Aims. Rheumatoid arthritis (RA) is a systematic autoimmune disorder, characterized by synovial inflammation, bone and cartilage destruction, and disease involvement in multiple organs. Although numerous drugs are employed in RA treatment, some respond little and suffer from severe side effects. This study aimed to screen the candidate therapeutic targets and promising drugs in a novel method. Methods. We developed a module-based and cumulatively scoring approach that is a deeper-layer application of weighted gene co-expression network (WGCNA) and connectivity map (CMap) based on the high-throughput datasets. Results. Four noteworthy RA-related modules were identified, revealing the immune- and infection-related biological processes and pathways involved in RA. HLA-DMA, HLA-DMB, HLA-DPA1, HLA-DPB1, HLA-DQB1, HLA-DRA, HLA-DRB1, BLNK, BTK, CD3D, CD4, IL2RG, INPP5D, LCK, PTPRC, RAC2, SYK, and VAV1 were recognized as the key hub genes with high connectivity in gene regulation networks and gene pathway networks. Moreover, the long noncoding RNAs (lncRNAs) in the RA-related modules, such as FAM30A and NEAT1, were identified as the indispensable interactors with the hub genes. Finally, candidate drugs were screened by developing a cumulatively scoring approach based on the selected modules. Niclosamide and the other compounds of T-type calcium channel blocker, IKK inhibitor, and PKC activator, HIF activator, and proteasome inhibitor, which harbour the similar gene signature with niclosamide, were promising drugs with high specificity and broad coverage for the RA-related modules. Conclusion. This study provides not only the promising targets and drugs for RA but also a novel methodological insight into the target and drug screening. Cite this article: Bone Joint Res 2020;9(8):501–514

Aims. Waiting times for arthroplasty surgery in Northern Ireland are among the longest in the NHS, which have been further lengthened by the onset of the COVID-19 global pandemic in March 2020. The Department of Health in Northern Ireland has announced a new Elective Care Framework (ECF), with the framework proposing that by March 2026 no patient will wait more than 52 weeks for inpatient/day case treatment. We aimed to assess the feasibility of achieving this with reference to total hip arthroplasty (THA) and total knee arthroplasty (TKA). Methods. Mathematical modelling was undertaken to calculate when the ECF targets will be achieved for THA and TKA, as well as the time when waiting lists for THA and TKA will be cleared. The number of patients currently on the waiting list and percentage operating capacity relative to pre-COVID-19 capacity was used to determine future projections. Results. As of May 2021, there were 3,757 patients awaiting primary THA and 4,469 patients awaiting primary TKA in Northern Ireland. Prior to April 2020, there were a mean 2,346 (2,085 to 2,610) patients per annum boarded for primary THA, a mean 2,514 (2,494 to 2,514) patients per annum boarded for primary TKA, and there were a mean 1,554 primary THAs and 1,518 primary TKAs performed per annum. The ECF targets for THA will only be achieved in 2030 if operating capacity is 200% of pre COVID-19 pandemic capacity and in 2042 if capacity is 170%. For TKA, the targets will be met in 2034 if capacity is 200% of pre-COVID-19 pandemic capacity. Conclusion. This modelling demonstrates that, in the absence of major funding and reorganization of elective orthopaedic care, the targets set out in the ECF will not be achieved with regard to THA and TKA. Waiting times for THA and TKA surgery in Northern Ireland are likely to remain greater than 52 weeks for most of this decade. Cite this article: Bone Jt Open 2022;3(4):302–306

