Citations

Abstract Femoroacetabular impingement with cam morphology that fails nonoperative management can be addressed with hip arthroscopy and cam resection. There exists a wide variation of cam morphology due to various etiologies that can make some cam lesions more challenging to address. A thorough preoperative evaluation and the utilization of a variety of intraoperative techniques can allow for adequate arthroscopic resection of these otherwise challenging cam lesions. In this technique video, we describe a systematic approach for the preoperative assessment of femoroacetabular impingement due to a cam lesion and consideration of different approaches for arthroscopic resection based on cam‐specific morphology.

Ultrasound shear wave elastography is a medical imaging technique where mechanical properties (e.g., shear modulus) of soft tissue are imaged with the goal of diagnosing disease. However, different sources of noise or error often lead to poor images that exacerbate uncertainty of medical diagnosis based on these techniques. Sources of uncertainty include scatterer positions and strengths (e.g., emanating from the cellular structure of tissue), other surrounding tissue not included in the image, and electronic noise, among others. In this work, we are developing Optimal Experimental Design (OED) techniques based on the simulation of the ultrasound imaging process and particle tracking to identify controls that maximize the quality of elastography images. Specifically, we propose a general formulation for OED where the observation error depends on both uncertain quantities and the variables to be inferred (e.g., shear moduli). Furthermore, we pose a nonlinear OED problem where the main design variables are the angles used in plane wave compounding for ultrasound motion tracking of propagating shear waves. The goal of the OED problem is to find the number and values of compounding angles that minimize bias and variance in the estimated shear modulus image. We will demonstrate our approach through various numerical examples.

Background Pancreatic ductal adenocarcinoma (PDAC), the most common malignant type of pancreatic cancer, is characterized by a dense desmoplastic stroma, low neoantigen burden, and a highly immunosuppressive tumor microenvironment (TME). Methods We present a novel strategy harnessing acute transplant rejection mechanisms by employing a recombinant oncolytic rVMG vector engineered to express murine alloantigens H-2Kb (rVMG-H-2Kb) or H-2Kk (rVMG-H-2Kk), thereby inducing tumor-specific antigenic mismatch responses. Results In vitro, rVMG-H-2Kb and rVMG-H-2Kk exhibited strong replication and cytolytic activity while inducing cell surface expression of both H-2Kk and endogenous H-2Kb, in addition to upregulation of antigen presentation genes (β2-microglobulin, Tap1, and Tapbp). In two immunocompetent PDAC models, intratumoral and systemic delivery of rVMG-H-2Kb and rVMG-H-2Kk delayed tumor progression, with rVMG-H-2Kk conferring a survival advantage. Multiplex immunohistochemistry and immunophenotyping revealed substantial TME remodeling, marked by increased effector T-cell infiltration, regulatory T-cell depletion, and reduced fibrosis. Spatial transcriptomics further showed compartment-specific immune activation and epithelial metabolic reprogramming, corroborating with enhanced tumor immunogenicity. Despite these effects, rVMG-H-2Kk also induced compensatory immunosuppressive pathways, including upregulation of antiviral response genes and immune checkpoint receptors such as programmed death-ligand-2. Importantly, combination therapy with rVMG-H-2Kk and murine checkpoint blockade (anti-programmed cell death protein-1 and anti-cytotoxic T-lymphocyte-associated protein 4) drastically improved survival compared to checkpoint blockade alone. Strikingly, surviving mice resisted tumor rechallenge, indicating the establishment of durable antitumor memory. Conclusion These findings establish rVMG-mediated alloantigen delivery as a novel immunotherapeutic platform capable of converting immune-cold tumors into immune-hot, sensitizing tumors to immune checkpoint inhibitors, and establishing durable antitumor immunity in PDAC.

