Aims. Several studies have reported that patients presenting during the evening or weekend have poorer quality healthcare. Our objective was to examine how timely surgery for patients with severe open tibial fracture varies by day and time of presentation and by type of hospital. This cohort study included patients with severe open tibial fractures from the Trauma Audit and Research Network (TARN). Methods. Provision of prompt surgery (debridement within 12 hours and soft-tissue coverage in 72 hours) was examined, using multivariate logistic regression to derive adjusted risk ratios (RRs). Time was categorized into three eight-hour intervals for each day of the week. The models were adjusted for treatment in a major trauma centre (MTC), sex, age, year of presentation, injury severity score, injury mechanism, and number of operations each patient received. Results. We studied 8,258 patients from 175 hospitals. Patients presenting during the day (08:00 to 15:59; risk ratio (RR) 1.11, 95% confidence interval (CI) 1.02 to 1.20) were more likely to receive debridement within 12 hours, and patients presenting at night (16:00 to 23:59; RR 0.56, 95% CI 0.51 to 0.62) were less likely to achieve the target; triage to a MTC had no effect. Day of presentation was associated with soft-tissue coverage within 72 hours; patients presenting on a Thursday or Friday being less likely to receive this surgery within 72 hours (Thursday RR 0.88, 95% CI 0.81 to 0.97; Friday RR 0.89, 95% CI 0.81 to 0.98), and the standard less likely to be achieved for those treated in ‘non-MTC’ hospitals (RR 0.76, 95% CI 0.70 to 0.82). Conclusion. Variations in care were observed for timely surgery for severe open tibial fractures with debridement surgery affected by time of presentation and soft-tissue coverage affected by day of presentation and type of hospital. The variation is unwarranted and highlights that there are opportunities to substantially improve the delivery and quality of care for patients with severe open tibial fracture. Cite this article: Bone Jt Open 2022;3(12):941–952

Aims. During the COVID-19 pandemic, drilling has been classified as an aerosol-generating procedure. However, there is limited evidence on the effects of bone drilling on splatter generation. Our aim was to quantify the effect of drilling on splatter generation within the orthopaedic operative setting. Methods. This study was performed using a Stryker System 7 dual rotating drill at full speed. Two fluid mediums (Videne (Solution 1) and Fluorescein (Solution 2)) were used to simulate drill splatter conditions. Drilling occurred at saw bone level (0 cm) and at different heights (20 cm, 50 cm, and 100 cm) above the target to simulate the surgeon ‘working arm length’, with and without using a drill guide. The furthest droplets were marked and the droplet displacement was measured in cm. A surgical microscope was used to detect microscopic droplets. Results. Bone drilling produced 5 cm and 7 cm droplet displacement using Solutions 1 and 2, respectively. Drilling at 100 cm above the target produced the greatest splatter generation with a 95 cm macroscopic droplet displacement using Solution 2. Microscopic droplet generation was noticed at further distances than what can be macroscopically seen using Solution 1 (98 cm). Using the drill guide, there was negligible drill splatter generation. Conclusion. Our study has shown lower than anticipated drill splatter generation. The use of a drill guide acted as a protective measure and significantly reduced drill splatter. We therefore recommend using a drill guide at all times to reduce the risk of viral transmission in the operative setting. Cite this article: Bone Jt Open 2021;2(9):752–756

Aims. The purpose of this study was to compare the radiological outcomes of manual versus robotic-assisted medial unicompartmental knee arthroplasty (UKA). Methods. Postoperative radiological outcomes from 86 consecutive robotic-assisted UKAs (RAUKA group) from a single academic centre were retrospectively reviewed and compared to 253 manual UKAs (MUKA group) drawn from a prior study at our institution. Femoral coronal and sagittal angles (FCA, FSA), tibial coronal and sagittal angles (TCA, TSA), and implant overhang were radiologically measured to identify outliers. Results. When assessing the accuracy of RAUKAs, 91.6% of all alignment measurements and 99.2% of all overhang measurements were within the target range. All alignment and overhang targets were simultaneously met in 68.6% of RAUKAs. When comparing radiological outcomes between the RAUKA and MUKA groups, statistically significant differences were identified for combined outliers in FCA (2.3% vs 12.6%; p = 0.006), FSA (17.4% vs 50.2%; p < 0.001), TCA (5.8% vs 41.5%; p < 0.001), and TSA (8.1% vs 18.6%; p = 0.023), as well as anterior (0.0% vs 4.7%; p = 0.042), posterior (1.2% vs 13.4%; p = 0.001), and medial (1.2% vs 14.2%; p < 0.001) overhang outliers. Conclusion. Robotic system navigation decreases alignment and overhang outliers compared to manual UKA. Given the association between component placement errors and revision in UKA, this strong significant improvement in accuracy may improve implant survival. Level of Evidence: III. Cite this article: Bone Jt Open 2021;2-3:191–197

