Citations

Abstract Background Computational modeling is a tool being deployed for orthopaedic solutions but its use in the hand and wrist remains limited. This work used a model to simulate a clinically relevant provocative scaphoid shift maneuver (SSM) with different levels of scapholunate interosseous ligament (SLIL) injuries to observe the effect on different metrics. Methods A personalized model simulated the full SSM motion cycle from ulnar deviation with extension to radial deviation with flexion informed by the participant’s motion obtained from dynamic computed tomography. Models repeated the SSM under different levels of SLIL injury and reported changes in joint kinematics, contact mechanics, and ligament forces. Results The fully injured model increased scaphoid dorsal translation, flexion, and radial deviation compared to the intact condition and caused a subluxation of the scaphoid. Radioscaphoid contact areas were approximately 200% greater in the fully injured model compared with all others and the fully injured model was the only condition where contact force decreased across the motion cycle. Ligament forces in the intact condition were on average 33.0 N and 54.2 N for the volar and dorsal SLIL, respectively. Lastly, the long radiolunate, an extrinsic stabilizer, had forces that increased following SLIL injury. Conclusions Computational models can successfully recreate clinically observed behaviors of an SSM, including scaphoid subluxation, while providing new insights via quantification of contact mechanics and ligament forces. Contact mechanics metrics may be important for understanding the long-term progression of untreated SLIL injuries to osteoarthritis. Additionally, ligament force metrics may explain the progression of SLIL injuries from volar SLIL to dorsal SLIL and highlight the importance of repairing extrinsic stabilizers of the joint, due to increased force sharing following SLIL injury. This work provides a pathway to future studies investigating the effects of SLIL injury and repair, both acutely and chronically.

Stereotactic arrhythmia radiotherapy (STAR) is emerging as a highly effective treatment for ventricular tachycardia (VT). Growing evidence indicates that STAR favorably reprograms the electrical substrate by speeding conduction and/or prolonging repolarization via modulation of ion channel expression, although the mechanisms by which single-fraction radiation mediates durable changes in gene expression are incompletely understood. Here, we identify dynamic changes in the cardiomyocyte epigenome and transcriptome after irradiation (IR) in vivo and in vitro, including durably increased expression and chromatin accessibility of Scn5a (encodes the α subunit of the sodium channel, Na V 1.5), demonstrating a role for epigenetic memory in conduction velocity (CV) increases observed after STAR. Transcriptomic and epigenetic sequencing further identified dynamic changes in gene expression and regulatory regions involved in cellular repolarization, calcium handling, and metabolism after IR. These changes were mirrored by dose-dependent and cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration, highlighting important cellular processes that may mediate the therapeutic effects of STAR. Overall, we found that cardiomyocytes exposed to a single fraction of high-dose IR exhibited epigenetic reprogramming that mediated broad and dynamic physiologic responses.

