Aims. The Uppföljningsprogram för cerebral pares (CPUP) Hip Score distinguishes between children with cerebral palsy (CP) at different levels of risk for displacement of the hip. The score was constructed using data from Swedish children with CP, but has not been confirmed in any other population. The aim of this study was to determine the calibration and discriminatory accuracy of this score in children with CP in Scotland. Methods. This was a total population-based study of children registered with the Cerebral Palsy Integrated Pathway Scotland. Displacement of the hip was defined as a migration percentage (MP) of > 40%. Inclusion criteria were children in Gross Motor Function Classification System (GMFCS) levels III to V. The calibration slope was estimated and Kaplan-Meier curves produced for five strata of CPUP scores to compare the observed with the predicted risk of displacement of the hip at five years. For discriminatory accuracy, the time-dependent area under the receiver operating characteristic curve (AUC) was estimated. In order to analyze differences in the performance of the score between cohorts, score weights, and subsequently the AUC, were re-estimated using the variables of the original score: the child’s age at the first examination, GMFCS level, head shaft angle, and MP of the worst hip in a logistic regression with imputation of outcomes for those with incomplete follow-up. Results. The discriminatory accuracy of the score in the new population of 367 children was high (AUC 0.78 (95% confidence interval (CI) 0.71 to 0.86)). The calibration of the score was insufficient (slope 0.48 (95% CI 0.31 to 0.65)), and the absolute risks of displacement of the hip in this population were overestimated. The AUC increased with re-estimated weights (0.85 (95% CI 0.79 to 0.91)). Conclusion. The CPUP Hip Score had a high ability to discriminate between children at different levels of risk for displacement of the hip. The score overestimated the absolute risks of displacement in this population, which may have resulted from differences in the way children were initially registered in the two programmes. The results are promising, but the score weights may need re-estimation before its clinical application in Scotland. Cite this article: Bone Joint J 2022;104-B(5):640–644

Aims. This study aimed to uncover the hub long non-coding RNAs (lncRNAs) differentially expressed in osteoarthritis (OA) cartilage using an integrated analysis of the competing endogenous RNA (ceRNA) network and co-expression network. Methods. Expression profiles data of ten OA and ten normal tissues of human knee cartilage were obtained from the Gene Expression Omnibus (GEO) database (GSE114007). The differentially expressed messenger RNAs (DEmRNAs) and lncRNAs (DElncRNAs) were identified using the edgeR package. We integrated human microRNA (miRNA)-lncRNA/mRNA interactions with DElncRNA/DEmRNA expression profiles to construct a ceRNA network. Likewise, lncRNA and mRNA expression profiles were used to build a co-expression network with the WGCNA package. Potential hub lncRNAs were identified based on an integrated analysis of the ceRNA network and co-expression network. StarBase and Multi Experiment Matrix databases were used to verify the lncRNAs. Results. We detected 1,212 DEmRNAs and 49 DElncRNAs in OA and normal knee cartilage. A total of 75 dysregulated lncRNA-miRNA interactions and 711 dysregulated miRNA-mRNA interactions were obtained in the ceRNA network, including ten DElncRNAs, 69 miRNAs, and 72 DEmRNAs. Similarly, 1,330 dysregulated lncRNA-mRNA interactions were used to construct the co-expression network, which included ten lncRNAs and 407 mRNAs. We finally identified seven hub lncRNAs, named MIR210HG, HCP5, LINC00313, LINC00654, LINC00839, TBC1D3P1-DHX40P1, and ISM1-AS1. Subsequent enrichment analysis elucidated that these lncRNAs regulated extracellular matrix organization and enriched in osteoclast differentiation, the FoxO signalling pathway, and the tumour necrosis factor (TNF) signalling pathway in the development of OA. Conclusion. The integrated analysis of the ceRNA network and co-expression network identified seven hub lncRNAs associated with OA. These lncRNAs may regulate extracellular matrix changes and chondrocyte homeostasis in OA progress. Cite this article:Bone Joint Res. 2020;9(3):90–98

