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Hyperglycemia in prediabetes is accompanied by increased amino acid (AA) concentrations and impaired suppression of glucagon secretion by glucose. It is unknown whether an abnormal response to AA contributes or hepatic steatosis exacerbates α-cell dysfunction. Therefore, lean participants and participants with obesity (with and without hepatic steatosis) were studied on two occasions in random order using a graded glucose infusion. Saline or an AA mixture was infused. The glucagon secretion rate (GSR) was derived from peripheral glucagon concentrations, and the change in glucose required to reduce GSR by 50% (G50) was calculated for each participant. AAs were measured during the experiment. On both occasions, experimental conditions produced a progressive rise in insulin secretion and an inverse exponential suppression of glucagon. G50 did not differ between groups in response to glucose alone. AA infusion did not change G50 in lean participants. G50 increased during AA infusion in participants with obesity with and without hepatic steatosis, leading us to report these participants as a single group. The relative change in AA concentrations across study days was generally similar between groups. We conclude that despite a normal response to glucose, obesity increases α-cell responses to AA in humans. Article Highlights The aim of this study was to understand the pathogenesis of α-cell dysfunction in prediabetes. The primary hypothesis was that α-cell responsivity to glucose (reduction of the glucagon secretion rate by 50%) is impaired by amino acid (AA) infusion. A secondary hypothesis was that this abnormal response is exacerbated by hepatic steatosis. AA infusion impaired α-cell suppression in response to rising glucose in participants with obesity, but not in lean participants, despite a normal response to glucose alone. This abnormal response was unaffected by the presence or absence of hepatic steatosis. It seems likely that an abnormal α-cell response to AAs precedes an abnormal response to glucose alone.

BACKGROUND: Anthracyclines are a widely used and effective class of chemotherapy. However, a major limitation for their use is cardiotoxicity, manifesting as systolic dysfunction, congestive heart failure, and arrhythmias. The objective of this study was to identify genes and genetic risk variants for doxorubicin-induced arrhythmia. METHODS: We performed genome-wide association studies and meta-analysis across 2 independent nonoverlapping, genetically homogenous data sets from the Molecular Epidemiology Resource (cases N=77, controls N=1184) and Tapestry (cases N=13, controls N=172). Doxorubicin-related arrhythmia was the primary cardiac outcome, followed by investigation of a broader phenotype of cardiac events. Effects of doxorubicin on top-associated genes were assessed by quantitative polymerase chain reaction on RNA extracted from human cardiomyocytes following treatment with doxorubicin and by echocardiography in a zebrafish model of doxorubicin-induced cardiomyopathy. RESULTS: In the meta-analysis, rs12151014 at the KCTD15 locus was associated with doxorubicin-related arrhythmia at the genome-wide significance (minor allele frequency in Molecular Epidemiology Resource cases 0.195 versus 0.069 in controls; Tapestry cases 0.192 versus 0.079 in controls) P =9.01×10 −9 ; odds ratio, 3.61. MMP 16 rs1094199 was associated with the broader phenotype of arrhythmia and heart failure (minor allele frequency in Molecular Epidemiology Resource cases 0.079 versus 0.019 in controls; Tapestry cases 0.038 versus 0.015) P =1.98×10 − 8 ; odds ratio=6.15. In human cardiomyocytes, MMP16 and KCTD15 gene expression was significantly downregulated by doxorubicin, and in a zebrafish MMP16 knockout was protective of doxorubicin-induced decline in left ventricular ejection fraction. CONCLUSIONS: Genetic variants at KCTD15 and MMP16 are associated with doxorubicin-related arrhythmia and cardiac events. MMP16 is a potential cardioprotective therapeutic target.

Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic progressive pulmonary fibrosis and high mortality. Genetic markers, summarized into a polygenic risk score (PRS), associate with IPF in well-phenotyped research cohorts. Objectives To evaluate the performance of the PRS using real-world data from routinely captured electronic healthcare records. Methods We conducted an observational study evaluating the association of a PRS for IPF with electronic healthcare record diagnosis of IPF as well as lung transplant-free survival in four independent cohorts; the Mass General Brigham Biobank (MGBB), Mayo Clinic Biobank (MCBB), Mayo Clinic Tapestry Cohort (Tapestry), and U.K. Biobank (UKBB). We used multivariable logistic regression and multivariable Cox proportional hazards models adjusting for age, gender, and principal components of ancestry. The cohorts then underwent fixed and random effects meta-analysis. Measurements and Main Results Of 37,709; 44,195; 43,202; and 447,422 participants from MGBB, MCBB, Tapestry and UKBB respectively, 1,015 (2.7%) 2,879 (6.5%), 1,310 (3.0%), and 2,742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis, OR 2.88 (95%CI 2.41-3.44) compared to all other individuals. A high-risk PRS also associated with the composite endpoint of mortality or lung transplant among those with an IPF diagnosis, HR 1.23(95%CI 1.11-1.35) compared to all other individuals. Conclusions A PRS can identify those at risk for an IPF diagnosis and mortality in biobank-scale data, which may have implications for clinical decisions. Further work is necessary to evaluate the utility of adding genetics in clinical settings.