Osteoarthritis (OA) is a degenerative disease resulting from progressive joint destruction caused by many factors. Its pathogenesis is complex and has not been elucidated to date. Advanced glycation end products (AGEs) are a series of irreversible and stable macromolecular complexes formed by reducing sugar with protein, lipid, and nucleic acid through a non-enzymatic glycosylation reaction (Maillard reaction). They are an important indicator of the degree of ageing. Currently, it is considered that AGEs accumulation in vivo is a molecular basis of age-induced OA, and AGEs production and accumulation in vivo is one of the important reasons for the induction and acceleration of the pathological changes of OA. In recent years, it has been found that AGEs are involved in a variety of pathological processes of OA, including extracellular matrix degradation, chondrocyte apoptosis, and autophagy. Clearly, AGEs play an important role in regulating the expression of OA-related genes and maintaining the chondrocyte phenotype and the stability of the intra-articular environment. This article reviews the latest research results of AGEs in a variety of pathological processes of OA, to provide a new direction for the study of OA pathogenesis and a new target for prevention and treatment. Cite this article: Bone Joint Res 2022;11(5):292–300

Aims. The Bundled Payments for Care Improvement (BPCI) initiative has identified pathways for improving the value of care. However, patient-specific modifiable and non-modifiable risk factors may increase costs beyond the target payment. We sought to identify risk factors for exceeding our institution’s target payment, the so-called ‘bundle busters’. Patients and Methods. Using our data warehouse and Centers for Medicare and Medicaid Services (CMS) data we identified all 412 patients who underwent total joint arthroplasty and qualified for our institution’s BPCI model, between July 2015 and May 2017. Episodes where CMS payments exceeded the target payment were considered ‘busters’ (n = 123). Risk ratios (RRs) were calculated using a modified Poisson regression analysis. Results. An increased risk of exceeding the target payment was significantly associated with increasing age (adjusted RR 1.04, 95% confidence interval (CI) 1.01 to 1.06) and body mass index (adjusted RR 1.03, 95% CI 1.003 to 1.06). Eight comorbid risk factors were also identified (all p < 0.05), only two of which were considered to be potentially modifiable (diabetes with complications and preoperative anaemia). An American Society of Anesthesiologist physical status classification system (ASA) score ≥ 3 (adjusted RR 2.3, 95% CI 1.67 to 3.18) and Charlson Comorbidity Index (CCI) ≥ 3 (adjusted RR 1.94, 95% CI 1.45 to 2.60) were risk factors for bundle busting. Conclusion. Non-modifiable preoperative risk factors can increase costs and exceed the target payment. Future bundled payment models should incorporate the stratification of risk. Cite this article: Bone Joint J 2019;101-B(7 Supple C):64–69

