Citations

Purpose To evaluate the clinical outcomes of patients with increased posterior tibial slope (PTS ≥12°) undergoing primary anterior cruciate ligament reconstruction (ACLR) with concomitant lateral extra‐articular tenodesis (LET) and to determine whether the addition of LET mitigates the elevated risk of graft failure associated with increased tibial slope. Methods This single‐center retrospective cohort study included patients ≥16 years who underwent primary ACLR with LET between 2013 and 2022 with a minimum 2‐year follow‐up. Patients were stratified by PTS ≥12° versus <12° and required preoperative lateral radiographs for slope measurement and high‐risk features (pivot shift ≥2, Beighton ≥4, or return to pivoting sports). Outcomes included graft failure, residual pivot shift, complications, and patient‐reported outcomes (International Knee Documentation Committee and Lysholm). Achievement of minimal clinically important difference was assessed. Multivariable logistic regression and Cox proportional hazards analysis were performed to identify independent predictors of graft failure. Results A total of 289 patients (mean follow‐up, 38 months) were included: 45 with PTS ≥12° (13.0° ± 1.2°) and 244 with PTS <12° (8.1° ± 1.5°). Graft failure occurred in 24% versus 18%, respectively ( P = .411). On multivariable Cox proportional hazards analysis, no independent predictor of graft failure was identified, including PTS (hazard ratio, 1.07 per degree; 95% confidence interval, 0.95‐1.19; P = .260). Complications and contralateral anterior cruciate ligament injury rates were similar between groups. On sex‐disaggregated analysis, similar patterns were observed in both male and female cohorts, with no significant between‐group differences in graft failure, retear, or complication rates by tibial slope. Patient‐reported outcomes were comparable at all time points. At final follow‐up, minimal clinically important difference achievement for International Knee Documentation Committee and Lysholm was 98% and 100%, respectively, with no between‐group differences. Conclusions In high‐risk patients with a PTS of ≥12°, primary ACLR with LET led to similar clinical results as patients with a PTS of 12 or less. A PTS of ≥12° may be considered an indication for the addition of an LET during primary ACLR. Level of Evidence Level III, retrospective comparative case series.

Abstract Orthoebolaviruses, including Ebola virus (EBOV) and Bundibugyo virus (BDBV), cause sporadic outbreaks and devastating hemorrhagic infections in humans. A significant challenge that impedes the study of filoviruses is that the infectious virus can only be handled in biosafety level 4 (BSL4) facilities due to their extreme virulence. Life cycle modeling systems that use minigenomes and transcription/replication-competent virus-like particles (trVLPs) are powerful tools for studying these virus’ biology and to explore antiviral therapies under BSL2 conditions. To date, these powerful tools have only been utilized in vitro in cell culture systems. In this work, we demonstrate the use of EBOV trVLPs in vivo. We report the fine specificity of first infection events in a model of EBOV injection in the skin. Cre recombinase expressing monocistronic EBOV trVLPs were packaged and used to inject Cre reporter mice intradermally (ID). Initial infection events were monitored in living animals by luciferase imaging and then by flow cytometry to track cell-specific expression of Cre-activated GFP. By this approach, EBOV trVLPs were shown to directly infect T cells, monocytes, dendritic cells (DCs) with notably high first infections of skin-resident Langerhans cells (LCs) in the skin barrier and its draining lymph node. EBOV trVLPs were next tested as an in vivo tool to assess antiviral therapies by testing the ability of an EBOV vaccine to reduce trVLP luciferase levels after infection in the skin. This work demonstrates first in vivo use of EBOV trVLPs and provides proof of concept for their use as an in vivo BSL2 model to more rapidly develop antiviral agents and vaccines.

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.

