Citations

Cardiovascular responses exhibited both sex-dependent and sex-independent alterations in acute pancreatitis models of differing severity. In cerulein-induced mild acute pancreatitis, both sexes showed enhanced cardiac systolic function with only modest differences in vascular permeability. In severe acute pancreatitis, vascular permeability was similar between sexes, but compensatory cardiac systolic augmentation was preserved only in females. Angiopoietin-2 was identified as a compensatory cardiac mediator in severe disease.

Messenger RNA (mRNA) therapeutics have transformed vaccination and protein replacement strategies, yet efforts to improve their performance have focused largely on sequence engineering, nucleotide modification, and delivery vehicles. Here we show that mRNA function can be controlled by rational design of higher-order RNA architectures. We develop self-assembling mRNA origami (mRNA-OG), a class of unimolecular RNA nanostructures that encode protein-coding sequences within higher-order, programmable, and compact nucleic acid architectures. Using computational design and experimental validation, we demonstrate that mRNA-OG folds into well-defined nanostructures while remaining translationally competent in mammalian cells. Although folded mRNA-OG recruits ribosomes comparably to unfolded constructs, it produces lower protein output, indicating that RNA architecture can directly influence translational efficiency. The compact geometry of mRNA-OG also enhances encapsulation by cationic lipid delivery systems, suggesting a structural route to improved cargo packaging. Beyond its effects on translation, mRNA architecture modulates innate immune recognition. In primary human dendritic cells, folded and unfolded mRNA-OG elicit distinct cytokine programs and differential activation of stress-response pathways, including a modest induction of the integrated stress response that is not fully explained by canonical PKR signaling. Our results establish programmable structure as a new design parameter for mRNA therapeutics that can affect its functionality, delivery properties, and immune sensing.

Introduction Krackow Type II valgus deformity is defined by attenuation of the medial collateral ligament (MCL). However, little quantitative information exists about associated intra-operative MCL laxity. Furthermore, a corollary may exist in varus deformity with associated lateral ligament laxity but is poorly described. Robotic-assisted total knee arthroplasty (raTKA) includes quantitative assessment of intraoperative ligament function. This study evaluated whether increased preoperative medial or lateral radiographic joint space width (JSW) in valgus or varus knees, was associated with increased intraoperative soft tissue laxity of the respective compartment. Methodology Intraoperative data from 348 consecutive raTKAs with 270 varus knees (hip-knee-ankle angle [HKA]<-2°), and 78 valgus knees, (HKA>2°) were retrospectively reviewed. For varus knees, lateral JSW was measured on preoperative, standing anteroposterior radiographs to determine lateral widening (threshold 8.0mm). For valgus knees, medial JSW was evaluated to determine medial widening (threshold 7.0mm). Intraoperative medial and lateral gaps at 0° and 90° had been recorded during manual stress testing. Linear regression was performed to determine associations between intra-operative gaps, radiographic JSW, and HKA. Results 51 varus knees demonstrated lateral widening and 15 valgus knees had medial widening. In varus knees, lateral JSW was positively associated with the lateral extension (β=0.76, P <0.001) and flexion (β=0.74, P <0.001) gaps. Similarly, for valgus knees, medial JSW was positively associated with the medial extension (β=0.75, P <0.001) and flexion (β=0.77, P <0.001) gaps. Conclusion Increased preoperative radiographic JSW of the medial and lateral compartment in valgus and varus knees, predicted increased intraoperative gaps of that compartment, consistent with ligament attenuation.

