorly understood. Among human tendons, hamstring tendon has markedly low pathology and can provide a prototypic healthy tendon reference. The aim of this study was to determine the transcriptomes and location of all cell types in healthy hamstring tendon. Using single nucleus RNA sequencing, we profiled the transcriptomes of 10 533 nuclei from four healthy donors and identified 12 distinct cell types. We confirmed the presence of two fibroblast cell types, endothelial cells, mural cells, and immune cells, and identified cell types previously unreported in tendons, including different skeletal muscle cell types, satellite cells, adipocytes, and undefined nervous system cells. The location of these cell types within tendon was defined using spatial transcriptomics and imaging, and potential transcriptional networks and cell-cell interactions were analyzed. We demonstrate that fibroblasts have the highest number of potential cell-cell interactions in our dataset, are present throughout the tendon, and play an important role in the production and organization of extracellular matrix, thus confirming their role as key regulators of hamstring tendon homeostasis. Overall, our findings underscore the complexity of the cellular networks that underpin healthy human tendon function and the central role of fibroblasts as key regulators of hamstring tendon tissue homeostasis.

Proresolving Mediators LXB4 and RvE1 Regulate Inflammation in Stromal Cells from Patients with Shoulder Tendon Tears.

Tendon stromal cells isolated from patients with chronic shoulder rotator cuff tendon tears have dysregulated resolution responses. Current therapies do not address the biological processes concerned with persistent tendon inflammation; therefore, new therapeutic approaches that target tendon stromal cells are required. We examined whether two specialized proresolving mediators (SPMs), lipoxin B4 (LXB4) and resolvin E1 (RvE1), modulate the bioactive lipid mediator profiles of IL-1ß-stimulated tendon cells derived from patients with shoulder tendon tears and healthy volunteers. We also examined whether LXB4 or RvE1 treatments moderated the proinflammatory phenotype of tendon tear stromal cells. Incubation of IL-1ß-treated patient-derived tendon cells in LXB4 or RvE1 up-regulated concentrations of SPMs. RvE1 treatment of diseased tendon stromal cells increased 15-epi-LXB4 and regulated postaglandin F2α. LXB4 or RvE1 also induced expression of the SPM biosynthetic enzymes 12-lipoxygenase and 15-lipoxygenase. RvE1 treatment up-regulated the proresolving receptor human resolvin E1 compared with vehicle-treated cells. Incubation in LXB4 or RvE1 moderated the proinflammatory phenotype of patient-derived tendon tear cells, regulating markers of tendon inflammation, including podoplanin, CD90, phosphorylated signal transducer and activator of transcription 1, and IL-6. LXB4 and RvE1 counterregulate inflammatory processes in tendon stromal cells, supporting the role of these molecules as potential therapeutics to resolve tendon inflammation.

15-Epi-LXA4 and MaR1 counter inflammation in stromal cells from patients with Achilles tendinopathy and rupture.

Resolution of inflammation is poorly understood in Achilles tendon disorders. Herein, we investigated the bioactive lipid mediator profiles of tendon-derived stromal cells isolated from patients with Achilles tendinopathy (AT) or Achilles rupture (AR) under baseline and IL-1ß-stimulated conditions. We also determined whether incubating these cells with 2 of the mediators produced by tendon-derived stromal cells, 15-epi-Lipoxin A4 (15-epi-LXA4) or maresin (MaR)-1, moderated their proinflammatory phenotype. Under baseline conditions, AT cells showed concurrent increased levels of proinflammatory eicosanoids and proresolving mediators compared with AR cells. IL-1ß treatment induced profound prostaglandin E2 release in AR compared with AT cells. Incubation of IL-1ß treated AT and AR tendon-derived stromal cells in 15-epi-LXA4 or MaR1 reduced proinflammatory eicosanoids and potentiated the release of proresolving mediators. These mediators also induced specialized proresolving mediator (SPM) biosynthetic enzymes arachidonate lipoxygenase (ALOX) 12 and ALOX15 and up-regulated the proresolving receptor ALX compared with vehicle-treated cells. Incubation in 15-epi-LXA4 or MaR1 also moderated the proinflammatory phenotype of AT and AR cells, regulating podoplanin, CD90, signal transducer and activator of transcription (STAT)-1, IL-6, IFN regulatory factor (IRF) 5, and TLR4 and suppressed c-Jun N-terminal kinase 1/2/3, Lyn, STAT-3, and STAT-6 phosphokinase signaling. In summary, we identify proresolving mediators that are active in AT and AR and propose SPMs, including 15-epi-LXA4 or MaR1, as a potential strategy to counterregulate inflammatory processes in these cells.-Dakin, S. G., Colas, R. A., Newton, J., Gwilym, S., Jones, N., Reid, H. A. B., Wood, S., Appleton, L., Wheway, K., Watkins, B., Dalli, J., Carr, A. J. 15-Epi-LXA4 and MaR1 counter inflammation in stromal cells from patients with Achilles tendinopathy and rupture.