Introduction. Virtual fracture clinics (VFCs) are being increasingly used to offer safe and efficient orthopaedic review without the requirement for face-to-face contact. With the onset of the COVID-19 pandemic, we sought to develop an online referral pathway that would allow us to provide definitive orthopaedic management plans and reduce face-to-face contact at the fracture clinics. Methods. All patients presenting to the emergency department from 21March 2020 with a musculoskeletal injury or potential musculoskeletal infection deemed to require orthopaedic input were discussed using a secure messaging app. A definitive management plan was communicated by an on-call senior orthopaedic decision-maker. We analyzed the time to decision, if further information was needed, and the referral outcome. An analysis of the orthopaedic referrals for the same period in 2019 was also performed as a comparison. Results. During the study period, 295 patients with mean age of 7.93 years (standard error (SE) 0.24) were reviewed. Of these, 25 (9.8%) were admitted, 17 (5.8%) were advised to return for planned surgical intervention, 105 (35.6%) were referred to a face-to-face fracture clinic, 137 (46.4%) were discharged with no follow-up, and seven (2.4%) were referred to other services. The mean time to decision was 20.14 minutes (SE 1.73). There was a significant difference in the time to decision between patients referred to fracture clinic and patients discharged (mean 25.25 minutes (SE 3.18) vs mean 2.63 (SE 1.42); p < 0.005). There were a total of 295 referrals to the fracture clinic for the same period in 2019 with a further 44 emergency admissions. There was a statistically significant difference in the weekly referrals after being triaged by the VFC (mean 59 (SE 5.15) vs mean 21 (SE 2.17); p < 0.001). Conclusion. The use of an electronic referral pathway to deliver a point of care virtual fracture clinic allowed for efficient use of scarce resources and definitive management plan delivery in a safe manner. Cite this article: Bone Joint Open 2020;1-6:293–301

Aims. Receptor activator of nuclear factor-κB ligand (RANKL) is a key molecule that is expressed in bone stromal cells and is associated with metastasis and poor prognosis in many cancers. However, cancer cells that directly express RANKL have yet to be unveiled. The current study sought to evaluate how a single subunit of G protein, guanine nucleotide-binding protein G(q) subunit alpha (GNAQ), transforms cancer cells into RANKL-expressing cancer cells. Methods. We investigated the specific role of GNAQ using GNAQ wild-type cell lines (non-small-cell lung cancer cell lines; A549 cell lines), GNAQ knockdown cell lines, and patient-derived cancer cells. We evaluated GNAQ, RANKL, macrophage colony-stimulating factor (M-CSF), nuclear transcription factor-κB (NF-κB), inhibitor of NF-κB (IκB), and protein kinase B (Akt) signalling in the GNAQ wild-type and the GNAQ-knockdown cells. Osteoclastogenesis was also evaluated in both cell lines. Results. In the GNAQ-knockdown cells, RANKL expression was significantly upregulated (p < 0.001). The expression levels of M-CSF were also significantly increased in the GNAQ-knockdown cells compared with control cells (p < 0.001). GNAQ knockdown cells were highly sensitive to tumour necrosis factor alpha (TNF-α) and showed significant activation of the NF-κB pathway. The expression levels of RANKL were markedly increased in GNAQ mutant compared with GNAQ wild-type in patient-derived tumour tissues. Conclusion. The present study reveals that the alterations of GNAQ activate NF-κB pathway in cancers, which increase RANKL and M-CSF expression and induce osteoclastogenesis in cancers. Cite this article:Bone Joint Res. 2020;9(1):29–35

Aims. The aim of our study is to investigate the effect induced by alternated mechanical loading on Notch-1 in mandibular condylar cartilage (MCC) of growing rabbits. Methods. A total of 64 ten-day-old rabbits were randomly divided into two groups according to dietary hardness: normal diet group (pellet) and soft diet group (powder). In each group, the rabbits were further divided into four subgroups by feeding time: two weeks, four weeks, six weeks, and eight weeks. Animals would be injected 5-bromo-2′-deoxyuridine (BrdU) every day for one week before sacrificing. Histomorphometric analysis of MCC thickness was performed through haematoxylin and eosin (HE) staining. Immunochemical analysis was done to test BrdU and Notch-1. The quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to measure expression of Notch-1, Jagged-1, and Delta-like 1 (Dll-1). Results. The thickness of MCC in the soft diet group was thinner than the one in normal diet group. Notch-1 was restricted in fibrous layer, proliferative layer, and hypertrophic layer. The expression of Notch-1 increased from two weeks to six weeks and then fell down. Notch-1 in normal diet group was higher than that in soft diet group in anterior part of MCC. The statistical differences of Notch-1 were shown at two, four, and six weeks (p < 0.05). The result of western blot and quantitative real-time PCR (qRT-PCR) showed the expression of Dll-1 and Jagged-1 rose from two to four weeks and started to decrease at four weeks. BrdU distributed in all layers of cartilage and subchondral bone. The number of BrdU-positive cells, which were less in soft diet group, was decreasing along with the experiment period. The significant difference was found at four, six, and eight weeks in anterior and posterior parts (p < 0.05). Conclusion. The structure and proliferation of MCC in rabbits were sensitive to dietary loading changes. The proper mechanical loading was essential for transduction of Notch signalling pathway and development of mandibular condylar cartilage. Cite this article: Bone Joint Res 2021;10(7):437–444

