Citations

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.

ABSTRACT Diagnosis The diagnosis of multiple myeloma requires ≥ 10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥ 60%, serum involved/uninvolved free light chain (FLC) ratio ≥ 100 (provided involved FLC is ≥ 100 mg/L and urine monoclonal protein is ≥ 200 mg/24 h), or > 1 focal lesion on magnetic resonance imaging. Risk Stratification High‐risk multiple myeloma is defined by the presence of del(17p), p53 mutation, or bi‐allelic del(1p); t(4;14), t(14;16), t(14;20) in combination with gain(1q) or del(1p); or gain(1q) plus del(1p). Initial Therapy Initial therapy consists of a quadruplet regimen consisting of anti‐CD38 monoclonal antibody (daratumumab or isatuximab) plus bortezomib, lenalidomide, dexamethasone (VRd) followed by autologous stem cell transplantation in eligible patients. Selected standard risk patients can delay transplant until first relapse. Frail patients who are not candidates for transplant are treated with a triplet regimen, either anti‐CD 38 antibody plus lenalidomide and dexamethasone, or VRd. Maintenance Therapy Standard maintenance is lenalidomide in combination with daratumumab or isatuximab. Lenalidomide is discontinued after 2 years in standard‐risk patients. Bortezomib plus lenalidomide is an alternative option for high‐risk myeloma. Management of Relapsed Disease Major options are chimeric antigen receptor T (CAR‐T) cell therapy, bispecific antibodies, various triplet regimens, and belantamab mafadotin. Management of Smoldering Multiple Myeloma Daratumumab for 3 years should be considered in high‐risk smoldering multiple myeloma.

Abstract Purpose Validate the semiquantitative (SQ)-MRI score for chronic pancreatitis (CP) diagnosis in an independent, multicenter cohort. Methods We analyzed MRIs performed at baseline in 337 participants with acute (AP) or recurrent AP (RAP) and 67 with non-calcific chronic pancreatitis (NCCP) enrolled in the PROCEED study from 6/2017 to 3/2023. MRIs were performed at multiple clinical centers using site-specific clinical protocols and a variety of MRI vendors to evaluate the SQ-MRI score in a real-world setting. The SQ-MRI score was calculated using the T1 signal intensity ratio of the pancreas to the spleen (T1 score), arteriovenous enhancement ratio (AVR), and pancreatic body diameter (PBD). We adjusted for confounding by participant characteristics via propensity score weighting. Results Median AVR was higher in AP/RAP (1.18, IQR: 0.97–1.44) than in the NCCP group (1.03, IQR: 0.78–1.22, p = 0.007). Pancreatic body diameters were larger in AP/RAP than in the NCCP group − 7–14 mm (10% vs 25%), 14–20 mm (40% vs 54%), and > 20 mm (50% vs 21%), respectively ( p < 0.01). Median T1 score was higher in AP/RAP (1.18, IQR: 0.96–1.40) than in the NCCP group (1.04, IQR: 0.86–1.32, p = 0.10). Median SQ-MRI score in the AP/RAP group was significantly lower, 1.91 (IQR: 0.97, 2.95), than in the NCCP group, 2.74 (IQR: 2.04–4.03) ( p < 0.001). The propensity score-adjusted AUC for SQ-MRI to distinguish AP/RAP from NCCP was 0.64, which was higher than for individual parameters. Conclusion We have validated the SQ-MRI score in a multicenter cohort using an independent, real-world MRI dataset.