Arthroscopic subacromial decompression for subacromial shoulder pain (CSAW): a multicentre, pragmatic, parallel group, placebo-controlled, three-group, randomised surgical trial.

BACKGROUND: Arthroscopic sub-acromial decompression (decompressing the sub-acromial space by removing bone spurs and soft tissue arthroscopically) is a common surgery for subacromial shoulder pain, but its effectiveness is uncertain. We did a study to assess its effectiveness and to investigate the mechanism for surgical decompression. METHODS: We did a multicentre, randomised, pragmatic, parallel group, placebo-controlled, three-group trial at 32 hospitals in the UK with 51 surgeons. Participants were patients who had subacromial pain for at least 3 months with intact rotator cuff tendons, were eligible for arthroscopic surgery, and had previously completed a non-operative management programme that included exercise therapy and at least one steroid injection. Exclusion criteria included a full-thickness torn rotator cuff. We randomly assigned participants (1:1:1) to arthroscopic subacromial decompression, investigational arthroscopy only, or no treatment (attendance of one reassessment appointment with a specialist shoulder clinician 3 months after study entry, but no intervention). Arthroscopy only was a placebo as the essential surgical element (bone and soft tissue removal) was omitted. We did the randomisation with a computer-generated minimisation system. In the surgical intervention groups, patients were not told which type of surgery they were receiving (to ensure masking). Patients were followed up at 6 months and 1 year after randomisation; surgeons coordinated their waiting lists to schedule surgeries as close as possible to randomisation. The primary outcome was the Oxford Shoulder Score (0 [worst] to 48 [best]) at 6 months, analysed by intention to treat. The sample size calculation was based upon a target difference of 4·5 points (SD 9·0). This trial has been registered at ClinicalTrials.gov, number NCT01623011. FINDINGS: Between Sept 14, 2012, and June 16, 2015, we randomly assigned 313 patients to treatment groups (106 to decompression surgery, 103 to arthroscopy only, and 104 to no treatment). 24 [23%], 43 [42%], and 12 [12%] of the decompression, arthroscopy only, and no treatment groups, respectively, did not receive their assigned treatment by 6 months. At 6 months, data for the Oxford Shoulder Score were available for 90 patients assigned to decompression, 94 to arthroscopy, and 90 to no treatment. Mean Oxford Shoulder Score did not differ between the two surgical groups at 6 months (decompression mean 32·7 points [SD 11·6] vs arthroscopy mean 34·2 points [9·2]; mean difference -1·3 points (95% CI -3·9 to 1·3, p=0·3141). Both surgical groups showed a small benefit over no treatment (mean 29·4 points [SD 11·9], mean difference vs decompression 2·8 points [95% CI 0·5-5·2], p=0·0186; mean difference vs arthroscopy 4·2 [1·8-6·6], p=0·0014) but these differences were not clinically important. There were six study-related complications that were all frozen shoulders (in two patients in each group). INTERPRETATION: Surgical groups had better outcomes for shoulder pain and function compared with no treatment but this difference was not clinically important. Additionally, surgical decompression appeared to offer no extra benefit over arthroscopy only. The difference between the surgical groups and no treatment might be the result of, for instance, a placebo effect or postoperative physiotherapy. The findings question the value of this operation for these indications, and this should be communicated to patients during the shared treatment decision-making process. FUNDING: Arthritis Research UK, the National Institute for Health Research Biomedical Research Centre, and the Royal College of Surgeons (England).

Construct Validity and Precision of Different Patient-reported Outcome Measures During Recovery After Upper Extremity Fractures.