Aims. To determine the role of early MRI in the management of suspected scaphoid fractures. Methods. A total of 337 consecutive patients presenting to an emergency department (ED) following wrist trauma over a 12-month period were prospectively included in this service evaluation project. MRI was not required in 62 patients with clear diagnoses, and 17 patients were not managed as per pathway, leaving a total of 258 patients with normal scaphoid series radiographs who were then referred directly from ED for an acute wrist MRI scan. Patient demographics, clinical details, outcomes, and complications were recorded at a minimum of a year following injury. Results. The median time from injury to ED presentation was one day and the median number of positive clinical signs was two out of three (snuffbox tenderness, tubercle tenderness, pain on telescoping). Of 258 patients referred for acute MRI, 208 scans were performed as 50 patients either did not tolerate (five patients) or did not attend their scan (45 patients). MRI scans demonstrated scaphoid fracture (13%), fracture of another bone (22%), scaphoid contusion (6%), other contusion/ligamentous injury (20%), or solely degenerative pathology (10%). Only 29% of scans showed no abnormality. Almost 50% of those undergoing MRI (100 patients) were discharged by ED with advice, with only one re-presentation. Of the 27 undisplaced occult scaphoid fractures, despite prompt cast immobilization, two experienced delayed union which was successfully treated with surgery. Conclusion. The use of MRI direct from ED enables prompt diagnosis and the early discharge of a large proportion of patients with normal radiographs following wrist trauma. Cite this article: Bone Jt Open 2021;2(6):447–453

Aims. Hand trauma accounts for one in five of emergency department attendances, with a UK incidence of over five million injuries/year and 250,000 operations/year. Surgical site infection (SSI) in hand trauma surgery leads to further interventions, poor outcomes, and prolonged recovery, but has been poorly researched. Antimicrobial sutures have been recognized by both the World Health Organization and the National Institute for Clinical Excellence as potentially effective for reducing SSI. They have never been studied in hand trauma surgery: a completely different patient group and clinical pathway to previous randomized clinical trials (RCTs) of these sutures. Antimicrobial sutures are expensive, and further research in hand trauma is warranted before they become standard of care. The aim of this protocol is to conduct a feasibility study of antimicrobial sutures in patients undergoing hand trauma surgery to establish acceptability, compliance, and retention for a definitive trial. Methods. A two-arm, multicentre feasibility RCT of 116 adult participants with hand and wrist injuries, randomized to either antimicrobial sutures or standard sutures. Study participants and outcome assessors will be blinded to treatment allocation. Outcome measures will be recorded at baseline (preoperatively), 30 days, 90 days, and six months, and will include SSI, patient-reported outcome measures, and return to work. Conclusion. This will inform a definitive trial of antimicrobial sutures in the hand and wrist, and will help to inform future upper limb trauma trials. The results of this research will be shared with the medical community through high impact publication and presentation. Cite this article: Bone Jt Open 2022;3(7):529–535

