Determining the Association Between Emergency Department Crowding and Debriefing After Pediatric Trauma Resuscitations.

BACKGROUND: Debriefing in the pediatric emergency department (PED) is an invaluable tool to improve team well-being, communication, and performance. Despite evidence, surveys have reported heavy workload as a barrier to debriefing leading to missed opportunities for improvement in an already busy ED. The study aims to determine the association between the incidence of debriefing after pediatric trauma resuscitations and PED crowding. METHODS: A total of 491 Trauma One activations in Riley Children's Hospital Pediatric Emergency Department that presented between April 2018 to December 2019 were included in the study. Debriefing documentations, patient demographics, time and date of presentation, mechanism of injury, injury severity score, disposition from PED, and length of stay (LOS) were collected and analyzed. The National Emergency Department Overcrowding Scale score at arrival, Average LOS, total PED census, total PED waiting room census, and rates of left without being seen were compared between groups. RESULTS: Of 491 Trauma One activations presented to our PED, 50 (10%) trauma evaluations had documented debriefing. The National Emergency Department Overcrowding Scale score at presentation was significantly lower in those with debriefing versus without debriefing. In addition, the PED hourly census, waiting room census, average LOS, and left without being seen were also significantly lower in the group with debriefing. In addition, trauma cases with debriefing had a higher proportion of patients with profound injuries and discharges to the morgue. CONCLUSIONS: Pediatric emergency department crowding is a significant barrier to debriefing after trauma resuscitations. However, profound injuries and traumatic pediatric deaths remain the strongest predictors in conducting debriefing regardless of PED crowding status.

Immunization Status and the Management of Febrile Children in the Pediatric Emergency Department: What Are We Doing?

OBJECTIVES: Widespread Haemophilus influenzae and Streptococcus pneumoniae immunization has decreased occult bacteremia and bacterial meningitis rates. Practice has evolved in pediatric emergency departments (PEDs) to favor fewer diagnostic tests for and empiric treatment of invasive bacterial infection. We lack evidence-based guidance on evaluation and treatment of unimmunized (UnI) or underimmunized (UnderI) febrile children. This study aims to determine how parental report of immunization status in febrile PED patients impacts rates of diagnostic testing, interventions, and hospital admissions. METHODS: This is a retrospective cohort study with chart review of encounters of children aged 3 to 36 months presenting to an academic, tertiary care PED in 2019 using International Classification of Diseases-10 code for fever (R50.9). Inclusion criteria were documented fever of 38°C and higher and well appearance. Encounters were excluded if there was a history of chronic illness or documentation of ill appearance or hemodynamic instability. Encounters were grouped by provider-documented immunization status. Fischer exact test and logistic regression compared rates of diagnostic testing (serum, urine or cerebrospinal fluid laboratory studies, and chest radiographs), interventions (intravenous fluid bolus, intravenous antibiotic or steroid administration, respiratory support, or breathing treatment), and hospital admissions between UnderI, UnI, and fully immunized (FI) groups. RESULTS: Of the 1813 encounters reviewed, 1093 (60%) included provider-documented immunization status and 788 (43%) met final inclusion criteria: 23 (2.1%) UnI, 44 (5.8%) UnderI, and 721 (92.1%) FI. The UnderI and UnI children experienced significantly higher rates of laboratory evaluation including complete blood count and blood culture, medical intervention, and antibiotic prescriptions while in the PED. No significant differences were observed for rates of chest radiographs, hospital admissions, or 72-hour PED return visits. CONCLUSIONS: Higher rates of laboratory testing and interventions were observed in UnderI and UnI versus FI febrile patients at a PED, likely demonstrating increased clinical suspicion for invasive bacterial infection in this group despite lacking national guidelines. Given continued vaccine hesitancy, further studies are needed for guiding management of febrile UnI and UnderI children presenting for emergency care.

A Quality Improvement Initiative to Decrease Time to Analgesia in Patients With Sickle Cell and Vaso-Occlusive Crisis: A Population With Disparities in Treatment.

