Characterization of tritiated JNJ-GluN2B-5 (3-[3H] 1-(azetidin-1-yl)-2-(6-(4-fluoro-3-methyl-phenyl)pyrrolo[3,2-b]pyridin-1-yl)ethanone), a high affinity GluN2B radioligand with selectivity over sigma receptors.

Here, we describe the characterization of a radioligand selective for GluN2B-containing NMDA receptors, 3-[3H] 1-(azetidin-1-yl)-2-(6-(4-fluoro-3-methyl-phenyl)pyrrolo[3,2-b]pyridin-1-yl)ethanone ([3H]-JNJ- GluN2B-5). In rat cortical membranes, the compound bound to a single site, and the following kinetic parameters were measured; association rate constant Kon = 0.0066 ± 0.0006 min-1 nM-1, dissociation rate constant Koff = 0.0210 ± 0.0001 min-1 indicating calculated KD = Koff/Kon = 3.3 ± 0.4 nM, (mean ± SEM, n = 3). The equilibrium dissociation constant determined from saturation binding experiments in rat cortex was KD of 2.6 ± 0.3 nM (mean ± SEM, n = 3). In contrast to the widely used GluN2B radioligand [3H]-Ro 25-6981, whose affinity Ki for sigma 1 and sigma 2 receptors are 2 and 189 nM, respectively, [3H]-JNJ-GluN2B-5 exhibits no measurable affinity for sigma 1 and sigma 2 receptors (Ki > 10 µM for both) providing distinct selectivity advantages. Anatomical distribution of [3H]-JNJ-GluN2B-5 binding sites in rat, mouse, dog, monkey, and human brain tissue was studied using in vitro autoradiography, which showed high specific binding in the hippocampus and cortex and negligible binding in the cerebellum. Enhanced selectivity for GluN2B-containing receptors translated to a good signal-to-noise ratio in both in vitro radioligand binding and in vitro autoradiography assays. In conclusion, [3H]-JNJ-GluN2B-5 is a high-affinity GluN2B radioligand with excellent signal-to-noise ratio and unprecedented selectivity.

Acute opioid overdose in pediatric patients.

Recent increases in pediatric and adolescent opioid fatalities mandate an urgent need for early consideration of possible opioid exposure and specific diagnostic and management strategies and interventions tailored to these unique populations. In contrast to adults, pediatric methods of exposure include accidental ingestions, prescription misuse, and household exposure. Early recognition, appropriate diagnostic evaluation, along with specialized treatment for opioid toxicity in this demographic are discussed. A key focus is on Naloxone, an essential medication for opioid intoxication, addressing its unique challenges in pediatric use. Unique pediatric considerations include recognition of accidental ingestions in our youngest population, critical social aspects including home safety and intentional exposure, and harm reduction strategies, mainly through Naloxone distribution and education on safe medication practices. It calls for a multifaceted approach, including creating pediatric-specific guidelines, to combat the opioid crisis among children and to work to lower morbidity and mortality from opioid overdoses.

ACR Appropriateness Criteria® Congenital or Acquired Heart Disease.

Pediatric heart disease is a large and diverse field with an overall prevalence estimated at 6 to 13 per 1,000 live births. This document discusses appropriateness of advanced imaging for a broad range of variants. Diseases covered include tetralogy of Fallot, transposition of great arteries, congenital or acquired pediatric coronary artery abnormality, single ventricle, aortopathy, anomalous pulmonary venous return, aortopathy and aortic coarctation, with indications for advanced imaging spanning the entire natural history of the disease in children and adults, including initial diagnosis, treatment planning, treatment monitoring, and early detection of complications. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Air Medical Transport of a 12-Year-Old Girl With Cerebral Gas Embolism Due to Helium Inhalation.

This case report describes the initial care and transport considerations of a pediatric patient who suffered from cerebral gas embolism sustained after inhalation of helium from a pressurized tank. The patient demonstrated neurologic symptoms necessitating hyperbaric oxygen therapy and required fixed wing air transport across a mountain range from a rural community hospital to a tertiary center for the treatment. We review the pathophysiology of cerebral gas embolism and strategies for transporting patients with cerebral gas embolism and other trapped gas.

