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Background: Transaminase and creatinine elevations have been well described in adults treated with remdesivir for COVID-19. It is hypothesized that a similar safety profile exists in children with COVID-19 treated with remdesivir, but available data are limited, especially in children < 12 months. The primary aim of this study was to determine the prevalence and timing of elevations in transaminases and creatinine in children with COVID-19 who were treated with remdesivir. Methods: This was a retrospective, observational cohort study including all pediatric patients admitted to a single, freestanding children’s hospital who were positive for COVID-19 and received at least 1 dose of remdesivir between 1/1/2020 and 5/31/2022. Available baseline and peak transaminase and creatinine concentrations were evaluated. Multivariable logistic regression analysis was performed to identify risk factors for transaminase elevation. Results: A total of 180 patients met inclusion criteria. Creatinine elevation of any grade was noted in 16% and remained elevated only in those with underlying chronic kidney disease. Transaminase elevation of any grade was noted in 58% of patients and remained elevated in only 1%. Older age and critical respiratory disease were associated with higher risk of significant transaminase elevation, whereas non-Hispanic ethnicity was strongly associated with protection against significant transaminase elevation. Conclusions: In our cohort of hospitalized children with COVID-19 who were treated with remdesivir, most patients experienced only mild transaminitis and normal creatinine concentrations. A limited number of patients experienced laboratory abnormalities which were transient, suggesting a favorable safety profile for remdesivir use in pediatrics. [ABSTRACT FROM AUTHOR]

Myocardial involvement was shown to be associated with an unfavorable prognosis in patients with COVID-19, which could lead to fatal outcomes as in myocardial injury-induced arrhythmias and sudden cardiac death. We hypothesized that magnetic resonance imaging (MRI) myocardial strain parameters are sensitive markers for identifying subclinical cardiac dysfunction associated with myocardial involvement in the post-acute sequelae of COVID-19 (PASC). This study evaluated 115 subjects, including 65 consecutive COVID-19 patients, using MRI for the assessment of either post-COVID-19 myocarditis or other cardiomyopathies. Subjects were categorized, based on the results of the MRI exams, as having either 'suspected' or 'excluded' myocarditis. A control group of 50 matched individuals was studied. Along with parameters of global cardiac function, the MRI images were analyzed for measurements of the myocardial T1, T2, extracellular volume (ECV), strain, and strain rate. Based on the MRI late gadolinium enhancement and T1/T2/ECV mappings, myocarditis was suspected in 7 out of 22 patients referred due to concern of myocarditis and in 9 out of 43 patients referred due to concern of cardiomyopathies. The myocardial global longitudinal, circumferential, and radial strains and strain rates in the suspected myocarditis group were significantly smaller than those in the excluded myocarditis group, which in turn were significantly smaller than those in the control group. The results showed significant correlations between the strain, strain rate, and global cardiac function parameters. In conclusion, this study emphasizes the value of multiparametric MRI for differentiating patients with myocardial involvement in the PASC based on changes in the myocardial contractility pattern and tissue structure. [ABSTRACT FROM AUTHOR]

Introduction: There are a significant number of patients with mucocutaneous bleeding, specifically heavy menstrual bleeding (HMB), who do not have a diagnosed bleeding disorder. These patients receive nontargeted interventions and may have suboptimal treatments. Functional assays, particularly for fibrinolytic and rare platelet function defects, are not robust and not readily available. Aim: We aimed to prospectively evaluate the prevalence of genetic defects associated with rare bleeding disorders and describe alterations of coagulation and fibrinolysis in a cohort of adolescents with HMB. Methods: We performed a prospective observational cohort study of patients with HMB and unexplained bleeding. The study utilized a next generation sequencing panel and investigational global assays of coagulation and fibrinolysis. Additionally, specific functional assays were performed to help characterize novel variants that were identified. Results: In 10 of the 17 patients (∼59%), genetic variants were identified on molecular testing. Thrombin generation by calibrated thromboelastography was not significantly altered in this patient population. The clot formation and lysis assay showed a trend towards increased fibrinolysis with rapid phase of decline in 23% of the patients. Further corresponding functional assays and study population are described. Conclusion: Our study describes a unique correlative model in a homogenous cohort of patients with HMB and unexplained bleeding which may inform future diagnostic algorithms, genotype–phenotype correlations as well as aid in specific targeted treatment approaches. Larger future studies may inform risk stratification of patients and improve health related outcomes in patients with HMB. [ABSTRACT FROM AUTHOR]

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with salinetreated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted. NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted. [ABSTRACT FROM AUTHOR]