INTRODUCTION: Vaso-occlusive crises (VOCs) are the leading cause of emergency department (ED) visits and hospitalizations in patients with sickle cell disease (SCD). Timely administration of analgesia, within 60 minutes of patient registration, is the standard of care for SCD patients with VOCs. Patients with VOCs have longer times to initial analgesia compared to similar painful conditions. The primary aim of the project is to have 75% of patients with VOCs receive initial analgesia within 60 minutes of being registered, the current recommended time frame from the National Heart, Lung, and Blood Institute (NHLBI). METHODS: A multi-disciplinary team used quality improvement (QI) methodology to develop a plan involving multiple Plan-Do-Study-Act (PDSA) cycles. A rapid evaluation process was employed which included notification of a patient with a VOC being placed in a room, rapid evaluation by all team members and use of an electronic order set. RESULTS: The aim was met 72% of the time during our intervention period, compared to 17% pre-intervention. Average time to initial analgesia was decreased from 61 minutes to 42 minutes (p-value < 0.001), while time to disposition was also decreased when time goals were achieved. CONCLUSION: Using a rapid evaluation process we were able to decrease time to initial analgesia in a patient population that has previously experienced delays in care and decrease overall time to disposition.

Identification of Bias in Ordering Further Imaging in Ethnic Groups With Indeterminate Ultrasound for Appendicitis.

Background Recent studies have shown a higher incidence of complications from acute appendicitis in Hispanic populations. Hispanic ethnicity alone has been shown to be a risk factor. In contrast, one study found little evidence of racial disparities in complication rates. The objective of this study was to identify physician bias regarding whether ethnicity drives further testing after initial radiologic imaging has been obtained in the evaluation of appendicitis in our pediatric emergency department (PED). The use of computed tomography (CT) scan in the diagnosis of appendicitis was compared between Hispanic versus non-Hispanic populations when ultrasound (US) was indeterminate. Methodology This is a retrospective cohort study of Hispanic and non-Hispanic patients aged 2-18 who presented to the PED with right lower quadrant abdominal pain over a one-year period (January 1, 2017 to December 29, 2017). Both groups were subdivided into positive, negative, or indeterminate US findings for appendicitis. Each subgroup was analyzed based on those who had CT imaging done. Results A total of 471 ultrasounds were performed, 162 Hispanic and 309 non-Hispanic patients. Indeterminate US scans were documented in 90/162 (56%) Hispanic versus 155/309 (50%) non-Hispanic patients. Of those with indeterminate US scans, 30% Hispanic versus 32% non-Hispanic patients received CT scans. Negative US scans were documented in 54/162 (33%) Hispanic versus 102/309 (33%) non-Hispanic patients. Of those with negative US scans, 7% Hispanic versus 5% non-Hispanic patients received CT scans. Chi-square analysis comparing both the proportion of CT scans received for indeterminate US scans (p=0.71) and negative US scans (p=0.52) showed no statistical significance. Conclusions There was no significant difference in the number of CT scans ordered for indeterminate US scans between Hispanic and non-Hispanic patients. One can infer that there is no inherent bias toward ordering advanced imaging in Hispanic children based on ethnicity alone.

Prevalence and Impact of Diagnosed and Undiagnosed Depression in the United States.

BACKGROUND: The objectives of this study were: 1) estimate the impact and severity of both diagnosed and undiagnosed depression in the general US population 2) explore the demographics of depression based on its common symptoms 3) interpret Patient Health Questionnaire-9 (PHQ-9) scores to improve accuracy in identifying individuals with depression. METHODS:  A random sample of 200 individuals was selected from a general US adult population to complete the Patient Health Questionnaire-9 (PHQ-9). RESULTS: Only 39.4% of respondents indicated that they had a formal diagnosis of depression. In contrast, 53% of participants have considered seeking help from a mental health professional. More importantly, 31.45% of respondents without a formal diagnosis had a PHQ-9 score of over 10 (moderate to severe depression). CONCLUSIONS: The results indicate that undiagnosed depression exists in the US population and suggest that access to mental health services needs to expand across the nation.

Telehealth in Response to the Rural Health Disparity.

The COVID-19 pandemic introduced lockdown and social distancing measures that made new methods of healthcare essential. Telehealth was introduced as a temporary measure but is being considered as a more permanent form of healthcare, particularly in rural areas, to provide more equitable healthcare. A survey was conducted on 200 rural dwellers (residents) regarding their experience with rural healthcare, any barriers to adequate healthcare, and openness to telehealth. The results demonstrated interest in telehealth and predominately positive experiences with telehealth in the areas where there was need and lack of access to healthcare, more commonly expressed in the younger age group. Quality healthcare should be equitable and available for every individual irrespective of zip code or the county they live. Telehealth is capable of bridging the gap of lack of access and transportation for individuals in rural areas to meet their healthcare needs in a timely fashion in the coming years.