Aims. A multicentre, randomized, clinician-led, pragmatic, parallel-group orthopaedic trial of two surgical procedures was set up to obtain high-quality evidence of effectiveness. However, the trial faced recruitment challenges and struggled to maintain recruitment rates over 30%, although this is not unusual for surgical trials. We conducted a qualitative study with the aim of gathering information about recruitment practices to identify barriers to patient consent and participation to an orthopaedic trial. Methods. We collected 11 audio recordings of recruitment appointments and interviews of research team members (principal investigators and research nurses) from five hospitals involved in recruitment to an orthopaedic trial. We analyzed the qualitative data sets thematically with the aim of identifying aspects of informed consent and information provision that was either unclear, disrupted, or hindered trial recruitment. Results. Recruiters faced four common obstacles when recruiting to a surgical orthopaedic trial: patient preferences for an intervention; a complex recruitment pathway; various logistical issues; and conflicting views on equipoise. Clinicians expressed concerns that the trial may not show significant differences in the treatments, validating their equipoise. However, they experienced role conflicts due to their own preference and perceived patient preference for an intervention arm. Conclusion. This study provided initial information about barriers to recruitment to an orthopaedic randomized controlled trial. We shared these findings in an all-site investigators’ meeting and encouraged researchers to find solutions to identified barriers; this led to the successful completion of recruitment. Complex trials may benefit for using of a mixed-methods approach to mitigate against recruitment failure, and to improve patient participation and informed consent. Cite this article: Bone Jt Open 2021;2(8):631–637

Objectives. The aim of this study was to identify key pathological genes in osteoarthritis (OA). Methods. We searched and downloaded mRNA expression data from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) of joint synovial tissues from OA and normal individuals. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analyses were used to assess the function of identified DEGs. The protein-protein interaction (PPI) network and transcriptional factors (TFs) regulatory network were used to further explore the function of identified DEGs. The quantitative real-time polymerase chain reaction (qRT-PCR) was applied to validate the result of bioinformatics analysis. Electronic validation was performed to verify the expression of selected DEGs. The diagnosis value of identified DEGs was accessed by receiver operating characteristic (ROC) analysis. Results. A total of 1085 DEGs were identified. KEGG pathway analysis displayed that Wnt was a significantly enriched signalling pathway. Some hub genes with high interactions such as USP46, CPVL, FKBP5, FOSL2, GADD45B, PTGS1, and ZNF423 were identified in the PPI and TFs network. The results of qRT-PCR showed that GADD45B, ADAMTS1, and TFAM were down-regulated in joint synovial tissues of OA, which was consistent with the bioinformatics analysis. The expression levels of USP46, CPVL, FOSL2, and PTGS1 in electronic validation were compatible with the bio-informatics result. CPVL and TFAM had a potential diagnostic value for OA based on the ROC analysis. Conclusion. The deregulated genes including USP46, CPVL, FKBP5, FOSL2, GADD45B, PTGS1, ZNF423, ADAMTS1, and TFAM might be involved in the pathology of OA. Cite this article: X. Zhang, Y. Bu, B. Zhu, Q. Zhao, Z. Lv, B. Li, J. Liu. Global transcriptome analysis to identify critical genes involved in the pathology of osteoarthritis. Bone Joint Res 2018;7:298–307. DOI: 10.1302/2046-3758.74.BJR-2017-0245.R1

Objectives. Osteoporosis is a systemic bone metabolic disease, which often occurs among the elderly. Angelica polysaccharide (AP) is the main component of angelica sinensis, and is widely used for treating various diseases. However, the effects of AP on osteoporosis have not been investigated. This study aimed to uncover the functions of AP in mesenchymal stem cell (MSC) proliferation and osteoblast differentiation. Methods. MSCs were treated with different concentrations of AP, and then cell viability, Cyclin D1 protein level, and the osteogenic markers of runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP-2) were examined by Cell Counting Kit-8 (CCK-8) and western blot assays, respectively. The effect of AP on the main signalling pathways of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Wnt/β-catenin was determined by western blot. Following this, si-H19#1 and si-H19#2 were transfected into MSCs, and the effects of H19 on cell proliferation and osteoblast differentiation in MSCs were studied. Finally, in vivo experimentation explored bone mineral density, bone mineral content, and the ash weight and dry weight of femoral bone. Results. The results revealed that AP significantly promoted cell viability, upregulated cyclin D1 and increased RUNX2, OCN, ALP, and BMP-2 protein levels in MSCs. Moreover, we found that AP notably activated PI3K/AKT and Wnt/β-catenin signalling pathways in MSCs. Additionally, the relative expression level of H19 was upregulated by AP in a dose-dependent manner. The promoting effects of AP on cell proliferation and osteoblast differentiation were reversed by H19 knockdown. Moreover, in vivo experimentation further confirmed the promoting effect of AP on bone formation. Conclusion. These data indicate that AP could promote MSC proliferation and osteoblast differentiation by regulating H19. Cite this article: X. Xie, M. Liu, Q. Meng. Angelica polysaccharide promotes proliferation and osteoblast differentiation of mesenchymal stem cells by regulation of long non-coding RNA H19: An animal study. Bone Joint Res 2019;8:323–332. DOI: 10.1302/2046-3758.87.BJR-2018-0223.R2

