The Current State of Advanced Pediatric Emergency Medicine Point-of-Care Ultrasound (POCUS) Training: Exploring Recent POCUS Fellowship Application Trends and Alternate Training Models.

OBJECTIVES: This study aims to assess the current state of advanced pediatric emergency medicine (PEM) point-of-care ultrasound (POCUS) training in North America, including trends in dedicated PEM POCUS fellowships and alternative advanced POCUS training pathways, to better guide future educational efforts within the field. METHODS: We identified and surveyed 22 PEM POCUS fellowship directors across the United States and Canada regarding PEM POCUS fellowship application trends, potential barriers to pursuing additional POCUS training, and novel training models that meet the needs of the PEM POCUS workforce. RESULTS: The past 5 years have seen a growth in both PEM POCUS fellowship program number and trainee positions available, with a general impression by fellowship directors of a high demand for faculty who have these training credentials. However, there was a discordant drop in fellowship applicants and corresponding match rate in 2022, the cause of which is not clear. A number of programs are offering alternative advanced training options including combined PEM/POCUS fellowships and POCUS tracks within PEM fellowship. CONCLUSION: As POCUS use within PEM evolves, a growing number of advanced training options are being developed. Understanding the motivations and barriers for pursuing advanced POCUS training can help to shape these options going forward, to ensure the experience incorporated within each model meets the needs of trainees, the needs of PEM divisions, and the future needs of our field.

Time of Observation in Xenobiotic Ingestions in Children: Is 6 Hours Too Long?

OBJECTIVES: Children endure a prolonged observation after xenobiotic ingestions, despite low associated morbidity and mortality. The primary objective was to describe the management and outcomes of acute xenobiotic exposures in asymptomatic pediatric patients presenting to the emergency department (ED). A secondary objective was to explore the impact of vital signs on the patients' management and outcomes. METHODS: We conducted a retrospective review of asymptomatic children (younger than 18 years) presenting to a pediatric ED after a toxic ingestion from 2014 to 2018. Ingestions of hydrocarbons, acetaminophen, salicylates, sulfonylureas, caustic, and/or extended release agents were excluded. Demographic and clinical data were abstracted. RESULTS: Of 2817 charts, we identified 109 asymptomatic patients with a mean age of 4.7 years. The average observation from registration to disposition was 4.06 hours. Five patients were admitted and were subsequently discharged within 24 hours. Of the discharged patients, 2 returned within 72 hours and were subsequently discharged home. A total of 321 asymptomatic patients presented with ≥1 abnormal vital signs (mean age, 6.6 years) and were observed in the ED for an average of 4.54 hours. They had a higher percentage of ingestions related to suicide attempts (odds ratio, 6.8). Twenty-two were admitted. Of those discharged home, 11 returned to the ED within 72 hours; all were subsequently discharged home. CONCLUSIONS: Prolonged observations may not be necessary after ingestions in asymptomatic children. Vital sign abnormalities at presentation did not impact disposition. Prospective studies are needed to determine the safety and efficacy of this shortened observation.

Structured Neonatal Point-of-Care Ultrasound Training Program.

OBJECTIVE: Point-of-care ultrasound (POC US) has been increasingly used by intensive care physicians. Growing use of POC US necessitates defining distinct clinical indications for its application, as well as structured POC US training programs. Homogeneous approach to POC US education combined with rigorous quality assurance should further enable POC US to become standard-of-care clinical tool. This study aimed to present the first, innovative, and structured POC US program in neonatal-perinatal medicine field. In addition, we reviewed the availability of the POC US training programs across different medical specialties. STUDY DESIGN: Available English-language publications on POC US training programs in general and neonatal-perinatal medicine were reviewed in this study. DISCUSSION: Mounting body of evidence suggests improved procedural completion rates, as well as clinical decision making with the use of POC US. However, limited research supported the existence of structured, comprehensive POC US programs. It was recognized that medical institutions need to develop syllabuses, teach, and credential increasing number of health care professionals in the use of POC US. We defined intuitive educational strategy that encompasses POC US clinical indications, educational curriculum, scanning protocols, competence evaluation, and finally credentialing process. In addition, we offered description of the imaging quality assurance, as well as POC US coding, and reimbursement. CONCLUSION: Future efforts need to be dedicated to the ongoing development of neonatal POC US as a clinical instrument. It should allow for eventual paradigm change and improved effectiveness in management of critically ill neonates.

Lessons From the Frontlines: Pandemic Response Among New York City Pediatric Emergency Medicine Fellowship Programs During COVID-19.

