NIHR Oxford Musculoskeletal Biomedical Research Centre

RASopathies are clinically overlapping neurodevelopmental syndromes resulting from germline mutations in genes involved in the rat sarcoma/mitogen-activated protein kinases (RAS/MAPK) pathway. Historically, RASopathies have been described by clinical phenotypes, such as Noonan syndrome and Neurofibromatosis type I. There is emerging evidence of the association between Noonan syndrome spectrum disorders (NSSD) and systemic lupus erythematosus (SLE). Here, we present an SLE patient diagnosed with SOS1-associated Noonan Syndrome (c.806 T>C; p.Met269Thr) as part of a research study. Reviewing the literature, we identified further 16 cases of NSSD associated with SLE. Nine out of 16 cases (56%) had a confirmed molecular diagnosis, with pathogenic missense variants identified in KRAS, PTPN11, and SHOC2 genes, the majority in the last. Variants in SHOC2 are the cause of only a small proportion of all presentations of NSSD. Our case represents the first reported case of SLE in a patient with a SOS1 pathogenic variant. Compared to the general SLE population, SLE in the presence of NSSD develops at a younger age, with a similar prevalence among females and males, suggesting a contribution of the RAS/MAPK pathway in the development of SLE.

Tendinopathy represents a major musculoskeletal health problem, yet its pathogenesis remains poorly understood. Tendinopathy development is studied in humans with early (<3 months of symptoms, n=14) (ET) or chronic (>3 months, n=16) (CT) patellar tendinopathy and in healthy subjects (n=15) (CTRL). Pain increases, and function declines with tendinopathy duration and correlated with tendon size (3T and 7T MRI). Tendon blood flow (Doppler ultrasonography) increases gradually in ET and CT, while peritendinous blood flow only rose in CT. Microscopy-based mapping (immunofluorescence microscopy and Cell DIVE) of vasculature shows marked changes in CT only, indicating flow increases in existing vessels early in tendinopathy, whereas angiogenesis is a late phenomenon. Cell DIVE indicates perivascular cell recruitment and potential lymphatic expansion in tendinopathy. Further, proteomics reveals that most matrix regulation occurs late in tendinopathy. Data from a previous study from the lab demonstrate faster treatment effect in tendinopathy with shorter symptom duration, supporting that early tissue changes may be more receptive to treatment. It is concluded that early tendinopathy is dominated by pain correlating with tendon swelling and hyperperfusion, whereas chronic tendinopathy is characterized by neovascularization and matrisome changes. These findings suggest that targeting early tissue changes can lead to superior treatment effects in tendinopathy.

Orthopedic trauma is a major cause of disability worldwide; around half of the people who sustain orthopedic trauma develop chronic pain. Quantitative Sensory Testing (QST) is a standardized method of assessing pain sensitivity, which may be useful in characterizing pain after injury and predicting chronic pain. This primary aim of this project was to test the feasibility of a portable QST battery, administered to adults 6-weeks post major orthopedic trauma and surgery. Twenty-nine participants (62% male; 52% black) who sustained major orthopedic trauma and surgery completed QST testing (including static measures, conditioned pain modulation, and mechanical temporal summation) at their 6-week postoperative visit and were invited to complete a 6-month follow-up survey. We examined feasibility and acceptability indices and explored associations between QST and clinical pain ratings. Of all eligible patients, 77% were recruited. QST procedures were feasible and tolerable. No participant declined participation, withdrew for reasons related to study procedures, or discontinued QST due to discomfort. No patient experienced increased clinical pain after QST. Exploratory analyses identified a positive association between static QST and pain interference at T1. Feasibility challenges included poor 6-month retention (57%) and difficulty administering QST to patients with upper extremity injuries. High rates of analgesic use before testing (38%) poses an additional barrier for future QST studies in this population. QST was acceptable and partially feasible; challenges included poor retention, high rates of analgesic use, and logistical barriers to accessing injury sites for testing. We pose several potential solutions for future research.

