Pediatric croup with COVID-19.

We describe three previously healthy children, admitted from our emergency department (ED) to our free-standing children's hospital, as the first documented cases of croup as a manifestation of SARS-CoV-2 infection. All three cases (ages 11 months, 2 years, and 9 years old) presented with non-specific upper-respiratory-tract symptoms that developed into a barky cough with associated stridor at rest and respiratory distress. All were diagnosed with SARS-CoV-2 by polymerase chain reaction testing from nasopharyngeal samples that were negative for all other pathogens including the most common etiologies for croup. Each received multiple (≥3) doses of nebulized racemic epinephrine with minimal to no improvement shortly after medication. All had a prolonged period of time from ED presentation until the resolution of their stridor at rest (13, 19, and 21 h). All received dexamethasone early in their ED treatment and all were admitted. All three received at least one additional dose of dexamethasone, an atypical treatment occurrence in our hospital, due to each patient's prolonged duration of symptoms. One child required heliox therapy and admission to intensive care. All patients were eventually discharged. Pathogen testing is usually not indicated in croup, but with "COVID-19 croup," SARS-CoV-2 testing should be considered given the prognostic significance and prolonged quarantine implications. Our limited experience with this newly described COVID-19 croup condition suggests that cases can present with significant pathology and might not improve as rapidly as those with typical croup.

Propofol Versus Dexmedetomidine for Procedural Sedation in a Pediatric Population.

OBJECTIVES: Frequently, infants and children require sedation to facilitate noninvasive procedures and imaging studies. Propofol and dexmedetomidine are used to achieve deep procedural sedation in children. The objective of this study was to compare the clinical safety and efficacy of propofol versus dexmedetomidine in pediatric patients undergoing sedation in a pediatric sedation unit. METHODS: A retrospective analysis of patients sedated with either propofol or dexmedetomidine in a pediatric sedation unit by pediatric emergency physicians was performed. Both medications were dosed per protocol with propofol 2 mg/kg induction and 150 µg · kg-1 · min-1 maintenance and dexmedetomidine 3 µg/kg induction for 10 minutes and 2 µg · kg-1 · h-1maintenance. The variables collected included drug dose, sedation time (time that the drug was given to the completion of the procedure), recovery time (end of the study to the return to the presedation sedation score for 15 minutes), need for dose rate changes, airway management, and adverse events. RESULTS: A total of 2432 children were included- 1503 who received propofol and 929 who received dexmedetomidine. Propofol and dexmedetomidine resulted in successful completion of the study in 98.8% and 99.7%, respectively (P = 0.02). The mean recovery time for propofol was 34.3 minutes, compared with 65.6 minutes for dexmedetomidine (P < 0.001). The need for unexpected airway management was 9.7% for propofol and 2.2% for dexmedetomidine (P < 0.001). Adverse events occurred in 8.6% and 6% of patients in the propofol and dexmedetomidine groups, respectively (P = 0.02). CONCLUSIONS: Propofol use led to significantly shorter recovery times, with an increased need for airway management, but rates of bag-mask ventilation (2.3%), airway obstruction (1.1%), and desaturation (1.6%) were low. No patients required intubation. Propofol is a reasonable alternative to dexmedetomidine, with a clinically acceptable safety profile.

Stimulation of cortical bone formation with thienopyrimidine based inhibitors of Notum Pectinacetylesterase.

A group of small molecule thienopyrimidine inhibitors of Notum Pectinacetylesterase are described. We explored both 2-((5,6-thieno[2,3-d]pyrimidin-4-yl)thio)acetic acids and 2-((6,7-thieno[3,2-d]pyrimidin-4-yl)thio)acetic acids. In both series, highly potent, orally active Notum Pectinacetylesterase inhibitors were identified.

4H-Thieno[3,2-c]chromene based inhibitors of Notum Pectinacetylesterase.

A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.

Optimizing Recognition and Management of Patients at Risk for Infection-Related Decompensation Through Team-Based Decision Making.