The global pandemic novel coronavirus 2019 has upended healthcare and medical education, particularly in disease epicenters such as New York City. In this piece, we seek to describe the collective experiences and lessons learned by the New York City pediatric emergency medicine fellowship directors in clinical, educational, investigative, and psychological domains, in hopes of engendering conversation and informing future disaster response efforts.

Overall survival benefits of first-line EGFR tyrosine kinase inhibitors in EGFR-mutated non-small-cell lung cancers: a systematic review and meta-analysis.

BACKGROUND: Accumulating data shows that exon 19 deletions and L858R, both activating epidermal growth factor receptor mutations in non-small-cell lung cancers (NSCLCs), are just two different entities in terms of prognosis and treatment response to tyrosine kinase inhibitors (TKIs). METHODS: A systematic review and meta-analysis of randomized controlled trials comparing TKIs with conventional chemotherapy was performed. Eight trials of 1498 patients and five trials of 1279 patients with either exon 19 deletions or L858R were included in the meta-analysis. RESULTS: TKI treatment demonstrated progression-free survival benefit in patients with exon 19 deletions (hazard ratio (HR): 0.27, 95% confidence interval (CI): 0.21-0.35) and L858R (HR: 0.45, 95% CI: 0.35-0.58). Patients with exon 19 deletions had significant overall survival (OS) benefit under TKI treatment (HR: 0.72, 95% CI: 0.60-0.88). Subgroup analyses showed that irreversible TKIs, but not reversible TKIs, had statistically significant OS benefit in these patients (irreversible TKIs, HR: 0.59, 95% CI: 0.47-0.73; reversible TKIs, HR: 0.84, 95% CI: 0.69-1.02). Patients with L858R demonstrated no OS benefit under first-line TKI use (HR: 1.15, 95% CI: 0.95-1.39). CONCLUSIONS: In patients with advanced NSCLC harbouring exon 19 deletions, TKIs are associated with better OS compared with conventional chemotherapy. Future clinical trials should take exon 19 deletions and L858R as distinct disease entities and evaluate the treatment efficacy separately.

Increased risk of second primary malignancies following uterine cancer: a population-based study in Taiwan over a 30-year period.

BACKGROUND: Previous studies assessing second primary malignancies (SPMs) after uterine cancer have been conducted in Western populations with conflicting results. This study aimed to define the incidence and risk of SPMs in Taiwanese patients with an initial diagnosis of uterine cancer. METHODS: Using population-based data from the Taiwan Cancer Registry for the period 1979-2008, we quantified standardized incidence ratios (SIRs) among 11,571 women with an initial diagnosis of uterine cancer. RESULTS: Among the 11,571 women, 555 (4.80%) developed at least one SPM during 69,987 person-years of follow-up. There was a 71% increased risk of SPM following uterine cancer (SIR=1.71, 95% CI, 1.57-1.86), with higher risks in the vagina/vulva (SIR=9.06), small intestine (SIR=8.45), ovary (SIR=4.15), urinary bladder (SIR=2.31), kidney (SIR=2.24), colorectum (SIR=2.24), lung (SIR=1.96), and breast (SIR=1.43). The risk of SPM was found to be the highest within the first 5 years after diagnosis of uterine cancer, with surveillance bias possibly contributing to the extremely high risk observed in the first follow-up year. The overall risk and pattern of SPM development observed in this study differed from those previously reported in Western populations, possibly because of the methodology and shorter follow-up period employed in this study. The cumulative incidence of SPMs was significantly higher in older patients (≥50 years) than in younger patients (P<0.001). CONCLUSIONS: To our knowledge, this is the first study in an Asian population to report 71% increased risk in SPMs in women previously diagnosed with uterine cancer. A younger age at diagnosis of uterine cancer conferred an increased risk of second malignancies, and SPMs worsened survivorship in patients who survived uterine cancer.

Prevalence of abnormal cases in an image bank affects the learning of radiograph interpretation.

