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Abstract Rationale: The club cell secretory protein (CC16), encoded by the SCGB1A1 gene, has an anti-inflammatory role in airways diseases, including asthma (Li, AJRCCM 2023; Voraphani, AJRCCM 2023). We hypothesize that additional pathway genes regulated or co-expressed with CC16 have cumulative effects on asthma severity outcomes by modulating airway inflammation and maintaining lung homeostasis. Methods: As published previously, four genes were downregulated in CC16 knockout experiments and correlated with CC16 levels: BPIFA1, SFTPD, LTF, and LYZ (Iannuzo, Front. Immunol 2023). We developed a four-gene biomarker score in 94 patients with asthma from the NHLBI-sponsored Severe Asthma Research Program (SARP3) who underwent research bronchoscopy for lower airway epithelial brushings, RNA isolation, and bulk RNA sequencing. We log-transformed the raw values of each transcript; obtained standardized residuals from regression models that included sex, age, and batch effects; and summed the standardized residuals of all four proteins to estimate a standardized sum score (Zhai, JACI Allergy 2024). Logistic regression models tested the four-gene score, three-gene score without LTF, and individual transcripts for associations with exacerbations during 12-month follow-up and zero-inflated negative binomial regression for number of exacerbations. Results: 30.85% percent of 94 patients experienced at least one exacerbation at the end of follow-up. The CC16-associated four-gene biomarker score showed protective effects on asthma exacerbation risk with a 54% percent reduction in exacerbation risk for every one-fold higher score (OR=0.46, 95% CI: 0.27-0.78, p =0.0040, Figure 1). Transcript expression of BPIFA1 (OR=0.87, 95% CI:0.66-1.16, p=0.337), SFTPD (OR=0.33, 95% CI:0.04-2.52, p=0.283), LYZ (OR=0.62, 95%CI:0.28-1.39, p=0.248), and LTF (OR=0.36, 95% CI:0.18-0.74, p=0.0053) all indicated protective directionality with respect to exacerbation risk. However, only LTF demonstrated a statistically significant association. When we excluded LTF, the remaining three-gene score showed a trend toward association with risk (OR=0.64, 95% CI:0.40-1.03, p=0.068) and was significantly associated with number of exacerbations (RR=0.49, 95% CI:0.26-0.95, p=0.034). Compared to LTF alone (OR=0.48, PPV=0.50, NPV=0.71, Sensitivity=0.14, AUC=0.65), the combined four-gene score (OR=0.46, PPV=0.60, NPV= 0.73, Sensitivity=0.21, AUC=0.68) showed improved predictive performance. Conclusions: We identified a CC16-associated transcriptomic predictive score for asthma exacerbations, with LTF showing the strongest effect. Although the other three genes showed individually weak and non-significant associations with exacerbations, the three gene score was significant for number of exacerbations.We demonstrate the potential of this transcriptomic score as a predictive biomarker for asthma severity-related outcomes. Further research investigating these genes and their interaction with other CC16-associated immune pathways could provide insight into therapeutic targets.

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

This work discusses nonhormonal treatment of menopausal vasomotor symptoms.

BACKGROUND: Children continue to undergo right hemicolectomy (RHC) for neuroendocrine tumors (NET) of the appendix based on adult guidelines. Appendectomy alone is recommended for the pediatric population; however, there are no data on safety of this approach in the setting of positive margins. This study aimed to determine the association between tumor characteristics and survival in a national cohort, hypothesizing that survival would be excellent despite high-risk features including positive margins on appendectomy. STUDY DESIGN: Patients 18 years of age or younger with NET of the appendix were identified in the National Cancer Database from 2004 to 2022 using ICD-O-3 codes. Characteristics of patients who underwent definitive appendectomy vs RHC were compared using chi-square tests. Five-year survival was determined for appendectomy patients with and without high-risk size, margin, and lymph node (LN) features. RESULTS: Of 1,339 patients, 1,156 (86%) underwent appendectomy and 183 (14%) RHC. Median age in both groups was 15 (13 to 17) years. Patients who underwent RHC had larger tumors (24% vs 4%, greater than 2 cm, p < 0.001), more lymphovascular invasion (31% vs 10%, p < 0.001), and were more likely to undergo LN assessment (82% vs 10%, p < 0.001) with a higher LN positivity rate (31% vs 16%, p = 0.006). There was no difference in margins status (p = 0.76). The 5- and 10-year survival was excellent regardless of tumor characteristics for patients overall (99.9% and 99.4%, respectively) and for those who underwent definitive appendectomy (99.9% and 99.2%). CONCLUSIONS: These data further support appendectomy as definitive management for children with appendiceal NET. Additional resection does not confer a survival benefit even in the setting of positive margins.