Aims. Circular RNA (circRNA) is involved in the regulation of articular cartilage degeneration induced by inflammatory factors or oxidative stress. In a previous study, we found that the expression of circStrn3 was significantly reduced in chondrocytes of osteoarthritis (OA) patients and OA mice. Therefore, the aim of this paper was to explore the role and mechanism of circStrn3 in osteoarthritis. Methods. Minus RNA sequencing, fluorescence in situ hybridization, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of circStrn3 in human and mouse OA cartilage tissues and chondrocytes. Chondrocytes were then stimulated to secrete exosomal miR-9-5p by cyclic tensile strain. Intra-articular injection of exosomal miR-9-5p into the model induced by destabilized medial meniscus (DMM) surgery was conducted to alleviate OA progression. Results. Tensile strain could decrease the expression of circStrn3 in chondrocytes. CircStrn3 expression was significantly decreased in human and mouse OA cartilage tissues and chondrocytes. CircStrn3 could inhibit matrix metabolism of chondrocytes through competitively ‘sponging’ miRNA-9-5p targeting Kruppel-like factor 5 (KLF5), indicating that the decrease in circStrn3 might be a protective factor in mechanical instability-induced OA. The tensile strain stimulated chondrocytes to secrete exosomal miR-9-5p. Exosomes with high miR-9-5p expression from chondrocytes could inhibit osteoblast differentiation by targeting KLF5. Intra-articular injection of exosomal miR-9-5p alleviated the progression of OA induced by destabilized medial meniscus surgery in mice. Conclusion. Taken together, these results demonstrate that reduction of circStrn3 causes an increase in miR-9-5p, which acts as a protective factor in mechanical instability-induced OA, and provides a novel mechanism of communication among joint components and a potential application for the treatment of OA. Cite this article: Bone Joint Res 2023;12(1):33–45

Aims. Osteoarthritis (OA) is characterized by persistent destruction of articular cartilage. It has been found that microRNAs (miRNAs) are closely related to the occurrence and development of OA. The purpose of the present study was to investigate the mechanism of miR-486 in the development and progression of OA. Methods. The expression levels of miR-486 in cartilage were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of collagen, type II, alpha 1 (COL2A1), aggrecan (ACAN), matrix metalloproteinase (MMP)-13, and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS4) in SW1353 cells at both messenger RNA (mRNA) and protein levels was determined by qRT-PCR, western blot, and enzyme-linked immunosorbent assay (ELISA). Double luciferase reporter gene assay, qRT-PCR, and western blot assay were used to determine whether silencing information regulator 6 (SIRT6) was involved in miR-486 induction of chondrocyte-like cells to a more catabolic phenotype. Results. Compared with osteonecrosis, the expression of miR-486 was significantly upregulated in cartilage from subjects with severe OA. In addition, overexpressed miR-486 promoted a catabolic phenotype in SW1353 cells by upregulating the expressions of ADAMTS4 and MMP-13 and down-regulating the expressions of COL2A1 and ACAN. Conversely, inhibition of miR-486 had the opposite effect. Furthermore, overexpression of miR-486 significantly inhibited the expression of SIRT6, confirming that SIRT6 is a direct target of miR-486. Moreover, SW1353 cells were transfected with small interfering RNA (si)-SIRT6 and it was found that SIRT6 was involved in and inhibited miR-486-induced changes to SW1353 gene expression. Conclusion. Our results indicate that miR-486 promotes a catabolic phenotype in SW1353 cells in OA by targeting SIRT6. Our findings might provide a potential therapeutic target and theoretical basis for OA. Cite this article: Bone Joint Res 2021;10(7):459–466

Aims. This study aimed, through bioinformatics analysis and in vitro experiment validation, to identify the key extracellular proteins of intervertebral disc degeneration (IDD). Methods. The gene expression profile of GSE23130 was downloaded from the Gene Expression Omnibus (GEO) database. Extracellular protein-differentially expressed genes (EP-DEGs) were screened by protein annotation databases, and we used Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) to analyze the functions and pathways of EP-DEGs. STRING and Cytoscape were used to construct protein-protein interaction (PPI) networks and identify hub EP-DEGs. NetworkAnalyst was used to analyze transcription factors (TFs) and microRNAs (miRNAs) that regulate hub EP-DEGs. A search of the Drug Signatures Database (DSigDB) for hub EP-DEGs revealed multiple drug molecules and drug-target interactions. Results. A total of 56 EP-DEGs were identified in the differential expression analysis. EP-DEGs were enriched in the extracellular structure organization, ageing, collagen-activated signalling pathway, PI3K-Akt signalling pathway, and AGE-RAGE signalling pathway. PPI network analysis showed that the top ten hub EP-DEGs are closely related to IDD. Correlation analysis also demonstrated a significant correlation between the ten hub EP-DEGs (p＜0.05), which were selected to construct TF–gene interaction and TF–miRNA coregulatory networks. In addition, ten candidate drugs were screened for the treatment of IDD. Conclusion. The findings clarify the roles of extracellular proteins in IDD and highlight their potential as promising novel therapeutic targets. Cite this article: Bone Joint Res 2023;12(9):522–535