BACKGROUND: Patient perceptions of their limitations after illness and injury can be quantified using patient-reported outcome measures (PROMs). Few studies have assessed construct validity (using correlations and factor analysis) and precision (floor and ceiling effects) of a range of frequently used PROMs longitudinally in a population of patients recovering from common upper extremity fractures according to area (general health, region-specific, or joint-specific measures) and mode of administration (fixed-scale or computer adaptive test). QUESTIONS/PURPOSES: (1) What is the strength of the correlation between different PROMs within 1 week, 2 to 4 weeks and 6 to 9 months after shoulder, elbow, and wrist fractures? (2) Using a factor analysis, what underlying constructs are being measured by these PROMs? (3) Are there strong floor and ceiling effects with these instruments? METHODS: Between January 2016 and August 2016, 734 patients recovering from an isolated shoulder, elbow, or wrist fracture completed physical-limitation PROMs at baseline (the initial office visit after diagnosis in the emergency department), 2 to 4 weeks after injury, and at the final assessment 6 to 9 months after injury. In all, 775 patients were originally approached; 31 patients (4%) declined to participate due to time constraints, four patients died of unrelated illness, and six patients were lost to follow-up. The PROMs included the PROMIS Physical Function (PF, a computer adaptive, general measure of physical function), the PROMIS Upper Extremity (UE, a computer adaptive measure of upper extremity physical function), the QuickDASH (a fixed-scale, region-specific measure), the Oxford Shoulder Score (OSS), the Oxford Elbow Score (OES) and the Patient-rated Wrist Evaluation (PRWE) (a fixed-scale, joint-specific measure), and the EQ-5D-3L (a fixed-scale measure of general health). PROMs were evaluated during recovery for construct validity (using correlations and factor analysis) and precision (using floor and ceiling effects). RESULTS: Physical-limitation PROMs were intercorrelated at all time points, and the correlation strengthened over time (for example, PROMIS UE and QuickDASH at 1 week, r = -0.4665; at 2 to 4 weeks, r = -0.7763; at 6 to 9 months, r = -0.8326; p < 0.001). Factor analysis generated two factors or groupings of PROMs that could be described as capability (perceived ability to perform or engage in activities), and quality of life (an overall sense of health and wellbeing) that varied by time point and fracture type, Joint-specific and general-health PROMs demonstrated high ceiling effects 6 to 9 months after injury and PROMIS PF, PROMIS UE and QuickDASH had no floor or ceiling effects at any time points. CONCLUSIONS: There is a substantial correlation between PROMs that assess physical limitations (based on anatomic region) and general health after upper extremity fractures, and these relationships strengthen during recovery. Regardless of the delivery mode or area of focus, PROMs largely appear to represent two underlying constructs: capability and quality of life. Computer adaptive tests may be favored over fixed-scale measures for their efficiency and limited censoring. LEVEL OF EVIDENCE: Level II, therapeutic study.

Psychosocial factors affecting variation in patient-reported outcomes after elbow fractures.

BACKGROUND: The purpose of this study was to identify factors associated with limitations in function measured by patient-reported outcome measures (PROMs) 6-9 months after elbow fractures in adults from a range of demographic, injury, psychological, and social variables measured within a week and 2-4 weeks after injury. METHODS: We enrolled 191 adult patients sustaining an isolated elbow fracture and invited them to complete PROMs at their initial visit to the orthopedic outpatient clinic (within a maximum of 1 week after fracture), between 2 and 4 weeks, and between 6 and 9 months after injury; 183 patients completed the final assessment. Bivariate analysis was performed, followed by multivariable regression analysis accounting for multicollinearity. This was evaluated using partial R2, correlation matrices, and variable inflation factor assessment. RESULTS: There was a correlation between multiple variables within a week of injury and 2-4 weeks after injury with PROMs 6-9 months after injury in bivariate analysis. Kinesiophobia measured within a week of injury and self-efficacy measured at 2-4 weeks were the strongest predictors of limitations 6-9 months after injury in multivariable regression. Regression models accounted for substantial variance in all PROMs at both time points. CONCLUSIONS: Developing effective coping strategies to overcome fears related to movement and reinjury and finding ways of persevering with activity despite pain within a month of injury may enhance recovery after elbow fractures. Heightened fears around movement and suboptimal coping ability are modifiable using evidence-based behavioral treatments.

What Factors Are Associated With Disability After Upper Extremity Injuries? A Systematic Review.