Aims. Aseptic loosening is a leading cause of uncemented arthroplasty failure, often accompanied by fibrotic tissue at the bone-implant interface. A biological target, neutrophil extracellular traps (NETs), was investigated as a crucial connection between the innate immune system’s response to injury, fibrotic tissue development, and proper bone healing. Prevalence of NETs in peri-implant fibrotic tissue from aseptic loosening patients was assessed. A murine model of osseointegration failure was used to test the hypothesis that inhibition (through Pad4-/- mice that display defects in peptidyl arginine deiminase 4 (PAD4), an essential protein required for NETs) or resolution (via DNase 1 treatment, an enzyme that degrades the cytotoxic DNA matrix) of NETs can prevent osseointegration failure and formation of peri-implant fibrotic tissue. Methods. Patient peri-implant fibrotic tissue was analyzed for NETs biomarkers. To enhance osseointegration in loose implant conditions, an innate immune system pathway (NETs) was either inhibited (Pad4-/- mice) or resolved with a pharmacological agent (DNase 1) in a murine model of osseointegration failure. Results. NETs biomarkers were identified in peri-implant fibrotic tissue collected from aseptic loosening patients and at the bone-implant interface in a murine model of osseointegration failure. Inhibition (Pad4-/-) or resolution (DNase 1) of NETs improved osseointegration and reduced fibrotic tissue despite loose implant conditions in mice. Conclusion. This study identifies a biological target (NETs) for potential noninvasive treatments of aseptic loosening by discovering a novel connection between the innate immune system and post-injury bone remodelling caused by implant loosening. By inhibiting or resolving NETs in an osseointegration failure murine model, fibrotic tissue encapsulation around an implant is reduced and osseointegration is enhanced, despite loose implant conditions. Cite this article: Bone Joint J 2021;103-B(7 Supple B):135–144

Aims. Open reduction in developmental dysplasia of the hip (DDH) is regularly performed despite screening programmes, due to failure of treatment or late presentation. A protocol for open reduction of DDH has been refined through collaboration between surgical, anaesthetic, and nursing teams to allow same day discharge. The objective of this study was to determine the safety and feasibility of performing open reduction of DDH as a day case. Methods. A prospectively collected departmental database was visited. All consecutive surgical cases of DDH between June 2015 and March 2020 were collected. Closed reductions, bilateral cases, cases requiring corrective osteotomy, and children with comorbidities were excluded. Data collected included demographics, safety outcome measures (blood loss, complications, readmission, reduction confirmation), and feasibility for discharge according to the Face Legs Activity Cry Consolidability (FLACC) pain scale. A satisfaction questionnaire was filled by the carers. Descriptive statistics were used for analysis. Results. Out of 168 consecutive DDH cases, 16 patients fit the inclusion criteria (age range 10 to 26 months, 13 female). Intraoperative blood loss ranged from "minimal" to 120 ml, and there were no complications or readmissions. The FLACC score was 0 for all patients. The carers satisfaction questionnaire expressed high satisfaction from the experience with adequate information and support provided. Conclusion. Open reduction in DDH, without corrective osteotomy, is safe and feasible to be managed as a day case procedure. It requires a clear treatment pathway, analgesia, sufficient counselling, and communication with carers. It is even more important during the COVID-19 pandemic when reduced length of hospital stay is likely to be safer for both patient and their parents. Cite this article: Bone Joint Open 2021;2(4):271–277