Erratum: Advancing medical technology innovation and clinical translation via a model of industry-enabled technical and educational support: Indiana Clinical and Translational Sciences Institute's Medical Technology Advance Program - ERRATUM.

[This corrects the article DOI: 10.1017/cts.2021.1.].

Advancing medical technology innovation and clinical translation via a model of industry-enabled technical and educational support: Indiana Clinical and Translational Sciences Institute's Medical Technology Advance Program.

The success rate for translation of newly engineered medical technologies into clinical practice is low. Traversing the "translational valleys of death" requires a high level of knowledge of the complex landscape of technical, ethical, regulatory, and commercialization challenges along a multi-agency path of approvals. The Indiana Clinical and Translational Sciences Institute developed a program targeted at increasing that success rate through comprehensive training, education, and resourcing. The Medical Technology Advance Program (MTAP) provides technical, educational, and consultative assistance to investigators that leverages partnerships with experts in the health products industry to speed progress toward clinical implementation. The training, resourcing, and guidance are integrated through the entire journey of medical technology translation. Investigators are supported through a set of courses that cover bioethics, ethical engineering, preclinical and clinical study design, regulatory submissions, entrepreneurship, and commercialization. In addition to the integrated technical and educational resources, program experts provide direct consultation for planning each phase along the life cycle of translation. Since 2008, nearly 200 investigators have gained assistance from MTAP resulting in over 100 publications and patents. This support via medicine-engineering-industry partnership provides a unique and novel opportunity to expedite new medical technologies into clinical and product implementation.

In vivo neuronal function of the fragile X mental retardation protein is regulated by phosphorylation.

Fragile X syndrome (FXS), caused by loss of the Fragile X Mental Retardation 1 (FMR1) gene product (FMRP), is the most common heritable cause of intellectual disability and autism spectrum disorders. It has been long hypothesized that the phosphorylation of serine 500 (S500) in human FMRP controls its function as an RNA-binding translational repressor. To test this hypothesis in vivo, we employed neuronally targeted expression of three human FMR1 transgenes, including wild-type (hFMR1), dephosphomimetic (S500A-hFMR1) and phosphomimetic (S500D-hFMR1), in the Drosophila FXS disease model to investigate phosphorylation requirements. At the molecular level, dfmr1 null mutants exhibit elevated brain protein levels due to loss of translational repressor activity. This defect is rescued for an individual target protein and across the population of brain proteins by the phosphomimetic, whereas the dephosphomimetic phenocopies the null condition. At the cellular level, dfmr1 null synapse architecture exhibits increased area, branching and bouton number. The phosphomimetic fully rescues these synaptogenesis defects, whereas the dephosphomimetic provides no rescue. The presence of Futsch-positive (microtubule-associated protein 1B) supernumerary microtubule loops is elevated in dfmr1 null synapses. The human phosphomimetic restores normal Futsch loops, whereas the dephosphomimetic provides no activity. At the behavioral level, dfmr1 null mutants exhibit strongly impaired olfactory associative learning. The human phosphomimetic targeted only to the brain-learning center restores normal learning ability, whereas the dephosphomimetic provides absolutely no rescue. We conclude that human FMRP S500 phosphorylation is necessary for its in vivo function as a neuronal translational repressor and regulator of synaptic architecture, and for the manifestation of FMRP-dependent learning behavior.

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P.

Fragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity.

Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by protein serine/threonine phosphatase 2A holoenzymes.