Discovery of a Series of Substituted 1H-((1,2,3-Triazol-4-yl)methoxy)pyrimidines as Brain Penetrants and Potent GluN2B-Selective Negative Allosteric Modulators.

Herein, we describe a series of substituted 1H-((1,2,3-triazol-4-yl)methoxy)pyrimidines as potent GluN2B negative allosteric modulators. Exploration of several five- and six-membered heterocycles led to the identification of O-linked pyrimidine analogues that possessed a balance of potency and desirable ADME profiles. Due to initial observations of metabolic saturation, early metabolite identification studies were conducted on compound 18, and the results drove further iterative optimization efforts to avoid the formation of undesired saturating metabolites. The comprehensive investigation of substitution on the pyrimidine moiety of the 1H-1,2,3-triazol-4-yl)methoxy)pyrimidines allowed for the identification of compound 31, which demonstrated high GluN2B receptor affinity, improved solubility, and a clean cardiovascular profile. Compound 31 was profiled in an ex vivo target engagement study in rats at a 10 mg/kg oral dose and achieved an ED50 of 1.7 mg/kg.

Characteristics of Pediatric Patient Transfers From General Emergency Departments in California From 2005 to 2018.

OBJECTIVE: Each year, approximately 300,000 pediatric patients are transferred out of emergency departments (EDs). Emergency department transfers may not only provide a higher level of care but also incur increased resource use and cost. Our objective was to identify hospital characteristics and patient demographics and conditions associated with ED transfer as well as the trend of transfers over time. METHODS: This was a retrospective cohort study of pediatric visits to EDs in California using the California Office of Statewide Health Planning and Development ED data set (2005-2018). Hospitals were categorized based on inpatient pediatric capabilities. Patients were characterized by demographics and Clinical Classifications Software diagnostic categories. Regression models were created to analyze likelihood of outcome of transfer compared with admission. RESULTS: Over the 14-year period, there were 38,117,422 pediatric visits to 364 EDs in California with a transfer rate of 1% to 2%. During this time, the overall proportion of pediatric transfers increased, whereas pediatric admissions decreased for all hospital types. Transfers were more likely in general hospitals without licensed pediatric beds (odds ratio [OR], 16.26; 95% confidence interval [CI], 15.87-16.67) and in general hospitals with licensed pediatric beds (OR, 3.54; 95% CI, 3.46-3.62) than in general hospitals with pediatric intensive care unit beds. Mental illness (OR, 61.00; 95% CI, 57.90-63.20), poisoning (OR, 11.78; 95% CI, 11.30-12.30), diseases of the circulatory system (OR, 6.13; 95% CI, 5.84-6.43), diseases of the nervous system (OR, 4.61; 95% CI, 4.46-4.76), and diseases of the blood and blood-forming organs (OR, 3.21; 95% CI, 3.62; 95% CI, 3.45-3.79) had increased odds of transfer. CONCLUSION: Emergency departments in general hospitals without pediatric intensive care units and patients' Clinical Classifications Software category were associated with increased likelihood of transfer. A higher proportion of patients with complex conditions are transferred than those with common conditions. General EDs may benefit from developing transfer processes and protocols for patients with complex medical conditions.

Marijuana use in children: An update focusing on pediatric tetrahydrocannabinol and cannabidiol use.

Cannabis is the most used recreational drug in the United States, and its use is increasing among children and adolescents.  With the increase in legalized use, there have been increases in intentional and accidental cannabis exposure in the pediatric population. There is also minimized perceived risk.  We review the current use of cannabis and its derivatives, the drug effects and clinical presentation, common misconceptions, pharmacology, and epidemiology. Finally, we review some long-term consequences of cannabis use.

ACR Appropriateness Criteria® Crohn Disease-Child.