Aims. The effect of the gut microbiota (GM) and its metabolite on bone health is termed the gut-bone axis. Multiple studies have elucidated the mechanisms but findings vary greatly. A systematic review was performed to analyze current animal models and explore the effect of GM on bone. Methods. Literature search was performed on PubMed and Embase databases. Information on the types and strains of animals, induction of osteoporosis, intervention strategies, determination of GM, assessment on bone mineral density (BMD) and bone quality, and key findings were extracted. Results. A total of 30 studies were included, of which six studies used rats and 24 studies used mice. Osteoporosis or bone loss was induced in 14 studies. Interventions included ten with probiotics, three with prebiotics, nine with antibiotics, two with short-chain fatty acid (SCFA), six with vitamins and proteins, two with traditional Chinese medicine (TCM), and one with neuropeptide Y1R antagonist. In general, probiotics, prebiotics, nutritional interventions, and TCM were found to reverse the GM dysbiosis and rescue bone loss. Conclusion. Despite the positive therapeutic effect of probiotics, prebiotics, and nutritional or pharmaceutical interventions on osteoporosis, there is still a critical knowledge gap regarding the role of GM in rescuing bone loss and its related pathways. Cite this article: Bone Joint Res 2021;10(1):51–59

Aims. The diagnosis of joint infections is an inexact science using combinations of blood inflammatory markers and microscopy, culture, and sensitivity of synovial fluid (SF). There is potential for small molecule metabolites in infected SF to act as infection markers that could improve accuracy and speed of detection. The objective of this study was to use nuclear magnetic resonance (NMR) spectroscopy to identify small molecule differences between infected and noninfected human SF. Methods. In all, 16 SF samples (eight infected native and prosthetic joints plus eight noninfected joints requiring arthroplasty for end-stage osteoarthritis) were collected from patients. NMR spectroscopy was used to analyze the metabolites present in each sample. Principal component analysis and univariate statistical analysis were undertaken to investigate metabolic differences between the two groups. Results. A total of 16 metabolites were found in significantly different concentrations between the groups. Three were in higher relative concentrations (lipids, cholesterol, and N-acetylated molecules) and 13 in lower relative concentrations in the infected group (citrate, glycine, glycosaminoglycans, creatinine, histidine, lysine, formate, glucose, proline, valine, dimethylsulfone, mannose, and glutamine). Conclusion. Metabolites found in significantly greater concentrations in the infected cohort are markers of inflammation and infection. They play a role in lipid metabolism and the inflammatory response. Those found in significantly reduced concentrations were involved in carbohydrate metabolism, nucleoside metabolism, the glutamate metabolic pathway, increased oxidative stress in the diseased state, and reduced articular cartilage breakdown. This is the first study to demonstrate differences in the metabolic profile of infected and noninfected human SF, using a noninfected matched cohort, and may represent putative biomarkers that form the basis of new diagnostic tests for infected SF. Cite this article: Bone Joint Res 2021;10(1):85–95

Aims. Bone metastasis ultimately occurs due to a complex multistep process, during which the interactions between cancer cells and bone microenvironment play important roles. Prior to colonization of the bone, cancer cells must succeed through a series of steps that will allow them to gain migratory and invasive properties; epithelial-to-mesenchymal transition (EMT) is known to be integral here. The aim of this study was to determine the effects of G protein subunit alpha Q (GNAQ) on the mechanisms underlying bone metastasis through EMT pathway. Methods. A total of 80 tissue samples from patients who were surgically treated during January 2012 to December 2014 were used in the present study. Comparative gene analysis revealed that the GNAQ was more frequently altered in metastatic bone lesions than in primary tumour sites in lung cancer patients. We investigated the effects of GNAQ on cell proliferation, migration, EMT, and stem cell transformation using lung cancer cells with GNAQ-knockdown. A xenograft mouse model tested the effect of GNAQ using micro-CT analyses and histological analyses. Results. GNAQ-knockdown showed down-regulation of tumour growth through mitogen-activated protein kinase (MAPK) signalling in lung cancer cells, but not increased apoptosis. We found that GNAQ-knockdown induced EMT and promoted invasiveness. GNAQ-knockdown cells injected into the bone marrow of murine tibia induced tumour growth and bone-to-lung metastasis, whereas it did not in control mice. Moreover, the knockdown of GNAQ enhanced cancer stem cell-like properties in lung cancer cells, which resulted in the development of resistance to chemotherapy. Conclusion. The present study reveals that the GNAQ-knockdown induced cancer stem cell-like properties. Cite this article: Bone Joint Res 2021;10(5):310–320