Abstract Glioblastoma (GBM) remains the most aggressive primary adult brain cancer with limited therapeutic options. Our prior research demonstrated that androgen receptor antagonists (ARAs) enhance survival in GBM mouse models by preferentially suppressing glioma stem cells. This study investigates the potential of ARAs as radiosensitizers in combination with radiotherapy (RT). Combined effects of ARAs and RT were evaluated using an orthotopic GBM mouse model. RNA-Seq and TCGA analyses delineated AR-associated regulatory networks, while integrated cellular and molecular approaches utilizing human and mouse GBM cell lines, as well as in patient-derived primary high-grade glioma cultures, interrogated signaling and immune paradigms. ARA treatment induced G2/M cell cycle arrest, apoptosis, and downregulated DNA repair genes, with AR expression correlating with the DNA repair and TGF-β pathway. In both immortalized GBM cell lines and primary high-grade glioma cultured cells, ARAs in combination with RT showed only a modest enhancement of radiosensitivity. However, in an orthotopic GBM mouse model, ARA + RT demonstrated a strong synergy, achieving 100% long-term survival, compared to less than 50% with ARA alone and 0% with RT alone. Mechanistically, ARA modulated the TGF-β pathway, durably switching from Smad3 linker to c-terminal phosphorylation (pSmad3C) and inhibiting LIF/STAT3 axis. Distinct TGF-βs ligand expression patterns were observed in ARA-treated GBM cells. A protein–protein interaction noted between AR and Smad3, which was disrupted following ARA treatment, leading to elevated protein levels and nuclear localization of pSmad3C (S423/425), indicating normalization/activation of the TGF-β/pSmad3C-dependent anti-tumorigenic cascade. Comprehensive analyses in GBM cell lines and mouse model tissues demonstrated pathway reprogramming characterized by elevated TGF-β2 and increased pSmad3C. Tissue analysis revealed immune activation in the tumor microenvironment, while peripheral blood and spleen showed systemic immune responses following ARA + RT. Our study provides novel insights into how ARAs enhance RT efficacy through immunomodulation involving TGF-β/pSmad3C cascade, offering therapeutic implications in GBM.

ABSTRACT Calcific tendinopathy is a common musculoskeletal disorder marked by calcium deposition within tendons, often accompanied by pain, impaired mobility, and in severe cases, ossification. However, the mechanisms underlying tendon mineralization remain poorly understood. In contrast to pathological human calcification, turkeys naturally develop tendon mineralization during growth without signs of inflammation or ossification. This study had two phases: an observational phase to assess onset and progression of calcification, and an interventional phase to evaluate the role of mechanical loading. In the observational phase, flexor tendons were collected from turkeys aged 1–16 weeks in a serial sacrifice study and analyzed by Von Kossa staining and biomechanical testing. Calcification began at 7 weeks, localized within organized collagen matrices, progressed through Weeks 8–14, and peaked by 16 weeks. In the interventional phase, nine female turkeys were randomized at 4 weeks into a transection group ( n = 3), sham group ( n = 3), and control group ( n = 3). Transection at the muscle–tendon junction eliminated mechanical loading. At 16 weeks, tendons were analyzed by histology, quantitative RT‐PCR, ICP‐MS, and biomechanical testing. Transected tendons showed a near‐complete absence of mineralization, reduced expression of osteogenic markers (osteopontin, osteocalcin, Runx‐2), and significantly lower calcium, magnesium, and phosphorus levels. Biomechanical testing indicated reduced stress relaxation, stiffness, and Young's modulus in the transected group. Tendon calcification in turkeys functioned as a mechanically regulated, nonpathological process. The study established a relevant model for early tendon mineralization and offered a basis for developing load‐dependent therapies for human tendon disease.

Abstract Cutaneous squamous cell carcinoma (cSCC) poses significant clinical challenges due to its rising incidence and potential for metastasis. Histopathologic risk stratification is further limited by substantial inter-observer variability. Unsupervised AI approaches based on content-based image retrieval offer scalable and interpretable decision support for diagnostic pathology. The objective of this study was to evaluate the use of image retrieval within histopathology atlases to stratify cSCC tumor differentiation from whole-slide images (WSIs), while comparing different patch selection and feature extraction strategies. This retrospective study included 552 archived WSIs comprising 385 well-differentiated, 102 moderately differentiated, and 66 poorly differentiated cases collected across Mayo Clinic sites in Arizona, Florida, and Minnesota. Image atlases were constructed using multiple patch aggregation strategies (Mosaic, Collage, and Montage) and deep learning encoders (KimiaNet, PathDino, and H-Optimus-0). A leave-one-WSI-out evaluation framework was used to assess differentiation classification performance using accuracy, specificity, sensitivity, and F1 score. Mosaic combined with KimiaNet achieved the highest Top-1 accuracy (74.9%) and specificity (92.6%), while Mosaic with H-Optimus-0 yielded the best Top-5 accuracy (79.0%) and macro-F1 score (62.6%). Collage combined with KimiaNet produced the highest Top-5 specificity (99.5%). The generalizability of the evaluated AI models varied across hospitals, reflecting differences in imaging protocols, staining practices, and patient populations. Overall, unsupervised image search and retrieval provides effective, annotation-free support for cSCC differentiation and has the potential to enhance dermatopathology workflows when appropriate combinations of patch selection and feature ex-traction methods are employed.