Crohn disease is an inflammatory condition of the gastrointestinal tract with episodes of exacerbation and remission occurring in children, adolescents, and adults. Crohn disease diagnosis and treatment depend upon a combination of clinical, laboratory, endoscopic, histological, and imaging findings. Appropriate use of imaging provides critical information in the settings of diagnosis, assessment of acute symptoms, disease surveillance, and therapy monitoring. Four variants are discussed. The first variant discusses the initial imaging for suspected Crohn disease before established diagnosis. The second variant pertains to appropriateness of imaging modalities during suspected acute exacerbation. The third variant is a substantial discussion of recommendations related to disease surveillance and monitoring of Crohn disease. Finally, panel recommendations and discussion of perianal fistulizing disease imaging completes the document. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Hemostatic Resuscitation of Pediatric Trauma Patients During Air Medical Transport: A Retrospective Matched Cohort Study.

OBJECTIVE: The objective of this study was to examine an academic air ambulance service's experience with prehospital transfusion of plasma and red blood cells in pediatric trauma for evidence of efficacy on the treatment of shock and coagulopathy. METHODS: All trauma patients < 18 years old transfused during transport by the University of Washington Airlift Northwest (Airlift) air medical transport service to Harborview Medical Center, Seattle, WA, were identified. Controls were matched 1:1 from pediatric trauma patients transported by Airlift before transfusion support became available. Demographics, injury scores, emergency department admission and interval laboratory values, blood product use, and hospital outcome measures were registered. RESULTS: Seventeen cases met the inclusion criteria and were matched by age and Injury Severity Score to 17 control patients (mean age = 10.5 vs. 10.9 years; New Injury Severity Score, 37 vs. 40.7). No significant differences in vital signs, shock index, or mortality were observed. Cases received less in-flight crystalloid (4.3 mL/kg vs. 16.9 mL/kg, P = .004), had higher admission fibrinogen levels (238 vs. 148mg/dL, P = .007), and shorter time to normalization of the international normalized ratio (6.4 vs. 19.1 hours, P = .04). CONCLUSIONS: In this small series, hemostatic resuscitation during air medical transport was associated with less crystalloid administration and better support of coagulation indices.

Drugs of Abuse-Opioids, Sedatives, Hypnotics.

Over the last 2 decades, prescription and nonprescription substance use has significantly increased. In this article, 3 particular drug classes-opioids, sedatives, and hypnotics-are discussed. For each class, a brief history of the agent, a description of relevant pharmacology, the clinical presentation of overdose, the management of specific drug overdoses, and a summary of salient points are presented. The intent is to provide a clinically relevant and comprehensive approach to understanding these potential substance exposures in order to provide a framework for management of opioid, sedative, and hypnotic overdoses.

A Framework for Quality Assurance of Pediatric Revisits to the Emergency Department.

BACKGROUND: Emergency department return visits significantly impact medical costs and patient flow. A comprehensive approach to understanding these patients is required to identify deficits in care, system level inefficiencies, and improve diagnosis specific management protocols. We aimed to identify factors needed to successfully analyze return visits to explore root causes leading to unplanned returns and inform system-level improvements. METHODS: A multidisciplinary committee collaborated to develop a quality review process for return visits within 72 hours to our pediatric emergency department that were then subsequently admitted to the hospital. The committee developed methodology and a web-based tool for chart review and analysis. RESULTS: Of 197,076 ED visits (159,164 discharged at initial visit), 5390 (3.4%) patients were discharged and represented to the ED within 72 hours and 1658 (1.0%) of those resulted in admission. Using defined criteria, approximately one third (n = 564) of revisits with admission were identified for chart review. Reason for revisit included natural progression of disease (67.6%), new condition or problem (11.2%), diagnostic error (6.9%), and scheduled or planned readmissions (3.5%). All diagnostic errors had not been previously identified by ED leadership. Of the reviewed cases, most were not preventable (84.0%); however, a number of system-level actions resulted from discussion of the potentially preventable revisits. CONCLUSIONS: Seventy-two-hour ED revisits were efficiently and systematically categorized with determination of root causes and preventability. This process resulted in shared provider-level feedback, identifying trends in revisits, and implementation of system-level actions, therefore, encouraging other institutions to adopt a similar process.

A Modified Delphi Study to Prioritize Content for a Simulation-based Pediatric Curriculum for Emergency Medicine Residency Training Programs.