Abstract Introduction Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy through enhancing T-cell-mediated immune responses but have also been associated with immune-related adverse events. Emerging literature suggests a potential association between ICI therapy and the development or reactivation of tuberculous mycobacterial infections. It is unclear whether ICI therapy is also linked to an increased risk of non-tuberculous mycobacterial (NTM) infections, though case reports are rapidly accumulating. We aim to better elucidate the potential association between ICIs and NTM infections through a case series. Case Series This series includes patients at Mayo Clinic who were diagnosed with active NTM infection during or after ICI use from January 1, 2012 to December 31, 2024. Data including demographics, malignancy details, ICI regimen and duration, timing and site of NTM infection, microbiologic findings, antimycobacterial therapy, and clinical outcomes were evaluated. There were seven patients with positive testing for NTM during or after ICI therapy. Two had one colony of M. gordonae on cultures which were determined by Infectious Disease to be contaminants. One case had a reported culture positive for M. franklinii at an outside hospital without further details available and thus was excluded from analysis. Chart review was performed for the remaining four patients with active NTM infection during or after ICI therapy. Two of the patients had underlying chronic obstructive pulmonary disease with a smoking history; these same two had primary lung malignancy. The other two patients had no known underlying lung disease or malignancy lung involvement (primary or metastatic). ICI therapies included PD-1, PD-L1, and CTLA-4 inhibitors. All four NTM infections predominant had lung involvement and were all different species; two were diagnosed while the patient was actively receiving ICI therapy and two were diagnosed several months after ICI discontinuation. Of the two receiving ICI therapy at the time of diagnosis, the ICI was held for 101 days for one patient and the other continued the ICI without interruption. Three received multi-agent therapy while the fourth declined treatment and died of malignancy complications soon after. The other three were alive at one year after NTM diagnosis and completed approximately one year of antimycobacterial therapy. Conclusions Tuberculous and non-tuberculous mycobacterial infections are increasingly seen after immune checkpoint inhibitor therapy. We present a series of four cases of NTM infections after or during ICI therapy for various types of malignancy with good outcomes after approximately one year of treatment. This abstract is funded by: None

ABSTRACT Early-life nutrition profoundly influences long-term metabolic health, and breast milk not only provides nutrients but also conveys maternal signals shaping infant metabolic development. While postpartum exercise by lactating women benefits maternal health, its impact on milk-borne signaling remains largely undefined. Small extracellular vesicles (sEVs) in breast milk are key mediators of maternal–infant communication because of their selectively packaged bioactive cargo and resistance to infant digestive enzymes and acids, enabling delivery of their cargo to peripheral tissues. Here, we show that a single session of moderate-intensity postpartum aerobic exercise robustly increases human breast milk sEV concentration, which persists for multiple post-exercise milk collections. Exercise enriches breast milk with sEVs containing regulatory metabolic cargo (proteins, miRNAs, and metabolites), which translates into enhanced mitochondrial capacity in neonatal-stage cells. These findings implicate sEVs as an exercise-responsive signaling compartment in breast milk capable of connecting postpartum maternal physical activity to beneficial infant metabolic programming. Highlights Acute moderate-intensity exercise increases human breast milk sEV concentration The exercise-mediated sEV increase lasts for multiple subsequent milk expressions Exercise coordinates a multi-omic enrichment of sEVs in breast milk Exercised breast milk sEVs enhance mitochondrial respiration in UC-MSCs