Protein serine/threonine phosphatase 2A (PP2A) regulates a wide variety of cellular signal transduction pathways. The predominant form of PP2A in cells is a heterotrimeric holoenzyme consisting of a scaffolding (A) subunit, a regulatory (B) subunit, and a catalytic (C) subunit. Although PP2A is known to regulate Raf1-MEK1/2-ERK1/2 signaling at multiple steps in this pathway, the specific PP2A holoenzymes involved remain unclear. To address this question, we established tetracycline-inducible human embryonic kidney 293 cell lines for overexpression of FLAG-tagged Balpha/delta regulatory subunits by approximately 3-fold or knock-down of Balpha by greater than 70% compared with endogenous levels. The expression of functional epitope-tagged B subunits was confirmed by the detection of A and C subunits as well as phosphatase activity in FLAG immune complexes from extracts of cells overexpressing the FLAG-Balpha/delta subunit. Western analysis of the cell extracts using phosphospecific antibodies for MEK1/2 and ERK1/2 demonstrated that activation of these kinases in response to epidermal growth factor was markedly diminished in Balpha knock-down cells but elevated in Balpha- and Bdelta-overexpressing cells as compared with control cells. In parallel with the activation of MEK1/2 and ERK1/2, the inhibitory phosphorylation site of Raf1 (Ser-259) was dephosphorylated in cells overexpressing Balpha or Bdelta. Pharmacological inhibitor studies as well as reporter assays for ERK-dependent activation of the transcription factor Elk1 revealed that the PP2A holoenzymes ABalphaC and ABdeltaC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. Together these findings indicate that PP2A ABalphaC and ABdeltaC holoenzymes function as positive regulators of Raf1-MEK1/2-ERK1/2 signaling by targeting Raf1.

From triplex to B-form duplex stabilization: reversal of target selectivity by aminoglycoside dimers.

Aminoglycosides have been shown to target A-form nucleic acids. Our work has previously shown that neomycin (and other aminoglycosides) bind and stabilize DNA/RNA triplexes and other A-form nucleic acids. We report herein the unexpected B-form duplex stabilization shown by aminoglycoside dimers (neomycin-neomycin and neomycin-tobramycin). The dimers are highly selective for AT rich duplexes and show high affinity (K(a) approximately 10(8)M(-1)) as determined by isothermal titration calorimetry.

Particle beam glow discharge mass spectrometry: spectral characteristics of nucleobases.

Use of a particle beam glow discharge (PB-GD) source for mass spectrometric determinations of deoxy- and ribonucleosides and nucleotides is described. Use of this combination of sample introduction and ion source decouples the vaporization and ionization steps, leading to very simple spectral structure. The mass spectra of these compounds are EI-like in nature, with clearly identified molecular ions and fragmentation patterns that are easily rationalized. The PB-GDMS combination can be operated in a flow injection mode wherein the analyte is injected directly into the solvent flow, or can also be coupled to a high-performance liquid chromatography (HPLC) system allowing LC/MS analysis of mixtures. Mass spectra obtained for nucleic acid bases, nucleosides, and nucleotides are readily obtained with injections of low-nanomole quantities. Representative PB-GDMS spectra for deoxy- and ribonucleosides, nucleotides, and mixed-base oligonucleotides are presented to demonstrate the capabilities of the GD source. Characteristic fragmentation peaks from the spectra of adenine, cytosine, guanine, and thymine were identified in 22-base sequences of single-stranded DNA. The PB-GD source is capable of producing spectra that may be used to identify the individual bases present in mixed-base DNA and RNA fragments.

Neomycin binding to Watson-Hoogsteen (W-H) DNA triplex groove: a model.

Neomycin is the most effective aminoglycoside (groove binder) in stabilizing a DNA triple helix. It stabilizes TAT, as well as mixed base DNA triplexes, better than known DNA minor groove binders (which usually destabilize the triplex) and polyamines. Neomycin selectively stabilizes the triplex (in the presence of salt), without any effect on the DNA duplex. (1) Triplex stabilization by neomycin is salt dependent (increased KCl and MgCl(2) concentrations decrease neomycin's effectiveness, at a fixed drug concentration). (2) Triplex stabilization by neomycin is pH dependent (increased pH decreases neomycin's effectiveness, at a fixed drug concentration). (3) CD binding studies indicate approximately 5-7 base triplets/drug apparent binding site, depending upon the structure/sequence of the triplex. (4) Neomycin shows nonintercalative groove binding to the DNA triplex, as evident from viscometric studies. (5) Neomycin shows a preference for stabilization of TAT triplets but can also accommodate CGC(+) triplets. (6) Isothermal titration calorimetry (ITC) studies reveal an association constant of approximately 2 x 10(5) M(-)(1) between neomycin and an intramolecular triplex and a higher K(a) for polydA.2polydT. (7) Binding/modeling studies show a marked preference for neomycin binding to the larger W-H groove. Ring I/II amino groups and ring IV amines are proposed to be involved in the recognition process. (8) The novel selectivity of neomycin is suggested to be a function of its charge and shape complementarity to the triplex W-H groove, making neomycin the first molecule that selectively recognizes a triplex groove over a duplex groove.