Objectives. Up to 10% of fractures result in undesirable outcomes, for which female sex is a risk factor. Cellular sex differences have been implicated in these different healing processes. Better understanding of the mechanisms underlying bone healing and sex differences in this process is key to improved clinical outcomes. This study utilized a macrophage–mesenchymal stem cell (MSC) coculture system to determine: 1) the precise timing of proinflammatory (M1) to anti-inflammatory (M2) macrophage transition for optimal bone formation; and 2) how such immunomodulation was affected by male versus female cocultures. Methods. A primary murine macrophage-MSC coculture system was used to demonstrate the optimal transition time from M1 to M2 (polarized from M1 with interleukin (IL)-4) macrophages to maximize matrix mineralization in male and female MSCs. Outcome variables included Alizarin Red staining, alkaline phosphatase (ALP) activity, and osteocalcin protein secretion. Results. We found that 96 hours of M1 phenotype in male cocultures allowed for maximum matrix mineralization versus 72 hours in female cocultures. ALP activity and osteocalcin secretion were also enhanced with the addition of IL-4 later in male versus female groups. The sex of the cells had a statistically significant effect on the optimal IL-4 addition time to maximize osteogenesis. Conclusion. These results suggest that: 1) a 72- to 96-hour proinflammatory environment is critical for optimal matrix mineralization; and 2) there are immunological differences in this coculture environment due to sex. Optimizing immunomodulation during fracture healing may enhance and expedite the bone regeneration response. These findings provide insight into precise immunomodulation for enhanced bone healing that is sex-specific. Cite this article: K. Nathan, L. Y. Lu, T. Lin, J. Pajarinen, E. Jämsen, J-F. Huang, M. Romero-Lopez, M. Maruyama, Y. Kohno, Z. Yao, S. B. Goodman. Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex. Bone Joint Res 2019;8:481–488. DOI: 10.1302/2046-3758.810.BJR-2018-0231.R2

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

The coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented challenges to healthcare systems worldwide. Orthopaedic departments have adopted business continuity models and guidelines for essential and non-essential surgeries to preserve hospital resources as well as protect patients and staff. These guidelines broadly encompass reduction of ambulatory care with a move towards telemedicine, redeployment of orthopaedic surgeons/residents to the frontline battle against COVID-19, continuation of education and research through web-based means, and cancellation of non-essential elective procedures. However, if containment of COVID-19 community spread is achieved, resumption of elective orthopaedic procedures and transition plans to return to normalcy must be considered for orthopaedic departments. The COVID-19 pandemic also presents a moral dilemma to the orthopaedic surgeon considering elective procedures. What is the best treatment for our patients and how does the fear of COVID-19 influence the risk-benefit discussion during a pandemic? Surgeons must deliberate the fine balance between elective surgery for a patient’s wellbeing versus risks to the operating team and utilization of precious hospital resources. Attrition of healthcare workers or Orthopaedic surgeons from restarting elective procedures prematurely or in an unsafe manner may render us ill-equipped to handle the second wave of infections. This highlights the need to develop effective screening protocols or preoperative COVID-19 testing before elective procedures in high-risk, elderly individuals with comorbidities. Alternatively, high-risk individuals should be postponed until the risk of nosocomial COVID-19 infection is minimal. In addition, given the higher mortality and perioperative morbidity of patients with COVID-19 undergoing surgery, the decision to operate must be carefully deliberated. As we ramp-up elective services and get “back to business” as orthopaedic surgeons, we have to be constantly mindful to proceed in a cautious and calibrated fashion, delivering the best care, while maintaining utmost vigilance to prevent the resurgence of COVID-19 during this critical transition period. Cite this article: Bone Joint Open 2020;1-6:222–228

