Aims. Patients receiving cemented hemiarthroplasties after hip fracture have a significant risk of deep surgical site infection (SSI). Standard UK practice to minimize the risk of SSI includes the use of antibiotic-loaded bone cement with no consensus regarding type, dose, or antibiotic content of the cement. This is the protocol for a randomized clinical trial to investigate the clinical and cost-effectiveness of high dose dual antibiotic-loaded cement in comparison to low dose single antibiotic-loaded cement in patients 60 years and over receiving a cemented hemiarthroplasty for an intracapsular hip fracture. Methods. The WHiTE 8 Copal Or Palacos Antibiotic Loaded bone cement trial (WHiTE 8 COPAL) is a multicentre, multi-surgeon, parallel, two-arm, randomized clinical trial. The pragmatic study will be embedded in the World Hip Trauma Evaluation (WHiTE) (ISRCTN 63982700). Participants, including those that lack capacity, will be allocated on a 1:1 basis stratified by recruitment centre to either a low dose single antibiotic-loaded bone cement or a high dose dual antibiotic-loaded bone cement. The primary analysis will compare the differences in deep SSI rate as defined by the Centers for Disease Control and Prevention within 90 days of surgery via medical record review and patient self-reported questionnaires. Secondary outcomes include UK Core Outcome Set for hip fractures, complications, rate of antibiotic prescription, resistance patterns of deep SSI, and resource use (more specifically, cost-effectiveness) up to four months post-randomization. A minimum of 4,920 patients will be recruited to obtain 90% power to detect an absolute difference of 1.5% in the rate of deep SSI at 90 days for the expected 3% deep SSI rate in the control group. Conclusion. The results of this trial will provide evidence regarding clinical and cost-effectiveness between low dose single and high dose dual antibiotic-loaded bone cement, which will inform policy and practice guidelines such as the National Institute for Health and Care Excellence guidance on management of hip fractures. Cite this article: Bone Jt Open 2021;2(2):72–78

Aims. Bacteriophages infect, replicate inside bacteria, and are released from the host through lysis. Here, we evaluate the effects of repetitive doses of the Staphylococcus aureus phage 191219 and gentamicin against haematogenous and early-stage biofilm implant-related infections in Galleria mellonella. Methods. For the haematogenous infection, G. mellonella larvae were implanted with a Kirschner wire (K-wire), infected with S. aureus, and subsequently phages and/or gentamicin were administered. For the early-stage biofilm implant infection, the K-wires were pre-incubated with S. aureus suspension before implantation. After 24 hours, the larvae received phages and/or gentamicin. In both models, the larvae also received daily doses of phages and/or gentamicin for up to five days. The effect was determined by survival analysis for five days and quantitative culture of bacteria after two days of repetitive doses. Results. In the haematogenous infection, a single combined dose of phages and gentamicin, and repetitive injections with gentamicin or in combination with phages, resulted in significantly improved survival rates. In the early-stage biofilm infection, only repetitive combined administration of phages and gentamicin led to a significantly increased survival. Additionally, a significant reduction in number of bacteria was observed in the larvae after receiving repetitive doses of phages and/or gentamicin in both infection models. Conclusion. Based on our results, a single dose of the combination of phages and gentamicin is sufficient to prevent a haematogenous S. aureus implant-related infection, whereas gentamicin needs to be administered daily for the same effect. To treat early-stage S. aureus implant-related infection, repetitive doses of the combination of phages and gentamicin are required. Cite this article: Bone Joint Res 2024;13(8):383–391

Objectives. We have increased the dose of tranexamic acid (TXA) in our enhanced total joint recovery protocol at our institution from 15 mg/kg to 30 mg/kg (maximum 2.5 g) as a single, intravenous (IV) dose. We report the clinical effect of this dosage change. Methods. We retrospectively compared two cohorts of consecutive patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) surgery in our unit between 2008 and 2013. One group received IV TXA 15 mg/kg, maximum 1.2 g, and the other 30 mg/kg, maximum 2.5 g as a single pre-operative dose. The primary outcome for this study was the requirement for blood transfusion within 30 days of surgery. Secondary measures included length of hospital stay, critical care requirements, re-admission rate, medical complications and mortality rates. Results. A total of 1914 THA and 2537 TKA procedures were evaluated. In THA, the higher dose of TXA was associated with a significant reduction in transfusion (p = 0.02, risk ratio (RR) 0.74, 95% confidence interval (CI) 0.58 to 0.96) and rate of re-admission (p < 0.001, RR 0.50, 95% CI 0.35 to 0.71). There were reductions in the requirement for critical care (p = 0.06, RR 0.55, 95% CI 0.31 to 1.00), and in the length of stay from 4.7 to 4.3 days (p = 0.02). In TKA, transfusion requirements (p = 0.049, RR 0.64, 95% CI 0.41 to 0.99), re-admission rate (p = 0.001, RR 0.56, 95% CI 0.39 to 0.80) and critical care requirements (p < 0.003, RR 0.34, 95% CI 0.16 to 0.72) were reduced with the higher dose. Mean length of stay reduced from 4.6 days to 3.6 days (p < 0.01). There was no difference in the incidence of deep vein thrombosis, pulmonary embolism, gastrointestinal bleed, myocardial infarction, stroke or death in THA and TKA between cohorts. Conclusion. We suggest that a single pre-operative dose of TXA, 30 mg/kg, maximum 2.5g, results in a lower transfusion requirement compared with a lower dose in patients undergoing elective primary hip and knee arthroplasty. However, these findings should be interpreted in the context of the retrospective non-randomised study design. Cite this article: R. J. M. Morrison, B. Tsang, W. Fishley, I. Harper, J. C. Joseph, M. R. Reed. Dose optimisation of intravenous tranexamic acid for elective hip and knee arthroplasty: The effectiveness of a single pre-operative dose. Bone Joint Res 2017;6:499–505. DOI: 10.1302/2046-3758.68.BJR-2017-0005.R1

Objectives. Computed tomography (CT) plays an important role in evaluating wear and periacetabular osteolysis (PAO) in total hip replacements. One concern with CT is the high radiation exposure since standard pelvic CT provides approximately 3.5 millisieverts (mSv) of radiation exposure, whereas a planar radiographic examination with three projections totals approximately 0.5 mSv. The objective of this study was to evaluate the lowest acceptable radiation dose for dual-energy CT (DECT) images when measuring wear and periacetabular osteolysis in uncemented metal components. Materials and Methods. A porcine pelvis with bilateral uncemented hip prostheses and with known linear wear and acetabular bone defects was examined in a third-generation multidetector DECT scanner. The examinations were performed with four different radiation levels both with and without iterative reconstruction techniques. From the high and low peak kilo voltage acquisitions, polychrmoatic images were created together with virtual monochromatic images of energies 100 kiloelectron volts (keV) and 150 keV. Results. We could assess wear and PAO while substantially lowering the effective radiation dose to 0.7 mSv for a total pelvic view with an accuracy of around 0.5 mm for linear wear and 2 mm to 3 mm for PAO. Conclusion. CT for detection of prosthetic wear and PAO could be used with clinically acceptable accuracy at a radiation exposure level equal to plain radiographic exposures. Cite this article: B. Sandgren, M. Skorpil, P. Nowik, H. Olivecrona, J. Crafoord, L. Weidenhielm, A. Persson. Assessment of wear and periacetabular osteolysis using dual energy computed tomography on a pig cadaver to identify the lowest acceptable radiation dose. Bone Joint Res 2016;5:307–313. DOI: 10.1302/2046-3758.57.2000566

Aims. There is increasing evidence to support the use of topical antibiotics to prevent surgical site infections. Although previous research suggests a minimal nephrotoxic risk with a single dose of vancomycin powder, fracture patients often require multiple procedures and receive additional doses of topical antibiotics. We aimed to determine if cumulative doses of intrawound vancomycin or tobramycin powder for infection prophylaxis increased the risk of drug-induced acute kidney injury (AKI) among fracture patients. Methods. This cohort study was a secondary analysis of single-centre Program of Randomized Trials to Evaluate Pre-operative Antiseptic Skin Solutions in Orthopaedic Trauma (PREP-IT) trial data. We included patients with a surgically treated appendicular fracture. The primary outcome was drug-induced AKI. The odds of AKI per gram of vancomycin or tobramycin powder were calculated using Bayesian regression models, which adjusted for measured confounders and accounted for the interactive effects of vancomycin and tobramycin. Results. Of the 782 included patients (mean age 48 years (SD 20); 59% male), 83% (n = 648) received at least one vancomycin dose (cumulative range 1 to 12 g). Overall, 45% of the sample received at least one tobramycin dose (cumulative range 1.2 to 9.6 g). Drug-induced AKI occurred in ten patients (1.2%). No association was found between the cumulative dose of vancomycin and drug-induced AKI (odds ratio (OR) 1.08 (95% credible interval (CrI) 0.52 to 2.14)). Additional doses of tobramycin were associated with a three-fold increase in the adjusted odds of drug-induced AKI (OR 3.66 (95% CrI 1.71 to 8.49)). Specifically, the risk of drug-induced AKI rose substantially after 4.8 g of tobramycin powder (7.5% (95% CrI 1.0 to 35.3)). Conclusion. Cumulative doses of vancomycin were not associated with an increased risk of drug-induced AKI among fracture patients. While the risk of drug-induced AKI remains less than 4% with three or fewer 1.2 g tobramycin doses, the estimated risk increases substantially to 8% after four cumulative doses. Level of evidence: Therapeutic Level III. Cite this article: Bone Jt Open 2022;3(4):284–290

