Citations

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Abstract Aims Transcatheter mitral valve replacement (TMVR) with the Tendyne Mitral Valve System is a treatment option for patients with severe symptomatic mitral regurgitation (MR) unsuitable for conventional mitral valve surgery or transcatheter edge-to-edge repair (TEER). This study sought to evaluate the safety and effectiveness of TMVR through 5-year follow-up. Methods and Results The Tendyne Expanded Clinical Study is a prospective, single-arm, multicentre study that enrolled patients between November 2014 and June 2020. The study enrolled 191 patients (mean age 74.1 ± 8.0 years, 62.8% male, 70.2% New York Heart Association Class (NYHA) class III/IV, 88.5% secondary MR), of whom 186 (97.4%) underwent TMVR with Tendyne. MR grade decreased from ≥3+ in 99.5% patients at baseline to grade ≤1+ in 95.3% at 5 years. In those patients surviving to 5 years (n = 49), durable symptomatic improvement was evidenced by 73.5% patients being in NYHA class I/II at 5 years. The Kansas City Cardiomyopathy Questionnaire overall summary score increased from 48.5 ± 22.5 points at baseline to 67.6 ± 21.5 points at 5 years. Serious adverse events that occurred through 5 years included life-threatening bleeding (11.5%), fatal bleeding (2.6%), renal insufficiency/failure (28.8%), endocarditis (7.3%), device thrombosis (5.8%), and new onset atrial fibrillation (13.1%). No structural device degeneration or device embolism occurred through 5 years. Conclusions The Tendyne TMVR was effective at achieving immediate and sustainable elimination of MR, which was associated with symptomatic improvement and absence of structural valve degeneration in a high-risk cohort over 5 years. These findings support TMVR with the Tendyne System as an alternative for patients with appropriate mitral valve anatomy and symptomatic secondary MR unsuitable for mitral surgery or TEER.

Cellular senescence is an irreversible stress response, which leads to loss of cellular function and remodeling of the cellular secretory profile. In humans, pancreatic β cells undergo cellular senescence during the progression to type 2 diabetes (T2D). However, the mechanism linking β cell senescence to islet dysfunction remains unknown, and thus the therapeutic potential of targeting senescent cells in T2D is not established. Herein, we identified a subpopulation of senescent β cells expressing p21, which emerged early in the progression of T2D in humans and mice. Spatial transcriptomics and proteomics analyses confirmed senescence and loss of cellular identity in this subpopulation in humans. Functional analysis revealed lack of glucose responsiveness, high basal insulin secretion, and transcription of senescence-associated secretory phenotype (SASP) factors. SASP factors from p21 + β cells induced secondary senescence in neighboring cells, characterized by dysfunction and loss of identity. JAK inhibitors counteracted the induction of secondary senescence and restored β cell function in islets from humans with T2D and in mice fed a high-fat diet. These findings reveal the critical role of p21 + β cells in T2D pathogenesis and the therapeutic potential of targeting this pathophysiological process.

ABSTRACT Biological aging greatly impacts the body’s ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell–resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20–80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34–69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A ⁺ senescent cells (SnCs) exhibit loss of β-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A ⁺ SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive ( CDKN2A ⁺) from a maladaptive ( CDKN1A ⁺) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.

Background: Variable terminology is used in the literature to describe facial synkinesis and hypertonicity following incomplete recovery from facial paralysis and its associated medical and surgical treatments. Study Objectives: Establish a nomenclature consensus for this condition among a group of facial nerve experts. Design Type: Consensus study. Methods: Using modified Delphi methodology, an international, multidisciplinary group of facial nerve experts reviewed the terminology for the name of the clinical condition and treatments of interest. Online surveys and a virtual discussion were performed to establish consensus, defined a priori as agreement by 80% of the group. Results: Twenty-five facial nerve experts established consensus after three Delphi rounds. Consensus terminology for the condition is “facial synkinesis” with 84% agreement. Medical treatment is termed “chemodenervation” with 100% agreement. Surgical treatments including “selective facial neurectomy,” “selective facial neurotomy,” “selective facial myectomy,” and “selective facial myotomy,” were defined and reached agreement of 100%. Conclusions: This international group of facial nerve experts has recommended standardized nomenclature for the condition of facial synkinesis and its various treatments. While “facial synkinesis” reached consensus as the preferred term, some experts noted it may insufficiently describe the full clinical spectrum, which includes muscle hypertonicity, weakness, and spontaneous twitching.

Abstract Current discussion surrounding the clinical capabilities of generative language models (GLMs) predominantly center around multiple-choice question-answer (MCQA) benchmarks derived from clinical licensing examinations. While accepted for human examinees, characteristics unique to GLMs bring into question the validity of such benchmarks. Here, we validate four benchmarks using eight GLMs, ablating for parameter size and reasoning capabilities, validating via prompt permutation three key assumptions that underpin the generalizability of MCQA-based assessments: that knowledge is applied, not memorized, that semantic consistency will lead to consistent answers, and that situations with no answers can be recognized. While large models are more resilient to our perturbations compared to small models, we globally invalidate these assumptions, with implications for reasoning models. Additionally, despite retaining the knowledge, small models are prone to answer memorization. All models exhibit significant failure in null-answer scenarios. We then suggest several adaptations for more robust benchmark designs more reflective of real-world conditions.