Aims. Hip fracture commonly affects the frailest patients, of whom many are care-dependent, with a disproportionate risk of contracting COVID-19. We examined the impact of COVID-19 infection on hip fracture mortality in England. Methods. We conducted a cohort study of patients with hip fracture recorded in the National Hip Fracture Database between 1 February 2019 and 31 October 2020 in England. Data were linked to Hospital Episode Statistics to quantify patient characteristics and comorbidities, Office for National Statistics mortality data, and Public Health England’s SARS-CoV-2 testing results. Multivariable Cox regression examined determinants of 90-day mortality. Excess mortality attributable to COVID-19 was quantified using Quasi-Poisson models. Results. Analysis of 102,900 hip fractures (42,630 occurring during the pandemic) revealed that among those with COVID-19 infection at presentation (n = 1,120) there was a doubling of 90-day mortality; hazard ratio (HR) 2.09 (95% confidence interval (CI) 1.89 to 2.31), while the HR for infections arising between eight and 30 days after presentation (n = 1,644) the figure was greater at 2.51 (95% CI 2.31 to 2.73). Malnutrition (1.45 (95% CI 1.19 to 1.77)) and nonoperative treatment (2.94 (95% CI 2.18 to 3.95)) were the only modifiable risk factors for death in COVID-19-positive patients. Patients who had tested positive for COVID-19 more than two weeks prior to hip fracture initially had better survival compared to those who contracted COVID-19 around the time of their hip fracture; however, survival rapidly declined and by 365 days the combination of hip fracture and COVID-19 infection was associated with a 50% mortality rate. Between 1 January and 30 June 2020, 1,273 (99.7% CI 1,077 to 1,465) excess deaths occurred within 90 days of hip fracture, representing an excess mortality of 23% (99.7% CI 20% to 26%), with most deaths occurring within 30 days. Conclusion. COVID-19 infection more than doubles the rate of early hip fracture mortality. Those contracting infection between 8 and 30 days after initial presentation are at even higher mortality risk, signalling the potential for targeted interventions during this period to improve survival. Cite this article: Bone Joint J 2022;104-B(10):1156–1167

Aims. The aim of this study was to report patient and clinical outcomes following robotic-assisted total knee arthroplasty (RA-TKA) at multiple institutions with a minimum two-year follow-up. Methods. This was a multicentre registry study from October 2016 to June 2021 that included 861 primary RA-TKA patients who completed at least one pre- and postoperative patient-reported outcome measure (PROM) questionnaire, including Forgotten Joint Score (FJS), Knee Injury and Osteoarthritis Outcomes Score for Joint Replacement (KOOS JR), and pain out of 100 points. The mean age was 67 years (35 to 86), 452 were male (53%), mean BMI was 31.5 kg/m. 2. (19 to 58), and 553 (64%) cemented and 308 (36%) cementless implants. Results. There were significant improvements in PROMs over time between preoperative, one- to two-year, and > two-year follow-up, with a mean FJS of 17.5 (SD 18.2), 70.2 (SD 27.8), and 76.7 (SD 25.8; p < 0.001); mean KOOS JR of 51.6 (SD 11.5), 85.1 (SD 13.8), and 87.9 (SD 13.0; p < 0.001); and mean pain scores of 65.7 (SD 20.4), 13.0 (SD 19.1), and 11.3 (SD 19.9; p < 0.001), respectively. There were eight superficial infections (0.9%) and four revisions (0.5%). Conclusion. RA-TKA demonstrated consistent clinical results across multiple institutions with excellent PROMs that continued to improve over time. With the ability to achieve target alignment in the coronal, axial, and sagittal planes and provide intraoperative real-time data to obtain balanced gaps, RA-TKA demonstrated excellent clinical outcomes and PROMs in this patient population. Cite this article: Bone Jt Open 2022;3(7):589–595

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

Aims. Cemented hemiarthroplasty is an effective form of treatment for most patients with an intracapsular fracture of the hip. However, it remains unclear whether there are subgroups of patients who may benefit from the alternative operation of a modern uncemented hemiarthroplasty – the aim of this study was to investigate this issue. Knowledge about the heterogeneity of treatment effects is important for surgeons in order to target operations towards specific subgroups who would benefit the most. Methods. We used causal forest analysis to compare subgroup- and individual-level treatment effects between cemented and modern uncemented hemiarthroplasty in patients aged > 60 years with an intracapsular fracture of the hip, using data from the World Hip Trauma Evaluation 5 (WHiTE 5) multicentre randomized clinical trial. EuroQol five-dimension index scores were used to measure health-related quality of life at one, four, and 12 months postoperatively. Results. Our analysis revealed a complex landscape of responses to the use of a cemented hemiarthroplasty in the 12 months after surgery. There was heterogeneity of effects with regard to baseline characteristics, including age, pre-injury health status, and lifestyle factors such as alcohol consumption. This heterogeneity was greater at the one-month mark than at subsequent follow-up timepoints, with particular regard to subgroups based on age. However, for all subgroups, the effect estimates for quality of life lay within the confidence intervals derived from the analysis of all patients. Conclusion. The use of a cemented hemiarthroplasty is expected to increase health-related quality of life compared with modern uncemented hemiarthroplasty for all subgroups of patients aged > 60 years with a displaced intracapsular fracture of the hip. Cite this article: Bone Joint J 2024;106-B(7):656–661