Aims. Prophylactic antibiotic regimens for elective primary total hip and knee arthroplasty vary widely across hospitals and trusts in the UK. This study aimed to identify antibiotic prophylaxis regimens currently in use for elective primary arthroplasty across the UK, establish variations in antibiotic prophylaxis regimens and their impact on the risk of periprosthetic joint infection (PJI) in the first-year post-index procedure, and evaluate adherence to current international consensus guidance. Methods. The guidelines for the primary and alternative recommended prophylactic antibiotic regimens in clean orthopaedic surgery (primary arthroplasty) for 109 hospitals and trusts across the UK were sought by searching each trust and hospital’s website (intranet webpages), and by using the MicroGuide app. The mean cost of each antibiotic regimen was calculated using price data from the British National Formulary (BNF). Regimens were then compared to the 2018 Philadelphia Consensus Guidance, to evaluate adherence to international guidance. Results. The primary choice and dosing of the prophylactic antimicrobial regimens varied widely. The two most used regimens were combined teicoplanin and gentamicin, and cefuroxime followed by two or three doses of cefuroxime eight-hourly, recommended by 24 centres (22.02%) each. The alternative choice and dosing of the prophylactic antimicrobial regimen also varied widely across the 83 centres with data available. Prophylaxis regimens across some centres fail to cover the likeliest causes of surgical site infection (SSI). Five centres (4.59%) recommend co-amoxiclav, which confers no Staphylococcus coverage, while 33 centres (30.28%) recommend cefuroxime, which confers no Enterococcus coverage. Limited adherence to 2018 Philadelphia Consensus Guidance was observed, with 67 centres (61.50%) not including a cephalosporin in their guidance. Conclusion. This analysis of guidance on antimicrobial prophylaxis in primary arthroplasty across 109 hospitals and trusts in the UK has identified widespread variation in primary and alternative antimicrobial regimens currently recommended. Cite this article: Bone Jt Open 2023;4(10):742–749

Aims. Antibiotic prophylaxis involving timely administration of appropriately dosed antibiotic is considered effective to reduce the risk of surgical site infection (SSI) after total hip and total knee arthroplasty (THA/TKA). Cephalosporins provide effective prophylaxis, although evidence regarding the optimal timing and dosage of prophylactic antibiotics is inconclusive. The aim of this study is to examine the association between cephalosporin prophylaxis dose, timing, and duration, and the risk of SSI after THA/TKA. Methods. A prospective multicentre cohort study was undertaken in consenting adults with osteoarthritis undergoing elective primary TKA/THA at one of 19 high-volume Australian public/private hospitals. Data were collected prior to and for one-year post surgery. Logistic regression was undertaken to explore associations between dose, timing, and duration of cephalosporin prophylaxis and SSI. Data were analyzed for 1,838 participants. There were 264 SSI comprising 63 deep SSI (defined as requiring intravenous antibiotics, readmission, or reoperation) and 161 superficial SSI (defined as requiring oral antibiotics) experienced by 249 (13.6%) participants within 365 days of surgery. Results. In adjusted modelling, factors associated with a significant reduction in any SSI and deep SSI included: correct weight-adjusted dose (any SSI; adjusted odds ratio (aOR) 0.68 (95% confidence interval (CI) 0.47 to 0.99); p = 0.045); commencing preoperative cephalosporin within 60 minutes (any SSI, aOR 0.56 (95% CI 0.36 to 0.89); p = 0.012; deep SSI, aOR 0.29 (95% CI 0.15 to 0.59); p < 0.001) or 60 minutes or longer prior to skin incision (aOR 0.35 (95% CI 0.17 to 0.70); p = 0.004; deep SSI, AOR 0.27 (95% CI 0.09 to 0.83); p = 0.022), compared to at or after skin incision. Other factors significantly associated with an increased risk of any SSI, but not deep SSI alone, were receiving a non-cephalosporin antibiotic preoperatively (aOR 1.35 (95% CI 1.01 to 1.81); p = 0.044) and changing cephalosporin dose (aOR 1.76 (95% CI 1.22 to 2.57); p = 0.002). There was no difference in risk of any or deep SSI between the duration of prophylaxis less than or in excess of 24 hours. Conclusion. Ensuring adequate, weight-adjusted dosing and early, preoperative delivery of prophylactic antibiotics may reduce the risk of SSI in THA/TKA, whereas the duration of prophylaxis beyond 24 hours is unnecessary. Cite this article: Bone Jt Open 2022;3(3):252–260

Aims. Acridine orange (AO) demonstrates several biological activities. When exposed to low doses of X-ray radiation, AO increases the production of reactive radicals (radiodynamic therapy (AO-RDT)). We elucidated the efficacy of AO-RDT in breast and prostate cancer cell lines, which are likely to develop bone metastases. Methods. We used the mouse osteosarcoma cell line LM8, the human breast cancer cell line MDA-MB-231, and the human prostate cancer cell line PC-3. Cultured cells were exposed to AO and radiation at various concentrations followed by various doses of irradiation. The cell viability was then measured. In vivo, each cell was inoculated subcutaneously into the backs of mice. In the AO-RDT group, AO (1.0 μg) was locally administered subcutaneously around the tumour followed by 5 Gy of irradiation. In the radiation group, 5 Gy of irradiation alone was administered after macroscopic tumour formation. The mice were killed on the 14th day after treatment. The change in tumour volume by AO-RDT was primarily evaluated. Results. The viability of LM8, MDA-MB-231, and PC-3 cells strongly decreased at AO concentration of 1.0 μg/ml and a radiation dose of 5 Gy. In xenograft mouse model, the AO-RDT also showed a strong cytocidal effect on tumour at the backside in osteosarcoma, breast cancer, and prostate cancer. AO-RDT treatment was more effective for tumour control than radiotherapy in breast cancer. Conclusion. AO-RDT was effective in preventing the proliferation of osteosarcoma, breast cancer, and prostate cancer cell lines in vitro. The reduction in tumour volume by AO-RDT was also confirmed in vivo. Cite this article: Bone Joint Res 2022;11(10):715–722

Aims. Tranexamic acid (TXA) is now commonly used in major surgical operations including orthopaedics. The TRAC-24 randomized control trial (RCT) aimed to assess if an additional 24 hours of TXA postoperatively in primary total hip (THA) and total knee arthroplasty (TKA) reduced blood loss. Contrary to other orthopaedic studies to date, this trial included high-risk patients. This paper presents the results of a cost analysis undertaken alongside this RCT. Methods. TRAC-24 was a prospective RCT on patients undergoing TKA and THA. Three groups were included: Group 1 received 1 g intravenous (IV) TXA perioperatively and an additional 24-hour postoperative oral regime, Group 2 received only the perioperative dose, and Group 3 did not receive TXA. Cost analysis was performed out to day 90. Results. Group 1 was associated with the lowest mean total costs, followed by Group 2 and then Group 3. The differences between Groups 1 and 3 (-£797.77 (95% confidence interval -1,478.22 to -117.32) were statistically significant. Extended oral dosing reduced costs for patients undergoing THA but not TKA. The reduced costs in Groups 1 and 2 resulted from reduced length of stay, readmission rates, emergency department attendances, and blood transfusions. Conclusion. This study demonstrated significant cost savings when using TXA in primary THA or TKA. Extended oral dosing reduced costs further in THA but not TKA. Cite this article: Bone Jt Open 2022;3(7):536–542