Aims. The study aimed to determine whether the microRNA miR21-5p (MiR21) mediates temporomandibular joint osteoarthritis (TMJ-OA) by targeting growth differentiation factor 5 (Gdf5). Methods. TMJ-OA was induced in MiR21 knockout (KO) mice and wild-type (WT) mice by a unilateral anterior crossbite (UAC) procedure. Mouse tissues exhibited histopathological changes, as assessed by: Safranin O, toluidine blue, and immunohistochemistry staining; western blotting (WB); and quantitative real-time polymerase chain reaction (RT-qPCR). Mouse condylar chondrocytes were transfected with a series of MiR21 mimic, MiR21 inhibitor, Gdf5 siRNA (si-GDF5), and flag-GDF5 constructs. The effects of MiR-21 and Gdf5 on the expression of OA related molecules were evaluated by immunofluorescence, alcian blue staining, WB, and RT-qPCR. Results. UAC altered the histological structure and extracellular matrix content of cartilage in the temporomandibular joint (TMJ), and KO of MiR21 alleviated this effect (p < 0.05). Upregulation of MiR21 influenced the expression of TMJ-OA related molecules in mandibular condylar chondrocytes via targeting Gdf5 (p < 0.05). Gdf5 overexpression significantly decreased matrix metalloproteinase 13 (MMP13) expression (p < 0.05) and reversed the effects of MiR21 (p < 0.05). Conclusion. MiR21, which acts as a critical regulator of Gdf5 in chondrocytes, regulates TMJ-OA related molecules and is involved in cartilage matrix degradation, contributing to the progression of TMJ-OA. Cite this article: Bone Joint Res 2020;9(10):689–700

Introduction. Accurate acetabular cup orientation could lead to successful surgical results in total hip arthroplasty (THA). We introduce a novel CT-based three-dimensional (3D) planning system, HipCOMPASS (Fig.1) and TARGET (Fig.2), which enable to design suitable alignment not only cup also surgical devices calculatingly, according to each pelvic inclination. Patients and Methods. We performed THA in 45 hips in 43 patients (female 37 and 6 men) between April 2014 and October 2015. Average age were 68 years old. THA operation was based on each parameter of the cup and device, providing a preoperative planning by ZedView system. HipCOMPASS and TARGET is linked with ZedView software, which is simultaneously calibrated adjustable parameters on this devices. Cup alignment was assessed by ZedView as well. Results. The differences of component alignment from the preoperative planning were shown in Tables. Conclusion. HipCOMPASS and TARGET might be more accurate than conventional method and more accessible system than navigation system in THA

Introduction. Accurate acetabular cup orientation could lead to successful surgical results in total hip arthroplasty (THA). We introduce a novel CT-based three-dimensional (3D) planning system, HipCOMPASS (Fg.1) and TARGET (Fig.2), which enable to design suitable alignment not only cup also surgical devices calculatingly, according to each pelvic inclination. Patients and methods. We performed THA in 13 patients (10 female and 3 men) between September 2014 and April 2014. Average age were 67 years old. THA operation was based on each parameter of the cup and device, providing a preoperative planning by ZedView system. HipCOMPASS and TARGET is linked with ZedView software, which is simultaneously calibrated adjustable parameters on this devices. Cup alignment was assessed by ZedView as well. Result. The differences of component alignment from the preoperative planning were shown in table. Conclusion. HipCOMPASS and TARGET might be more accurate than conventional method and more accessible system than navigation system in THA

