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Primary atrial fibrillation (AF)-mediated cardiomyopathy is a retrospective diagnosis in which left ventricular ejection fraction (LVEF) normalizes following catheter ablation. Identifying prospectively which patients will achieve LVEF normalization remains challenging. To determine predictors of LVEF normalization in patients with AF-mediated cardiomyopathy following catheter ablation. This was a pooled analysis of the CAMERA-MRI and CAMERA-MRI II multicenter randomized trials, which included baseline and serial cardiac magnetic resonance. This sub-study included all patients who underwent catheter ablation. LVEF normalization predictors were assessed using univariable and multivariable logistic regression. Continuous variables were dichotomized to develop a practical score, internally validated through bootstrap resampling (200 iterations) and 5-fold cross-validation. 113 patients (mean age, 60.6 ± 11.1 years; 13.3% female; 90.3% persistent AF; baseline LVEF, 31.0% ± 8.7%) were included, and 70 (63.7%) achieved LVEF normalization on serial cardiac magnetic resonance. On multivariable analysis, there were 3 independent predictors: normal indexed LV end-diastolic volume (odds ratio [OR], 3.20; 95% confidence interval [CI], 1.20-8.56; P = .021), absence of alternate etiology (OR, 4.31; 95% CI, 1.14-16.39; P = .023), and absence of late gadolinium enhancement (OR, 2.53; 95% CI, 1.01-6.39; P = .049), with an area under the curve of 0.788 (95% CI, 0.703-0.873). Normalization likelihood by score was 12% (0/3), 38% (1/3), 67% (2/3), and 88% (3/3). Absence of late gadolinium enhancement, normal LV volumes, and absence of an alternative etiology identified that the AF-induced cardiomyopathy phenotype is most likely to achieve LVEF normalization following catheter ablation.
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The International Consortium for Innovation & Quality in Pharmaceutical Development (IQ) Preclinical Safety Leadership Group (DruSafe) sponsored the formation of a Testicular Toxicology Working Group (TTWG) which conducted an industry-wide survey to gather information and gain insight into the process by which companies evaluate, interpret and modify drug development programs in response to testicular toxicity in nonclinical toxicology studies. Nineteen (19) IQ member companies participated, providing information on 127 test items reported to be associated with testicular toxicity during drug development. The majority of test items were small molecules, with nearly half of test items being developed for oncology indications. Evidence of testicular toxicity in human clinical trials was rare (1.6%); however, most test items lacked sufficient clinical data. When exposure multiples at the no observed adverse effect level (NOAEL) were known, >80% of responses received reported that testicular toxicity had no negative effect on clinical development. Use of in vitro or ex vivo assays were utilized on a case-by-case basis, with assays being used to answer specific questions and/or evaluate specific mechanisms and/or manifestations of testicular toxicity. Biomarkers, utilized when cause for concern occurred on specific programs and primarily for investigational purposes, predominantly included assessment of serum hormones.
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The Lancet Oncology Commission on Global Cancer Surgery recommended that access to and the quality of surgical care be improved. This study aimed to understand differences in surgical quality between emergency and elective resection among patients with potentially curative colorectal cancer. This preplanned secondary analysis included patients undergoing only curative-intent surgery for colorectal cancer from three contemporary global prospective cohort studies (GlobalSurg-3, 5506 patients; CovidSurg-Cancer, 6719 patients; APOLLO, 876 patients) registered from 2018 to 2023. Hierarchical multilevel logistic regression models quantified associations between the urgency of surgery (elective versus emergency) and surgical quality, measured by margin-positive resection, adjusting for patient, disease, and health system factors. Bootstrap multivariable simulations evaluated effect modification by country income level, cancer stage, and location. Of the 45 699 patients registered, 13 101 across 95 countries were included in this analysis. Overall, 678 patients (5.4%) had margin-positive resections, with higher rates in the emergency than elective surgery group (13.7 versus 4.5%; P < 0.0001). In adjusted multilevel models, emergency surgery was associated with increased odds of margin-positive resections (adjusted odds ratio 2.45, 95% confidence interval (c.i.) 1.86 to 3.22), consistent across all country income groups and robust to alternative health system indicators. Bootstrap-derived absolute risk differences revealed the greatest disparities in patients with stage III-IV rectal cancers, with absolute differences of 12.6% (95% c.i. 10.2 to 15.7) in high-income countries, 19.0% (95% c.i. 13.6 to 23.9) in upper middle-income countries, and 14.1% (95% c.i. 10.9 to 16.5) in lower middle- and low-income countries. Variance decomposition demonstrated that hospital- and country-level factors accounted for 76% of the explained variation in surgical quality. Emergency surgery was associated with a two- to threefold increase in the risk of margin-positive resections globally, independent of resource availability, highlighting a neglected area of global surgical practice. These findings challenge the assumption that poorer outcomes after emergency surgery are due to advanced disease stage. For patients presenting as an emergency with potentially curative resection, enhanced decision-making around resectability, ensuring specialist surgeon availability, and developing bridge-to-surgery pathways represent immediate, low-cost strategies to improve global cancer outcomes.
Microalgae are emerging as valuable model systems for studying epigenetic regulation in unicellular eukaryotes and as promising platforms for biotechnological lipid production. In these organisms, DNA and RNA methylation, histone modifications, and non-coding RNAs form interconnected regulatory layers that shape chromatin structure, genome stability, transcriptional responses, and metabolic plasticity. This review synthesizes current knowledge on epigenetic mechanisms in microalgae, with particular emphasis on environmental responsiveness, and links to lipid metabolism. The major epigenetic pathways will be described in model species, including cytosine and adenine DNA methylation, RNA methylation, histone post-translational modifications, and RNA-guided silencing mediated by small and long non-coding RNAs. Then it will be reported how environmental drivers such as salinity, nutrient limitation, light, temperature, and carbon availability remodel the microalgal epigenome. Finally, the evidence connecting epigenetic regulation to lipid accumulation will be presented, including methylation-dependent carbon reallocation, histone-modification dynamics under nutrient stress, and RNA-based regulation of lipid-related genes. Chemical perturbation and emerging epigenome-editing approaches further support the functional relevance of these pathways, although interpretation remains complicated by stress-associated secondary effects and strong lineage dependence. Overall, available studies indicate that epigenetic regulation contributes to both environmental acclimation and metabolic rewiring in microalgae, but direct causal links to lipid productivity remain limited to a small number of systems. A better mechanistic understanding of these processes will be essential for exploiting epigenetic regulation as a lever for strain improvement and sustainable lipid biotechnology.
We introduce stable real-space invariants (SRSIs), topological invariants defined from adiabatic deformations between Wannier states, generalizing previously discovered local and composite real-space invariants. SRSIs are Z- and Zn-valued (n = 2, 4) linear combinations of Wannier state multiplicities characterizing the stable equivalence of atomic insulators. We enumerate all SRSIs in nonmagnetic space groups with and without spin-orbit coupling. ZSRSIs are in one-to-one correspondence with momentum-space symmetry data and thus determine symmetry indicators of topology (SIs). ZnSRSIs capture real-space information beyond momentum-space symmetry data and SIs. Applying SRSIs to split elementary band representations (EBRs) whose symmetry data decomposes into positive sums of other EBR symmetry data, we diagnose the topology of all 211 cases across 51 space groups except for 8 exceptions in 5 space groups. Our results solidify Topological Quantum Chemistry beyond SIs and momentum-space symmetry data. Finally, we use SRSIs to diagnose an obstructed atomic insulator in a realistic material.
Understanding the earliest pathological changes in Alzheimer disease (AD) is critical for improving early intervention strategies. However, the relationship between amyloid plaque characteristics and early behavioral and molecular alterations remains unclear. We used 6-month-old female APPswe/PS1dE9 mice, a model of early amyloid-dominant pathology, to assess cognition and emotionality across a battery of behavioral tests. Amyloid plaques were quantified using Congo red staining; RT-qPCR and GFAP immunoreactivity were used to assess molecular and glial changes. APPswe/PS1dE9 mice exhibited increased anxiety-like behavior without significant changes in overall locomotor activity. Small plaques (<100 μm2) predominated across all regions; however, behavioral measures of hyperactivity and anxiety correlated specifically with the density and size of large (>200 μm2) plaques. Gene expression changes, including altered SYP, IGF1, TNF, and IL6 expression, were observed primarily in the midbrain and did not correlate with amyloid plaque characteristics. These findings demonstrate that large amyloid plaques, rather than total plaque burden, are selectively associated with early behavioral alterations in APPswe/PS1dE9 mice. Moreover, the midbrain emerges as an early site of molecular dysregulation despite limited plaque deposition. Together, these results support the use of 6-month-old APPswe/PS1dE9 mice as a model of early, amyloid-dominant stages of AD.
The introduction of European-style agriculture to the Upper Mississippi River Basin (U.S.) severely destabilized geomorphic systems and hydrologic regimes. Minnesota's Whitewater River Valley exemplifies this phenomenon in microcosm as severe erosion, sedimentation, and flooding forced residents to abandon their villages and farmland within a century of habitation. Federal agencies studied this at the basin scale and, via transect boring and elevation surveys, built a near-140-year record of floodplain evolution along 107 cross sections. Here, we distill eight decades of historical primary source materials into digitized and geospatially registered (meta)data that capture the initial geomorphic state of the river-valley network and its response to anthropogenic forcing and landscape transformation between the 19th and 20th centuries. Patterns of aggradation and incision demonstrate floodplain construction and long-profile evolution-frequently simulated but rarely observed-alongside concurrent channel geometry adjustments. By converting this data into distributable and georeferenced digital forms, we provide an exemplary record of impacts to fluvial systems via agricultural intensification and ground-truth efforts to simulate and predict landscape evolution in accessible multi-format.
Migraine is a common neurological disorder that can severely diminish quality of life. Quantifying migraine-related changes in a real-world population over time can increase understanding of the natural history of migraine and improve clinical care of individuals with migraine. The Observational survey of the Epidemiology, treatment, and Care Of MigrainE (OVERCOME) is a web-based study that longitudinally assessed migraine-related outcomes in a demographically representative adult population with migraine in the United States. Migraine disease status was classified as "overall improved," "overall worsened," or "no net change" based on changes in monthly headache days (MHDs), the Migraine Disability Assessment Scale (MIDAS) score, and the Migraine-Specific Quality-of-Life Questionnaire-Role Function-Restrictive (MSQ-RFR) domain score over 1 year. Migraine-related characteristics and patient-reported outcomes were evaluated for each group. Among 11,634 individuals with migraine who completed the baseline and 1-year follow-up surveys, 40.4% were classified as having "overall improved," 24.1% as having "overall worsened," and 35.5% as having "no net change" migraine status at 1 year. The "overall improved" group reported decreases in MHDs [mean change from baseline (SD), -3.2 (5.0)] and MIDAS score [-15.4 (26.2)] and improvements in MSQ-RFR score [+ 13.7 (21.6)]. Additionally, the impact of migraine on work decreased, there was less stigma, and this group was less likely to overuse acute medications. The "overall worsened" group experienced more MHDs [+ 3.4 (5.7)], increased MIDAS score [+ 18.8 (29.0)], and worsening MSQ-RFR score [-14.1 (21.1)]. Migraine had a greater negative impact on their working lives, and they had a greater need for acute and preventive medications for migraine. MHD, MIDAS score, and MSQ-RFR score together provide a robust characterization of overall change in migraine over time. This study demonstrates the profound effect of improvement or worsening of migraine symptoms on workplace productivity, migraine-related stigma, physical function, and need for treatment.
Advancements in endoscopic ultrasound-guided tissue acquisition (EUS-TA) for solid pancreatic masses have prompted updates in society guideline recommendations. However, the extent to which these recommendations have been adopted in clinical practice remains unclear. Thus, we sought to characterize current practice patterns and beliefs regarding EUS-TA for solid pancreatic masses in a large, international cohort of endosonographers. We developed and distributed an electronic survey to 1,281 endosonographers worldwide between September and November 2024. The survey aimed to evaluate EUS-TA practices across six domains: A) needle selection, B) sampling technique, C) method guiding the number of passes, D) specimen handling, E) quality indicator (QI) monitoring, and F) factors influencing decision-making. The response rate was 30% (n = 376). Most endosonographers often or always use fine needle biopsy (FNB) needles (90%) of 22-gauge (85%) and Franseen design (53%). The majority use a fanning technique (79%) and perform ≤ 10 actuations (60%). The number of FNB passes is mostly guided by visual on-site evaluation (60%). Advanced EUS imaging utilization was low (EUS elastography: 14%; contrast-enhanced EUS: 8%). Institutional QI monitoring was reported by 51% of endosonographers. Compared to other regions, endosonographers in North America are more likely to use rapid on-site evaluation, but less likely to use advanced EUS imaging modalities or have QI monitoring (all p < 0.001). There are significant global variations in EUS-TA practices for solid pancreatic masses. These survey data provide a benchmark to guide standardization, inform quality monitoring, and support evolving technologies to optimize diagnostic outcomes and patient care worldwide.
Deep learning models deployed in clinical imaging frequently encounter distribution shifts, yet most out-of-distribution (OOD) detection methods are evaluated only on controlled research datasets. As a result, it is unclear whether existing approaches can reliably identify segmentation failures that arise in real-world clinical practice. We evaluated six OOD detection methods on a deployed liver CT segmentation model (3D nnU-Net) using internal data from 400 patients and external data from 100 patients collected across nearly 70 sites in 7 countries. One method was Pairwise Surface DSC, a surface-based extension of Pairwise DSC, that we introduced. OOD performance was measured using sensitivity, AUROC, and balanced accuracy, with thresholds determined on an independent cohort of 400 patients using the Youden J statistic. Statistical significance was assessed using McNemar tests and stratified bootstraps (α = 0.05) with Benjamini-Hochberg correction. Pairwise Surface DSC was the top-performing method, with perfect sensitivities (1.00), near-perfect AUROCs (0.97 internal; 1.00 external), and the highest balanced accuracies (0.94 internal; 0.88 external; p < 0.001). These results show that automated failure detection for liver CT segmentation is clinically feasible and that Pairwise Surface DSC is a promising candidate for deployment. Our code is available at https://github.com/mckellwoodland/liver_ct_ood_translation.
Predicting plant functioning in a warming world requires capturing its divergent responses to hot versus dry vapour pressure deficit (VPD) increases. Stomatal responses to VPD are typically studied without disentangling the effects of RH and temperature, creating uncertainties for future plant functioning. We tested how air temperature and RH independently impact the stomatal slope parameter ( g 1 ), a proxy for water-use efficiency, and whether these effects were captured by the Unified Stomatal Optimization, Least-Cost and Generalized Stomatal Optimization (GSO) stomatal conductance models. Using a leaf gas exchange data set, we found that both effects were positive, incentivizing stomatal opening under warming and humidification. Of the three models, only the GSO model correctly predicted the observed positive RH- g 1 relationship by accounting for a hydraulic constraint on g 1 . The GSO model captured better the large magnitude of the observed positive temperature- g 1 relationships, by accounting for hydraulic and thermal effects that seek to maintain stable leaf osmotic pressures, and explained its interspecific variation through hydraulic traits. Our results suggest that increasing dry VPD (driven by low RH) creates hydraulic stress that increases water-use efficiency and closes stomata quickly. In contrast, increasing hot VPD (driven by high air temperature) decreases water-use efficiency and slows stomatal closure if soil-to-leaf hydraulic transport is maintained.
To establish a unified terminology and management framework for testicular developmental disorders (TDDs) through a comprehensive review of the literature and an international expert consensus. Although these disorders, ranging from testicular agenesis to regression and dysgenesis, are clinically significant, inconsistent terminology has led to confusion in diagnosis and management. Between January and March 2025, a thorough literature review was conducted across PubMed, Scopus, MEDLINE, and Embase to identify studies addressing the definition, histopathology, and management of testicular remnants, vanishing testis, agenesis, streak dysgenetic gonad, hypoplasia, atrophy, and hypotrophy. Findings were summarized and critically analyzed by an informal international expert panel comprising pediatric urologists, endocrinologists, geneticists and pathologists. The consensus process aimed to standardize definitions and management strategies when high-level evidence was lacking. Seven distinct entities were identified within the TDD spectrum. Testicular remnants ("nubbins") and vanishing testes were determined to represent different endpoints of the same regression process, with viable germ cells found in 0-16% of remnants and an overall theoretical malignancy risk below 1%. Dysgenetic gonads associated with Y-chromosome material carried a markedly higher risk (30-50%) of gonadoblastoma, for which prophylactic gonadectomy may be advised. Testicular aplasia and hypoplasia were primarily linked to genetic and hormonal causes, while atrophy and hypotrophy were associated with secondary ischemic or acquired processes. Diagnostic laparoscopy remains the gold standard for non-palpable testis evaluation. This consensus provides a standardized classification and management framework for TDDs, clarifying previously ambiguous terminology. Most entities demonstrate negligible malignant potential, except for dysgenetic gonads containing Y-chromosome material. The proposed framework enhances diagnostic accuracy, facilitates international comparability, and supports individualized, evidence-based management in pediatric urology.
Acute cholecystitis affects ∼200,000 individuals annually in the United States, with laparoscopic cholecystectomy as the gold standard treatment. However, in high-risk surgical candidates, alternative drainage methods are necessary. Percutaneous transhepatic gallbladder drainage (PT-GBD) has traditionally served as the primary alternative intervention, offering rapid decompression, but is limited by a negative impact on the patient's quality of life, the risk of long-term or even permanent tube placement, adverse events, and high recurrence rates. Endoscopic approaches, such as endoscopic transpapillary gallbladder drainage (ET-GBD) and, more recently, endoscopic ultrasound-guided gallbladder drainage (EUS-GBD), have emerged as viable alternatives to PT-GBD. EUS-GBD, first introduced in 2007, offers technical and clinical outcomes comparable to PT-GBD with fewer adverse events, shorter hospital stays, and lower rates of recurrence. The introduction of lumen-apposing metal stents (LAMS) has revolutionized EUS-GBD, simplifying deployment and enabling subsequent internal gallbladder access, which allows additional interventions such as cholecystoscopy and stone removal. EUS-GBD is now supported by international guidelines, and 1 device has achieved FDA approval for the management of acute cholecystitis in nonsurgical candidates. Proper patient selection is essential, guided by multidisciplinary evaluation, with EUS-GBD contraindicated in specific scenarios such as gallbladder perforation, coagulopathy, and large-volume ascites. Technical considerations include choice of access site (transgastric versus transduodenal), stent type, and procedural route [direct (freehand) or wire-guided]. Postprocedural care and stent management remain variable and nonstandardized. Emerging data suggest that interval cholecystectomy can still be performed safely after EUS-GBD. As adoption of EUS-GBD with LAMS expands, structured training and standardization of practice are crucial to optimizing outcomes.
Clinical data surrounding treatment patterns and reasons for discontinuation of oral systemics (OS) for the treatment of adult patients with moderate-severe atopic dermatitis (AD) remain limited. AD-REAL descriptively reports the discontinuation rates and treatment responses at week (W) 24 for patients with AD initiating new OS treatments. AD-REAL is a 12-month, multinational, observational cohort study of adult patients with moderate-to-severe AD commencing either conventional systemics (CS) or baricitinib. Other Janus kinase inhibitors (JAKis) were analyzed ad hoc. The primary objective reported the discontinuation rate of patients at W24 from baseline. Secondary objectives reported outcomes for Eczema Area and Severity index (EASI), Itch Numerical Rating Scale (NRS), and pain NRS. At baseline (N = 313), patients initiated CS (N = 113), baricitinib (N = 87), and other JAKi (N = 92), with a mean EASI of 19.8, 15.8, and 16.4, respectively. At W24, the Kaplan-Meier cumulative incidence of initial treatment discontinuation was 50.8% (95% confidence interval [95% CI] 40.9, 59.8) for CS, 29.0% (95% CI 19.8, 38.8) for baricitinib, and 18.8% (95% CI 11.5, 27.5) for other JAKi. The primary reason for discontinuation of baricitinib and other JAKi was primary lack of effectiveness, while CS discontinued owing to the addition of concomitant systemic treatment, adverse events, and patient/physician decisions. Of the baricitinib and other JAKi cohorts, 81.0% and 84.2% achieved an EASI ≤ 7 score, 38.1% and 38.2% improvement in pain, and 42.0% and 38.5% improvement in itch, while 63.1%, 16.7%, and 14.3% achieved these outcomes for CS, respectively. In this descriptive observational cohort study, patients treated with baricitinib and other JAKi reported numerically lower discontinuation rates and numerically improved clinical outcomes than patients treated with CS. Similar to early reports of baricitinib effectiveness in treating an itch-dominant subpopulation of patients with AD, patients receiving baricitinib in clinical practice reported improved outcomes for severe itch.
Long-chain omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) support cardiovascular health; however, athletes often exhibit Omega-3 Index (O3I) levels below 8%, a threshold associated with reduced cardiovascular disease (CVD) risk, suggesting insufficient dietary intake of DHA and EPA. Therefore, the objective of this study was to characterise the O3I, dietary intake of DHA and EPA, and supplement use in a large cohort of highly trained, elite and world class (Tier 3-5) Australian based athletes. In this multi-site cross-sectional study, 595 male and female athletes (18-45 years) from 17 sports provided a dried blood spot for whole blood fatty acid analysis and completed a dietary survey. The O3I was derived using a validated conversion algorithm. Dietary DHA and EPA intake was assessed using a marine food frequency questionnaire. Group comparisons were conducted using Mann-Whitney U and independent-samples t-tests, and differences across intake quartiles were assessed using Kruskal-Wallis tests. Mean (SD) O3I was 5.88 ± 1.40%, with 3% of athletes < 4%, 60% between 4-6%, 30% between 6-8%, and only 7% ≥ 8%. O3I increased across DHA + EPA intake quartiles (p < 0.001) and was higher in males than females (p < 0.01). Athletes reporting omega-3 supplement use (19%) had higher O3I (Median [IQR]) compared with non-users (7.02 [6.28-8.01%] vs 5.38 [4.82-6.02%]; p < 0.001). Median total daily DHA + EPA intake was 261 mg/day, with 72% of athletes consuming < 500 mg/day. Daily whole-food intake of DHA + EPA was modest and did not differ by sex. Most athletes based in Australia had O3I below the ≥ 8% CVD risk reduction threshold, highlighting opportunities for organisations and sporting bodies to support initiatives that increase DHA and EPA intake.
Multidrug-resistant TB (MDR-TB) in children remains a major public health challenge. Although treatment is free of direct charge in many countries, it can impose substantial indirect and non-medical costs on affected households. Evidence on the economic burden of childhood MDR-TB on families remains limited. A cross-sectional household survey was conducted in the Western Cape, South Africa, among 45 households with a child <15 years who initiated MDR-TB treatment between 2018 and 2021. Socio-economic status, costs of accessing care, and health-related quality of life (HRQoL) were assessed and linked to health service utilisation data to estimate household-level costs. The median total cost per household was ZAR 7,443 (US$504) per episode of care (interquartile range: ZAR 4,119-13,207), with indirect costs accounting for the largest share of household costs. Twenty-three (51.1%) of households incurred catastrophic health expenditure, defined as >20% of annual household income. Costs increased with hospital-based care, longer treatment duration, and more frequent caregiver visits. The HRQoL of children was generally high, though not uniformly distributed. Childhood MDR-TB places substantial financial burden on already vulnerable households. Economic evaluations and care models should incorporate household costs and consider strategies to reduce the indirect burden of treatment on families.
Gastric ultrasound (GUS) has been used by anesthesiologists, critical care physicians, and radiologists for various clinical applications. Emergency physicians have begun to adopt this technique to the emergency setting. This study aims to determine the diagnostic test characteristics of GUS for prandial status by emergency physicians. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis-Diagnostic Test Accuracy (PRISMA-DTA) guideline, we conducted a systematic review of diagnostic test characteristics of emergency physician-performed GUS for prandial status. We identified nine studies (n = 659) of emergency physician-performed GUS. Four studies evaluated adults (n = 173) and five studies evaluated pediatric patients (n = 486). Based on QUADAS-2 definitions, studies were highly applicable. However, studies were of low to very low quality and at a high risk of bias. In adults, GUS was 86-100% sensitive and 70-92% specific for prandial status, with 100% feasibility. In pediatric patients, GUS was 82-84% sensitive and 22-74% specific for prandial status, with 85-100% feasibility. In most cases, GUS was performed in less than 5 min. In the studies identified by this systematic review, point-of-care GUS by emergency physicians was highly feasible across adult and pediatric populations. This imaging modality has fair to excellent test characteristics for assessing prandial status in adults. Test characteristics in pediatric patients ranged from very poor to good. Accordingly, GUS is a potentially helpful adjunct for assessing gastric content and volume (i.e., full vs. empty stomach) that would benefit from further prospective investigation. Nevertheless, caution should be adopted prior to incorporating GUS into clinical decision making.