Abstract When evaluating malignant anterior mediastinal masses, thymic carcinoma and lymphoma represent the most common etiologies. We present a case of a patient with an incidentally found anterior mediastinal mass, initially suspected to be thymic carcinoma, who was ultimately diagnosed with primary mediastinal classical Hodgkin lymphoma. A 55-year-old woman with no contributory past medical history presented to her primary care provider with several weeks of cough which was unresponsive to antibiotics and corticosteroids. A chest x-ray demonstrated a large mediastinal mass and subsequent CT chest further revealed an anterior mediastinal mass measuring 15 x 6 x 13 cm. A PET-CT showed intense FDG uptake in the mediastinal mass (SUVmax 14.5) and FDG-avid right pleural lesions suggestive of metastases (SUVmax 4.5). She was referred to outpatient pulmonary clinic. Given imaging findings, thymic carcinoma was initially favored. Following multidisciplinary discussion with Thoracic Surgery, neoadjuvant chemotherapy was recommended prior to any consideration of surgical resection given the size and involvement of mediastinal structures. Thus, CT-guided biopsy was pursued to confirm the diagnosis, but unexpectedly revealed classical Hodgkin lymphoma of the nodular sclerosis subtype. She was diagnosed with stage IVA disease and urgently initiated chemotherapy with nivolumab, doxorubicin, vinblastine, and dacarbazine (N-AVD). A repeat PET-CT two months after initiation of treatment demonstrated marked metabolic and anatomic response, with the mediastinal mass reduced to 8.9 x 5.4 cm with an SUVmax of 2.1. Similarly, the FDG-avid pleural metastases had a decrease in SUVmax to 1.0. The patient was continued on the same treatment regimen. Although thymic carcinoma was initially suspected, a biopsy was obtained because surgical resection was not planned as the initial step in management. Typically, thymic malignancies are not biopsied prior to surgery due to the risk of tumor seeding and the preference for definitive resection, with some exceptions. In this case, the decision to biopsy resulted in the unexpected diagnosis of primary mediastinal classical Hodgkin lymphoma, a particularly rare entity among anterior mediastinal masses. This case underscores the importance of individualized diagnostic strategies and the role of tissue confirmation when clinical or therapeutic circumstances deviate from standard practices. This abstract is funded by: None

Abstract Plasmacytomas are a form of plasma cell malignancy which can occur as isolated lesions or as part of systemic multiple myeloma. We present a case of a patient whose evaluation for an incidentally found lung mass led to the diagnosis of multiple myeloma. A 65-year-old man with no remarkable past medical history presented to the emergency department with two days of fever, cough, and chills. A chest x-ray demonstrated findings suggestive of pneumonia as well as a “smoothly marginated density in the left lung apex.” CT chest further revealed a destructive mass involving the left third rib measuring 7.6 x 4.6 cm; it was difficult to determine from imaging if the mass originated from the lung, pleura, or bone. PET-CT showed significant FDG avidity of the mass (SUVmax 40.2) and FDG-avid left mediastinal and supraclavicular lymph nodes. He subsequently presented to outpatient pulmonary clinic for further evaluation. Given imaging findings, primary lung malignancy or soft tissue sarcoma was initially suspected. He underwent CT-guided biopsy of the mass with pathology showing a kappa light chain-restricted plasmacytoma. Serum studies demonstrated a markedly elevated kappa/lambda ratio of 132. Bone marrow biopsy confirmed a kappa light chain-restricted plasma cell myeloma with 20% plasma cells. On review of previous labs, the patient was noted to have anemia (hemoglobin 11.9 g/dL) previously attributed to iron deficiency anemia as well as hypercalcemia (10.3 mg/dL). Renal function was normal. He was diagnosed with multiple myeloma and started on daratumumab, bortezomib, lenalidomide, and dexamethasone (Dara-VRD), with favorable response to treatment. The presence of plasmacytomas is clinically important to recognize in multiple myeloma as they are predictors of poorer outcomes. The site of origin also carries prognostic implications: paraskeletal plasmacytomas arising from bone marrow are associated with better outcomes than extramedullary plasmacytomas which result from hematogenous spread. In one study, paraskeletal plasmacytomas were found to occur in 17.6% of patients with multiple myeloma, with 40% located in the chest; similarly, extramedullary plasmacytomas were associated with the lungs or pleura in 23% of patients. Altogether, this case underscores the importance of considering plasmacytomas in the differential of a lung mass, particularly if there is osseous involvement. This abstract is funded by: None