Objectives. Osteoarthritis (OA) is characterised by articular cartilage degradation. MicroRNAs (miRNAs) have been identified in the development of OA. The purpose of our study was to explore the functional role and underlying mechanism of miR-138-5p in interleukin-1 beta (IL-1β)-induced extracellular matrix (ECM) degradation of OA cartilage. Materials and Methods. Human articular cartilage was obtained from patients with and without OA, and chondrocytes were isolated and stimulated by IL-1β. The expression levels of miR-138-5p in cartilage and chondrocytes were both determined. After transfection with miR-138-5p mimics, allele-specific oligonucleotide (ASO)-miR-138-5p, or their negative controls, the messenger RNA (mRNA) levels of aggrecan (ACAN), collagen type II and alpha 1 (COL2A1), the protein levels of glycosaminoglycans (GAGs), and both the mRNA and protein levels of matrix metalloproteinase (MMP)-13 were evaluated. Luciferase reporter assay, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot were performed to explore whether Forkhead Box C1 (FOCX1) was a target of miR-138-5p. Further, we co-transfected OA chondrocytes with miR-138-5p mimics and pcDNA3.1 (+)-FOXC1 and then stimulated with IL-1β to determine whether miR-138-5p-mediated IL-1β-induced cartilage matrix degradation resulted from targeting FOXC1. Results. MiR-138-5p was significantly increased in OA cartilage and in chondrocytes in response to IL-1β-stimulation. Overexpression of miR-138-5p significantly increased the IL-1β-induced downregulation of COL2A1, ACAN, and GAGs, and increased the IL-1β-induced over expression of MMP-13.We found that FOXC1 is directly regulated by miR-138-5p. Additionally, co-transfection with miR-138-5p mimics and pcDNA3.1 (+)-FOXC1 resulted in higher levels of COL2A1, ACAN, and GAGs, but lower levels of MMP-13. Conclusion. miR-138-5p promotes IL-1β-induced cartilage degradation in human chondrocytes, possibly by targeting FOXC1. Cite this article: Y. Yuan, G. Q. Zhang, W. Chai,M. Ni, C. Xu, J. Y. Chen. Silencing of microRNA-138-5p promotes IL-1β-induced cartilage degradation in human chondrocytes by targeting FOXC1: miR-138 promotes cartilage degradation. Bone Joint Res 2016;5:523–530. DOI: 10.1302/2046-3758.510.BJR-2016-0074.R2

In total hip arthroplasty (THA), acetabular cup orientation is critical for avoiding edge-loading and implant-implant impingement, which may lead to serious complications such as dislocation, mechanical loosening, accelerated wear, or implant breakage. Many studies recommended to place the acetabular cup radiographically at an inclination of <50° to avoid edge-loading. Simultaneously, larger prosthetic ROMs than the patients’ ROM during daily activities are needed to minimize impingement related complications. Several three-dimensional computer simulation studies have been done for optimal cup orientation to avoid prosthetic impingement within possible hip ROMs in the late 1990s. However, the reference angles in the directions of flexion, extension, external rotation and internal rotation at 90 ° flexion as possible hip ROMs have not been consistent in previous simulation studies. Thus, different reference angles of hip ROMs resulted in different optimal cup orientation. Therefore, to give accurate information about the reference hip ROM, we measured passive hip ROMs intraoperatively using a navigation system in 91 patients. Pelvic and femoral coordinate systems referred a functional pelvic plane in the supine position and a retrocondylar plane, respectively. The neutral position of the hip ROM was defined as the position in which corresponding axes of the pelvic and femoral coordinate systems were parallel. Maximum flexion, extension, external rotation and abduction were 120°, 36 °, 43 ° and 55 °, respectively. Moreover, we investigated the hip ROM during five traditional Japanese hip positions which required large hip flexion and internal rotation angles in five healthy female volunteers by a 3D image matching technique using an open-configuration MRI. Maximum flexion was 122 ° and maximum internal rotation was 40 ° at more than 90 ° of flexion position. Therefore, we recommended using 120 ° for flexion, 40 ° for extension, 40 ° for external rotation and 40 ° for internal rotation at 90 ° flexion as the reference ROM when calculating an optimum cup orientation. We calculated radiographic cup anteversion, when radiographic cup inclination was 40 °, without prosthesis impingement in the reference hip ROMs using computer aided design models of prosthesis, which included a cementless CentPillar stem with a head 32mm in diameter and cementless Trident cup with a flat liner. The results showed the optimal cup target zone existed when the stem anteversion was between 20 ° and 45 °. The size of the target zone was widest when the stem anteversion was 30 °, and then it was plus or minus 5 ° of inclination and anteversion from the center of the zone. To eliminate outliers of cup orientation form the target zone, a computer assisted system such as navigation is recommended