Pediatric dermatofibromas are considered rare in young children and have not been well characterized, often misdiagnosed clinically. We performed a retrospective case series of children younger than 18 years with histopathologically diagnosed dermatofibromas at our institutions and evaluated age at onset and diagnosis, sex, lesion location, and size, associated symptoms, change over time, and pre‐biopsy diagnosis. Overall, dermatofibromas were most common on the back and chest (20/53; 38%), followed by the legs (15/53; 28%) and arms (12/53; 23%) with the most common pre‐biopsy diagnosis of "cyst" (23/53; 43%), followed by dermatofibroma (16/53; 30%), and pilomatricoma (12/53; 23%). Our study reinforces previous findings of truncal predominance of pediatric dermatofibromas, different from adults. [ABSTRACT FROM AUTHOR]

Background: Parenteral (intravenous) nutrition is lifesaving for patients with intestinal failure, but long-term use of parenteral nutrition often leads to liver disease. SEFA-6179 is a synthetic medium-chain fatty acid analogue designed to target multiple fatty acid receptors regulating metabolic and inflammatory pathways. We hypothesized that SEFA-6179 would prevent hepatosteatosis and lipotoxicity in a murine model of parenteral nutrition-induced hepatosteatosis. Methods: Two in vivo experiments were conducted. In the first experiment, six-week-old male mice were provided an ad lib fat-free high carbohydrate diet (HCD) for 19 days with orogastric gavage of either fish oil, medium-chain triglycerides, or SEFA-6179 at a low (0.3mmol/kg) or high dose (0.6mmol/kg). In the second experiment, six-week-old mice were provided an ad lib fat-free high carbohydrate diet for 19 days with every other day tail vein injection of saline, soybean oil lipid emulsion, or fish oil lipid emulsion. Mice then received every other day orogastric gavage of medium-chain triglyceride vehicle or SEFA-6179 (0.6mmol/kg). Hepatosteatosis was assessed by a blinded pathologist using an established rodent steatosis score. Hepatic lipid metabolites were assessed using ultra-high-performance liquid chromatography-mass spectrometry. Effects of SEFA-6179 on fatty acid oxidation, lipogenesis, and fatty acid uptake in human liver cells were assessed in vitro. Results: In the first experiment, mice receiving the HCD with either saline or medium-chain triglyceride treatment developed macrovesicular steatosis, while mice receiving fish oil or SEFA-6179 retained normal liver histology. In the second experiment, mice receiving a high carbohydrate diet with intravenous saline or soybean oil lipid emulsion, along with medium chain triglyceride vehicle treatment, developed macrovescular steatosis. Treatment with SEFA-6179 prevented steatosis. In each experiment, SEFA-6179 treatment decreased arachidonic acid metabolites as well as key molecules (diacylglycerol, ceramides) involved in lipotoxicity. SEFA-6179 increased both β- and complete fatty oxidation in human liver cells, while having no impact on lipogenesis or fatty acid uptake. Conclusions: SEFA-6179 treatment prevented hepatosteatosis and decreased toxic lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis. An increase in both β- and complete hepatic fatty acid oxidation may underlie the reduction in steatosis. [ABSTRACT FROM AUTHOR]

Background: Enteral drug therapy is challenging in short bowel syndrome with intestinal failure (SBS‐IF) because of unpredictable absorption. SEFA‐6179 is an enterally administered medium‐chain fatty acid analogue under development for intestinal failure–associated liver disease. We investigate the pharmacokinetics of two SEFA‐6179 formulations in two large‐animal models of SBS‐IF, including a new pseudojejunostomy model. Methods: Twenty Yucatan minipigs were obtained. Half underwent pre‐resection pharmacokinetic study with single‐dose SEFA‐6179 administration. All minipigs then underwent 90% jejunoileal resection, with either a jejunoileal anastomosis or bypass of the intraperitoneal colon with anastomosis just proximal to the rectum (pseudojejunostomy). On postoperative day 3, a single‐dose pharmacokinetic study was performed. Results: Both SBS‐IF models were well tolerated. Compared with the jejunoileal anastomosis minipigs, pseudojejunostomy minipigs had a more severe malabsorptive phenotype with weight loss by postoperative day 4 (+0.1 vs −0.9 kg, P = 0.03) and liquid diarrhea (Bristol 5 vs Bristol 7, P = 0.0007). Compared with pre‐resection minipigs, both jejunoileal and pseudojejunostomy minipigs had lower total plasma exposure of SEFA‐6179 measured by area under the curve (jejunoileal: 37% less, P = 0.049; pseudojejunostomy: 74% less, P = 0.0001). Peak plasma concentration was also lower in the pseudojejunostomy group compared with pre‐resection (65% less, P = 0.04), but not lower in the jejunoileal group (P = 0.47). Conclusion: In two SBS‐IF minipig models, SEFA‐6179 had substantially decreased absorption compared with pre‐resection minipigs. Dose optimization for different intestinal anatomy and function may be required. We describe a new SBS‐IF pseudojejunostomy model that may improve the translation of preclinical research to patients with SBS‐IF who have enterostomies. [ABSTRACT FROM AUTHOR]

