Aims. Pellino1 (Peli1) has been reported to regulate various inflammatory diseases. This study aims to explore the role of Peli1 in the occurrence and development of osteoarthritis (OA), so as to find new targets for the treatment of OA. Methods. After inhibiting Peli1 expression in chondrocytes with small interfering RNA (siRNA), interleukin (IL)-1β was used to simulate inflammation, and OA-related indicators such as synthesis, decomposition, inflammation, and apoptosis were detected. Toll-like receptor (TLR) and nuclear factor-kappa B (NF-κB) signalling pathway were detected. After inhibiting the expression of Peli1 in macrophages Raw 264.7 with siRNA and intervening with lipopolysaccharide (LPS), the polarization index of macrophages was detected, and the supernatant of macrophage medium was extracted as conditioned medium to act on chondrocytes and detect the apoptosis index. The OA model of mice was established by destabilized medial meniscus (DMM) surgery, and adenovirus was injected into the knee cavity to reduce the expression of Peli1. The degree of cartilage destruction and synovitis were evaluated by haematoxylin and eosin (H&E) staining, Safranin O/Fast Green staining, and immunohistochemistry. Results. In chondrocytes, knockdown of Peli1 produced anti-inflammatory and anti-apoptotic effects by targeting the TLR and NF-κB signalling pathways. We found that in macrophages, knockdown of Peli1 can inhibit M1-type polarization of macrophages. In addition, the corresponding conditioned culture medium of macrophages applied to chondrocytes can also produce an anti-apoptotic effect. During in vivo experiments, the results have also shown that knockdown Peli1 reduces cartilage destruction and synovial inflammation. Conclusion. Knockdown of Peli1 has a therapeutic effect on OA, which therefore makes it a potential therapeutic target for OA. Cite this article: Bone Joint Res 2023;12(2):121–132

Aims. Degenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive. Methods. Predicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis. Results. The TWAS detected 420 DCS genes with p < 0.05 in skeletal muscle, such as ribosomal protein S15A (RPS15A) (PTWAS = 0.001), and 110 genes in whole blood, such as selectin L (SELL) (PTWAS = 0.001). Comparison with the DCS RNA expression profile identified 12 common genes, including Apelin Receptor (APLNR) (PTWAS = 0.001, PDEG = 0.025). In total, 148 DCS-enriched Gene Ontology (GO) terms were identified, such as mast cell degranulation (GO:0043303); 15 DCS-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified, such as the sphingolipid signalling pathway (ko04071). Nine terms, such as degradation of the extracellular matrix (R-HSA-1474228), were common to the TWAS enrichment results and the RNA expression profile. Conclusion. Our results identify putative susceptibility genes; these findings provide new ideas for exploration of the genetic mechanism of DCS development and new targets for preclinical intervention and clinical treatment. Cite this article: Bone Joint Res 2023;12(1):80–90

Aims. This is a multicentre, prospective assessment of a proportion of the overall orthopaedic trauma caseload of the UK. It investigates theatre capacity, cancellations, and time to surgery in a group of hospitals that is representative of the wider population. It identifies barriers to effective practice and will inform system improvements. Methods. Data capture was by collaborative approach. Patients undergoing procedures from 22 August 2022 and operated on before 31 October 2022 were included. Arm one captured weekly caseload and theatre capacity. Arm two concerned patient and injury demographics, and time to surgery for specific injury groups. Results. Data was available from 90 hospitals across 86 data access groups (70 in England, two in Wales, ten in Scotland, and four in Northern Ireland). After exclusions, 709 weeks' of data on theatre capacity and 23,138 operations were analyzed. The average number of cases per operating session was 1.73. Only 5.8% of all theatre sessions were dedicated day surgery sessions, despite 29% of general trauma patients being eligible for such pathways. In addition, 12.3% of patients experienced at least one cancellation. Delays to surgery were longest in Northern Ireland and shortest in England and Scotland. There was marked variance across all fracture types. Open fractures and fragility hip fractures, influenced by guidelines and performance renumeration, had short waits, and varied least. In all, nine hospitals had 40 or more patients waiting for surgery every week, while seven had less than five. Conclusion. There is great variability in operative demand and list provision seen in this study of 90 UK hospitals. There is marked variation in nearly all injuries apart from those associated with performance monitoring. There is no evidence of local network level coordination of care for orthopaedic trauma patients. Day case operating and pathways of care are underused and are an important area for service improvement. Cite this article: Bone Jt Open 2023;4(6):463–471

