The Fate of the Inconclusive Periprosthetic Joint Infection Workup and Reliability of Data Points.

In 2018, periprosthetic joint infection (PJI) criteria were revised to include a new category labeled "inconclusive." The purpose of this study was to characterize and describe the fate of the inconclusive PJI workup and to analyze preoperative factors associated with outcomes. We reviewed all PJI workups at our institution during a 3-year period (426 patients). Patients were labeled "infected," "not infected," or "inconclusive" according to 2018 PJI preoperative criteria. In addition to standard diagnostic variables, the presence or absence of clinical elements that increase the pretest probability of infection were collected. Patients with any missing preoperative diagnostic test results and those with clinical follow-up less than 30 days were excluded. Logistic regression was used to identify the factors associated with infection. Two hundred ninety-six workups remained after exclusion criteria were applied, consisting of 66 (22.2%) with a preoperative score of 6 or greater defined as infected, 52 (17.6%) inconclusive (score 2-5), and 178 (60.1%) not infected (score 0-1). Postoperative re-scoring of the inconclusive group based on intraoperative findings as per the 2018 criteria identified 6 of 52 (11.5%) as infected, 12 (23.1%) inconclusive, and 34 (65.4%) not infected. Among those preoperatively scored as inconclusive, variables statistically correlated with the presence of infection included history of PJI, factors that increase skin barrier penetration (eg, psoriasis and venous stasis), and presence of comorbidities predisposing to infection. For patients labeled inconclusive, clinical elements of the pretest probability for infection (eg, history of prior PJI) were as reliable as any diagnostic test, including alpha-defensin, in the diagnosis of PJI. [Orthopedics. 2023;46(5):e291-e297.].

Midterm Survivorship of Robotic-Assisted Lateral Unicompartmental Knee Arthroplasty.

BACKGROUND: Lateral unicompartmental knee arthroplasty (UKA) is a popular alternative to total knee arthroplasty (TKA) for patients with isolated lateral compartment osteoarthritis. Few studies have investigated outcomes following robotic-assisted lateral UKA. The purpose of this study is to evaluate mid-term survivorship and patient-reported outcomes of robotic-assisted lateral UKA. METHODS: A retrospective case series was conducted on all robotic-assisted lateral UKAs performed by a single surgeon between 2013 and 2019. Patient demographics, surgical variables, and Kozinn and Scott criteria were collected. Implant survivorship was estimated using the Kaplan-Meier method with all-cause reoperation and conversion to TKA as endpoints. Participating patients were assessed for patient satisfaction and the Forgotten Joint Score-12. Correlations between patient demographics and patient outcome scores were investigated. RESULTS: In total, 120 lateral UKAs were identified, 84 of which met inclusion criteria, with a mean follow-up of 4.0 years (range 2.0-7.0). Five-year survivorship was 92.9% (95% confidence interval [CI] 84.5-96.7) with all-cause reoperation as the endpoint, and 100% (95% CI 95.0-100) with conversion to TKA as the endpoint. One patient was converted to TKA after the 5-year mark, resulting in a 6-year survival for conversion to TKA of 88.9% (95% CI 44.9-98.5). Average Forgotten Joint Score-12 score was 82.7/100, and patient satisfaction 4.7/5. Mean coronal plane correction was 2.5° ± 1.9° toward the mechanical axis. Neither final postoperative alignment nor failure to meet classic Kozinn and Scott criteria for UKA resulted in differences in patient-reported outcomes. CONCLUSION: The current study demonstrates high mid-term survivorship and excellent patient-reported outcomes with robotic-assisted lateral UKA. Robotic-assisted lateral UKA is a viable treatment option for isolated lateral compartment arthritis even in patients who do not meet classic indications.

Utilization of technology-assisted total hip arthroplasty in the United States from 2005 to 2018.