Abstract Background OnabotulinumtoxinA (BoNT‐A) is an established preventive treatment for chronic migraine but involves 31 to 40 injections per session, often causing discomfort and post‐procedural headaches. Remote electrical neuromodulation (REN) is a noninvasive therapy with efficacy in migraine treatment via conditioned pain modulation but has not been evaluated for procedural pain. This study evaluated REN's effectiveness in reducing acute procedural pain and postprocedural headache associated with BoNT‐A injections. Methods This was an investigator‐initiated single‐center, randomized, single‐blind, sham‐controlled crossover study enrolled 80 adults (aged 22 to 74 years) with chronic migraine undergoing routine BoNT‐A treatment. Each participant received one injection session without a device, followed by sessions using active REN and sham in randomized order. REN was applied to the upper arm 10 min prior to injections and removed after injection completion. Pain intensity was measured using a visual analog scale (0 to 100) at pre‐procedure, intra‐procedure, and post‐procedure time points. The primary outcome was procedural pain intensity, and secondary outcomes included post‐procedural headache incidence and adverse events. Due to clear benefit, the study was terminated early based on predefined stopping criteria. Results Final analysis of 60 participants (mean age 48.0 years; 49/60, 82% female) demonstrated that pre‐procedural pain levels were not significantly different between baseline and the active REN or sham ( p > 0.999 and p = 0.485, respectively). However, during and after BoNT‐A administration, the active REN group reported significantly lower pain scores compared to both the sham and baseline conditions. At intra‐procedure, the REN group experienced a mean pain reduction of 15.0 points ( p < 0.001), and at post‐procedure experienced a 19.1‐point reduction ( p < 0.001). Sham treatment did not result in significant pain reduction compared to baseline ( p > 0.999 for both intra‐procedure and post‐procedure). Additionally, REN lowered the incidence of headache as an adverse event, with only 15% (8/52) of participants experiencing post‐procedural headache compared to 55% (29/53) in the sham group and 39% (23/59) at baseline (odds ratio = 0.28, 95% confidence interval: 0.10 to 0.69, p = 0.008). No additional adverse events were reported. Conclusions REN significantly reduces procedural pain and post‐procedural headache associated with BoNT‐A injections for chronic migraine and may serve as a noninvasive, easily implemented pain management strategy for acute procedural pain. REN represents a promising approach to improving patient comfort during routine migraine treatment as well as reducing post‐procedural headache.

