Citations

Abstract Background : Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts. Methods : Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE -ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure. Results : Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC=0.91, PPV=0.80; DIAGNOSE CTE: AUC=0.84, PPV=0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players. Conclusion : TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.

Abstract Purpose We evaluated healthcare resource utilization (HCRU) and costs in patients with eosinophilic granulomatosis with polyangiitis (EGPA). Methods Patients with newly diagnosed EGPA (2017–2021), ≥12 months’ pre-diagnosis health plan enrollment, and ≥1 inpatient or ≥2 outpatient claims with an EGPA diagnosis were included. Follow-up was from EGPA diagnosis until disenrollment or database end. HCRU and health insurer payment costs during follow-up were compared with those for matched cohorts of general insured patients without EGPA (comparison A) and without EGPA but with severe uncontrolled asthma (SUA; comparison B). Results In comparison A, all-cause HCRU was higher in the EGPA cohort (n = 213) versus matched patients (n = 779) for all clinical encounters/pharmacy claim types; annualized, mean total all-cause costs were 16-fold higher ($117,563/patient) versus matched patients ($7,520/patient). In comparison B, all-cause HCRU was higher for the EGPA cohort (n = 182) versus the matched SUA cohort (n = 640) for all clinical encounters/pharmacy claim types, with 5-fold higher mean total all-cause costs ($118,127/patient vs $22,286/patient). In both EGPA cohorts, HCRU and associated costs increased between the baseline and follow-up periods. Conclusions These findings highlight the need for more effective treatments to reduce the clinical and economic burden of EGPA.

This study aims to evaluate the implementation of the uterine sliding sign in routine pelvic ultrasound examinations for improving the diagnosis of deep endometriosis. A retrospective analysis was conducted at Mayo Clinic’s Florida and Arizona campuses, including 200 premenopausal and perimenopausal women with chronic pelvic pain, infertility, or suspected endometriosis. Sonographers performed a uterine sliding maneuver during transvaginal ultrasound, and the acquisition times were recorded. Sonographer experience and the time required to perform the sliding sign were analyzed using Microsoft Excel. The median acquisition time for the uterine sliding sign was 26 seconds, with no statistically significant difference based on sonographer experience. The addition of this maneuver extended the ultrasound examination by <1 minute on average, regardless of sonographer experience level. Incorporating the uterine sliding sign into routine pelvic ultrasound protocols is a quick and efficient method that enhances the detection of deep endometriosis, potentially reducing the significant diagnostic delay associated with endometriosis. This study supports the feasibility and minimal time impact of implementing the Society of Radiologists in Ultrasound (SRU) recommendations for augmented pelvic ultrasound in clinical practice.

We report correlative circulating tumor DNA (ctDNA) analyses from TRANSFORM (ClinicalTrials.gov identifier: NCT03575351 ) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma (LBCL). ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (measurable residual disease [MRD] neg ) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel–treated patients achieving MRD neg . Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival (PFS), and duration of response among patients in complete response (CR) and MRD neg . ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. MRD neg remained significantly associated with EFS after adjusting for positron emission tomography (PET) response, while interaction testing revealed a significant interaction between PET status and treatment arm for EFS. Liso-cel achieved deeper, more durable molecular clearance by ctDNA, consistent with superior EFS and PFS versus ASCT for second-line LBCL treatment. ctDNA-MRD provided prognostic value beyond PET, supporting its role as a complementary biomarker for treatment response and relapse prediction.

Background/Objectives: KRAS G12C mutations define a clinically actionable subset of solid tumors, particularly non–small cell lung cancer. Clinical responses to approved covalent inhibitors remain limited by intrinsic and acquired resistance, highlighting the need for structurally distinct inhibitor scaffolds to expand therapeutic options. The objective of this study was to identify novel covalent binders targeting the KRAS G12C switch-II pocket through large-scale in silico screening and experimental validation. Methods: More than 1.9 million small molecules from diverse commercial libraries were screened using covalent docking, followed by multi-stage refinement incorporating molecular dynamics simulations, MM/GBSA free-energy estimation, and cancer-focused QSAR modeling. Results: This integrated workflow yielded 50 prioritized compounds spanning several chemically distinct scaffold classes. These candidates displayed favorable predicted binding energetics, stable ligand-protein interactions over extended simulation timescales, and low structural similarity to clinically approved KRAS G12C inhibitors sotorasib and adagrasib. Benchmarking against these clinical agents, using identical computational parameters, yielded comparable predicted binding energies for several candidate molecules. In cellular NanoBRET target-engagement assays, selected scaffolds, including K788-7251 and AN-989/14669131, exhibited sub-micromolar engagement of KRAS G12C with minimal endothelial cytotoxicity. Conclusions: Collectively, these findings identify structurally distinct, KRAS G12C inhibitor chemotypes and provide tractable starting points for the development of next-generation targeted therapies.

ABSTRACT Distal urethral strictures involving the meatus and fossa navicularis present unique challenges for reconstructive urologists due to the short segment’s proximity to the glans and high stakes for cosmetic and functional outcomes. Traditional approaches such as ventral meatotomy, skin-flap urethroplasty, and 2-stage techniques are known to compromise cosmesis, increase the risk of urethrocutaneous fistula, and have high recurrence rates, particularly in patients with lichen sclerosis (LS). The evolution of one-sided dorsal onlay urethroplasty with buccal mucosa graft has increased the success rates of single-stage urethroplasties by emphasizing preservation of tissue vascularity, leading to robust graft support. Traditionally, literature described the one-sided dorsal onlay urethroplasty through a perineal incision. This review seeks to describe the refinement of this technique, adapting the one-sided dorsal onlay concept to distal strictures by accessing the urethra through a subcoronal, ventral, or penoscrotal incision. Ventral penile incisions may limit unnecessary dissection, preserve glans architecture, and allow for supine positioning, thereby mitigating risks associated with high dorsal lithotomy. All while retaining the advantages of a well-vascularized dorsal graft bed. Limited reports describe high rates of anatomic and functional success and low complication rates across etiologies, including LS, iatrogenic, and hypospadias repair. Failures tend to be focal and amenable to minor interventions.