Citations

Abstract Motivation Illumina DNA methylation arrays have evolved rapidly, expanding genomic coverage while introducing backward incompatibilities by removing many CpG sites present in earlier versions. These changes result in systematic missing values when integrating data across array generations and substantially limiting the reuse of legacy datasets. Results We developed a two-stage framework for imputing missing DNA methylation values. The procedure first imputes randomly missing values using standard imputation techniques and then addresses systematic missingness using multi-output machine learning models, including support vector regression, nearest-neighbor methods, random forest models, and deep neural networks. When evaluated on real datasets with up to fifty percent induced missingness, the proposed framework consistently outperformed conventional imputation approaches. It also accurately imputes the missing CpG sites between methylation arrays and reduced representation bisulfite sequencing data, enabling robust cross-platform data integration. Analyses of large brain tumor methylation datasets demonstrate that the method restores array-specific methylation patterns while preserving biological complexity. Importantly, imputing missing methylation sites significantly improves the performance of epigenetic age prediction models. Availability and implementation This tool is implemented in the Python package “ultra-impute,” freely available at https://github.com/liguowang/ultra-impute. A code snippet demonstrating the usage of the ultra-impute package is provided in a Jupyter Notebook (https://github.com/liguowang/ultra-impute/blob/master/doc/Tutorial.ipynb).

ABSTRACT Background One in five emergency department (ED) visits is by older adults aged 65+ years. Clinical practice guidelines are needed to optimize patient care by translating the best available evidence into actionable recommendations to guide person‐centered management for this medically complex and growing patient population. Our objective was to understand contributors' experiences and share best practices to inform other guideline working groups. Methods We conducted a qualitative study based on thematic analysis with an interpretivist paradigm in June–July 2025, using semi‐structured interviews of Geriatric Emergency Department (GED) Guidelines 2.0 contributors to understand their experiences. Interviews were transcribed, independently reviewed by team members, and reflexively coded to identify themes. Results We interviewed 18 participants. Four main themes emerged: (1) motivations for participation, (2) varying opportunities to be involved, (3) personal benefits, and (4) challenges for improvement. Participants contrasted the strengths of shared learning and development with the burdens of organization and coordination. Conclusion Contributors to the GED Guidelines 2.0 reported a positive experience. They joined because they wanted to contribute to better care of older patients and to achieve personal and professional goals. Many cited that their roles aligned with their strengths and expertise. They also gained skills and knowledge on systematic reviews and benefited from networking. Future groups planning a similar process should consider having multiple levels of leadership, experts in systematic reviews, regular reminders, and creative incentives to improve the process and foster improved networking opportunities within their disciplines.

Background: Loeys–Dietz syndrome (LDS) is an autosomal dominant aortopathy characterized by aggressive aneurysm formation and arterial dissections. Pregnancy-related outcomes and timing of LDS diagnosis remain poorly characterized. Methods: Demographics, genetic, obstetric, and vascular data was collected from genetically or clinically confirmed individuals with LDS seen at the three Mayo Clinic sites from 2018 to 2025. Aneurysm progression, new aneurysm formation, and arterial dissections were recorded across all vascular beds. Vascular events were assessed during pregnancy, within 12 months postpartum, and during breastfeeding. Comparative analyses were performed between women with and without a history of pregnancy, and a single-arm descriptive analysis was conducted among patients who experienced vascular complications during the peripartum period. Continuous variables were compared using the Mann–Whitney U test, while categorical variables were analyzed using chi-square or Fisher exact tests. Results: Of 47 women with LDS, 24 had a history of pregnancy, accounting for 54 pregnancies. In the comparative analysis, age at LDS diagnosis differed significantly between women with and without a prior pregnancy: women without prior pregnancy were diagnosed at a younger age (median 23.5 years [IQR 10.8–41.0], n = 23) than those who had been pregnant (median 53.5 years [IQR 43.0–59.3], n = 24). Among pregnant women, the median age at first pregnancy was 28 years (IQR 23–34); only 4 (16.7%) knew their diagnosis before pregnancy. Of 54 pregnancies, 40 (74.1%) resulted in live birth, with 23 (57.5%) vaginal and 17 (42.5%) cesarean deliveries; preterm delivery occurred in 1 (2.5%) pregnancy, and postpartum hemorrhage in 2 (5.0%). No maternal deaths, aortic dissections, or uterine ruptures occurred during gestation or the first postpartum year. In addition, 14 women (58.3%) developed aneurysms, 6 (25.0%) experienced at least one arterial dissection, and 7 (29.2%) required surgical repair, predominantly involving the ascending and abdominal aorta. The prevalence of vascular complications did not differ significantly between groups. Conclusions: In this LDS cohort, pregnancy and the early postpartum period were not accompanied by acute aortic catastrophes, despite frequent diagnostic delay. Although women without prior pregnancy were diagnosed at a younger age, the overall burden of vascular and morphologic complications did not differ significantly by pregnancy history. These findings highlight the importance of long-term cardiovascular follow-up in women with LDS.

