Citations

Introduction Infection following extensor mechanism reconstruction with Marlex mesh is a devastating and limb threatening complication. The purpose of this study was to evaluate whether vancomycin-loaded mesh reduced staphylococcal infection in a murine extensor mechanism reconstruction model with Marlex mesh. Methods Mouse-sized, eight-layer Marlex mesh constructs were fabricated to simulate clinical reconstruction and soaked in a vancomycin solution (50 mg/mL) for in vitro and in vivo testing. Three methicillin-resistant clinical isolates from human periprosthetic knee infections were evaluated: Staphylococcus aureus, Staphylococcus epidermidis , and Staphylococcus lugdunensis. In vitro testing assessed vancomycin loading, mechanical properties, antibacterial activity, and early biofilm inhibition. For in vivo experiments, plain or vancomycin-loaded Marlex meshes were implanted into the murine extensor mechanism and inoculated intraoperatively (5 per group per isolate). Meshes and surrounding tissues were harvested on postoperative day 9 for quantitative culture. Results For all three isolates, vancomycin-loaded Marlex mesh exhibited sustained antibacterial activity for up to 3 days in vitro based on zone of inhibition testing (days 1–3, p < 0.0001 for each isolate). In vitro testing of biofilm inhibition demonstrated significant reduction in biofilm-associated colony-forming units at 6 hours after inoculation and remained low thereafter (p<0.05 for each isolate). In vivo , vancomycin-loaded Marlex mesh reduced bacterial burden on meshes and surrounding tissues by > 3 log₁₀ compared with plain mesh for all three isolates (p<0.01 for both mesh and tissue for all isolates). Conclusion Vancomycin-loaded Marlex mesh provided sustained local antibacterial activity and significantly reduced staphylococcal infection without compromising mechanical properties in a murine extensor mechanism reconstruction model. This approach may represent a promising adjunct to reduce infection risk in extensor mechanism reconstructions with Marlex mesh after total knee arthroplasty.

Background: Infection following extensor mechanism reconstruction (EMR) with Marlex mesh (C.R. Bard) is devastating and limb-threatening. The purpose of this study was to evaluate whether vancomycin-loaded mesh reduces staphylococcal infection in a murine EMR model. Methods: Mouse-sized, 8-layer mesh constructs were fabricated to simulate clinical reconstruction and soaked in a vancomycin solution (50 mg/mL) for in vitro and in vivo testing. Three methicillin-resistant clinical isolates from human periprosthetic Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus lugdunensis knee infections were evaluated. In vitro testing assessed vancomycin loading capacity, mechanical properties, antibacterial activity, and inhibition of biofilm formation. For in vivo experiments, plain or vancomycin-loaded mesh was implanted into C57BL/6 mouse extensor mechanisms, which were intraoperatively contaminated with 1 of the 3 study isolates (5 per group). Mesh and surrounding tissue were harvested for quantitative culture on postoperative day 9. Results: For all 3 isolates, vancomycin-loaded mesh produced zones of inhibition and exhibited antibacterial activity through at least 3 days in vitro (p < 0.0001). Mechanical testing revealed that loading mesh with vancomycin did not negatively impact tensile strength, hysteresis, or suture pull-through properties. In vitro testing of inhibition of biofilm formation demonstrated reduced colony-forming units 6 hours after inoculation, which remained low throughout the 9-day experimental period (p < 0.05 for all isolates). In vivo, vancomycin-loaded mesh reduced bacterial burden on mesh and in surrounding tissue by >3 log 10 compared with plain mesh for all 3 isolates (p < 0.01 for both mesh and tissue). Conclusions: Vancomycin-loaded mesh provided in vitro antibacterial activity without compromising mesh mechanical properties and reduced staphylococcal infection in a murine EMR model. Further work is needed to evaluate translational potential and safety before clinical application. Clinical Relevance: Mesh-associated infection after EMR is devastating and difficult to treat. These preclinical findings suggest that local vancomycin delivery may serve as an adjunct to systemic prophylaxis, warranting further study before clinical use.

Aims Two-stage exchange arthroplasty with an antibiotic-eluting cement spacer remains the predominant strategy in the USA for managing chronic periprosthetic joint infection (PJI) following total hip arthroplasty (THA). The aim of this study was to evaluate a commercially available, partially intraoperatively fabricated articulating high-dose antibiotic cement spacer, focusing on survival, complications, and patient-reported outcomes. Methods A total of 298 patients (302 THAs) underwent two-stage exchange arthroplasty for PJI using a specific articulating antibiotic spacer between August 2005 and May 2022. Patients with a previous failed two-stage exchange were excluded, although 121 THAs (302, 40%) had undergone previous PJI-related procedures. The mean age of the patients was 65 years (SD 11), the mean BMI was 32 kg/m 2 (SD 7), and 116 (38%) were female. Most patients were classified as McPherson host B (158; 52%) and limb grade 2 (165; 55%), and 265 (88%) met the 2011 Musculoskeletal Infection Society criteria. The mean follow-up was six years (2 to 16). Results At five years after reimplantation, survival free of reinfection, aseptic rerevision, any rerevision, or any reoperation were 89% (95% CI 85.2 to 93.1), 93% (95% CI 89.3 to 96.1), 86% (95% CI 81.3 to 90.3), and 80% (95% CI 74.7 to 84.9), respectively. Dislocation accounted for most aseptic rerevisions (15/20). McPherson host C (HR 3.7 (95% CI 1.4 to 9.6); p = 0.007) and limb grade 3 (HR 3.3 (95% CI 1.0 to 11.1); p = 0.049) were significantly associated with an increased risk of reinfection. The mean Harris Hip Score at the latest follow-up was 76 (29 to 100). A total of 17 patients underwent revision or removal of a spacer for concerns about persistent infection and two for dislocation of the spacer. Eight patients underwent a non-rerevision reoperation during the spacer interval for wound drainage (n = 5), dislocation of the spacer (n = 2), and perispacer fracture (n = 1). A total of 26 spacer-related complications were treated nonoperatively (15 perispacer fractures, 11 dislocations). Dislocation of the spacer was strongly associated with dislocation after reimplantation (HR 6.2 (95% CI 2.3 to 16.9); p < 0.001). Conclusion This commercially available, partially intraoperatively fabricated articulating spacer showed excellent reinfection-free five-year survival (89%). Spacer-related fracture and dislocation each occurred in 5% of patients. Dislocation of the spacer significantly increased the risk of dislocation following reimplantation, supporting the use of higher-stability bearings in these high-risk patients. Cite this article: Bone Joint J 2026;108-B(9):1104–1112.

Aims Extensor mechanism disruption is a major complication following total knee arthroplasty, with treatment often consisting of extensor mechanism reconstruction utilizing monofilament polypropylene mesh (Marlex mesh, C. R. Bard, Inc). Infection following this procedure is devastating, often resulting in revision surgery and mesh removal, with permanent limb dysfunction. This study evaluated the in vitro ability of vancomycin-loaded polypropylene mesh to inhibit growth of isolates of three Staphylococcus species from patients with periprosthetic joint infection. Methods The mesh was prepared in two configurations – single-layer and eight-layer – and soaked for ten minutes in either sterile water (control) or vancomycin solution (50 mg/ml), after which the mesh was placed on tryptic soy agar plates inoculated with staphylococci and incubated at 37°C for 18 to 24 hours. Zones of inhibition were measured daily over seven days, with mesh transferred to freshly inoculated plates daily. Testing was performed in triplicate, with experiments repeated three times for each bacterial isolate. A total of 30 clinical isolates were tested (five methicillin-susceptible Staphylococcus epidermidis , five methicillin-resistant S. epidermidis , ten methicillin-resistant Staphylococcus aureus , and ten Staphylococcus lugdunensis ). Results Across all species, the eight-layer vancomycin-loaded mesh produced statistically significantly larger median zones of inhibition than the single-layer mesh. The antibacterial activity of the eight-layer mesh persisted through to day 7, while the single-layer mesh showed reduced activity by days 4 to 5. Conclusion Compared with single-layer vancomycin-loaded mesh, multilayer vancomycin-loaded mesh, which mimics clinical application, provides enhanced and sustained antibacterial activity in vitro. Cite this article: Bone Joint Res 2026;15(8):998–1004.

Abstract Background There is limited data on immune checkpoint inhibitor (ICI) use in patients with non-small cell lung cancer (NSCLC) and known pericardial effusions. Methods This international multi-center observational retrospective study included patients with advanced NSCLC with or without pericardial effusions receiving ICIs. Immune-related adverse events (irAEs) were graded per CTCAE v5.0. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Cox proportional hazards multivariable models assessed the association between survival outcomes and clinicopathologic variables, and an inverse probability of treatment weighting (IPTW) model compared outcomes between the two groups. Results A total of 1248 patients with advanced NSCLC treated with ICIs across 13 institutions were included. Of these, 85 patients (6.8%) had pre-existing pericardial effusions. Compared to controls, patients with pericardial effusions were younger (median age 63 vs 67 years, P = .007), diagnosed more frequently with PD-L1 positive tumors (96% vs 76%, P &lt; .001), and had a higher median number of baseline metastatic sites (3 vs 1, P &lt; .001). IrAEs were similar between both groups (42% vs 38%), and no cardiac irAEs occurred in patients with pericardial effusions. PFS (median 5.6 vs 4.6 months, P = .3) and OS (median 10.2 vs 14.7 months, P = .50) were not statistically different between patients with pericardial effusions and the controls, respectively. In both multivariable and IPTW models, pericardial effusions were not associated with PFS or OS. Conclusions Among patients with NSCLC and pre-existing pericardial effusions, ICIs demonstrate meaningful clinical benefit similar to those without effusions, with no new cardiac or severe toxicities.

Abstract Early-phase clinical trials of Bruton’s tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate clashes with the adenine ring of ATP and the adenine-mimetic moiety of BTK inhibitors and degraders. Combining BTK degraders with venetoclax mitigated the expansion of BTK A428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies.

Abstract Background: The limited efficacy of oncolytic virotherapy (OV) in gastrointestinal malignancies has been attributed to an immunologically inert tumor microenvironment. While cisplatin is widely used as a cytotoxic agent, its immunomodulatory effects remain incompletely defined. We hypothesized that cisplatin may reprogram the tumor immune landscape to enable more effective OV-mediated anti-tumor responses. Methods: We evaluated the effects of cisplatin in combination with two distinct oncolytic platforms, vesicular stomatitis virus (VSV) and adenovirus (AdV), across both in vitro and in vivo colorectal cancer models. In vivo efficacy was assessed using MC38 subcutaneous and peritoneal metastatic models, with analysis of tumor growth, survival, and toxicity. Immune profiling was performed using single-cell RNA sequencing (scRNA-seq), flow cytometry, and bulk RNA sequencing to interrogate changes in CD8+ T cell states and functional programs. Guided by these preclinical findings, a clinical trial combining XELOX, PD-1 blockade, and OV therapy was initiated (ChiCTR2500107607). Results: Cisplatin markedly enhanced OV-mediated anti-tumor efficacy across models, resulting in sustained tumor control and improved survival in both subcutaneous and peritoneal disease settings. This effect was conserved across viral platforms, indicating a virus-agnostic interaction. Mechanistically, cisplatin induced a robust interferon (IFN)–dominant transcriptional program, characterized by upregulation of interferon-stimulated genes, including IRF7, IRF9, and ISG15. Single-cell analysis revealed that combination therapy reshaped the CD8+ T cell compartment, promoting the expansion of a population with transcriptional and functional features of central memory T cells (Tcm), alongside reduced exhaustion signatures. These changes were accompanied by enhanced cytokine signaling pathways associated with T cell maintenance and function, including IL-2, IL-7, and IL-15. In vitro, the combination of cisplatin and OV increased tumor cell death and interferon-γ production, supporting a model in which cytotoxic and immunostimulatory effects are mechanistically linked. A phase I clinical trial has been initiated. In gastric cancer, patients with retroperitoneal metastases are being treated with OV in combination with PD-1 blockade (ongoing). In colorectal cancer, the strategy is being evaluated in the neoadjuvant setting with an rectal preservation approach. Conclusions: Our findings identify a previously unrecognized role for cisplatin in priming an interferon-driven immune program that promotes Tcm differentiation and function, thereby enabling durable responses to oncolytic virotherapy. This work provides a mechanistic rationale for leveraging chemotherapy-induced immune reprogramming to enhance viro-immunotherapy and supports the clinical translation of this strategy in gastrointestinal malignancies. Citation Format: Joseph Brandon. Parker, Zhongyi Dong, Tao Liu, Qisen Guo, Haoyu Zhang, Bo Ni, Long Bai, Yiwen Chen, Jiasheng Zong, Xiang Xia, Jiaojiao Zheng, Hoang Tran Pham, Aya Elalfy, Demarcus Ingram, Ahmed Abdel-Hakeem, Muhammad Ali, Shannon Hartzell, Zizhen Zhang, Vivienne Yang. Cisplatin primes an interferon-driven CD8+ central memory T cell program to enable oncolytic virotherapy in gastrointestinal cancer malignancies [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B024.