e19033 Background: CLL tends to affect older individuals, and older patients often endure greater health disparities and treatment burdens that may impact their access to healthcare resources, adherence to treatment regimens and treatment outcomes (UN, Health Inequalities in Old Age). This study aimed to assess treatment utilization patterns, discontinuation, and healthcare resource utilization (HCRU) of 1L use of BTKi in CLL, focusing on older patients ≥65 years (yrs). Methods: A retrospective observational study using the Symphony Integrated Dataverse was conducted to identify adult CLL patients initiating a 1L BTKi (zanubrutinib [ZANU], acalabrutinib [ACA] or ibrutinib [IBR]) treatment regimen from 02/2022 and 09/2024 (index period). Patients were required to have ≥30 days of continuous enrollment in the pre- and post-index periods. Patients initiating a BTKi were further categorized by age at index date. Patient sociodemographic, clinical characteristics, and outcomes were reported in overall and older (≥65 yrs) CLL patients by each BTKi group. Treatment discontinuation rate was examined at 60, 90, 120, 150, 180, and 360 days, and by median time to discontinuation (TTD), estimated using the Kaplan-Meier method, censoring patients at the end of follow-up. HCRU (outpatient, inpatient, and other services) was evaluated during time on treatment and over the follow-up period and reported as per-patient-per-year (PPPY). Results: A total of 6,846 patients initiated a 1L BTKi (ZANU: n=1,853; ACA: 3,519; IBR: 1,474) for CLL during the index period. Patients receiving ZANU were older (mean age: 70.9 yrs; 78% ≥65 yrs) than those receiving ACA (69.4 yrs; 71% ≥65 yrs) and IBR (69.6 yrs; 73% ≥65 yrs). Payer type and geography were significantly different across each BTKi group ( p <.001). There were no significant differences across the BTKis regarding baseline comorbidities. ZANU patients had the longest estimated median TTD overall (ZANU: 18.9 months [m], ACA: 17.8 m, IBR: 14.5 m; p <.001) and in patients ≥65 yrs (ZANU: 17.2 m, ACA: 15.2 m, IBR: 12.6 m; p <.001). ZANU patients also had the lowest estimated discontinuation rates at 60- , 90-, 120-, 150-, 180-, and 360-days post BTKi initiation in the overall and ≥65 yrs groups. There were significant differences across the BTKi group for inpatient visits PPPY in all patients and ≥65 yrs with ZANU having the lowest visits of the BTKis (ZANU: 2.6, ACA: 3.6, IBR: 4.6; p =.029 and ZANU: 2.5, ACA: 4.3, IBR: 5.3; p =.004, respectively). Conclusions: This real-world study demonstrated that CLL patients treated with ZANU had longer TTD, lower discontinuation rates, and less HCRU than ACA and IBR across all patients and specifically in older patients ≥65 yrs. Further studies on long-term and clinical outcomes are warranted.

ABSTRACT Cellular senescence is a stress response mechanism marked by irreversible growth arrest, upregulation of antiapoptotic pathways, loss of cellular function, and remodelling of the cellular secretory profile. In both humans and mice, pancreatic β-cells undergo senescence with age and insulin resistance. Targeted removal of senescent cells in mouse models of diabetes improves glucose homeostasis, demonstrating the role β-cell senescence in diabetes progression. In contrast, β-cell senescence also promotes immune surveillance, promoting β-cell survival and function. Thus, a better understanding of senescent cells’ phenotypic and functional heterogeneity is needed to develop effective therapeutic strategies. Herein, we show that subpopulations of senescent β-cells in mice and humans, which were identified through the expression of Cdkn1a (encoding p21 Cip1 ) and Cdkn2a (encoding p16 Ink4a ) by single-cell RNA sequencing (scRNA-seq), flow cytometry, spatial transcriptomics, and spatial proteomics, exhibit distinct transcriptional and functional identities. The predominant senescent β-cell subpopulation expressed Cdkn1a and was characterized by a lack of glucose responsiveness, high basal insulin secretion, and transcription of canonical SASP factors. The SASP of Cdkn1a -expressing β-cells had non-cell autonomous effects on neighbouring cells. A subset of four SASP factors from Cdkn1a + cells was sufficient to induce secondary senescence and β-cell dysfunction in vitro . JAK inhibitors (JAK1/2 and JAK1/3) counteracted secondary senescence induction and restored β-cell function in high-fat diet-fed mice and human islets from donors with or without type 2 diabetes. GRAPHICAL ABSTRACT

Abstract Melanoma is characterized by its rapid progression and high mortality rates, making early and accurate detection essential for improving patient outcomes. This paper presents a comprehensive review of significant advancements in early melanoma detection, with a focus on integrating computer vision and deep learning techniques. This study investigates cutting-edge neural networks such as YOLO, GAN, Mask R-CNN, ResNet, and DenseNet to explore their application in enhancing early melanoma detection and diagnosis. These models were critically evaluated for their capacity to enhance dermatological imaging and diagnostic accuracy, crucial for effective melanoma treatment. Our research demonstrates that these AI technologies refine image analysis and feature extraction, and enhance processing capabilities in various clinical settings. Additionally, we emphasize the importance of comprehensive dermatological datasets such as PH2, ISIC, DERMQUEST, and MED-NODE, which are crucial for training and validating these sophisticated models. Integrating these datasets ensures that the AI systems are robust, versatile, and perform well under diverse conditions. The results of this study suggest that the integration of AI into melanoma detection marks a significant advancement in the field of medical diagnostics and is expected to have the potential to improve patient outcomes through more accurate and earlier detection methods. Future research should focus on enhancing these technologies further, integrating multimodal data, and improving AI decision interpretability to facilitate clinical adoption, thus transforming melanoma diagnostics into a more precise, personalized, and preventive healthcare service.