Context: Traditional Chinese medicine (TCM) techniques, grounded in TCM theory, offer flexible and personalized therapeutic strategies. Increasing evidence indicates that gut microbiota dysbiosis is closely associated with the onset and progression of various diseases, highlighting a complex mutual relationship. Investigating the interaction between TCM techniques and gut microbiota may provide both a theoretical and practical foundation for clinical application. However, comprehensive systematic analyses remain limited. Objective: This study aimed to identify core themes and emerging trends in research on the interactions between TCM techniques and gut microbiota. In addition, it sought to explore underlying correlations using data mining approaches to provide insights supporting clinical applications and mechanistic studies. Materials and Methods: A systematic literature review was conducted using the Web of Science Core Collection and China National Knowledge Infrastructure for bibliometric analysis. Co-occurrence analysis was performed using CiteSpace software to identify research characteristics and development trends. Key data were extracted and visualized through an interactive network diagram generated with Cytoscape. Results: Current research predominantly focuses on acupoint application, moxibustion, and TCM enema, all of which exhibit significant effects in promoting beneficial microbiota and suppressing pathogenic strains. The regulatory impact of these TCM techniques on gut microbiota is closely associated with inflammatory response pathways and immunity. Conclusions: TCM techniques are extensively applied in disease management. Among them, moxibustion, acupoint application, TCM enema, and Tuina remain prominent and evolving areas of interest. Further empirical research is warranted to elucidate the biological mechanism underpinning these effects within the guidance of TCM pattern theory.

Background Monensin, a Na + ionophore, can increase cytosolic Ca 2+ ([Ca 2+ ] i ) by reversing the Na + /Ca 2+ exchange mechanism. This study provided additional insights into the mechanism of this Na + ionophore-induced increase in [Ca 2+ ] i , and emphasized the critical role of phospholipase C (PLC) in amplifying Na + /Ca 2+ exchange-induced Ca 2+ influx and subsequent arachidonic acid (AA) release in FRTL-5 thyroid cells. The possible involvement of protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and GTP-binding (G) protein in mediating monensin-induced AA release was also explored. Methods FRTL-5 thyroid cells were maintained in Coon's modified Ham's F-12 medium supplemented with a 6-hormone (6H) mixture. Cytosolic Ca 2+ was measured by using indo-1 AM and a dual-wave-length spectrofluorometer. Release of 3 H-labeled inositol trisphosphates and arachidonic acid were determined by a scintillation counter. Results In Hank's balanced salt solution with Ca 2+ (HBSS+), monensin (100 µmol/L) induced a 2.3-fold sustained Ca 2+ increase associated with IP 3 generation and a 6-fold increase in AA release. Deletion of extracellular Ca 2+ , or replacement of Na + by choline chloride in the medium, reduced the [Ca 2+ ] i increase by 77% and completely prevented the monensin-induced rise in AA release. Similar inhibitory effects were observed in cells pretreated with a Na + channel blocker, or Na + /Ca 2+ exchange inhibitors. In HBSS without Ca 2+ (HBSS-), monensin induced a 1-fold transient [Ca 2+ ] i increase but did not increase the AA. This Ca 2+ increase was not suppressed by U-73122, a PLC inhibitor. In HBSS+, U-73122 did not affect the monensin-induced initial transient peak increase of [Ca 2+ ] i , but reduced the sustained second phase of [Ca 2+ ] i from 400 nmol/L to 250 nmol/L, and completely blocked AA release. A phospholipase A 2 (PLA 2 ) inhibitor blocked the monensin-induced AA release without affecting the [Ca 2+ ] i increase. Inhibition of PKC prevented 87% to 94% of the monensin-stimulated AA release. The monensin-induced AA release was also inhibited 94% by pertussis and 51% by a MAP kinase cascade inhibitor. Conclusions The results suggest that monensin initiates an increase in [Ca 2+ ] i via a Na + /Ca 2+ exchange mechanism that triggers more pronounced and sustained [Ca 2+ ] i increase via activation of PLC and Ca 2+ influx. The PLC activation, followed by sustained Ca 2+ influx and PKC activation, is a prerequisite for PLA 2 -mediated processes in monensin-challenged FRTL-5 thyroid cells. Key words: FRTL-5 thyroid cells • phospholipases • protein kinase C • MAP kinase • cell calcium