Aims. Weightbearing instructions after musculoskeletal injury or orthopaedic surgery are a key aspect of the rehabilitation pathway and prescription. The terminology used to describe the weightbearing status of the patient is variable; many different terms are used, and there is recognition and evidence that the lack of standardized terminology contributes to confusion in practice. Methods. A consensus exercise was conducted involving all the major stakeholders in the patient journey for those with musculoskeletal injury. The consensus exercise primary aim was to seek agreement on a standardized set of terminology for weightbearing instructions. Results. A pre-meeting questionnaire was conducted. The one-day consensus meeting, including patient representatives, identified three agreed terms only to be used in defining the weightbearing status of the patient: 1) non-weightbearing; 2) limited weightbearing; and 3) unrestricted weightbearing. Conclusion. This study represents the first and only exercise in standardizing rehabilitation terminology in orthopaedics, as agreed by all major stakeholders in the patient pathway and the patients themselves. The standardization of language allows for higher-quality and more accurate research to be conducted, and is one small part of the bigger picture in increasing the mobility of patients after orthopaedic injury or surgery. Cite this article: Bone Joint J 2024;106-B(9):1016–1020

Aims. Ankle fractures are common injuries and the third most common fragility fracture. In all, 40% of ankle fractures in the frail are open and represent a complex clinical scenario, with morbidity and mortality rates similar to hip fracture patients. They have a higher risk of complications, such as wound infections, malunion, hospital-acquired infections, pressure sores, veno-thromboembolic events, and significant sarcopaenia from prolonged bed rest. Methods. A modified Delphi method was used and a group of experts with a vested interest in best practice were invited from the British Foot and Ankle Society (BOFAS), British Orthopaedic Association (BOA), Orthopaedic Trauma Society (OTS), British Association of Plastic & Reconstructive Surgeons (BAPRAS), British Geriatric Society (BGS), and the British Limb Reconstruction Society (BLRS). Results. In the first stage, there were 36 respondents to the survey, with over 70% stating their unit treats more than 20 such cases per year. There was a 50:50 split regarding if the timing of surgery should be within 36 hours, as per the hip fracture guidelines, or 72 hours, as per the open fracture guidelines. Overall, 75% would attempt primary wound closure and 25% would utilize a local flap. There was no orthopaedic agreement on fixation, and 75% would permit weightbearing immediately. In the second stage, performed at the BLRS meeting, experts discussed the survey results and agreed upon a consensus for the management of open elderly ankle fractures. Conclusion. A mutually agreed consensus from the expert panel was reached to enable the best practice for the management of patients with frailty with an open ankle fracture: 1) all units managing lower limb fragility fractures should do so through a cohorted multidisciplinary pathway. This pathway should follow the standards laid down in the "care of the older or frail orthopaedic trauma patient" British Orthopaedic Association Standards for Trauma and Orthopaedics (BOAST) guideline. These patients have low bone density, and we should recommend full falls and bone health assessment; 2) all open lower limb fragility fractures should be treated in a single stage within 24 hours of injury if possible; 3) all patients with fragility fractures of the lower limb should be considered for mobilisation on the day following surgery; 4) all patients with lower limb open fragility fractures should be considered for tissue sparing, with judicious debridement as a default; 5) all patients with open lower limb fragility fractures should be managed by a consultant plastic surgeon with primary closure wherever possible; and 6) the method of fixation must allow for immediate unrestricted weightbearing. Cite this article: Bone Jt Open 2024;5(3):236–242

