Microglial P2Y6 calcium signaling promotes phagocytosis and shapes neuroimmune responses in epileptogenesis.

Microglial calcium signaling is rare in a baseline state but strongly engaged during early epilepsy development. The mechanism(s) governing microglial calcium signaling are not known. By developing an in vivo uridine diphosphate (UDP) fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP can signal through the microglial-enriched P2Y6 receptor to increase calcium activity during epileptogenesis. P2Y6 calcium activity is associated with lysosome biogenesis and enhanced production of NF-κB-related cytokines. In the hippocampus, knockout of the P2Y6 receptor prevents microglia from fully engulfing neurons. Attenuating microglial calcium signaling through calcium extruder ("CalEx") expression recapitulates multiple features of P2Y6 knockout, including reduced lysosome biogenesis and phagocytic interactions. Ultimately, P2Y6 knockout mice retain more CA3 neurons and better cognitive task performance during epileptogenesis. Our results demonstrate that P2Y6 signaling impacts multiple aspects of myeloid cell immune function during epileptogenesis.

The Impact of Preoperative Weight Loss Timing on Surgical Outcomes in Total Hip Arthroplasty.

BACKGROUND: Elevated body mass index (BMI) increases surgical complications post-total hip arthroplasty (THA). However, the effects of rapid weight loss pre-THA remain unclear. This study evaluated patients who had initial BMIs between 40 and 50, and then achieved a BMI under 35 at various intervals before their THA. Comparisons were made with consistent obese and nonobese groups to understand potential complications. METHODS: Using a national database, we categorized THA patients based on initial BMI and weight loss timing before the surgery. These were contrasted with those maintaining a steady BMI of 20 to 30 or 40 to 50. We monitored outcomes like periprosthetic joint infections (PJI), surgical site infections (SSI), and noninfectious revisions for 2 years postsurgery, incorporating demographic considerations. Statistical analyses utilized Chi-square tests for categorical outcomes and Student's t-tests for continuous variables. RESULTS: Among patients who had a BMI of 45 to 50, weight loss 3 to 9 months presurgery increased PJI risks at 90 days (Odds Ratios [OR]: 2.15 to 5.22, P < .001). However, weight loss a year before the surgery lowered the PJI risk (OR: 0.14 to 0.27, P < .005). Constantly obese patients faced heightened PJI risks 1 to 2 years postsurgery (OR: 1.64 to 1.95, P < .015). Regarding SSI, risks increased with weight loss 3 to 9 months before surgery, but decreased when weight loss occurred a year earlier. In the BMI 40 to 45 group, weight loss 3 to 6 months presurgery showed higher PJI and SSI at 90 days (P < .001), with obese participants consistently at greater risk. CONCLUSIONS: While high BMI poses THA risks, weight loss timing plays a crucial role in postoperative complications. Weight loss closer to the surgery (0 to 9 months) can heighten risks, but shedding weight a year in advance seems beneficial. Conversely, initiating weight loss approximately a year before surgery offers potential protective effects against postoperative issues. This highlights the importance of strategic weight management guidance for patients considering THA, ensuring optimal surgical results and reducing potential adverse outcomes.

Immediate weightbearing is safe after revision total hip arthroplasty for Vancouver B2/B3 periprosthetic femur fractures.