OBJECTIVES: Pediatric training is an essential component of emergency medicine (EM) residency. The heterogeneity of pediatric experiences poses a significant challenge to training programs. A national simulation curriculum can assist in providing a standardized foundation of pediatric training experience to all EM trainees. Previously, a consensus-derived set of content for a pediatric curriculum for EM was published. This study aimed to prioritize that content to establish a pediatric simulation-based curriculum for all EM residency programs. METHODS: Seventy-three participants were recruited to participate in a three-round modified Delphi project from 10 stakeholder organizations. In round 1, participants ranked 275 content items from a published set of pediatric curricular items for EM residents into one of four categories: definitely must, probably should, possibly could, or should not be taught using simulation in all residency programs. Additionally, in round 1 participants were asked to contribute additional items. These items were then added to the survey in round 2. In round 2, participants were provided the ratings of the entire panel and asked to rerank the items. Round 3 involved participants dichotomously rating the items. RESULTS: A total of 73 participants participated and 98% completed all three rounds. Round 1 resulted in 61 items rated as definitely must, 72 as probably should, 56 as possibly could, 17 as should not, and 99 new items were suggested. Round 2 resulted in 52 items rated as definitely must, 91 as probably should, 120 as possibly could, and 42 as should not. Round 3 resulted in 56 items rated as definitely must be taught using simulation in all programs. CONCLUSIONS: The completed modified Delphi process developed a consensus on 56 pediatric items that definitely must be taught using simulation in all EM residency programs (20 resuscitation, nine nonresuscitation, and 26 skills). These data will serve as a targeted needs assessment to inform the development of a standard pediatric simulation curriculum for all EM residency programs.

Incentives and barriers to pursuing pediatric emergency medicine fellowship: A cross-sectional survey of emergency residents.

BACKGROUND: Pediatric emergency physicians complete either a pediatric or emergency residency before fellowship training. Fewer emergency graduates are pursuing a pediatric emergency fellowship during the past decade, and the reasons for this decrease are unclear. OBJECTIVES: The purpose of this study was to explore emergency residents' incentives and barriers to pursuing a fellowship in pediatric emergency medicine (PEM). METHODS: This was a cross-sectional survey-based study. In 2016, we emailed the study survey to all Emergency Medicine Residents' Association (EMRA) members. Survey questions included respondents' interest in a PEM fellowship and perceived incentives and barriers to PEM. RESULTS: Of 6620 EMRA members in 2016, 322 (5.0%) responded to the survey. Respondents were 59.6% male, with a mean age of 30.6 years. A total of 105 respondents (32.6%) were in their first year of emergency medicine residency, 92 (28.6%) were in their second year, 77 (23.9%) were in their third year, and 48 (14.9%) were in their fourth or fifth year. A total of 102 (31.8%) respondents planned to pursue fellowship training, whereas 120 (37.4%) were undecided. A total of 140 (43.8%) respondents reported considering a PEM fellowship at some point. Among these respondents, the most common incentives for PEM fellowship were (1) a desire to improve pediatric care in community emergency departments (86, 26.7%), (2) to develop an academic focus (54, 16.8%), and (3) because a mentor encouraged a PEM fellowship (40, 12.4%). A perceived lack of financial benefit (142, 44.1%) and length of PEM fellowship training (89, 27.6%) were the most commonly reported barriers. CONCLUSION: In a cross-sectional survey of EMRA members, almost half of the respondents considered a PEM fellowship. PEM leaders who want to promote emergency medicine to pediatric emergency residents will need to leverage the incentives and mitigate the perceived barriers to a PEM fellowship to increase the number of emergency residency applicants.

Is National Resident Matching Program Rank Predictive of Resident Performance or Post-graduation Achievement? 10 Years at One Emergency Medicine Residency.