BackgroundProximal humeral fractures (PHFs) are common injuries, but their management has remained controversial. Recent high-level evidence from randomized clinical trials has shown that for many PHFs, surgical treatment is not superior to non-surgical treatment. Our primary aim was to conduct a multi-nation assessment of temporal trends and changes in surgical treatment of isolated PHF in Denmark, England, and Sweden. A secondary aim was to estimate the incidence of serious adverse events (SAEs) within 30 days (and death within 90 days) of primary surgery.MethodsThis population-based cohort study presents routinely collected data from Danish, English, and Swedish patient registries and electronic health records from 1998 to 2018. All adult patients with isolated PHFs combined with predefined surgical procedure codes were included. Age- and sex-specific incidence rates (IRs) of surgery and each surgical procedure per calendar year were calculated. Kaplan–Meier plots displayed patient survival for the study period. Incidence proportions of SAEs within 30 days (and death within 90 days) of surgery were computed.ResultsA total of 54,077 primary surgical procedures, performed in 53,852 patients with isolated PHF, were included. Denmark and Sweden had the highest IR of surgery, with Denmark peaking at 17.4/100,000 person-years in 2011 and Sweden peaking at 18/100,000 person-years in 2013, while England peaked at 5/100,000 person-years in 2010. From 2004, plate fixation was the leading surgical procedure in Denmark and Sweden, while arthroplasty was the most frequent in England. The IR of surgery in Denmark and Sweden was 8–10 times higher for women aged 80 years than that observed in England. The 30-day incidence of SAEs varied between countries, ranging from 0.03% to 3.51%.ConclusionsVariations in surgical practice for isolated PHF exist between Denmark, England, and Sweden, with differences in overall IRs of surgery and preferred procedures. A complex interplay between hospitals, surgeons, healthcare systems, and evidence-based factors is likely to explain such variations. However, in all three countries, the IR of surgery, particularly for the use of locking plates, demonstrated a decline from 2013, coinciding with high-quality trials and meta-analyses suggesting that evidence-based factors are becoming more prominent in orthopaedic treatment decisions.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12916-025-04414-2.

Labels for neck pain after a motor vehicle crash (MVC) influenced recovery expectations and management preferences. Research is needed to understand why these expectations and preferences varied based on the label given. To explore how people perceive different labels for neck pain after an MVC. We performed a content analysis of qualitative data from a randomised controlled study. 2229 participants with and without neck pain read a vignette describing a patient with neck pain after an MVC, using one of five labels: whiplash injury, whiplash-associated disorder, post-traumatic neck pain, neck pain, or neck strain. Participants provided free-text responses on the label's meaning, associated words/feelings, required health services/treatments, and any confusion about the label. Compared to neck strain, post-traumatic neck pain, whiplash-associated disorder, and neck pain more commonly evoked negative feelings about symptom severity and prognosis (4.7% for neck strain versus 7.2%-16.0% for other labels) and psychological distress (7.3% versus 13.0%-30.3%). Regarding treatment preference, neck pain most commonly promoted need for passive physical therapies (21.6%) and imaging (9.8%), whereas neck strain most often promoted need for exercise (11.6%) and rarely imaging (3.4%). Neck pain was the most confusing label (39.9%), while whiplash injury was the least (14.8%), with confusion arising from vagueness or a mismatch with diagnostic expectations. The meanings, feelings and confusions evoked by neck pain labels after an MVC may explain their impact on recovery expectations and management preferences. Clinicians may consider avoid labels associated with negative feelings and lower preferences for guideline-recommended treatments.

