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Abstract Background Prostaglandin E2 (PGE2) exerts paradoxical effects in asthma, acting as both a protective mediator and a contributor to pathology depending on context. Its role is shaped by type 2 (T2)-status, eosinophilia, and exacerbation frequency. In epithelial cell cultures from asthmatic and healthy individuals, interleukin (IL)-13 suppresses PGE2 synthesis genes (PTGS2 and PGES) while upregulating HPGD, which encodes for the PGE2 catabolic enzyme 15-prostaglandin dehydrogenase (15-PGDH) (PMID:16751012), suggesting diminished PGE2 availability during T2 inflammation. Similarly, in aspirin-exacerbated respiratory disease (AERD), impaired cyclooxygenase disrupts PGE2 biosynthesis, fueling unchecked leukotriene production and eosinophilic inflammation (PMID: 30516547), underscoring PGE2’s protective role in limiting disease progression. Conversely, in nasal polyps, tuft cells are activated by IL-13 to produce PGE2 (PMID: 35608904), highlighting PGE2’s potential pathogenicity. Objective To assess associations between PGE2-pathway gene expression in bronchial brushings and asthma severity, and to determine how nasal polyp history modifies these relationships. Methods We analyzed bronchial epithelial brushings from 109 adults with asthma (mean age 42.4±12.1, 64% female, 52% severe asthma, 18% nasal polyps) using normalized and batch-corrected RNA-seq data from the baseline visit in the Severe Asthma Research Program (SARP)3 (PMID: 36796454). Age-adjusted and nasal polyp-adjusted relationships were calculated between ratios of PGE2 synthesis and metabolism genes and clinical outcomes (ASSESS score, FEV1 %predicted). The composite PGE2 score (PMID: 35608904), derived from nasal polyp analysis, was calculated from the average scaled log-normalized expression of six PGE2-responsive genes. All data were analyzed using a linear regression mixed model with a random effect for site. Results Ratios of PGE2 synthesis genes (PTGS1/2, PTGES2) to HPGD were significantly associated with greater disease severity (change in ASSESS Score) (Fig.1A, solid lines) and lower lung function (change in FEV1 %predicted) (Fig.1B, solid lines). These relationships persisted after adjusting for nasal polyps (Fig.1, dashed lines). The composite PGE2 score was also related to disease severity (Fig.1A, black solid line) but attenuated when nasal polyps were accounted for (Fig.1A, black dashed lines). Interestingly, lower lung function remained associated with the PGE2 score even after nasal polyp adjustment (Fig.1B, dashed black lines). Conclusions Our analysis demonstrates that the balance between PGE2 synthesis and degradation in the bronchial epithelium is closely linked to asthma severity and lung function, independent of nasal polyp status. Future work will integrate transcriptomic and clinical data longitudinally to establish whether PGE2 could serve as a biomarker for asthma trajectory. This abstract is funded by: HL115118 (LCD), U10HL109152 (S.E.W.), U10HL109172 (to E.I. and B.D.L), U10HL109168 (N.N.J.), U10HL109250 (S.C.E), U10HL109164 (W.C.M), U10HL109257 (M.C), and U10HL109146 (to P.G.W. and S.A.C.)

While the field of anesthesiology has a storied history of innovation, especially related to patient safety, contemporary anesthesiologists face growing barriers to innovation from complex regulatory requirements and financial constraints. The Biodesign framework offers a systematic approach to medical technology development that can be applied to the perioperative space to address these challenges. This process begins with identification and screening of high-value clinical needs, followed by generation and evaluation of potential solutions, and culminates in strategy development, business planning, and fundraising. Each stage is designed to guide clinicians from early observation through translation into viable technologies. By adopting this structured method, anesthesiologists are well-positioned to transform clinical insights into scalable solutions, ensuring the specialty continues to advance patient safety and care in the face of evolving clinical demands.