INTRODUCTION: Modular fluted, tapered stems provide a reliable treatment for Vancouver B2/B3 fractures. Historically, these patients had weightbearing restrictions postoperatively. Although full immediate postoperative weightbearing may provide benefits in this patient population, stem subsidence is a concern. QUESTIONS/PURPOSES: The objective of this study was to investigate the effect of post-operative weight-bearing status on stem subsidence in patients treated with modular tapered stems for Vancouver B2 and B3 periprosthetic fractures. We sought to answer two questions: (1) Does full immediate postoperative weightbearing after revision total hip arthroplasty for periprosthetic femur fracture lead to increased stem subsidence compared to protected weightbearing? (2) Is there a mortality difference between these two groups of patients with different weightbearing restrictions? METHODS: From 2009 to 2015 all patients who underwent revision for Vancouver B2/B3 fractures were made non-weightbearing (NWB) for six weeks postoperatively. After 2015, immediate weightbearing as tolerated (WBAT) was allowed postoperatively. We compared stem subsidence between immediate postoperative and final radiographs. Additionally, we performed a Kaplan-Meijer analysis with one-year mortality as an endpoint. RESULTS: The final cohort included forty-seven patients with an average follow-up of 254 days. The average stem subsidence was 1.0 mm (95 % CI, 0.5-1.5 mm) in the NWB cohort and 0.3 mm (95 % CI, 0-0.7 mm) in the WBAT cohort (P = 0.10). In our survivorship analysis, we noted no deaths in the WBAT cohort compared to 17 % mortality in the NWB cohort at the one-year timepoint. CONCLUSION: Allowing patients to weight bear immediately after revision does not increase stem subsidence. Further studies are needed to determine whether early weightbearing provides a mortality benefit.

Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria.

Cerebral malaria is the deadliest complication that can arise from Plasmodium infection. CD8 T-cell engagement of brain vasculature is a putative mechanism of neuropathology in cerebral malaria. To define contributions of brain endothelial cell major histocompatibility complex (MHC) class I antigen-presentation to CD8 T cells in establishing cerebral malaria pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules, specifically from brain endothelium. This strategy allowed us to avoid off-target effects on iron homeostasis and class I-like molecules, which are known to perturb Plasmodium infection. This is the first endothelial-specific ablation of individual class-I molecules enabling us to interrogate these molecular interactions. In these studies, we interrogated human and mouse transcriptomics data to compare antigen presentation capacity during cerebral malaria. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we observed that H-2Kb and H-2Db class I molecules regulate distinct patterns of disease onset, CD8 T-cell infiltration, targeted cell death and regional blood-brain barrier disruption. Strikingly, ablation of either molecule from brain endothelial cells resulted in reduced CD8 T-cell activation, attenuated T-cell interaction with brain vasculature, lessened targeted cell death, preserved blood-brain barrier integrity and prevention of ECM and the death of the animal. We were able to show that these events were brain-specific through the use of parabiosis and created the novel technique of dual small animal MRI to simultaneously scan conjoined parabionts during infection. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium differentially regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria.

TREM2 mediates MHCII-associated CD4+ T cell response against gliomas.

BACKGROUND: Myeloid cells comprise up to 50% of the total tumor mass in glioblastoma (GBM) and have been implicated in promoting tumor progression and immunosuppression. Modulating the response of myeloid cells to the tumor has emerged as a promising new approach for cancer treatment. In this regard, we focus on the Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which has recently emerged as a novel immune modulator in peripheral tumors. METHODS: We studied the TREM2 expression profile in various patient tumor samples and conducted single-cell transcriptomic analysis in both glioblastoma patients and the GL261 mouse glioma model. We utilized multiple mouse glioma models and employed state-of-the-art techniques such as in vivo two-photon imaging, spectrum flow cytometry, and in vitro co-culture assays to study TREM2 function in myeloid cell-mediated phagocytosis of tumor cells, antigen presentation, and response of CD4+ T cells within the tumor hemispheres. RESULTS: Our research revealed significantly elevated levels of TREM2 expression in brain tumors compared to other types of tumors in patients. TREM2 was predominantly localized in tumor-associated myeloid cells and was highly expressed in nearly all microglia, as well as various subtypes of macrophages. Surprisingly, in pre-clinical glioma models, TREM2 deficiency did not confer a beneficial effect; instead, it accelerated glioma progression. Through detailed investigations, we determined that TREM2 deficiency impaired the ability of tumor-myeloid cells to phagocytose tumor cells and led to reduced expression of MHCII. This deficiency further significantly decreased the presence of CD4+ T cells within the tumor hemispheres. CONCLUSIONS: Our study unveiled a previously unrecognized protective role of tumor-myeloid TREM2. Specifically, we found TREM2 enhance the phagocytosis of tumor cells and promote an immune response by facilitating MHCII-associated CD4+ T cell responses against gliomas.