Introduction:Percutaneous tenotomy is an emerging, minimally-invasive procedure to treat muscle and tendon contractures, including those resulting from spasticity. Such contractures often cause pain, functional impairment, impact quality of life and may not respond to conservative or medical therapy. Further, spastic contractures typically affect frail, older patients unsuitable for management with open surgical procedures. We undertook the first PRISMA-compliant systematic review exploring use of percutaneous tenotomy to manage contractures occurring in the context of spasticity in adults.Methods:We searched 6 databases for primary research papers featuring an entirely adult sample undergoing percutaneous tenotomy, published in either English or French. Quality assessment was performed using the Oxford Centre for Evidence-Based Medicine Scale and the Methodological Index for Non-Randomized Studies. Synthesis of included study data was performed where possible.Results:Six studies were included, reporting 160 patients undergoing more than 430 tenotomies to 27 different tendons. All were low quality. Synthesis of evidence across studies indicated that percutaneous tenotomy has a low complication rate and may support patients to obtain a range of post-operative goals, including improved skin hygiene, ease of patient care and joint range. However, synthesis across studies was limited by heterogenous patient assessment and poor reporting.Conclusion:This review found some evidence supporting the safety and efficacy of percutaneous tenotomy in adults with contracture, but higher-quality studies are required. Further work should standardise the approach and reporting of these procedures to facilitate evidence synthesis and to develop best practice.

ObjectivesThe study aimed to identify key priorities for improving a transitional adolescent and young adult rheumatology service through a comprehensive mixed methods service evaluation.MethodsWe used a group concept mapping methodology. Patients (ages 16–25 years) attending an adolescent and young adult (AYA) rheumatology clinic completed idea generation, sorting and rating activities related to their experiences in the AYA service. Multidimensional scaling and hierarchical cluster analysis were applied to the sorted ideas to generate a concept map containing themed clusters of ideas. Rating data were analysed to identify themed clusters containing specific ideas to determine whether these were being successfully met and to identify specific targets for future service improvements.ResultsA total of 48 patients participated in idea generation, 10 in sorting and 37 in rating activities. The concept map revealed six key themed clusters: Rheumatology Service Contact and Personal Information, Employment and Education Support and Advice, Mental Health and Well-being Support, Education and Advice About My Condition, General Clinic Improvements and Young Adult Specific Clinic Improvements. Specific improvement targets were identified within each of these themed clusters.ConclusionThis group concept mapping evaluation identified that the AYA rheumatology service was successfully meeting the needs of patients in many ways and helped to identify specific targets for future improvements. The resulting concept map provides a platform for use in partnership with patients to facilitate the co-design of future clinic improvements.

Abstract Serum creatine kinase (CK) is a routinely measured biomarker of muscle damage, yet the genetic factors underlying inter-individual variation in CK levels remain poorly defined. Here we present the largest multi-ancestry genome-wide association meta-analysis of serum CK to date, comprising 237,255 participants spanning Admixed American, African American, East Asian, European and Middle Eastern populations. We identify 107 independent loci at genome-wide significance (P&lt;5x10 -8 ), 98 of which are previously unreported, with pronounced enrichment for genes expressed in skeletal and cardiac muscle and overlap with pathways related to muscle structure and function. Notably, eight loci map to genes implicated in Mendelian myopathies, underscoring a continuum from common regulatory variation to rare pathogenic mutations. Integrative quantitative trait locus (QTL)-based Mendelian randomization and colocalization implicate several genes in CK regulation, most prominently SMAD3 , KLF5 and STAT3 within the transforming growth factor beta signalling pathway. CK levels show positive genetic correlations with traits reflecting tissue damage and muscle mass, and negative correlations with C-reactive protein, indicating pleiotropic effects on muscle biology and enzyme clearance. Together, these findings delineate the genetic architecture of serum CK across diverse populations and provide insight into the genetic basis of muscle-damage risk and subclinical CK elevation.

Abstract mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, i.e. they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability. In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex-vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low-dose mTOR inhibition. To test this in vivo , we conducted a placebo-controlled experimental medicine trial in older adults administered with low-dose rapamycin. p21, a marker of DNA damage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycin’s exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure, and even the hazards of cosmic radiation in space travel.

Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naive CD4+ T cells. Our data demonstrates that LCK mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic LCK/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.