INTRODUCTION: Each year residency programs expend considerable effort ranking applicants for the National Residency Matching Program (NRMP). We explored the relationship between residents' NRMP rank list position as generated at our institution and their performance in residency and post-graduation to determine whether such efforts are justified. METHODS: Faculty who were present for the 10 consecutive study years at an allopathic emergency medicine residency retrospectively evaluated residents on their overall performance, medical knowledge, and interpersonal skills. Residency graduates were surveyed regarding their current position, hours of clinical practice, academic, teaching and leadership roles, and publications. We compared match position to performance using graphical techniques as the primary form of analysis. RESULTS: Ten faculty evaluated the 107 residents who graduated from the program during these 10 years by class year. Eighty-four residents responded to the survey. In general, we found little correlation between NRMP rank and faculty rank of resident performance. There was also little correlation between position in the NRMP rank list and the probability of having an academic career, publishing research, or having a teaching or leadership role. CONCLUSION: We found that the position on our NRMP rank list was of little value in predicting which residents would do best in residency or take on academic or leadership roles once graduated. Residencies should evaluate the processes they use to generate their rank list to determine whether the ranking process is sufficiently predictive to warrant the effort expended.

1H-Pyrrolo[3,2-b]pyridine GluN2B-Selective Negative Allosteric Modulators.

Herein, we disclose a series of selective GluN2B negative allosteric modulators containing a 1H-pyrrolo[3,2-b]pyridine core. Lead optimization efforts included increasing brain penetration as well as decreasing cytochrome P450 inhibition and hERG channel binding. The series was also optimized to reduce metabolic turnover in human and rat. Compounds 9, 25, 30, and 34 have good in vitro GluN2B potency and good predicted absorption, but moderate to high projected clearance. They were assessed in vivo to determine their target engagement. All four compounds achieved >75% receptor occupancy after an oral dose of 10 mg/kg in rat. Compound 9 receptor occupancy was measured in a dose-response experiment, and its ED50 was found to be 2.0 mg/kg.

2018 Academic Emergency Medicine Consensus Conference: Advancing Pediatric Emergency Medicine Education Through Research and Scholarship.

To achieve high-quality emergency care for pediatric patients nationwide, it is necessary to define the key elements for pediatric emergency medicine (PEM) education and scholarship that would: 1) close the gaps in fundamental PEM education and 2) promote systems and standards that assure an ongoing communication of best practices between tertiary pediatric institutions, general (nonchildren's) hospital emergency departments, and urgent care centers. A working group of medical educators was formed to review the literature, develop a framework for consensus discussion at the breakout session, and then translate their findings into recommendations for future research and scholarship. The breakout session consensus discussion yielded many recommendations. The group concluded that future progress depends on multicenter collaborations as a PEM education research network and a unified vision for PEM education that bridges organizations, providers, and institutions to assure the best possible outcomes for acutely ill or injured children.

Postoperative Tonsillectomy Hemorrhage.

Post-tonsillectomy hemorrhage represents a potentially life-threatening condition that occurs in up to 5% of pediatric patients. Minor bleeding often precedes severe hemorrhage. Patients with minor or self-resolving bleeding should be observed in the emergency department or admitted for monitoring. Patients with severe bleeding should be immediately assessed for airway and hemodynamic stability. Management of severe bleeding includes immediate surgical consultation or initiation of the transfer process to a center with surgical capabilities, direct pressure to the site of hemorrhage with or without the additional of a hemostatic agent, possible rapid sequence intubation, and management of hemodynamic instability with volume resuscitation.

Catecholaminergic Polymorphic Ventricular Tachycardia.

Catecholaminergic polymorphic ventricular tachycardia is a rare cause of exercise-induced arrhythmia and sudden cardiac death in the pediatric patient. This arrhythmia is difficult to diagnose in the emergency department, given the range of presentations; thus, a familiarity with and high index of suspicion for this pathology are crucial. Furthermore, recognition of the characteristic electrocardiogram findings and knowledge of the management of the symptomatic patient are necessary, given the risk of arrhythmia recurrence and cardiac arrest. In this review, we discuss the presentation, differential diagnosis, and management of catecholaminergic polymorphic ventricular tachycardia for the emergency care provider.

Identification of (R)-(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor.

The synthesis and SAR of a series of 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine P2X7 antagonists are described. Addressing P2X7 affinity and liver microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridines ultimately leading to the identification of 1 (JNJ 54166060). 1 is a potent P2X7 antagonist with an ED50 = 2.3 mg/kg in rats, high oral bioavailability and low-moderate clearance in preclinical species, acceptable safety margins in rats, and a predicted human dose of 120 mg of QD. Additionally, 1 possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism.