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Epithelial damage leads to early reactive oxygen species (ROS) signaling, which regulates sensory neuron regeneration and tissue repair. How the initial type of tissue injury influences early damage signaling and regenerative growth of sensory axons remains unclear. Previously we reported that thermal injury triggers distinct early tissue responses in larval zebrafish. Here, we found that thermal but not mechanical injury impairs sensory axon regeneration and function. Real-time imaging revealed an immediate tissue response to thermal injury characterized by the rapid Arp2/3-dependent migration of keratinocytes, which was associated with tissue scale ROS production and sustained sensory axon damage. Isotonic treatment was sufficient to limit keratinocyte movement, spatially restrict ROS production, and rescue sensory neuron function. These results suggest that early keratinocyte dynamics regulate the spatial and temporal pattern of long-term signaling in the wound microenvironment during tissue repair.

Background Observational reports suggest that supplementation that increases citric acid cycle intermediates via anaplerosis may have therapeutic advantages over traditional medium-chain triglyceride (MCT) treatment of long-chain fatty acid oxidation disorders (LC-FAODs) but controlled trials have not been reported. The goal of our study was to compare the effects of triheptanoin (C7), an anaplerotic seven-carbon fatty acid triglyceride, to trioctanoin (C8), an eight-carbon fatty acid triglyceride, in patients with LC-FAODs. Methods A double blinded, randomized controlled trial of 32 subjects with LC-FAODs (carnitine palmitoyltransferase-2, very long-chain acylCoA dehydrogenase, trifunctional protein or long-chain 3-hydroxy acylCoA dehydrogenase deficiencies) who were randomly assigned a diet containing 20% of their total daily energy from either C7 or C8 for 4 months was conducted. Primary outcomes included changes in total energy expenditure (TEE), cardiac function by echocardiogram, exercise tolerance, and phosphocreatine recovery following acute exercise. Secondary outcomes included body composition, blood biomarkers, and adverse events, including incidence of rhabdomyolysis. Results Patients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% ( p  = 0.046) while experiencing a 20% ( p  = 0.041) decrease in LV wall mass on their resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate-intensity exercise stress test when compared to patients taking C8. There was no difference in TEE, phosphocreatine recovery, body composition, incidence of rhabdomyolysis, or any secondary outcome measures between the groups. Conclusions C7 improved LV ejection fraction and reduced LV mass at rest, as well as lowering heart rate during exercise among patients with LC-FAODs. Clinical Trial Registration: Clinicaltrials.gov NCT01379625.

The function of macrophages in vitro is linked to their metabolic rewiring. However, macrophage metabolism remains poorly characterized in situ. Here, we used two-photon intensity and lifetime imaging of autofluorescent metabolic coenzymes, nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD), to assess the metabolism of macrophages in the wound microenvironment. Inhibiting glycolysis reduced NAD(P)H mean lifetime and made the intracellular redox state of macrophages more oxidized, as indicated by reduced optical redox ratio. We found that TNFα+ macrophages had lower NAD(P)H mean lifetime and were more oxidized compared to TNFα− macrophages. Both infection and thermal injury induced a macrophage population with a more oxidized redox state in wounded tissues. Kinetic analysis detected temporal changes in the optical redox ratio during tissue repair, revealing a shift toward a more reduced redox state over time. Metformin reduced TNFα+ wound macrophages, made intracellular redox state more reduced and improved tissue repair. By contrast, depletion of STAT6 increased TNFα+ wound macrophages, made redox state more oxidized and impaired regeneration. Our findings suggest that autofluorescence of NAD(P)H and FAD is sensitive to dynamic changes in intracellular metabolism in tissues and can be used to probe the temporal and spatial regulation of macrophage metabolism during tissue damage and repair.

In 2022, National Comprehensive Cancer Network updated the phrase of “complete circumferential peripheral and deep margin assessment (CCPDMA)” to “peripheral and deep en face margin assessment (PDEMA),” which was meant to create more consistency across all treatment modalities and provide clarity to the meaning of total margin evaluation. The aim of this project was to investigate the interpretation of PDEMA across pertinent specialties and to identify any existing knowledge gaps in hopes of improving clinical performance of institutional practice. An electronic survey was administered to medical professionals within the divisions of dermatology and otolaryngology retrieving demographic data and assessing respondents’ knowledge on tissue processing techniques and PDEMA. Of the four knowledge-based assessment questions administered, dermatology respondents answered three questions with > 80% accuracy and one question with < 65% accuracy. Otolaryngology respondents answered one question with > 80% accuracy and three with < 65% accuracy. Both groups answered the knowledge-based question evaluating the concept of “what must be true for Mohs or PDEMA to have value” with under 65% accuracy. When comparing dermatology and otolaryngology respondents, only one question which evaluated the proper methods to “achieve processing of the epidermal edge and the base of the tumor along a single plane in the lab” significantly differed between groups, with a percentage correct of 96% for dermatologists compared to 54% for otolaryngologists ( p  < 0.001). Results were found to be similar when resident physicians were removed from analysis. The overall percent correct for knowledge-based questions was shifted higher for dermatologists compared to otolaryngologists ( p  = 0.014). This trend was also redemonstrated when analyzing the data excluding residents ( p  = 0.053).

BackgroundThe aerosolized calfactant decreased the need for intubation in neonates with respiratory distress syndrome (AERO-02 trial).ObjectiveTo determine the oxygenation response to aerosolized calfactant among infants born 28 0/7–36 6/7 weeks with RDS in the AERO-02 trial.MethodsTrends in hourly fraction of oxygen (FiO2), mean airway pressure (MAP) and respiratory severity score (RSS) were compared between the aerosolized calfactant (AC) and usual care (UC) groups from time of randomization for 72 h.ResultsA total of 353 subjects were included in the study. FiO2, MAP, and RSS were lower in the UC group. FiO2 decrease was seen after the first aerosolized calfactant dose.ConclusionFiO2, MAP, and RSS were lower in the UC group. This is likely due to early and higher rate of liquid surfactant administration in the UC group. Decrease in FiO2 was noted in the AC group after the first aerosolization.

While lumbar puncture (LP) remains gold standard for assessing intracranial pressure (ICP), LP can be difficult to perform and lead to complications. Noninvasive correlations for elevated ICP via ocular ultrasound (OUS) have shown mixed results. The primary objective of this study is to identify the frequency and test characteristics of the crescent sign on OUS for elevated ICP. Secondary objectives include comparison of test characteristics to optic nerve sheath diameter (ONSD) and optic disc elevation (ODE). Single center, prospective, observational cohort study enrolling adults (age ≥ 18 years) who presented to an outpatient Neurology LP clinic. An OUS protocol was performed prior to scheduled LP, with measurement of the opening pressure (OP) by manometry. Patients were excluded if LP was unable to be completed (for any reason) or if completed in the sitting position. Elevated OP was defined as ≥25cmH2O. In total, 68 patients were enrolled; seven were excluded due to no OP measured, leaving 61 patients for analysis. Forty-six patients had normal OP, while 15 had elevated OP. The crescent sign was observed in 19 patients (31 %). Overall sensitivity, specificity, and accuracy of the crescent sign was 67 %, 80 %, and 74 %, respectively. Comparison of accuracy between the six other OUS findings demonstrated no significant differences between test characteristics (p > 0.10 for each). The crescent sign was observed in 31 % of patients, with moderate sensitivity, specificity, and accuracy for elevated ICP. This study has several limitations and evaluations in the acute care setting are needed.

Vitamin C levels are known rapidly decrease in adult critical illness. Vitamin C scavenges free radicals, provides critical protection of the endothelial barrier, and improves endothelial responsiveness to catecholamines. Children with congenital heart disease and undergoing cardiac surgery might be at increased risk for low circulating vitamin C levels. A prospective single-center observational study investigated perioperative changes in vitamin C levels in critically ill Children who underwent congenital heart surgery using CPB. Vitamin C serum levels were collected preoperatively and postoperatively (upon admission to the ICU, 24 and 72 h). Linear mixed-effect model was used to estimate mean circulating concentration of vitamin C and to estimate changes in concentration over time. Primary outcome was change in circulating levels of vitamin C before and after CPB. Secondary outcomes were hospital length of stay (LOS), acute kidney injury (AKI), and illness severity. Forty-one patients with a median age of 4.5 [interquartile range (IQR) 2.6–65.6] months at the time of surgery were consented and enrolled. Median CPB duration was 130 [90–175] minutes, and hospital LOS was 9.1 [5.2–19] days. Mean vitamin C levels (μmol/L) before CPB, at PICU admission, 24 h, and 72 h were 82.0 (95% CI 73.4–90.7), 53.4 (95% CI 44.6,62.0), 55.1 (95% CI 46.3,63.8), and 59.2 (95% CI 50.3,68.1), respectively. Upon postoperative admission to the PICU, vitamin C levels decreased by 28.7 (95% CI 20.6–36.8; p  < 0.001) μmol/L, whereas levels at 24 and 72 h recovered and did not differ substantially from concentrations reported upon PICU admission ( p  > 0.15). Changes in vitamin C concentration were not associated with CPB time, STAT mortality category, age, or PIM3. Three patients had post-CPB hypovitaminosis C or vitamin C deficiency. Reduction in vitamin C levels was not associated with hospital LOS ( p  = 0.673). A 25 μmol/L decrease in vitamin C levels upon PICU admission was associated with developing AKI (aOR = 3.65; 95% CI 1.01–18.0, p  = 0.049). Pediatric patients undergoing cardiac surgery with CPB showed decreased vitamin C levels during the immediate postoperative period. Effects of hypovitaminosis C and vitamin C deficiency in this population remain unclear.