Abstract Rationale Asthma contributes substantially to healthcare burden and morbidity through frequent exacerbations. Emerging evidence suggests that genetic factors play a crucial role in modulating susceptibility to asthma exacerbations. To better understand the genetic architecture of exacerbations, we conducted a genome-wide association study (GWAS) in the Tapestry cohort. Methods The Tapestry Study, a large-scale, decentralized and clinical grade genomic sequencing study, conducted Exome+® sequencing at Helix, Inc. on 98,075 Mayo Clinic participants. After excluding patients with ≥10 pack-years of smoking and/or emphysema, we performed a GWAS of asthma exacerbations in 3,960 adults with asthma based on ICD codes. Cases (n = 1,059) were defined as individuals who experienced at least two exacerbations between 2020 and 2025; the remaining 2,901 individuals served as controls. Asthma exacerbations were defined by oral or systemic corticosteroid prescriptions with durations ranging from 3 days up to 28 days. Logistic regression models adjusted for age, sex, BMI, and the first six principal components of ancestry. Replication was performed in 1,273 asthma patients (439 African Americans and 834 non-Hispanic Whites) from the NHLBI-sponsored Severe Asthma Research Program (SARP 1-3), with adjustments for age, sex, BMI, and the first 10 principal components of ancestry. Results Based on a minor allele frequency (MAF) threshold of > 0.05, we analyzed 5,256,135 genome-wide variants. Genome-wide significant associations for asthma exacerbations (p < 5.0 × 10⁻8) included loci at a pseudogene in SMPD4P1 (rs680548, MAF = 0.39, OR = 1.37, p = 9.10 × 10⁻9). Additional variants showing suggestive associations included loci within ENDOD1 (rs638776, OR = 0.69, p = 1.20 × 10⁻6), PCSK2 (rs2206454, OR = 1.32, p = 3.53 × 10⁻6), RBFOX1 (rs17667084, OR = 0.60, p = 5.11 × 10⁻6), and CDC42EP3 (rs721660, OR = 1.29, p = 5.68 × 10⁻6). Subthreshold associations in Tapestry including loci at CDC42EP3 (rs4670213, OR = 1.27, p = 1.41x10-5, MAF = 0.36), and SDR39U1 (rs12587663,OR = 0.83, p = 5.86x10-4, MAF = 0.46) were replicated in the SARP longitudinal visit 5 with p-values of 8.523x10-3 (rs4670213, OR = 1.78), and 2.88x10-4 (rs12587663,OR=0.43), respectively. Conclusion Our GWAS for asthma exacerbations in the Tapestry cohort identified variant loci relevant to mitophagy mechanisms (CDC42EP3, PMID: 40783597), immune signaling and RNA splicing regulation (RBFOX1, PMID: 31301374), and neuromodulatory pathways (PCSK2, PMID: 32794589), all previously implicated in asthma pathophysiology. Collectively, these findings highlight potential novel genetic contributors to asthma exacerbations and provide a foundation for improving risk stratification and therapeutic targeting in asthma management. This abstract is funded by: This abstract is funded by: Mayo Clinic Funding: X01 from the NHLBI for TOPMed whole-genome sequencing and NIH grants R01 HL142992, HL69116, HL69167, HL69170, HL69174, U10 HL109164, U10 HL109257, U10 HL109146, U10 HL109172, U10 HL109250, U10 HL109250, U10 HL109250, U10 HL109168, U10 HL109152, U10 HL109086, U10 HL109046.

Background: Pregnancy in teenagers and emerging adults is associated with an increased risk of adverse outcomes. Similarly, pregnancies complicated by pregestational and gestational diabetes mellitus (GDM) carry a higher risk of complications. However, limited data exist on the intersection of these two high-risk conditions. Our objective was to establish the prevalence of teenage and emerging adult pregnancies complicated by diabetes in a population-based cohort and compare outcomes to pregnancies uncomplicated by diabetes, noting a background prevalence of GDM of 8.1% and pregestational diabetes of 1.2% across all age groups in the United States. Methods: This is a retrospective cohort study conducted in Olmsted County, Minnesota, USA. It includes female residents aged ≤21 years with a pregnancy ICD-10 code between January 1, 2013, and December 31, 2022. The main outcome measures assessed include maternal characteristics and maternal and fetal pregnancy outcomes. Results: A total of 1491 pregnancies in 1379 individuals were identified and included. In total, 68 (4.6%) pregnancies were complicated by diabetes: 51 (3.4%) with GDM and 17 (1.1%) with pregestational diabetes. In this study, pregnancies with diabetes had higher rates of adverse outcomes including cesarean delivery (GDM 29.4% vs. pregestational 60.0% vs. no diabetes 17.0%, P < 0.001), preeclampsia (GDM 15.7% vs. pregestational 40.0% vs. no diabetes 7.3%, P < 0.001), large-for-gestational-age neonates (GDM 13.7% vs. pre-existing 50.0% vs. no diabetes 5.8%, P < 0.001), and neonatal hypoglycemia (GDM 42.6% vs. pregestational 60.0% vs. no diabetes 13.3%, P < 0.001). Conclusions: The prevalence of pregestational diabetes in our teenage and emerging adult population is similar to that of the general pregnancy population; however, the prevalence of GDM is significantly lower. Overall, diabetes in teenage pregnancy is associated with an elevated risk of adverse maternal and neonatal outcomes. Future research should evaluate interventions aimed at reducing adverse pregnancy outcomes in this vulnerable population.