Aims. Elective orthopaedic surgery was cancelled early in the COVID-19 pandemic and is currently running at significantly reduced capacity in most institutions. This has resulted in a significant backlog to treatment, with some hospitals projecting that waiting times for arthroplasty is three times the pre-COVID-19 duration. There is concern that the patient group requiring arthroplasty are often older and have more medical comorbidities—the same group of patients advised they are at higher risk of mortality from catching COVID-19. The aim of this study is to investigate the morbidity and mortality in elective patients operated on during the COVID-19 pandemic and compare this to a pre-pandemic cohort. Primary outcome was 30-day mortality. Secondary outcomes were perioperative complications, including nosocomial COVID-19 infection. These operations were performed in a district general hospital, with COVID-19 acute admissions in the same building. Methods. Our institution reinstated elective operations using a “Blue stream” pathway, which involves isolation before and after surgery, COVID-19 testing pre-admission, and separation of ward and theatre pathways for “blue” patients. A register of all arthroplasties was taken, and their clinical course and investigations recorded. Results. During a seven-month period, 340 elective arthroplasties were performed. There was zero mortality. One patient had a positive swab for COVID-19 while an inpatient, but remained asymptomatic. There were two readmissions within a 12-week period for hip dislocation. Patients had a mean age of 68 years (28 to 90), mean BMI of 30 kg/m. 2. (19.0 to 45.6), and mean American Society of Anesthesiologists grade of 2 (1 to 3). Conclusion. Results show no increased morbidity or mortality in this cohort of patients compared to the same hospital’s morbidity and mortality pre-COVID-19. The screened pathway for elective patients is effective in ensuring that patients can be safely operated on electively in an acute hospital. This study should reassure clinicians and patients that arthroplasties can be carried out safely when the appropriate precautions are in place. Cite this article: Bone Jt Open 2021;2(11):940–944

Aims. Circular RNAs (circRNAs) are a novel type of non-coding RNA that plays major roles in the development of diverse diseases including osteonecrosis of the femoral head (ONFH). Here, we explored the impact of hsa_circ_0066523 derived from forkhead box P1 (FOXP1) (also called circFOXP1) on bone mesenchymal stem cells (BMSCs), which is important for ONFH development. Methods. RNA or protein expression in BMSCs was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot, respectively. Cell Counting Kit 8 (CCK8) and 5-ethynyl-2’-deoxyuridine (EdU) were used to analyze cell proliferation. Alkaline phosphatase (ALP) activity, ALP staining, and Alizarin Red S staining were employed to evaluate the osteoblastic differentiation. Chromatin immunoprecipitation (ChIP), luciferase reporter, RNA pull down, and RNA immunoprecipitation (RIP) assays were combined for exploring molecular associations. Results. Circ_0066523 was upregulated in osteogenic induction process of BMSCs. Silencing circ_0066523 restrained the proliferation and osteogenic differentiation of BMSCs. Mechanistically, circ_0066523 activated phosphatidylinositol-4,5-bisphosphate 3-kinase / AKT serine/threonine kinase 1 (PI3K/AKT) pathway via recruiting lysine demethylase 5B (KDM5B) to epigenetically repress the transcription of phosphatase and tensin homolog (PTEN). Functionally, AKT signalling pathway agonist or PTEN knockdown counteracted the effects of silenced circ_0066523 on BMSC proliferation and differentiation. Conclusion. Circ_0066523 promotes the proliferation and differentiation of BMSCs by epigenetically repressing PTEN and therefore activating AKT pathway. This finding might open new avenues for the identification of therapeutic targets for osteoblast differentiation related diseases such as ONFH. Cite this article: Bone Joint Res 2021;10(8):526–535

Aims. The aim of this study was to investigate the global and local impact of fat on bone in obesity by using the diet-induced obese (DIO) mouse model. Methods. In this study, we generated a diet-induced mouse model of obesity to conduct lipidomic and 3D imaging assessments of bone marrow fat, and evaluated the correlated bone adaptation indices and bone mechanical properties. Results. Our results indicated that bone mass was reduced and bone mechanical properties were impaired in DIO mice. Lipidomic sequencing and bioinformatic analysis identified 373 differential lipids, 176 of which were upregulated and 197 downregulated. Functional enrichment analysis revealed a significant downregulation of the pathways: fat digestion and absorption (ko04975) and lipolysis regulation in adipocytes (ko04923) in DIO mice, leading to local fat accumulation. The use of 3D imaging confirmed the increase in fat accumulation within the bone marrow cavity of obese mice. Conclusion. Our study sheds light on the intricate interplay between fat and bone, and provides a non-toxic and non-invasive method for measuring marrow adipose tissue. Cite this article: Bone Joint Res 2023;12(9):580–589

