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Age-related gastrointestinal dysfunction is common, but the mechanisms of aging-associated smooth muscle failure remain unclear. We show that aging in mice slows whole gut and colonic transit, increases regional stiffness, and reduces smooth muscle contractility. Inducible smooth muscle cell (SMC)– specific deletion of Piezo1 preserved youthful transit and force generation, whereas Piezo1 activation in young mice phenocopied aging-associated transit delay. Single-cell transcriptomics, RNA velocity, stiffness-controlled cell and tissue cultures, and pharmacologic studies revealed that Piezo1 couples increased stiffness to Ca 2+ –calcineurin–NFAT signaling, loss of contractile gene programs, leading to age- related contractile loss and contractile-to-synthetic SMC remodeling and gut wall stiffening. Human intestinal SMCs supported conservation of this pathway, and PIEZO1 gain-of-function carriers showed a trend toward delayed colonic transit. Thus, maladaptive SMC Piezo1 mechanotransduction is a targetable mechanism of aging-associated gut dysmotility. Aging alters organ structure, yet how these changes drive functional decline remains poorly defined. We show that progressive stiffening of the gut with age activates the mechanosensitive ion channel Piezo1 in smooth muscle cells, initiating a maladaptive response that impairs contractility and slows intestinal transit. On the other hand, deletion of smooth muscle Piezo1 prevents age-related gut dysmotility. These findings reveal that age-related physical shifts actively drive functional decline through mechanotransduction pathways. By identifying Piezo1 as a critical link between tissue mechanics and organ aging, this work provides a framework for understanding how mechanical cues contribute to age-related dysfunction in the gut and possibly other smooth muscle organs.

Importance There is no consensus on staging and surveillance imaging for cutaneous squamous cell carcinoma (CSCC). Although imaging has been shown to affect management, broad recommendations from the National Comprehensive Cancer Network have led to variability in clinical practice. Objective To develop multidisciplinary consensus recommendations on the use of staging and surveillance imaging of localized CSCC. Evidence Review A multidisciplinary expert panel across academic and clinical practice settings convened a Delphi consensus, with 3 iterative survey rounds from January to June 2025. Data were analyzed from February 2025 to January 2026. Eligibility defined by at least 1 to 2 CSCC publications during the previous 5 years, involvement in a relevant clinical trial, experience treating at least 3 patients monthly with CSCC, and/or 5 years or longer of clinical practice. Fifty-four experts were invited and 45 (83%) completed all 3 rounds and were included in the final analysis. Structured Delphi surveys evaluated clinical scenarios, imaging modalities, and surveillance strategies for CSCC. Consensus and near-consensus recommendations were generated, defined as 80% or greater and 70% to 79% agreement, respectively. Findings The 45 participants (21 female individuals [47%] and 24 male individuals [53%]; 14 Asian individuals [31%], 1 multiracial individual [2%], and 30 White individuals [67%]) consisted of dermatology (15 [33%]), medical oncology (7 [16%]), radiation oncology (9 [20%]), radiology (9 [20%]), surgery (3 [7%]), and otolaryngology specialists (2 [4%]). The Delphi panel recommended staging and surveillance for CSCCs with at least a 15% risk of metastasis. Consensus or near consensus was reached to recommend staging and surveillance imaging for tumors with a concern for metastasis, bone invasion, invasion beyond subcutaneous fat, large-caliber nerve invasion, or a diameter of 4 cm or larger or the combination of tumors with poorly differentiated histology and any of the following: diameter of 2 cm or larger, lymphovascular invasion and subcutaneous fat invasion, or lymphovascular invasion and small-caliber perineural invasion. Computed tomography imaging was the preferred modality for nodal staging (38 [84%]) and surveillance (35 [78%]). For surveillance duration, consensus was reached to provide imaging for at least 2 years, and near consensus was reached for at least 3 years. Conclusions and Relevance This study provides an expert consensus–based framework to standardize imaging in localized CSCC that may inform future guidelines.

