Applying models of care for total hip and knee arthroplasty: External validation of a published predictive model to identify extended stay risk prior to lower-limb arthroplasty.

OBJECTIVE: This study aimed to externally validate a reported model for identifying patients requiring extended stay following lower limb arthroplasty in a new setting. DESIGN: External validation of a previously reported prognostic model, using retrospective data. SETTING: Medium-sized hospital orthopaedic department, Australia. PARTICIPANTS: Electronic medical records were accessed for data collection between Sep-2019 and Feb-2020 and retrospective data extracted from 200 randomly selected total hip or knee arthroplasty patients. INTERVENTION: Participants received total hip or knee replacement between 2-Feb-16 and 4-Apr-19. This study was a non-interventional retrospective study. MAIN MEASURES: Model validation was assessed with discrimination, calibration on both original and adjusted forms of the candidate model. Decision curve analysis was conducted on the outputs of the adjusted model to determine net benefit at a predetermined decision threshold (0.5). RESULTS: The original model performed poorly, grossly overestimating length of stay with mean calibration of -3.6 (95% confidence interval -3.9 to -3.2) and calibration slope of 0.52. Performance improved following adjustment of the model intercept and model coefficients (mean calibration 0.48, 95% confidence interval 0.16 to 0.80 and slope of 1.0), but remained poorly calibrated at low and medium risk threshold and net benefit was modest (three additional patients per hundred identified as at-risk) at the a-priori risk threshold. CONCLUSIONS: External validation demonstrated poor performance when applied to a new patient population and would provide limited benefit for our institution. Implementation of predictive models for arthroplasty should include practical assessment of discrimination, calibration and net benefit at a clinically acceptable threshold.

Persistent knee extension deficits are common after anterior cruciate ligament reconstruction: a systematic review and meta-analysis of randomised controlled trials.

PURPOSE: Knee extension deficits complicate recovery from ACL injury and reconstruction; however, the incidence of knee extension loss is not well defined. The aim of this review was to identify the incidence of loss of extension (LOE) following ACL rupture and reconstruction, explore the definitions of knee extension deficits reported and identify prognostic factors affecting LOE incidence. METHODS: A systematic search was conducted in Medline, Cochrane Library and PEDro for studies in publication up to November 2021, with no restrictions on publication year. References were screened and assessed for inclusion using predetermined eligibility criteria. Randomised controlled trials (RCTs) that quantified knee angle, loss of extension or incidence of extension deficit were included for quality assessment and data extraction. Statistical summaries were generated and meta-analyses performed in two parts to examine: (i) the probability of a datapoint being zero incidence compared to a nonzero incidence and (ii) the relationship between the predictors and nonzero LOE incidence. RESULTS: A sample of 15,494 studies were retrieved using the search criteria, with 53 studies meeting eligibility criteria. The pooled results from 4991 participants were included for analysis, with 4891 participants who had undergone ACLR. The proportion of included studies judged at an overall low risk of bias was small (7.8%). The observed group and study were the most important predictors for whether a datapoint reported an incidence of extension deficit. Time to follow-up (P < 0.001) and graft type (P = 0.02) were found to have a significant influence on nonzero LOE incidence (%). Covariate adjusted estimates of average LOE indicated 1 in 3 patients presenting with LOE at 12 month follow-up, reducing to 1 in 4 at 2 years. CONCLUSIONS: This review examined the definitions for the measurement and interpretation of postoperative knee extension and established the trajectory of knee extension deficit after ACL injury and reconstruction. While factors associated with loss of extension were identified, the exact trajectory of knee extension deficits was difficult to infer due to discrepancies in measurement techniques and patient variation. On average, 1 in 3 patients may present with loss of extension of at least 3 degrees at 12-month follow-up, decreasing to 1 in 4 at 2 years. These results may be used by clinicians as an upper threshold for acceptable complication rates following ACLR. Future work should focus on LOE as a clinically relevant complication of ACL injury and treatment with appropriate attention to standardisation of definitions, measurements and better understanding of natural history. PROSPERO REGISTRATION NUMBER: CRD42018092295. LEVEL OF EVIDENCE: Level I.

Cellular Sources and Regional Variations in the Expression of the Neuroinflammatory Marker Translocator Protein (TSPO) in the Normal Brain.

The inducible expression of the mitochondrial translocator protein 18 kDa (TSPO) by activated microglia is a prominent, regular feature of acute and chronic-progressive brain pathology. This expression is also the rationale for the continual development of new TSPO binding molecules for the diagnosis of "neuroinflammation" by molecular imaging. However, there is in the normal brain an ill-defined, low-level constitutive expression of TSPO. Taking advantage of healthy TSPO knockout mouse brain tissue to validate TSPO antibody specificity, this study uses immunohistochemistry to determine the regional distribution and cellular sources of TSPO in the normal mouse brain. Fluorescence microscopy revealed punctate TSPO immunostaining in vascular endothelial cells throughout the brain. In the olfactory nerve layers and glomeruli of the olfactory bulb, choroid plexus and ependymal layers, we confirm constitutive TSPO expression levels similar to peripheral organs, while some low TSPO expression is present in regions of known neurogenesis, as well as cerebellar Purkinje cells. The distributed-sparse expression of TSPO in endothelial mitochondria throughout the normal brain can be expected to give rise to a low baseline signal in TSPO molecular imaging studies. Finally, our study emphasises the need for valid and methodologically robust verification of the selectivity of TSPO ligands through the use of TSPO knockout tissues.