Abstract BCMA-directed CAR T-cell and T-cell engager (TCE) therapies produce high response rates in relapsed multiple myeloma, yet most patients progress. Prior work identified TNFRSF17 alterations mediating antigen escape in up to 43% of TCE progressions. To evaluate the generalizability of these findings and examine antigen-loss-independent resistance, we performed whole-exome sequencing on 32 paired pre- and post-treatment progression bone marrow samples from 15 patients (5 CAR T, 10 TCE); two patients received both agents. TNFRSF17 alterations were infrequent and restricted to TCE recipients (one concurrent frameshift and missense mutation; two heterozygous copy-number losses); no biallelic loss or CAR T-associated events were observed. In contrast, deleterious/loss-of-function variants in NF-κB, PI3K-AKT-mTOR, and MAPK/ERK pathways were universal in pre-treatment samples and acquired or clonally enriched in 80% of patients at progression. Acquired events included loss-of-function alterations in CYLD , activating mutations in KRAS , NRAS and BRAF , and acquired TP53 mutations. In this series, antigen escape via TNFRSF17 /BCMA alteration was uncommon. Instead, pre-existing, acquired and clonally enriched pathogenic variants in NF-κB, PI3K-AKT-mTOR and MAPK cascades, together with TP53 mutation, emerged as a frequent finding. These alterations suggest that deregulation of BCMA-downstream survival signaling, enhanced proliferative fitness, and elevation of apoptotic threshold constitute antigen-loss-independent mechanisms of resistance.

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.

Purpose To compare lower extremity soft tissue injury and revision surgery rates for patients with anorexia nervosa (AN) and bulimia nervosa (BN) compared with matched controls. Methods This retrospective cohort study used a deidentified claims database. Patients were included if they carried an International Classification of Diseases code for AN or BN. Respective matched cohorts for AN and BN were created using propensity score matching. Primary and revision surgeries for anterior cruciate ligament (ACL) reconstruction, posterior cruciate ligament reconstruction, knee collateral ligament reconstruction, meniscus repair or meniscectomy, and any ankle ligament reconstruction were identified by their CPT codes. Patients over the age of 40 and without a minimum 2‐year follow‐up after primary surgery were excluded. Differences in prevalence and revision rates were analyzed. Results A total of 56,146 patients with AN and 42,630 patients with BN were included in this study with equal numbers in respective matched cohorts. Patients with BN showed an increased risk of ACL injury (relative risk = 1.32, P = .019), medial collateral ligament injury (1.17, 0.04), calcaneofibular sprain (1.92, <0.001), deltoid sprain (1.41, 0.004), and unspecified ankle sprain (1.44, <0.001). Patients with AN showed an increased risk for calcaneofibular sprain (1.25, 0.007), deltoid sprain (1.28, 0.015), and unspecified ankle sprain (1.17, <0.001). Patients with BN were more likely to have revision ACL repair (1.89, 0.02), partial meniscus revision (3.44, <0.001) and any meniscus revision (4.74, <0.001) while patients with AN were more likely to have an ACL revision (2.81, <0.001), partial meniscus (4.37, <0.001), and any meniscus (4.52, <0.001). Conclusions In this study, patients with AN and BN had a significantly increased risk for various knee and ankle injuries and revision surgeries compared with matched controls. Additionally, patients with AN and BN who sustained these injuries were more likely to undergo a revision surgical procedure within the first 5 years of the primary procedure. Level of Evidence Level III, retrospective comparative study.

Background Studies suggest that hypoperfusion from heart failure (HF) may contribute to cognitive decline. However, the relationship between the HF subtypes and cognition remains poorly described in real‐world populations. Methods We conducted a cross‐sectional study of patients aged ≥18 years seen at the Mayo Clinic in 2022 who underwent echocardiogram and cognitive assessment within 1 year. HF was classified per the 2022 American Heart Association as no HF, HF with preserved ejection fraction (EF), HF with mildly reduced EF, and HF with reduced EF. Cognitive impairment was categorized using the Montreal Cognitive Assessment score as normal (≥26), mild (18–25), and moderate to severe (<18). Linear regression assessed EF–Montreal Cognitive Assessment correlation and logistic regression the association between HF subtypes and cognitive dysfunction, adjusting for age, sex, race, and vascular risk factors. Results A total of 1592 patients met inclusion criteria (mean age, 75.7±13.8 years; 48.5% women). Lower EF was associated with worse cognitive performance (postadjustment β=0.033, P =0.013). Patients with HF with reduced EF and patients with HF with preserved EF had significantly lower Montreal Cognitive Assessment scores than those without HF (17.6±6.2 and 18.9±5.8 versus 19.9±6.0, P <0.001). The prevalence of moderate to severe cognitive impairment was highest in HF with reduced EF (43.3%), followed by HF with preserved EF (34.4%), no heart failure (28.6%), and HF with mildly reduced EF (23.4%) (adjusted trend P =0.032). Conclusions HF, independent of ejection fraction alone, is associated with cognitive impairment. Further studies should confirm these findings and evaluate the impact of interventions targeting EF and HF subtypes on cognitive outcomes.