AbstractIntroductionActive learning engages learners in constructing knowledge through interactive strategies such as simulation, small‐group discussion, and peer instruction. Although recognized as a superior approach to traditional passive learning, its adoption has been inconsistent. Barriers include reliance on traditional lectures, lack of training, and limited time to develop materials. Simulation educators have a unique skill set that may inform and support active learning initiatives.MethodsFifteen emergency medicine simulation experts convened to define the unique skill set of simulation educators and identify transferable simulation‐based medical education (SBME) skills and concepts to promote effective active learning beyond the simulation lab. Workgroup members are simulation education directors who have undergone specialized training in SBME. During biweekly meetings over 6 months, workgroup members reviewed primary literature in SBME and active learning, along with relevant simulation educator training materials. Objectives were achieved through iterative review, group conceptualization, and expert consensus.Unique treatmentThe increasing prevalence of SBME in medical education, along with the growth of simulation fellowships, has produced a group of education experts with shared competencies. Simulation educators acquire expertise in psychological safety, facilitation, communication, and debriefing, through specialized training and extensive experience. These skills are critical for active learning environments where learners benefit from structured, engaging, and psychologically safe experiences.Implications for educatorsKey transferable SBME topics were identified for use in active learning environments outside of the simulation lab: (1) psychological safety, (2) facilitation strategies, and (3) communication techniques. Transferable tools and concepts were identified to promote efficacy and learner engagement during active learning in diverse environments. Simulation educators’ expertise is an underutilized resource for faculty development initiatives aimed at advancing active learning. This work advocates for leveraging simulation educators’ skills to close the active learning implementation gap, enhance learner outcomes, and meet the evolving needs of contemporary medical education.

Abstract Introduction Female sexual dysfunctions (FSDs) are prevalent yet underrecognized concerns among menopausal women, particularly those aged 65 and older. Age- and menopause-related sexual health issues often go unaddressed due to societal stigma and misconceptions, leading many women to attribute their symptoms to a normal part of aging. This perception limits diagnosis and treatment of conditions like hypoactive sexual desire disorder and genitourinary syndrome of menopause. Objective This study aims to compare sexual function and distress between women aged 50-64 and those aged 65 and older, with a focus on addressing critical knowledge gaps in sexual function among older women. Methods This cross-sectional study included women aged 50 and above who visited Mayo Clinic Women’s Health Clinics in Rochester, MN; Scottsdale, AZ; and Jacksonville, FL between, May 1, 2015, and August 31, 2022. Participants completed the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale (FSDS-R), along with assessments of chief sexual health complaints, mood (PHQ-9), and anxiety (GAD-7) included in the Data Registry on Experiences of Aging, Menopause, and Sexuality (DREAMS). Results Among 4900 women included in the analysis, the median number of sexual health complaints was 2.0 in midlife (50-64 yrs) and 1.0 in older (65+ yrs) age groups (p = 0.004). Chief complaints of loss of sexual desire (47.6% vs. 33.4%; p &lt; 0.001) and reduced genital sensation (16.9% vs. 13.0%; p = 0.024) were more common in the midlife age group. No significant differences were found in rates of complaints of vaginal dryness (51.2% vs. 52.5%; p = 0.57), painful intercourse (32.6% vs 30.7%; p = 0.38), or of difficulties with arousal or orgasm (24.0% vs 20.8%; p = 0.09). Midlife age women were also more likely to report pelvic pain (6.7% vs. 4.5%; p = 0.050), while older women reported more genital pain (8.1% vs. 5.8%; p = 0.038). FSFI scores indicated age-related differences in desire (2.4 vs. 3.0; p &lt; 0.001), lubrication (3.9 vs. 3.6; p &lt; 0.001), and pain (4.8 vs. 4.0; p &lt; 0.001), aligning with the chief complaints, while arousal (3.6, p = 0.890), orgasm (4.0, p = 0.926), and satisfaction (4.4, p = 0.346) scores were similar between groups. Total FSFI scores showed no significant difference between the age groups (total = 22.2 vs 21.2, p = 0.109). Median FSDS-R scores indicated higher distress in the midlife group (15.0 vs. 13.0; p = 0.015), while overall FSD prevalence (FSFI ≤26.55 and FSDS ≥11) was similar between groups (56.2% vs 51.8%; p = 0.056). Conclusions Midlife and older women were equally likely to experience FSD in women presenting to women’s health clinics, but older women reported less distress. These results are strikingly similar to previous research indicating that while older women have FSD, there is less distress associated with it. Raising awareness and promoting open dialogue can help older women recognize that their sexual health concerns are both valid and treatable, ultimately improving quality of life. Disclosure No.