Aims. To investigate the impact of consecutive perioperative care transitions on in-hospital recovery of patients who had primary total knee arthroplasty (TKA) over an 11-year period. Methods. This observational cohort study used electronic health record data from all patients undergoing preoperative screening for primary TKA at a Northern Netherlands hospital between 2009 and 2020. In this timeframe, three perioperative care transitions were divided into four periods: Baseline care (Joint Care, n = 171; May 2009 to August 2010), Function-tailored (n = 404; September 2010 to October 2013), Fast-track (n = 721; November 2013 to May 2018), and Prehabilitation (n = 601; June 2018 to December 2020). In-hospital recovery was measured using inpatient recovery of activities (IROA), length of stay (LOS), and discharge to preoperative living situation (PLS). Multivariable regression models were used to analyze the impact of each perioperative care transition on in-hospital recovery. Results. The four periods analyzed involved 1,853 patients (65.9% female (1,221/1,853); mean age 70.1 years (SD 9.0)). IROA improved significantly with each transition: Function-tailored (0.9 days; p < 0.001 (95% confidence interval (CI) -0.32 to -0.15)), Fast-track (0.6 days; p < 0.001 (95% CI -0.25 to -0.16)), and Prehabilitation (0.4 days; p < 0.001 (95% CI -0.18 to -0.10)). LOS decreased significantly in Function-tailored (1.1 days; p = 0.001 (95% CI -0.30 to -0.06)), Fast-track (0.6 days; p < 0.001 (95% CI -0.21 to -0.05)), and Prehabilitation (0.6 days; p < 0.001 (95%CI -0.27 to -0.11)). Discharge to PLS increased in Function-tailored (77%), Fast-track (91.6%), and Prehabilitation (92.6%). Post-hoc analysis indicated a significant increase after the transition to the Fast-track period (p < 0.001 (95% CI 3.19 to 8.00)). Conclusion. This study highlights the positive impact of different perioperative care procedures on in-hospital recovery of patients undergoing primary TKA. Assessing functional recovery, LOS, and discharge towards PLS consistently, provides hospitals with valuable insights into postoperative recovery. This can potentially aid planning and identifying areas for targeted improvements to optimize patient outcomes. Cite this article: Bone Joint J 2024;106-B(6):573–581

Aims. The cemented Oxford unicompartmental knee arthroplasty (OUKA) features two variants: single and twin peg OUKA. The purpose of this study was to assess the stability of both variants in a worst-case scenario of bone defects and suboptimal cementation. Methods. Single and twin pegs were implanted randomly allocated in 12 pairs of human fresh-frozen femora. We generated 5° bone defects at the posterior condyle. Relative movement was simulated using a servohydraulic pulser, and analyzed at 70°/115° knee flexion. Relative movement was surveyed at seven points of measurement on implant and bone, using an optic system. Results. At the main fixation zone, the twin peg shows less relative movement at 70°/115°. At the transition zone, relative movements are smaller for the single peg for both angles. The single peg shows higher compression at 70° flexion, whereas the twin peg design shows higher compression at 115°. X-displacement is significantly higher for the single peg at 115°. Conclusion. Bony defects should be avoided in OUKA. The twin peg shows high resilience against push-out force and should be preferred over the single peg. Cite this article: Bone Joint Res 2022;11(2):82–90

Aims. Adenosine, lidocaine, and Mg. 2+. (ALM) therapy exerts differential immuno-inflammatory responses in males and females early after anterior cruciate ligament (ACL) reconstruction (ACLR). Our aim was to investigate sex-specific effects of ALM therapy on joint tissue repair and recovery 28 days after surgery. Methods. Male (n = 21) and female (n = 21) adult Sprague-Dawley rats were randomly divided into ALM or Saline control treatment groups. Three days after ACL rupture, animals underwent ACLR. An ALM or saline intravenous infusion was commenced prior to skin incision, and continued for one hour. An intra-articular bolus of ALM or saline was also administered prior to skin closure. Animals were monitored to 28 days, and joint function, pain, inflammatory markers, histopathology, and tissue repair markers were assessed. Results. Despite comparable knee function, ALM-treated males had reduced systemic inflammation, synovial fluid angiogenic and pro-inflammatory mediators, synovitis, and fat pad fibrotic changes, compared to controls. Within the ACL graft, ALM-treated males had increased expression of tissue repair markers, decreased inflammation, increased collagen organization, and improved graft-bone healing. In contrast to males, females had no evidence of persistent systemic inflammation. Compared to controls, ALM-treated females had improved knee extension, gait biomechanics, and elevated synovial macrophage inflammatory protein-1 alpha (MIP-1α). Within the ACL graft, ALM-treated females had decreased inflammation, increased collagen organization, and improved graft-bone healing. In articular cartilage of ALM-treated animals, matrix metalloproteinase (MMP)-13 expression was blunted in males, while in females repair markers were increased. Conclusion. At 28 days, ALM therapy reduces inflammation, augments tissue repair patterns, and improves joint function in a sex-specific manner. The study supports transition to human safety trials. Cite this article: Bone Joint Res 2024;13(6):279–293

