Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.

Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATPlo acetyl-CoAhi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ERrich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation.

AdipoRon reduces TGFß1-mediated collagen deposition in vitro and alleviates knee stiffness in vivo.

Arthrofibrosis, which causes joint motion restrictions, is a common complication following total knee arthroplasty (TKA). Key features associated with arthrofibrosis include myofibroblast activation, knee stiffness, and excessive scar tissue formation. We previously demonstrated that adiponectin levels are suppressed within the knee tissues of patients affected by arthrofibrosis and showed that AdipoRon, an adiponectin receptor agonist, exhibited anti-fibrotic properties in human mesenchymal stem cells. In this study, the therapeutic potential of AdipoRon was evaluated on TGFß1-mediated myofibroblast differentiation of primary human knee fibroblasts and in a mouse model of knee stiffness. Picrosirius red staining revealed that AdipoRon reduced TGFß1-induced collagen deposition in primary knee fibroblasts derived from patients undergoing primary TKA and revision TKA for arthrofibrosis. AdipoRon also reduced mRNA and protein levels of ACTA2, a key myofibroblast marker. RNA-seq analysis corroborated the anti-myofibrogenic effects of AdipoRon. In our knee stiffness mouse model, 6 weeks of knee immobilization, to induce a knee contracture, in conjunction with daily vehicle (DMSO) or AdipoRon (1, 5, and 25 mg/kg) via intraperitoneal injections were well tolerated based on animal behavior and weight measurements. Biomechanical testing demonstrated that passive extension angles (PEAs) of experimental knees were similar between vehicle and AdipoRon treatment groups in mice evaluated immediately following immobilization. Interestingly, relative to vehicle-treated mice, 5 mg/kg AdipoRon therapy improved the PEA of the experimental knees in mice that underwent 4 weeks of knee remobilization following the immobilization and therapy. Together, these studies revealed that AdipoRon may be an effective therapeutic modality for arthrofibrosis.

Comparative transcriptomic analysis of Staphylococcus epidermidis associated with periprosthetic joint infection under in vivo and in vitro conditions.

Staphylococcus epidermidis is part of the commensal microbiota of the skin and mucous membranes, though it can also act as a pathogen in certain scenarios, causing a range of infections, including periprosthetic joint infection (PJI). Transcriptomic profiling may provide insights into mechanisms by which S. epidermidis adapts while in a pathogenic compared to a commensal state. Here, a total RNA-sequencing approach was used to profile and compare the transcriptomes of 19 paired PJI-associated S. epidermidis samples from an in vivo clinical source and grown in in vitro laboratory culture. Genomic comparison of PJI-associated and publicly available commensal-state isolates were also compared. Of the 1919 total transcripts found, 145 were from differentially expressed genes (DEGs) when comparing in vivo or in vitro samples. Forty-two transcripts were upregulated and 103 downregulated in in vivo samples. Of note, metal sequestration-associated genes, specifically those related to staphylopine activity (cntA, cntK, cntL, and cntM), were upregulated in a subset of clinical in vivo compared to laboratory grown in vitro samples. About 70% of the total transcripts and almost 50% of the DEGs identified have not yet been annotated. There were no significant genomic differences between known commensal and PJI-associated S. epidermidis isolates, suggesting that differential genomics may not play a role in S. epidermidis pathogenicity. In conclusion, this study provides insights into phenotypic alterations employed by S epidermidis to adapt to infective and non-infected microenvironments, potentially informing future therapeutic targets for related infections.

Midterm outcomes of total hip arthroplasty after internal hemipelvectomy and iliofemoral arthrodesis.

BACKGROUND AND OBJECTIVES: Recent studies have reported acceptable outcomes after arthrodesis takedown and conversion to total hip arthroplasty (THA); however, there are no reports on outcomes after oncologic resection, which are inherently complex and may portend poorer outcomes. The purpose of this study was to examine the surgical and functional outcomes of patients who underwent prior hemipelvectomy for tumor resection and were later converted to THA. METHODS: All patients who had prior iliofemoral arthrodesis after oncologic resection that were later converted to THA at a single institution were examined. Charts were reviewed for demographic information, operative information, functional outcomes, and complications/reoperations. RESULTS: All three patients in this study were males who underwent internal hemipelvectomies for chondrosarcoma. Patients were converted to THA at a mean of 26 years after arthrodesis. Mean follow-up after conversion to THA was 7.4 years. During this follow-up period, two of the three patients required revision surgery. At last follow-up, the mean Harris Hip Score was 81 and the mean Mayo Hip Score was 67, and all patients were ambulatory without significant pain. CONCLUSIONS: Overall, patients who undergo iliofemoral arthrodesis after oncologic hemipelvectomy and are later converted to THA can expect to have a reasonable outcome, despite a high rate of complications and revision surgery.

Tips and Tricks to Save You During Revision Total Knee Arthroplasty.

The number of revision total knee arthroplasties (TKAs) performed annually continues to rise. This article is a summary of a symposium on revision TKAs presented at the 2023 American Association of Hip and Knee Surgeons annual meeting. It will provide an overview of the surgical tips and tricks for exposure and component removal, use of metaphyseal fixation and stems to manage bone loss and optimize fixation, constraint in TKA, as well as how to manage extensor mechanism disruptions with a synthetic mesh reconstruction. LEVEL OF EVIDENCE: V.

Total Hip Arthroplasty Following Operative Fixation of Acetabular Fracture: A Contemporary Series.

BACKGROUND: Total hip arthroplasty (THA) is the operation of choice for salvage of post-traumatic arthritis following acetabular fracture. While high failure rates have been reported for these procedures, existing literature reports mainly on historical implant designs and techniques. We aimed to describe implant survivorships, complications, radiographic results, and clinical outcomes of contemporary THA following prior open reduction internal fixation (ORIF) of an acetabular fracture. METHODS: We identified 104 patients undergoing THA following prior ORIF of an acetabular fracture from 2000 to 2015 via our institutional total joint registry. Mean age at THA was 50 years (range, 18 to 79 years), 71% were men, and mean body mass index was 27 (range, 18 to 52). All patients were implanted with uncemented acetabular components, and 89% had uncemented stems. Some hardware from prior fixation was retained in 94% of cases. Mean follow-up was 10 years (range, 2 to 21 years). RESULTS: The 10-year survivorships free of any revision and any reoperation were 98% and 97%, respectively. There were 4 revisions: 1 each for psoas tendonitis, dislocation, acetabular aseptic loosening, and periprosthetic joint infection. There were 9 complications that did not lead to reoperation: 5 dislocations, 2 periprosthetic femur fractures, 1 sciatic nerve palsy, and 1 case of symptomatic heterotopic ossification. All unrevised components appeared radiographically well-fixed. Mean Harris Hip Score improved from mean 50 preoperatively to mean 82 at 5 years (P < .001). CONCLUSIONS: In this series of contemporary THAs following prior acetabular fracture ORIF, revision-free survivorship was excellent with only a single case of acetabular aseptic loosening. These results are encouraging and suggest that contemporary implants and techniques have notably improved on historic results. LEVEL OF EVIDENCE: Therapeutic, Level IV.

New Ceramic Heads With Titanium Sleeves on Retained Femoral Components: Results of Over 500 Revision Total Hip Arthroplasties.

BACKGROUND: Ceramic heads are frequently combined with titanium sleeves in revision total hip arthroplasties (THAs), ostensibly to protect the ceramic head from existing damage to the retained trunnion. Although widely adopted, data on the performance and safety of this construct are minimal. The purpose of this study was to describe implant survivorships, radiographic results, and clinical outcomes of patients who underwent revision THA with a ceramic head and titanium sleeve on a retained femoral component. METHODS: We identified 516 revision THAs with femoral component retention (328 acetabular-only revisions and 188 bearing surface exchanges) treated with a new ceramic head and titanium sleeve between 2000 and 2020. Mean age at revision was 64 years, 56% were women, and mean body mass index was 30. The indications for revision THA were adverse local tissue reaction (25%), acetabular loosening (24%), dislocation (17%), infection (5%), and other (29%). Kaplan-Meier survivorships were analyzed, radiographs reviewed, and Harris Hip Scores evaluated. Mean follow-up was 4 years (range, 2 to 10). RESULTS: There were no reoperations or failures for ceramic head fracture, taper corrosion, or head/sleeve disengagement. The 10-year survivorship free of any re-revision was 85%. Indications for the 57 re-revisions included dislocation (33), infection (13), acetabular component loosening (7), periprosthetic fracture (2), psoas impingement (1), and sciatic nerve irritation (1). The 10-year survivorship free of any reoperation was 82%. There were an additional 14 reoperations. Radiographically, 1.9% had progressive femoral radiolucent lines, and 4.7% had progressive acetabular radiolucent lines. Mean Harris Hip Score was 81 at 2 years. CONCLUSIONS: New ceramic heads with titanium sleeves in revision THAs with retained femoral components were durable and reliable with no cases of ceramic head fracture or taper complications at mean 4-year follow-up, including those revised for adverse local tissue reaction. LEVEL OF EVIDENCE: IV.

Obesity and Primary Total Hip Arthroplasty: The Absolute versus Relative Risk of Periprosthetic Joint Infection at 15 Years.

BACKGROUND: To make an informed decision about total hip arthroplasty (THA), surgeons and patients need to understand the absolute and relative risks of periprosthetic joint infection (PJI). We sought to evaluate the long-term risk of PJI following primary THA stratified by body mass index (BMI) and PJI-related risk factors. METHODS: We identified 21,550 primary THAs performed from 2000 to 2021 at a single institution. Patients were stratified as having 0, 1, or ≥ 2 PJI risk factors (diabetes, chronic kidney disease, nonprimary osteoarthritis, immunosuppression, or active smoking) and into BMI categories. The 15-year cumulative risk of PJI was evaluated by BMI and PJI risk factors. RESULTS: For the entire cohort, the 15-year absolute risk of PJI was 2%. For patients who did not have PJI risk factors, the absolute risk of PJI at 15 years was 1% in normal weight, 2% in class III obesity, and 4% in class IV obesity. Patients who had class III and IV obesity had a 3-times and 9-times higher relative risk of PJI, respectively (P = .03, P < .001). Among patients who had ≥ 2 PJI risk factors, the absolute risk of PJI at 15 years was 2% in normal weight, 4% in class III obesity, and 18% in class IV obesity. CONCLUSIONS: Healthy patients who had class III and IV obesity had a 3-times and 9-times increased risk of PJI at 15 years relative to normal weight patients. However, the absolute risk of PJI at 15 years was 2 and 4%, respectively. Given emerging data questioning whether BMI modification decreases PJI risk, surgeons and patients must consider both a 3-times to 9-times increased relative risk of PJI and a 2 to 4% absolute risk of PJI at 15 years for healthy patients who had a BMI ≥ 40. LEVEL OF EVIDENCE: IV.

Association Between Tranexamic Acid and Decreased Periprosthetic Joint Infection Risk in Patients Undergoing Total Hip and Knee Arthroplasty: A Systematic Review and Meta-Analysis of Over 2 Million Patients.

BACKGROUND: The purpose of this study was to perform a systematic review and meta-analysis to evaluate the association between tranexamic acid (TXA) use during primary total hip arthroplasty (THA) and primary total knee arthroplasty (TKA), and the risk of developing periprosthetic joint infection (PJI) after these procedures. METHODS: A systematic review was carried out from inception to October 17, 2022. There were 6 studies that were ultimately included in the meta-analysis. The association between the development of PJI and TXA was analyzed using odds ratios (ORs) with 95% confidence intervals (CIs) and estimates of risk difference (RD). Subgroup analysis was performed to evaluate only studies reporting out to 90 days of follow-up versus more than 90 days of follow-up. RESULTS: Among 2,098,469 arthroplasties, TXA utilization was associated with an overall lower risk of PJI (OR = 0.63 [95% CI 0.42 to 0.96], P < .001) and a 0.4% lower incidence of PJI (RD = -0.0038, 95% CI [-0.005 to -0.002], P < .001). When subgrouping the studies according to length of follow-up, TXA was associated with a lower risk of PJI (OR = 0.43 [95% CI 0.35 to 0.53], P < .001) and a 1% lower incidence of PJI (RD = -0.0095 [95% CI -0.013 to -0.005], P < .001) in patients followed for more than 90 days. CONCLUSIONS: This meta-analysis demonstrates that TXA use is associated with a reduced risk of PJI, with our RD analysis identifying an approximately 0.4% reduction in PJI rates with TXA use. These findings provide even more data to support the routine use of TXA during primary THA and primary TKA.

Systemic Osteoporosis and Osteopenia Among Periprosthetic Fractures After Total Hip Arthroplasty.

BACKGROUND: Most periprosthetic fractures following total hip arthroplasty (THA) are fragility fractures that qualify patients for osteoporosis diagnoses. However, it remains unknown how many patients were diagnosed who had osteoporosis before injury or received the proper evaluation, diagnosis, and treatment after injury. METHODS: We identified 171 Vancouver B2 (109) and B3 (62) periprosthetic femur fractures treated with a modular fluted tapered stem from 2000 to 2018 at one institution. The mean patient age was 75 years (range, 35 to 94), 50% were women, and the mean BMI was 29 (range, 17 to 60). We identified patients who had osteoporosis or osteopenia diagnoses, a fracture risk assessment tool (FRAX), bone mineral density (BMD) testing, an endocrinology consult, and osteoporosis medications. Age-appropriate BMD testing was defined as no later than one year after the recommended ages of 65 (women) or 70 years (men). The mean follow-up was 11 years (range, 4 to 21). RESULTS: Falls from standing height caused 94% of fractures and thus, by definition, qualified as osteoporosis-defining events. The prevalence of osteoporosis diagnosis increased from 20% before periprosthetic fracture to 39% after (P < 0.001). The prevalence of osteopenia diagnosis increased from 13% before the fracture to 24% after (P < 0.001). The prevalence of either diagnosis increased from 24% before fracture to 44% after (P < 0.001). No patients had documented FRAX scores before fracture, and only 2% had scores after. The prevalence of BMD testing was 21% before fracture and 22% after (P = 0.88). By the end of the final follow-up, only 16% had received age-appropriate BMD testing. The proportion of patients who had endocrinology consults increased from 6% before the fracture to 25% after (P < 0.001). The proportion on bisphosphonate therapy was 19% before fracture and 25% after (P = 0.08). CONCLUSIONS: Although most periprosthetic fractures following THA are fragility fractures that qualify patients for osteoporosis diagnoses, there remain major gaps in diagnosis, screening, endocrinology follow-up, and treatment. Like non-arthroplasty fragility fractures, a systematic approach is needed after periprosthetic fractures.

Periprosthetic Hip and Knee Infection: Is an Ipsilateral Uninfected Total Joint Arthroplasty at Risk?

BACKGROUND: Periprosthetic joint infections (PJIs) of total hip arthroplasty (THA) or total knee arthroplasty (TKA) may occur in the setting of an uninfected ipsilateral prosthetic joint. However, the risk to that uninfected ipsilateral joint is unknown. We analyzed the survivorship free from PJI in at risk THAs and TKAs following treatment of an ipsilateral knee or hip PJI, respectively. METHODS: Using our institutional total joint registry, we identified 205 patients who underwent treatment for PJI (123 THAs and 83 TKAs) with an at-risk ipsilateral in situ knee or hip, respectively, between 2000 and 2019. In total, 54% of index PJIs were chronic and 46% were acute. The mean age was 70 years, 47% were female, and the mean body mass index was 32. Kaplan-Meier survivorship analyses were performed. Mean follow-up was 6 years. RESULTS: The 5-year survivorship free of PJI in an at-risk THA after an ipsilateral TKA was treated for PJI was 97%. The 5-year survivorship free of PJI in an at-risk TKA when the ipsilateral THA was treated for PJI was 99%. Three PJIs occurred (2 THAs and 1 TKA), all over 1 year from the index ipsilateral PJI treatment. One hip PJI was an acute hematogenous infection that resulted from pneumonia. The other 2 new PJIs were caused by the same organism as the index PJI and were due to a failure of source control at the index joint. CONCLUSIONS: When diagnosed with PJI in a single joint, the risk of developing PJI in an ipsilateral prosthetic joint within 5 years was low (1 to 3% risk). In the rare event of an ipsilateral infection, all occurred greater than one year from the index PJI and 2 of 3 were with the same organism when source infection control failed. LEVEL OF EVIDENCE: Prognostic Level III.

Porous Tantalum Tibial Metaphyseal Cones in Revision Total Knee Arthroplasty: Excellent 10-Year Survivorship.

BACKGROUND: Highly porous metal tibial metaphyseal cones (TMCs) are commonly utilized in revision total knee arthroplasty (TKA) to address bone loss and obtain biologic fixation. Mid-term (5 to 10 year) studies have previously demonstrated excellent survivorship and high rates of osseointegration, but longer-term studies are lacking. We aimed to assess long-term (≥ 10 year) implant survivorship, complications, and clinical and radiographic outcomes after revision TKA with TMCs. METHODS: Between 2004 and 2011, 228 revision TKAs utilizing porous tantalum TMCs with stemmed tibial components were performed at a single institution and were retrospectively reviewed. The mean age at revision was 65 years, the mean body mass index was 33, and 52% were women. Implant survivorship, complications, and clinical and radiographic outcomes were assessed. The mean follow-up was 6.3 years. RESULTS: The 10-year survivorship free of aseptic loosening leading to TMC removal was 97%, free of any TMC removal was 88%, free of any re-revision was 66%, and free of any reoperation was 58%. The most common indications for re-revision were periprosthetic joint infection, instability, and aseptic femoral component loosening. The 10-year nonoperative complication rate was 24%. The mean Knee Society scores increased from 38 preoperatively to 69 at 10 years. There were 8 knees that had evidence of partial, progressive tibial radiolucencies at 10 years. CONCLUSIONS: Porous tantalum TMCs demonstrated persistently durable longer-term survivorship with a low rate of implant removal. The rare implant removals for component loosening or instability were offset by those required for periprosthetic joint infection, which accounted for 80% of cone removals. Porous tantalum TMCs provide an extremely reliable tool to address tibial bone loss and achieve durable long-term fixation in revision TKA. LEVEL OF EVIDENCE: IV.

The Chitranjan S. Ranawat Award: Manipulation Under Anesthesia to Treat Postoperative Stiffness After Total Knee Arthroplasty: A Multicenter Randomized Clinical Trial.

BACKGROUND: Manipulation under anesthesia (MUA) occurs in 4% of patients after total knee arthroplasty (TKA). Anti-inflammatory medications may target arthrofibrosis pathogenesis, but the data are limited. This multicenter randomized clinical trial investigated the effect of adjuvant anti-inflammatory medications with MUA and physical therapy on range of motion (ROM) and outcomes. METHODS: There were 124 patients (124 TKAs) who developed stiffness after primary TKA for osteoarthritis enrolled across 15 institutions. All received MUA when ROM was < 90° at 4 to 12 weeks postoperatively. Randomization proceeded via a permuted block design. Controls received MUA and physical therapy, while the treatment group also received one dose of pre-MUA intravenous dexamethasone (8 mg) and 14 days of oral celecoxib (200 mg). The ROM and clinical outcomes were assessed at 6 weeks and 1 year. This trial was registered with ClinicalTrials.gov. RESULTS: The ROM significantly improved a mean of 46° from a pre-MUA ROM of 72 to 118° immediately after MUA (P < .001). The ROM was similar between the treatment and control groups at 6 weeks following MUA (101 versus 99°, respectively; P = .35) and at one year following MUA (108 versus 108°, respectively; P = .98). Clinical outcomes were similar at both end points. CONCLUSIONS: In this multicenter randomized clinical trial, the addition of intravenous dexamethasone and a short course of oral celecoxib after MUA did not improve ROM or outcomes. However, MUA provided a mean ROM improvement of 46° immediately, 28° at 6 weeks, and 37° at 1 year. Further investigation in regards to dosing, duration, and route of administration of anti-inflammatory medications remains warranted. LEVEL OF EVIDENCE: Level 1, RCT.

Prevalence of AAV2.5 neutralizing antibodies in synovial fluid and serum of patients with osteoarthritis.

Osteoarthritis (OA) is a leading cause of disability with no cure and only supportive therapy. Adeno-associated virus (AAV) serotype 2.5 is being used in a Phase I clinical trial to deliver the interleukin-1 receptor antagonist into knee joints with OA. Neutralizing antibodies (Nab) directed against AAV2.5, if present, could inhibit gene transfer. Here, we report the prevalence of AAV2.5 Nab in the sera and synovial fluids of patients with OA. Nab titers were measured by their ability to inhibit in vitro transduction by AAV2.5 encoding GFP. Of 44 synovial fluids from patients with mid-stage and advanced OA, 43% had undetectable Nab; 25% had low titers (<1:100), 16% had medium titers (1:100-1:1000) and 16% had high titers (>1:1000) of Nab. Titers of AAV2.5 Nabs correlated with those of AAV2, but not with those of AAV5. Serum titers of AAV2.5 Nab correlated positively with titers in synovial fluid, and were never less than the matched synovial fluid titers. These findings suggest that high titers of Nab against AAV2.5 are uncommon in the synovial fluids of patients with OA, and individuals with high synovial fluid Nab titers can be identified by measuring titers in the serum.