Despite the vast quantities of published artificial intelligence (AI) algorithms that target trauma and orthopaedic applications, very few progress to inform clinical practice. One key reason for this is the lack of a clear pathway from development to deployment. In order to assist with this process, we have developed the Clinical Practice Integration of Artificial Intelligence (CPI-AI) framework – a five-stage approach to the clinical practice adoption of AI in the setting of trauma and orthopaedics, based on the IDEAL principles (. https://www.ideal-collaboration.net/. ). Adherence to the framework would provide a robust evidence-based mechanism for developing trust in AI applications, where the underlying algorithms are unlikely to be fully understood by clinical teams. Cite this article: Bone Joint Res 2024;13(9):507–512

Aims. The aim of this study was to explore clinicians’ experience of a paediatric randomized controlled trial (RCT) comparing surgical reduction with non-surgical casting for displaced distal radius fractures. Methods. Overall, 22 staff from 15 hospitals who participated in the RCT took part in an interview. Interviews were informed by phenomenology and analyzed using thematic analysis. Results. Analysis of the findings identified the overarching theme of “overcoming obstacles”, which described the challenge of alleviating staff concerns about the use of non-surgical casting and recruiting families where there was treatment uncertainty. In order to embed and recruit to the Children’s Radius Acute Fracture Fixation Trial (CRAFFT), staff needed to fit the study within clinical practice, work together, negotiate treatment decisions, and support families. Conclusion. Recruiting families to this RCT was challenging because staff were uncertain about longer-term patient outcomes, and the difficulties were exacerbated by interdisciplinary tensions. Strong family and clinician beliefs, coupled with the complex nature of emergency departments and patient pathways that differed site-by-site, served as barriers to recruitment. Cementing a strong research culture, and exploring families’ treatment preferences, helped to overcome recruitment obstacles. Cite this article: Bone Jt Open 2024;5(4):324–334

Aims. The aim of this study was to surveil whether the standard operating procedure created for the NHS Golden Jubilee sufficiently managed COVID-19 risk to allow safe resumption of elective orthopaedic surgery. Methods. This was a prospective study of all elective orthopaedic patients within an elective unit running a green pathway at a COVID-19 light site. Rates of preoperative and 30-day postoperative COVID-19 symptoms or infection were examined for a period of 40 weeks. The unit resumed elective orthopaedic services on 29 June 2020 at a reduced capacity for a limited number of day-case procedures with strict patient selection criteria, increasing to full service on 29 August 2020 with no patient selection criteria. Results. A total of 2,373 cases were planned in the 40-week study period. Surgery was cancelled in 59 cases, six (10.2%) of which were due to having a positive preoperative COVID-19 screening test result. Of the remaining 2,314, 996 (43%) were male and 1,318 (57%) were female. The median age was 67 years (interquartile range 59.2 to 74.6). The median American Society of Anesthesiologists grade was 2. Hip and knee arthroplasties accounted for the majority of the operations (76%). Six patients tested positive for COVID-19 preoperatively (0.25%) and 39 patients were tested for COVID-19 within 30 days after discharge, with only five patients testing positive (0.22%). Conclusion. Through strict application of a COVID-19 green pathway, elective orthopaedic surgery could be safely delivered to a large number of patients with no selection criteria. Cite this article: Bone Jt Open 2021;2(11):951–957

Aims. Tert-butylhydroquinone (tBHQ) has been identified as an inhibitor of oxidative stress-induced injury and apoptosis in human neural stem cells. However, the role of tBHQ in osteoarthritis (OA) is unclear. This study was carried out to investigate the role of tBHQ in OA. Methods. OA animal model was induced by destabilization of the medial meniscus (DMM). Different concentrations of tBHQ (25 and 50 mg/kg) were intraperitoneally injected in ten-week-old female mice. Chondrocytes were isolated from articular cartilage of mice and treated with 5 ng/ml lipopolysaccharide (LPS) or 10 ng/ml interleukin 1 beta (IL-1β) for 24 hours, and then treated with different concentrations of tBHQ (10, 20, and 40 μM) for 12 hours. The expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in blood were measured. The expression levels of interleukin 6 (IL-6), IL-1β, and tumour necrosis factor alpha (TNF-α) leptin in plasma were measured using enzyme-linked immunoabsorbent assay (ELISA) kits. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathway proteins, and macrophage repolarization-related markers, were detected by western blot. Results. Tert-butylhydroquinone significantly attenuated cartilage destruction in DMM-induced mice in vivo. It demonstrated clear evidence of inhibiting IL-1β-induced chondrocyte apoptosis, inflammation, and differentiation defect in vitro. Meanwhile, tBHQ inhibited LPS-induced activation of NF-κB and MAPK signalling pathways, and also inhibited LPS-induced reactive oxygen species production and macrophages repolarization in vitro. Conclusion. Taken together, tBHQ might be a potential therapeutic strategy for protecting against OA development. Cite this article: Bone Joint Res 2021;10(11):704–713

