Citations

Abstract INTRODUCTION Repetitive head impacts (RHI) from contact sports may cause a unique pattern of white matter hyperintensities (WMH) on T2‐weighted fluid‐attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), termed RHI‐associated WMH (RHI‐WMH). These lesions are punctate, circular, and located at the gray–white matter boundary, an area vulnerable to trauma‐related damage. METHODS We investigated the association of RHI with these lesions in two aging cohorts: (1) former American football players versus asymptomatic unexposed men and (2) individuals with RHI from various contact sports versus non‐RHI participants. RHI‐WMH were assessed using visual ratings and a novel automated quantification pipeline. RESULTS Individuals with RHI had greater RHI‐WMH by both detection methods in both cohorts. RHI‐WMH were associated with plasma neurofilament light and p‐tau231, and flortaucipir positron emission tomography (PET) uptake. DISCUSSION RHI‐WMH may represent a new supportive biomarker for the detection of RHI‐related neuropathologies later in life.

Morel-Lavallee lesions (MLLs) are traumatic closed degloving injuries with operative intervention (OI), especially excisional debridement, remaining the mainstay of treatment. However, high-quality evidence describing operative techniques and outcomes remains limited. This study aimed to characterize current OI practices and associated outcomes, especially among patients undergoing excisional debridement, hypothesizing an increased risk of wound complications with this approach for MLLs. Methods This prospective (2021-2024), multicenter, observational study was conducted across 15 trauma centers and included patients diagnosed with MLL who underwent OI. The association between operative technique (eg, excisional debridement) and the primary outcome of wound complications was evaluated. Wound complications were defined as cellulitis, deep wound infection, skin necrosis, necrotizing soft tissue infection (NSTI), and/or organized hematoma. Results Of 88 MLL patients undergoing OI, 36 (40.9%) had excisional debridement, with 4 (11.1%) limited excision to skin, 20 (55.6%) extended to subcutaneous tissue, and 12 (33.3%) down to muscle. Excisional debridement had higher rates of skin necrosis (22.2% vs. 1.9%, P = .002). Although overall rates of wound complications were statistically similar between cohorts (33.3% vs. 17.3%, P = .098), univariate analysis demonstrated excisional debridement had increased risk of wound complications (OR 2.52, CI 1.07-5.97, P = .035). Conclusion This prospective multicenter study over three years demonstrated that a fifth of MLLs undergoing excisional debridement developed postoperative skin necrosis. Excisional debridement also had a more than two-fold increased risk of wound complications compared to other OIs. These findings underscore the importance of investigating alternative operative techniques, such as incision and drainage or minimally invasive debridement methods.

Abstract Alzheimer's disease (AD) is neuropathologically defined by amyloid‐beta (Aβ) plaques and tau neurofibrillary tangles. However, co‐pathologies and other pathobiological processes are involved in the pathogenesis of AD, contributing to neurodegeneration and clinical symptoms. The most common co‐pathologies in people with AD are alpha‐synucleinopathy, vascular brain injury and transactive response DNA‐binding protein of 43 kDa‐related pathology. Neuroinflammation, iron accumulation, cholinergic dysfunction and cellular senescence are recognized pathobiological processes beyond Aβ‐ and tau‐related pathology. However, the exact mechanisms by which these co‐pathologies and pathobiological processes contribute to the neurodegeneration and clinical symptoms in people with AD remain unclear. The individual combination of these co‐pathologies and pathobiological processes increases phenotypical heterogeneity in people with AD. This highlights the unmet need to advance their current understanding, and the field strives to develop accurate biomarkers for personalized assessment and investigation. Elucidating this biologic‐clinical complexity and heterogeneity is crucial for increasing our current understanding of AD, with implications for diagnosis, prognosis and therapeutics.