Succinate produced by the commensal protist Tritrichomonas musculis (T. mu) stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does not mediate antihelminth immunity nor alter protist colonization. Here, we report that microbial-derived succinate increases Paneth cell numbers and profoundly alters the antimicrobial peptide (AMP) landscape in the small intestine. Succinate was sufficient to drive this epithelial remodeling, but not in mice lacking tuft cell chemosensory components required to detect this metabolite. Tuft cells respond to succinate by stimulating type 2 immunity, leading to interleukin-13-mediated epithelial and AMP expression changes. Moreover, type 2 immunity decreases the total number of mucosa-associated bacteria and alters the small intestinal microbiota composition. Finally, tuft cells can detect short-term bacterial dysbiosis that leads to a spike in luminal succinate levels and modulate AMP production in response. These findings demonstrate that a single metabolite produced by commensals can markedly shift the intestinal AMP profile and suggest that tuft cells utilize SUCNR1 and succinate sensing to modulate bacterial homeostasis. [ABSTRACT FROM AUTHOR]

Objectives: Percutaneous electrical nerve field stimulation (PENFS) has documented efficacy for irritable bowel syndrome (IBS) via plausible vagal neuromodulation effects. The vagus nerve may affect gut microbiome composition via brain–gut–microbiome signaling. We aimed to investigate gut microbiome alterations by PENFS therapy in adolescent IBS patients. Methods: A prospective study of females with IBS aged 11–18 years receiving PENFS therapy for 4 weeks with pre‐ and post‐intervention stool sampling was conducted. Outcome surveys completed pre‐therapy, weekly, and post‐therapy included IBS‐Severity Scoring System (IBS‐SSS), Visceral Sensitivity Index (VSI), Functional Disability Inventory (FDI), and the global symptom response scale (SRS). Bacterial DNA was extracted from stool samples followed by 16S rRNA amplification and sequencing. QIIME 2 (version 2022.2) was used for analyses of α and β diversity and differential abundance by group. Results: Twenty females aged 15.6 ± 1.62 years were included. IBS‐SSS, VSI, and FDI scores decreased significantly after PENFS therapy (P < 0.0001, P = 0.0003, P = 0.0004, respectively). No intra‐ or interindividual microbiome changes were noted pre‐ versus post‐therapy or between responders and non‐responders. When response was defined by 50‐point IBS‐SSS score reduction, α diversity was higher in responders compared with non‐responders at week 4 (P = 0.033). There was higher abundance of Blautia in excellent responders versus non‐responders. Conclusions: There were no substantial microbial diversity alterations with PENFS. Subjects with excellent therapeutic response showed an enrichment of relative abundance of Blautia, which may indicate that patients with specific microbial signature have a more favorable response to PENFS. [ABSTRACT FROM AUTHOR]

Numerous studies have investigated the efficacy of intralesional immunotherapy for warts, but there are a lack of studies investigating the efficacy of alternative intralesional immunotherapies following failure of initial intralesional immunotherapy. In this retrospective study, we aimed to investigate the efficacy of intralesional measles, mumps, and rubella vaccine for the treatment of pediatric warts following failure of intralesional therapy with Candida antigen. Following intralesional measles, mumps, and rubella vaccine administration, 8/51 (15.5%) patients had complete resolution of their warts, 6/51 (12%) had near complete resolution, 19/51 (37%) had partial improvement, 12/51 (23.5%) had no change, and 6/51 (12%) had worsening. Although limited by retrospective nature and low sample size, our results demonstrate that intralesional immunotherapy with measles, mumps, and rubella vaccine provides an alternative therapeutic option for the treatment of recalcitrant pediatric warts in patients who fail to respond to intralesional Candida antigen. [ABSTRACT FROM AUTHOR]

Aortopulmonary collaterals (APCs) develop universally, but to varying degrees, in patients with single ventricle congenital heart disease (CHD). Despite their ubiquitous presence, APCs remain poorly understood. We sought to evaluate the association between APC burden and common non-invasive clinical variables. We conducted a single center, retrospective study of patients with single ventricle CHD and previous Glenn palliation who underwent pre-Fontan cardiac magnetic resonance (CMR) imaging from 3/2018 to 3/2021. CMR was used to quantify APC flow, which was normalized to aortic (APC/QAo) and pulmonary vein (APC/QPV) blood flow. Univariate, multivariable, and classification and regression tree (CART) analyses were done to investigate the potential relationship between CMR-quantified APC burden and clinical variables. A total of 29 patients were included, all of whom had increased APC flow (APC/QAo: 26.9, [22.0, 39.1]%; APC/QPV: 39.4 [33.3, 46.9]%), but to varying degrees (APC/QAo: range 11.9–44.4%; APC/QPV: range 17.7–60.0%). Pulmonary artery size (Nakata index, at pre-Fontan CMR) was the only variable associated with APC flow on multivariable analysis (APC/QAo: p = 0.020, R2 = 0.19; APC/QPV: p = 0.0006, R2 = 0.36) and was the most important variable associated with APC burden identified by CART analysis (size inversely related to APC flow). APC flow is universally increased but highly variable in patients with single ventricle CHD and Glenn circulation. Small branch pulmonary artery size is a key factor associated with increased APC burden; however, the pathogenesis of APCs is likely multifactorial. Further research is needed to better understand APC pathogenesis, including predisposing and mitigating factors. [ABSTRACT FROM AUTHOR]