Objective: Health care delivery has undergone a shift from in-person visits to more remote consultations via telehealth. Despite the increasing adoption of telehealth for tertiary medical centers’ new patient visits, its impact on subsequent in-person health care utilization has not been widely studied. Our objective was to examine differences in health care services used by patients who established care in-person versus those who initiated care remotely via telehealth. Methods: We conducted a retrospective review of all patients who established care at one of our three main Mayo Clinic campuses through either an in-person or telemedicine visit between September 1, 2023, and September 30, 2024. We analyzed aggregate data related to downstream in-person services encompassing diagnostic studies, outpatient procedures, surgical procedures (referred to as “surgical yield”), specialist consultations, and follow-up appointments. Results: This study evaluated 252,356 new patient visits, of which 14,915 (5.9%) were performed remotely via telemedicine. Patients who established care in-person had an average of 10.47 subsequent in-person visits. Among patients who initiated care via telemedicine, 62.7% (9,351) later received in-person services, with an average of 16 in-person visits per patient. Surgical yield was higher for patients who started remotely via telehealth and then came on-site, at 29% compared to 16% for those who started with an on-site visit. States bordering the clinic locations had increased percentages of in-person visits compared to states that required patients to travel longer distances. Conclusions: Patients who established care through an initial telemedicine appointment and then came on-site had more downstream encounters and surgical procedures than those who began in-person. This may be due to the ability to efficiently coordinate multiple appointments within a condensed timeframe, optimizing the planning of on-site visits. Additionally, both patients and providers may selectively utilize telemedicine to identify individuals who would derive the greatest benefit from in-person care.

Background: Telomeres are repetitive sequences at the end of linear chromosomes that preserve genetic information. Patients with telomere biology disorders (TBDs) are subject to multiorgan manifestations, which include the liver. However, due to the rare nature of the disorder, these manifestations are not fully characterized. Methods: Here, we describe the hepatic manifestations of patients with TBD at a large tertiary center within a specialized TBD clinic; 121 consecutive patients with TBD seen from 2017 to 2024 were included. The median age of the TBD diagnosis was 43 years old, with 60% male. The most common pathogenic/likely pathogenic variant was TERT (25%), followed by RTEL1 (10%) and TERC (7%). Results: Evidence of hepatic involvement in TBD was observed in 60% of patients (73 of 121), as determined by imaging studies or abnormal liver chemistries. Hepatic steatosis was the most prevalent imaging finding (56%), while a cholestatic pattern of liver injury was the predominant laboratory abnormality (73%). Biopsy-proven portosinusoidal vascular disorder was present in 4 patients. Findings of portal hypertension were observed in 25 patients (34%), with decompensation observed in 12 patients (16%). Traditional liver imaging modalities (computer tomography, ultrasound, and MRI) were compared with magnetic resonance elastography in 41 patients. Of these, 7 patients had abnormal magnetic resonance elastography with normal traditional imaging (17%), indicating higher sensitivity of magnetic resonance elastography to detect liver involvement. Conclusions: This study describes the liver manifestations within a cohort of patients with TBD with findings of portosinusoidal vascular disorder and hepatopulmonary syndrome similar to other cohorts and a noted higher prevalence of hepatic steatosis as compared with the general population. Liver stiffness measurements, integrated with imaging and laboratory testing, further improve characterization of hepatic manifestations in TBD.

Introduction: Flipped classroom models, which use active, case-based discussion, have shown promise across graduate medical education. Previous literature demonstrates that transitioning to a flipped classroom model resulted in significant increases in overall Orthopaedic In-Training Examination (OITE) scores. This observational study retrospectively compares foot and ankle OITE scores for orthopaedic surgery residents before and after implementation of a flipped classroom curriculum. Methods: This retrospective study reviewed OITE scores for orthopaedic residents, comparing a lecture-based curriculum (n = 49) to a flipped classroom curriculum (n = 61). Residents who started their second year in July 2020 or later were defined as treated. The curriculum is given to the postgraduate year-2 (PGY2) residents only. Percentage of correct foot and ankle questions (F&A) were analyzed via mixed-effects models using random-subject intercepts. Fixed effects included PGY, overall performance on other sections, and flipped classroom status. All statistical analyses were performed in R version 4.4.1. Results: Residents in the flipped classroom cohort demonstrated a statistically significant increase in F&A questions answered correctly. The average increase was 7% (95% confidence interval: 4%, 10%; p < 0.001). This improvement trend became clearly visible in PGY3 and grew stronger in senior residents. Specifically, PGY3 residents improved their mean percentage correct from 62.26% to 66.07% (p = 0.16). PGY4 residents improved from 69.16% to 74.83% (p = 0.013), and PGY5 residents improved from 69.03% to 75.53% (p = 0.006). Historically, approximately 75% of traditional PGY5 residents scored lower on the F&A section than on the rest of the examination. Conversely, in the flipped classroom group, approximately 75% of PGY4 and PGY5 residents scored higher on the F&A section compared with other sections Discussion: The implementation of a flipped classroom model was associated with a statistically significant improvement in resident performance on the F&A section of the OITE. The educational benefits of this curriculum appear cumulative over the course of residency, with the most substantial performance gains realized by senior residents in their fourth and fifth years of training. Level of Evidence: Level III , Observational Study. See Instructions for Authors for a complete description of levels of evidence.