Aims. Arthroplasty surgery of the knee and hip is performed in two to three million patients annually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiotics, and implant retention (DAIR) surgery aimed at cleaning the infected prosthesis often fails, subsequently requiring invasive revision of the complete prosthetic reconstruction. Infection-specific imaging may help to guide DAIR. In this study, we evaluated a bacteria-specific hybrid tracer (. 99m. Tc-UBI. 29-41. -Cy5) and its ability to visualize the bacterial load on femoral implants using clinical-grade image guidance methods. Methods. 99m. Tc-UBI. 29-41. -Cy5 specificity for Stapylococcus aureus was assessed in vitro using fluorescence confocal imaging. Topical administration was used to highlight the location of S. aureus cultured on femoral prostheses using fluorescence imaging and freehand single photon emission CT (fhSPECT) scans. Gamma counting and fhSPECT were used to quantify the bacterial load and monitor cleaning with chlorhexidine. Microbiological culturing helped to relate the imaging findings with the number of (remaining) bacteria. Results. Bacteria could be effectively stained in vitro and on prostheses, irrespective of the presence of biofilm. Infected prostheses revealed bacterial presence on the transition zone between the head and neck, and in the screw hole. Qualitative 2D fluorescence images could be complemented with quantitative 3D fhSPECT scans. Despite thorough chlorhexidine treatments, 28% to 44% of the signal remained present in the locations of the infection that were identified using imaging, which included 500 to 2,000 viable bacteria. Conclusion. The hybrid tracer . 99m. Tc-UBI. 29-41. -Cy5 allowed effective bacterial staining. Qualitative real-time fluorescence guidance could be effectively combined with nuclear imaging that enables quantitative monitoring of the effectiveness of cleaning strategies. Cite this article: Bone Joint Res 2023;12(1):72–79

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

Aims. The rate of dislocation when traditional single bearing implants are used in revision total hip arthroplasty (THA) has been reported to be between 8% and 10%. The use of dual mobility bearings can reduce this risk to between 0.5% and 2%. Dual mobility bearings are more expensive, and it is not clear if the additional clinical benefits constitute value for money for the payers. We aimed to estimate the cost-effectiveness of dual mobility compared with single bearings for patients undergoing revision THA. Methods. We developed a Markov model to estimate the expected cost and benefits of dual mobility compared with single bearing implants in patients undergoing revision THA. The rates of revision and further revision were calculated from the National Joint Registry of England and Wales, while rates of transition from one health state to another were estimated from the literature, and the data were stratified by sex and age. Implant and healthcare costs were estimated from local procurement prices and national tariffs. Quality-adjusted life-years (QALYs) were calculated using published utility estimates for patients undergoing THA. Results. At a minimum five-year follow-up, the use of dual mobility was cost-effective with an estimated incremental cost-effectiveness ratio (ICER) of between £3,006 and £18,745/QALY for patients aged < 55 years and between 64 and 75 years, respectively. For those aged > 75 years dual mobility was only cost-effective if the timeline was beyond seven years. The use of dual mobility bearings was cost-saving for patients aged < 75 years and cost-effective for those aged > 75 years if the time horizon was beyond ten years. Conclusion. The use of dual mobility bearings is cost-effective compared with single bearings in patients undergoing revision THA. The younger the patient is, the more likely it is that a dual mobility bearing can be more cost-effective and even cost-saving. The results are affected by the time horizon and cost of bearings for those aged > 75 years. For patients aged > 75 years, the surgeon must decide whether the use of a dual mobility bearing is a viable economic and clinical option. Cite this article: Bone Joint J 2020;102-B(9):1128–1135