Aims. Spinopelvic mobility plays an important role in functional acetabular component position following total hip arthroplasty (THA). The primary aim of this study was to determine if spinopelvic hypermobility persists or resolves following THA. Our second aim was to identify patient demographic or radiological factors associated with hypermobility and resolution of hypermobility after THA. Methods. This study investigated patients with preoperative posterior hypermobility, defined as a change in sacral slope (SS) from standing to sitting (ΔSS. stand-sit. ) ≥ 30°. Radiological spinopelvic parameters, including SS, pelvic incidence (PI), lumbar lordosis (LL), PI-LL mismatch, anterior pelvic plane tilt (APPt), and spinopelvic tilt (SPT), were measured on preoperative imaging, and at six weeks and a minimum of one year postoperatively. The severity of bilateral hip osteoarthritis (OA) was graded using Kellgren-Lawrence criteria. Results. A total of 136 patients were identified as having preoperative spinopelvic hypermobility. At one year after THA, 95% (129/136) of patients were no longer categorized as hypermobile on standing and sitting radiographs (ΔSS. stand-sit. < 30°). Mean ΔSS. stand-sit. decreased from 36.4° (SD 5.1°) at baseline to 21.4° (SD 6.6°) at one year (p < 0.001). Mean SS. seated. increased from baseline (11.4° (SD 8.8°)) to one year after THA by 11.5° (SD 7.4°) (p < 0.001), which correlates to an 8.5° (SD 5.5°) mean decrease in seated functional cup anteversion. Contralateral hip OA was the only radiological predictor of hypermobility persisting at one year after surgery. The overall reoperation rate was 1.5%. Conclusion. Spinopelvic hypermobility was found to resolve in the majority (95%) of patients one year after THA. The increase in SS. seated. was clinically significant, suggesting that current target recommendations for the hypermobile patient (decreased anteversion and inclination) should be revisited. Cite this article: Bone Joint J 2021;103-B(12):1766–1773

Aims. To devise a method to quantify and optimize tightness when inserting cortical screws, based on bone characterization and screw geometry. Methods. Cortical human cadaveric diaphyseal tibiae screw holes (n = 20) underwent destructive testing to firstly establish the relationship between cortical thickness and experimental stripping torque (T. str. ), and secondly to calibrate an equation to predict T. str. Using the equation’s predictions, 3.5 mm screws were inserted (n = 66) to targeted torques representing 40% to 100% of T. str. , with recording of compression generated during tightening. Once the target torque had been achieved, immediate pullout testing was performed. Results. Cortical thickness predicted T. str. (R. 2. = 0.862; p < 0.001) as did an equation based on tensile yield stress, bone-screw friction coefficient, and screw geometries (R. 2. = 0.894; p < 0.001). Compression increased with screw tightness up to 80% of the maximum (R. 2. = 0.495; p < 0.001). Beyond 80%, further tightening generated no increase in compression. Pullout force did not change with variations in submaximal tightness beyond 40% of T. str. (R. 2. = 0.014; p = 0.175). Conclusion. Screw tightening between 70% and 80% of the predicted maximum generated optimum compression and pullout forces. Further tightening did not considerably increase compression, made no difference to pullout, and increased the risk of the screw holes being stripped. While further work is needed for development of intraoperative methods for accurate and reliable prediction of the maximum tightness for a screw, this work justifies insertion torque being considerably below the maximum. Cite this article: Bone Joint Res 2020;9(8):493–500

Transforming growth factor-beta2 (TGF-β2) is recognized as a versatile cytokine that plays a vital role in regulation of joint development, homeostasis, and diseases, but its role as a biological mechanism is understood far less than that of its counterpart, TGF-β1. Cartilage as a load-resisting structure in vertebrates however displays a fragile performance when any tissue disturbance occurs, due to its lack of blood vessels, nerves, and lymphatics. Recent reports have indicated that TGF-β2 is involved in the physiological processes of chondrocytes such as proliferation, differentiation, migration, and apoptosis, and the pathological progress of cartilage such as osteoarthritis (OA) and rheumatoid arthritis (RA). TGF-β2 also shows its potent capacity in the repair of cartilage defects by recruiting autologous mesenchymal stem cells and promoting secretion of other growth factor clusters. In addition, some pioneering studies have already considered it as a potential target in the treatment of OA and RA. This article aims to summarize the current progress of TGF-β2 in cartilage development and diseases, which might provide new cues for remodelling of cartilage defect and intervention of cartilage diseases

Aims. Patient-specific instrumentation of total knee arthroplasty (TKA) is a technique permitting the targeting of individual kinematic alignment, but deviation from a neutral mechanical axis may have implications on implant fixation and therefore survivorship. The primary objective of this randomized controlled study was to compare the fixation of tibial components implanted with patient-specific instrumentation targeting kinematic alignment (KA+PSI) versus components placed using computer-assisted surgery targeting neutral mechanical alignment (MA+CAS). Tibial component migration measured by radiostereometric analysis was the primary outcome measure (compared longitudinally between groups and to published acceptable thresholds). Secondary outcome measures were inducible displacement after one year and patient-reported outcome measures (PROMS) over two years. The secondary objective was to assess the relationship between alignment and both tibial component migration and inducible displacement. Patients and Methods. A total of 47 patients due to undergo TKA were randomized to KA+PSI (n = 24) or MA+CAS (n = 23). In the KA+PSI group, there were 16 female and eight male patients with a mean age of 64 years (. sd. 8). In the MA+CAS group, there were 17 female and six male patients with a mean age of 63 years (. sd. 7). Surgery was performed using cemented, cruciate-retaining Triathlon total knees with patellar resurfacing, and patients were followed up for two years. The effect of alignment on tibial component migration and inducible displacement was analyzed irrespective of study group. Results. There was no difference over two years in longitudinal migration of the tibial component between the KA+PSI and MA+CAS groups (reaching median maximum total point motion migration at two years of 0.40 mm for the KA+PSI group and 0.37 mm for the MA+CAS group, p = 0.82; p = 0.68 adjusted for age, sex, and body mass index (BMI) for all follow-ups). Both groups had mean migrations below acceptable thresholds. There was no difference in inducible displacement (p = 0.34) or PROMS (p = 0.61 for the Oxford Knee Score) between groups. There was no correlation between alignment and tibial component migration or alignment and inducible displacement. These findings support non-neutral alignment as a viable option with this component, with no evidence that it compromises fixation. Conclusion. Kinematic alignment using patient-specific instrumentation in TKA was associated with acceptable tibial component migration, indicating stable fixation. These results are supportive of future investigations of kinematic alignment. Cite this article: Bone Joint J 2019;101-B:929–940

Aims. The aim of this study was to examine whether socioeconomic status (SES) is associated with a higher risk of infections following total hip arthroplasty (THA) at 30 and 90 days. Methods. We obtained individual-based information on SES markers (cohabitation, education, income, and savings) on 103,901 THA patients from Danish health registries between 1 January 1995 and 31 December 2017. The primary outcome measure was any hospital-treated infection (i.e. all infections). The secondary outcomes were further specified to specific hospital-treated infections (pneumonia, urinary tract infection, and periprosthetic joint infection). The primary timepoint was within 90 days. In addition, the outcomes were further evaluated within 30 days. We calculated the cumulative incidence, and used the pseudo-observation method and generalized linear regression to estimate adjusted risk ratios (RRs) with 95% confidence intervals (CIs) for each marker. Results. The cumulative incidence of any infection at 90 days was highest in patients who lived alone (1.5% (95% CI 1.3 to 1.6)) versus cohabitant (0.7% (95% CI 0.7 to 0.8)), had the lowest educational achievement (1.1% (95% CI 1.0 to 1.2)) versus highest (0.7% (95% CI 0.5 to 0.8)), had the lowest income (1.6% (95% CI 1.5 to 1.70)) versus highest (0.4% (95% CI 0.3 to 0.5)), or had lowest savings (1.3% (95% CI 1.2 to 1.4)) versus highest (0.7% (95% CI 0.6 to 0.8)). Within 90 days, the RRs for any infection were 1.3 (95% CI 1.2 to 1.4) for patients living alone versus cohabiting, 1.2 (95% CI 1.0 to 1.3) for low education achievement versus high, 1.7 (95% CI 1.4 to 2.1) for low income versus high income, and 1.5 (95% CI 1.4 to 1.8) for low savings versus high savings. The same trends were also seen for any infections within the first 30 days. Conclusion. Our study provides evidence that socioeconomic inequality adversely influences the risk of infection after THA, thus contributing to healthcare disparities and inequalities. We found that living alone, low educational achievement, low income, or low savings were associated with higher risks of infections within the first 30 and 90 days after THA. Therefore, the development of targeted intervention strategies with the aim of increasing awareness of patients identified as being at greatest risk is needed to mitigate the impact of SES on the risk of infections following THA. Cite this article: Bone Joint J 2022;104-B(2):221–226

