Citations

Objective: The recent advances in computational power have enabled the use of in-silico approaches in studying physiological flows. In this study, we aim to develop a digital twin of the human stomach, StomachSim, to simulate gastric biomechanics in case of motility disorders and surgery. Methods: A physiologically realistic model of the stomach, including the antral motility, is synthesized based on in-vivo imaging data. The mixing and gastric emptying are simulated using computational fluid dynamics (CFD). Fundic accommodation, terminal antral contraction, and the phasic opening of the pyloric sphincter are incorporated into the model. The enlargement and disruption of pyloric sphincter due to pyloric intervention procedures or pyloric incompetence is also implemented. The influence of food properties (density and viscosity), motility disorders (50% reduced amplitude of antral contractions), and pyloric intervention procedures on gastric mixing, duodenogastric reflux, and solid-food trituration is investigated. The gastric emptying rate and the transpyloric pressure gradient predicted by the model were in good agreement with existing in-vivo measurements in the literature. Results: Reduced antral motility led to inefficient mixing of gastric contents and 49% lower pressure forces and 33% reduced hydrodynamic shear stresses on solid food particles. In cases with pyloric incompetence, reduced motility resulted in 66% lower duodenogastric reflux rate. When the gastric contents were of higher viscosity, the proximal stomach applied a higher pressure to achieve the same emptying rate resulting in reduced duodenogastric reflux. Higher viscosity also led to over 7 times increased shear stresses on solid food particles. Food density, on the other hand, primarily affected the transport of refluxed contents – when the gastric contents were lighter, duodenal contents entering the stomach settled along the lower antrum, and when the gastric contents were heavier, the reflux contents were transported proximally towards the esophagus. Conclusion: The digital-twin model presented in this study allows the exploration of a wide set of parameters related to gastric function. Our simulations quantify the consequences of motility disorders on gastric digestion and duodenogastric reflux. The model also reports detailed force characteristics of solid food particles undergoing trituration. StomachSim offers a novel and potentially effective modality for examining the effect of gastric conditions and gastric surgical procedures on gastric function. The authors acknowledge support from NSF award CBET 2019405. This abstract was presented at the American Physiology Summit 2025 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 Purpose: Navtemadlin is a potent small-molecule inhibitor of MDM2, which has completed a phase 0 window-of-opportunity study in glioblastoma (GBM). To optimally interpret the clinical data, a detailed analysis of navtemadlin pharmacokinetics (PK), pharmacodynamics, and efficacy was performed in GBM patient-derived xenografts (PDX). Experimental Design: Response to navtemadlin was characterized in vitro and in vivo in GBM PDXs with and without MDM2 amplification. Efficacy in vivo was integrated with measured plasma and intra-tumoral drug levels to develop a translational PK/efficacy model comparing exposure effective in PDX to exposure achieved in phase 0 patient samples. Results: In vitro, navtemadlin showed robust on-target activity in TP53–wild-type GBM. In vivo efficacy strongly correlated with MDM2 amplification status. In subcutaneous PDXs, navtemadlin significantly extended survival when dosed at 25 mg/kg in an MDM2-amplified PDX compared with 100 mg/kg in a non-amplified PDX. Central nervous system distribution was limited by blood–brain barrier efflux (Kp_brain = 0.009). In an MDM2-amplified orthotopic PDX model, navtemadlin was ineffective at 100 mg/kg; when established in mice with deficient blood–brain barrier efflux (Rag−/−Abcb1a−/−Abcg2−/−), 25 mg/kg doubled survival. A tumor PK/efficacy model was built to define target exposure for efficacy in GBM, using the effective 25 mg/kg dose. Modeled exposures exceeded this threshold in three (of 16) tumor samples from phase 0 study patients at the 240 mg dose level. Conclusions: Navtemadlin efficacy was highly dependent on adequate brain penetration. Our translational PK/efficacy model suggests that the minimum effective tumor exposures were achieved only in a minority of patients with GBM.