BACKGROUND AND OBJECTIVES: Craniopharyngiomas are complex intracranial tumors that pose significant challenges in surgical management. We aimed to develop risk-stratified surgical outcome benchmarks for adult patients undergoing endoscopic craniopharyngioma resection by using the Registry of Adenomas of the Pituitary and Related Disorders database to facilitate comparisons across institutions and guide clinical decision-making. METHODS: A retrospective cohort of adult patients (18 years and older) with craniopharyngioma undergoing a first-time endoscopic transnasal surgery across 14 academic centers in the United States was analyzed using data collected from 2011 to 2024. Patients were stratified into low-risk and high-risk cohorts based on criteria including age, body mass index, selected tumor characteristics (size, infundibular relationship, intraventricular extension), and previous radiation. Surgical outcomes were analyzed, and benchmarking ranges were defined using the established methodology. RESULTS: The overall cohort included 318 patients with a mean age of 50 years. Upon benchmarking analysis (50th-75th percentile performance), low-risk patients (n = 136) had a median length of stay of 4.0 to 6.0 days, 90-day readmission rates of 15.5% to 22.2%, skilled nursing facility discharge rates of <1.0%, postoperative cerebrospinal fluid leak incidence of <1.0% to 14.3%, gross total resection rates of 50.0% to 60.8%, new postoperative arginine vasopressin deficiency rates of 33.3% to 50.0%, and tumor progression/recurrence rates of <1.0% to 18.3% over a median follow-up period of 27.0 (IQR 10.5-56.5) months. Benchmarking ranges were proposed for each outcome to facilitate cross-institutional comparisons. CONCLUSION: Establishing surgical outcome benchmarks for adult patients undergoing craniopharyngioma resection using data from the Registry of Adenomas of the Pituitary and Related Disorders provides a framework for assessing surgical performance and guiding clinical decision-making. Benchmark ranges can inform institutional quality improvement efforts, perioperative risk stratification, and patient counseling regarding expected postoperative outcomes.

Skeletal muscle is a heterogenous tissue composed of fibers (i.e., cells) with distinct metabolic and contractile properties. Muscle fibers are classified into 2 separate groups: Type 1 fibers which are primarily oxidative, and Type 2 fibers (further subdivided to Types 2a and 2x) which are predominantly glycolytic. Acute exercise induces transcriptional changes in skeletal muscle. However, these changes have been studied at the whole muscle level. The effects of exercise on differential gene expression in distinct muscle fiber types in response to acute exercise remains unclear. In this study, we evaluated gene expression in Type 1, 2a, and 2x muscle fibers in response to acute aerobic exercise. Muscle biopsies were collected from 5 (31±3 yrs) apparently healthy individuals before and 3hrs following an acute 45 min session of cycling exercise performed at 65% of maximal heart rate. Individual muscle fibers (n=138) were isolated from the muscle biopsy sample manually under a microscope. Half of the fiber was used to characterize it as Type 1, 2a, or 2x based on its myosin heavy chain isoform expression content using single fiber SDS-PAGE. The other half of the fiber underwent RNA sequencing. The effects of exercise on fiber types were analyzed using subject specific pseudo-bulk differential expression before and after exercise (Type 1 n=28, 2a n=28, and 2x n=12). Gene counts were normalized as counts per million (CPM) and log2 transformed with a pseudocount of +1. The top 200 differentially expressed genes (DEG’s) were then used to calculate fold changes between fiber types at baseline and in response to exercise. After exercise, 73.5% of DEG’s were upregulated in Type 1 fibers, 52% were upregulated in Type 2a fibers, and 60.5% were downregulated in 2x fibers, relative to baseline. Type 1 fibers showed the greatest increases in gene expression (notably, TPM1 log2FC = 2.46, ATP2A1 log2FC = 3.23, and UQCRB log2FC=0.39) and displayed transcriptional changes consistent with oxidative phosphorylation, calcium signaling, and cytoskeletal remodeling pathways. Type 2a fibers displayed modest increases (ATP2A1 log2FC = 0.34, TNNC2 log2FC = 0.21 and ENO3 log2FC=0.35) and an overall upregulation of glycogenic/gluconeogenesis pathways. Conversely, Type 2x fibers exhibited broad transcriptional suppression and downregulation of calcium signaling pathways. In conclusion, acute aerobic exercise induces gene expression in muscle that is fiber type-specific. Type 1 fibers upregulate genes related to oxidative phosphorylation and calcium signaling, whereas Type 2a fibers upregulate genes related to glycolysis. 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.