Phage Therapy as a Novel Therapeutic for the Treatment of Bone and Joint Infections.

Solutions for bone and joint infection (BJI) are needed where conventional treatments are inadequate. Bacteriophages (phages) are naturally occurring viruses that infect bacteria and have been harnessed for refractory bone and joint infections (BJI) in many case reports. Here we examine the safety and efficacy of English-language published cases of BJI since 2010 with phage therapy. From 33 reported cases of BJI treated with phage therapy, 29 (87%) achieved microbiological or clinical success, 2 (5.9%) relapsed with the same organisms, and 2 (5.9%) with a different organism. Of these 4 relapses, all but 1 had eventual clinical resolution with additional surgery or phage treatments. Eight out of 33 cases (24%) reported mild, transient adverse events with no serious events reported. Further work is needed to understand the true efficacy of phages and the role of phages in BJI. Opportunities lay ahead for thoughtfully designed clinical trials adapted to individualized therapies.

Targeted Versus Shotgun Metagenomic Sequencing-based Detection of Microorganisms in Sonicate Fluid for Periprosthetic Joint Infection Diagnosis.

BACKGROUND: Next-generation sequencing (NGS) is increasingly used for periprosthetic joint infection (PJI) diagnosis, but its clinical utility is poorly defined. Shotgun metagenomic sequencing (sNGS) has been reported to identify PJI pathogens undetected by culture in sonicate fluid. However, sNGS is complex and costly. Here, 16S ribosomal RNA (rRNA) gene-based targeted metagenomic sequencing (tNGS) was compared to sNGS of sonicate fluid for microbial detection and identification in patients with total hip arthroplasty (THA) and total knee arthroplasty (TKA) failure. METHODS: A convenience sample of sonicate fluids derived from patients who had undergone THA or TKA removal, enriched with culture negative PJI cases, was tested. Samples had been previously tested by sNGS. For tNGS, samples were extracted, amplified by polymerase chain reaction targeting the V1 to V3 regions of the 16S rRNA gene, and sequenced on an Illumina MiSeq. RESULTS: A total of 395 sonicate fluids, including 208 from subjects with PJI, were studied. Compared with sonicate fluid culture, tNGS had higher positive percent agreement (72.1 vs 52.9%, P < .001), detecting potential pathogens in 48.0% of culture-negative PJIs. There was no difference between the positive percent agreement of tNGS (72.1%) and sNGS (73.1%, P = .83). CONCLUSIONS: 16S rRNA gene-based tNGS is a potential diagnostic tool for PJI pathogen identification in sonicate fluid from failed THAs and TKAs in culture-negative cases, with similar performance characteristics to sNGS.

The epigenetic regulator BRD4 is required for myofibroblast differentiation of knee fibroblasts.

Arthrofibrosis, which is characterized by excessive scar tissue and limited motion, can complicate the daily functioning of patients after total knee arthroplasty (TKA). Molecular hallmarks of arthrofibrosis include pathologic accumulation of myofibroblasts and disproportionate collagen deposition. Epigenetic mechanisms, including posttranslation modification of histones, control gene expression and may regulate fibrotic events. This study assessed the role of the bromodomain and extra-terminal (BET) proteins on myofibroblast differentiation. This group of epigenetic regulators recognize acetylated lysines and are targeted by a class of drugs known as BET inhibitors. RNA-seq analysis revealed robust mRNA expression of three BET members (BRD2, BRD3, and BRD4) while the fourth member (BRDT) is not expressed in primary TKA knee outgrowth fibroblasts. RT-qPCR and western blot analyses revealed that BET inhibition with the small molecule JQ1 impairs TGFß1-induced expression of ACTA2, a key myofibroblast marker, in primary outgrowth knee fibroblasts. Similarly, JQ1 administration also reduced COL3A1 mRNA levels and collagen deposition as monitored by picrosirius red staining. Interestingly, the inhibitory effects of JQ1 on ACTA2 mRNA and protein expression, as well as COL3A1 expression and collagen deposition, were paralleled by siRNA-mediated depletion of BRD4. Together, these data reveal that BRD4-mediated epigenetic events support TGFß1-mediated myofibroblast differentiation and collagen deposition as seen in arthrofibrosis. To our knowledge, these are the first studies that assess epigenetic regulators and their downstream events in the context of arthrofibrosis. Future studies may reveal clinical utility for drugs that target epigenetic pathways, specifically BET proteins, in the prevention and treatment of arthrofibrosis.

Current Practice Trends in Primary Hip and Knee Arthroplasties Among Members of the American Association of Hip and Knee Surgeons.

During the 2022 Annual Meeting of the American Association of Hip and Knee Surgeons, an audience response poll was conducted to establish current practice patterns among American Association of Hip and Knee Surgeons members. There were 49 multiple-choice questions pertaining to routine practices surrounding primary total hip arthroplasties and primary total knee arthroplasties posed to over 4,000 in-person and 400 virtual meeting attendees. Responses were submitted via a mobile application (ie, app). Poll responses were collated and results from the 2022 poll were compared to poll results from 2009, 2018, and 2020.

Femoral Head Length Impact on Outcomes Following Total Hip Arthroplasty in 36 Millimeter Cobalt Chrome-on-Highly Crosslinked Polyethylene Articulations.

BACKGROUND: Despite concerns for corrosion, dislocation, and periprosthetic femur fractures, minimal literature has investigated the effect of adjusting femoral head length on outcomes after primary total hip arthroplasty (THA). Therefore, we aimed to investigate the effect of femoral head length on the risk of any revision and reoperation following cobalt chromium (CoCr)-on-highly crosslinked polyethylene (HXLPE) THAs. METHODS: Between 2004 and 2018, we identified 1,187 primary THAs with CoCr-on-HXLPE articulations using our institutional total joint registry. The mean age at THA was 71 years (range, 19-97), 40% were women, and mean body mass index was 30 (range, 10-68). All THAs using 36 mm diameter femoral heads were included. Neutral (0 mm), positive, or negative femoral head lengths were used in 42, 31, and 27% of the THAs, respectively. Kaplan-Meier survivorship was assessed. The mean follow-up was 7 years (range, 2-16). RESULTS: The 10-year survivorships free of any revision or reoperation were 94 and 92%, respectively. A total of 47 revisions were performed, including periprosthetic femur fracture (17), periprosthetic joint infection (8), dislocation (7), aseptic loosening of either component (6), corrosion (4), and other (5). Nonrevision reoperations included wound revision (11), open reduction and internal fixation of periprosthetic femur fracture (4), and abductor repair (2). Multivariable analyses found no significant associations between femoral head length and revision or reoperation. CONCLUSION: Altering femoral head lengths in 36 mm CoCr-on-HXLPE THAs did not affect outcomes. Surgeons should select femoral head lengths that optimize hip stability and center of rotation. LEVEL OF EVIDENCE: III.

Primary Total Hip Arthroplasty in Dialysis-Dependent Patients: 35% Mortality at 5 years.

BACKGROUND: Limited knowledge exists on contemporary results of primary total hip arthroplasty (THA) in dialysis-dependent patients. We sought to analyze the mortality rates and cumulative incidences of any revision or reoperation in dialysis-dependent patients undergoing primary THAs. METHODS: We identified 24 dialysis-dependent patients who underwent 28 primary THAs between 2000 and 2019 using our institutional total joint registry. Mean age was 57 years (range, 32 to 86), with 43% being women and mean body mass index was 31 (range, 20 to 50). The leading cause for dialysis was diabetic nephropathy (18%). The mean preoperative creatinine and glomerular filtration rate were 6 mg/dL and 13 mL/min, respectively. Kaplan-Meier survivorship methods and a competing risk analysis using death as the competing risk were performed. The mean follow-up was 7 years (range, 2 to 15). RESULTS: The 5-year survivorship free from death was 65%. The 5-year cumulative incidence of any revision was 8%. There were a total of 3 revisions as follows: 2 for aseptic loosening of the femoral component and one for a Vancouver B2 fracture. The 5-year cumulative incidence of any reoperation was 19%. There were 3 additional reoperations, and all were irrigation and debridement. Postoperative creatinine and glomerular filtration rate were 6 mg/dL and 15 mL/min, respectively. At a mean of 2 years after THA, 25% successfully received a renal transplant. CONCLUSIONS: Dialysis-dependent patients undergoing primary THAs had high 5-year mortality (35%) but an acceptably low cumulative incidence of any revision. While renal metrics remained consistent after THA, only one in 4 patients underwent successful renal transplant. LEVEL OF EVIDENCE: IV.