Importance Cerebral hemodynamic impairment in patients with asymptomatic internal carotid artery (ICA) stenosis is associated with reduced cognition. It is uncertain whether revascularization might be an effective treatment for cognitive impairment in these patients. Objective To test whether any cognitive benefit from revascularization of high-grade, asymptomatic ICA stenosis varies based on the degree of baseline cerebral hemodynamic impairment. Design, Setting, and Participants This substudy was conducted within a multicenter phase 3 randomized clinical trial. Adults (aged 35-86 years) without dementia with eighth-grade education or higher and unilateral asymptomatic ICA stenosis greater than or equal to 70% were enrolled from January 2018 to July 2024 at 61 sites in North America (last follow-up in July 2025). Of 607 participants screened from 2485 in CREST-2, 392 were enrolled. Magnetic resonance or computed tomographic perfusion imaging tested for baseline hemodynamic impairment defined by delayed time-to-peak (TTP) arrival of intravenous contrast in the hemisphere ipsilateral minus contralateral to the stenotic artery. Intervention Carotid revascularization (endarterectomy or stenting) plus intensive medical management (IMM) vs IMM alone. Main Outcomes and Measures The primary outcome was the difference in composite cognitive z score over 1 year based on 5 cognitive tests. The primary analysis tested for an interaction between treatment group (revascularization vs IMM alone) and degree of baseline hemodynamic impairment among those with reduced baseline cognition (cognitive z score ≤−1.0 SD). Results Of 392 participants enrolled (mean age, 71 years; 125 [32%] females), 61 were excluded for missing baseline imaging and 40 for missing cognitive examinations or other covariates, leaving 291 with complete data. Fifty-one had reduced cognition at baseline (25 in the revascularization group and 26 in the IMM alone group). TTP ranged from no interhemispheric TTP delay to a more-than-2-second delay. Mean (SD) cognitive z scores were −1.36 (0.51) at baseline and −1.17 (0.47) at 1 year in the revascularization group and −1.34 (0.83) at baseline and −1.01 (0.97) at 1 year in the IMM alone group. The primary analysis showed no difference in cognition by treatment group over 1 year, adjusting for treatment group × hemodynamic status interaction and other covariates (adjusted difference in cognitive z score, −0.15 SD [95% CI, −0.54 to 0.24]). The interaction was not significant (β estimate = 0.018 [95% CI, −0.025 to 0.061]; P = .40). Conclusions and Relevance In this substudy of a randomized clinical trial, there was no differential effect of revascularization vs IMM alone on cognition over 1 year by cerebral hemodynamic status among those with baseline reduced cognition, suggesting that revascularization does not improve cognitive dysfunction by restoring flow to the brain in chronic asymptomatic carotid stenosis. Trial Registration ClinicalTrials.gov Identifier: NCT03121209

Abstract Purpose Large language models (LLMs) have proven performance for certain diagnostic tasks; however, limited studies have evaluated their consistency in recommending appropriate medication regimens for a given diagnosis. Medication management is a complex task that requires synthesis of drug formulation and complete order instructions for safe use. Here, the performance of GPT-4o, an LLM available with OpenAI’s ChatGPT, was tested on 3 medication management tasks. Methods GPT-4o performance was tested on 3 medication tasks: identifying available formulations for a given generic drug name, identifying drug-drug interactions (DDIs) for a given medication regimen, and preparing a medication order for a given generic drug name. For each experiment, the model’s raw text response was captured exactly as returned and evaluated using clinician evaluation in addition to standard LLM metrics, including Term Frequency-Inverse Document Frequency (TF-IDF) vectors, normalized Levenshtein similarity, and Recall-Oriented Understudy for Gisting Evaluation (ROUGE-1/ROUGE-L) F1 score between each response and its reference string. Results For the first task of drug-formulation matching, GPT-4o had 49% accuracy for generic medications being matched to all available formulations, with an average of 1.23 omissions per medication and 1.14 hallucinations per medication. For the second task of drug-drug interaction identification, the accuracy was 54.7% for identifying the DDI pair. For the third task, GPT-4o generated order sentences containing no medication or abbreviation errors in 65.8% of the cases. Conclusion Model performance for basic medication tasks was consistently poor. This evaluation highlights the need for domain-specific training through clinician-annotated datasets and a comprehensive evaluation framework for benchmarking performance.