BACKGROUND: Psychosocial factors are key determinants of health after upper extremity injuries. However, a systematic review is needed to understand which psychosocial factors are most consistently associated with disability and how the language, conceptualization, and types of measures used to assess disability impact these associations in upper extremity injuries. QUESTIONS/PURPOSES: (1) What factors are most consistently associated with disability after upper extremity injuries in adults? (2) What are the trends in types of outcome measures and conceptualization of disability in patients' upper extremity injuries? METHODS: We searched multiple electronic databases (PubMED, OVIDSP, PsycInfo, Google Scholar, ISI Web of Science) between January 1, 1996, and December 31, 2016, using terms related to the "upper extremity", "outcome measurement", and "impairment, psychological, social or symptomatic" variables. We included all studies involving adult patients with any musculoskeletal injury and excluded those that did not use patient-reported outcome measures. We identified and screened 9339 studies. Of these, we retained 41 studies that involved conditions ranging from fractures to soft tissue injuries in various regions of the arm. We conducted quality assessment using a 10-item validated checklist and a five-tier strength of evidence assessment. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria and registered the review before performing our search (PROSPERO: CRD42017054048). None of the authors received any funding to perform this work. RESULTS: Disability after upper extremity injury was most consistently associated with depression (21 cohorts), catastrophic thinking (13 cohorts), anxiety (11 cohorts), pain self-efficacy (eight cohorts), and pain interference (seven cohorts). Social and demographic factors were also associated with disability. Measures of impairment such as ROM and injury severity were least associated with disability. There has been a gradual increase in use of region or condition-specific patient-reported outcome measures and measures of psychological, social, and symptomatic factors over a period since the introduction of the World Health Organization (WHO) International Classification of Functioning, Disability and Health (ICF) around 2000. Approximately 17% of studies (n = 454 of 2628) had instances of unclear, conflicting, or inappropriate terminology and 11% of studies (n = 257 of 2628) involved misrepresentations of outcome measures related to disability. CONCLUSIONS: Psychologic and social factors are most consistently associated with disability than factors related to impairment. Further research involving the assessment of depression, anxiety, and coping strategies in cohorts with specific injuries may support decision-making regarding the provision of emotional support and psychologic therapies during recovery. Using the WHO ICF framework to conceptualize disability is key in increasing strength of evidence and allowing accurate comparisons of research in this field. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Chronic inflammation is a feature of Achilles tendinopathy and rupture.

BACKGROUND: Recent investigation of human tissue and cells from positional tendons such as the rotator cuff has clarified the importance of inflammation in the development and progression of tendon disease. These mechanisms remain poorly understood in disease of energy-storing tendons such as the Achilles. Using tissue biopsies from patients, we investigated if inflammation is a feature of Achilles tendinopathy and rupture. METHODS: We studied Achilles tendon biopsies from symptomatic patients with either mid-portion tendinopathy or rupture for evidence of abnormal inflammatory signatures. Tendon-derived stromal cells from healthy hamstring and diseased Achilles were cultured to determine the effects of cytokine treatment on expression of inflammatory markers. RESULTS: Tendinopathic and ruptured Achilles highly expressed CD14+ and CD68+ cells and showed a complex inflammation signature, involving NF-κB, interferon and STAT-6 activation pathways. Interferon markers IRF1 and IRF5 were highly expressed in tendinopathic samples. Achilles ruptures showed increased PTGS2 and interleukin-8 expression. Tendinopathic and ruptured Achilles tissues expressed stromal fibroblast activation markers podoplanin and CD106. Tendon cells isolated from diseased Achilles showed increased expression of pro-inflammatory and stromal fibroblast activation markers after cytokine stimulation compared with healthy hamstring tendon cells. CONCLUSIONS: Tissue and cells derived from tendinopathic and ruptured Achilles tendons show evidence of chronic (non-resolving) inflammation. The energy-storing Achilles shares common cellular and molecular inflammatory mechanisms with functionally distinct rotator cuff positional tendons. Differences seen in the profile of ruptured Achilles are likely to be attributable to a superimposed phase of acute inflammation and neo-vascularisation. Strategies that target chronic inflammation are of potential therapeutic benefit for patients with Achilles tendon disease.

Recovery of Comfort and Capability After Upper Extremity Fracture Is Predominantly Associated With Mindset: A Longitudinal Cohort From the United Kingdom.