Aims. The aim of this study was to determine the fracture haematoma (fxH) proteome after multiple trauma using label-free proteomics, comparing two different fracture treatment strategies. Methods. A porcine multiple trauma model was used in which two fracture treatment strategies were compared: early total care (ETC) and damage control orthopaedics (DCO). fxH was harvested and analyzed using liquid chromatography-tandem mass spectrometry. Per group, discriminating proteins were identified and protein interaction analyses were performed to further elucidate key biomolecular pathways in the early fracture healing phase. Results. The early fxH proteome was characterized by immunomodulatory and osteogenic proteins, and proteins involved in the coagulation cascade. Treatment-specific proteome alterations were observed. The fxH proteome of the ETC group showed increased expression of pro-inflammatory proteins related to, among others, activation of the complement system, neutrophil functioning, and macrophage activation, while showing decreased expression of proteins related to osteogenesis and tissue remodelling. Conversely, the fxH proteome of the DCO group contained various upregulated or exclusively detected proteins related to tissue regeneration and remodelling, and proteins related to anti-inflammatory and osteogenic processes. Conclusion. The early fxH proteome of the ETC group was characterized by the expression of immunomodulatory, mainly pro-inflammatory, proteins, whereas the early fxH proteome of the DCO group was more regenerative and osteogenic in nature. These findings match clinical observations, in which enhanced surgical trauma after multiple trauma causes dysbalanced inflammation, potentially leading to reduced tissue regeneration, and gained insights into regulatory mechanisms of fracture healing after severe trauma. Cite this article: Bone Joint Res 2024;13(5):214–225

Aims. The effects of remnant preservation on the anterior cruciate ligament (ACL) and its relationship with the tendon graft remain unclear. We hypothesized that the co-culture of remnant cells and bone marrow stromal cells (BMSCs) decreases apoptosis and enhances the activity of the hamstring tendons and tenocytes, thus aiding ACL reconstruction. Methods. The ACL remnant, bone marrow, and hamstring tendons were surgically harvested from rabbits. The apoptosis rate, cell proliferation, and expression of types I and III collagen, transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), and tenogenic genes (scleraxis (SCX), tenascin C (TNC), and tenomodulin (TNMD)) of the hamstring tendons were compared between the co-culture medium (ACL remnant cells (ACLRCs) and BMSCs co-culture) and control medium (BMSCs-only culture). We also evaluated the apoptosis, cell proliferation, migration, and gene expression of hamstring tenocytes with exposure to co-culture and control media. Results. Compared to BMSCs-only culture medium, the co-culture medium showed substantially decreased early and late apoptosis rates, attenuation of intrinsic and extrinsic apoptotic pathways, and enhanced proliferation of the hamstring tendons and tenocytes. In addition, the expression of collagen synthesis, TGF-β, VEGF, and tenogenic genes in the hamstring tendons and tenocytes significantly increased in the co-culture medium compared to that in the control medium. Conclusion. In the presence of ACLRCs and BMSCs, the hamstring tendons and tenocytes significantly attenuated apoptosis and enhanced the expression of collagen synthesis, TGF-β, VEGF, and tenogenic genes. This in vitro study suggests that the ACLRCs mixed with BMSCs could aid regeneration of the hamstring tendon graft during ACL reconstruction. Cite this article: Bone Joint Res 2023;12(1):9–21