BACKGROUND: Successful outcomes in total hip arthroplasty (THA) rely in part on accurate component positioning, which may be optimized through the use of computer navigation and robot-assistance. Therefore, we queried a large national database to characterize national trends in technology-assisted THA utilization, determine whether these technologies were associated with increased hospital charges, and identify demographic factors associated with technology-assisted THA. METHODS: Using the Nationwide Inpatient Sample database, patients that underwent conventional THA, computer-navigated THA, and robot-assisted THA from 2005 to 2018 were identified. Patient and hospital demographics, charge data, and payer characteristics were collected. Temporal trends in utilization were reported. Univariate analyses were performed to compare differences between groups with multiple logistic regression analysis to account for confounders. RESULTS: In total, 3,428,208 patients undergoing THA from 2005 to 2018 were identified, of which 63,136 (1.8%) used computer navigation and 32,660 (1.0%) used robot-assistance. National utilization of computer navigation in THA increased from 0.1% to 1.9% between 2005 and 2018, while utilization of robot-assisted THA increased from <0.1% to 2.1% from 2008 to 2018. On multivariate analysis, technology-assisted THA was most commonly performed in urban hospitals in the Northeastern United States. Median hospital charges were increased for technology-assisted THAs relative to conventional THAs ($66,089 ± $254 vs $55,418 ± $43). CONCLUSIONS: Computer navigation and robot-assistance in THA demonstrated a consistent increase in utilization during the period examined, representing 4.0% of THAs performed in 2018. Patient and hospital characteristics including risk of mortality, geographic region, and teaching status were associated with increased utilization. Utilization of computer navigation was associated with increased hospital charges.

Cost-effectiveness of Single vs Double Debridement and Implant Retention for Acute Periprosthetic Joint Infections in Total Knee Arthroplasty: A Markov Model.

BACKGROUND: Periprosthetic joint infection (PJI) is a common cause of revision total knee surgery. Although debridement and implant retention (DAIR) has lower success rates in the chronic setting, it is an accepted treatment of acute PJI, whether postoperatively or with late hematogenous seeding. There are two broad DAIR strategies: single debridement and planned double debridement. The purpose of this study is to evaluate the cost-effectiveness of single vs double DAIR for acute PJI in total knee arthroplasty. METHODS: A decision tree using single or double DAIR as the treatment strategy for acute PJI was constructed. Quality-adjusted life years and costs associated with the two treatment arms were calculated. Treatment success rates, failure rates, and mortality rates were derived from the literature. Medical costs were derived from both the literature and Medicare data. A cost-effectiveness plane was constructed from multiple Monte Carlo trials. A sensitivity analysis identified parameters most influencing the optimal strategy decision. RESULTS: Double DAIR was the optimal treatment strategy both in terms of the health utility state (82% of trials) and medical cost (97% of trials). Strategy tables demonstrated that as long as the success rate of double debridement is 10% or greater than the success rate of a single debridement, the two-stage protocol is cost-effective. CONCLUSIONS: A double DAIR protocol is more cost-effective than single DAIR from a societal perspective.

Single-stage bilateral reverse total shoulder arthroplasty for bilateral posterior shoulder fracture-dislocation following seizure: A case report.

INTRODUCTION: Posterior shoulder dislocations comprise a small percentage of shoulder dislocations. Even more uncommon are posterior shoulder fracture-dislocations, which are commonly associated with trauma, seizures, and electrical shock. PRESENTATION OF CASE: We present the case of a 64-year-old right-hand dominant male who sustained bilateral shoulder posterior fracture-dislocations after a hypoglycemia-induced seizure. The patient was treated with bilateral reverse total shoulder arthroplasties in a single-stage. He recovered well and continues to have excellent function and range of motion at 4-year follow-up. DISCUSSION: Treatment options for proximal humerus fracture-dislocations include open reduction internal fixation (ORIF), hemiarthroplasty, and reverse total shoulder arthroplasty (RTSA). The indications for reverse total shoulder arthroplasty continue to expand. CONCLUSION: This is a rare case of bilateral posterior shoulder fracture-dislocations. In similar cases, simultaneous reverse total shoulder arthroplasties can be considered as a viable treatment option.

Population-based Survivorship of Computer-navigated Versus Conventional Total Knee Arthroplasty.