Abstract Introduction: Monitoring minimal residual disease (MRD) is critical in multiple myeloma (MM) to predict outcomes and guide therapy. Traditional bone marrow (BM) aspirates for MRD detection are invasive and limited by sample quality. We therefore explored cell-free DNA (cfDNA) fragmentation as a less invasive alternative for MRD detection. Methods: We performed 30-40X whole-genome sequencing (WGS) on peripheral blood cfDNA from 45 MM patients, collecting baseline (n = 45) and follow-up samples (n = 98) from eight Canadian sites (M4 and IMMAGINE studies) and one U.S. site (SPORE study), plus 25 healthy controls. Samples were collected post-induction therapy (n = 13), 100 days post-autologous stem cell transplantation (ACST, n = 36), and during maintenance therapy (n = 49). Multiparameter flow cytometry (MFC) MRD testing was conducted on 77 samples. We evaluated insert size metrics and MM-specific chromatin accessibility (from Ordoñez et al., 2020) using Griffin (described in Doebley et al., 2022). Results: Baseline samples had a higher proportion of short fragments (20-150 bp) than follow-up samples (p = 0.0037) and healthy controls (p = 0.019). A fragment score (FS) based on weighted fragment distribution (per Vessies et al., 2022) was highest at baseline (mean = -0.384), followed by MRD-positive (mean = -0.495) and MRD-negative (mean = -0.550) samples. MRD-negative FS was lower than baseline samples (p &lt; 0.001) but higher than healthy controls (mean = -0.639; p = 0.016). Baseline samples had lower coverage at MM-specific chromatin regions than MRD timepoints (p &lt; 0.05; baseline mean = 0.982; MRD-positive = 0.989; MRD-negative = 0.994; healthy = 0.993), suggesting higher transcriptional activity pre-treatment. MRD-negative samples had higher coverage than MRD-positive cases (p &lt; 0.01). Using logistic regression, we assessed the predictive performance of FS and coverage at MM-specific sites. FS alone achieved an AUC of 0.632 (sensitivity [SN] 39.4%, specificity [SP] 92.1%, accuracy [AC] 67.6%). Coverage yielded an AUC of 0.681 (SN 75.8%, SP 60.5%, AC 67.6%). Combining FS and coverage at MM sites improved performance (AUC = 0.734; SN 48.5%, SP 92.1%, AC 71.8%). We next evaluated whether adjusting the BM tumor cell percentage cutoff by MFC could improve performance. At 0.017% (1 in 5, 789 cells) for MRD positivity, the combined model’s accuracy reached 83% with an AUC of 0.757 (SN 17%, SP 97%). Conclusions: cfDNA fragmentomic analysis achieved high specificity (92-97%) in detecting MRD, providing a less invasive alternative to facilitate serial monitoring. While sensitivity remains an area for improvement, the high specificity of cfDNA makes it valuable for confirming MRD negativity and reducing invasive procedures. Future efforts aim to enhance sensitivity by integrating additional fragmentomic features. Citation Format: Dor D. Abelman, Jenna Eagles, Aimee Wong, Saumil Shah, Stephanie Pedersen, Stephenie Prokopec, David S. Scott, Sarah Bridges, Darrell White, Irwindeep Sandhu, Kevin Song, Esteban Braggio, Alli Murugesan, Anthony Reiman, Suzanne Trudel, Trevor J. Pugh. Tumor-independent monitoring of minimal residual disease in multiple myeloma using cfDNA fragmentomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3250.