Aims. Prompt and sufficient broad-spectrum empirical antibiotic treatment is key to preventing infection following open tibial fractures. Succeeding co-administration, we dynamically assessed the time for which vancomycin and meropenem concentrations were above relevant epidemiological cut-off (ECOFF) minimal inhibitory concentrations (T > MIC) in tibial compartments for the bacteria most frequently encountered in open fractures. Low and high MIC targets were applied: 1 and 4 µg/ml for vancomycin, and 0.125 and 2 µg/ml for meropenem. Methods. Eight pigs received a single dose of 1,000 mg vancomycin and 1,000 mg meropenem simultaneously over 100 minutes and 10 minutes, respectively. Microdialysis catheters were placed for sampling over eight hours in tibial cancellous bone, cortical bone, and adjacent subcutaneous adipose tissue. Venous blood samples were collected as references. Results. Across the targeted ECOFF values, vancomycin displayed longer T > MIC in all the investigated compartments in comparison to meropenem. For both drugs, cortical bone exhibited the shortest T > MIC. For the low MIC targets and across compartments, mean T > MIC ranged between 208 and 449 minutes (46% to 100%) for vancomycin and between 189 and 406 minutes (42% to 90%) for meropenem. For the high MIC targets, mean T > MIC ranged between 30 and 446 minutes (7% to 99%) for vancomycin and between 45 and 181 minutes (10% to 40%) for meropenem. Conclusion. The differences in the T > MIC between the low and high targets illustrate how the interpretation of these results is highly susceptible to the defined MIC target. To encompass any trauma, contamination, or individual tissue differences, a more aggressive dosing approach may be considered to achieve longer T > MIC in all the exposed tissues, and thereby lower the risk of acquiring an infection after open tibial fractures. Cite this article: Bone Joint Res 2022;11(2):112–120

Aims. The use of fluoroscopy in orthopaedic surgery creates risk of radiation exposure to surgeons. Appropriate personal protective equipment (PPE) can help mitigate this. The primary aim of this study was to assess if current radiation protection in orthopaedic trauma is safe. The secondary aims were to describe normative data of radiation exposure during common orthopaedic procedures, evaluate ways to improve any deficits in protection, and validate the use of electronic personal dosimeters (EPDs) in assessing radiation dose in orthopaedic surgery. Methods. Radiation exposure to surgeons during common orthopaedic trauma operations was prospectively assessed using EPDs and thermoluminescent dosimeters (TLDs). Normative data for each operation type were calculated and compared to recommended guidelines. Results. Current PPE appears to mitigate more than 90% of ionizing radiation in orthopaedic fluoroscopic procedures. There is a higher exposure to the inner thigh during seated procedures. EPDs provided results for individual procedures. Conclusion. PPE currently used by surgeons in orthopaedic trauma theatre adequately reduces radiation exposure to below recommended levels. Normative data per trauma case show specific anatomical areas of higher exposure, which may benefit from enhanced radiation protection. EPDs can be used to assess real-time radiation exposure in orthopaedic surgery. There may be a role in future medical wearables for orthopaedic surgeons. Cite this article: Bone Jt Open 2022;3(11):907–912

Aims. Ankle fracture fixation is commonly performed by junior trainees. Simulation training using cadavers may shorten the learning curve and result in a technically superior surgical performance. Methods. We undertook a preliminary, pragmatic, single-blinded, multicentre, randomized controlled trial of cadaveric simulation versus standard training. Primary outcome was fracture reduction on postoperative radiographs. Results. Overall, 139 ankle fractures were fixed by 28 postgraduate year three to five trainee surgeons (mean age 29.4 years; 71% males) during ten months' follow-up. Under the intention-to-treat principle, a technically superior fixation was performed by the cadaveric-trained group compared to the standard-trained group, as measured on the first postoperative radiograph against predefined acceptability thresholds. The cadaveric-trained group used a lower intraoperative dose of radiation than the standard-trained group (mean difference 0.011 Gym. 2. , 95% confidence interval 0.003 to 0.019; p = 0.009). There was no difference in procedure time. Conclusion. Trainees randomized to cadaveric training performed better ankle fracture fixations and irradiated patients less during surgery compared to standard-trained trainees. This effect, which was previously unknown, is likely to be a consequence of the intervention. Further study is required. Cite this article: Bone Jt Open 2023;4(8):594–601

Aims. The aim of this study was to identify the effect of the manufacturing characteristics of polyethylene acetabular liners on the survival of cementless and hybrid total hip arthroplasty (THA). Methods. Prospective cohort study using linked National Joint Registry (NJR) and manufacturer data. The primary endpoint was revision for aseptic loosening. Cox proportional hazard regression was the primary analytical approach. Manufacturing variables included resin type, crosslinking radiation dose, terminal sterilization method, terminal sterilization radiation dose, stabilization treatment, total radiation dose, packaging, and face asymmetry. Total radiation dose was further divided into G1 (no radiation), G2 (> 0 Mrad to < 5 Mrad), G3 (≥ 5 Mrad to < 10 Mrad), and G4 (≥ 10 Mrad). Results. A total of 5,329 THAs were revised, 1,290 of which were due to aseptic loosening. Total radiation dose, face asymmetry, and stabilization treatments were found to significantly affect implant survival. G1 had the highest revision risk for any reason and for aseptic loosening and G3 and G4 the lowest. Compared with G1, the adjusted hazard ratio for G2 was 0.74 (95% confidence interval (CI) 0.64 to 0.86), G3 was 0.36 (95% CI 0.30 to 0.43), and G4 was 0.38 (95% CI 0.31 to 0.47). The cumulative incidence of revision for aseptic loosening at 12 years was 0.52 and 0.54 per 100 THAs for G3 and G4, respectively, compared with 1.95 per 100 THAs in G1. Asymmetrical liners had a lower revision risk due to aseptic loosening and reasons other than aseptic loosening compared with symmetric (flat) liners. In G3 and G4, stabilization with vitamin E and heating above melting point performed best. Conclusion. Polyethylene liners with a total radiation dose of ≥ 5 Mrad, an asymmetrical liner face, and stabilization with heating above the melting point demonstrate best survival. Cite this article: Bone Joint J 2020;102-B(1):90–101

Aims. A growing number of fractures progress to delayed or nonunion, causing significant morbidity and socioeconomic impact. Localized delivery of stem cells and subcutaneous parathyroid hormone (PTH) has been shown individually to accelerate bony regeneration. This study aimed to combine the therapies with the aim of upregulating fracture healing. Methods. A 1.5 mm femoral osteotomy (delayed union model) was created in 48 female juvenile Wistar rats, aged six to nine months, and stabilized using an external fixator. At day 0, animals were treated with intrafracture injections of 1 × 10. 6. cells/kg bone marrow mesenchymal stem cells (MSCs) suspended in fibrin, daily subcutaneous injections of high (100 μg/kg) or low (25 μg/kg) dose PTH 1-34, or a combination of PTH and MSCs. A group with an empty gap served as a control. Five weeks post-surgery, the femur was excised for radiological, histomorphometric, micro-CT, and mechanical analysis. Results. Combination therapy treatment led to increased callus formation compared to controls. In the high-dose combination group there was significantly greater mineralized tissue volume and trabecular parameters compared to controls (p = 0.039). This translated to significantly improved stiffness (and ultimate load to failure (p = 0.049). The high-dose combination therapy group had the most significant improvement in mean modified Radiographic Union Score for Tibia fractures (RUST) compared to controls (13.8 (SD 1.3) vs 5.8 (SD 0.5)). All groups demonstrated significant increases in the radiological scores – RUST and Allen score – histologically compared to controls. Conclusion. We demonstrate the beneficial effect of localized MSC injections on fracture healing combined with low- or high-dose teriparatide, with efficacy dependent on PTH dose. Cite this article: Bone Joint Res 2021;10(10):659–667

Aims. To investigate the effect of polyethylene manufacturing characteristics and irradiation dose on the survival of cemented and reverse hybrid total hip arthroplasties (THAs). Methods. In this registry study, data from the National Joint Registry of England, Wales, Northern Ireland and the Isle of Man (NJR) were linked with manufacturing data supplied by manufacturers. The primary endpoint was revision of any component. Cox proportional hazard regression was a primary analytic approach adjusting for competing risk of death, patient characteristics, head composition, and stem fixation. Results. A total of 290,770 primary THAs were successfully linked with manufacturing characteristics. Overall 4,708 revisions were analyzed, 1,260 of which were due to aseptic loosening. Total radiation dose was identified as a risk factor and included in the Cox model. For statistical modelling of aseptic loosening, THAs were grouped into three categories: G1 (no radiation); G2 ( > 0 to < 5 Mrad); and G3 ( ≥ 5 Mrad). G1 had the worst survivorship. The Cox regression hazard ratio for revision due to aseptic loosening for G2 was 0.7 (95% confidence interval (CI) 0.58 to 0.83), and for G3 0.4 (95% CI 0.30 to 0.53). Male sex and uncemented stem fixation were associated with higher risk of revision and ceramic heads with lower risk. Conclusion. Polyethylene irradiation was associated with reduced risk of revision for aseptic loosening. Radiation doses of ≥ 5 Mrad were associated with a further reduction in risk. Cite this article: Bone Joint Res 2020;9(9):563–571