Introduction: Point-of-care ultrasound (POCUS) is integral to emergency medicine (EM) training. It is unclear how EM residents use POCUS and how these skills are maintained as they progress in residency training. The purpose of this study was to evaluate resident use of POCUS at various timepoints in EM training. Methods: This was a retrospective cohort study of EM residents at a single, three-year training program between July 1, 2014–June 30, 2022. Residents were included if they had completed three consecutive years of training and an ultrasound rotation in their postgraduate year (PGY)-1. The following time points were assessed: PGY-1 rotation and 3-, 6-, 12-, 18-, and 24-months post-rotation. Number of scans, accuracy of interpretation, acceptability for credit, and percentage of technically limited studies (TLS) were collected at each point. We analyzed performance characteristics using mixed-effects binomial logistic regression with time as a fixed effect and resident as a random effect. Models were fit separately for each performance characteristic and likelihood ratio tests were performed to determine whether performance varied over time. Results: A total of 65 residents were included with a total of 13,229 exams performed during the study period. Cardiac and focused assessment with sonography in trauma examinations were performed most commonly. Overall accuracy of all exams during the examination period was 97.1% (95% confidence interval [CI] 96.2-98.0%), TLS was 14.5% (95% CI 9.7-20.6%), and acceptability was 82.9% (95% CI 76.3-88.2%). Trend over time (3, 6, 12, 18, and 24 months) found no differences in accuracy (P = 0.84), TLS (P = 0.20), or acceptability (P = 0.28). Further analyses by individual exam types also showed no significant differences in accuracy, acceptability, nor TLS. Conclusion: Accuracy, acceptability, and percentage of technically limited scans did not significantly vary over time, suggesting that POCUS skills are maintained from PGY-1 rotation to each time point evaluated in this study.

Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of adult C57BL6 wild-type mice treated with a single systemic dose of MAM acetate display DNA damage (O⁶-methyldeoxyguanosine lesions, O⁶-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O⁶-mG DNA methyltransferase (MGMT) showed elevated O⁶-mG DNA damage starting at 48 hours post-treatment. The DNA damage was linked to changes in the expression of genes in cell-signaling pathways associated with cancer, human neurodegenerative disease, and neurodevelopmental disorders. These data are consistent with the established developmental neurotoxic and carcinogenic properties of MAM in rodents. They also support the hypothesis that early-life exposure to MAM-glucoside (cycasin) has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for food or medicine, or both. These findings suggest environmental genotoxins, specifically MAM, target common pathways involved in neurodegeneration and cancer, the outcome depending on whether the cell can divide (cancer) or not (neurodegeneration). Exposure to MAM-related environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer's disease.

Introduction: Patients seen per hour (PPH) is a popular metric for emergency medicine (EM) resident efficiency, although it is likely insufficient for encapsulating overall efficiency. In this study we explored the relationship between higher patient complexity, acuity on shift, and markers of clinical efficiency. Methods: We performed a retrospective analysis using electronic health record data of the patients seen by EM residents during their final year of training who graduated between 2017–2020 at a single, urban, academic hospital. We compared the number of PPH seen during the third (final) year to patient acuity (Emergency Severity Index), complexity (Current Procedural Terminology codes [CPT]), propensity for admissions, and generated relative value units (RVU). Results: A total of 46 residents were included in the analysis, representing 178,037 total cases. The number of PPH increased from first to second year of residency and fell slightly during the third year of residency. Overall, for each 50% increase in the odds of treating a patient requiring high-level evaluation and management (CPT code 99215), there was a 7.4% decrease in mean PPH. Each 50% increase in odds of treating a case requiring hospital admission was associated with a 6.7% reduction (95%confidence interval [CI] 0.73–12%; P = 0.03) in mean PPH. Each 0.1-point increase in PPH was associated with a 262 (95% CI 157–367; P < 0.001) unit increase in average RVUs generated. Conclusion: Seeing a greater number of patients per hour was associated with a lower volume of complex patients and patients requiring admission among EM residents.