Aims. Periprosthetic hip-joint infection is a multifaceted and highly detrimental outcome for patients and clinicians. The incidence of prosthetic joint infection reported within two years of primary hip arthroplasty ranges from 0.8% to 2.1%. Costs of treatment are over five-times greater in people with periprosthetic hip joint infection than in those with no infection. Currently, there are no national evidence-based guidelines for treatment and management of this condition to guide clinical practice or to inform clinical study design. The aim of this study is to develop guidelines based on evidence from the six-year INFection and ORthopaedic Management (INFORM) research programme. Methods. We used a consensus process consisting of an evidence review to generate items for the guidelines and online consensus questionnaire and virtual face-to-face consensus meeting to draft the guidelines. Results. The consensus panel comprised 21 clinical experts in orthopaedics, primary care, rehabilitation, and healthcare commissioning. The final output from the consensus process was a 14-item guideline. The guidelines make recommendations regarding increased vigilance and monitoring of those at increased risk of infection; diagnosis including strategies to ensure the early recognition of prosthetic infection and referral to orthopaedic teams; treatment, including early use of DAIR and revision strategies; and postoperative management including appropriate physical and psychological support and antibiotic strategies. Conclusion. We believe the implementation of the INFORM guidelines will inform treatment protocols and clinical pathways to improve the treatment and management of periprosthetic hip infection. Cite this article: Bone Jt Open 2023;4(4):226–233

Aims. Knee osteoarthritis (OA) involves a variety of tissues in the joint. Gene expression profiles in different tissues are of great importance in order to understand OA. Methods. First, we obtained gene expression profiles of cartilage, synovium, subchondral bone, and meniscus from the Gene Expression Omnibus (GEO). Several datasets were standardized by merging and removing batch effects. Then, we used unsupervised clustering to divide OA into three subtypes. The gene ontology and pathway enrichment of three subtypes were analyzed. CIBERSORT was used to evaluate the infiltration of immune cells in different subtypes. Finally, OA-related genes were obtained from the Molecular Signatures Database for validation, and diagnostic markers were screened according to clinical characteristics. Quantitative reverse transcription polymerase chain reaction (qRT‐PCR) was used to verify the effectiveness of markers. Results. C1 subtype is mainly concentrated in the development of skeletal muscle organs, C2 lies in metabolic process and immune response, and C3 in pyroptosis and cell death process. Therefore, we divided OA into three subtypes: bone remodelling subtype (C1), immune metabolism subtype (C2), and cartilage degradation subtype (C3). The number of macrophage M0 and activated mast cells of C2 subtype was significantly higher than those of the other two subtypes. COL2A1 has significant differences in different subtypes. The expression of COL2A1 is related to age, and trafficking protein particle complex subunit 2 is related to the sex of OA patients. Conclusion. This study linked different tissues with gene expression profiles, revealing different molecular subtypes of patients with knee OA. The relationship between clinical characteristics and OA-related genes was also studied, which provides a new concept for the diagnosis and treatment of OA. Cite this article: Bone Joint Res 2023;12(12):702–711

Aims. This study was performed to explore the effect of melatonin on pyroptosis in nucleus pulposus cells (NPCs) and the underlying mechanism of that effect. Methods. This experiment included three patients diagnosed with lumbar disc herniation who failed conservative treatment. Nucleus pulposus tissue was isolated from these patients when they underwent surgical intervention, and primary NPCs were isolated and cultured. Western blotting, reverse transcription polymerase chain reaction, fluorescence staining, and other methods were used to detect changes in related signalling pathways and the ability of cells to resist pyroptosis. Results. Western blot analysis confirmed the expression of cleaved CASP-1 and melatonin receptor (MT-1A-R) in NPCs. The cultured NPCs were identified by detecting the expression of CD24, collagen type II, and aggrecan. After treatment with hydrogen peroxide, the pyroptosis-related proteins NLR family pyrin domain containing 3 (NLRP3), cleaved CASP-1, N-terminal fragment of gasdermin D (GSDMD-N), interleukin (IL)-18, and IL-1β in NPCs were upregulated, and the number of propidium iodide (PI)-positive cells was also increased, which was able to be alleviated by pretreatment with melatonin. The protective effect of melatonin on pyroptosis was blunted by both the melatonin receptor antagonist luzindole and the nuclear factor erythroid 2–related factor 2 (Nrf2) inhibitor ML385. In addition, the expression of the transcription factor Nrf2 was up- or downregulated when the melatonin receptor was activated or blocked by melatonin or luzindole, respectively. Conclusion. Melatonin protects NPCs against reactive oxygen species-induced pyroptosis by upregulating the transcription factor Nrf2 via melatonin receptors. Cite this article: Bone Joint Res 2023;12(3):202–211