Aims. The purpose of this study was to evaluate the cost of reverse shoulder arthroplasty (RSA) for patients with a proximal humerus fracture, using time-driven activity based costing (TDABC), and to compare treatment costs with reimbursement under the Healthcare Resource Groups (HRGs). Methods. TDABC analysis based on the principles outlined by Kaplan and a clinical pathway that has previously been validated for this institution was used. Staffing cost, consumables, implants, and overheads were updated to reflect 2019/2020 costs. This was compared with the HRG reimbursements. Results. The mean cost of a RSA is £7,007.46 (£6,130.67 to £8,824.67). Implants and staffing costs were the primary cost drivers, with implants (£2,824.80) making up 40% of the costs. Staffing costs made up £1,367.78 (19%) of overall costs. The total tariff, accounting for market force factors and high comorbidities, reimburses £4,629. If maximum cost and minimum reimbursement is applied the losses to the trust are £4,828.67. Conclusion. RSA may be an effective and appropriate surgical option in the treatment of proximal humerus fractures; however, a cost analysis at our centre has demonstrated the financial burden of this surgery. Given its increasing use in trauma, there is a need to work towards generating an HRG that adequately reimburses providers. Cite this article: Bone Jt Open 2020;1-12:731–736

Aims. The primary aim is to estimate the current and potential number of patients on NHS England orthopaedic elective waiting lists by November 2020. The secondary aims are to model recovery strategies; review the deficit of hip and knee arthroplasty from National Joint Registry (NJR) data; and assess the cost of returning to pre-COVID-19 waiting list numbers. Methods. A model of referral, waiting list, and eventual surgery was created and calibrated using historical data from NHS England (April 2017 to March 2020) and was used to investigate the possible consequences of unmet demand resulting from fewer patients entering the treatment pathway and recovery strategies. NJR data were used to estimate the deficit of hip and knee arthroplasty by August 2020 and NHS tariff costs were used to calculate the financial burden. Results. By November 2020, the elective waiting list in England is predicted to be between 885,286 and 1,028,733. If reduced hospital capacity is factored into the model, returning to full capacity by November, the waiting list could be as large as 1.4 million. With a 30% increase in productivity, it would take 20 months if there was no hidden burden of unreferred patients, and 48 months if there was a hidden burden, to return to pre-COVID-19 waiting list numbers. By August 2020, the estimated deficits of hip and knee arthroplasties from NJR data were 18,298 (44.8%) and 16,567 (38.6%), respectively, compared to the same time period in 2019. The cost to clear this black log would be £198,811,335. Conclusion. There will be up to 1.4 million patients on elective orthopaedic waiting lists in England by November 2020, approximate three-times the pre-COVID-19 average. There are various strategies for recovery to return to pre-COVID-19 waiting list numbers reliant on increasing capacity, but these have substantial cost implications. Cite this article: Bone Jt Open 2021;2(2):103–110

Aims. Urgent referral to a specialist centre for patients with a soft-tissue sarcoma (STS) has been recommended by the National Institute for Health and Care Excellence (NICE) in the UK since 2006. However, the impact of this recommendation on the prognosis for these patients remains unclear. We aimed to determine the impact of the NICE guidelines on the disease-specific survival (DSS) of patients with an STS. Methods. A total of 2,427 patients with an STS referred to a supraregional centre in the ten-year periods before (n = 1,386) and after (n = 1,041) the issue of the NICE guidelines were evaluated. Results. The mean size of the tumour was significantly smaller at the time of diagnosis (10.3 cm (SD 6.5) vs 9.1 cm (SD 6.2); p < 0.001) and the number of patients who had undergone an inadvertent excision significantly decreased (28% (n = 389) vs 20% (n = 204); p < 0.001) following the introduction of the NICE guidelines. The five-year DSS was 63% in the pre-NICE and 71% in post-NICE groups (p < 0.001). The improved survival was more significant for those with a high-grade tumour (pre-NICE, 48%; post-NICE, 68%; p < 0.001). In those with a high-grade tumour, the mean size of the tumour (11.6 cm (SD 6.2) vs 9.6 cm (SD 5.8); p < 0.001) and the number of patients with metastasis at the time of diagnosis (15% (n = 124 vs 10% (n = 80); p = 0.007) significantly decreased in the post-NICE group. Conclusion. An improvement in survival was seen after the introduction of the NICE guidelines, especially in patients with a high-grade STS. More patients were referred at an earlier stage, indicating a clearer pathway after the issue of national policy for the management of STSs in the UK. Cite this article: Bone Joint J 2021;103-B(3):569–577