ABSTRACT Background Immune checkpoint inhibitors (ICIs) enhance anti‐tumour immunity by modulating immune pathways but can also trigger immune‐related adverse events. We aimed to evaluate the risk of developing coeliac disease (CeD) among patients with malignancy treated with ICIs. Methods Using the TriNetX US Collaborative Network, we identified adults (≥ 18 years) diagnosed with malignancies for which ICIs are routinely used between January 2010 and December 2024 and stratified them by exposure to immune checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, tremelimumab, or avelumab). Patients with pre‐existing celiac disease (CeD) were excluded. Cohorts were propensity score matched for demographics and autoimmune comorbidities. The primary outcome was incident CeD occurring ≥ 90 days after the index event. Adjusted hazard ratios (aHRs) were calculated, with subgroup analyses by age and sex. Statistical significance was defined as p < 0.05. Results After propensity score matching, 158,208 patients were included in each cohort. CeD was diagnosed more frequently among patients exposed to ICIs than among matched controls (0.152% vs. 0.071%; aHR 3.95, 95% CI 3.11–5.03; p < 0.001), corresponding to a number needed to harm (NNH) of 1235. The increased risk persisted across sex and age subgroups, including females (aHR 3.43, 95% CI 2.55–4.62), males (aHR 5.36, 95% CI 3.53–8.12), with the risk being highest among patients older than 60 years (0.14% vs. 0.06%; aHR 4.24, 95% CI 3.17–5.67; p < 0.001). Conclusion In this large real‐world cohort, ICI exposure was associated with nearly a fourfold increase in the risk of being diagnosed with CeD compared with matched controls.

Abstract Purpose To evaluate the association of long-term, continuous tirzepatide use with cardiometabolic risk parameters and estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk in real-world practice. Methods This multicenter retrospective observational study included 1,028 adults with overweight or obesity who received weekly subcutaneous tirzepatide for at least 12 months within the Mayo Clinic Health System from June 2022 through May 2024. ASCVD risk analyses included 275 individuals with complete baseline and 12-month follow-up data. Outcomes were changes in cardiometabolic parameters, estimated 10-year ASCVD risk, and ASCVD risk category. Results At 12 months, median total body weight loss (TBWL) was 12.6%. Fasting glucose, HbA1c, triglycerides, and alanine aminotransferase decreased by 19.5%, 16.0%, 8.5%, and 10.6%, respectively, whereas HDL cholesterol increased by 11.3% (all P &lt; .001). Mean 10-year ASCVD risk did not change significantly overall (mean relative change, −3.7%; P = .18), but changes differed by TBWL category (ANOVA, P &lt; .001). ASCVD risk decreased among individuals achieving 10%–20% TBWL (−9.6%; P = .009) and &gt;20% TBWL (−14.2%; P = .005), but not among those achieving &lt;10% TBWL (+7.7%; P = .22). Low-risk prevalence increased from 38.3% to 46.4% (P &lt; .001), with 11.7% transitioning from higher-risk categories to low risk. Main findings Continuous tirzepatide use for at least 12 months was associated with clinically meaningful improvements in cardiometabolic parameters. Reductions in estimated 10-year ASCVD risk were observed among individuals achieving at least 10% TBWL, supporting greater weight loss as an important marker of cardiovascular risk improvement.

Primary mediastinal B-cell lymphoma (PMBCL) is a rare form of large B-cell lymphoma (LBCL) with around 90% of patients cured with frontline treatment. For relapsed or refractory (R/R) disease, the optimal treatment is unclear. CD19 chimeric antigen receptor-T cell (CAR-T) has been established as the preferred second line (2L) treatment for primary refractory or early relapsing LBCL based on the overall survival benefits observed in the landmark phase III trials. However, PMBCL patients were underrepresented on these pivotal studies. This study evaluated outcomes of 252 patients treated with 2L therapies for R/R PMBCL at 14 US institutions between 2001 and 2025. Platinum-based salvage with intent to proceed to high dose therapy and autologous stem cell transplant (HDT/ASCT) (platinum cohort) and CD19 CAR-T (CAR-T cohort) were given as 2L therapy in the real-world setting in 157 and 26 patients, respectively. Overall response rate (ORR), complete response (CR) rate and median progression-free survival (PFS) were significantly higher in the CAR-T cohort compared with the platinum cohort (ORR: 91.3% vs 44.2%, p &lt;0.001; CR 65.2% vs 14.7%, p&lt;0.001; median PFS not reached vs 3.5 months, hazard ratio (HR) 0.28, 95% CI 0.15-0.54, p=0.001). No significant difference was observed in overall survival. This study demonstrated superior response rate and PFS of CD19 CAR-T over platinum-based salvage with intent to proceed to HDT/ASCT as 2L treatment for R/R PMBCL.