Aims. This study aimed to explore the role of small colony variants (SCVs) of Staphylococcus aureus in intraosseous invasion and colonization in patients with periprosthetic joint infection (PJI). Methods. A PJI diagnosis was made according to the MusculoSkeletal Infection Society (MSIS) for PJI. Bone and tissue samples were collected intraoperatively and the intracellular invasion and intraosseous colonization were detected. Transcriptomics of PJI samples were analyzed and verified by polymerase chain reaction (PCR). Results. SCVs can be isolated from samples collected from chronic PJIs intraoperatively. Transmission electron microscopy (TEM) and immunofluorescence (IF) showed that there was more S. aureus in bone samples collected from chronic PJIs, but much less in bone samples from acute PJIs, providing a potential mechanism of PJI. Immunofluorescence results showed that SCVs of S. aureus were more likely to invade osteoblasts in vitro. Furthermore, TEM and IF also demonstrated that SCVs of S. aureus were more likely to invade and colonize in vivo. Cluster analysis and principal component analysis (PCA) showed that there were substantial differences in gene expression profiles between chronic and acute PJI. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these differentially expressed genes were enriched to chemokine-related signal pathways. PCR also verified these results. Conclusion. Our study has shown that the S. aureus SCVs have a greater ability to invade and colonize in bone, resulting in S. aureus remaining in bone tissues long-term, thus explaining the pathogenesis of chronic PJI. Cite this article: Bone Joint Res 2022;11(12):843–853

Aims. Rotator cuff muscle atrophy and fatty infiltration affect the clinical outcomes of rotator cuff tear patients. However, there is no effective treatment for fatty infiltration at this time. High-intensity interval training (HIIT) helps to activate beige adipose tissue. The goal of this study was to test the role of HIIT in improving muscle quality in a rotator cuff tear model via the β3 adrenergic receptor (β3AR). Methods. Three-month-old C57BL/6 J mice underwent a unilateral rotator cuff injury procedure. Mice were forced to run on a treadmill with the HIIT programme during the first to sixth weeks or seventh to 12th weeks after tendon tear surgery. To study the role of β3AR, SR59230A, a selective β3AR antagonist, was administered to mice ten minutes before each exercise through intraperitoneal injection. Supraspinatus muscle, interscapular brown fat, and inguinal subcutaneous white fat were harvested at the end of the 12th week after tendon tear and analyzed biomechanically, histologically, and biochemically. Results. Histological analysis of supraspinatus muscle showed that HIIT improved muscle atrophy, fatty infiltration, and contractile force compared to the no exercise group. In the HIIT groups, supraspinatus muscle, interscapular brown fat, and inguinal subcutaneous white fat showed increased expression of tyrosine hydroxylase and uncoupling protein 1, and upregulated the β3AR thermogenesis pathway. However, the effect of HIIT was not present in mice injected with SR59230A, suggesting that HIIT affected muscles via β3AR. Conclusion. HIIT improved supraspinatus muscle quality and function after rotator cuff tears by activating systemic sympathetic nerve fibre near adipocytes and β3AR. Cite this article: Bone Joint Res 2023;12(8):455–466

Aims. A national screening programme has existed in the UK for the diagnosis of developmental dysplasia of the hip (DDH) since 1969. However, every aspect of screening and treatment remains controversial. Screening programmes throughout the world vary enormously, and in the UK there is significant variation in screening practice and treatment pathways. We report the results of an attempt by the British Society for Children’s Orthopaedic Surgery (BSCOS) to identify a nationwide consensus for the management of DDH in order to unify treatment and suggest an approach for screening. Methods. A Delphi consensus study was performed among the membership of BSCOS. Statements were generated by a steering group regarding aspects of the management of DDH in children aged under three months, namely screening and surveillance (15 questions), the technique of ultrasound scanning (eight questions), the initiation of treatment (19 questions), care during treatment with a splint (ten questions), and on quality, governance, and research (eight questions). A two-round Delphi process was used and a consensus document was produced at the final meeting of the steering group. Results. A total of 60 statements were graded by 128 clinicians in the first round and 132 in the second round. Consensus was reached on 30 out of 60 statements in the first round and an additional 12 in the seond. This was summarized in a consensus statement and distilled into a flowchart to guide clinical practice. Conclusion. We identified agreement in an area of medicine that has a long history of controversy and varied practice. None of the areas of consensus are based on high-quality evidence. This document is thus a framework to guide clinical practice and on which high-quality clinical trials can be developed. Cite this article: Bone Joint J 2023;105-B(2):209–214