OBJECTIVES: To determine the relative influence of mindset and fracture severity on 9-month recovery trajectories of pain and capability after upper extremity fractures. DESIGN: Secondary use of longitudinal data. SETTING: Single Level-1 trauma center in Oxford, United Kingdom. PATIENT SELECTION: English-speaking adults with isolated proximal humerus, elbow, or distal radius fracture managed operatively or nonoperatively were included, and those with multiple fractures or cognitive deficit were excluded. OUTCOME MEASURES AND COMPARISONS: Incapability (Quick-DASH) and pain intensity (11-point rating scale) were measured at baseline, 2-4 weeks, and 6-9 months after injury. Cluster analysis was used to identify statistical groupings of mindset (PROMIS Depression and Anxiety, Pain Catastrophizing Scale, and Tampa Scale for Kinesiophobia) and fracture severity (low/moderate/high based on OTA/AO classification). The recovery trajectories of incapability and pain intensity for each mindset grouping were assessed, accounting for various fracture-related aspects. RESULTS: Among 703 included patients (age 59 ± 21 years, 66% women, 16% high-energy injury), 4 statistical groupings with escalating levels of distress and unhelpful thoughts were identified (fracture severity was omitted considering it had no differentiating effect). Groups with less healthy mindset had a worse baseline incapability (group 2: ß = 4.1, 3: ß = 7.5, and 4: ß = 17) and pain intensity (group 3: ß = 0.70 and 4: ß = 1.4) (P < 0.01). Higher fracture severity (ß = 4.5), high-energy injury (ß = 4.0), and nerve palsy (ß = 8.1) were associated with worse baseline incapability (P < 0.01), and high-energy injury (ß = 0.62) and nerve palsy (ß = 0.76) with worse baseline pain intensity (P < 0.01). Groups 3 and 4 had a prolonged rate of recovery of incapability (ß = 1.3, ß = 7.0) and pain intensity (ß = 0.19, ß = 1.1) (P < 0.02). CONCLUSIONS: Patients with higher levels of unhelpful thinking and feelings of distress regarding symptoms experienced worse recovery of pain and incapability, with a higher effect size than fracture location, fracture severity, high-energy injury, and nerve palsy. These findings underline the importance of anticipating and addressing mental health concerns during recovery from injury. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Randomized feasibility study of an autologous protein solution versus corticosteroids injection for treating subacromial pain in the primary care setting - the SPiRIT trial.

Aims: The primary aim of this study was to assess the feasibility of recruiting and retaining patients to a patient-blinded randomized controlled trial comparing corticosteroid injection (CSI) to autologous protein solution (APS) injection for the treatment of subacromial shoulder pain in a community care setting. The study focused on recruitment rates and retention of participants throughout, and collected data on the interventions' safety and efficacy. Methods: Participants were recruited from two community musculoskeletal treatment centres in the UK. Patients were eligible if aged 18 years or older, and had a clinical diagnosis of subacromial impingement syndrome which the treating clinician thought was suitable for treatment with a subacromial injection. Consenting patients were randomly allocated 1:1 to a patient-blinded subacromial injection of CSI (standard care) or APS. The primary outcome measures of this study relate to rates of recruitment, retention, and compliance with intervention and follow-up to determine feasibility. Secondary outcome measures relate to the safety and efficacy of the interventions. Results: A total of 53 patients were deemed eligible, and 50 patients (94%) recruited between April 2022 and October 2022. Overall, 49 patients (98%) complied with treatment. Outcome data were collected in 100% of participants at three months and 94% at six months. There were no significant adverse events. Both groups demonstrated improvement in patient-reported outcome measures over the six-month period. Conclusion: Our study shows that it is feasible to recruit to a patient-blinded randomized controlled trial comparing APS and CSI for subacromial pain in terms of clinical outcomes and health-resource use in the UK. Safety and efficacy data are presented.

A protocol for the conduct of a multicentre, prospective, randomized superiority trial of surgical versus non-surgical interventions for humeral shaft fractures.

Aims: Fractures of the humeral shaft represent 3% to 5% of all fractures. The most common treatment for isolated humeral diaphysis fractures in the UK is non-operative using functional bracing, which carries a low risk of complications, but is associated with a longer healing time and a greater risk of nonunion than surgery. There is an increasing trend to surgical treatment, which may lead to quicker functional recovery and lower rates of fracture nonunion than functional bracing. However, surgery carries inherent risk, including infection, bleeding, and nerve damage. The aim of this trial is to evaluate the clinical and cost-effectiveness of functional bracing compared to surgical fixation for the treatment of humeral shaft fractures. Methods: The HUmeral SHaft (HUSH) fracture study is a multicentre, prospective randomized superiority trial of surgical versus non-surgical interventions for humeral shaft fractures in adult patients. Participants will be randomized to receive either functional bracing or surgery. With 334 participants, the trial will have 90% power to detect a clinically important difference for the Disabilities of the Arm, Shoulder and Hand questionnaire score, assuming 20% loss to follow-up. Secondary outcomes will include function, pain, quality of life, complications, cost-effectiveness, time off work, and ability to drive. Discussion: The results of this trial will provide evidence regarding clinical and cost-effectiveness between surgical and non-surgical treatment of humeral shaft fractures. Ethical approval has been obtained from East of England - Cambridge Central Research Ethics Committee. Publication is anticipated to occur in 2024.