Autoimmune diseases arise when B and T lymphocytes lose tolerance to self. Yet in most disorders, the underlying molecular determinants, including autoantibodies, epitopes and lymphocyte clones that drive tissue injury remain undefined. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare and often fatal pediatric neuroendocrine syndrome with strong evidence of antigen-driven paraneoplastic autoimmunity, including association with the intracellular autoantigen ZSCAN1. However, the effector immune circuit and the epitope-level determinants operating within the hypothalamus and brainstem have remained unknown. To address this challenge in ROHHAD and more broadly in autoimmune disease, we developed the Autoimmune Epitope and immunoGlobulin/Immune-receptor identification System (AEGIS), an integrated framework that links immune repertoires to their cognate self-epitopes. AEGIS combines B cell and T cell receptor profiling from sites of tissue injury with high-resolution epitope mapping, direct sequencing of antigen-specific autoantibodies, in silico antibody-antigen folding, selection, and T cell antigen discovery. Applied to a deeply phenotyped child with ROHHAD, AEGIS revealed a compartmentalized, clonally restricted immune response in which brain-deposited IgG and expanded cerebrospinal fluid B cell and CD4 T cell clonotypes converged on shared ZSCAN1 epitopes, resolved to minimal determinants and peptide-MHC ligands. These findings provide a clone- and epitope-linked mechanistic map of ROHHAD autoimmunity and establish a generalizable framework for identifying candidate pathogenic clones and antigens across diverse autoimmune diseases.

Background/Objectives: To identify predictors of successful fusion and adjacent segment disease (ASD) following ALIF. Methods: Records of patients undergoing one- or two-level ALIF were queried for baseline and postoperative radiographic data, demographics, operative notes, and implant characteristics. All had ≥1 year of follow-up with CT, and multivariable Cox regression was used to identify predictors of radiographic fusion through the interbody, ASD, and ASD requiring reoperation. Results: In total, 177 patients (median 59 yr; 52.5% male) were treated at 245 unique levels, of which 193 fused (81.3% with posterior fixation and 59.6% with standalone), 43 had ASD (17.6%), and 14 had ASD requiring reoperation (5.7%). Fusion was predicted by anterior cage placement (HR 0.94/mm; 95% CI [0.90, 0.98]; p = 0.003) and BMP use (HR 1.92; [1.15, 3.18]; p = 0.012). Radiographic ASD was predicted by older age (HR 1.08 per year; [1.03, 1.14]; p < 0.001), undergoing a revision [vs. index] fusion operation (HR 3.51; [1.44; 8.59]; p = 0.006), lower preoperative disc height (HR 0.83/mm; [0.74, 0.94]; p = 0.003), and preoperative facet vacuum phenomenon (HR 2.46; [1.18, 5.15]; p = 0.017). None of the extracted variables predicted reoperation for ASD. Conclusions: BMP use along with anterior cage placement and posterior fixation may improve the odds of fusion through the interbody following one- or two-level ALIF. Adjacent segment pathology is more common in patients with greater preoperative degenerative pathology (vacuum sign; more collapsed disc) and advanced age. Pelvic fixation did not improve fusion odds, but the data highlight the benefits of supplementary posterior fixation vs. standalone ALIF.

Purpose: To determine the clinical utility of the assessment of preoperative orbital compliance in predicting the amount of postoperative proptosis reduction in patients with stable-phase thyroid eye disease who undergo orbital fat decompression surgery. Methods: A retrospective chart review was conducted of stable-phase thyroid eye disease patients who underwent orbital fat decompression by a single surgeon. Orbital compliance was measured preoperatively as axial globe displacement (in millimeters) using a Hertel exophthalmometer. Displacement ≥2.5 mm was classified as high compliance and <2.5 mm as low compliance. Radiographic thyroid eye disease type, preoperative proptosis, and intraoperative fat volume removed were recorded. Linear regression analysis determined whether orbital compliance independently predicted postoperative proptosis reduction. Levene’s test assessed variability between groups. Results: Forty-six orbits from 24 patients were included, 15 orbits with low compliance and 31 with high orbital compliance. Patients with high orbital compliance had a mean postoperative proptosis reduction of 3.19 mm (range 0.5–6.0 mm) while patients with low orbital compliance had a mean proptosis reduction of 2.67 mm (range 2.0–3.5 mm). On average, higher preoperative orbital compliance led to 0.959 mm greater proptosis reduction compared with low orbital compliance, when accounting for radiographic thyroid eye disease type and volume of fat removed intraoperatively ( p = 0.048). Variability in proptosis reduction was higher among the high orbital compliance group ( p = 0.00085). Conclusions: Higher preoperative orbital compliance results in greater proptosis reduction. However, patients with high orbital compliance have greater variability in proptosis reduction, suggesting that surgical outcomes are less predictable among these patients.