Introduction. Soft tissue balancing in total knee arthroplasty surgery may prove necessary to elevate patient satisfaction and functional outcome beyond the current fair average. A new generation of contact load sensors embedded in trial tibial liners provides quantification of loads, direction, and an indirect assessment of ligamentous tension. With this technology, quantified intra-operative balancing may potentially restore compartmental load distribution to a more physiological and functional degree. Objective. 1). To define a clinically useful target zone for balancing of the soft tissue envelope of knees at the time of surgery using numerical data from load sensors in tibial liner trial components. 2). To validate the boundaries of the target zone on a medial v. lateral contact load scatterplot with PROMs. Method. This study is a prospective IRB approved clinical study of 104 patients (112 knees) from a single surgeon. The intra-operative balancing aim was the restoration of a physiological compartmental load distribution, defined as less than 15 pounds of load differential between the medial and lateral compartments throughout flexion. This was performed using an algorithmic method of soft tissue releases combined with minor joint line obliquity adjustments within 3 degrees of neutral. Medial v. lateral contact load data was produced at 10, 45, 90° flexion as part of the balancing and final verification process. For all cases the pre and post-operative (4weeks, 3months, 6months) varus and valgus soft tissue envelope was measured with a calibrated and validated knee fixture. The KSS scores were obtained at each measurement interval. Results. The majority of knees were successfully balanced within a cluster zone as shown in Fig. 1. The concept of a safe target zone was developed to define a safe zone of balancing with higher predictive value for satisfaction and function. This was created using a best-fit rhomboid area, whose perimeter uses the fusion of a square area defined by min / max absolute loads and a triangular area defined by relative compartmental load ratios (Compartmental Load Ratio=Med Load/Total Load). The best-fit load boundaries to optimize patient satisfaction are 12.5 lbs.-38 lbs. (static load) and 44%–59% (relative load distribution) (Fig.2). Using these boundaries 83% of the cases in the safe zone area scored above 80% on the satisfaction score at 6 months compared to 36% for those outside the rhomboid area (Fig. 3). Conclusions. Balancing by load distribution uses a combination of distinct single surgical variable corrections of soft tissue releases and minor bone adjustments. Using a systematic balancing algorithm, the medial and lateral compartmental loads can predictably be balanced within a defined target zone, delineated by absolute load values and by relative compartmental load ratios. Based on this series the method is proving reproducible. The accuracy obtained by matching patient satisfaction values appears to validate the potential of a target zone as a safe and predictable clinical tool for balancing. For figures/tables, please contact authors directly.

Aims. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) have been reported to be a promising cellular therapeutic approach for various human diseases. The current study aimed to investigate the mechanism of BMSC-derived exosomes carrying microRNA (miR)-136-5p in fracture healing. Methods. A mouse fracture model was initially established by surgical means. Exosomes were isolated from BMSCs from mice. The endocytosis of the mouse osteoblast MC3T3-E1 cell line was analyzed. CCK-8 and disodium phenyl phosphate microplate methods were employed to detect cell proliferation and alkaline phosphatase (ALP) activity, respectively. The binding of miR-136-5p to low-density lipoprotein receptor related protein 4 (LRP4) was analyzed by dual luciferase reporter gene assay. HE staining, tartrate-resistant acid phosphatase (TRAP) staining, and immunohistochemistry were performed to evaluate the healing of the bone tissue ends, the positive number of osteoclasts, and the positive expression of β-catenin protein, respectively. Results. miR-136-5p promoted fracture healing and osteoblast proliferation and differentiation. BMSC-derived exosomes exhibited an enriched miR-136-5p level, and were internalized by MC3T3-E1 cells. LRP4 was identified as a downstream target gene of miR-136-5p. Moreover, miR-136-5p or exosomes isolated from BMSCs (BMSC-Exos) containing miR-136-5p activated the Wnt/β-catenin pathway through the inhibition of LRP4 expression. Furthermore, BMSC-derived exosomes carrying miR-136-5p promoted osteoblast proliferation and differentiation, thereby promoting fracture healing. Conclusion. BMSC-derived exosomes carrying miR-136-5p inhibited LRP4 and activated the Wnt/β-catenin pathway, thus facilitating fracture healing. Cite this article: Bone Joint Res 2021;10(12):744–758