Objectives. Activation of the leptin pathway is closely correlated with human knee cartilage degeneration. However, the role of the long form of the leptin receptor (Ob-Rb) in cartilage degeneration needs further study. The aim of this study was to determine the effect of increasing the expression of Ob-Rb on chondrocytes using a lentiviral vector containing Ob-Rb. Methods. The medial and lateral cartilage samples of the tibial plateau from 12 osteoarthritis (OA) patients were collected. Ob-Rb messenger RNA (mRNA) was detected in these samples. The Ob-Rb-overexpressing chondrocytes and controls were treated with different doses of leptin for two days. The activation of the p53/p21 pathway and the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells were evaluated. The mammalian target of rapamycin (mTOR) signalling pathway and autophagy were detected after the chondrocytes were treated with a high dose of leptin. Results. In total, 12 cases were found to have severe medial cartilage wear compared with the lateral cartilage. Immunofluorescence showed that the expression of Ob-Rb in the medial cartilage of the tibial plateau was high. High levels of leptin led to cell cycle arrest and inhibited autophagy. After overexpression of Ob-Rb, the physiological dose of leptin induced cell senescence in the chondrocytes. High doses of leptin inhibited autophagy by activating the mTOR signalling pathway. Blockade of the mTOR signalling pathway could restore autophagy and partially reverse senescence induced by leptin in chondrocytes. Conclusion. In summary, the present study demonstrated that high doses of leptin induce cell senescence by activating the mTOR pathway in chondrocytes from OA cartilage. Highly expressed Ob-Rb accelerates chondrocyte senescence by activating the leptin pathway in OA. Cite this article: X. Zhao, P. Huang, G. Li, L. Zhendong, G. Hu, Q. Xu. Activation of the leptin pathway by high expression of the long form of the leptin receptor (Ob-Rb) accelerates chondrocyte senescence in osteoarthritis. Bone Joint Res 2019;8:425–436. DOI: 10.1302/2046-3758.89.BJR-2018-0325.R2

Aims. To evaluate if, for orthopaedic trainees, additional cadaveric simulation training or standard training alone yields superior radiological and clinical outcomes in patients undergoing dynamic hip screw (DHS) fixation or hemiarthroplasty for hip fracture. Methods. This was a preliminary, pragmatic, multicentre, parallel group randomized controlled trial in nine secondary and tertiary NHS hospitals in England. Researchers were blinded to group allocation. Overall, 40 trainees in the West Midlands were eligible: 33 agreed to take part and were randomized, five withdrew after randomization, 13 were allocated cadaveric training, and 15 were allocated standard training. The intervention was an additional two-day cadaveric simulation course. The control group received standard on-the-job training. Primary outcome was implant position on the postoperative radiograph: tip-apex distance (mm) (DHS) and leg length discrepancy (mm) (hemiarthroplasty). Secondary clinical outcomes were procedure time, length of hospital stay, acute postoperative complication rate, and 12-month mortality. Procedure-specific secondary outcomes were intraoperative radiation dose (for DHS) and postoperative blood transfusion requirement (hemiarthroplasty). Results. Eight female (29%) and 20 male trainees (71%), mean age 29.4 years, performed 317 DHS operations and 243 hemiarthroplasties during ten months of follow-up. Primary analysis was a random effect model with surgeon-level fixed effects of patient condition, patient age, and surgeon experience, with a random intercept for surgeon. Under the intention-to-treat principle, for hemiarthroplasty there was better implant position in favour of cadaveric training, measured by leg length discrepancy ≤ 10 mm (odds ratio (OR) 4.08 (95% confidence interval (CI) 1.17 to 14.22); p = 0.027). There were significantly fewer postoperative blood transfusions required in patients undergoing hemiarthroplasty by cadaveric-trained compared to standard-trained surgeons (OR 6.00 (95% CI 1.83 to 19.69); p = 0.003). For DHS, there was no significant between-group difference in implant position as measured by tip-apex distance ≤ 25 mm (OR 6.47 (95% CI 0.97 to 43.05); p = 0.053). No between-group differences were observed for any secondary clinical outcomes. Conclusion. Trainees randomized to additional cadaveric training performed hip fracture fixation with better implant positioning and fewer postoperative blood transfusions in hemiarthroplasty. This effect, which was previously unknown, may be a consequence of the intervention. Further study is required. Cite this article: Bone Jt Open 2023;4(8):602–611

Objectives. Prosthetic joint infection (PJI) is a devastating complication following total joint arthroplasty. Non-contact induction heating of metal implants is a new and emerging treatment for PJI. However, there may be concerns for potential tissue necrosis. It is thought that segmental induction heating can be used to control the thermal dose and to limit collateral thermal injury to the bone and surrounding tissues. The purpose of this study was to determine the thermal dose, for commonly used metal implants in orthopaedic surgery, at various distances from the heating centre (HC). Methods. Commonly used metal orthopaedic implants (hip stem, intramedullary nail, and locking compression plate (LCP)) were heated segmentally using an induction heater. The thermal dose was expressed in cumulative equivalent minutes at 43°C (CEM43) and measured with a thermal camera at several different distances from the HC. A value of 16 CEM43 was used as the threshold for thermal damage in bone. Results. Despite high thermal doses at the HC (7161 CEM43 to 66 640 CEM43), the thermal dose at various distances from the HC was lower than 16 CEM43 for the hip stem and nail. For the fracture plate without corresponding metal screws, doses higher than 16 CEM43 were measured up to 5 mm from the HC. Conclusion. Segmental induction heating concentrates the thermal dose at the targeted metal implant areas and minimizes collateral thermal injury by using the non-heated metal as a heat sink. Implant type and geometry are important factors to consider, as they influence dissipation of heat and associated collateral thermal injury. Cite this article: B. G. Pijls, I. M. J. G. Sanders, E. J. Kuijper, R. G. H. H. Nelissen. Segmental induction heating of orthopaedic metal implants. Bone Joint Res 2018;7:609–619. DOI: 10.1302/2046-3758.711.BJR-2018-0080.R1

Aims. Autologous chondrocyte implantation (ACI) is a promising treatment for articular cartilage degeneration and injury; however, it requires a large number of human hyaline chondrocytes, which often undergo dedifferentiation during in vitro expansion. This study aimed to investigate the effect of suramin on chondrocyte differentiation and its underlying mechanism. Methods. Porcine chondrocytes were treated with vehicle or various doses of suramin. The expression of collagen, type II, alpha 1 (COL2A1), aggrecan (ACAN); COL1A1; COL10A1; SRY-box transcription factor 9 (SOX9); nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX); interleukin (IL)-1β; tumour necrosis factor alpha (TNFα); IL-8; and matrix metallopeptidase 13 (MMP-13) in chondrocytes at both messenger RNA (mRNA) and protein levels was determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot. In addition, the supplementation of suramin to redifferentiation medium for the culture of expanded chondrocytes in 3D pellets was evaluated. Glycosaminoglycan (GAG) and collagen production were evaluated by biochemical analyses and immunofluorescence, as well as by immunohistochemistry. The expression of reactive oxygen species (ROS) and NOX activity were assessed by luciferase reporter gene assay, immunofluorescence analysis, and flow cytometry. Mutagenesis analysis, Alcian blue staining, reverse transcriptase polymerase chain reaction (RT-PCR), and western blot assay were used to determine whether p67. phox. was involved in suramin-enhanced chondrocyte phenotype maintenance. Results. Suramin enhanced the COL2A1 and ACAN expression and lowered COL1A1 synthesis. Also, in 3D pellet culture GAG and COL2A1 production was significantly higher in pellets consisting of chondrocytes expanded with suramin compared to controls. Surprisingly, suramin also increased ROS generation, which is largely caused by enhanced NOX (p67. phox. ) activity and membrane translocation. Overexpression of p67. phox. but not p67. phox. AD (deleting amino acid (a.a) 199 to 212) mutant, which does not support ROS production in chondrocytes, significantly enhanced chondrocyte phenotype maintenance, SOX9 expression, and AKT (S473) phosphorylation. Knockdown of p67. phox. with its specific short hairpin (sh) RNA (shRNA) abolished the suramin-induced effects. Moreover, when these cells were treated with the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) inhibitor LY294002 or shRNA of AKT1, p67. phox. -induced COL2A1 and ACAN expression was significantly inhibited. Conclusion. Suramin could redifferentiate dedifferentiated chondrocytes dependent on p67. phox. activation, which is mediated by the PI3K/AKT/SOX9 signalling pathway. Cite this article: Bone Joint Res 2022;11(10):723–738