Abstract Interstitial cells of Cajal (ICC) regulate gastrointestinal motility by generating electrical slow waves that orchestrate downstream calcium (Ca 2 + ) waves and coordinate smooth muscle contractions. A reduced ICC number has been reported in diabetic gastroparesis patients and in mouse models of delayed gastric emptying (DGE). However, functional changes in ICC propagating across the gastric regions in intact stomach are not well understood. The aim of this study was to develop an imaging approach to visualize ICC Ca 2+ waves in mouse stomach and determine spatiotemporal changes in mice with DGE. Tamoxifen‐treated B6.GCaMP5‐KitCreERT2 female mice were used as non‐diabetic controls (Non‐Db), while mice treated with streptozocin to induce diabetes were categorized as having normal (Db‐NGE) or delayed (Db‐DGE) gastric emptying based on emptying of solids. The ICC Ca 2+ network was imaged from excised intact mouse stomachs and subsequently opened along the lesser curvature and pinned flat. ICC Ca 2+ waves typically propagated along the greater curvature from the fundus–corpus line toward the antrum. The propagation length of ICC Ca 2+ activity was significantly decreased in Db‐DGE compared to Non‐Db and Db‐NGE and correlated to longer GE times. There was also a decrease in frequency, and the velocity was significantly faster in stomachs from Db‐DGE compared to Non‐Db and Db‐NGE. All experimental groups exhibited similar proportions of aberrant Ca 2+ propagation patterns (e.g., retrograde waves), but ectopic initiation only occurred in Db‐DGE stomachs. Thus, DGE is possibly driven by dysfunction in Ca 2+ activity in the ICC network that propagates rapidly over short distances, resulting in uncoordinated, non‐phasic muscle activity. image Key points Dysfunction of the interstitial cells of Cajal (ICC) has been implicated in diabetic gastroparesis but the changes in spatiotemporal properties of ICC network activity are not known. We developed an ex vivo Ca 2+ imaging approach to visualize ICC network activity across the entire stomach and determined changes in ICC Ca 2+ activity in a diabetic mouse model of delayed gastric emptying (GE). Decreased frequency and increased velocity of ICC Ca 2+ activity was observed in stomachs of diabetic mice with delayed GE. Ectopic initiation was a key feature associated with delayed GE. The propagation length of ICC Ca 2+ activity was inversely correlated to GE times and significantly reduced in stomach preparations from diabetic mice with delayed GE.

Background: Diabetic gastroparesis (DG) is associated with a loss in anti-inflammatory muscularis macrophages (MMs), contributing to delayed gastric emptying (DGE). Lyve1 macrophages, known for their anti-inflammatory phenotype, are involved in lipid metabolism across organs. While diabetes is typically associated with increased lipid levels, the dependence of lipid handling on altered function of Lyve1+ MMs in the stomach remains unknown. Aim: To investigate lipid accumulation in MMs and test the effect of palmitate and CD36 on Lyve1+ macrophages. Methods: FACS sorted CD45+ cells were isolated from the gastric muscularis of non-diabetic mice and analyzed using 10X Genomics Cellranger and Seurat package. Gene Set Enrichment Analysis was performed to identify enriched pathways. Separately, the cells underwent flow cytometry to identify Lyve1+/- MMs then determining lipid accumulation by LipidTox intensity. RAW 264.7 macrophage cells were cultured with macrophage colony stimulating factor (M-CSF), IL-4, and dexamethasone for 7 days to induce Lyve1 expression. RNA was collected from cells treated with palmitate and a CD36 inhibitor, Sulfosuccinimidyl oleate (SSO), for RT-qPCR. Lyve1+ and Lyve1- macrophages treated with 300µM palmitate overnight were collected for lipidomic analysis. Untargeted lipidomic analysis was done with Thermo Orbitrap Exploris 120, and data were analyzed using principal component analysis for group clustering and unpaired t-tests for differential analysis. Results: Unbiased clustering analysis revealed 6 transcriptionally distinct gastric MM populations, one of which was notably enriched in Lyve1 expression. Pathway analysis identified that Lyve1 enriched cluster was associated with lysosomal pathways and receptors involved in lipid uptake, such as CD36, as well as anti-inflammatory markers such as HO1 and CD206. Flow cytometry quantification showed that Lyve1+ MMs had higher accumulation of lipids compared to Lyve1- MMs (10.1±0.7 vs 2.9±0.2 mean fluorescence intensity/cell count, p=0.0002). RT-qPCR validated that Lyve1+ RAW 264.7 macrophages exhibited significantly higher expression of Lyve1 (6.95 times fold change, p=0.023) and CD36 (3.27 times fold change, p=0.011) compared to Lyve1- macrophages. Post palmitate treatment, Lyve1+ macrophages had increased expression of the pro-apoptotic gene caspase-3 (12.15-times fold change, p=0.033), as well as the fatty acid oxidation marker ACADM (4.98 times fold change, p=0.045). Notably, these differences were not found in the presence of SSO. Lipidomic analysis identified 171 differentially expressed lipids, particularly increased levels of ceramides and diacylglycerols in Lyve1+ macrophages compared to Lyve1- macrophages when both are treated with palmitate. Conclusions: Lyve1+ macrophages preferentially uptake lipids compared to Lyve1- macrophages consistent with increased expression of CD36. Lipid treatment of Lyve1+ macrophages increases expression of apoptosis and oxidation markers in a CD36-dependent manner that may lead to cell loss. These mechanisms may contribute to Lyve1+ MMs loss in DG. Funding: DK127992; DK129297; DK115255; ANMS Young Investigator grant; AGA grant#36; P30DK084567; Robert and Arlene Kogod Center on Aging Fundamental Mechanisms of Aging Award. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