Context.— Pathology is essential to global health care, yet disparities remain in access to education and training. The College of American Pathologists (CAP) Foundation addresses these gaps through grants and awards that support trainees, early-career pathologists, and initiatives promoting equity worldwide. Since 2015, total funding has increased from $18,400 to $84,098, an astounding 357%. Objective.— To evaluate the CAP Foundation Grants and Awards Program during a 10-year period, assessing financial investment, award distribution, recipient characteristics, and impact. Design.— A mixed-methods retrospective study integrated (1) quantitative analysis of program data, (2) qualitative feedback from awardees, and (3) a quantitative award impact survey of past CAP Foundation awardees. Variables included demographics, award type, funding amounts, geographic distribution, and career stage. Surveys assessed professional development, mentorship, and long-term engagement with CAP. Results.— From 2015 to 2024, a total of 744 applicants submitted 760 applications, resulting in 355 awards across 14 categories. Applications increased more than 8-fold, peaking in 2023, with surges during the COVID-19 pandemic. Medical student applications grew from 1 in 2020 to 17 in 2024 (76% annual growth); 9 of 12 Medical Student Travel Award recipients (75%) entered pathology residency. Geographic disparities were noted, with smaller residency programs showing higher per capita application rates. Among 174 survey respondents, 129 (74%) reported networking benefits, 127 (73%) learning benefits, and 99 (57%) mentorship benefits, though only 49 (28%) sustained long-term mentoring relationships. Conclusions.— The CAP Foundation’s awards program has expanded access, supported career development, and fostered future pathologists. Strengthening long-term mentorship and bridging education-to-practice gaps may further enhance its impact.

Convergent framework for future POC cancer diagnostics aligning clinical needs (why), enabling technologies (how), and translational bridges. It integrates lab-on-chip biosensing and analytics for decentralized, early, longitudinal care.

Objectives: This study aims to identify retinal biomarkers of NOTCH3 mutation carriers using optical coherence tomography (OCT) data from the UK Biobank. Methods: We conducted a cross-sectional, matched case-control study of individuals with or without NOTCH3 mutation from the UK Biobank between 2006 and 2010. All participants had macular OCT scan and cognitive assessment. Cases were identified based on pathogenic/likely pathogenic NOTCH3 mutations and 1:1 matched with controls based on age, sex, hypertension, diabetes mellitus, and cigarette smoking status. Baseline characteristics and cognitive test scores were compared using χ 2 or Mann-Whitney U test appropriately. Macular thickness at central, inner, and outer subfields and at each retinal layer was compared using Wilcoxon signed-rank test. Results: Our analysis included 134 participants (67 cases, 67 controls) with a mean age of 54 ± 9 years. NOCTH3 mutation carriers performed worse in prospective memory ( P =0.043), verbal and numerical reasoning ( P =0.178), visual memory ( P =0.227), and processing speed ( P =0.101) than matched controls. There were no differences in visual acuity between the 2 groups. NOTCH3 mutation carriers had significantly thinner macular inner subfield at the superior ( P =0.006), temporal ( P =0.008), and nasal ( P =0.034) quadrants, and significantly thinner macular RNFL ( P =0.008) compared with age-, sex-, and vascular risk factor-matched controls. Conclusion: The presence of NOTCH3 mutation is associated with reduced thickness in the inner macular subfield and macular RFNL. These retinal changes may reflect early pericyte dysfunction and microvascular ischemia. Longitudinal studies are needed to assess the temporal relationship between these retinal changes, cerebrovascular disease progression, and clinical severity of disease.

Abstract The phase 1/2 Intergroup study E4412 investigated checkpoint blockade with nivolumab (Nivo) and ipilimumab (Ipi) combined with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) in relapsed/refractory classic Hodgkin lymphoma. A total of 147 patients aged ≥12 years were randomized between BV/Nivo and BV/Ipi/Nivo; 132 patients were included in the primary efficacy analysis. The complete response (CR) rate, was 64.7% (52.2, 75.9) for BV/Nivo and 70.3% (57.6, 81.1) for BV/Ipi/Nivo (1-sided P = .29). The median survival follow-up was 38.0 months (interquartile range, 32.6-48.1). Progression-free survival (PFS) did not significantly differ between the 2 arms (hazard ratio [HR], 0.78, confidence interval [CI], 0.39-1.57; 1-sided P = .24). Treatment-related grade 3+ toxicities in the adult cohort, excluding rash, were similar between both arms (38.5% BV/Nivo and 39.3% BV/Ipi/Nivo); there was a higher frequency of grade 3 rash with BV/Ipi/Nivo (24.6%) compared with BV/Nivo (9.2%). We compared PFS by stem cell transplantation (SCT) status in a planned before hoc comparison; 58 patients received SCT, and 36-month PFS (from SCT) was >90% for both arms. Sixty-six patients were progression free after the first scan and did not undergo SCT. The 36-month PFS was 73.0% (54.5, 85.0) for BV/Ipi/Nivo compared with 45.8% (26.3, 63.4) for BV/Nivo (HR, 0.45; CI, 0.19-1.08; 1-sided P = .03). The study did not meet its primary end point of superior CR rate for the triplet, but it supports the use of checkpoint antibody-drug conjugate induction prior to auto SCT, and there is an intriguing signal of disease control for patients wishing to defer or avoid SCT with the triplet of BV/Ipi/Nivo. This trial was registered at www.clinicaltrials.gov as NCT01896999.