Abstract Purpose To report historical patterns of pharmaceutical expenditures, to identify factors that may influence future spending, and to predict growth in drug spending in 2026 in the United States, with a focus on the nonfederal hospital and clinic sectors. Methods Historical patterns were assessed by examining data on drug purchases from manufacturers using the IQVIA National Sales Perspectives database. Factors that may influence drug spending in hospitals and clinics in 2026 were reviewed—including new drug approvals, patent expirations, and potential new policies or legislation. Focused analyses were conducted for biosimilars, cancer drugs, endocrine drugs, generics, specialty drugs, and vaccines. For nonfederal hospitals, clinics, and overall (all sectors), estimates for growth of pharmaceutical expenditures in 2026 were made based on a combination of quantitative analyses and expert opinion. Results In 2025, overall pharmaceutical expenditures in the US grew 12.7% compared to 2024, for a total of $915.2 billion. Utilization (a 9.3% increase) drove this increase, while growth due to new drugs (0.9%) and price increases (1.2%) had a modest impact. Tirzepatide was the new top drug in 2025, followed by semaglutide and apixiban. Drug expenditures were $42.9 billion (a 9.6% increase) and $190.5 billion (a 19.0% increase) in nonfederal hospitals and in clinics, respectively. In clinics, volume drove drug expense growth, contributing with a 13.6% increase, while price and new drugs each contributed with a 2.7% increase. In nonfederal hospitals, expenditure growth was driven by increases in volume (4.6%), new products (3.7%), and prices (1.5%). Several new drugs that will influence spending are expected to be approved in 2026. Specialty, endocrine, and cancer drugs will continue to drive expenditures. Conclusion For 2026, we expect overall prescription drug spending to rise by 10.0% to 12.0%, whereas in clinics and hospitals we anticipate increases of 14.0%-16.0% and 4.0%-6.0%, respectively, compared to 2025. These national estimates of future pharmaceutical expenditure growth may not be representative of any health system because of the myriad of local factors that influence actual spending

Background: Stable osteochondritis dissecans (OCD) lesions are primarily treated nonoperatively. Nonoperative treatment includes several recommendations, including the use of an unloader brace. However, little is known about the clinical effectiveness of unloader bracing and its influence on OCD healing, return to sports, and patient-reported outcomes (PROs). The purpose of this investigation was to evaluate the impact of unloader bracing on patients with stable medial femoral condyle (MFC) OCD lesions treated nonoperatively. Purpose: To investigate the influence of valgus unloader bracing on the success of treating stable MFC OCD with nonoperative treatment strategies. Study Design: Cohort study; Level of evidence, 2. Methods: The authors used a prospective cohort of patients receiving nonoperative care for stable MFC knee OCD lesions. The primary variable of interest was the efficacy of bracing. The primary outcomes were transition from nonoperative care to surgical intervention, return-to-play (RTP) clearance, and PROs. Bivariate testing was used to determine if there were differences between groups. Chi-square testing was used to determine if there were differences in rates of transition to surgery by group. The timing of the transition by each group was assessed using a Wilcoxon rank-sum test, given the nonparametric nature of the data. Kaplan-Meier survival analysis was used to calculate time at risk, incidence rate, and survival times for each group. Results: A total of 185 knees (bracing group: 123 [66.5%] knees; no-bracing group: 62 [33.5%] knees) were analyzed. Overall, 142 (76.8%) knees were successfully treated nonoperatively. Transition to surgery occurred in 43 (23.2%) knees. There were no differences in transition to surgery by groups, with no differences seen by group. Of the knees that did not transition to surgical care, 65 (71.4%) in the bracing group and 38 (74.5%) in the no-bracing group received RTP clearance ( P = .693). PRO scores were similar between the 2 groups at the time of RTP clearance. Conclusion: The inclusion of an unloader brace in the nonoperative treatment for stable MFC OCD lesions did not decrease the likelihood of patients undergoing surgical intervention or improve their PRO scores at the time of RTP clearance. Registration: NCT02771496 (ClinicalTrials.gov identifier).

Abstract A short diagnosis-to-treatment interval independently predicts inferior outcomes in follicular lymphoma. Using international discovery and validation cohorts, we demonstrate its prognostic value beyond established prognostic indices, with implications for risk stratification, clinical trial design, and interpretation.

