Citations

Food allergies are a significant public health concern in the United States. Fatality from food-induced anaphylaxis is associated with delayed administration of epinephrine. Utah children were at increased risk for school-related anaphylaxis due to a lack of school nurses, adequately trained staff, and a standardized approach to food allergy emergency management. In collaboration with the Utah School Nurses Association, the Utah Food Allergy Network, and the Utah Department of Health & Human Services, among other contributors, we aimed to accomplish the following goals: (1) develop and implement a web-based curriculum to train school staff to recognize and respond to anaphylaxis in school settings; (2) educate school officials on existing legal protections for layperson first responders; and (3) facilitate acquisition of unassigned epinephrine for use in schools through existing charitable pharmaceutical programs. From 2012 to 2023, our training program was completed 5759 times by individuals representing 421 Utah schools. The course was most frequently completed by teachers (n = 3006, 52.2%), office staff (n = 1480, 25.7%), and principals (n = 276, 4.8%). Since 2015, we have maintained an average year-to-year retention rate of greater than 68%. We observed a 245% increase in the number of schools with unassigned epinephrine. Due to this intervention, many Utah schools now prepare employees to administer epinephrine in the case of anaphylactic emergencies. Although school nurses play a significant role, their coverage is inadequate to meet the needs of all students at risk for anaphylaxis. Training volunteers to recognize and respond to anaphylaxis in school settings is needed to reduce delays in treatment and improve outcomes.

Objective Medium‐vessel vasculitis involving the visceral vasculature in adults is rare. Pancreatic ductal adenocarcinoma (PDAC) has been implicated in medium artery vascular thickening secondary to extravascular migratory metastasis with involvement of the celiac and superior mesenteric vessels. Methods Patients presenting to the rheumatology vasculitis subspecialty clinic were retrospectively identified using an electronic health record data exploration tool evaluating for diagnosis of pancreatic cancer, periaortitis, and vasculitis between January 2015 and December 2024. Results We retrospectively identified four patients with PDAC initially presenting with periarterial thickening of the celiac and superior celiac and superior mesenteric vessels (100% White, 50% male, median age 70.5 years). All four patients had abdominal pain with significant unintentional weight loss, with a median weight loss of 25 pounds (range 25–50 pounds). The median time to correct diagnosis was 221 days (range 162–340 days). All four patients had an elevated carbohydrate antigen 19‐9 level (range from 114 to 10,702, with a median of 341.5 U/mL). All four patients were diagnosed with endoscopic ultrasound–guided fine‐needle aspirations. The median number of biopsies required to make the diagnosis was three. Conclusion Isolated celiac and superior mesenteric periarterial thickening or “cuffing” is a vasculitis mimic that should prompt a comprehensive malignancy workup. Expedited referral to a tertiary center is essential given difficulty in tissue sampling with conventional methods and to avoid further delays in diagnosis.

Abstract In both type 1 and type 2 diabetes (T1D and T2D), insulin-producing β cells undergo progressive dysfunction due to inflammation, leading to impaired glucose responsiveness, dedifferentiation, and cell loss. While bile acid (BA) dysregulation under diabetic conditions is known to influence metabolic and inflammatory pathways, its mechanistic role in β cell regulation remains incompletely defined 1–3 . Here we show that bile acid sensor Farnesoid X receptor (FXR) and Bromodomain and Extra-Terminal motif (BET) signaling cooperatively regulates β cell inflammatory response and β cell identity. We identified the physiological protein-protein interaction between FXR and the bromodomain-containing protein 4 (BRD4) as a regulatory axis that protects against β cell dysfunction. We show that FXR activation by Fexaramine (Fex) together with BRD4 inhibition by JQ1 synergistically suppressed IL-1β-induced inflammation while also improving β cell identity and insulin secretion in both db/db model and high-fat diet (HFD) plus multi low-dose streptozotocin (MLD-STZ) model of diabetes. Importantly, this cooperative effect is abolished in β cell–specific FXR knockout (βFXRKO) mice, establishing that FXR is required for the functional synergy between these pathways in vivo . Mechanistically, structure-guided modeling and mutational analyses identified a direct interaction between FXR and the BD2 domain of BRD4, depending on specific lysine acetylation sites. Additionally, inhibition of the BD2 domain of BET combined with FXR activation markedly improved β cell survival in human T1D and T2D models established from human pluripotent stem cell (hPSC)-derived islet-like organoids (HILOs). Collectively, these findings establish a BA–bromodomain axis as a transcriptional interface linking metabolic signaling and chromatin regulation, and highlight FXR–BET targeting as a promising strategy to counter progressive β cell failure in diabetes.

Abstract Somatic mutations that arise post-zygotically create genetic diversity among normal human cells and provide key insights into human development and aging. Fibroblast-derived induced pluripotent stem cells (iPSCs) have proved to be a useful system for disease modelling; however, due to their clonal nature, iPSC lines carry somatic mutations inherited from the founder cells, raising concerns about their genomic integrity. At the same time, this clonality enables single-cell–level discovery of somatic mutations and the reconstruction of developmental lineages. In living individuals, though, this approach requires invasive biopsies and is limited to skin-derived lineages. Here, we generated 33 urine-derived iPSC lines from four males representing two father– son relationships, performed shallow whole-genome sequencing of the lines and analyzed somatic mutations. Derived iPSCs representing single cells from urine carried a few hundred of somatic single-nucleotide variants per genome, dominated by endogenous, clock-like mutational signatures and lacking environmental imprints such as UV-associated mutations. Copy-number analysis identified somatic CNVs in most of the lines and revealed higher CNV burdens in fathers than in sons, consistent with age-related structural mosaicism. Shared mutations across lines enabled reconstruction of cell lineage phylogenetic trees. In summary, urine-derived iPSCs showed genomic alterations comparable to those in fibroblast-derived iPSC lines and represent a valuable non-invasive alternative for disease modeling. Overall, this study provides the first genome-wide characterization of somatic mutations in urine-derived iPSCs and establishes them as a practical and non-invasive platform for charting somatic mutation landscapes and tracing developmental lineages in living humans.

PURPOSE GBM AGILE (ClinicalTrials.gov identifier: NCT03970447 ) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. METHODS Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. RESULTS When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. CONCLUSION GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

Emergence of epidemic viruses in new hosts threatens both human and other animal populations, and often involves virus evolution to overcome barriers that normally prevent efficient infection and spread in that host. After transfer the separated viruses will evolve in parallel as they spread within the original and new hosts. Here we examine the details of a virus involved in such a host-jumping event, where we define the natural evolution of feline panleukopenia virus (FPV) over 60 y, clarify the origins of the new pandemic canine parvovirus (CPV) that arose in the 1970s, and compare the separate evolution of those viruses over 47 y in cats or dogs. Several live-attenuated FPV vaccine viruses originated from early-1960s isolates or were a recombinant of an early virus, and many sequences in databases proved to be vaccine-derived. The sequences of wild viruses showed that FPV-like strains evolved at less than one-third the rate observed for CPV in dogs, and the higher rate of CPV evolution has been consistent since 1979, when a genetic variant became widespread. The common ancestor of the CPV lineage was related to FPVs from Europe and contained several unique host-adaptive capsid changes associated with canine transferrin receptor type-1 binding. Although the FPV vaccine strains are around 60 y old, little selection for antigenic variation was observed. The distinct evolutionary patterns of these closely related viruses circulating for decades in different hosts emphasize the complex evolution associated with viral epidemic emergence and spread in endemic and new hosts.

Primary and metastatic brain tumors exhibit resistance to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8 + T cell infiltration and functionality in established tumors, identification of neoantigens support emerging immunopreventative tactics against brain cancer. Functionally potent tissue-resident memory CD8 + T cells (T RM ) can be generated in the brain following peripheral infection or vaccination. However, the ability of brain T RM to prevent intracranial malignancy remains unknown. Here, mice were seeded with tumor-specific or bystander brain T RM via peripheral infection prior to depletion of circulating memory T cells (T CIRCM ) and subsequent brain tumor challenge. Tumor-specific brain T RM durably protected mice against intracranial malignancy even in the absence T CIRCM . These brain T RM persisted in tumor-surviving mice and protected against a second antigen-matched challenge. Importantly, a translationally-relevant mRNA-lipid nanoparticle (LNP) vaccine phenocopied peripheral infection-induced outcomes, generating functional brain T RM that controlled tumor growth. Altogether, this work points to the utility of brain T RM in cancer immunoprevention, supporting the development of antitumor mRNA-LNP vaccines to bolster brain immunity.

Background In low-gradient severe aortic stenosis (AS), reduced left ventricular ejection fraction (LVEF <50%) is practically used to define low flow and prompt dobutamine stress echocardiography to discern pseudo-severe AS. In patients with preserved LVEF, stroke volume index (SVI) <35 mL/m² is typically used. However, both are volume-based surrogates. Transaortic flow rate (TAFR), calculated as stroke volume divided by left ventricular ejection time, may better reflect true flow. Nonetheless, comparative data between TAFR and established metrics remain limited. We aimed to evaluate the prognostic value of TAFR in symptomatic low-gradient severe AS. Methods We retrospectively identified patients with low-gradient severe AS (AVA ≤1 cm 2 and peak velocity (Vmax) <4 m/s or mean gradient (MG) <40 mm Hg) who underwent transcatheter aortic valve replacement at Mayo Clinic sites (2017–2023). The primary outcome was 1-year all-cause mortality. Survival was assessed using Kaplan-Meier and Cox proportional hazards models. Results Among 475 patients included (mean age 85±8 years; 49% women), 242 (51%) had TAFR <220 mL/s, 165 (35%) had EF <50%, and 221 (47%) had SVI <35 mL/m 2 . Low TAFR was significantly associated with higher 1-year mortality even after stratifying by EF or SVI. In multivariate analysis, TAFR was an independent predictor of mortality (HR 2.38; 95% CI 1.19 to 4.76, p=0.014) after adjusting for reduced LVEF, low SVI, gender, chronic kidney disease and mitral and tricuspid regurgitation. Conclusions In patients with symptomatic low-gradient severe AS, low TAFR, not SVI or LVEF, is independently associated with mortality and may offer more accurate measure of flow state for clinical staging.

Abstract A short diagnosis-to-treatment interval independently predicts inferior outcomes in follicular lymphoma. Using international discovery and validation cohorts, we demonstrate its prognostic value beyond established prognostic indices, with implications for risk stratification, clinical trial design, and interpretation.

Abstract Hairy cell leukemia (HCL) and HCL variant (HCLv) are distinct, rare, and chronic splenic B-cell lymphomas/leukemias that partially overlap in clinicopathologic presentation but differ in genetic basis, prognosis, and management. HCL is caused by the BRAF-V600E kinase–activating mutation in &gt;95% of the patients, usually has excellent responses to chemotherapy with purine analogues, and is also amenable to BRAF inhibitor–based targeted treatments. In contrast, HCLv lacks BRAFV600E mutation, requires combined therapy with purine analogues in addition to rituximab, and generally shows less durable responses. Here, an international team of hematologists, experts on these rare diseases, was convened by the Hairy Cell Leukemia Foundation to update the previous guidelines (published in 2017) by providing a summary of current methods to diagnose and manage patients with HCL and HCLv as well as a prospective on newer targeted therapies to further improve outcomes.