Why does my shoulder hurt? A review of the neuroanatomical and biochemical basis of shoulder pain.

If a patient asks 'why does my shoulder hurt?' the conversation will quickly turn to scientific theory and sometimes unsubstantiated conjecture. Frequently, the clinician becomes aware of the limits of the scientific basis of their explanation, demonstrating the incompleteness of our understanding of the nature of shoulder pain. This review takes a systematic approach to help answer fundamental questions relating to shoulder pain, with a view to providing insights into future research and novel methods for treating shoulder pain. We shall explore the roles of (1) the peripheral receptors, (2) peripheral pain processing or 'nociception', (3) the spinal cord, (4) the brain, (5) the location of receptors in the shoulder and (6) the neural anatomy of the shoulder. We also consider how these factors might contribute to the variability in the clinical presentation, the diagnosis and the treatment of shoulder pain. In this way we aim to provide an overview of the component parts of the peripheral pain detection system and central pain processing mechanisms in shoulder pain that interact to produce clinical pain.

Unhelpful thoughts and distress regarding symptoms are associated with recovery from upper extremity fracture.

BACKGROUND: There is evidence that thoughts and emotions regarding symptoms are strongly associated with levels of comfort and capability for a given injury or disease. Longitudinal data from a large cohort of people recovering from an upper extremity fracture provided an opportunity to study how these mindset factors evolve during recovery. METHODS: Seven hundred and four adults (66% women, mean age 59 ± 21 years) recovering from upper extremity fracture completed two measures of reaction to symptoms (the Pain Catastrophizing Scale and the Tampa Scale of Kinesiophobia), a visual analog scale of pain intensity, and two measures of magnitude of incapability 1 week, 3 to 4 weeks, and 6 to 9 months after fracture. RESULTS: Exploratory factor analysis identified distinct groupings of questions addressing unhelpful thoughts and feelings of distress regarding symptoms. The number of distinct question groupings of mindset factors diminished over time. Variations in those groupings of mindset factors were associated with a notable amount of the variation in comfort and capability at all time points. Questions pertaining to unhelpful thoughts about symptoms had stronger associations with comfort and capability than questions measuring distress about symptoms, more so as recovery progressed. CONCLUSIONS: The need to integrate mental health into musculoskeletal is bolstered by the observation that mindsets-interpretation of symptoms in particular-are key contributors to comfort and capability.

Artificial neural networks outperform linear regression in estimating 9-month patient-reported outcomes after upper extremity fractures with increasing number of variables.

Objective: To compare performance between linear regression (LR) and artificial neural network (ANN) models in estimating 9-month patient-reported outcomes (PROs) after upper extremity fractures using various subsets of early mental, social, and physical health variables. Methods: We studied 734 patients with isolated shoulder, elbow, or wrist fracture who completed demographics, mental and social health measures, and PROs at baseline, 2-4 weeks, and 6-9 months postinjury. PROs included 3 measures of capability (QuickDASH, PROMIS-UE-PF, PROMIS-PI) and one of pain intensity. We developed ANN and LR models with various selections of variables (20, 23, 29, 34, and 54) to estimate 9-month PROs using a training subset (70%) and internally validated them using another subset (15%). We assessed the accuracy of the estimated value being within one MCID of the actual 9-month PRO value in a test subset (15%). Results: ANNs outperformed LR in estimating 9-month outcomes in all models except the 20-variable model for capability measures and 20-variable and 23-variable models for pain intensity. The accuracy of ANN versus LR in the primary model (29-variable) was 83% versus 73% (Quick-DASH), 68% versus 65% (PROMIS-UE-PF), 66% versus 62% (PROMIS-PI), and 78% versus 65% (pain intensity). Mental and social health factors contributed most to the estimations. Conclusion: ANNs outperform LR in estimating 9-month PROs, particularly with a larger number of variables. Given the otherwise relatively comparable performance, aspects such as practicality of collecting greater sets of variables, nonparametric distribution, and presence of nonlinear correlations should be considered when deciding between these statistical methods.

Understanding patient experience of distal tibia or ankle fracture: a qualitative systematic review.