INTRODUCTION. Soft tissue balancing in knee arthroplasty remains an art. To make it a science reliable quantification and reference values for soft tissue tension and contact loads are necessary. This study intends to prove the concept of a compartmental load safe target zone as a clinical tool for balancing total knee arthroplasties by studying the relationship between post- balancing compartmental load distribution and patient satisfaction at 6 months. MATERIALS AND METHODS. In this prospective non-randomised clinical series of 102 patients (110 knees), medial and lateral loads were recorded intra-operatively using a tibial liner load sensor system. All knees were balanced using specific algorithm sequences with a goal of equal distribution between compartments. A safe target zone area was defined on a scatterplot graph displaying lateral versus medial loads. Individual points on the graft were coded with their satisfaction score at 6 months. RESULTS. Eighty-two (82) cases satisfied the study criteria and were analysed. The boundaries of the safe zone were defined by combining absolute and relative load values. Fifty-seven (57) knees fitted in the defined zone and 25 lied outside. Excellent satisfaction scores were 4.2 times more likely to be in the safe zone. Poor scores were twice more likely to lie outside the zone. In the zone the median satisfaction score was 36/40, whereas outside the zone it fell to 31/40. DISCUSSION. Load balancing of knee arthroplasty is a useful clinical tool. Early studies by a developing group showed increased satisfaction rates. One problem remains the subjectivity of testing at the time of surgery. Other studies have also pointed to the difficulty in defining a target zone for balancing. Using specific ligamentous balance algorithms it is now possible to predictably achieve a balanced load differential within 15 lbs between compartments. In this paper, we have demonstrated in a prospective series that a target zone can be defined as an area rather than a single ideal value. Within this zone satisfaction scores reach 90–95%. Of all excellent results there are 4.2 more within the zone than outside. Balancing a knee arthroplasty to medial and lateral compartment load values defined by a safe target zone can therefore be predictive of patient satisfaction

Osteoarthritis (OA) is the most common cause of joint disease and associated disability. Despite this, its pathogenesis remains incompletely understood and no specific drug exists to prevent or reverse the structural changes in OA. Basic calcium phosphate (BCP) crystals are extremely common in OA. BCP crystals consist primarily of hydroxyapatite, with smaller amounts of octacalcium phosphate, tricalcium phosphate and magnesium whitlockite. They are present in 100% of joints at the time of knee and hip joint replacement surgery. Their presence strongly correlates with radiographic severity of osteoarthitis. In mice, intra-articular BCP crystals elicit synovial inflammation and cartilage degradation. The potential mechanisms by which calcium-containing crystals may promote articular damage have been studied in the laboratory setting and in vitro properties of BCP crystals have been observed that emphasise their pathogenic potential. BCP crystals interact with articular cells such as fibroblasts and chondrocytes to induce mitogenesis with resultant cellular proliferation likely leading to synovial lining hypertrophy. BCP crystals also upregulate production of cytokines such as tumour necrosis factor alpha (TNF-α), interleukin 1 (IL-1), increase prostaglandin E2 via the cyclooxygenase pathway, stimulate matrix metalloproteinases production and increase nitrous oxide production. Therefore, BCP crystals have potent biologic effects and represent a potential therapeutic target in OA