Aims. The primary aim was to determine the influence of COVID-19 on 30-day mortality following hip fracture. Secondary aims were to determine predictors of COVID-19 status on presentation and later in the admission; the rate of hospital acquired COVID-19; and the predictive value of negative swabs on admission. Methods. A nationwide multicentre retrospective cohort study was conducted of all patients presenting with a hip fracture to 17 Scottish centres in March and April 2020. Demographics, presentation blood tests, COVID-19 status, Nottingham Hip Fracture Score, management, length of stay, and 30-day mortality were recorded. Results. In all, 78/833 (9.4%) patients were diagnosed with COVID-19. The 30-day survival of patients with COVID-19 was significantly lower than for those without (65.4% vs 91%; p < 0.001). Diagnosis of COVID-19 within seven days of admission (likely community acquired) was independently associated with male sex (odds ratio (OR) 2.34, p = 0.040, confidence interval (CI) 1.04 to 5.25) and symptoms of COVID-19 (OR 15.56, CI 6.61 to 36.60, p < 0.001). Diagnosis of COVID-19 made between seven and 30 days of admission to hospital (likely hospital acquired) was independently associated with male sex (OR 1.73, CI 1.05 to 2.87, p = 0.032), Nottingham Hip Fracture Score ≥ 7 (OR 1.91, CI 1.09 to 3.34, p = 0.024), pulmonary disease (OR 1.68, CI 1.00 to 2.81, p = 0.049), American Society of Anesthesiologists (ASA) grade ≥ 3 (OR 2.37, CI 1.13 to 4.97, p = 0.022), and length of stay ≥ nine days (OR 1.98, CI 1.18 to 3.31, p = 0.009). A total of 38 (58.5%) COVID-19 cases were probably hospital acquired infections. The false-negative rate of a negative swab on admission was 0% in asymptomatic patients and 2.9% in symptomatic patients. Conclusion. COVID-19 was independently associated with a three times increased 30-day mortality rate. Nosocomial transmission may have accounted for approximately half of all cases during the first wave of the pandemic. Identification of risk factors for having COVID-19 on admission or acquiring COVID-19 in hospital may guide pathways for isolating or shielding patients respectively. Length of stay was the only modifiable risk factor, which emphasizes the importance of high-quality and timely care in this patient group. Cite this article: Bone Joint J 2021;103-B(5):888–897

Aims. Fibrinolysis plays a key transition step from haematoma formation to angiogenesis and fracture healing. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical modality proven to enhance fibrinolytic factors. This study investigates the effect of LMHFV on fibrinolysis in a clinically relevant animal model to accelerate osteoporotic fracture healing. Methods. A total of 144 rats were randomized to four groups: sham control; sham and LMHFV; ovariectomized (OVX); and ovariectomized and LMHFV (OVX-VT). Fibrinolytic potential was evaluated by quantifying fibrin, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) along with healing outcomes at three days, one week, two weeks, and six weeks post-fracture. Results. All rats achieved healing, and x-ray relative radiopacity for OVX-VT was significantly higher compared to OVX at week 2. Martius Scarlet Blue (MSB) staining revealed a significant decrease of fibrin content in the callus in OVX-VT compared with OVX on day 3 (p = 0.020). Mean tPA from muscle was significantly higher for OVX-VT compared to OVX (p = 0.020) on day 3. Mechanical testing revealed the mean energy to failure was significantly higher for OVX-VT at 37.6 N mm (SD 8.4) and 71.9 N mm (SD 30.7) compared with OVX at 5.76 N mm (SD 7.1) (p = 0.010) and 17.7 N mm (SD 11.5) (p = 0.030) at week 2 and week 6, respectively. Conclusion. Metaphyseal fracture healing is enhanced by LMHFV, and one of the important molecular pathways it acts on is fibrinolysis. LMHFV is a promising intervention for osteoporotic metaphyseal fracture healing. The improved mechanical properties, acceleration of fracture healing, and safety justify its role into translation to future clinical studies. Cite this article: Bone Joint Res 2021;10(1):41–50