Introduction and aim. Newborn blood spot screening (NBS) uses genetic technology to screen for selected genetic, endocrine, and metabolic disorders. The purpose of the study was to assess the knowledge of newborn blood spot genetic screening among expectant mothers. Material and methods. Between October 2015 and January 2016, a 20 question, multiple-choice questionnaire was administered to expectant mothers presenting for a pre-natal ultrasound at the Maternal Fetal Care Center in Milwaukee, Wisconsin Froedtert Hospital. Statistical analysis used Chi-Square or Fisher's exact test for categorical variables. Results. 103 women completed the survey; 34% believed that education regarding screening is incomplete and 39% believed that it needs improvement. 27% knew the purpose of newborn screening. Conclusion. Many mothers lack general and specific knowledge about NBS and the diseases screened for. Health education that provides accurate and complete information on the newborn blood spot screening should be provided to all parents prior to the administering of any genetic testing. Key areas that should be targeted include: purpose of NBS, screened diseases and how to interpret the results of the test. [ABSTRACT FROM AUTHOR]

Vaccine type and timing are critical issues to prevent unintended infections in those on immunosuppressive therapies. We retrospectively chart reviewed patients at Children's Wisconsin Pediatric Dermatology Clinic on immunosuppressives and immunomodulators between 11/1/2012 and 6/1/2020 and found that approximately 76% of patient encounters do not have documented vaccine counseling in the medical chart before initiation of immunosuppressives and immunomodulators. As age increased, vaccine counseling was less likely to be documented (odds ratio: 0.89; 95% confidence interval: 0.84–0.95, p =.001). In addition, 13 patient encounters (4%) were not up to date with live vaccines before immunosuppressive or immunomodulating therapy. There is an opportunity to improve clinical processes to ensure documentation of vaccination status and vaccine counseling before starting immunosuppressive and immunomodulator medications in a pediatric dermatology clinic. [ABSTRACT FROM AUTHOR]

Infants with congenital diaphragmatic hernia (CDH) may require cardiopulmonary bypass and systemic anticoagulation. Expeditious lung growth while on bypass is essential for survival. Previously, we demonstrated that heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). We investigated the effects of the direct thrombin inhibitors (DTIs) bivalirudin and argatroban. In vitro assays of lung endothelial cell proliferation and apoptosis were performed. C57BL/6 J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were pre-loaded with normal saline (control), bivalirudin, argatroban, or heparin and outcomes were assessed on postoperative day 8. Heparin administration inhibited endothelial cell proliferation in vitro and significantly decreased lung volume in vivo, while bivalirudin and argatroban preserved lung growth. These findings correlated with changes in alveolarization on morphometric analysis. Treadmill exercise tolerance testing demonstrated impaired exercise performance in heparinized mice; bivalirudin/argatroban did not affect exercise tolerance. On lung protein analysis, heparin decreased angiogenic signaling which was not impacted by bivalirudin or argatroban. Together, this data supports the use of DTIs as alternatives to heparin for systemic anticoagulation in CDH patients on bypass. Based on this work, clinical studies on the impact of heparin and DTIs on CDH outcomes are warranted. [ABSTRACT FROM AUTHOR]