Aims. Continuous local antibiotic perfusion (CLAP) has recently attracted attention as a new drug delivery system for orthopaedic infections. CLAP is a direct continuous infusion of high-concentration gentamicin (1,200 μg/ml) into the bone marrow. As it is a new system, its influence on the bone marrow is unknown. This study aimed to examine the effects of high-concentration antibiotics on human bone tissue-derived cells. Methods. Cells were isolated from the bone tissue grafts collected from six patients using the Reamer-Irrigator-Aspirator system, and exposed to different gentamicin concentrations. Live cells rate, apoptosis rate, alkaline phosphatase (ALP) activity, expression of osteoblast-related genes, mineralization potential, and restoration of cell viability and ALP activity were examined by in vitro studies. Results. The live cells rate (the ratio of total number of cells in the well plate to the absorbance-measured number of live cells) was significantly decreased at ≥ 500 μg/ml of gentamicin on day 14; apoptosis rate was significantly increased at ≥ 750 μg/ml, and ALP activity was significantly decreased at ≥ 750 μg/ml. Real-time reverse transcription-polymerase chain reaction results showed no significant decrease in the ALP and activating transcription factor 4 transcript levels at ≥ 1,000 μg/ml on day 7. Mineralization potential was significantly decreased at all concentrations. Restoration of cell viability was significantly decreased at 750 and 1,000 μg/ml on day 21 and at 500 μg/ml on day 28, and ALP activity was significantly decreased at 500 μg/ml on day 28. Conclusion. Our findings suggest that the exposure concentration and duration of antibiotic administration during CLAP could affect cell functions. However, further in vivo studies are needed to determine the optimal dose in a clinical setting. Cite this article: Bone Joint Res 2024;13(3):91–100

Aims. Orthopaedic infection is a potentially serious complication of elective and emergency trauma and orthopaedic procedures, with a high associated burden of morbidity and cost. Optimization of vitamin D levels has been postulated to be beneficial in the prevention of orthopaedic infection. This study explores the role of vitamin D in orthopaedic infection through a systematic review of available evidence. Methods. A comprehensive search was conducted on databases including Medline and Embase, as well as grey literature such as Google Scholar and The World Health Organization Database. Pooled analysis with weighted means was undertaken. Results. Pooled analysis of four studies including 651 patients found the mean 25(OH)D level to be 50.7 nmol/l with a mean incidence of infection of 70%. There was a paucity of literature exploring prophylactic 25(OH)D supplementation on reducing orthopaedic infection, however, there was evidence of association between low 25(OH)D levels and increased incidence of orthopaedic infection. Conclusion. The results indicate a significant proportion of orthopaedic patients have low 25(OH]D levels, as well as an association between low 25(OH)D levels and orthopaedic infection, but more randomized controlled trials need to be conducted to establish the benefit of prophylactic supplementation and the optimum regimen by dose and time. Cite this article: Bone Jt Open 2021;2(9):721–727

Aims. The aim of this study was to examine whether tourniquet use can improve perioperative blood loss, early function recovery, and pain after primary total knee arthroplasty (TKA) in the setting of multiple-dose intravenous tranexamic acid. Methods. This was a prospective, randomized clinical trial including 180 patients undergoing TKA with multiple doses of intravenous tranexamic acid. One group was treated with a tourniquet during the entire procedure, the second group received a tourniquet during cementing, and the third group did not receive a tourniquet. All patients received the same protocol of intravenous tranexamic acid (20 mg/kg) before skin incision, and three and six hours later (10 mg/kg). The primary outcome measure was perioperative blood loss. Secondary outcome measures were creatine kinase (CK), CRP, interleukin-6 (IL-6), visual analogue scale (VAS) pain score, limb swelling ratio, quadriceps strength, straight leg raising, range of motion (ROM), American Knee Society Score (KSS), and adverse events. Results. The mean total blood loss was lowest in the no-tourniquet group at 867.32 ml (SD 201.11), increased in the limited-tourniquet group at 1024.35 ml (SD 176.35), and was highest in the tourniquet group at 1,213.00 ml (SD 211.48). The hidden blood loss was lowest in the no-tourniquet group (both p < 0.001). There was less mean intraoperative blood loss in the tourniquet group (77.48 ml (SD 24.82)) than in the limited-tourniquet group (137.04 ml (SD 26.96)) and the no-tourniquet group (212.99 ml (SD 56.35); both p < 0.001). Patients in the tourniquet group showed significantly higher levels of muscle damage and inflammation biomarkers such as CK, CRP, and IL-6 than the other two groups (p < 0.05). Outcomes for VAS pain scores, limb swelling ratio, quadriceps strength, straight leg raising, ROM, and KSS were significantly better in the no-tourniquet group at three weeks postoperatively (p < 0.05), but there were no significant differences at three months. No significant differences were observed among the three groups with respect to transfusion rate, thrombotic events, or the length of hospital stay. Conclusion. Patients who underwent TKA with multiple doses of intravenous tranexamic acid but without a tourniquet presented lower total blood loss and hidden blood loss, and they showed less postoperative inflammation reaction, less muscle damage, lower VAS pain score, and better early knee function. Our results argue for not using a tourniquet during TKA. Cite this article: Bone Joint Res 2020;9(6):322–332

Aims. A fracture of the hip is the most common serious orthopaedic injury, and surgical site infection (SSI) is one of the most significant complications, resulting in increased mortality, prolonged hospital stay and often the need for further surgery. Our aim was to determine whether high dose dual antibiotic impregnated bone cement decreases the rate of infection. Patients and Methods. A quasi-randomised study of 848 patients with an intracapsular fracture of the hip was conducted in one large teaching hospital on two sites. All were treated with a hemiarthroplasty. A total of 448 patients received low dose single-antibiotic impregnated cement (control group) and 400 patients received high dose dual-antibiotic impregnated cement (intervention group). The primary outcome measure was deep SSI at one year after surgery. Results. The rate of deep SSI was 3.5% in the control group and 1.1% in the intervention group (p = 0.041; logistic regression adjusting for age and gender). The overall rate of non-infective surgical complications did not differ between the two groups (unadjusted chi-squared test; p > 0.999). Conclusion. The use of high dose dual-antibiotic impregnated cement in these patients significantly reduces the rate of SSI compared with standard low dose single antibiotic loaded bone cement. Cite this article: Bone Joint J 2016;98-B:1534–1541

Aims. We wanted to evaluate the effects of a bone anabolic agent (bone morphogenetic protein 2 (BMP-2)) on an anti-catabolic background (systemic or local zoledronate) on fixation of allografted revision implants. Methods. An established allografted revision protocol was implemented bilaterally into the stifle joints of 24 canines. At revision surgery, each animal received one BMP-2 (5 µg) functionalized implant, and one raw implant. One group (12 animals) received bone graft impregnated with zoledronate (0.005 mg/ml) before impaction. The other group (12 animals) received untreated bone graft and systemic zoledronate (0.1 mg/kg) ten and 20 days after revision surgery. Animals were observed for an additional four weeks before euthanasia. Results. No difference was detected on mechanical implant fixation (load to failure, stiffness, energy) between local or systemic zoledronate. Addition of BMP-2 had no effect on implant fixation. In the histomorphometric evaluation, implants with local zoledronate had more area of new bone on the implant surface (53%, p = 0.025) and higher volume of allograft (65%, p = 0.007), whereas implants in animals with systemic zoledronate had the highest volume of new bone (34%, p = 0.003). Systemic zoledronate with BMP-2 decreased volume of allograft by 47% (p = 0.017). Conclusion. Local and systemic zoledronate treatment protects bone at different stages of maturity; local zoledronate protects the allograft from resorption and systemic zoledronate protects newly formed bone from resorption. BMP-2 in the dose evaluated with experimental revision implants was not beneficial, since it significantly increased allograft resorption without a significant compensating anabolic effect. Cite this article: Bone Joint Res 2021;10(8):488–497

Objectives. Experimental studies indicate that non-steroidal anti-inflammatory drugs (NSAIDs) may have negative effects on fracture healing. This study aimed to assess the effect of immediate and delayed short-term administration of clinically relevant parecoxib doses and timing on fracture healing using an established animal fracture model. Methods. A standardized closed tibia shaft fracture was induced and stabilized by reamed intramedullary nailing in 66 Wistar rats. A ‘parecoxib immediate’ (Pi) group received parecoxib (3.2 mg/kg bodyweight twice per day) on days 0, 1, and 2. A ‘parecoxib delayed’ (Pd) group received the same dose of parecoxib on days 3, 4, and 5. A control group received saline only. Fracture healing was evaluated by biomechanical tests, histomorphometry, and dual-energy x-ray absorptiometry (DXA) at four weeks. Results. For ultimate bending moment, the median ratio between fractured and non-fractured tibia was 0.61 (interquartile range (IQR) 0.45 to 0.82) in the Pi group, 0.44 (IQR 0.42 to 0.52) in the Pd group, and 0.50 (IQR 0.41 to 0.75) in the control group (n = 44; p = 0.068). There were no differences between the groups for stiffness, energy, deflection, callus diameter, DXA measurements (n = 64), histomorphometrically osteoid/bone ratio, or callus area (n = 20). Conclusion. This study demonstrates no negative effect of immediate or delayed short-term administration of parecoxib on diaphyseal fracture healing in rats. Cite this article: G. A. Hjorthaug, E. Søreide, L. Nordsletten, J. E. Madsen, F. P. Reinholt, S. Niratisairak, S. Dimmen. Short-term perioperative parecoxib is not detrimental to shaft fracture healing in a rat model. Bone Joint Res 2019;8:472–480. DOI: 10.1302/2046-3758.810.BJR-2018-0341.R1

Aims. Flucloxacillin is commonly administered intravenously for perioperative antimicrobial prophylaxis, while oral administration is typical for prophylaxis following smaller traumatic wounds. We assessed the time, for which the free flucloxacillin concentration was maintained above the minimum inhibitory concentration (fT > MIC) for methicillin-susceptible Staphylococcus aureus in soft and bone tissue, after intravenous and oral administration, using microdialysis in a porcine model. Methods. A total of 16 pigs were randomly allocated to either intravenous (Group IV) or oral (Group PO) flucloxacillin 1 g every six hours during a 24-hour period. Microdialysis was used for sampling in cancellous and cortical bone, subcutaneous tissue, and the knee joint. In addition, plasma was sampled. The flucloxacillin fT > MIC was evaluated using a low MIC target (0.5 μg/ml) and a high MIC target (2.0 μg/ml). Results. Intravenous administration resulted in longer fT > MIC (0.5 μg/ml) compared to oral administration, except for cortical bone. In Group IV, all pigs reached a concentration of 0.5 μg/ml in all compartments. The mean fT > MIC (0.5 μg/ml) was 149 minutes (95% confidence interval (CI) 119 to 179; range 68 to 323) in subcutaneous tissue and 61 minutes (95% CI 29 to 94; range 0 to 121) to 106 minutes (95% CI 76 to 136; range 71 to 154) in bone tissue. In Group PO, 0/8 pigs reached a concentration of 0.5 μg/ml in all compartments. For the high MIC target (2.0 μg/ml), fT > MIC was close to zero minutes in both groups across compartments. Conclusion. Although intravenous administration of flucloxacillin 1 g provided higher fT > MIC for the low MIC target compared to oral administration, concentrations were surprisingly low, particularly for bone tissue. Achievement of sufficient bone and soft tissue flucloxacillin concentrations may require a dose increase or continuous administration. Cite this article: Bone Joint Res 2021;10(1):60–67

Objectives. Injectable Bromelain Solution (IBS) is a modified investigational derivate of the medical grade bromelain-debriding pharmaceutical agent (NexoBrid) studied and approved for a rapid (four-hour single application), eschar-specific, deep burn debridement. We conducted an ex vivo study to determine the ability of IBS to dissolve-disrupt (enzymatic fasciotomy) Dupuytren’s cords. Materials and Methods. Specially prepared medical grade IBS was injected into fresh Dupuytren’s cords excised from patients undergoing surgical fasciectomy. These cords were tested by tension-loading them to failure with the Zwick 1445 (Zwick GmbH & Co. KG, Ulm, Germany) tension testing system. Results. We completed a pilot concept-validation study that proved the efficacy of IBS to induce enzymatic fasciotomy in ten cords compared with control in ten cords. We then completed a dosing study with an additional 71 cords injected with IBS in descending doses from 150 mg/cc to 0.8 mg/cc. The dosing study demonstrated that the minimal effective dose of 0.5 cc of 6.25 mg/cc to 5 mg/cc could achieve cord rupture in more than 80% of cases. Conclusions. These preliminary results indicate that IBS may be effective in enzymatic fasciotomy in Dupuytren’s contracture. Cite this article: Dr G. Rubin. A new bromelain-based enzyme for the release of Dupuytren’s contracture: Dupuytren’s enzymatic bromelain-based release. Bone Joint Res 2016;5:175–177. DOI: 10.1302/2046-3758.55.BJR-2016-0072

Aims. The aim of this study was to systematically compare the safety and accuracy of robot-assisted (RA) technique with conventional freehand with/without fluoroscopy-assisted (CT) pedicle screw insertion for spine disease. Methods. A systematic search was performed on PubMed, EMBASE, the Cochrane Library, MEDLINE, China National Knowledge Infrastructure (CNKI), and WANFANG for randomized controlled trials (RCTs) that investigated the safety and accuracy of RA compared with conventional freehand with/without fluoroscopy-assisted pedicle screw insertion for spine disease from 2012 to 2019. This meta-analysis used Mantel-Haenszel or inverse variance method with mixed-effects model for heterogeneity, calculating the odds ratio (OR), mean difference (MD), standardized mean difference (SMD), and 95% confidence intervals (CIs). The results of heterogeneity, subgroup analysis, and risk of bias were analyzed. Results. Ten RCTs with 713 patients and 3,331 pedicle screws were included. Compared with CT, the accuracy rate of RA was superior in Grade A with statistical significance and Grade A + B without statistical significance. Compared with CT, the operating time of RA was longer. The difference between RA and CT was statistically significant in radiation dose. Proximal facet joint violation occurred less in RA than in CT. The postoperative Oswestry Disability Index (ODI) of RA was smaller than that of CT, and there were some interesting outcomes in our subgroup analysis. Conclusion. RA technique could be viewed as an accurate and safe pedicle screw implantation method compared to CT. A robotic system equipped with optical intraoperative navigation is superior to CT in accuracy. RA pedicle screw insertion can improve accuracy and maintain stability for some challenging areas. Cite this article: Bone Joint Res 2020;9(10):653–666

Aims. The purpose of our study was to determine whether mesenchymal stem cells (MSCs) are an effective and safe therapeutic agent for the treatment of knee osteoarthritis (OA), owing to their cartilage regeneration potential. Methods. We searched PubMed, Embase, and the Cochrane Library, with keywords including “knee osteoarthritis” and “mesenchymal stem cells”, up to June 2019. We selected randomized controlled trials (RCTs) that explored the use of MSCs to treat knee OA. The visual analogue scale (VAS), Western Ontario and McMaster University Osteoarthritis Index (WOMAC), adverse events, and the whole-organ MRI score (WORMS) were used as the primary evaluation tools in the studies. Our meta-analysis included a subgroup analysis of cell dose and cell source. Results. Seven trials evaluating 256 patients were included in the meta-analysis. MSC treatment significantly improved the VAS (mean difference (MD), –13.24; 95% confidence intervals (CIs) –23.28 to –3.20, p = 0.010) and WOMAC (MD, –7.22; 95% CI –12.97 to –1.47, p = 0.010). The low-dose group with less than 30 million cells showed lower p-values for both the VAS and WOMAC. Adipose and umbilical cord–derived stem cells also had lower p-values for pain scores than those derived from bone marrow. Conclusion. Overall, MSC-based cell therapy is a relatively safe treatment that holds great potential for OA, evidenced by a positive effect on pain and knee function. Using low-dose (25 million) and adipose-derived stem cells is likely to achieve better results, but further research is needed. Cite this article: Bone Joint Res 2020;9(10):719–728

Aims. We aimed to establish the short- and long-term efficacy of corticosteroid injection for coccydynia, and to determine if betamethasone or triamcinolone has the best effect. Methods. During 2009 to 2016, we treated 277 patients with chronic coccydynia with either one 6 mg betamethasone or one 20 mg triamcinolone cortisone injection. A susequent injection was given to 62 (26%) of the patients. All were reviewed three to four months after injection, and 241 replied to a questionnaire a mean of 36 months (12 to 88) after the last injection. No pain at the early review was considered early success. When the patient had not been subsequently operated on, and indicated on the questionnaire that they were either well or much better, it was considered a long-term success. Results. At the three- to four-month review, 22 (9%) reported that they had no pain. The long-term success of one injection was 15% and rose to 29% after a second injection. Logistic regression tests showed that both early success (odds ratio (OR) 5.5, 95% confidence interval (CI) 2.1 to 14.4; p = 0.001) and late success (OR 3.7, 95% CI 1.7 to 8.3; p = 0.001) was greater with triamcinolone than with betamethasone. Late success was greater for patients with symptoms for less than 12 months (OR 3.0, 95% CI 1.4 to 6.7; p = 0.006). We saw no complications of the injections. Conclusion. We conclude that the effect of corticosteroid injection for coccygodynia is moderate, possibly because we used modest doses of the drugs. Even so, they seem worthwhile as they are easily and quickly performed, and complications are rare. If the choice is between injections of betamethasone or triamcinolone, the latter should be selected. Cite this article: Bone Joint Open 2020;1-11:709–714