OBJECTIVES: Using a large image bank, we systematically examined how the use of different ratios of abnormal to normal cases affects trainee learning. METHODS: This was a prospective, double-blind, randomised, three-arm education trial conducted in six academic training programmes for emergency medicine and paediatric residents in post-licensure years 2-5. We developed a paediatric ankle trauma radiograph case bank. From this bank, we constructed three different 50-case training sets, which varied in their proportions of abnormal cases (30%, 50%, 70%). Levels of difficulty and diagnoses were similar across sets. We randomly assigned residents to complete one of the training sets. Users classified each case as normal or abnormal, specifying the locations of any abnormalities. They received immediate feedback. All participants completed the same 20-case post-test in which 40% of cases were abnormal. We determined participant sensitivity, specificity, likelihood ratio and signal detection parameters. RESULTS: A total of 100 residents completed the study. The groups did not differ in accuracy on the post-test (p = 0.20). However, they showed considerable variation in their sensitivity-specificity trade-off. The group that received a training set with a high proportion of abnormal cases achieved the best sensitivity (0.69, standard deviation [SD] = 0.24), whereas the groups that received training sets with medium and low proportions of abnormal cases demonstrated sensitivities of 0.63 (SD = 0.21) and 0.51 (SD = 0.24), respectively (p < 0.01). Conversely, the group with a low proportion of abnormal cases demonstrated the best specificity (0.83, SD = 0.10) compared with the groups with medium (0.70, SD = 0.15) and high (0.66, SD = 0.17) proportions of abnormal cases (p < 0.001). The group with a low proportion of abnormal cases had the highest false negative rate and missed fractures one-third more often than the groups that trained on higher proportions of abnormal cases. CONCLUSIONS: Manipulating the ratio of abnormal to normal cases in learning banks can have important educational implications.

RAZOR EX anthrax air detection system.

The RAZOR EX Anthrax Air Detection System, developed by Idaho Technology, Inc. (ITI), is a qualitative method for the detection of Bacillus anthracis spores collected by air collection devices. This system comprises a DNA extraction kit, a freeze-dried PCR reagent pouch, and the RAZOR EX real-time PCR instrument. Each pouch contains three assays, which distinguish potentially virulent B. anthracis from avirulent B. anthracis and other Bacillus species. These assays target the pXO1 and pXO2 plasmids and chromosomal DNA. When all targets are detected, the instrument makes an "anthrax detected" call, meaning that virulence genes of the anthrax bacillus are present. This report describes results from AOAC Method Developer (MD) and Independent Laboratory Validation (ILV) studies, which include matrix, inclusivity/exclusivity, environmental interference, upper and lower LOD of DNA, robustness, product consistency and stability, and instrument variation testing. In the MD studies, the system met the acceptance criteria for sensitivity and specificity, and the performance was consistent, stable, and robust for all components of the system. For the matrix study, the acceptance criteria of 95/96 expected calls was met for three of four matrixes, clean dry filters being the exception. Ninety-four of the 96 clean dry filter samples tested gave the expected calls. The nucleic acid limit of detection was 5-fold lower than AOAC's acceptable minimum detection limit. The system demonstrated no tendency for false positives when tested with Bacillus cereus. Environmental substances did not inhibit accurate detection of B. anthracis. The ILV studies yielded similar results for the matrix and inclusivity/exclusivity studies. The ILV environmental interference study included environmental substances and environmental organisms. Subsoil at a high concentration was found to negatively interfere with the pXO1 reaction. No interference was observed from the environmental organisms. The nucleic acid LOD, however, was 10 times higher (1 pg/reaction, equivalent to about 200 spores) than that found in the MD study. These results indicate that the RAZOR System is a sensitive and specific system that accurately identifies B. anthracis in aerosol matrixes and in the presence of interfering substances, and that the method can be performed by an independent laboratory and achieve similar results.

Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/hepatitis B core antibody positive patients receiving rituximab-containing combination chemotherapy without routine antiviral prophylaxis.

The use of rituximab has been associated with increased risk of hepatitis B virus (HBV) reactivation in patients who are hepatitis B surface antigen (HBsAg) negative and antihepatitis B core antibody (anti-HBc) positive. We aim to determine the rate of HBV reactivation in this group of patients who received rituximab-containing combination chemotherapy without concomitant antiviral prophylaxis and to identify potential risk factors for reactivation. Sixty-two HBsAg negative/anti-HBc positive patients with B-cell lymphoma treated with rituximab-based immunochemotherapy from 2006 to 2009 were included. None of the patients received concomitant antiviral prophylaxis. In this cohort, 48 (77%) patients received rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), eight (13%) received rituximab with cyclophosphamide, vincristine and prednisolone, and six (10%) received other chemotherapy regimens. Two patients suffered HBV reactivation; both were above 70 years of age, received R-CHOP chemotherapy and were negative for antihepatitis B surface antibody (anti-HBs) at baseline. One of the two patients reactivated shortly after completion of R-CHOP chemotherapy while the other reactivated during rituximab maintenance treatment. Thus, the overall reactivation rate in this cohort of patients is 3% (2/62), 4% (2/48), and 25% (1/4) in patients who received R-CHOP chemotherapy and who received rituximab maintenance, respectively. The rate of HBV reactivation is low in patients who are HBsAg negative/anti-HBc positive receiving rituximab-based combination chemotherapy without concomitant antiviral prophylaxis. However, elderly patients, particularly those without anti-HBs, seemed particularly at risk.