BACKGROUND: The goal of computer navigation in total knee arthroplasty (TKA) is to improve the accuracy of alignment. However, the relationship between this technology and implant longevity has not been established. The purpose of this study was to analyze survivorship of computer-navigated TKAs compared with traditionally instrumented TKAs. METHODS: The PearlDiver Medicare database was used to identify patients who underwent a primary TKA using conventional instrumentation versus computer navigation between 2005 and 2014. Conventional and computer-navigated cohorts were matched by age, sex, year of procedure, comorbidities, and geographic region. Kaplan-Meier curves were generated to estimate survivorship with aseptic mechanical complications, periprosthetic joint infection, and all-cause revision as end points. RESULTS: During the study period, 75,709 patients who underwent a computer-navigated TKA were identified and matched to a cohort of 75,676 conventional TKA patients from a cohort of 1,607,803 conventional TKA patients. No difference existed in survival between conventional instrumentation (94.7%) and navigated TKAs (95.1%, P = 0.06) at 5 years. A modest decrease was found in revisions secondary to mechanical complications associated with navigation (96.1%) compared with conventional instrumentation (95.7%, P = 0.02) at 5 years. No differences in revision rates because of periprosthetic joint infection were observed (97.9% versus 97.9% event-free survival, P = 0.30). In a subgroup of Medicare patients younger than 65 years of age, use of computer navigation was associated with a decrease in all-cause revision (91.4% versus 89.6% event free survival, P = 0.01) and revision secondary to mechanical complications (89.6% versus 87.8% event-free survival, P = 0.01) at 5 years. DISCUSSION: Among Medicare patients, no notable difference existed in TKA survival associated with the use of computer navigation at the 5-year follow-up. Use of computer navigation was associated with a slight decrease in revisions secondary to mechanical failure. Although improved survivorship was associated with patients younger than 65 years of age who had a navigated TKA, generalizability of these findings is limited given the unique characteristics of this Medicare subpopulation.

Trends in computer navigation and robotic assistance for total knee arthroplasty in the United States: an analysis of patient and hospital factors.

BACKGROUND: Computer navigation and robotic assistance technologies are used to improve the accuracy of component positioning in total knee arthroplasty (TKA), with the goal of improving function and optimizing implant longevity. The purpose of this study was to analyze trends in the use of technology-assisted TKA, identify factors associated with the use of these technologies, and describe potential drivers of cost. METHODS: The Nationwide Inpatient Sample database was used to identify patients who underwent TKA using conventional instrumentation, computer navigation, and robot-assisted techniques between 2005 and 2014. Variables analyzed include patient demographics, hospital and payer types, and hospital charges. Descriptive statistics were used to describe trends. Univariate and multivariate analyses were performed to identify differences between conventional and technology-assisted groups. RESULTS: Our analysis identified 6,060,901 patients who underwent TKA from 2005 to 2014, of which 273,922 (4.5%) used computer navigation and 24,084 (0.4%) used robotic assistance. The proportion of technology-assisted TKAs steadily increased over the study period, from 1.2% in 2005 to 7.0% in 2014. Computer navigation increased in use from 1.2% in 2005 to 6.3% in 2014. Computer navigation was more likely to be used in the Western United States, whereas robot-assisted TKAs were more likely to be performed in the Northeast. Increased hospital charges were associated with the use of technology assistance ($53,740.1 vs $47,639.2). CONCLUSIONS: The use of computer navigation and robot-assisted TKA steadily increased over the study period, accounting for 7.0% of TKAs performed in the United States in 2014. Marked regional differences in the use of these technologies were identified. The use of these technologies was associated with increased hospital charges.

The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors.

The formation, function, and plasticity of synapses require dynamic changes in synaptic receptor composition. Here, we identify the sorting receptor SorCS1 as a key regulator of synaptic receptor trafficking. Four independent proteomic analyses identify the synaptic adhesion molecule neurexin and the AMPA glutamate receptor (AMPAR) as major proteins sorted by SorCS1. SorCS1 localizes to early and recycling endosomes and regulates neurexin and AMPAR surface trafficking. Surface proteome analysis of SorCS1-deficient neurons shows decreased surface levels of these, and additional, receptors. Quantitative in vivo analysis of SorCS1-knockout synaptic proteomes identifies SorCS1 as a global trafficking regulator and reveals decreased levels of receptors regulating adhesion and neurotransmission, including neurexins and AMPARs. Consequently, glutamatergic transmission at SorCS1-deficient synapses is reduced due to impaired AMPAR surface expression. SORCS1 mutations have been associated with autism and Alzheimer disease, suggesting that perturbed receptor trafficking contributes to synaptic-composition and -function defects underlying synaptopathies.