Spectral flow cytometry identifies distinct nonneoplastic plasma extracellular vesicle phenotype in glioblastoma patients.

Background: Glioblastoma (GBM) is the most common malignant brain tumor and has a poor prognosis. Imaging findings at diagnosis and in response to treatment are nonspecific. Developing noninvasive assays to augment imaging would be helpful. Plasma extracellular vesicles (EVs) are a promising biomarker source for this. Here, we develop spectral flow cytometry techniques that demonstrate differences in bulk plasma EV phenotype between GBM patients and normal donors that could serve as the basis of a liquid biopsy. Methods: Plasma EVs were stained for EV-associated tetraspanins (CD9/CD63/CD81), markers indicating cell of origin (CD11b/CD31/CD41a/CD45), and actin/phalloidin (to exclude cell debris). EVs were analyzed using spectral flow cytometry. Multiparametric analysis using t-distributed stochastic neighbor embedding (t-SNE) and self-organizing maps on flow cytometry data (FlowSOM) was performed comparing GBM and normal donor (ND) plasma EVs. Results: Size exclusion chromatography plus spectral-based flow cytometer threshold settings enriched plasma EVs while minimizing background noise. GBM patients had increased CD9+, CD63+, CD81+, and myeloid-derived (CD11b+) EVs. Multiparametric analysis demonstrated distinct surface marker expression profiles in GBM plasma EVs compared to ND EVs. Fifteen plasma EV sub-populations differing in size and surface marker expression were identified, six enriched in GBM patients and two in normal donors. Conclusions: Multiparametric analysis demonstrates that GBM patients have a distinct nonneoplastic plasma EV phenotype compared to ND. This simple rapid analysis can be performed without purifying tumor EVs and may serve as the basis of a liquid biopsy.

Salphage: Salvage bacteriophage therapy for a chronic Enterococcus faecalis prosthetic joint infection.

Chronic prosthetic joint infections are difficult to treat without conducting revision surgery because conventional antibiotics cannot eradicate bacteria that reside in biofilms. Consequently, novel therapeutics are needed to help treat prosthetic joint infections with one being bacteriophage therapy given its innate biofilm activity. Herein a sixty-nine-year-old man with a recalcitrant Enterococcus faecalis prosthetic joint infection is discussed. The patient was successfully treated with personalized bacteriophage therapy and after two years of follow up he has not had a clinical recurrence. Overall, this case report supports that bacteriophage therapy for prosthetic joint infections has promise to reduce the morbidity that is associated with current treatments. However, more research is needed to assess whether this therapeutic is helping eradicate infections or if it is making bacteria less pathogenic. This is an important point which will need to be evaluated as this therapeutic continues to be developed for all infections.

Microglial P2Y6 calcium signaling promotes phagocytosis and shapes neuroimmune responses in epileptogenesis.

Microglial calcium signaling is rare in a baseline state but shows strong engagement during early epilepsy development. The mechanism and purpose behind microglial calcium signaling is not known. By developing an in vivo UDP fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP signals to the microglial P2Y6 receptor for broad increases in calcium signaling during epileptogenesis. UDP-P2Y6 signaling is necessary for lysosome upregulation across limbic brain regions and enhances production of pro-inflammatory cytokines-TNFα and IL-1ß. Failures in lysosome upregulation, observed in P2Y6 KO mice, can also be phenocopied by attenuating microglial calcium signaling in Calcium Extruder ("CalEx") mice. In the hippocampus, only microglia with P2Y6 expression can perform full neuronal engulfment, which substantially reduces CA3 neuron survival and impairs cognition. Our results demonstrate that calcium activity, driven by UDP-P2Y6 signaling, is a signature of phagocytic and pro-inflammatory function in microglia during epileptogenesis.