Introduction Software packages for quantification of CT perfusion parameters allow quick visualization of perfusion deficits to support clinical decision making in acute ischemic stroke (AIS). Several packages are now commercially available for automated quantification of ischemic core, penumbra volumes, and mismatch ratios to indicate eligibility for reperfusion therapies. This study explored the agreement between two software packages, Brainomix 360 e‐CTP and Rapid CTP, in prospective, real‐world use. Methods Consecutive patients scanned for suspected stroke at three comprehensive stroke centers over 90 days from May to July 2024 were included in the study. Eligibility for the current analysis was limited to discharge diagnosis of AIS and CTP imaging processed by both Brainomix and Rapid software. Software processing was conducted in real time after image acquisition. The presence of large vessel occlusion (LVO) was determined from review of electronic medical records. CTP core (CBF<30%) and penumbra (Tmax>6s) volumes from Brainomix and Rapid were recorded for each case. Mismatch ratios were calculated (penumbra÷core volume); positive mismatch was defined according to DEFUSE‐3 criteria (core<70ml, penumbra>15ml, mismatch ratio > 1.8). The correlations and linear regressions between Brainomix and Rapid were computed for core, penumbra and mismatch ratios, and their concordance for mismatch positivity was assessed. Results 137 patients were scanned and received a final diagnosis of AIS. Of these, only 38 had imaging processed by both Brainomix and Rapid. Median age was 69 years (interquartile range: 57‐77.5y); 16 (42%) were female; 13 (34%) had LVO. Linear models between Brainomix and Rapid's outputs for CBF and Tmax volumes are shown in Figure 1a and 1b. The correlation between software outputs for CBF volume was r=0.70 (p<.001), and for Tmax volume was r=0.72 (p<.001). Mismatch ratios were calculated for the 13 cases with LVO (Figure 1c). The linear model between mismatch ratios was not significant, with four Rapid outputs showing infinite mismatch ratios (due to having CBF volumes of 0ml). Concordance between software for mismatch positivity was good; 8/13 cases showed mismatch on both softwares; 1 case showed mismatch on Brainomix only; 1 for Rapid only; and 3 cases showed mismatch on neither software. Conclusion This prospective study, despite limited sample size (N=38), showed good correlations between Brainomix 360 e‐CTP and Rapid CTP for calculation of both core and penumbra volumes. Although mismatch ratios showed less agreement, the categorization of mismatch positivity showed good concordance between software platforms. image

The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.

Background: We aimed to evaluate the outcomes of patients with confirmed and possible cardiac sarcoidosis who had an ICD implant and identify predictors of ventricular arrhythmias and mortality in this patient population. Methods: We performed a retrospective study patients with a diagnosis of cardiac sarcoidosis (CS) at Mayo Clinic and had an ICD implanted for primary or secondary prevention indication. Adult patients (≥18 years) with a diagnosis of possible or confirmed (biopsy-proven) CS with an ICD implanted between 1993 and 2022 were included. Primary outcomes included sustained ventricular arrhythmia (VT) resulting in a documented appropriate ICD shock and death from any cause. Secondary outcomes included ICD-related complications. Results: We identified 148 patients, in which 23 patients (15.5%) experienced VT events with a total of 160 treated episodes. 4 patients (2.7%) experienced inappropriate ICD shocks (11 episodes). During a median follow up of 3.1 years, 26 patients deceased, and the overall survival was 98% and 77% at 1 and 5 year. Older age, CAD, CKD, paced rhythm and QRS duration were associated with worse survival (Figure 1 – 4) . Device related complications were rare, except for the higher percentage of CHF in patients with VT after implant, however this was not statistically significant. Patients with ICD therapies were younger (53 vs 58 years, p=0.029), had higher LGE burden (26.9 vs 16.3%, p=0.01), and higher percentage of LV mass (26.9 vs 16.3, p=0.011). Multivariate logistic regression model which showed that patients with biopsy proven sarcoidosis had significantly higher odds of VT events (OR: 3.04, 95% CI: 1.02 to 9.08, p = 0.046). In patients with increased LV mass (every 10 g increase), the odds of developing VT increased by 1.49 (95% CI: 1.02 to 2.19, p = 0.041). LV mass and LGE percentage showed fair ability of predicting the outcome by ROC analysis. Youden’s index showed 26 for LV mass and 16% for LGE percent as the optimal cut-off points for predicting VT outcomes (Figure 5) . The sensitivity, specificity, positive predictive value, negative predictive value were 81.8%, 74.1%, 37.5%, 95.6% and 75.4% respectively for an LV mass of 26 grams and 81.8%, 63.8%, 30.0%, 94.9% and 66.7% respectively for an LGE percentage of 16%. Conclusion: LGE burden continues to be a major predictor for VT events in patients with CS. Myocardial tissue burden and electrical abnormalities from CS predict mortality than myocardial function loss.