INTRODUCTION: Pediatric sepsis is a leading cause of death among children. Electronic alert systems may improve early recognition but do not consistently result in timely interventions given the multitude of clinical presentations, lack of treatment consensus, standardized order sets, and inadequate interdisciplinary team-based communication. We conducted a quality improvement project to improve timely critical treatment of patients at risk for infection-related decompensation (IRD) through team-based communication and standardized treatment workflow. METHODS: We evaluated children at risk for IRD as evidenced by the activation of an electronic alert system (Children at High Risk Alert Tool [CAHR-AT]) in the emergency department. Outcomes were assessed after multiple improvements including CAHR-AT implementation, clinical coassessment, visual cues for situational awareness, huddles, and standardized order sets. RESULTS: With visual cue activation, initial huddle compliance increased from 7.8% to 65.3% ( p < .001). Children receiving antibiotics by 3 hours postactivation increased from 37.9% pre-CAHR-AT to 50.7% posthuddle implementation ( p < .0001); patients who received a fluid bolus by 3 hours post-CAHR activation increased from 49.0% to 55.2% ( p = .001). CONCLUSIONS: Implementing a well-validated electronic alert tool did not improve quality measures of timely treatment for high-risk patients until combined with team-based communication, standardized reassessment, and treatment workflow.

Development of a high-throughput human HepG(2) dual luciferase assay for detection of metabolically activated hepatotoxicants and genotoxicants.

Hepatic toxicity remains a major concern for drug failure; therefore, a thorough examination of chemically induced liver toxicity is essential for a robust safety evaluation. Current hypotheses suggest that the metabolic activation of a drug to a reactive intermediate is an important process. In this article, we describe a new high-throughput GADD45beta reporter assay developed for assessing potential liver toxicity. Most importantly, this assay utilizes a human cell line and incorporates metabolic activation and thus provides significant advantage over other comparable assays used to determine hepatotoxicity. Our assay has low compound requirement and relies upon 2 reporter genes cotransfected into the HepG(2) cells. The gene encoding Renilla luciferase is fused to the CMV promoter and provides a control for cell numbers. The firefly luciferase gene is fused to the GADD45beta promoter and used to report an increase in DNA damage. A dual luciferase assay is performed by measuring the firefly and Renilla luciferase activities in the same sample. Results are expressed as the ratio of the 2 luciferase activities; increases over the control are interpreted as evidence of stress responses. This mammalian dual luciferase reporter has been characterized with, and without, metabolic activation using positive and negative control agents. Our data demonstrate that this assay provides for an assessment of potential toxic metabolites, is adaptable to a high-throughput platform, and yields data that accurately and reproducibly detect hepatotoxicants.

Biologic and chemical terrorism in children: an assessment of residents' knowledge.

This study was conducted to determine the baseline fund of knowledge of pediatric and emergency medicine residents at a single institution in the medical management of pediatric victims of biologic and chemical terrorism. A test covering essential content was developed and validated by experts. The test was given anonymously to volunteer pediatric and emergency medicine residents at a single institution. The test was readministered 5 months after a lecture on the content. The 34 pediatric residents and 15 emergency medicine residents scored a median of 65% and 73%, respectively (P = .03). Residents from both specialties combined scored a median of 70% correct versus those residents who did not attend the lecture. Pediatric and emergency medicine residents are significantly unprepared to manage pediatric victims of biologic and chemical terrorism. Education curriculums on this topic must be incorporated into these residencies. The traditional lecture format may not be the most effective technique.

Antidiabetic activity of passive nonsteroidal glucocorticoid receptor modulators.