To systematically review qualitative studies of patients with distal tibia or ankle fracture, and explore their experience of injury and recovery. We undertook a systematic review of qualitative studies. Five databases were searched from inception to 1 February 2022. All titles and abstracts were screened, and a subset were independently assessed. Methodological quality was appraised using the Critical Appraisal Skills Programme (CASP) checklist. The GRADE-CERQual checklist was used to assign confidence ratings. Thematic synthesis was used to analyze data with the identification of codes which were drawn together to form subthemes and then themes. From 2,682 records, 15 studies were reviewed in full and four included in the review. A total of 72 patients were included across the four studies (47 female; mean age 50 years (17 to 80)). Methodological quality was high for all studies, and the GRADE-CERQual checklist provided confidence that the findings were an adequate representation of patient experience of distal tibia or ankle fracture. A central concept of 'being the same but different' conveyed the substantial disruption to patients' self-identity caused by their injury. Patient experience of 'being the same but different' was expressed through three interrelated themes, with seven subthemes: i) being proactive where persistence, doing things differently and keeping busy prevailed; ii) living with change including symptoms, and living differently due to challenges at work and leisure; and iii) striving for normality, adapting while lacking in confidence, and feeling fearful and concerned about the future. Ankle injuries were disruptive, draining, and impacted on patients' wellbeing. Substantial short- and longer-term challenges were experienced during recovery. Rehabilitation and psychosocial treatment strategies may help to ameliorate these challenges. Patients may benefit from clinicians being cognisant of patient experience when assessing, treating, and discussing expectations and outcomes with patients.

Reverse shoulder arthroplasty versus hemiarthroplasty versus non-surgical treatment for older adults with acute 3- or 4-part fractures of the proximal humerus: study protocol for a randomised controlled trial (PROFHER-2: PROximal Fracture of Humerus Evaluation by Randomisation - Trial Number 2).

BACKGROUND: Proximal humerus fractures (PHF) are common and painful injuries, with the majority resulting from falls from a standing height. As with other fragility fractures, its age-specific incidence is increasing. Surgical treatment with hemiarthroplasty (HA) and reverse shoulder arthroplasty (RSA) have been increasingly used for displaced 3- and 4-part fractures despite a lack of good quality evidence as to whether one type of arthroplasty is superior to the other, and whether surgery is better than non-surgical management. The PROFHER-2 trial has been designed as a pragmatic, multicentre randomised trial to compare the clinical and cost-effectiveness of RSA vs HA vs Non-Surgical (NS) treatment in patients with 3- and 4-part PHF. METHODS: Adults over 65 years of age presenting with acute radiographically confirmed 3- or 4-part fractures, with or without associated glenohumeral joint dislocation, who consent for trial participation will be recruited from around 40 National Health Service (NHS) Hospitals in the UK. Patients with polytrauma, open fractures, presence of axillary nerve palsy, pathological (other than osteoporotic) fractures, and those who are unable to adhere to trial procedures will be excluded. We will aim to recruit 380 participants (152 RSA, 152 HA, 76 NS) using 2:2:1 (HA:RSA:NS) randomisation for 3- or 4-part fractures without joint dislocation, and 1:1 (HA:RSA) randomisation for 3- or 4-part fracture dislocations. The primary outcome is the Oxford Shoulder Score at 24 months. Secondary outcomes include quality of life (EQ-5D-5L), pain, range of shoulder motion, fracture healing and implant position on X-rays, further procedures, and complications. Independent Trial Steering Committee and Data Monitoring Committee will oversee the trial conduct, including the reporting of adverse events and harms. DISCUSSION: The PROFHER-2 trial is designed to provide a robust answer to guide the treatment of patients aged 65 years or over who sustain 3- and 4-part proximal humeral fractures. The pragmatic design and recruitment from around 40 UK NHS hospitals will ensure immediate applicability and generalisability of the trial findings. The full trial results will be made available in a relevant open-access peer-reviewed journal. TRIAL REGISTRATION: ISRCTN76296703. Prospectively registered on 5th April 2018.

A systematic review of outcome reporting in clinical trials of distal tibia and ankle fractures : the need for a core outcome set.