Aims. Tibial plateau fractures (TPFs) are complex injuries around the knee caused by high- or low-energy trauma. In the present study, we aimed to define the distribution and frequency of TPF lines using a 3D mapping technique and analyze the rationalization of divisions employed by frequently used classifications. Methods. In total, 759 adult patients with 766 affected knees were retrospectively reviewed. The TPF fragments on CT were multiplanar reconstructed, and virtually reduced to match a 3D model of the proximal tibia. 3D heat mapping was subsequently created by graphically superimposing all fracture lines onto a tibia template. Results. The cohort included 405 (53.4%) cases with left knee injuries, 347 (45.7%) cases with right knee injuries, and seven (0.9%) cases with bilateral injuries. On mapping, the hot zones of the fracture lines were mainly concentrated around the anterior cruciate ligament insertion, posterior cruciate ligament insertion, and the inner part of the lateral condyle that extended to the junctional zone between Gerdy’s tubercle and the tibial tubercle. Moreover, the cold zones were scattered in the posteromedial fragment, superior tibiofibular syndesmosis, Gerdy’s tubercle, and tibial tubercle. TPFs with different Orthopaedic Trauma Association/AO Foundation (OTA/AO) subtypes showed peculiar characteristics. Conclusion. TPFs occurred more frequently in the lateral and intermedial column than in the medial column. Fracture lines of tibial plateau occur frequently in the transition zone with marked changes in cortical thickness. According to 3D mapping, the four-column and nine-segment classification had a high degree of matching as compared to the frequently used classifications. Cite this article: Bone Joint Res 2020;9(6):258–267

Introduction. The aim of this study is to report the 30 day COVID-19 related morbidity and mortality of patients assessed as SARS-CoV-2 negative who underwent emergency or urgent orthopaedic surgery in the NHS during the peak of the COVID-19 pandemic. Method. A retrospective, single centre, observational cohort study of all patients undergoing surgery between 17 March 2020 and 3May 2020 was performed. Outcomes were stratified by British Orthopaedic Association COVID-19 Patient Risk Assessment Tool. Patients who were SARS-CoV-2 positive at the time of surgery were excluded. Results. Overall, 96 patients assessed as negative for SARS-CoV-2 at the time of surgery underwent 100 emergency or urgent orthopaedic procedures during the study period. Within 30 days of surgery 9.4% of patients (n = 9) were found to be SARS-CoV-2 positive by nasopharyngeal swab. The overall 30 day mortality rate across the whole cohort of patients during this period was 3% (n = 3). Of those testing positive for SARS-CoV-2 66% (n = 6) developed significant COVID-19 related complications and there was a 33% 30-day mortality rate (n = 3). Overall, the 30-day mortality in patients classified as BOA low or medium risk (n = 69) was 0%, whereas in those classified as high or very high risk (n = 27) it was 11.1%. Conclusion. Orthopaedic surgery in SARS-CoV-2 negative patients who transition to positive within 30 days of surgery carries a significant risk of morbidity and mortality. In lower risk groups, the overall risk of becoming SARS-CoV-2 positive, and subsequently developing a significant postoperative related complication, was low even during the peak of the pandemic. In addition to ensuring patients are SARS-CoV-2 negative at the time of surgery it is important that the risk of acquiring SARS-CoV-2 is minimized through their recovery. Cite this article: Bone Joint Open 2020;1-8:474–480