Obesity is associated with altered skeletal muscle protein metabolism. While plasma amino acids (AA) stimulate protein synthesis in muscle, it remains unclear how aerobic exercise modifies this response in obesity. In this study, we evaluated basal and amino acid-stimulated skeletal muscle protein fractional synthesis rate (FSR) in humans with obesity, induced by a primed, constant AA infusion (15% Clinisol; 4 mg·kg FFM-1·min-1), immediately after a single bout of acute aerobic exercise. We studied two groups of subjects with obesity: Group 1: AA infusion alone for 240 mins (AA; N = 8; BMI: 34.9 ± 1 kg/m 2 ; body fat percent: 35.2 ± 2) and group 2: acute aerobic exercise followed by AA infusion for 240 mins (AA+EX; N=8; BMI: 36.1 ± 2 kg/m 2 ; body fat percent: 42.4 ± 2). Subjects in the AA+EX group performed 45 minutes of cycling on a stationary bike at 65% VO2 max, and their amino acid infusion started immediately after the exercise ended. A d10-leucine tracer was infused for the entire duration of the study to measure mixed-muscle protein FSR (MMP-FSR). Muscle biopsies from the vastus lateralis were taken at baseline, 45 mins after the start of the amino acid infusion and at the end of the infusion study to determine MMP-FSR. Baseline MMP-FSR values did not differ between groups (p > 0.05). Participants receiving the AA infusion alone exhibited a significant increase in MMP-FSR from baseline to post-infusion (0.060 ± 0.005 to 0.119 ± 0.011 %/hr; p < 0.0001), whereas the AA+EX group showed no significant change from baseline (0.067 ± 0.004 to 0.084 ± 0.009 %/hr; p > 0.05). Plasma insulin concentrations increased significantly in response to the amino acid infusion (p < 0.0001) but did not differ between groups (p > 0.05). Baseline amino acid concentrations were not different between groups (p > 0.05). Among the plasma amino acids (μmol/L) changed, baseline plasma leucine (AA:137 ± 8, AA+EX: 144 ± 10; p > 0.05) increased significantly in both groups during AA infusion but was higher in the AA (424 ± 15) than the AA+EX (226 ± 13) group (p< 0.0001). Similarly, baseline plasma valine (AA: 226 ± 7, AA+EX: 234 ± 19; p > 0.05) increased significantly in both groups during AA infusion but was higher in the AA (553 ± 28) than the AA+EX (456 ± 23) group (p< 0.002). In contrast baseline arginine (AA: 59 ± 5, AA+EX: 71±11; p > 0.05), although it increased significantly in both groups during AA infusion, was lower in the AA (197 ± 3) than the AA+EX (266 ± 11) group (p< 0.0001). Despite marked increases in plasma amino acid and insulin concentrations, the AA+EX group exhibited a blunted muscle protein synthesis response to amino acid stimulation compared with the AA group. In conclusion, aerobic exercise blunts the amino acid-stimulated increase in muscle anabolism in the immediate period after exercise in humans with obesity. This research was supported by the National Institutes of Health/ National Institute of Diabetes and Digestive and Kidney Diseases. 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.