AIMS: To describe outcome reporting variation and trends in non-pharmacological randomized clinical trials (RCTs) of distal tibia and/or ankle fractures. METHODS: Five electronic databases and three clinical trial registries were searched (January 2000 to February 2022). Trials including patients with distal tibia and/or ankle fractures without concomitant injuries were included. One reviewer conducted all searches, screened titles and abstracts, assessed eligibility, and completed data extraction; a random 10% subset were independently assessed and extracted by a second reviewer at each stage. All extracted outcomes were mapped to a modified version of the International Classification of Functioning, Disability and Health framework. The quality of outcome reporting (reproducibility) was assessed. RESULTS: Overall, 105 trials (n = 16 to 669 participants) from 27 countries were included. Trials compared surgical interventions (n = 62), post-surgical management options (n = 17), rehabilitative interventions (n = 14), surgical versus non-surgical interventions (n = 6), and pre-surgical management strategies (n = 5). In total, 888 outcome assessments were reported across seven domains: 263 assessed body structure or function (85.7% of trials), 136 activities (68.6% of trials), 34 participation (23.8% of trials), 159 health-related quality of life (61.9% of trials), 247 processes of care (80% of trials), 21 patient experiences (15.2% of trials), and 28 economic impact (8.6% of trials). From these, 337 discrete outcomes were described. Outcome reporting was inconsistent across trials. The quality of reporting varied widely (reproducibility ranged 4.8% patient experience to 100% complications). CONCLUSION: Substantial heterogeneity in outcome selection, assessment methods, and reporting quality were described. Despite the large number of outcomes, few are reported across multiple trials. Most outcomes are clinically focused, with little attention to the long-term consequences important to patients. Poor reporting quality reduces confidence in data quality, inhibiting data synthesis by which to inform care decisions. Outcome reporting guidance and standardization, which captures the outcomes that matter to multiple stakeholders, are urgently required.Cite this article: Bone Jt Open 2022;3(10):832-840.

Symptoms of depression and catastrophic thinking attenuate the relationship of pain intensity and magnitude of incapability with fracture severity.

OBJECTIVE: The relative association of pain intensity and magnitude of incapability with pathophysiology, accounting for psychological factors, is incompletely understood. Using moderation analysis, we assessed the association of pain intensity and magnitude of incapability (dependent variables) with fracture severity (independent variable) and the influence of symptoms of depression and catastrophic thinking (moderators) at early and later stages of recovery. METHODS: A cohort of 731 patients recovering from a shoulder, elbow, or wrist fracture, completed self-reported measures of pain intensity, upper extremity capability, symptoms of depression, and catastrophic thinking between 2 and 4 weeks after injury and again between 6 and 9 months after injury. Fracture severity was rated by clinicians, and we used multivariable regression analysis to examine interaction effects of fracture severity, depression, catastrophic thinking, pain intensity, and magnitude of incapability at early and later stages of recovery. RESULTS: Symptoms of depression and catastrophic thinking attenuate the relationship between pain intensity and fracture severity at earlier and later stages of recovery. Symptoms of depression and catastrophic thinking also attenuate the relationship between the magnitude of incapability and fracture severity, but only at early stages of recovery. CONCLUSION: The relative divergence of pain intensity and magnitude of incapability from the level of fracture severity due to the moderating effects of unhelpful thinking and distress, signals a benefit to anticipating mental health opportunities during recovery after fracture. Fracture management can incorporate measures of unhelpful thinking and symptoms of distress to better address these opportunities and ensure comprehensive optimization of recovery. LEVEL OF EVIDENCE: Level IIc, prognostic.

Thalamic atrophy associated with painful osteoarthritis of the hip is reversible after arthroplasty: a longitudinal voxel-based morphometric study.

OBJECTIVE: Voxel-based morphometry (VBM) is a method of assessing brain gray matter volume that has previously been applied to various chronic pain conditions. From this previous work, it appears that chronic pain is associated with altered brain morphology. The present study was undertaken to assess these potential alterations in patients with painful hip osteoarthritis (OA). METHODS: We studied 16 patients with unilateral right-sided hip pain, before and 9 months after hip arthroplasty. This enabled comparison of gray matter volume in patients with chronic musculoskeletal pain versus healthy controls, as well as identification of any changes in volume following alleviation of pain (after surgery). Assessment involved self-completion questionnaires to assess pain, function, and psychosocial variables, and magnetic resonance imaging scanning of the brain for VBM analysis. RESULTS: Significant differences in brain gray matter volume between healthy controls and patients with painful hip arthritis were seen. Specifically, areas of the thalamus in patients with chronic OA pain exhibited decreased gray matter volume. Furthermore, when these preoperative changes were compared with the brain morphology of the patients 9 months after surgery, the areas of reduced thalamic gray matter volume were found to have "reversed" to levels seen in healthy controls. CONCLUSION: Our findings confirm that gray matter volume decreases within the left thalamus in the presence of chronic pain and disability in patients with hip OA. The results also show that these thalamic volume changes reverse after hip arthroplasty and are associated with decreased pain and increased function. These findings have potential implications with regard to optimizing the timing of orthopedic interventions such as arthroplasty.