Checkpoints to the Brain: Directing Myeloid Cell Migration to the Central Nervous System.

Myeloid cells are a unique subset of leukocytes with a diverse array of functions within the central nervous system during health and disease. Advances in understanding of the unique properties of these cells have inspired interest in their use as delivery vehicles for therapeutic genes, proteins, and drugs, or as "assistants" in the clean-up of aggregated proteins and other molecules when existing drainage systems are no longer adequate. The trafficking of myeloid cells from the periphery to the central nervous system is subject to complex cellular and molecular controls with several 'checkpoints' from the blood to their destination in the brain parenchyma. As important components of the neurovascular unit, the functional state changes associated with lineage heterogeneity of myeloid cells are increasingly recognized as important for disease progression. In this review, we discuss some of the cellular elements associated with formation and function of the neurovascular unit, and present an update on the impact of myeloid cells on central nervous system (CNS) diseases in the laboratory and the clinic. We then discuss emerging strategies for harnessing the potential of site-directed myeloid cell homing to the CNS, and identify promising avenues for future research, with particular emphasis on the importance of untangling the functional heterogeneity within existing myeloid subsets.

Multimodal thromboprophylaxis in low-risk patients undergoing lower limb arthroplasty: A retrospective observational cohort analysis of 1400 patients with ultrasound screening.

PURPOSE: This study reports the results of a multimodal thromboprophylaxis protocol for lower limb arthroplasty involving risk stratification, intraoperative calf compression, aspirin prophylaxis and early (within 4 h) post-operative mobilisation facilitated by the use of local infiltration analgesia. The study also aimed to identify risk factors for venous thromboembolism (VTE) within a 3-month period following surgery for patients deemed not at elevated risk. METHODS: Patients undergoing knee/hip arthroplasty or hip resurfacing were preoperatively screened for VTE risk factors, and those at standard risk were placed on a thromboprophylaxis protocol consisting of intraoperative intermittent calf compression during surgery, 300 mg/day aspirin for 6 weeks from surgery and early mobilisation. Patients were screened bilaterally for deep vein thrombosis (DVT) on post-operative days 10-14. If proximal DVT was detected, patients were anticoagulated and outcomes were recorded. Symptomatic VTE within 3 months of surgery were recorded separately. Patient notes were retrospectively collated and cross-validated against ultrasound reports. RESULTS: At initial screening, the rate of proximal DVT was 0.54% (1.1% for knee and 0.27% for hip), and distal DVT was 6.63% (20.11% for knee and 2.31% for hip). One small, nonfatal pulmonary embolism (PE) was detected within 3 months of surgery (0.28% of total knee arthroplasty patients or 0.07% of total). All proximal DVTs were treated successfully with anticoagulants; however, one patient suffered a minor PE approximately 10 months post-operatively. Regression analysis identified knee implant and advanced age as independent risk factors for VTE in this cohort. CONCLUSION: Although knee arthroplasty patients remained at higher risk than hip replacement/resurfacing patients, the incidence and outcomes of VTE remained positive compared with protocols involving extended immobilisation, and episodes of PE were extremely rare. Thus, we conclude that patients at standard preoperative risk of VTE may safely be taken through the post-operative recovery process with a combination of intraoperative mechanical prophylaxis, early mobilisation and post-operative aspirin, with closer attention required for older patients and those undergoing knee surgery.

Limited penetration of cobalt and chromium ions into the cerebrospinal fluid following metal on metal arthroplasty: a cross-sectional analysis.

Background: The purpose of this study was to determine the concentration of cobalt (Co) and chromium (Cr) ions in synovial fluid, blood plasma and cerebrospinal fluid (CSF) of patients with metal-on-metal (MoM) implants, and to assess the relationship between implant history and patient characteristics with ion concentrations in CSF.Methods: An observational, non-randomised cross-sectional study was conducted with patients presenting to a single surgeon for treatment of degenerative conditions of the hip and knee. Blood and fluid samples were collected intraoperatively and analysed for proteins and trace elements.Results: Overall, the presence of an implant was associated with significantly higher Co and Cr concentrations in plasma (controls 5-115 nmol/L Co, 5-232 nmol/L Cr; well-functioning implant recipients 5-469 nmol/L Co, 5-608 nmol/L Cr; hip revisions 6-546 nmol/L Co, 5-573 nmol/L Cr), and for Cr concentrations in CSF (controls 5-24 nmol/L; well-functioning implant recipients 6-36 nmol/L, hip revisions 7-32 nmol/L). In absolute terms, <1% of the levels observed in the joint fluid and <15% of plasma metals appeared in the CSF. Multivariable regression models suggested different transfer mechanisms of Co and Cr to the CSF, with the presence of an implant not associated with ion levels.Conclusion: The presence of MoM implants is associated with significantly higher plasma levels of Co and Cr but not CSF levels, and the CSF/plasma ratio appears to be influenced by the plasma concentration in a nonlinear fashion. Co and Cr may be transferred to the CSF by different mechanisms, and their concentrations appears dependent on other factors yet to be identified. Although higher levels of plasma ions are associated with above average CSF metal concentrations, the thresholds for neurotoxicity remain unclear and require further study.