Base-pair neutral homozygotes can be discriminated by calibrated high-resolution melting of small amplicons.

Genotyping by high-resolution melting analysis of small amplicons is homogeneous and simple. However, this approach can be limited by physical and chemical components of the system that contribute to intersample melting variation. It is challenging for this method to distinguish homozygous G::C from C::G or A::T from T::A base-pair neutral variants, which comprise approximately 16% of all human single nucleotide polymorphisms (SNPs). We used internal oligonucleotide calibrators and custom analysis software to improve small amplicon (42-86 bp) genotyping on the LightScanner. Three G/C (PAH c.1155C>G, CHK2 c.1-3850G>C and candidate gene BX647987 c.261+22,290C>G) and three T/A (CPS1 c.3405-29A>T, OTC c.299-8T>A and MSH2 c.1511-9A>T) human single nucleotide variants were analyzed. Calibration improved homozygote genotyping accuracy from 91.7 to 99.7% across 1105 amplicons from 141 samples for five of the six targets. The average T(m) standard deviations of these targets decreased from 0.067 degrees C before calibration to 0.022 degrees C after calibration. We were unable to generate a small amplicon that could discriminate the BX647987 c.261+22,290C>G (rs1869458) SNP, despite reducing standard deviations from 0.086 degrees C to 0.032 degrees C. Two of the sites contained symmetric nearest neighbors adjacent to the SNPs. Unexpectedly, we were able to distinguish these homozygotes by T(m) even though current nearest neighbor models predict that the two homozygous alleles would be identical.

Pediatric emergency medicine point-of-care ultrasound: summary of the evidence.

The utility of point-of-care ultrasound is well supported by the medical literature. Consequently, pediatric emergency medicine providers have embraced this technology in everyday practice. Recently, the American Academy of Pediatrics published a policy statement endorsing the use of point-of-care ultrasound by pediatric emergency medicine providers.  To date, there is no standard guideline for the practice of point-of-care ultrasound for this specialty. This document serves as an initial step in the detailed "how to" and description of individual point-of-care ultrasound examinations.  Pediatric emergency medicine providers should refer to this paper as reference for published research, objectives for learners, and standardized reporting guidelines.

Genetic selection for modulators of a retinoic-acid-responsive reporter in human cells.

We used a genetic screening methodology, a human cell line bearing a retinoic-acid-responsive enhanced GFP reporter, and a flow sorter to recover dominant modulators of reporter expression. Four inducers and three suppressors that were fused to the C terminus of a protein scaffold for stability were isolated and their mechanisms of action studied. Mutagenesis experiments indicated that six of these dominant agents exerted their effects at the protein level. The single cDNA coding fragment that was isolated comprised the central 64-amino-acid section of human cyclophilin B, which contained its peptidyl-prolyl isomerase domain; this cyclophilin fragment repressed expression of the retinoic-acid-responsive reporter. The remaining clones encoded peptides shorter than 30 amino acids unrelated to known gene open reading frames. Genetic epistasis studies between the strongest inducer, R3, and a dominant-negative mutant of RARalpha suggest that the two factors function in the same pathway. Transcript microarray analyses suggest that R3 induced a subset of the retinoid-responsive genes in melanoma cells. Finally, yeast two-hybrid assays and co-immunoprecipitation studies of human cell extracts identified PAT1 as a protein that interacts with R3.

Detection of Dengue Virus in Mosquito Extracts and Human Clinical Samples Using a Field Expedient Molecular Platform.

Dengue fever occurs in localized outbreaks and can significantly erode troop strength and mission readiness. Timely identification of dengue virus (DENV) provides for rapid and appropriate patient management decisions, such as medical evacuation and supportive therapies, as well as help to promote Force Health Protection through vector control and personal protective measures. The "Ruggedized" Advanced Pathogen Identification Device is a field-friendly PCR (Polymerase Chain Reaction) platform that can be used to facilitate early identification of DENV. We developed a dry-format PCR assay on this platform. The assay demonstrated 100% analytical specificity for detecting dengue using a cross-reactivity panel. We used a panel of 102 acute, DENV isolation positive serum samples and 25 DENV negative samples; the assay demonstrated a clinical sensitivity of 97.1% (95% C.I. 91.6-99.4%) and specificity of 96.0% (95% C.I. 79.7-99.9%) in identifying patients with dengue infection. We also used the assay to test mosquito homogenates from 28 adult female Aedes aegypti. A single DENV infected mosquito was identified using the PCR assay and confirmed using immunofluorescence as a reference method. Much of the testing was performed under austere field conditions. Together, our results demonstrate the utility of this assay for detecting DENV in vector and human samples in field environments.