We previously reported 5-year results of 57 patients with major acetabular defects (Paprosky 2B through 3B) who underwent full (31) or half (26) cup-cage reconstructions. This study provides an update with 8.8-year mean follow-up. The 10-year cumulative incidence of and survivorship free from revision, reoperation, and complications were estimated. The 10-year cumulative incidence of revision was 14% for full and 12% for half constructs. The incidence of revision for aseptic loosening was 4.3% and 4.6%, respectively. The 10-year survivorship free from aseptic loosening for patients with pelvic discontinuity was 88.9% (95% confidence interval [CI], 70.6% to 100%) and 85.7% (95% CI, 61.8% to 100%), respectively; no patient without pelvic discontinuity required revision for aseptic loosening. The 10-year cumulative incidence of complications was 42% for all patients, including a 15% incidence of dislocation. Thus, both full and half cup-cage constructs provided durable fixation for complex acetabular bone loss at 10 years, although dislocation remains a concern. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Importance Ischemic heart disease (IHD), the leading cause of death in the US, is predominantly due to modifiable risk factors. Estimates of IHD mortality attributable to risk factors provide evidence for health policy decision-making. Objective To estimate the burden of IHD death attributable to risk factors in the US from 1990-2023. Design, Setting, and Participants The Global Burden of Disease Study 2023 (GBD 2023) used vital records and a broad set of epidemiologic data to estimate IHD death rates, risk factor exposure, and relative risk curves for risk-outcome pairs for 1990-2023 for the general population. Data analysis was performed from October 2024 to December 2025. Exposure Twelve metabolic, behavioral, and environmental risk factors. Main Outcomes and Measures The primary outcomes were IHD death rates per 100 000 persons, counts, and attributable risks from 1990-2023 by age, sex, and US state. Estimates include 95% uncertainty intervals (UI). IHD death rates were estimated using ensemble modeling methods. Risk exposures were estimated using bayesian meta-regression methods. Relative risks were estimated following the Burden of Proof framework. Results In 2023, there were 473 000 IHD deaths (95% UI, 414 000-510 000) in the US, a decrease of 58.7% (95% UI, 56.8%-61.0%) in age-standardized rate since 1990. Between 2010 and 2023, there was a 19.0% decrease (95% UI, 15.0%-22.9%) for males and a 24.5% decrease (95% UI, 20.3%-29.7%) for females in IHD death rates. High systolic blood pressure (SBP), dietary risks, and high low-density lipoprotein cholesterol (LDL-C) were the leading risk factors for IHD deaths in 2023, accounting for 47.2% (95% UI, 36.4%-57.0%), 38.6% (95% UI, 17.2%-56.8%), and 28.5% (95% UI, 19.3%-39.6%) of IHD deaths, respectively. Increased exposure to several risk factors substantially increased their attributable burden for IHD deaths in 2023, with high fasting plasma glucose (FPG) increasing 38.8% (95% UI, 11.5%-81.1%) and high body mass index (BMI) increasing 54.5% (95% UI, 41.8%-66.3%) since 1990. Smoking and particulate matter pollution had the greatest decrease in attributable IHD mortality since 1990, at 33.3% (95% UI, 23.6%-41.7%) and 74.9% (95% UI, 46.7%-88.8%), respectively. Conclusion and Relevance Per the results of this systematic analysis of GBD 2023, a total of 88.7% (95% UI, 83.4%-92.5%) of IHD deaths were attributable to modifiable risk factors in the US in 2023, with high SBP, dietary risks, and high LDL-C being the greatest contributors. High BMI and high FPG showed the largest attribution increases, while exposure to other risks did not increase significantly for the population.

Background: Greater trochanteric (GT) fractures after total hip arthroplasty (THA) are typically managed nonoperatively. However, outcome data for patient counseling remain limited. We evaluated the nonoperative results, focusing on fracture union rates and the presence of persistent limp in relation with fracture location, displacement magnitude, and direction. Methods: We retrospectively reviewed 82 postoperative GT fractures not associated with trochanteric osteolysis following primary THA performed between 1984 and 2020. The mean follow-up was 9 years. Fracture location was classified relative to the contralateral lesser trochanter as tip, waist, or base. Initial displacement, migration, final displacement, and bony union were assessed radiographically. Clinical outcomes included the presence of a persistent limp and Harris Hip Score. Multivariable analyses were performed to identify factors associated with nonunion and limp. Results: Fractures were classified as tip (n = 32), waist (n = 29), or base (n = 21). The mean initial displacement was 8.9 mm, with 43% displaced >10 mm. Initial displacement was significantly lower in base fractures (4.8 mm) compared with tip (10.1 mm) or waist (10.8 mm) fractures (p < 0.05). The mean final displacement was 14.6 mm. 45% of fractures achieved complete bony union, and 38% of patients demonstrated a persistent limp. In multivariable analysis, greater final displacement (>12 mm), and tip and waist fractures were independently associated with nonunion. Posterior fracture displacement was significantly associated with persistent limp. Conclusions: Outcomes following nonoperative management of GT fractures after THA depend on fracture morphology and displacement characteristics. Tip and waist fractures and fractures with final displacement >12 mm have a higher risk of nonunion, whereas posterior and superior displacement is associated with persistent limp. Greater than 20 mm of displacement is associated with both limp and nonunion. These findings may assist surgeons in counseling patients and in identifying fracture patterns at higher risk for adverse outcomes of nonoperative management. Level of Evidence: Level III (Prognostic Study). See Instructions for Authors for a complete description of levels of evidence.