Background: Physical inactivity and sedentary behavior are modifiable risk factors for chronic disease and all-cause mortality that may have been negatively impacted by the COVID-19 shutdowns. Methods: Accelerometry data was retrospectively collected from 332 permanent pacemaker (PPM) and 244 implantable cardiac defibrillation (ICD) patients for 6 time points: March 15-May 15, 2020 (pandemic period), January 1-March 14, 2020, October 1-December 31, 2019, March 15-May 15, 2019, January 1-March 14, 2019, and October 1-December 31, 2018. Paired t-tests, with Bonferroni correction, were used to compare time periods. Results: Activity significantly decreased during the pandemic period compared to one year prior by an average of 0.53 ± 1.18h/day (P < 0.001) for PPM patients and 0.51 ± 1.2h/day (P < 0.001) for ICD patients. Stratification of subjects by active time (< 2 versus ≥ 2h/day) showed patients with < 2h, particularly those with ICDs, had modestly greater activity reductions with the pandemic onset. Logistical regression analyses suggest a trend toward a greater reduction in active time at the onset of the pandemic and an increased risk of hospital or emergency department (ED) admission for PPM patients, but not ICD patients. Conclusion: The onset of the pandemic in the United States was associated with a significant drop in PPM and ICD patient active hours that was modestly more pronounced in less active patients and cannot be explained by one year of aging or seasonal variation. If sustained, these populations may experience excess cardiovascular morbidity. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to quantify the association between duration of labor induction in nulliparous women with hypertensive disorders of pregnancy and maternal and neonatal morbidity.Methods: This was a secondary analysis of a multicenter cohort study of 228,438 deliveries in 19 U.S. hospitals. The analysis included nulliparous women ≥18 years old with singleton gestation diagnosed with hypertensive disorders of pregnancy and undergoing induction of labor for that indication. Duration of labor induction, defined as time from admission to delivery, was examined by 4 h intervals from <12 h to ≥24 h in relation to maternal and neonatal composite outcomes. Maternal composite outcome included operative vaginal delivery, chorioamnionitis, blood transfusion, intensive care unit admission, placental abruption, 3rd or 4th degree perineal laceration, endometritis, postpartum hemorrhage, or venous thromboembolism. Neonatal composite outcome included neonatal intensive care unit (NICU) admission, respiratory distress syndrome, 5-minute Apgar score ≤7, seizure, infection, intrapartum meconium aspiration, intracranial hemorrhage, shoulder dystocia, and neonatal death. The trends in proportions of outcomes that occurred at different intervals were examined by Cochran-Armitage trend test. Relative risks were calculated with <12 h as the reference category and potential confounders adjusted by log-binomial or Poisson regression. Possible correlations within centers were taken into account using generalized estimating equations.Results: A total of 3,990 women met inclusion criteria. The median labor duration was 19.8 h (interquartile range 12.9 h-27.9h), with 849 (21.3%) lasting <12 h and 1,426 (35.7%) >24 h. The frequency of composite maternal outcome was not associated with labor duration; however, the rates of chorioamnionitis (p < .001) and postpartum hemorrhage (p < .001) increased as labor duration increased. The frequency of composite neonatal outcome was greater with increasing labor duration (p < .001). After multivariable adjustment, duration of labor induction was associated with increased risks of maternal composite outcome after 24 h (aRR 1.39, 95% CI 1.20-1.62) and neonatal composite outcome after 24 h (aRR 1.32, 95% CI 1.11-1.56).Conclusions: In nulliparous women with hypertensive disorders of pregnancy, duration of labor induction was associated with increased risks for maternal and neonatal morbidity after 24 h. [ABSTRACT FROM AUTHOR]

Obesity is a global epidemic that drives morbidity and mortality through cardiovascular disease, diabetes, and non‐alcoholic fatty liver disease (NAFLD). No definitive therapy has been approved to improve glycemic control and treat NAFLD in obese patients. Here, we investigated a semi‐synthetic, long chain, structurally‐engineered fatty acid‐1024 (SEFA‐1024), as a treatment for obesity‐induced hyperglycemia, insulin‐resistance, and fatty liver disease in rodent models. A single dose of SEFA‐1024 was administered to evaluate glucose tolerance and active glucagon‐like peptide 1 (GLP‐1) in lean rats in the presence and absence of a DPP‐4 inhibitor. The effects of SEFA‐1024 on weight loss and glycemic control were assessed in genetic (ob/ob) and environmental (high‐fat diet) murine models of obesity. Liver histology, serum liver enzymes, liver lipidomics, and hepatic gene expression were also assessed in the high‐fat diet murine model. SEFA‐1024 reversed obesity‐associated insulin resistance and improved glycemic control. SEFA‐1024 increased active GLP‐1. In a long‐term model of diet‐induced obesity, SEFA‐1024 reversed excessive weight gain, hepatic steatosis, elevated liver enzymes, hepatic lipotoxicity, and promoted fatty acid metabolism. SEFA‐1024 is an enterohepatic‐targeted, eicosapentaenoic acid derivative that reverses obesity‐induced dysregulated glucose metabolism and hepatic lipotoxicity in genetic and dietary rodent models of obesity. The mechanism by which SEFA‐1024 works may include increasing aGLP‐1, promoting fatty acid oxidation, and inhibiting hepatic triglyceride formation. SEFA‐1024 may serve as a potential treatment for obesity‐related diabetes and NAFLD. [ABSTRACT FROM AUTHOR]