Objectives. To investigate the appropriate dose and interval for the administration of triamcinolone acetonide (TA) in treating tendinopathy to avoid adverse effects such as tendon degeneration and rupture. Methods. Human rotator cuff-derived cells were cultured using three media: regular medium (control), regular medium with 0.1 mg/mL of TA (low TA group), and with 1.0 mg/mL of TA (high TA group). The cell morphology, apoptosis, and viability were assessed at designated time points. Results. In the low TA group, the cells became flattened and polygonal at seven days then returned to normal at 21 days. The cell apoptosis ratio and messenger ribonucleic acid expression of caspase-3, 7, 8, and 9 increased, and viability was reduced in the low and high groups at seven days. In the low TA group, apoptosis and viability returned to normal at 21 days, however, in the high TA group, the cell morphology, apoptosis ratio, caspase-3, 7, 8, and 9 and viability did not return by day 21. Re-administration was performed in the low TA group at 7-, 14-, and 21-day intervals, and cell viability did not return to the control level at the 7- and 14-day intervals. Conclusion. A 0.1 mg/mL dose of TA temporarily decreased cell viability and increased cell apoptosis, which was recovered at 21 days, however, 1 mg/mL of TA caused irreversible damage to cell morphology and viability. An interval > three weeks was needed to safely re-administer TA. These findings may help determine the appropriate dose and interval for TA injection therapy. Cite this article: Bone Joint Res 2014;3:328–34

Objectives. The surface of pure titanium (Ti) shows decreased histocompatibility over time; this phenomenon is known as biological ageing. UV irradiation enables the reversal of biological ageing through photofunctionalisation, a physicochemical alteration of the titanium surface. Ti implants are sterilised by UV irradiation in dental surgery. However, orthopaedic biomaterials are usually composed of the alloy Ti6Al4V, for which the antibacterial effects of UV irradiation are unconfirmed. Here we evaluated the bactericidal and antimicrobial effects of treating Ti and Ti6Al4V with UV irradiation of a lower and briefer dose than previously reported, for applications in implant surgery. Materials and Methods. Ti and Ti6Al4V disks were prepared. To evaluate the bactericidal effect of UV irradiation, Staphylococcus aureus 834 suspension was seeded onto the disks, which were then exposed to UV light for 15 minutes at a dose of 9 J/cm. 2. To evaluate the antimicrobial activity of UV irradiation, bacterial suspensions were seeded onto the disks 0, 0.5, one, six, 24 and 48 hours, and three and seven days after UV irradiation as described above. In both experiments, the bacteria were then harvested, cultured, and the number of colonies were counted. Results. No colonies were observed when UV irradiation was performed after the bacteria were added to the disks. When the bacteria were seeded after UV irradiation, the amount of surviving bacteria on the Ti and Ti6Al4V disks decreased at 0 hours and then gradually increased. However, the antimicrobial activity was maintained for seven days after UV irradiation. Conclusion. Antimicrobial activity was induced for seven days after UV irradiation on both types of disk. Irradiated Ti6Al4V and Ti had similar antimicrobial properties. Cite this article: T. Itabashi, K. Narita, A. Ono, K. Wada, T. Tanaka, G. Kumagai, R. Yamauchi, A. Nakane, Y. Ishibashi. Bactericidal and antimicrobial effects of pure titanium and titanium alloy treated with short-term, low-energy UV irradiation. Bone Joint Res 2017;6:108–112. DOI: 10.1302/2046-3758.62.2000619

Aims

Osteosarcoma is the most common primary bone malignancy among children and adolescents. We investigated whether benzamil, an amiloride analogue and sodium-calcium exchange blocker, may exhibit therapeutic potential for osteosarcoma in vitro.

Objectives. This study was conducted to evaluate the cytokine-release kinetics of platelet-rich plasma (PRP) according to different activation protocols. Methods. Two manual preparation procedures (single-spin (SS) at 900 g for five minutes; double-spin (DS) at 900 g for five minutes and then 1500 g for 15 minutes) were performed for each of 14 healthy subjects. Both preparations were tested for platelet activation by one of three activation protocols: no activation, activation with calcium (Ca) only, or calcium with a low dose (50 IU per 1 ml PRP) of thrombin. Each preparation was divided into four aliquots and incubated for one hour, 24 hours, 72 hours, and seven days. The cytokine-release kinetics were evaluated by assessing PDGF, TGF, VEGF, FGF, IL-1, and MMP-9 concentrations with bead-based sandwich immunoassay. Results. The concentration of cytokine released from PRP varied over time and was influenced by various activation protocols. Ca-only activation had a significant effect on the DS PRPs (where the VEGF, FGF, and IL-1 concentrations were sustained) while Ca/thrombin activation had effects on both SS and DS PRPs (where the PDGF and VEGF concentrations were sustained and the TGF and FGF concentrations were short). The IL-1 content showed a significant increase with Ca-only or Ca/thrombin activation while these activations did not increase the MMP-9 concentration. Conclusion. The SS and DS methods differed in their effect on cytokine release, and this effect varied among the cytokines analysed. In addition, low dose of thrombin/calcium activation increased the overall cytokine release of the PRP preparations over seven days, relative to that with a calcium-only supplement or non-activation. Cite this article: Professor J. H. Oh. Cytokine-release kinetics of platelet-rich plasma according to various activation protocols. Bone Joint Res 2016;5:37–45. doi: 10.1302/2046-3758.52.2000540

Objective. Clinical studies of patients with bone sarcomas have been challenged by insufficient numbers at individual centres to draw valid conclusions. Our objective was to assess the feasibility of conducting a definitive multi-centre randomised controlled trial (RCT) to determine whether a five-day regimen of post-operative antibiotics, in comparison to a 24-hour regimen, decreases surgical site infections in patients undergoing endoprosthetic reconstruction for lower extremity primary bone tumours. . Methods. We performed a pilot international multi-centre RCT. We used central randomisation to conceal treatment allocation and sham antibiotics to blind participants, surgeons, and data collectors. We determined feasibility by measuring patient enrolment, completeness of follow-up, and protocol deviations for the antibiotic regimens. . Results. We screened 96 patients and enrolled 60 participants (44 men and 16 women) across 21 sites from four countries over 24 months (mean 2.13 participants per site per year, standard deviation 2.14). One participant was lost to follow-up and one withdrew consent. Complete data were obtained for 98% of eligible patients at two weeks, 83% at six months, and 73% at one year (the remainder with partial data or pending queries). In total, 18 participants missed at least one dose of antibiotics or placebo post-operatively, but 93% of all post-operative doses were administered per protocol. . Conclusions. It is feasible to conduct a definitive multi-centre RCT of post-operative antibiotic regimens in patients with bone sarcomas, but further expansion of our collaborative network will be critical. We have demonstrated an ability to coordinate in multiple countries, enrol participants, maintain protocol adherence, and minimise losses to follow-up. Cite this article: Bone Joint Res;4:154–162

Aims

This study aimed to assess the risk of acute kidney injury (AKI) associated with combined intravenous (IV) and topical antibiotic therapy in patients undergoing treatment for periprosthetic joint infections (PJIs) following total knee arthroplasty (TKA), utilizing the Kidney Disease: Improving Global Outcomes (KDIGO) criteria for classification.

Aims

Rotator cuff (RC) injuries are characterized by tendon rupture, muscle atrophy, retraction, and fatty infiltration, which increase injury severity and jeopardize adequate tendon repair. Epigenetic drugs, such as histone deacetylase inhibitors (HDACis), possess the capacity to redefine the molecular signature of cells, and they may have the potential to inhibit the transformation of the fibro-adipogenic progenitors (FAPs) within the skeletal muscle into adipocyte-like cells, concurrently enhancing the myogenic potential of the satellite cells.