Modulation of mouse macrophage polarization in vitro using IL-4 delivery by osmotic pumps.

Modulation of macrophage polarization is emerging as promising means to mitigate wear particle-induced inflammation and periprosthetic osteolysis. As a model for continuous local drug delivery, we used miniature osmotic pumps to deliver IL-4 in order to modulate macrophage polarization in vitro from nonactivated M0 and inflammatory M1 phenotypes towards a tissue regenerative M2 phenotype. Pumps delivered IL-4 into vials containing mouse bone marrow macrophage (mBMM) media. This conditioned media (CM) was collected at seven day intervals up to four weeks (week 1 to week 4 samples). IL-4 concentration in the CM was determined by ELISA and its biological activity was assayed by exposing M0 and M1 mBMMs to week 1 or week 4 CM. The IL-4 concentration in the CM approximated the mathematically calculated amount, and its biological activity was well retained, as both M0 and M1 macrophages exposed to either the week 1 or week 4 CM assumed M2-like phenotype as determined by qRT-PCR, ELISA, and immunocytochemistry. The results show that IL-4 can be delivered using osmotic pumps and that IL-4 delivered can modulate macrophage phenotype. Results build a foundation for in vivo studies using our previously validated animal models and provide possible strategies to locally mitigate wear particle-induced macrophage activation and periprosthetic osteolysis.

Specific disruption of hippocampal mossy fiber synapses in a mouse model of familial Alzheimer's disease.

The earliest stages of Alzheimer's disease (AD) are characterized by deficits in memory and cognition indicating hippocampal pathology. While it is now recognized that synapse dysfunction precedes the hallmark pathological findings of AD, it is unclear if specific hippocampal synapses are particularly vulnerable. Since the mossy fiber (MF) synapse between dentate gyrus (DG) and CA3 regions underlies critical functions disrupted in AD, we utilized serial block-face electron microscopy (SBEM) to analyze MF microcircuitry in a mouse model of familial Alzheimer's disease (FAD). FAD mutant MF terminal complexes were severely disrupted compared to control - they were smaller, contacted fewer postsynaptic spines and had greater numbers of presynaptic filopodial processes. Multi-headed CA3 dendritic spines in the FAD mutant condition were reduced in complexity and had significantly smaller sites of synaptic contact. Significantly, there was no change in the volume of classical dendritic spines at neighboring inputs to CA3 neurons suggesting input-specific defects in the early course of AD related pathology. These data indicate a specific vulnerability of the DG-CA3 network in AD pathogenesis and demonstrate the utility of SBEM to assess circuit specific alterations in mouse models of human disease.

Enhancement of BMP-2 induced bone regeneration by SDF-1α mediated stem cell recruitment.

Treatment of critical size bone defects is challenging. Recent studies showed that the cytokine stromal cell-derived factor 1 alpha (SDF-1α) has potential to improve the bone regenerative effect of low bone morphogenetic protein 2 (BMP-2) concentrations. The goal of this study was to demonstrate the combined effect of SDF-1α and BMP-2 on bone regeneration and stem cell recruitment using a critical size femoral bone defect model. A total of 72 mice were randomized to six groups. External fixators were implanted onto the right femur of each mouse and 3 mm defects were created. Depending on the group affiliation, adenovirally activated fat tissue grafts expressing SDF-1α or/and BMP-2 were implanted at the defect site. One day after operation, 1×106 murine mesenchymal stromal cells (MSCs), lentivirally transduced to express the gene enhanced green fluorescent protein (eGFP), firefly luciferase, and CXCR4 were injected systemically in selected groups. Migration of the injected MSCs was observed by bioluminescence imaging on days 0, 2, 4, 6, 8, 10, 12, 14, 21, 28, and 42. After 6 weeks, animals were euthanized and 80 µm CT-scans were performed. For histological investigations, hematoxylin and eosin-, tartrate-resistant acid phosphatase-, alkaline phosphatase-, and anti-eGFP-stained sections were prepared. BMP-2 and SDF-1α combined at the defect site increased bone volume (BV) (2.72 mm³; 95% CI 1.95-3.49 mm³) compared with the negative control group (1.80 mm³; 95% CI 1.56-2.04 mm³; p<0.05). In addition, histological analysis confirmed a higher degree of bone healing in the BMP-2 and SDF-1α combined group compared with the negative control group. Bioluminescence imaging demonstrated higher numbers of migrated MSCs toward the defect site in the presence of both BMP-2 and SDF-1α at the defect site. Furthermore, eGFP-labeled migrated MSCs were found in all defect areas, when cells were injected. The ratio of osteoblasts to osteoclasts, assessed by immunohistological staining, was higher and thus showed a trend toward more bone formation for the combined use of BMP-2 and SDF-1α compared with all other groups. This study demonstrated that SDF-1α enhanced BMP-2 mediated bone healing in a critical size segmental bone defect model. Notably, both proteins alone also provided a cumulative effect on MSC attraction toward the site of injury.

Macrophage polarization in response to wear particles in vitro.

Total joint replacement is a highly successful surgical procedure for treatment of patients with disabling arthritis and joint dysfunction. However, over time, with high levels of activity and usage of the joint, implant wear particles are generated from the articulating surfaces. These wear particles can lead to activation of an inflammatory reaction, and subsequent bone resorption around the implant (periprosthetic osteolysis). Cells of the monocyte/macrophage lineage orchestrate this chronic inflammatory response, which is dominated by a pro-inflammatory (M1) macrophage phenotype rather than an anti-inflammatory pro-tissue healing (M2) macrophage phenotype. While it has been shown that interleukin-4 (IL-4) selectively polarizes macrophages towards an M2 anti-inflammatory phenotype which promotes bone healing, rather than inflammation, little is known about the time course in which this occurs or conditions in which repolarization through IL-4 is most effective. The goal of this work was to study the time course of murine macrophage polarization and cytokine release in response to challenge with combinations of polymethyl methacrylate (PMMA) particles, lipopolysaccharide (LPS) and IL-4 in vitro. Treatment of particle-challenged monocyte/macrophages with IL-4 led to an initial suppression of pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) production and subsequent polarization into an M2 anti-inflammatory phenotype. This result was optimized when IL-4 was delivered before PMMA particle challenge, to an M1 phenotype rather than to uncommitted (M0) macrophages. The effects of this polarization were sustained over a 5-day time course. Polarization of M1 macrophages into an M2 phenotype may be a strategy to mitigate wear particle associated periprosthetic osteolysis.

Deconstructing complexity: serial block-face electron microscopic analysis of the hippocampal mossy fiber synapse.

The hippocampal mossy fiber (MF) terminal is among the largest and most complex synaptic structures in the brain. Our understanding of the development of this morphologically elaborate structure has been limited because of the inability of standard electron microscopy techniques to quickly and accurately reconstruct large volumes of neuropil. Here we use serial block-face electron microscopy (SBEM) to surmount these limitations and investigate the establishment of MF connectivity during mouse postnatal development. Based on volume reconstructions, we find that MF axons initially form bouton-like specializations directly onto dendritic shafts, that dendritic protrusions primarily arise independently of bouton contact sites, and that a dramatic increase in presynaptic and postsynaptic complexity follows the association of MF boutons with CA3 dendritic protrusions. We also identify a transient period of MF bouton filopodial exploration, followed by refinement of sites of synaptic connectivity. These observations enhance our understanding of the development of this highly specialized synapse and illustrate the power of SBEM to resolve details of developing microcircuits at a level not easily attainable with conventional approaches.

Stem cell attraction via SDF-1α expressing fat tissue grafts.

Mesenchymal stromal cell (MSCs) are key cellular components for site-specific tissue regeneration. The chemokine stromal derived factor 1 alpha (SDF-1α) is known to attract stem cells via the C-X-C chemokine receptor-4 (CXCR4) receptor. The aim of the study was to develop a model for stem cell attraction using SDF-1α overexpressing fat tissue grafts. Murine MSCs were lentiviral transduced to express the genes for enhanced green fluorescent protein, firefly luciferace, and human CXCR4 (hCXCR4). Murine fat tissue was adenoviral transduced to express SDF-1α and red fluorescent protein transgenes. MSCs were cultured on transwells with SDF-1α containing supernatants from transduced fat tissue. The numbers of migrated MSCs in four groups (with hCXCR4 positive (+) or hCXCR4 negative (-) MSCs with or without SDF-1α containing supernatant) were investigated. After 36 h of culture, 9025 ± 925 cells migrated through the membrane of the transwells in group 1 (CXCR4+/SDF-1α+), 4817 ± 940 cells in group 2 (CXCR4-/SDF-1α+), 2050 ± 766 cells in group 3 (CXCR4+/SDF-1α-), and 2108 ± 426 cells in group 4 (CXCR4-/SDF-1α-). Both, the presence of SDF-1α and the expression of hCXCR4 significantly increased the migration rates (p < 0.0001). MSCs overexpressing the CXCR4 receptor by lentiviral transduction are highly attracted by medium from SDF-1α expressing fat tissue in vitro. Thus, SDF-1α activated tissue grafts may be a strategy to enhance site-specific musculoskeletal tissue regeneration.

Role of direct estrogen receptor signaling in wear particle-induced osteolysis.

Estrogen withdrawal following surgical ovariectomy was recently shown to mitigate particle-induced osteolysis in the murine calvarial model. Currently, we hypothesize that estrogen receptors (ERs) were involved in this paradoxical phenomenon. To test this hypothesis, we first evaluated polyethylene (PE) particle-induced osteolysis in the murine calvarial model, using wild type (WT) C57BL6J female mice, ERα deficient (ERαKO) mice, and WT mice either treated with 17ß-estradiol (E2) or with the ER pan-antagonist ICI 182,780. According to micro-CT and histomorphometry, we showed that bone resorption was consistently altered in both ERαKO and ICI 182,780 treated mice as compared to WT and E2 groups. Then, we demonstrated that ER disruption consistently decreased both PE and polymethylmethacrylate (PMMA) particle-induced production of TNF-α by murine macrophages in vitro. Similar results were obtained following ER blockade using ICI 182,780 in RAW 264.7 and WT macrophages. ER disruption and pre treatment with ICI 182,780 resulted in a consistent down-regulation of particle-induced TNF-α mRNA expression relative to WT macrophages or untreated RAW cells. These results indicate that the response to wear particles involves estrogen receptors in female mice, as part of macrophage activation. Estrogen receptors may be considered as a future therapeutic target for particle-induced osteolysis.

NeuroD2 regulates the development of hippocampal mossy fiber synapses.

BACKGROUND: The assembly of neural circuits requires the concerted action of both genetically determined and activity-dependent mechanisms. Calcium-regulated transcription may link these processes, but the influence of specific transcription factors on the differentiation of synapse-specific properties is poorly understood. Here we characterize the influence of NeuroD2, a calcium-dependent transcription factor, in regulating the structural and functional maturation of the hippocampal mossy fiber (MF) synapse. RESULTS: Using NeuroD2 null mice and in vivo lentivirus-mediated gene knockdown, we demonstrate a critical role for NeuroD2 in the formation of CA3 dendritic spines receiving MF inputs. We also use electrophysiological recordings from CA3 neurons while stimulating MF axons to show that NeuroD2 regulates the differentiation of functional properties at the MF synapse. Finally, we find that NeuroD2 regulates PSD95 expression in hippocampal neurons and that PSD95 loss of function in vivo reproduces CA3 neuron spine defects observed in NeuroD2 null mice. CONCLUSION: These experiments identify NeuroD2 as a key transcription factor that regulates the structural and functional differentiation of MF synapses in vivo.