ABSTRACT Background and Aims Women now comprise over half of US medical school matriculants yet remain underrepresented in academic leadership, including emergency medicine (EM). Leadership training within medical education is variable, particularly in communication, conflict management, negotiation, and operations. Concurrently, large language models (LLMs) are emerging as accessible tools to support leadership skill development. This study aimed to develop and evaluate an AI‐augmented leadership skills workshop designed to address the leadership gap for women in academic emergency medicine. Materials and Methods The Academy for Women in Academic Emergency Medicine (AWAEM) developed and piloted a leadership development workshop at the 2025 Society for Academic Emergency Medicine Annual Meeting. The curriculum integrated evidence‐based leadership frameworks with experiential small‐group learning and structured demonstrations of LLM use. Educational strategies included brief didactics, reflection on lived leadership challenges, peer discussion, and guided LLM‐supported simulation of leadership conversations. Pre‐workshop and postworkshop surveys and qualitative feedback were collected to assess participant confidence and perceived utility. Results Participants demonstrated increased confidence in navigating power‐differential conversations and initiating negotiations following the workshop. There was greater reported intent to apply leadership frameworks and to utilize LLMs for leadership‐related tasks. Qualitative feedback highlighted themes of empowerment, practical applicability, and the importance of a psychologically safe, gender‐informed learning environment. Participants identified LLMs as a novel and accessible adjunct to traditional leadership development resources. Discussion and Conclusions An AI‐augmented, experiential leadership workshop is a feasible and scalable approach to addressing persistent leadership development gaps for women in academic emergency medicine. Integrating LLM‐supported practice with established leadership frameworks may enhance learner confidence and engagement. This model offers a practical strategy to support leadership skills for women physicians needed to navigate systemic barriers and advance into leadership roles.

Abstract INTRODUCTION The vascular endothelial growth factor (VEGF) signaling family plays a role in neurodegenerative diseases, including Alzheimer's disease (AD). Previous work has shown widespread effects of the members FLT1 , FLT4 , and VEGFB on AD outcomes. However, these analyses have focused within the non‐Hispanic White (NHW) population. METHODS The goal of this study was to analyze the effects of the VEGF family in underrepresented populations, leveraging large and diverse bulk RNA sequencing and tandem mass tag–mass spectrometry (TMT‐MS) proteomic data. Outcomes included measures of AD pathology and diagnosis. RESULTS Within underrepresented populations, we replicated previously reported effects of FLT1 and FLT4 , whereby higher protein abundance was observed in the AD brain and was associated with higher neuropathology burden. In stratified analyses, these associations were largely consistent across race and ethnicity. DISCUSSION This multi‐omic study on the role of the VEGF family in AD emphasizes the need for more representative studies focused on therapeutic targets for AD. Highlights Vascular endothelial growth factor (VEGF) genes and proteins were quantified in four different brain regions. Samples included participants from four different populations. Previously observed effects were replicated in diverse populations. This study is the largest multi‐omic study of the vascular endothelial growth factor (VEGF) genes among Alzheimer's disease (AD) participants from diverse populations.