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P &amp;lt; .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P &amp;lt; .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P &amp;lt; .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P &amp;lt; .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

BACKGROUND: Hemorrhagic risk in dural arteriovenous fistulas (dAVFs) is largely determined by venous anatomy, but the contribution of systemic cardiovascular factors and their medical therapy remains poorly defined. This study examined associations between cardiovascular risk factors and antithrombotic use and hemorrhagic presentation, angiographic obliteration, and early functional outcomes after treatment. METHODS: We analyzed 1350 adults with intracranial dAVFs from the international Consortium for Dural Arteriovenous Fistula Outcomes Research registry, which retrospectively accrued cases across 14 centers in 4 countries between 1990 and 2017. Demographics, cardiovascular comorbidities, antithrombotic use, angioarchitectural features, treatment strategies, and follow-up outcomes were collected from prospectively maintained databases. Primary end points were hemorrhagic presentation, angiographic obliteration, and 90-day functional status after treatment. Univariable and multivariable logistic regressions were performed with model-specific adjustments. RESULTS: Hemorrhage occurred in 375 patients (27.8%) and was most strongly associated with high-grade dAVF classification and male sex; antithrombotic therapy was associated with lower odds of hemorrhagic presentation. Other cardiovascular risk factors showed no independent relationship with bleeding. Angiographic obliteration was achieved in 621 of 845 patients (73.5%). Hemorrhagic onset, high dAVF grade, and surgical treatment were independently associated with angiographic obliteration, whereas smoking and embolization demonstrated only nonsignificant trends after adjustment. At 90 days, 934 patients (88.9%) were functionally independent. Baseline modified Rankin Scale score was the strongest factor associated with 90-day functional outcome, while neither cardiovascular comorbidities nor treatment modality independently influenced functional status. CONCLUSIONS: In this large multicenter dAVF cohort, hemorrhagic presentation was most strongly associated with venous angioarchitecture. Male sex and antithrombotic therapy were also independently associated with hemorrhagic presentation. Angiographic obliteration was common, particularly among surgically treated lesions, and 90-day functional outcome was most strongly associated with baseline functional status.

Abstract Background Lung cancer is the leading cause of cancer-related death, and the most common cancer diagnosed globally. Approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC). After initial surgical treatment, adjuvant therapy with conventional or targeted chemotherapy can help optimize survival. These treatments, however, must be tailored to each patients’ problematic situation, including cancer characteristics and goals of care. Shared decision making (SDM) is a method of care by which patients and clinicians work together to form plans of care that advance the patient’s problematic human situation. This method often requires evaluating alternative options, “trying them on” for fit given their practical demands and favorable and unfavorable effects. Tools used within the encounter can facilitate and support SDM conversations, yet none exist for considering care post-surgical treatment of NSCLC. Therefore, we aimed to evaluate the effectiveness of a novel encounter tool for SDM, NSCLC Choice, compared to usual care at improving SDM and reducing decisional conflict for patients with resected early-stage NSCLC considering adjuvant treatment. Methods We will conduct a parallel, patient-level randomized trial comparing NSCLC Choice with usual care. Patients will be eligible if they are adults with stage >1B NSCLC eligible for postsurgical adjuvant chemotherapy. Allocation will be central and post-consent. Patients will be blinded to our trial hypothesis, instead of being invited to evaluate an educational intervention. Our primary outcome is SDM quality, which we will assess using participant reported measures (patient SDM-Q-9) obtained immediately post-encounter and an observer measure estimated from video recording of trial encounters in both arms (OPTION12). With resources to conduct a 100-patient trial, we will have >80% power to detect a 12-point medium difference between arms in patient-reported SDM-Q-9. We will also assess the secondary outcomes of knowledge about the disease and the features of treatment options using an ad hoc questionnaire, decisional conflict using the Decisional Conflict Scale, and patient and clinician satisfaction using the metrics used in prior SDM intervention trials. We will also determine encounter length using video recordings. Discussion In testing NSCLC Choice, we seek to determine the extent to which this intervention can improve care for patients with NSCLC considering adjuvant therapy after surgery. In addition, we expect to determine whether this intervention is satisfactory to participants and feasible in practice. If successful, this study will result in an evidence-based tool for promoting patient-centered conversations around NSCLC and cancer care those fits. Trial Registration: NCT06122064 ClinicalTrials.gov