Our knowledge regarding baroreflex regulation of subpopulations of differently sized sympathetic action potentials (APs) remains incomplete. This study tested the hypothesis that baroreflex sigmoid morphology varies across AP subpopulations. In 12 healthy individuals (6 females; 32 ± 5 years), we measured diastolic blood pressure (DBP; brachial artery catheter) and muscle sympathetic APs (peroneal microneurography; continuous wavelet transform) during a modified Oxford protocol (100 μg nitroprusside bolus, 150 μg phenylephrine bolus). Baroreflex sigmoids (four-parameter logistic functions) modelled the relationship between DBP and sympathetic AP discharge probability for 10 normalized AP clusters. For each AP cluster, baroreflex sigmoid morphology was quantified by max gain, threshold, centering, and saturation pressures, and operating and response ranges. One-way analyses of variance and Dunnett post-hoc tests were performed. Data are mean ± SD. At the centering pressure of the baroreflex sigmoid, max gain was greater for medium APs (e.g., Cluster 3: -5.6 ± 2.9%/mmHg) compared to small (e.g., Cluster 1: -1.4 ± 1.1%/mmHg; P < 0.01) and large APs (e.g., Cluster 9: -0.6 ± 0.4%/mmHg; P < 0.01). Discharge probability at the centering pressure was also greater for medium APs (e.g., Cluster 3: 61 ± 22%) compared to small (e.g., Cluster 1: 12 ± 10%; P < 0.01) and large APs (e.g., Cluster 9: 3 ± 3%; P < 0.01). There were no differences in the saturation pressure (i.e., DBP where any further reduction does not elicit an increase in AP discharge probability) between AP clusters (main effect P = 0.22). The threshold pressure (i.e., DBP where any further reductions elicit an increase in AP discharge probability) was greater for medium (e.g., Cluster 3: 78 ± 8mmHg) compared to large APs (e.g., Cluster 9: 74 ± 11mmHg; P = 0.03). The operating range (i.e., Threshold – Saturation DBP) was greater for medium (e.g., Cluster 3: 14 ± 3mmHg) compared to large APs (e.g., Cluster 9: 8 ± 5mmHg; P < 0.01). There were no differences in the threshold pressure or operating range of medium compared to small APs (both P ≥ 0.82). The response range (i.e., Saturation – Threshold discharge probability) was greater for medium (e.g., Cluster 3: 26 ± 13%) compared to small (e.g., Cluster 1: 5 ± 4%; P < 0.01) and large APs (e.g., Cluster 9: 1 ± 1%; P < 0.01). These data confirm prior work using linear modeling and spontaneous approaches to quantify sympathetic AP baroreflex gain and extend to demonstrate variation in the morphology of the baroreflex sigmoid. During large changes in blood pressures, we identify differences in broader features of baroreflex control (e.g., threshold pressure, operating range, and response range) between AP subpopulations that support strong baroreflex regulation over medium-sized APs. 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.

OBJECTIVE Adamantinomatous craniopharyngioma (ACP) is a rare type of brain tumor that affects a wide age range, from children to older adults. Due to the rarity of the disease, existing studies are predominantly limited to single-center or single-surgeon experiences, often lacking statistical power and generalizability. The aim of this study was to address this gap by providing a comprehensive analysis of ACP outcomes based on a large multicenter cohort from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). METHODS This multicenter retrospective cohort study was conducted via the RAPID consortium and assessed patients with histologically confirmed ACP treated surgically between August 2000 and November 2024 at high-volume pituitary centers across the United States. RESULTS Among the 359 patients (206 male, median age at primary surgery of 47 years) included in the analysis, 76% underwent endoscopic transsphenoidal surgery and 22% underwent craniotomy. Gross-total resection was achieved in 45% and subtotal resection in 47%. Notably, 120 of 311 patients (39%) presented with preoperative hypothalamic-pituitary axis dysfunction. Following all treatments, permanent hypothyroidism was reported in 40% of patients, adrenal insufficiency in 33%, and arginine vasopressin deficiency in 19%. Of 263 patients who underwent primary surgery, radiation therapy was administered in 84 (32%). Progression-free survival (PFS) declined from 66% at 1 year to 31% at 6 years. In the multivariable analysis, independent predictors of worse PFS included subtotal resection (HR 0.22, 95% CI 0.11–0.42; p = 0.001), partial resection (HR 0.11, 95% CI 0.04–0.28, p = 0.001), larger tumor size (HR 0.77, 95% CI 0.64–0.94; p = 0.009), and tumor extension beyond the sella and suprasellar regions (HR 0.21, 95% CI 0.06–0.74; p = 0.016). Primary surgery and salvage surgery groups showed comparable PFS. CONCLUSIONS In this large multicenter cohort study, gross-total resection was achieved in fewer than half of patients and was independently associated with improved PFS. Approximately one-third of patients underwent radiation therapy after primary surgery. These findings provide robust evidence supporting the prognostic value of extent of resection and inform contemporary treatment algorithms for ACP. The high incidence of postoperative endocrinopathy underscores the need for individualized multidisciplinary long-term care. While the retrospective design is a limitation, the multicenter approach enhances the generalizability of these results.

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.