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INTRODUCTION: Mechanical loosening is a leading cause of failure of total knee arthroplasties (TKAs) for which obesity may be a risk factor. With rising rates of obesity and increasing incidence of TKA, the identification of factors to mitigate this cause of failure is necessary. The purpose of this study is to determine if the use of a tibial stem extender (TSE) decreases the risk of mechanical loosening in patients with obesity undergoing TKA. MATERIALS: The American Joint Replacement Registry (AJRR) and linked Center of Medicare Services (CMS) claims database were utilized to identify a patient cohort with a body mass index of 30 kg/m2 or greater and age 65 years or older who underwent primary elective TKA between 2012 and 2021. METHODS: Patients were divided into cohorts based on obesity class and TSE utilization. The estimated association of TSE use, BMI categories, and covariates with the risk of revisions for mechanical loosening in both unadjusted and adjusted settings was determined. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for the risk of mechanical loosening were calculated. RESULTS: 258,775 TKA cases were identified. 538 of 257,194 (0.21%) patients who did not receive a TSE and one patient out of 1,581 (0.06%) with a TSE were revised for mechanical loosening. In adjusted analysis, TSE use was not protective against mechanical loosening and BMI > 40 was not a significant risk factor. CONCLUSION: Use of a TSE was not found to be protective against mechanical loosening in patients with obesity; however, analysis was limited by the small number of outcome events in the cohort. Further analysis with a larger cohort of patients with TSE and a longer follow up time is necessary to corroborate this finding.

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PURPOSE OF REVIEW: Spondylolysis remains one of the most common causes of lower back pain in the pediatric and adolescent populations and is particularly prevalent in young sporting individuals. Despite this, approaches to diagnostic imaging and both conservative and surgical treatment vary widely among surgeons. The current review investigates recent literature on the etiology, clinical presentation, diagnosis, and treatment of spondylolysis. In particular, it interrogates the use of various advanced imaging modalities (CT, MRI, SPECT) in diagnosis as well as common surgical approaches to the condition. RECENT FINDINGS: Recent data has provided more information on how pars defect laterality, stage, and presence or absence of bone marrow edema impact healing potential. Other studies have highlighted the advantages of using MRI for spondylolysis diagnosis. Other data has provided more clarity on which adults may benefit from direct pars repair, while other studies have compared the various techniques for direct repair of pars defects. While the exact cause of spondylolysis remains unclear, there is growing understanding of the behavioral, genetic, and biomechanical risk factors that predispose individuals to the condition. MRI may be emerging as the advanced imaging modality of choice for diagnosis due to its lack of radiation and comparable sensitivity to other advanced imaging techniques. Conservative treatment remains the first step in management due to excellent outcomes in most patients, with surgical intervention rarely necessary. In patients that do require surgery, direct repair using a pedicle screw-based approach is preferred over spinal fusion and other direct repair techniques.

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ABSTRACT: The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.

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BACKGROUND AND PURPOSE: The µ-opioid receptor (µ receptor) is the primary target for opioid analgesics. The 7-transmembrane (TM) and 6TM µ receptor isoforms mediate inhibitory and excitatory cellular effects. Here, we developed compounds selective for 6TM- or 7TM-µ receptors to further our understanding of the pharmacodynamic properties of µ receptors. EXPERIMENTAL APPROACH: We performed virtual screening of the ZINC Drug Now library of compounds using in silico 7TM- and 6TM-µ receptor structural models and identified potential compounds that are selective for 6TM- and/or 7TM-µ receptors. Subsequently, we characterized the most promising candidate compounds in functional in vitro studies using Be2C neuroblastoma transfected cells, behavioural in vivo pain assays using various knockout mice and in ex vivo electrophysiology studies. KEY RESULTS: Our virtual screen identified 30 potential candidate compounds. Subsequent functional in vitro cellular assays shortlisted four compounds (#5, 10, 11 and 25) that demonstrated 6TM- or 7TM-µ receptor-dependent NO release. In in vivo pain assays these compounds also produced dose-dependent hyperalgesic responses. Studies using mice that lack specific opioid receptors further established the µ receptor-dependent nature of identified novel ligands. Ex vivo electrophysiological studies on spontaneous excitatory postsynaptic currents in isolated spinal cord slices also validated the hyperalgesic properties of the most potent 6TM- (#10) and 7TM-µ receptor (#5) ligands. CONCLUSION AND IMPLICATIONS: Our novel compounds represent a new class of ligands for µ receptors and will serve as valuable research tools to facilitate the development of opioids with significant analgesic efficacy and fewer side-effects.

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The G protein-coupled µ-opioid receptor (µ-OR) mediates the majority of analgesia effects for morphine and other pain relievers. Despite extensive studies of its structure and activation mechanisms, the inherently low maturation efficiency of µ-OR represents a major hurdle to understanding its function. Here we computationally designed µ-OR mutants with altered stability to probe the relationship between cell-surface targeting, signal transduction, and agonist efficacy. The stabilizing mutation T315Y enhanced µ-OR trafficking to the plasma membrane and significantly promoted the morphine-mediated inhibition of downstream signaling. In contrast, the destabilizing mutation R165Y led to intracellular retention of µ-OR and reduced the response to morphine stimulation. These findings suggest that µ-OR stability is an important factor in regulating receptor signaling and provide a viable avenue to improve the efficacy of analgesics.

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