Abstract Objective Interictal epileptiform spikes (IESs) are widely used biomarkers of epileptogenic tissue in presurgical epilepsy evaluation. However, their reliability for seizure onset zone (SOZ) localization in high‐density intracranial electroencephalography (iEEG) remains inconsistent. It is underexplored whether this variability reflects methodological differences across detection algorithms or a limitation of IESs as a biomarker. This study evaluates whether IES detection alone provides sufficient spatial specificity for accurate SOZ localization in iEEG. Methods We systematically benchmarked eight established IES detection algorithms using iEEG recordings from 35 patients with drug‐resistant focal epilepsy. To provide a clinically meaningful reference, algorithm performance was evaluated against the clinically defined SOZ. To refine detection outputs and move beyond only IES detection, we applied masking strategies to isolate informative IES subsets based on rate, amplitude, frequency, and co‐occurrence with high‐frequency oscillations (HFOs). Conceptually, masking acts as a spatial refinement strategy that progressively restricts diffuse IES activity to more focal, pathologically relevant event populations. Results Despite substantial variability in detection characteristics, SOZ localization performance (ratio of events originating from SOZ divided by total number of events) converged within a narrow range (.23–.51), suggesting that IESs exhibit an intrinsic ceiling in SOZ localization performance when used alone. Amplitude‐based masking yielded modest improvements, whereas frequency‐based masking reduced performance. In contrast, IES‐HFO co‐occurrence markedly improved localization, particularly when combined with rate‐based masking, achieving a median SOZ localization ratio of .89, exceeding IESs (.37) and HFOs (.63) evaluated independently. Significance These findings demonstrate that IES‐based SOZ localization may require moving beyond detection‐only approaches. The integration of informed, biomarker‐driven masking strategies provides a more robust framework for identifying the activity most relevant to the epileptogenic network and paves the way for future incorporation into the clinical decision‐making pipeline.

Background: The Accreditation Council for Graduate Medical Education (ACGME) case log system establishes minimum clinical experiences for anesthesiology residency. While core program requirements were last updated in 2016, case log minimums themselves have not undergone a major revision in approximately two decades. Consequently, current requirements may not fully reflect changes in anesthetic practice and the evolving scope of perioperative medicine. In anticipation of major ACGME revisions in 2027, this study aimed to develop consensus-driven recommendations for modernizing residency case logs. Methods: A three-round modified Delphi study was conducted with a nationally representative panel of 60 stakeholders, including anesthesiology residency program directors and academic and private practice anesthesiologists. Panelists evaluated a comprehensive list of potential case categories across three domains: technical skills, surgical case characteristics, and patient demographics. In Round 1, panelists proposed minimum numbers or suggested that no requirement was necessary. Rounds 2 and 3 utilized iterative feedback to determine consensus on the necessity of requirements and specific minimum thresholds. Consensus was defined as at least two-thirds agreement. Results: Sixty invited experts completed all three rounds (100% response rate). The panel reached consensus to recommend new minimum requirements across several areas not currently tracked with minimums, including arterial lines (40), central lines (20), fiberoptic intubation (10), one-lung ventilation (10), neuromonitoring (10), POCUS (10 Cardiac, 10 Lung), and NORA (20 cases). Regarding existing requirements, consensus was reached to recommend increasing total peripheral nerve blocks from 40 to 60, with added requirements for anatomic specificity, and cardiac case minimums from 20 to 25. The panel also established consensus definitions for life-threatening pathologies to standardize reporting. The panel did not achieve consensus on several areas, including, for example, whether a minimum requirement for patients younger than 3 months should be maintained. Conclusion: These findings provide stakeholder-validated recommendations to inform upcoming ACGME requirement revisions.