Chemogenetic manipulation of CX3CR1+ cells transiently induces hypolocomotion independent of microglia.

Chemogenetic approaches using Designer Receptors Exclusively Activated by Designer Drugs (DREADD, a family of engineered GPCRs) were recently employed in microglia. Here, we used Cx3cr1CreER/+:R26hM4Di/+ mice to express Gi-DREADD (hM4Di) on CX3CR1+ cells, comprising microglia and some peripheral immune cells, and found that activation of hM4Di on long-lived CX3CR1+ cells induced hypolocomotion. Unexpectedly, Gi-DREADD-induced hypolocomotion was preserved when microglia were depleted. Consistently, specific activation of microglial hM4Di cannot induce hypolocomotion in Tmem119CreER/+:R26hM4Di/+ mice. Flow cytometric and histological analysis showed hM4Di expression in peripheral immune cells, which may be responsible for the hypolocomotion. Nevertheless, depletion of splenic macrophages, hepatic macrophages, or CD4+ T cells did not affect Gi-DREADD-induced hypolocomotion. Our study demonstrates that rigorous data analysis and interpretation are needed when using Cx3cr1CreER/+ mouse line to manipulate microglia.

Brain resident memory T cells rapidly expand and initiate neuroinflammatory responses following CNS viral infection.

The contribution of circulating verses tissue resident memory T cells (TRMs) to clinical neuropathology is an enduring question due to a lack of mechanistic insights. The prevailing view is TRMs are protective against pathogens in the brain. However, the extent to which antigen-specific TRMs induce neuropathology upon reactivation is understudied. Using the described phenotype of TRMs, we found that brains of naïve mice harbor populations of CD69+ CD103- T cells. Notably, numbers of CD69+ CD103- TRMs rapidly increase following neurological insults of various origins. This TRM expansion precedes infiltration of virus antigen-specific CD8 T cells and is due to proliferation of T cells within the brain. We next evaluated the capacity of antigen-specific TRMs in the brain to induce significant neuroinflammation post virus clearance, including infiltration of inflammatory myeloid cells, activation of T cells in the brain, microglial activation, and significant blood brain barrier disruption. These neuroinflammatory events were induced by TRMs, as depletion of peripheral T cells or blocking T cell trafficking using FTY720 did not change the neuroinflammatory course. Depletion of all CD8 T cells, however, completely abrogated the neuroinflammatory response. Reactivation of antigen-specific TRMs in the brain also induced profound lymphopenia within the blood compartment. We have therefore determined that antigen-specific TRMs can induce significant neuroinflammation, neuropathology, and peripheral immunosuppression. The use of cognate antigen to reactivate CD8 TRMs enables us to isolate the neuropathologic effects induced by this cell type independently of other branches of immunological memory, differentiating this work from studies employing whole pathogen re-challenge. This study also demonstrates the capacity for CD8 TRMs to contribute to pathology associated with neurodegenerative disorders and long-term complications associated with viral infections. Understanding functions of brain TRMs is crucial in investigating their role in neurodegenerative disorders including MS, CNS cancers, and long-term complications associated with viral infections including COVID-19.

Systemic immune derangements are shared across various CNS pathologies and reflect novel mechanisms of immune privilege.

Background: The nervous and immune systems interact in a reciprocal manner, both under physiologic and pathologic conditions. Literature spanning various CNS pathologies including brain tumors, stroke, traumatic brain injury and de-myelinating diseases describes a number of associated systemic immunologic changes, particularly in the T-cell compartment. These immunologic changes include severe T-cell lymphopenia, lymphoid organ contraction, and T-cell sequestration within the bone marrow. Methods: We performed an in-depth systematic review of the literature and discussed pathologies that involve brain insults and systemic immune derangements. Conclusions: In this review, we propose that the same immunologic changes hereafter termed 'systemic immune derangements', are present across CNS pathologies and may represent a novel, systemic mechanism of immune privilege for the CNS. We further demonstrate that systemic immune derangements are transient when associated with isolated insults such as stroke and TBI but persist in the setting of chronic CNS insults such as brain tumors. Systemic immune derangements have vast implications for informed treatment modalities and outcomes of various neurologic pathologies.