Aims. Sarcopenia is characterized by a generalized progressive loss of skeletal muscle mass, strength, and physical performance. This systematic review primarily evaluated the effects of sarcopenia on postoperative functional recovery and mortality in patients undergoing orthopaedic surgery, and secondarily assessed the methods used to diagnose and define sarcopenia in the orthopaedic literature. Methods. A systematic search was conducted in MEDLINE, EMBASE, and Google Scholar databases according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Studies involving sarcopenic patients who underwent defined orthopaedic surgery and recorded postoperative outcomes were included. The quality of the criteria by which a diagnosis of sarcopenia was made was evaluated. The quality of the publication was assessed using Newcastle-Ottawa Scale. Results. A total of 365 studies were identified and screened, 26 full-texts were reviewed, and 19 studies were included in the review. A total of 3,009 patients were included, of whom 2,146 (71%) were female and 863 (29%) were male. The mean age of the patients was 75.1 years (SD 7.1). Five studies included patients who underwent spinal surgery, 13 included hip or knee surgery, and one involved patients who underwent fixation of a distal radial fixation. The mean follow-up was 1.9 years (SD 1.9; 5 days to 5.6 years). There was wide heterogeneity in the measurement tools which were used and the parameters for the diagnosis of sarcopenia in the studies. Sarcopenia was associated with at least one deleterious effect on surgical outcomes in all 19 studies. The postoperative rate of mortality was reported in 11 studies (57.9%) and sarcopenia was associated with poorer survival in 73% (8/11) of these. The outcome was most commonly assessed using the Barthel Index (4/19), and sarcopenic patients recorded lower scores in 75% (3/4) of these. Sarcopenia was defined using the gold-standard three parameters (muscle strength, muscle quantity or quality, and muscle function) in four studies (21%), using two parameters in another four (21%) and one in the remaining 11 (58%). The methodological quality of the studies was moderate to high. Conclusion. There is much heterogeneity in the reporting of the parameters which are used for the diagnosis of sarcopenia, and evaluating the outcome of orthopaedic surgery in sarcopenic patients. However, what data exist suggest that sarcopenia impairs recovery and increases postoperative mortality, especially in patients undergoing emergency surgery. Further research is required to develop processes that allow the accurate diagnosis of sarcopenia in orthopaedics, which may facilitate targeted pre- and postoperative interventions that would improve outcomes. Cite this article: Bone Joint J 2022;104-B(3):321–330

Aims. Acquired heterotopic ossification (HO) is a debilitating disease characterized by abnormal extraskeletal bone formation within soft-tissues after injury. The exact pathogenesis of HO remains unknown. It was reported that BRD4 may contribute to osteoblastic differentiation. The current study aims to determine the role of BRD4 in the pathogenesis of HO and whether it could be a potential target for HO therapy. Methods. Achilles tendon puncture (ATP) mouse model was performed on ten-week-old male C57BL/6J mice. One week after ATP procedure, the mice were given different treatments (e.g. JQ1, shMancr). Achilles tendon samples were collected five weeks after treatment for RNA-seq and real-time quantitative polymerase chain reaction (RT-qPCR) analysis; the legs were removed for micro-CT imaging and subsequent histology. Human bone marrow mesenchymal stem cells (hBMSCs) were isolated and purified bone marrow collected during surgeries by using density gradient centrifugation. After a series of interventions such as knockdown or overexpressing BRD4, Alizarin red staining, RT-qPCR, and Western Blot (Runx2, alkaline phosphatase (ALP), Osx) were performed on hBMSCs. Results. Overexpression of BRD4 enhanced while inhibition of Brd4 suppressed the osteogenic differentiation of hBMSCs in vitro. Overexpression of Brd4 increased the expression of mitotically associated long non-coding RNA (Mancr). Downregulation of Mancr suppressed the osteoinductive effect of BRD4. In vivo, inhibition of BRD4 by JQ1 significantly attenuated pathological bone formation in the ATP model (p = 0.001). Conclusion. BRD4 was found to be upregulated in HO and Brd4-Mancr-Runx2 signalling was involved in the modulation of new bone formation in HO. Cite this article: Bone Joint Res 2021;10(10):668–676