OBJECTIVE This study investigated the relationship between diabetes and the incidence of postoperative dysphagia following cervical spine surgery (CSS). METHODS A prospectively collected multi-institutional quality registry was retrospectively reviewed. Patients who underwent CSS were categorized on the basis of diabetes status, and correlations with preoperative and postoperative Eating Assessment Tool-10 (EAT-10) dysphagia questionnaire scores were assessed. Mixed-effects logistic regressions were performed to examine the impact of preoperative diabetes on postoperative dysphagia. RESULTS Of the 2001 patients who met the inclusion criteria, 400 (20%) had diabetes. Baseline dysphagia rates were not significantly different between groups (18% vs 14%, p = 0.08). Patients with diabetes had a significantly higher incidence of dysphagia at 1 month (66% vs 54%, p = 0.002), 3 months (39% vs 26%, p < 0.001), and 12 months (33% vs 24%, p = 0.004) after surgery compared to patients without diabetes. Including baseline dysphagia as a fixed effect, multivariable analysis indicated that diabetes was a significant predictor of postoperative dysphagia at 1 month (OR 1.46, p = 0.041) and 3 months (OR 1.63, p = 0.001) but not at 12 months (OR 1.21, p = 0.3). In patients with no baseline dysphagia, those with diabetes (329 of 400 [82.3%]) had a significantly higher incidence of new dysphagia than nondiabetics at 1 month (62% vs 50%, p = 0.003), 3 months (34% vs 21%, p < 0.001), and 12 months (27% vs 18%, p = 0.001). The mean change in EAT-10 scores between baseline and 12 months was significantly worse in patients with preoperative diabetes (2.440 ± 5.013 vs 1.688 ± 4.139, p = 0.025). Multivariable analysis indicated that diabetes was a significant predictor of new postoperative dysphagia at 1 month (OR 1.49, p = 0.040) and 3 months (OR 1.81, p < 0.001) but not at 12 months (OR 1.31, p = 0.2). CONCLUSIONS Diabetes is a significant risk factor for experiencing postoperative dysphagia following CSS. Diabetes correlated with higher incidence of dysphagia at all postoperative time points and was a strong independent predictor of postoperative dysphagia at 1 and 3 months.

Abstract Scientific foundation models learn high-dimensional representations from diverse data modalities, yet what they encode and how to extract that knowledge remain open questions. Here we show that probing the internal representations of Evo 2, a 7-billion-parameter genomic foundation model, enables accurate and interpretable genetic variant effect prediction. We introduce a covariance-based probe that captures second-order structure from Evo 2 sequence embeddings to predict variant pathogenicity across variant types and functional consequences, matching or exceeding specialized predictors within their domains. To ground these predictions in known biological mechanisms, we train a complementary panel of probes on existing annotations to detect which genomic properties are disrupted by a variant. This categorized evidence is then integrated with each variant’s genomic context through a language model to generate variant-specific mechanistic hypotheses. Our pathogenicity predictions correlate with experimental measures of variant function, clinical penetrance, and biobank disease associations while the mechanistic hypotheses are consistent with expert reviews, known mechanism classes, and downstream molecular readouts. We release pathogenicity scores, disruption profiles, and contextualized interpretations for 4.2 million variants from the ClinVar database as an open resource through the Evo Variant Effect Explorer (EVEE). More broadly, this structured probing approach offers a general framework for interrogating foundation models across scientific disciplines and grounding their outputs in existing domain concepts.

Abstract Background Approximately 12 000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. Methods We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA, and adult). Results The cohort of 21 712 CNS tumors included 5351 tumors from AYAs (25%), which showed a mixed pattern, with tumors typical of childhood (eg, medulloblastoma) as well as those common in older adults (eg, glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. Conclusion Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

Abstract Immune effector cell–associated enterocolitis (IEC-EC) has been observed after ciltacabtagene autoleucel (cilta-cel [Carvykti]) chimeric antigen receptor T-cell (CAR-T) therapy. It is associated with dismal outcomes and is poorly characterized. Here, we examined its clinical features, risk factors, and proposed management strategies. Among the 229 consecutive patients who received cilta-cel at Mayo Clinic, 9 (3.9%) presented with a nonresolving, nonbloody, grade 3 diarrhea, often requiring prolonged total parenteral nutrition. Gastrointestinal coinfections were seen in most patients. Median time from CAR-T infusion to symptom onset was 85 days (range, 35-166), and there appeared to be a latency from symptom onset to endoscopic evaluation. Histopathology findings resembling a graft-versus-host disease pattern of mucosal injury were most seen on duodenal biopsies, whereas 2 cases had patterns akin to a T-cell lymphoproliferative disorder (1 CD4+ and 1 CD8+). Independent associated factors for IEC-EC included high-risk disease as defined by the International Myeloma Society and International Myeloma Working Group, prolonged cytokine release syndrome, and antecedent delayed neurotoxicity. Response to first-line therapy comprising IV or oral corticosteroids, bile acid sequestrants, IV immunoglobulin, and antimicrobial-directed therapy was poor, with no durable responses. Biologic therapy appeared to induce durable responses in 3 of the 5 patients (2/2 vedolizumab; 1/3 infliximab); none of the responders had gastrointestinal coinfection. Early gastroenterology input for endoscopic evaluation with the inclusion of duodenal biopsy is a key component for diagnosis. Early institution of biologic therapy after failure of a short course of corticosteroids should be considered.