Antigen recognition detains CD8+ T cells at the blood-brain barrier and contributes to its breakdown.

Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system (CNS) are early hallmarks of multiple sclerosis (MS). High numbers of CD8+ T cells are found in MS lesions, and antigen (Ag) presentation at the BBB has been proposed to promote CD8+ T cell entry into the CNS. Here, we show that brain endothelial cells process and cross-present Ag, leading to effector CD8+ T cell differentiation. Under physiological flow in vitro, endothelial Ag presentation prevented CD8+ T cell crawling and diapedesis resulting in brain endothelial cell apoptosis and BBB breakdown. Brain endothelial Ag presentation in vivo was limited due to Ag uptake by CNS-resident macrophages but still reduced motility of Ag-specific CD8+ T cells within CNS microvessels. MHC class I-restricted Ag presentation at the BBB during neuroinflammation thus prohibits CD8+ T cell entry into the CNS and triggers CD8+ T cell-mediated focal BBB breakdown.

Tobacco and Cannabis Use Have a Synergistic Association on Infection Risk Following Total Knee Arthroplasty.

BACKGROUND: Studies suggest an increase in the number of combined users of tobacco and cannabis. Therefore, we specifically assessed tobacco, cannabis, and combined users who underwent primary total knee arthroplasty (TKA) to determine 90-day to 2-year: (1) odds of periprosthetic joint infection; (2) odds of revision; and (3) medical complications. METHODS: We queried a national, all payer database of patients undergoing primary TKA between 2010 and 2020. Patients were stratified according to current use of tobacco products (n = 30,000), cannabis (n = 400), or a combination (n = 3,526). These were defined according to International Classification of Disease codes, Ninth and Tenth Editions. Patients were tracked from the 2 years before TKA through 2 years afterwards. A fourth group of TKA recipients who did not have tobacco nor cannabis use was used as a matching cohort. Periprosthetic joint infections (PJIs), revisions, and other medical/surgical complications from 90 days through 2 years were evaluated between these cohorts using bivariate analyses. Multivariate analyses assessed independent risk factors for PJI at 90 days through 2 years, adjusted for patient demographics and health metrics. RESULTS: Combined tobacco and cannabis use were associated with the highest rates of PJI following TKA. The odds of 90-day PJI risk among cannabis, tobacco, and combined users was 1.60, 2.14, and 3.39, respectively, as compared to the matched cohort (P < .001). Co-users had the highest and significantly increased revision odds at 2 years following TKA (odds ratio = 1.52, 95% confidence interval, 1.15 to 2.00). At 1 and 2 years following TKA, cannabis, tobacco, and co-users had higher rates of myocardial infarctions, respiratory failures, surgical site infections, and manipulations under anesthesia when compared to the matched cohort (all P < .001). CONCLUSION: Tobacco and cannabis use before primary TKA demonstrated a synergistic association on PJI risk from 90 days through 2 years. Although the harms of tobacco use are well-known, this additional knowledge about cannabis should be incorporated in the shared decision-making discussions in the pre-operative setting to best prepare for expected risks following primary TKA.

TREM2 mediates MHCII-associated CD4+ T cell response against gliomas.

Triggering receptor expressed on myeloid cells 2 (TREM2) was recently highlighted as a novel immune suppressive marker in peripheral tumors. The aim of this study was to characterize TREM2 expression in gliomas and investigate its contribution in glioma progression by using Trem2-/- mouse line. Our results showed that higher TREM2 expression was correlated with poor prognosis in glioma patients. Unexpectedly, TREM2 deficiency did not have a beneficial effect in a pre-clinical model of glioma. The increased TREM2 expression in glioma was likely due to increased myeloid cell infiltration, as evidenced by our single-cell analysis showing that almost all microglia and macrophages in gliomas were TREM2+. Furthermore, we found that deficiency of TREM2 impaired tumor-myeloid phagocytosis and MHCII presentation, and significantly reduced CD4+ T cells in tumor hemispheres. Our results revealed a previously unrecognized protective role of tumor-myeloid TREM2 in promoting MHCII-associated CD4+ T cell response against gliomas.