Background: The prevalence of problematic Internet use (PIU) among adolescents and young adults (AYA) was approximately 9–11% before the COVID-19 pandemic. The purpose of this study was to determine the prevalence of PIU among AYAs (especially younger adolescents) during the COVID-19 pandemic using the Problematic and Risky Internet Use Screening Scale (PRIUSS). Additionally, we examined the relationship between PIU, depression and anxiety among AYAs during the same period. Methods: A descriptive-analysis survey study was completed over a 6-month period from January 4, 2021, to June 30, 2021. It was conducted at a tertiary care Adolescent Medicine Clinic with AYAs age 12–21. The PRIUSS screened for PIU, the PHQ-9A [Patient Health Questionnaire-9A] screened for depression, and the GAD-7 [General Anxiety Disorder-7] screened for generalized anxiety. Fisher's exact test, the Mann–Whitney test and Spearman correlations were performed. Results: A positive PRIUSS score was observed in 18% of the 447 participants. Of these participants, 44% had a pre-existing diagnosis of depression, 39% had a pre-existing diagnosis of anxiety and 29% had a pre-existing diagnosis of depression and anxiety. There was a positive correlation between PRIUSS, PHQ-9A and GAD-7 total scores. A higher PRIUSS score was associated with a higher PHQ-9A and GAD-7 score (p < 0.001). There was also a positive correlation between a positive PRIUSS score and a pre-existing diagnosis of depression (p < 0.001). Conclusions: This study showed a higher prevalence of PIU during the COVID-19 pandemic using the PRIUSS. In addition, a positive correlation between PRIUSS scores and pre-existing diagnosis of depression, positive GAD-7 and PHQ-9A scores was noted. In conclusion, medical providers should consider screening for PIU in AYAs with positive mental health screens. [ABSTRACT FROM AUTHOR]

Morbidity and mortality for neonates with congenital diaphragmatic hernia-associated pulmonary hypoplasia remains high. These patients may be deficient in vascular endothelial growth factor (VEGF). Our lab previously established that exogenous VEGF164 accelerates compensatory lung growth (CLG) after left pneumonectomy in a murine model. We aimed to further investigate VEGF-mediated CLG by examining the role of the heparin-binding domain (HBD). Eight-week-old, male, C57BL/6J mice underwent left pneumonectomy, followed by post-operative and daily intraperitoneal injections of equimolar VEGF164 or VEGF120, which lacks the HBD. Isovolumetric saline was used as a control. VEGF164 significantly increased lung volume, total lung capacity, and alveolarization, while VEGF120 did not. Treadmill exercise tolerance testing (TETT) demonstrated improved functional outcomes post-pneumonectomy with VEGF164 treatment. In lung protein analysis, VEGF treatment modulated downstream angiogenic signaling. Activation of epithelial growth factor receptor and pulmonary cell proliferation was also upregulated. Human microvascular lung endothelial cells (HMVEC-L) treated with VEGF demonstrated decreased potency of VEGFR2 activation with VEGF121 treatment compared to VEGF165 treatment. Taken together, these data indicate that the VEGF HBD contributes to angiogenic and proliferative signaling, is required for accelerated compensatory lung growth, and improves functional outcomes in a murine CLG model. [ABSTRACT FROM AUTHOR]

Individuals with single ventricle congenital heart disease (CHD) undergo multiple staged surgical palliations. Staged single ventricle palliation with a superior cavopulmonary connection (SCPC) in infancy followed by a Fontan in early childhood relies on passive, unobstructed pulmonary blood flow and normal pulmonary vasculature. We hypothesized that patients with echocardiographic identification of retrograde flow in a branch pulmonary artery (PA) after SCPC or Fontan are at increased risk for adverse outcomes. We conducted a retrospective chart review of patients seen at Children's Wisconsin from 1999 to 2019. Inclusion criteria included a history of single ventricle congenital heart disease and surgical palliation with a superior cavopulmonary connection (SCPC). We created two cohorts based on transthoracic echocardiographic identification of branch PA flow patterns: those with color Doppler-defined pulmonary artery flow reversal (PA reversal cohort) and those with normal anterograde flow (Non-reversal cohort). We identified 21 patients in the PA reversal cohort and 539 patients in the Non-reversal cohort. The PA reversal cohort had increased hospital length of stay after SCPC palliation (p < 0.001) and decreased transplant-free survival (p = 0.032), but there was no difference in overall survival (p = 0.099). There was no difference in hospital length of stay after Fontan (p = 0.17); however, the PA reversal cohort was significantly less likely to progress to Fontan palliation during early childhood (p = 0.005). Echocardiographic color Doppler identification of branch PA flow reversal in patients with single ventricle physiology is a high-risk indicator for adverse short- and long-term outcomes. [ABSTRACT FROM AUTHOR]

Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Current management of CDH is primarily supportive and mortality rates of the most severely affected children have remained unchanged in the last few decades. Previous work in our lab has demonstrated the importance of vascular endothelial growth factor (VEGF)-mediated angiogenesis in accelerating compensatory lung growth. In this study, we evaluated the potential for Roxadustat (FG-4592), a prolyl hydroxylase inhibitor known to increase endogenous VEGF, in accelerating compensatory lung growth. Treatment with Roxadustat increased lung volume, total lung capacity, alveolarization, and exercise tolerance compared to controls following left pneumonectomy. However, this effect was likely modulated not only by increased VEGF, but rather also by decreased pigment epithelium-derived factor (PEDF), an anti-angiogenic factor. Furthermore, this mechanism of action may be specific to Roxadustat. Vadadustat (AKB-6548), a structurally similar prolyl hydroxylase inhibitor, did not demonstrate accelerated compensatory lung growth or decreased PEDF expression following left pneumonectomy. Given that Roxadustat is already in Phase III clinical studies for the treatment of chronic kidney disease-associated anemia with minimal side effects, its use for the treatment of pulmonary hypoplasia could potentially proceed expeditiously. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) of patients with pacemakers remains concerning because of possible magnetic field effects on the device. Many pacemaker models are labeled as non-conditional, or contraindicated for MRI, or do not have any specific safety guidelines listed. This study describes our experience with pacemaker function and adverse events in pediatric and young adult patients after clinically indicated MRI scanning at 1.5 Tesla (T). We hypothesized that generator battery voltage, pacemaker lead threshold, and lead impedance would not be altered by MRI. This was a retrospective review of Children's Wisconsin clinical MRI data for all patients with pacemakers scanned between January 1, 2010 and March 31, 2018. Pacemakers were interrogated by the Electrophysiology Team before and immediately after MRI and at outpatient follow up. Twenty-one patients underwent forty-four MRI scans. No significant immediate changes were seen in any pacemaker parameter for any manufacturer/model/lead at the time of MRI. At first clinical follow up post MRI, (median 4.4 months, range 0.2–12.3), battery voltage was reduced (2.78 V pre-MRI versus 2.77 V at follow up, p = 0.02), but there were no other significant changes. No adverse events were noted. Pediatric patients with pacemakers, including those with epicardial leads, can be scanned at 1.5 T safely without alteration in pacemaker function. Using appropriate precautions, pediatric patients with pacemakers can be imaged with MRI. [ABSTRACT FROM AUTHOR]

Background: Dietary strategies can aid in the management of critically ill patients. Very-low-carbohydrate diets have been shown to improve glucose control and the inflammatory response. We aimed to determine the effects of a eucaloric ketogenic diet (EKD) enriched with ω-3 fatty acids (O3KD) on glucose levels and inflammation in mice with endotoxemia.Methods: Adult mice were fed 1 of 3 diets (control diet [CD], EKD, or O3KD). After 4 weeks, each group received saline or Escherichia coli lipopolysaccharide (LPS) (5 mg/kg) intraperitoneally during the postprandial (PPP) or postabsorptive (PAP) periods. Blood glucose was measured at 0, 15, 30, 60, 90, 120, 180, and 240 minutes. Serum tumor necrosis factor (TNF)-α and interleukin (IL) 6 were measured by enzyme-linked immunosorbent assay. Distribution of serum fatty acids was determined by gas liquid chromatography. Hepatic expression of genes involved in inflammation, as well as glucose and lipid metabolism, were determined by quantitative polymerase chain reaction.Results: During the PPP, glucose curves were comparable among the experimental groups. During the PAP, EKD showed a more pronounced increase in glucose levels at the first hour after LPS challenge compared with the CD-LPS group. During the PAP, IL6 was lower in O3KD-LPS compared with CD-LPS and EKD-LPS groups. These differences disappeared in the PPP. Similarly, TNF-α was lower in the O3KD-LPS group compared with the EKD-LPS group. The O3KD significantly increased the serum levels of the ω-3 eicosapentaenoic and docosahexaenoic acids and decreased the ω-6 arachidonic acid.Conclusion: An O3KD leads to reduced inflammation and maintains glucose homeostasis in mice with endotoxemia. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is caused by mutations of the gene encoding the CF transmembrane conductance regulator. It remains unclear whether the abnormal immune response in CF involves extrinsic signals released from the external or internal environment. We sought to characterize the peripheral immune signatures in CF and its association with clinical phenotypes. Healthy peripheral blood mononuclear cells (PBMCs) were cultured with plasma from CF probands (CFPs) or healthy control subjects (HCs) followed by nCounter gene and microRNA (miRNA) profiling. A discovery cohort of 12 CFPs and 12 HCs and a validation cohort of 103 CFPs and 31 HCs (our previous microarray data [GSE71799]) were analyzed to characterize the composition of cultured immune cells and establish a miRNA-mRNA network. Cell compositions and miRNA profiles were associated with clinical characteristics of the cohorts. Significantly differentially expressed genes and abundance of myeloid cells were downregulated in PMBCs after culture with CF plasma (P<0.05). Top-ranked miRNAs that increased in response to CF plasma (adjusted P <0.05) included miR-155 and miR-146a, which target many immune-related genes, such as IL-8. Pseudomonas aeruginosa infection was negatively associated with abundance of monocytes and the presence of those regulatory miRNAs. Extrinsic signals in plasma from patients with CF led to monocyte inactivation and miRNA upregulation in PBMCs. An improved understanding of the immune effects of extrinsic factors in CF holds great promise for integrating immunomodulatory cell therapies into current treatment strategies in CF. [ABSTRACT FROM AUTHOR]