Abstract Background: Multiple myeloma (MM) remains incurable, though key advances such as chimeric antigen receptor T-cells (CAR-T) and immunomodulatory agents, now evolving toward cereblon E3 ligase modulatory drugs (CELMoDs), have substantially improved the longevity and quality of life for patients (pts). Idecabtagene vicleucel (ide-cel) is a CAR-T targeting B-cell maturation antigen (BCMA), now US FDA-approved for pts who have received ≥2 prior lines of therapy including a proteasome inhibitor, immunomodulatory agent, and CD38 monoclonal antibody. Ide-cel was initially FDA-approved for ≥4 prior lines of therapy based on the KarMMa-1 study, which demonstrated a median progression-free survival (PFS) of 8.8 months across all cell doses and median overall survival (OS) of 19.4 months (Munshi et al., New Eng J Med 2021). Although promising, the fact that virtually all pts relapse post-ide-cel indicates that further progress is needed. To that end, iberdomide is an investigational CELMoD that in combination with dexamethasone has demonstrated a 30% response rate in early phase studies of triple class-refractory MM (Lonial et al., Lancet Haem 2022). Additionally, in laboratory-based correlative studies, iberdomide, at doses of ≤1 mg (well below the recommended phase 2 dose of 1.6 mg) was shown to augment immune function, including enhanced T-cell activation and cytotoxicity, and modulation of the cytokine milieu (Amatangelo et al., Cell Rep Med 2024). Iberdomide's combined properties of direct MM cytotoxicity and T-cell potentiation have clear, potential relevance to CAR-T clinically, providing the conceptual basis for the CADMIUM study (NCT06179888), exploring the effects of iberdomide as post-ide-cel maintenance therapy in MM. Study Design and Methods: This is a randomized phase II trial with a safety run-in to evaluate if treatment with iberdomide maintenance post-ide-cel can significantly improve PFS vs. standard of care (SOC) observation without therapy, in pts with relapsed/refractory MM with ≥4 prior lines of therapy, who have received ide-cel within 3 months of registration, and no evidence of MM progression or additional MM therapy since ide-cel. Pre-ide-cel iberdomide exposure is permissible but refractoriness is not. The safety run-in will confirm tolerability of the iberdomide dose to be carried forward, where doses to be tested include: iberdomide 1 mg orally on days 1-21 of a 28-day cycle (dose level 1; DL1) and iberdomide 0.7 mg on days 1-21 of a 28-day cycle (DL2). Dose-limiting toxicities (DLTs) include any of the following during the DLT period of a pt's first three months on iberdomide: prolonged Grade 3 non-hematologic toxicities, Grade 4 non-hematologic toxicities, prolonged Grade 4 neutropenia or thrombocytopenia, or any adverse event requiring iberdomide interruption for >4 weeks. Six pts will be enrolled onto DL1; if at most 1 of these pts has a DLT, DL1 will be carried forward to the randomized part of the study. Otherwise, 6 pts will be enrolled onto DL2. The randomized part of the trial will randomize 60 pts 1:1 to either iberdomide or SOC observation without therapy. A 1-sided log-rank test with α=0.15 has 81% power to detect a true hazard ratio (iberdomide/SOC) of 0.55 or less, corresponding to an improvement in median PFS to 16 vs. 8.8 months with SOC. One interim analysis for futility is planned. Secondary outcomes include OS, best response by International Myeloma Working Group (IMWG) criteria, and deepening of response, particularly conversion to complete response with a bone marrow minimal disease-negative state by Adaptive clonoSEQ (sensitivity 1e-6). Robust correlative studies will include CAR-T persistence, assays of T- and other immune cell function, and pathological analyses of whether BCMA expression on MM cells (prior to enrollment or at relapse) or other markers predict clinical outcomes. Study status: To date, 12 pts have been screened, with 7 pts enrolled on study as part of the safety run-in (1 patient replaced). Enrollment data will be updated at presentation. Notably, an amendment is forthcoming which will enhance correlative studies and broaden eligibility criteria to include patients who have received ≥2 prior lines of therapy, conforming with ide-cel's current FDA label. Study COI: BMS is supporting correlative studies. Study Support: U10CA180821, U10CA180882; BMS; U10CA180868 (NRG Oncology); http://acknowledgements.alliancefound.org

Abstract Clinical flow cytometry laboratories are facing rising test volumes, greater assay complexity, and increasing requirements for quality control and assay validation. In response, the International Clinical Cytometry Society (ICCS) conducted a workload survey in early 2023 to gather updated information on assay volumes, complexity, staffing, and technology. Data analysis focused on identifying correlations between length of time to introduce new assays and other factors as a means to gain insight about laboratories that seem to be either adapting or struggling. Flow cytometry assays were categorized into 3 levels of technical/interpretative complexity: high (e.g., measurable/minimal residual disease (MRD assays)), moderate (e.g., leukemia/lymphoma assays (Assays L&L ), excluding MRD assays), and low (e.g., CD4 count). Annual assays per staff member were calculated according to staff involved in case sign‐out (Staff Signout ) or other laboratory operations (Staff LabOps ). Respondents were from 101 laboratories in the United States (69.3%), Canada (4.0%), and other countries (26.7%). Low, moderate, and high technical/interpretative complexity assays were performed in 85.1%, 97.0%, and 47.5% of all laboratories, respectively. Median annual total assays (Assays Total ) per laboratory were 3515 and, based on complexity, were 1518.5 (low), 1808.8 (moderate), and 350 (high). Among all laboratories, the median time (interquartile range) to introduce new Assays L&L was 6 mos. (4–12 mos.), to introduce MRD assays was 11 mos. (5–12 mos.), and to validate/go‐live with new cytometers was 8 mos. (4–12 mos.); these times positively correlated with each other. This study confirmed significantly increased workload since the prior ICCS 2013 workload survey with a concurrent decrease in Staff LabOps . Faster introduction of new assays correlated with other successes, including quicker validation of and going live with new cytometers. Among all laboratories, those that performed myeloid MRD assays versus those that did not were also found to be faster to introduce new assays. The need for sufficient staffing has been emphasized because laboratories with both higher annual volumes of myeloma MRD assays and higher ratios of Assays Total per Staff LabOps were slower to introduce new assays. “Lack of staff and/or time dedicated or protected for assay development” and, more generally, “staff number” were the most commonly identified major barriers for new assay development, with the former specifically linked to slower introduction of new assays among all laboratories.