FilmArray, an automated nested multiplex PCR system for multi-pathogen detection: development and application to respiratory tract infection.

The ideal clinical diagnostic system should deliver rapid, sensitive, specific and reproducible results while minimizing the requirements for specialized laboratory facilities and skilled technicians. We describe an integrated diagnostic platform, the "FilmArray", which fully automates the detection and identification of multiple organisms from a single sample in about one hour. An unprocessed biologic/clinical sample is subjected to nucleic acid purification, reverse transcription, a high-order nested multiplex polymerase chain reaction and amplicon melt curve analysis. Biochemical reactions are enclosed in a disposable pouch, minimizing the PCR contamination risk. FilmArray has the potential to detect greater than 100 different nucleic acid targets at one time. These features make the system well-suited for molecular detection of infectious agents. Validation of the FilmArray technology was achieved through development of a panel of assays capable of identifying 21 common viral and bacterial respiratory pathogens. Initial testing of the system using both cultured organisms and clinical nasal aspirates obtained from children demonstrated an analytical and clinical sensitivity and specificity comparable to existing diagnostic platforms. We demonstrate that automated identification of pathogens from their corresponding target amplicon(s) can be accomplished by analysis of the DNA melting curve of the amplicon.

Risk of intracranial pathologic conditions requiring emergency intervention after a first complex febrile seizure episode among children.

OBJECTIVE: To determine the likelihood of intracranial pathologic conditions requiring emergency neurosurgical or medical intervention among children without meningitis who presented to the pediatric emergency department after a first complex febrile seizure. METHODS: We performed a retrospective review of prospectively collected data for children in neurologically normal condition who presented to a single pediatric emergency department after a first complex febrile seizure (focal, multiple, or prolonged). The complex febrile seizure classification was determined independently by 2 epileptologists. The presence of intracranial pathologic conditions was determined through review of neuroimaging results, telephone interviews, or medical record review. RESULTS: Data for 71 children with first complex febrile seizures were analyzed. Fifty-one (72%) had a single complex feature (20 focal, 22 multiple, and 9 prolonged), and 20 (28%) had multiple complex features. None of the 71 patients (1-sided 95% confidence interval: 4%) had intracranial pathologic conditions that required emergency neurosurgical or medical intervention. CONCLUSIONS: For children with first complex febrile seizures, the risk of intracranial pathologic conditions that require emergency neurosurgical or medical intervention is low, which suggests that routine emergency neuroimaging for this population is unnecessary.

Stable expression of Anthozoa fluorescent proteins in mammalian cells.

BACKGROUND: Fluorescent proteins have become invaluable reporters in many areas of cellular and developmental biology. An enhanced version of the Aequorea victoria green fluorescent protein (AvEGFP) is the most widely used fluorescent protein. For a variety of reasons, it is useful to have alternative fluorescent proteins to AvEGFP. METHODS: The cDNA sequences for enhanced variants of the Anemonia cyan fluorescent protein (AmCyan1), as well as the Zoanthus green (ZsGreen1) and yellow (ZsYellow1) fluorescent proteins, were cloned downstream of a constitutive cytomegalovirus (CMV) promoter within a retroviral expression vector. NIH3T3, HEK293, SW620, and WM35 cells were transduced with recombinant retroviruses at a low multiplicity of infection (MOI) to bias for single-copy integration. Both unselected and stably selected cells transduced with the retroviral expression constructs were characterized. Expression of each fluorescent protein in cells was detected using flow cytometry and fluorescence microscopy with filter sets typically used for AvEGFP/fluorescein isothiocyanate (FITC) detection and was compared with the expression of AvEGFP. In addition, a fluorescence plate reader with several excitation and emission filter sets was used for detection. RESULTS: Expression of each protein was observable by fluorescence microscopy. Under given conditions of flow cytometry, the ZsGreen1 mean fluorescence was approximately 3-fold, 10-fold, and 50-fold greater than that of AvEGFP, ZsYellow1, and AmCyan1, respectively. AmCyan1, ZsGreen1, and AvEGFP were detected by a fluorescence plate reader. CONCLUSION: We determined that fluorescent proteins from Anthozoa species are detectable using a standard flow cytometer and fluorescence microscope. All of the mammalian cell lines tested expressed detectable levels of fluorescent proteins from stable integrated provirus. In cell lines where the AvEGFP protein is toxic or poorly expressed, these Anthozoa fluorescent proteins may serve as alternative fluorescent reporters.