Objectives. Adult mice lacking the transcription factor NFAT1 exhibit osteoarthritis (OA). The precise molecular mechanism for NFAT1 deficiency-induced osteoarthritic cartilage degradation remains to be clarified. This study aimed to investigate if NFAT1 protects articular cartilage (AC) against OA by directly regulating the transcription of specific catabolic and anabolic genes in articular chondrocytes. Methods. Through a combined approach of gene expression analysis and web-based searching of NFAT1 binding sequences, 25 candidate target genes that displayed aberrant expression in Nfat1. -/-. AC at the initiation stage of OA, and possessed at least four NFAT1 binding sites in the promoter of each gene, were selected and tested for NFAT1 transcriptional activities by chromatin immunoprecipitation (ChIP) and promoter luciferase reporter assays using chondrocytes isolated from the AC of three- to four-month-old wild-type mice or Nfat1. -/-. mice with early OA phenotype. Results. Chromatin immunoprecipitation assays revealed that NFAT1 bound directly to the promoter of 21 of the 25 tested genes encoding cartilage-matrix proteins, growth factors, inflammatory cytokines, matrix-degrading proteinases, and specific transcription factors. Promoter luciferase reporter assays of representative anabolic and catabolic genes demonstrated that NFAT1-DNA binding functionally regulated the luciferase activity of specific target genes in wild-type chondrocytes, but not in Nfat1. -/-. chondrocytes or in wild-type chondrocytes transfected with plasmids containing mutated NFAT1 binding sequences. Conclusion. NFAT1 protects AC against degradation by directly regulating the transcription of target genes in articular chondrocytes. NFAT1 deficiency causes defective transcription of specific anabolic and catabolic genes in articular chondrocytes, leading to increased matrix catabolism and osteoarthritic cartilage degradation. Cite this article: M. Zhang, Q. Lu, T. Budden, J. Wang. NFAT1 protects articular cartilage against osteoarthritic degradation by directly regulating transcription of specific anabolic and catabolic genes. Bone Joint Res 2019;8:90–100. DOI: 10.1302/2046-3758.82.BJR-2018-0114.R1

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

Upper limb amputations, ranging from transhumeral to partial hand, can be devastating for patients, their families, and society. Modern paradigm shifts have focused on reconstructive options after upper extremity limb loss, rather than considering the amputation an ablative procedure. Surgical advancements such as targeted muscle reinnervation and regenerative peripheral nerve interface, in combination with technological development of modern prosthetics, have expanded options for patients after amputation. In the near future, advances such as osseointegration, implantable myoelectric sensors, and implantable nerve cuffs may become more widely used and may expand the options for prosthetic integration, myoelectric signal detection, and restoration of sensation. This review summarizes the current advancements in surgical techniques and prosthetics for upper limb amputees. Cite this article: Bone Joint J 2021;103-B(3):430–439

Aims. Current treatments of prosthetic joint infection (PJI) are minimally effective against Staphylococcus aureus biofilm. A murine PJI model of debridement, antibiotics, and implant retention (DAIR) was used to test the hypothesis that PlySs2, a bacteriophage-derived lysin, can target S. aureus biofilm and address the unique challenges presented in this periprosthetic environment. Methods. The ability of PlySs2 and vancomycin to kill biofilm and colony-forming units (CFUs) on orthopaedic implants were compared using in vitro models. An in vivo murine PJI model of DAIR was used to assess the efficacy of a combination of PlySs2 and vancomycin on periprosthetic bacterial load. Results. PlySs2 treatment reduced 99% more CFUs and 75% more biofilm compared with vancomycin in vitro. A combination of PlySs2 and vancomycin in vivo reduced the number of CFUs on the surface of implants by 92% and in the periprosthetic tissue by 88%. Conclusion. PlySs2 lysin was able to reduce biofilm, target planktonic bacteria, and work synergistically with vancomycin in our in vitro models. A combination of PlySs2 and vancomycin also reduced bacterial load in periprosthetic tissue and on the surface of implants in a murine model of DAIR treatment for established PJI. Cite this article: Bone Joint J 2020;102-B(7 Supple B):3–10