Introduction. Recent studies of novel healthcare episode payment models, such as the Bundled Payments for Care Improvement (BPCI) initiative, have demonstrated pathways for improving value. However, these models may not provide appropriate payments for patients with significant medical comorbidities or complications. The objective of this study was to identify risk factors for exceeding our institution's target payment, the so-called “bundle busters.”. Methods. After receiving an exemption from the Institutional Review Board, we queried our institutional data warehouse for all patients (n=412) that underwent total joint arthroplasty (TJA) of the hip (n=192), knee (n=207), or ankle (n=13), and qualified for our institution's bundled payments model during the study time period (July 2015 – May 2017). Patients with medical conditions that were not well controlled or were potentially optimizable were all sent for preoperative medical optimization prior to surgery. For each 90-day episode, patient characteristics, medical comorbidities, perioperative data, and payments from the Centers for Medicare and Medicaid Services (CMS) were obtained. Episodes where Medicare payments exceeded the target payment were considered “busters”. The busters were older, and had higher comorbidity scores (all, p<0.01). Variables were summarized using descriptive statistics and risk ratios were calculated using a modified Poisson regression analysis. Results. Of the 412 patients, 123 were bundle busters (30%). There was a median institutional loss of $11,797 (IQR, $4,312 – $26,771) for the bundle busters and a median gain of $7,402 ($5,657 – $9,206) for the non-busters. Of the 32 risk factors evaluated, 11 were identified as Independent risk factors for busting the bundle (all, p<0.05). Nine of the 11 (82%) are non-modifiable risk factors and include age, disease specific diagnoses (fracture and avascular necrosis), and medical comorbidities (congestive heart failure, pulmonary circulation disorders, renal disease, cardiac arrhythmia, chronic pulmonary disease, and neurological disorder). The remaining two medical comorbidities are potentially modifiable and include diabetes with complications, and preoperative anemia. Conclusion. Though modifiable risk factors should continue to be optimized prior to TJA, as they were in this population, there are still many non-modifiable preoperative risk factors that can lead to costs exceeding the BPCI established institutional payment goal. As such, further work with payors may be needed to help fairly and appropriately consider these non-modifiable factors which result in increased costs

Background

Although described as a commensal bacterium with low pathogenicity, Cutibacterium acnes involvement has been reported in many clinical entities: infections associated with devices, such as shoulder prosthetic joint infections, osteosynthesis, breast implants or cerebrospinal fluid shunts. Various studies show that C. acnes grows as a biofilm, contributing to its persistence by allowing its escape from the action of the immune system and antibiotics.

Objectives. This study aimed to investigate the functional effects of microRNA (miR)-214-5p on osteoblastic cells, which might provide a potential role of miR-214-5p in bone fracture healing. Methods. Blood samples were obtained from patients with hand fracture or intra-articular calcaneal fracture and from healthy controls (HCs). Expression of miR-214-5p was monitored by qRT-PCR at day 7, 14 and 21 post-surgery. Mouse osteoblastic MC3T3-E1 cells were transfected with antisense oligonucleotides (ASO)-miR-214-5p, collagen type IV alpha 1 (COL4A1) vector or their controls; thereafter, cell viability, apoptotic rate, and the expression of collagen type I alpha 1 (COL1A1), type II collagen (COL-II), and type X collagen (COL-X) were determined. Luciferase reporter assay, qRT-PCR, and Western blot were performed to ascertain whether COL4A1 was a target of miR-214-5p. Results. Plasma miR-214-5p was highly expressed in patients with bone fracture compared with HCs after fracture (p < 0.05 or p < 0.01). Inhibition of miR-214-5p increased the viability of MC3T3-E1 cells and the expressions of COL1A1 and COL-X, but decreased the apoptotic rate and COL-II expression (p < 0.05 or p < 0.01). COL4A1 was a target of miR-214-5p, and was negatively regulated by miR-214-5p (p < 0.05 or p < 0.01). Overexpression of COL4A1 showed a similar impact on cell viability, apoptotic rate, and COL1A1, COL-II, and COL-X expressions inhibiting miR-214-5p (p < 0.01). Conclusion. Inhibition of miR-214-5p promotes cell survival and extracellular matrix (ECM) formation of osteoblastic MC3T3-E1 cells by targeting COL4A1. Cite this article: Q. S. Li, F. Y. Meng, Y. H. Zhao, C. L. Jin, J. Tian, X. J. Yi. Inhibition of microRNA-214-5p promotes cell survival and extracellular matrix formation by targeting collagen type IV alpha 1 in osteoblastic MC3T3-E1 cells. Bone Joint Res 2017;6:464–471. DOI: 10.1302/2046-3758.68.BJR-2016-0208.R2