Abstract We conducted a post hoc analysis of data from Blood and Marrow Transplant Clinical Trials Network 1506 (MORPHO), a randomized trial of gilteritinib vs placebo as posttransplantation maintenance for patients with FLT3-ITD–mutated acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT), focusing the interactions between conditioning regimen intensity, measurable residual disease (MRD), and NPM1 comutation status reported from diagnosis. Comparing FLT3-ITD MRD before and after conditioning, there was no difference between myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) in eradication or reduction of FLT3-ITD MRD. For participants who were FLT3-ITD MRD negative before HCT, there was no difference in the cumulative incidence of relapse during follow-up between those receiving MAC vs RIC. NPM1 comutation was associated with the largest magnitude of relapse-free survival benefit from post-HCT gilteritinib, and in these participants, post-HCT gilteritinib in the setting of RIC appeared to be as effective as MAC at preventing relapse. MAC appeared superior to RIC in preventing relapse only in participants who were NPM1 wild type at diagnosis and FLT3-ITD MRD positive before HCT. Our findings suggest that only a subset of patients with FLT3-ITD AML undergoing HCT may benefit from MAC and that, similar to AML therapy before HCT, the intensity of the HCT regimen should be adapted according to the molecular features of the disease. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

Objectives: The delirium course of critically ill adults can be classified into trajectories based on the severity and duration of delirium as shown by a recent study. It is unknown whether these trajectories and associated outcomes are reproducible. We aimed to define delirium severity trajectories using the Intensive Care Delirium Screening Checklist (ICDSC) and delirium duration and evaluate the association of trajectory membership with clinical characteristics and 30-day post-discharge mortality. Design: Population-based retrospective cohort. Setting: Fourteen medical-surgical ICUs in Alberta, Canada from January 1, 2014, to December 21, 2019. Patients: We included adult patients (≥ 18 yr old) with an ICU length of stay of greater than or equal to 24 hours, an ICDSC score indicating delirium (≥ 4), and 30-day follow-up data were included. Group-based trajectory modeling identified trajectories over a 7-day period with SAS v9.4 (SAS Institute, Cary, NC). Interventions: None. Measurements and Main Results: Demographic (age, sex) and clinical data (2 × d ICDSC score, comorbidities, illness severity, admission reason, procedures, length of stay, in-hospital, and 30-d post-discharge mortality) were captured from electronic medical records. In total, 21,071 patients were included, with a median age of 59 years (interquartile range, 46–70 yr), 59% male (n = 12,547), and 3% died at 30 days (n = 541). The five-trajectory model was selected. These trajectories followed previously defined patterns: 1) Mild-Brief (19.4%); 2); Severe-Rapid Recovers (18.5%); 3) Severe-Slow Recovers (31%); 4) Mild-Accelerating (14.1%); and 5) Severe-Nonrecovers (16.9%). Trajectory membership was not significantly associated with 30-day post-discharge mortality; however, clinically relevant trends were observed. Conclusions: The current study substantiates the proof-of-concept model of five delirium severity trajectories. Trajectory membership did not predict 30-day post-discharge mortality. Further research is needed to understand the associations between trajectory membership, biological-based biomarkers, and patient-relevant outcomes.

Abstract Objective Allergic fungal rhinosinusitis (AFRS) is characterized by type I immunoglobulin E (IgE)‐mediated hypersensitivity reactions to fungal antigens. This systematic review and meta‐analysis assessed the efficacy of biologics in the management of refractory AFRS. Data Sources PubMed, SCOPUS, Embase, Web of Science, and Cochrane. Review Methods Changes in Sino‐Nasal Outcome Test (SNOT)‐22 scores, endoscopic findings, serum eosinophil count, and total IgE levels were assessed in patients with refractory AFRS after receiving biologic therapy. Subgroup analyses were conducted to evaluate the individual efficacy of each biologic agent, including dupilumab, mepolizumab, and omalizumab. Results A total of 60 patients from 6 studies were analyzed. Biologics showed a significant improvement in SNOT‐22 scores (standard mean difference 1.1607 [95% CI 0.5549; 1.7664]), endoscopic scores (2.1953 [1.4181; 2.9725]), serum eosinophil count (1.1649 [0.7735; 1.5563]), and total IgE level (1.0700 [0.4052; 1.7348]). Dupilumab, mepolizumab, and omalizumab all enhanced SNOT‐22 and endoscopic scores. Additionally, dupilumab significantly reduced total IgE levels (1.2981 [0.4063; 2.1900]), whereas both dupilumab (0.9274 [0.1592; 1.6957]) and mepolizumab (1.2324 [0.9215; 1.5433]) significantly lowered the serum eosinophil counts. Conclusion The agents significantly improved nasal symptoms, laboratory findings, and endoscopic scores. These findings support the potential role of biologics as a therapeutic option for patients with AFRS who are unresponsive to conventional treatments.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