Tissue-resident memory T cell maintenance during antigen persistence requires both cognate antigen and interleukin-15.

Our understanding of tissue-resident memory T (TRM) cell biology has been largely developed from acute infection models in which antigen is cleared and sterilizing immunity is achieved. Less is known about TRM cells in the context of chronic antigen persistence and inflammation. We investigated factors that underlie TRM maintenance in a kidney transplantation model in which TRM cells drive rejection. In contrast to acute infection, we found that TRM cells declined markedly in the absence of cognate antigen, antigen presentation, or antigen sensing by the T cells. Depletion of graft-infiltrating dendritic cells or interruption of antigen presentation after TRM cells were established was sufficient to disrupt TRM maintenance and reduce allograft pathology. Likewise, removal of IL-15 transpresentation or of the IL-15 receptor on T cells during TRM maintenance led to a decline in TRM cells, and IL-15 receptor blockade prevented chronic rejection. Therefore, antigen and IL-15 presented by dendritic cells play nonredundant key roles in CD8 TRM cell maintenance in settings of antigen persistence and inflammation. These findings provide insights that could lead to improved treatment of chronic transplant rejection and autoimmunity.

Anti-PD-1 and Extended Half-life IL2 Synergize for Treatment of Murine Glioblastoma Independent of Host MHC Class I Expression.

Glioblastoma (GBM) is the most common malignant brain tumor in adults, responsible for approximately 225,000 deaths per year. Despite preclinical successes, most interventions have failed to extend patient survival by more than a few months. Treatment with anti-programmed cell death protein 1 (anti-PD-1) immune checkpoint blockade (ICB) monotherapy has been beneficial for malignant tumors such as melanoma and lung cancers but has yet to be effectively employed in GBM. This study aimed to determine whether supplementing anti-PD-1 ICB with engineered extended half-life IL2, a potent lymphoproliferative cytokine, could improve outcomes. This combination therapy, subsequently referred to as enhanced checkpoint blockade (ECB), delivered intraperitoneally, reliably cures approximately 50% of C57BL/6 mice bearing orthotopic GL261 gliomas and extends median survival of the treated cohort. In the CT2A model, characterized as being resistant to CBI, ECB caused a decrease in CT2A tumor volume in half of measured animals similar to what was observed in GL261-bearing mice, promoting a trending survival increase. ECB generates robust immunologic responses, features of which include secondary lymphoid organ enlargement and increased activation status of both CD4 and CD8 T cells. This immunity is durable, with long-term ECB survivors able to resist GL261 rechallenge. Through employment of depletion strategies, ECB's efficacy was shown to be independent of host MHC class I-restricted antigen presentation but reliant on CD4 T cells. These results demonstrate ECB is efficacious against the GL261 glioma model through an MHC class I-independent mechanism and supporting further investigation into IL2-supplemented ICB therapies for tumors of the central nervous system.

Assessment of Chimeric Antigen Receptor T Cell-Associated Toxicities Using an Acute Lymphoblastic Leukemia Patient-derived Xenograft Mouse Model.

Chimeric antigen receptor T (CART) cell therapy has emerged as a powerful tool for the treatment of multiple types of CD19+ malignancies, which has led to the recent FDA approval of several CD19-targeted CART (CART19) cell therapies. However, CART cell therapy is associated with a unique set of toxicities that carry their own morbidity and mortality. This includes cytokine release syndrome (CRS) and neuroinflammation (NI). The use of preclinical mouse models has been crucial in the research and development of CART technology for assessing both CART efficacy and CART toxicity. The available preclinical models to test this adoptive cellular immunotherapy include syngeneic, xenograft, transgenic, and humanized mouse models. There is no single model that seamlessly mirrors the human immune system, and each model has strengths and weaknesses. This methods paper aims to describe a patient-derived xenograft model using leukemic blasts from patients with acute lymphoblastic leukemia as a strategy to assess CART19-associated toxicities, CRS, and NI. This model has been shown to recapitulate CART19-associated toxicities as well as therapeutic efficacy as seen in the clinic.