Proliferation of synovial Mesenchymal Stromal/Stem Cells (MSCs) leads to synovial hyperplasia (SH) following Joint Surface Injury (JSI). Uncontrolled Yap activity causes tissue overgrowth due to modulation of MSC proliferation. We hypothesised that YAP plays a role in SH following JSI. A spatiotemporal analysis of Yap expression was performed using the JSI model in C57Bl/6 mice. Synovial samples from patients were similarly analysed. Gdf5-Cre;Yap1fl/fl;Tom mice were created to determine the effect YAP1 knockout in Gdf5 lineage cells on SH after JSI. In patients, Yap expression was upregulated in activated synovium, including a subset of CD55 positive fibroblast-like synoviocytes in the synovial lining (SL). Cells staining positive for the proliferation marker Ki67 expressed active YAP. In mice, Yap was highly expressed in injured knee joint synovium compared to controls. Yap mRNA levels at 2 (p<0.05) and 8 days (p<0.001) after injury were increased. Conditional Yap1 knockout in Gdf5 progeny cells prevented hyperplasia of synovial lining (SL) after JSI. Cellularity was significantly decreased in the SL but not in the sub-lining of injured Yap1 knockout- compared to control mice. The percentage of cells in synovium that were Tom+ increased in response to JSI in control and haplo-insufficient but not in YAP1 knockout mice (p<0.05). Modulation of YAP and proliferation of MSCs in the synovium after JSI provides a system to study the role of SH after trauma in re-establishing joint homeostasis and is a potential novel therapeutic target for the treatment of post traumatic OA

Purpose. The prevention of a subsequent, contralateral hip fracture is targeted as an avoidable event in the elderly. Fall prevention and bone strengthening measures have met with limited success and the urgency of their effect is undetermined. Our objective was to evaluate the time to second hip fracture (the time between a first and a subsequent, contralateral fracture) in elderly patients, using a population-based administrative health data set. Method. The 58,286 records of persons older than 60 yrs and hospitalized for a hip fracture between 1985 and 2005 were obtained from a Provincial administrative health database. We excluded non-traumatic cases and identified the care episodes related to a subsequent hip fracture for each patient using unique identifiers. We used a 5 year “wash-out period” to avoid counting a second fracture as a first one. We calculated the proportion of first and second fractures and sex distribution over time (fiscal years) and quantified the time between first and second fracture, while correlating it to age, sex and fracture type. Results. Overall, 3,866 patients sustained a second hip fracture between 1990 and 2005; 3,119 (81%) were women, in contrast to 73% for primary fractures (chi-square =137.8, df=1, p<0.001). In 33% cases, the type of a subsequent fracture (transcervical vs pertrochanteric) was different from the first. The median time from first fracture was 3 years, 90% occurred by 9yrs. The age at the first fracture most influenced the time to second fracture. The median time (90th percentile in parentheses) between fractures decreased as patients got older and was 5 (13), 4 (10), 3 (7), 2 (5) years for patients who were correspondingly 60–69, 70–79, 80–89 and 90+ years old at first fracture. Conclusion. Among survivors of an initial hip fracture, the occurrence of a second hip fracture appears to affect a greater proportion of women than primary fractures. Our results identify the time frame which preventative interventions should target when aiming at reducing second hip fractures, that target being increasingly small (from 5 to 2 years) as patients age. This information identifies a time frame researchers must target as they seek new fracture prevention methods. In the shorter term however, these data could influence health administrators and policy makers as they decide to support one hip fracture prevention method over another

Aims

To explore key stakeholder views around feasibility and acceptability of trials seeking to prevent post-traumatic osteoarthritis (PTOA) following knee injury, and provide guidance for next steps in PTOA trial design.