Objectives. After an injury, the biological reattachment of tendon to bone is a challenge because healing takes place between a soft (tendon) and a hard (bone) tissue. Even after healing, the transition zone in the enthesis is not completely regenerated, making it susceptible to re-injury. In this study, we aimed to regenerate Achilles tendon entheses (ATEs) in wounded rats using a combination of kartogenin (KGN) and platelet-rich plasma (PRP). Methods. Wounds created in rat ATEs were given three different treatments: kartogenin platelet-rich plasma (KGN-PRP); PRP; or saline (control), followed by histological and immunochemical analyses, and mechanical testing of the rat ATEs after three months of healing. Results. Histological analysis showed well organised arrangement of collagen fibres and proteoglycan formation in the wounded ATEs in the KGN-PRP group. Furthermore, immunohistochemical analysis revealed fibrocartilage formation in the KGN-PRP-treated ATEs, evidenced by the presence of both collagen I and II in the healed ATE. Larger positively stained collagen III areas were found in both PRP and saline groups than those in the KGN-PRP group. Chondrocyte-related genes, SOX9 and collagen II, and tenocyte-related genes, collagen I and scleraxis (SCX), were also upregulated by KGN-PRP. Moreover, mechanical testing results showed higher ultimate tensile strength in the KGN-PRP group than in the saline control group. In contrast, PRP treatment appeared to have healed the injured ATE but induced no apparent formation of fibrocartilage. The saline-treated group showed poor healing without fibrocartilage tissue formation in the ATEs. Conclusions. Our results show that injection of KGN-PRP induces fibrocartilage formation in the wounded rat ATEs. Hence, KGN-PRP may be a clinically relevant, biological approach to regenerate injured enthesis effectively. Cite this article: J. Zhang, T. Yuan, N. Zheng, Y. Zhou, M. V. Hogan, J. H-C. Wang. The combined use of kartogenin and platelet-rich plasma promotes fibrocartilage formation in the wounded rat Achilles tendon entheses. Bone Joint Res 2017;6:231–244. DOI: 10.1302/2046-3758.64.BJR-2017-0268.R1

The August 2014 Spine Roundup. 360 . looks at: rhBMP complicates cervical spine surgery; posterior longitudinal ligament revisited; thoracolumbar posterior instrumentation without fusion in burst fractures; risk modelling for VTE events in spinal surgery; the consequences of dural tears in microdiscectomy; trends in revision spinal surgery; radiofrequency denervation likely effective in facet joint pain and hooks optimally biomechanically transition posterior instrumentation

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Prior cost-effectiveness analyses on osseointegrated prosthesis for transfemoral unilateral amputees have analyzed outcomes in non-USA countries using generic quality of life instruments, which may not be appropriate when evaluating disease-specific quality of life. These prior analyses have also focused only on patients who had failed a socket-based prosthesis. The aim of the current study is to use a disease-specific quality of life instrument, which can more accurately reflect a patient’s quality of life with this condition in order to evaluate cost-effectiveness, examining both treatment-naïve and socket refractory patients.

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The involvement of cyclin D1 in the proliferation of microglia, and the generation and maintenance of bone cancer pain (BCP), have not yet been clarified. We investigated the expression of microglia and cyclin D1, and the influences of cyclin D1 on pain threshold.

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Impaired fracture repair in patients with type 2 diabetes mellitus (T2DM) is not fully understood. In this study, we aimed to characterize the local changes in gene expression (GE) associated with diabetic fracture. We used an unbiased approach to compare GE in the fracture callus of Zucker diabetic fatty (ZDF) rats relative to wild-type (WT) littermates at three weeks following femoral osteotomy.

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The aim of this study was to report the meaningful values of the EuroQol five-dimension three-level questionnaire (EQ-5D-3L) and EuroQol visual analogue scale (EQ-VAS) in patients undergoing primary knee arthroplasty (KA).

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The principles of evidence-based medicine (EBM) are the foundation of modern medical practice. Surgeons are familiar with the commonly used statistical techniques to test hypotheses, summarize findings, and provide answers within a specified range of probability. Based on this knowledge, they are able to critically evaluate research before deciding whether or not to adopt the findings into practice. Recently, there has been an increased use of artificial intelligence (AI) to analyze information and derive findings in orthopaedic research. These techniques use a set of statistical tools that are increasingly complex and may be unfamiliar to the orthopaedic surgeon. It is unclear if this shift towards less familiar techniques is widely accepted in the orthopaedic community. This study aimed to provide an exploration of understanding and acceptance of AI use in research among orthopaedic surgeons.

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Our objective was describing an algorithm to identify and prevent vascular injury in patients with intrapelvic components.