Background Alzheimer's disease (AD) and related dementias are leading causes of death worldwide. While socioeconomic status (SES) is a critical determinant, its impact on mortality after diagnosis remains understudied. Objective To investigate the roles of neighborhood-level and individual-level SES in predicting mortality risk among older adults with incident dementia. Methods We analyzed data from 924 participants with incident dementia from the Mayo Clinic Study of Aging (N = 6909), a cohort with clinical follow-up visits every 15 months. We assessed mortality risk using Cox's time-varying survival regression, adjusting for time-fixed and time-varying covariates. Primary predictors were neighborhood-level SES (Area Deprivation Index [ADI]) and individual-level SES (housing-based SES index [HOUSES], education, and occupation). We also applied a random survival forest model to assess the predictive contribution of SES indicators and identify influential predictors. Results 857 participants (92.7%) died, with a median time from dementia diagnosis to death of 29 months (IQR: 12–54). Lower SES measured by HOUSES was associated with increased mortality risk (HR 1.28, 95% CI 1.07–1.52). Conversely, ADI, education, and occupation were not associated with mortality. Male sex, older age, congestive heart failure and diabetes were associated with higher mortality risk. In predictive analysis, HOUSES ranked among the top 10 contributors to mortality risk. Conclusions Among older adults with dementia, lower HOUSES was associated with higher mortality risk beyond neighborhood-level deprivation, education, and occupation. Integrating this housing-based individual-level SES measure into dementia care planning may help identify patients with greater socioeconomic vulnerability and inform mortality risk stratification.

Background: Tobacco use is a known risk factor for poor healing after rotator cuff repair (RCR), but the effects of nontobacco nicotine products remain unclear. Purpose: To compare postoperative complications among nontobacco nicotine users, tobacco users, and nonusers undergoing RCR. Study Design: Cohort study; Level of evidence, 3. Methods: Using the PearlDiver database, the authors identified patients who underwent arthroscopic RCR with ≥2 years of follow-up. Three 1:1 propensity-matched comparisons were conducted: nontobacco nicotine users versus nonusers (n = 4844), tobacco users versus nonusers (n = 19,182), and nontobacco nicotine users vs tobacco users (n = 4882). Outcomes included 90-day complications and 2-year revision surgeries. Results: Nontobacco nicotine users had mildly higher rates of lysis of adhesions than controls (0.7% vs 0.4%; OR, 1.95; P = .033) but no other significant differences. Tobacco users showed increased rates of acute kidney injury (AKI), pneumonia, infections, emergency department (ED) visits, readmissions, and revision surgery compared to controls. Compared to tobacco users, nontobacco nicotine users had moderately strong lower risks of pneumonia (0.6% vs 1.2%; OR, 0.46), ED visits (8.8% vs 13.6%; OR, 0.62), and readmissions (0.8% vs 1.5%; OR, 0.54) (all P < .01). Conclusion: While nontobacco nicotine use was associated with a modestly increased risk of lysis of adhesions after RCR, it did not significantly elevate the risk of major medical complications, infections, or revision surgery when compared to nonnicotine users. In contrast, tobacco users demonstrated consistently worse postoperative outcomes across multiple domains, including higher rates of AKI, pneumonia, surgical site infection, ED visits, readmissions, and revision procedures. Notably, when compared directly to tobacco users, nontobacco nicotine users had significantly lower rates of pneumonia, ED utilization, and readmissions. These findings suggest that although nontobacco nicotine products may not be entirely benign, their perioperative risk profile appears to be less severe than that of traditional tobacco use.