The advent of high-throughput sequencing technologies has revolutionized cardiovascular genetics, generating vast amounts of data. A major challenge in the genomic era is the efficient and accurate identification of causative genetic variants associated with cardiovascular disease. Artificial intelligence (AI)-driven computational approaches offer a powerful solution by enabling the automation of variant classification, improving consistency and reproducibility, and enhancing predictive accuracy. These methods may guide not only variant classification, variant effect prediction, and clinical prioritization, but also open the door to data-driven precision medicine, enabling more accurate and individualized diagnoses and targeted therapeutic strategies tailored to each patient’s unique genetic and clinical profile. This state-of-the-art review provides a structured overview of AI methodologies applied to cardiovascular genomics, beginning with rule-based expert systems that encode standardized guidelines for consistent variant interpretation. Next, we examine machine learning approaches capable of identifying complex patterns in annotated multimodal clinical and multi-omic datasets. The role of deep learning algorithms is highlighted for their ability to extract features from high-dimensional, unstructured data relevant to cardiovascular disease. In addition, the potential of generative AI is explored, including applications in synthetic data generation, variant impact prediction, and automated summarization of biomedical literature. Despite advances, several challenges remain, including data heterogeneity, the need for explainable AI models to elucidate the decision mechanisms, and the complexity linked to the integration of AI-based tools into clinical workflows. Addressing these issues requires interdisciplinary collaboration among clinicians, geneticists, data scientists, and bioinformaticians to ensure the effective translation of AI-generated insights into clinical practice. This review aims to provide a comprehensive perspective on the evolving role of AI in cardiovascular genomics and its implications for advancing precision medicine.

Polycythemia vera is characterized by erythrocytosis and increased risk of thrombosis. Sapablursen is an antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6), increases hepcidin production, and reduces iron availability for erythropoiesis. IMPRSSION; an ongoing phase 2a, randomized, open-label study includes patients meeting 2016 WHO criteria for polycythemia vera, requiring ≥3 phlebotomies within 6 months of screening and ≥1 phlebotomy within the last 12 weeks. Cohort A (120 or 80 mg) and Cohort B (40 mg) received sapablursen subcutaneously once every 4 weeks (Q4W). The primary efficacy endpoint was the reduction in phlebotomy frequency from baseline to weeks 17-37 in patients who received ≥1 dose. Forty-nine patients received ≥1 sapablursen dose (median age 61 years; 82% male). The baseline mean±SD weekly phlebotomy rate was 0.15±0.07 in Cohort A; 0.17±0.07 in Cohort B and was reduced by -0.10 (95%CI, -0.13, -0.07; n=32;p&lt;0.0001) in Cohort A; -0.10 (95%CI, -0.14, -0.06; n=17;p=0.0001) in Cohort B. Sapablursen reduced the median (IQR) number of phlebotomies from 5.0 (3.0-6.0,Cohort A; 3.5-6.5,Cohort B) at baseline (26-weeks) to 0 (0-1.0) in the efficacy evaluation window (20-weeks) in Cohort A and 1.5 (0-2.5) in Cohort B. Most adverse events were mild or moderate; anemia and fatigue were most common. The mean change in MPN-SAF-TSS at week 37 was -6.21 points (95%CI: -10.56, -1.85, p=0.0052) in Cohort A; -2.71 points in Cohort B (95% CI: -8.33, 2.91, p=0.34). Sapablursen reduced phlebotomy need, improved symptoms, and was safe and well-tolerated in patients with polycythemia vera. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov: NCT05143957)