Intestinal failure-associated liver disease (IFALD) is a risk of parenteral nutrition (PN)-dependence. Intravenous soybean oil-based parenteral fat can exacerbate the risk of IFALD while intravenous fish oil can minimize its progression, yet the mechanisms by which soybean oil harms and fish oil protects the liver are uncertain. Properties that differentiate soybean and fish oils include α-tocopherol and phytosterol content. Soybean oil is rich in phytosterols and contains little α-tocopherol. Fish oil contains abundant α-tocopherol and little phytosterols. This study tested whether α-tocopherol confers hepatoprotective properties while phytosterols confer hepatotoxicity to intravenous fat emulsions. Utilizing emulsions formulated in the laboratory, a soybean oil emulsion (SO) failed to protect from hepatosteatosis in mice administered a PN solution enterally. An emulsion of soybean oil containing α-tocopherol (SO+AT) preserved normal hepatic architecture. A fish oil emulsion (FO) and an emulsion of fish oil containing phytosterols (FO+P) protected from steatosis in this model. Expression of hepatic acetyl CoA carboxylase (ACC) and peroxisome proliferator-activated receptor gamma (PPARγ), was increased in animals administered SO. ACC and PPARγ levels were comparable to chow-fed controls in animals receiving SO+AT, FO, and FO+P. This study suggests a hepatoprotective role for α-tocopherol in liver injury induced by the enteral administration of a parenteral nutrition solution. Phytosterols do not appear to compromise the hepatoprotective effects of fish oil. [ABSTRACT FROM AUTHOR]

Background Fish oil (FO) intravenous lipid emulsions (ILEs) are used as a monotherapy to treat parenteral nutrition (PN)-associated liver disease and provide essential fatty acids (EFAs) needed to sustain growth and prevent EFA deficiency (EFAD). Studies have suggested that medium-chain triglycerides (MCTs) and α-tocopherol have anti-inflammatory properties. Objective The purpose of this study was to test whether FO-ILEs containing MCTs and/or additional α-tocopherol decrease the inflammatory response to an endotoxin challenge compared with FO-ILE alone and preserve the ability to prevent PN-induced liver injury in mice. Methods A murine model of PN-induced hepatosteatosis was used to compare the effects of ILEs formulated in the laboratory containing varying ratios of FO and MCTs, and subsequently FO- and 50:50 FO:MCT-ILE plus 500 mg/L α-tocopherol (FO + AT and 50:50 + AT, respectively). C57BL/6 mice receiving unpurified diet (UPD), PN-equivalent diet (PN) + saline, and PN + soybean oil (SO)-ILE served as controls. After 19 d, mice received an intraperitoneal saline or endotoxin challenge 4 h before being killed. Serum and livers were harvested for histologic analysis, fatty acid profiling, and measurement of systemic inflammatory markers (tumor necrosis factor-α, interleukin-6). Results All ILEs were well tolerated and prevented biochemical EFAD. Livers of mice that received saline and SO developed steatosis. Mice that received 30:70 FO:MCT developed mild hepatosteatosis. All other FO-containing ILEs preserved normal hepatic architecture. Mice that received FO- or SO-ILE had significantly elevated systemic inflammatory markers after endotoxin challenge compared with UPD-fed controls, whereas 50:50 FO:MCT, 30:70 FO:MCT, FO + AT, and 50:50 + AT groups had significantly lower inflammatory markers similar to those seen in UPD-fed controls. Conclusions Mixed FO/MCT and the addition of α-tocopherol to FO improved the inflammatory response to endotoxin challenge compared with FO-ILE alone while still preventing PN-induced liver injury and EFAD in mice. There was no synergistic relation between α-tocopherol and MCTs. [ABSTRACT FROM AUTHOR]

Polyunsaturated fatty acids serve multiple functions in neurodevelopment and neurocognitive function. Intravenous lipid emulsions are administered to children that are dependent on parenteral nutrition to provide the essential fatty acids needed to sustain growth and development. One of these emulsions, derived from fish-oil, is particularly poor in the traditional essential fatty acids, linoleic and alpha-linolenic acids. However, it does contain adequate amounts of its main derivatives, arachidonic acid (ARA) and docosahexaenoic acid (DHA), respectively. This skewed composition has raised concern about the sole use of fish-oil based lipid emulsions in children and how its administration can be detrimental to their neurodevelopment. Using a custom-made diet that contains ARA and DHA as a sole source of polyunsaturated fatty acids, we bred and fed mice for multiple generations. Compared to adult, chow-fed mice, animals maintained on this special diet showed similar outcomes in a battery of neurocognitive tests performed under controlled conditions. Chow-fed mice did perform better in the rotarod test for ataxia and balance, although both experimental groups showed a conserved motor learning capacity. Conversely, mice fed the custom diet rich in DHA and ARA showed less neophobia than the chow-fed animals. Results from these experiments suggest that providing a diet where ARA and DHA are the sole source of polyunsaturated fatty acids is sufficient to support gross visual, cognitive, motor, and social development in mice. [ABSTRACT FROM AUTHOR]