Efficacy and safety of culture-expanded, mesenchymal stem/stromal cells for the treatment of knee osteoarthritis: a systematic review protocol.

BACKGROUND: Osteoarthritis is a progressive multifactorial condition of the musculoskeletal system with major symptoms including pain, loss of function, damage of articular cartilage and other tissues in the affected area. Knee osteoarthritis imposes major individual and social burden, especially with the cost and complexity of surgical interventions. Mesenchymal stem/stromal cells have been indicated as a treatment for degenerative musculoskeletal conditions given their capacity to differentiate into tissues of the musculoskeletal system. METHODS: A systematic search will be conducted in Medline, Embase, Cochrane Library, Scopus and relevant trial databases of English, Japanese, Korean, German, French, Italian, Spanish and Portuguese language papers published or in press to June 2018, with no restrictions on publication year applied. References will be screened and assessed for eligibility by two independent reviewers as per PRISMA guidelines. Cohort, cross-sectional or case controlled studies will be included for the analysis. Data extraction will be conducted using a predefined template and quality of evidence assessed. Statistical summaries and meta-analyses will be performed as necessary. DISCUSSION: Results will be published in relevant peer-reviewed scientific journals and presented at national or international conferences by the investigators. TRIAL REGISTRATION: The protocol was registered on the PROSPERO international prospective register of systematic reviews prior to commencement, CRD42018091763 .

Quality in practice: implementation of a clinical outcomes registry in regenerative medicine.

BACKGROUND: The aim of this didactic article is to describe the implementation of a clinical outcomes registry within a clinical setting for musculoskeletal regenerative medicine. A patient-centred clinical registry, designed and implemented into the practice of a musculoskeletal clinic specializing in regenerative medicine. METHODS: A focus on patient outcomes at all levels of the patient journey was established to monitor and continually improve care. The registry was designed to monitor the diagnosis, treatment and outcomes of musculoskeletal pathologies of the shoulder, elbow, hip, knee, foot and spine presenting to the clinic. Specifically, the registry was designed for surveillance, tracking, and reporting of efficacy and adverse events of cellular-based therapies. RESULTS: The registry has completed its implementation phase and is now in a pilot period to confirm data collection processes and user feedback. Initial findings indicate suboptimal data entry compliance in key areas that were rectified by refining data fields, reimaging within existing operating systems, and linkage to external supporting documents. CONCLUSIONS: The key impacts of the registry implementation have been to (I) redefine criteria for treatment success and failure within the area of biologic treatments in musculoskeletal practice; (II) instigate discussion, and document standardized treatment pathways, clinical handover processes and shared decision-making with patients; and (III) act as a catalyst to target deficiencies in staff knowledge and skills in the areas of patient management and interaction, clinical documentation and administration processes. A practice registry provides a platform for monitoring treatment safety and efficacy in the context of biologic therapies in musculoskeletal medicine. Registries of this kind will contribute to ongoing discourse regarding best value treatments in the musculoskeletal context.

The 18 kDa translocator protein, microglia and neuroinflammation.

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is expressed in the injured brain. It has become known as an imaging marker of "neuroinflammation" indicating active disease, and is best interpreted as a nondiagnostic biomarker and disease staging tool that refers to histopathology rather than disease etiology. The therapeutic potential of TSPO as a drug target is mostly based on the understanding that it is an outer mitochondrial membrane protein required for the translocation of cholesterol, which thus regulates the rate of steroid synthesis. This pivotal role together with the evolutionary conservation of TSPO has underpinned the belief that any loss or mutation of TSPO should be associated with significant physiological deficits or be outright incompatible with life. However, against prediction, full Tspo knockout mice are viable and across their lifespan do not show the phenotype expected if cholesterol transport and steroid synthesis were significantly impaired. Thus, the "translocation" function of TSPO remains to be better substantiated. Here, we discuss the literature before and after the introduction of the new nomenclature for TSPO and review some of the newer findings. In light of the controversy surrounding the function of TSPO, we emphasize the continued importance of identifying compounds with confirmed selectivity and suggest that TSPO expression is analyzed within specific disease contexts rather than merely equated with the reified concept of "neuroinflammation."