Primary total hip arthroplasty complications and costs in liver transplant recipients: a matched analysis using a national database.

BACKGROUND: The number of liver transplant recipients (LTR) is worldwide increasing and, as the survival is improving as well, there is an increasing number of patients needing total hip arthroplasty (THA). There might be increased risks for this specific group of patients and due to their comorbidities costs might be higher too. Using a big national database outcome and cost of THA should be compared between liver transplant recipients and the general population. METHODS: The study was performed using a collection of Medicare, Medicaid, and private insurance claims. Length of stay (LOS), 30-day readmissions, complications rates up to 5 years, and 90-day total cost of care between liver transplant recipients and matched non-transplant patients should be compared. All primary THAs from 2010 to 2019 were identified. 513 patients with a liver transplant before their THA were matched to 10,759 patients without a history of solid organ transplant at a 1:20 ratio based on age, sex, Charlson Comorbidity Index, obesity, and diabetes status. RESULTS: LTR had a longer average LOS (4.2 vs. 3.4 days, p < 0.001). There was no difference in the thirty-day readmissions (5.7% vs. 4.1%, p = 0.117) and 90-day dislocation rates (2.9% vs. 2.4%, p = 0.600). Total costs in the first ninety days after THA were not different between the LTR and controls (p = 0.756). CONCLUSIONS: These findings suggest that complications and costs are no major point of concern in patients with liver transplant that are operated with THA.

Experience Using Adjuvant Bacteriophage Therapy for the Treatment of 10 Recalcitrant Periprosthetic Joint Infections: A Case Series.

Periprosthetic joint infections are a devastating complication of joint replacement surgery. One novel therapeutic that has potential to change the current treatment paradigm is bacteriophage therapy. Herein, we discuss our experiences with bacteriophage therapy for 10 recalcitrant periprosthetic joint infections and review the treatment protocols utilized to achieve successful outcomes.

Myeloid cell MHC I expression drives CD8+ T cell activation in nonalcoholic steatohepatitis.

Background & aims: Activated CD8+ T cells are elevated in Nonalcoholic steatohepatitis (NASH) and are important for driving fibrosis and inflammation. Despite this, mechanisms of CD8+ T cell activation in NASH are largely limited. Specific CD8+ T cell subsets may become activated through metabolic signals or cytokines. However, studies in NASH have not evaluated the impact of antigen presentation or the involvement of specific antigens. Therefore, we determined if activated CD8+ T cells are dependent on MHC class I expression in NASH to regulate fibrosis and inflammation. Methods: We used H2Kb and H2Db deficient (MHC I KO), Kb transgenic mice, and myeloid cell Kb deficient mice (LysM Kb KO) to investigate how MHC class I impacts CD8+ T cell function and NASH. Flow cytometry, gene expression, and histology were used to examine hepatic inflammation and fibrosis. The hepatic class I immunopeptidome was evaluated by mass spectrometry. Results: In NASH, MHC class I isoform H2Kb was upregulated in myeloid cells. MHC I KO demonstrated protective effects against NASH-induced inflammation and fibrosis. Kb mice exhibited increased fibrosis in the absence of H2Db while LysM Kb KO mice showed protection against fibrosis but not inflammation. H2Kb restricted peptides identified a unique NASH peptide Ncf2 capable of CD8+ T cell activation in vitro. The Ncf2 peptide was not detected during fibrosis resolution. Conclusion: These results suggest that activated hepatic CD8+ T cells are dependent on myeloid cell MHC class I expression in diet induced NASH to promote inflammation and fibrosis. Additionally, our studies suggest a role of NADPH oxidase in the production of Ncf2 peptide generation.