During the last decades, several research groups have used bisphosphonates for local application to counteract secondary bone resorption after bone grafting, to improve implant fixation or to control bone resorption caused by bone morphogenetic proteins (BMPs). We focused on zoledronate (a bisphosphonate) due to its greater antiresorptive potential over other bisphosphonates. Recently, it has become obvious that the carrier is of importance to modulate the concentration and elution profile of the zoledronic acid locally. Incorporating one fifth of the recommended systemic dose of zoledronate with different apatite matrices and types of bone defects has been shown to enhance bone regeneration significantly in vivo. We expect the local delivery of zoledronate to overcome the limitations and side effects associated with systemic usage; however, we need to know more about the bioavailability and the biological effects. The local use of BMP-2 and zoledronate as a combination has a proven additional effect on bone regeneration. This review focuses primarily on the local use of zoledronate alone, or in combination with bone anabolic factors, in various preclinical models mimicking different orthopaedic conditions. Cite this article: I. Qayoom, D. B. Raina, A. Širka, Š. Tarasevičius, M. Tägil, A. Kumar, L. Lidgren. Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. Bone Joint Res 2018;7:548–560. DOI: 10.1302/2046-3758.710.BJR-2018-0015.R2

Aims

There is a lack of biomaterial-based carriers for the local delivery of rifampicin (RIF), one of the cornerstone second defence antibiotics for bone infections. RIF is also known for causing rapid development of antibiotic resistance when given as monotherapy. This in vitro study evaluated a clinically used biphasic calcium sulphate/hydroxyapatite (CaS/HA) biomaterial as a carrier for dual delivery of RIF with vancomycin (VAN) or gentamicin (GEN).

Aims

The optimum type of antibiotics and their administration route for treating Gram-negative (GN) periprosthetic joint infection (PJI) remain controversial. This study aimed to determine the GN bacterial species and antibacterial resistance rates related to clinical GN-PJI, and to determine the efficacy and safety of intra-articular (IA) antibiotic injection after one-stage revision in a GN pathogen-induced PJI rat model of total knee arthroplasty.

Aims

To estimate the potential cost-effectiveness of adalimumab compared with standard care alone for the treatment of early-stage Dupuytren’s disease (DD) and the value of further research from an NHS perspective.

Desmoid tumours are a rare fibroblastic proliferation of monoclonal origin, arising in deep soft-tissues. Histologically, they are characterized by locally aggressive behaviour and an inability to metastasize, and clinically by a heterogeneous and unpredictable course. Desmoid tumours can occur in any anatomical site, but commonly arise in the limbs. Despite their benign nature, they can be extremely disabling and sometimes life-threatening, causing severe pain and functional limitations. Their surgical management is complex and challenging, due to uncertainties surrounding the biological and clinical behaviour, rarity, and limited available literature. Resection has been the first-line approach for patients with a desmoid tumour but, during the last few decades, a shift towards a more conservative approach has occurred, with an initial ‘wait and see’ policy. Many medical and regional forms of treatment are also available for the management of this condition, and others have recently emerged with promising results. However, many areas of controversy remain, and further studies and global collaboration are needed to obtain prospective and randomized data, in order to develop an appropriate shared stepwise approach.

Cite this article: Bone Joint J 2023;105-B(7):729–734.

Objectives. Bioresorbable orthopaedic devices with calcium phosphate (CaP) fillers are commercially available on the assumption that increased calcium (Ca) locally drives new bone formation, but the clinical benefits are unknown. Electron beam (EB) irradiation of polymer devices has been shown to enhance the release of Ca. The aims of this study were to: 1) establish the biological safety of EB surface-modified bioresorbable devices; 2) test the release kinetics of CaP from a polymer device; and 3) establish any subsequent beneficial effects on bone repair in vivo. Methods. ActivaScrew Interference (Bioretec Ltd, Tampere, Finland) and poly(L-lactide-co-glycolide) (PLGA) orthopaedic screws containing 10 wt% β-tricalcium phosphate (β-TCP) underwent EB treatment. In vitro degradation over 36 weeks was investigated by recording mass loss, pH change, and Ca release. Implant performance was investigated in vivo over 36 weeks using a lapine femoral condyle model. Bone growth and osteoclast activity were assessed by histology and enzyme histochemistry. Results. Calcium release doubled in the EB-treated group before returning to a level seen in untreated samples at 28 weeks. Extensive bone growth was observed around the perimeter of all implant types, along with limited osteoclastic activity. No statistically significant differences between comparative groups was identified. Conclusion. The higher than normal dose of EB used for surface modification did not adversely affect tissue response around implants in vivo. Surprisingly, incorporation of β-TCP and the subsequent accelerated release of Ca had no significant effect on in vivo implant performance, calling into question the clinical evidence base for these commercially available devices. Cite this article: I. Palmer, S. A. Clarke, F. J Buchanan. Enhanced release of calcium phosphate additives from bioresorbable orthopaedic devices using irradiation technology is non-beneficial in a rabbit model: An animal study. Bone Joint Res 2019;8:266–274. DOI: 10.1302/2046-3758.86.BJR-2018-0224.R2

Aims

There is a considerable challenge in treating bone infections and orthopaedic device-associated infection (ODAI), partly due to impaired penetration of systemically administrated antibiotics at the site of infection. This may be circumvented by local drug administration. Knowledge of the release kinetics from any carrier material is essential for proper application. Ceftriaxone shows a particular constant release from calcium sulphate (CaSO₄) in vitro, and is particularly effective against streptococci and a large portion of Gram-negative bacteria. We present the clinical release kinetics of ceftriaxone-loaded CaSO₄ applied locally to treat ODAI.

Aims

This study intended to investigate the effect of vericiguat (VIT) on titanium rod osseointegration in aged rats with iron overload, and also explore the role of VIT in osteoblast and osteoclast differentiation.

Aims

The incidence of limb fractures in patients living with HIV (PLWH) is increasing. However, due to their immunodeficiency status, the operation and rehabilitation of these patients present unique challenges. Currently, it is urgent to establish a standardized perioperative rehabilitation plan based on the concept of enhanced recovery after surgery (ERAS). This study aimed to validate the effectiveness of ERAS in the perioperative period of PLWH with limb fractures.

Objectives. The purpose of this study was to refine an accepted contaminated rat femur defect model to result in an infection rate of approximately 50%. This threshold will allow examination of treatments aimed at reducing infection in open fractures with less risk of type II error. Methods . Defects were created in the stablised femurs of anaethetised rats, contaminated with Staphylococcus aureus and then debrided and irrigated six hours later. After 14 days, the bone and implants were harvested for separate microbiological analysis. This basic model was developed in several studies by varying the quantity of bacterial inoculation, introducing various doses of systemic antibiotics with and without local antibiotics. Results . The bacterial inoculation associated with a 50% infection rate was established as 1 × 10. 2. colony forming units (CFU). With an initial bacterial inoculum of 1 × 10. 5. CFU, the dose of systemic antibiotics associated with 50% infection was 5 mg/Kg of cafazolin injected sub-cutaneously every 12 hours, starting at the time of the first debridment and continuing for 72 hours (seven doses). The systemic dose of cafazolin was lowered to 2 mg/Kg when antibiotic polymethyl methacrylate beads were used concurrently with the same amount of bacterial inoculation. Conclusion. This model of open fracture infection has been further refined with potential for local and systemic antibiotics. This is a versatile model and with the concepts presented herein, it can be modified to evaluate various emerging therapies and concepts for open fractures. Cite this article: Bone Joint Res 2014;3:187–92

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by progressive cartilage degradation, synovial membrane inflammation, osteophyte formation, and subchondral bone sclerosis. Pathological changes in cartilage and subchondral bone are the main processes in OA. In recent decades, many studies have demonstrated that activin-like kinase 3 (ALK3), a bone morphogenetic protein receptor, is essential for cartilage formation, osteogenesis, and postnatal skeletal development. Although the role of bone morphogenetic protein (BMP) signalling in articular cartilage and bone has been extensively studied, many new discoveries have been made in recent years around ALK3 targets in articular cartilage, subchondral bone, and the interaction between the two, broadening the original knowledge of the relationship between ALK3 and OA. In this review, we focus on the roles of ALK3 in OA, including cartilage and subchondral bone and related cells. It may be helpful to seek more efficient drugs or treatments for OA based on ALK3 signalling in future.

Aims

cAMP response element binding protein (CREB1) is involved in the progression of osteoarthritis (OA). However, available findings about the role of CREB1 in OA are inconsistent. 666-15 is a potent and selective CREB1 inhibitor, but its role in OA is unclear. This study aimed to investigate the precise role of CREB1 in OA, and whether 666-15 exerts an anti-OA effect.

Aims

To investigate the optimal thresholds and diagnostic efficacy of commonly used serological and synovial fluid detection indexes for diagnosing periprosthetic joint infection (PJI) in patients who have rheumatoid arthritis (RA).