10051 Background: CBL0137 is a novel agent that targets the FAcilitates Chromatin Transcription complex (FACT), a histone chaperone that regulates chromatin remodeling during transcription, replication, and DNA repair. CBL0137 has been shown to have anti-tumor activity in multiple preclinical models of pediatric cancer. We report the phase 1 trial of CBL0137 in children with relapsed or refractory solid tumors including central nervous system (CNS) tumors or lymphoma (NCT04870944). Methods: Patients (age 12 months to 21 years) with relapsed/refractory solid tumors, central nervous system tumors or lymphoma were eligible. In the dose escalation phase, a rolling-six design was used to evaluate CBL0137 administered intravenously (IV) once per week on Days 1 and 8 of a 21-day cycle. The starting dose was 400 mg/m 2 , with escalation to the adult phase 2 dose (RP2D) of 540 mg/m 2 . The maximum tolerated dose (MTD) was determined based on cycle 1 dose limiting toxicity (DLT) using Common Toxicity Criteria for Adverse Events (v5). Pharmacokinetics (PK) and cytokine analyses were performed during cycle 1. Seven additional patients ( < 18 years old) were accrued to a PK expansion cohort at the RP2D. Results: Sixteen patients were enrolled; 14 were evaluable for DLT assessment (12 at 400mg/m 2 [6 in dose escalation and 6 in PK expansion] and 2 at 540mg/m 2 ). The median (range) age was 10 (4-20) years. Diagnoses included high grade glioma (n = 6), osteosarcoma (n = 5), ependymoma (n = 2), neuroblastoma, hepatoblastoma and Burkitt’s lymphoma (1 each). One of 12 evaluable patients treated at 400 mg/m 2 experienced a DLT: Grade 3 photosensitivity. At 540 mg/m 2 , the two evaluable patients both had fever and dose limiting Grade 3 hypotension. Non-dose limiting Grade 3-4 toxicities included anemia, lymphopenia, neutropenia, thrombocytopenia, hypokalemia, anorexia, photosensitivity and fever. For both dose levels, a total of 12 patients were reported to have at least one episode of Grades 1-3 fever and/or Grade 1 cytokine release syndrome (CRS). PK parameters (mean±SD) for CBL0137 (400 mg/m 2 ) were T max = 0.7 ± 0.5 h, C max = 1310 ± 417 ng/mL, and AUC 0-24h = 15300 ± 6790 h·ng/mL. Given the unexpected toxicities of fever, hypotension, and CRS, cytokine samples were collected in patients enrolled in the PK expansion cohort; all had Grade 1 CRS and significantly elevated levels of both IL-10 (adj p = 0.001) and IL-1RA (adj p < 0.001) at 24 hours vs pre-infusion. Conclusions: The RP2D and MTD of CBL0137 in children and adolescents with solid or CNS tumors is 400mg/m 2 IV weekly on Days 1 and 8 of 21-day cycles. CBL0137 leads to immune activation, with cytokine elevation and the possibility of CRS, an unexpected toxicity not previously reported in adults. A Phase 2 cohort in patients with Diffuse Midline Glioma is ongoing and includes further assessment of immune activation. Clinical trial information: NCT04870944 .

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

ABSTRACTMost discussions about discrimination and bias in anatomical research papers have been limited to terminology relating to race/ethnicity and gender/sex. However, as editors of anatomical journals, the authors of this article have frequently observed broader instances of potential discrimination and bias within anatomical research. These often stem from differences among authors' backgrounds, traditions, cultures, religions, provenance/origins, and workplace affiliations. In view of the limited discourse on this topic, we seek in this article to establish a consensus among editors of anatomical journals and to propose new Guidelines Against Discrimination and Bias in Anatomical Research Papers (GDBARP). We have identified multiple factors that can contribute to discrimination and bias, underscoring the need for greater awareness and proactive measures. It is imperative in anatomical research to respect authors, reviewers, and editors regardless of their background, culture, traditions, sex, ethnicity, language, religion, or ethical perspectives.