Much has been learned about the consequences of glucocorticoid receptor antagonism by studying steroidal active antagonists such as RU-38486 (1). In the liver glucocorticoid receptor antagonism suppresses hepatic glucose production decreasing plasma glucose levels; however, extrahepatic antagonism produces several undesirable side effects including activation of the hypothalamic pituitary adrenal axis. A series of nonsteroidal passive N-(3-dibenzylamino-2-alkyl-phenyl)-methanesulfonamide glucocorticoid receptor modulators was discovered. Liver selective and systemically available members of this series were found and characterized in diabetes and side effect rodent models. A highly liver selective member of this series, acid 14, shows efficacy in the ob/ob model of diabetes. It lowers plasma glucose, cholesterol, and free fatty acid concentrations and reduces the rate of body weight gain. The structurally related systemically available passive modulator 12 lowers glucose, HbA(1c), triglyceride, free fatty acid, and cholesterol levels. Interestingly, it did not acutely activate the hypothalamic pituitary adrenal axis in unstressed CD-1 mice or have the abortive effects observed with 1. These results indicate that passive GR antagonists may have utility as antidiabetic agents.

2-Pyridyl P1'-substituted symmetry-based human immunodeficiency virus protease inhibitors (A-792611 and A-790742) with potential for convenient dosing and reduced side effects.

A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification of the core regiochemistry and stereochemistry significantly affected the potency, metabolic stability, and oral bioavailability of the inhibitors, as did the variation of a pendent arylmethyl P3 group. Optimization led to the selection of two compounds, 10c (A-790742) and 9d (A-792611), for advancement to preclinical studies. Both compounds displayed low nanomolar potency against wild type HIV in the presence of human serum, low rates of metabolism in human liver microsomes, and high oral bioavailability in animal models. The compounds were examined in a preclinical model for the hyperbilirubinemia observed with some HIV PIs, and both exhibited less bilirubin elevation than comparator compounds. X-ray crystallographic analyses of the new cores were used to examine differences in their binding modes. The antiviral activity of the compounds against protease inhibitor resistant strains of HIV was also determined.

Antivenom therapy for snakebites in children: is there evidence?

PURPOSE OF REVIEW: A new Fab fragment antivenom (CroFab) for the treatment of crotaline envenomation, the predominant venomous snakebite in the United States, has drastically changed snakebite management since its release in December 2000. This review examines the evidence supporting the use of CroFab, with particular attention on the pediatric population. RECENT FINDINGS: The published experience with CroFab in humans consists of six studies and some case reports. These publications demonstrate that CroFab is highly efficacious in treating both the local and systemic toxic effects of crotaline envenomation. They identify an important phenomenon of recurrent or delayed toxicity in some patients. The studies report a very low incidence of acute or delayed hypersensitivity reactions to the antivenom. They suggest comparable efficacy and safety of CroFab in the pediatric population as in adults. SUMMARY: Based on limited data, CroFab has been shown to be a safe and efficacious antivenom for use in children as well as adults. Further studies are needed to refine our understanding of its efficacy, safety, indications, and dosing.

Antibiotic-induced mesenteric adenopathy in an intussusception mouse model: a randomized, controlled trial.

BACKGROUND: Idiopathic intussusception is a leading cause of intestinal obstruction in young children. Although the etiology remains obscure, lymphoid hyperplasia is found in a majority of cases. Antibiotics, the most frequently prescribed medication class in the pediatric population, have been recently associated with intussusception. The authors sought to determine whether enteral antibiotic exposure influences the development of mesenteric adenopathy, bowel dilation or intussusception in an animal model. MATERIALS AND METHODS: The authors conducted a randomized, controlled animal trial using a previously described intussusception model. Mice were gavaged with normal saline, amoxicillin-clavulanate or azithromycin twice daily for 5 days to assess the influence of enteral antibiotic exposure on intussusception, mesenteric adenopathy and bowel dilation. One pediatric surgeon performed all laparotomies and was blinded to group designation. Chi2 and Fisher exact tests were used to evaluate differences between antibiotic exposed and control groups. RESULTS: Mesenteric adenopathy was identified in 4.1% of the normal saline controls compared with 54.1% (P < 0.01) and 38.9% (P < 0.01) of the amoxicillin-clavulanate and azithromycin exposed animals, respectively. A total of four intussusceptions were observed in the antibiotic-exposed groups combined whereas no intussusception cases were identified in the control group (P = 0.30). CONCLUSIONS: This is the first study to describe a significant association between antibiotic use and mesenteric adenopathy in any animal species.