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Supplemental Digital Content is available in the text., OBJECTIVES: Firearm-related injury is the second leading cause of injury and death for children 1–18 years old in United States. The objective of our study was to analyze the outcomes of children admitted to the PICU with firearm injuries. DESIGN: Retrospective study. SETTING: PICUs in United States contributing data to Virtual Pediatric Systems, LLC, from January 2009 to December 2017. PATIENTS: Children age 1 month to 18 years old admitted to the PICU with firearm injury, identified by external cause of injury E-codes and International Classification of Diseases, 9th Edition, and International Classification of Diseases, 10th Edition, codes were identified. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 1,447 cases identified of which 175 (12%) died in the PICU. Unintentional firearm injury (67.7%) and assault with a firearm injury (20%) comprised 90% of the cases. Males comprised 78% of the cohort (1,122) and race distribution included 45% Black (646), 27% White (390), and 12% Hispanic (178). Among the children who died in the PICU, 55% were 13–18 years old. Children attempting suicide with a firearm were more likely to die in the PICU as compared to the other causes of firearm injury. Based on their Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scores at discharge, there is high morbidity in children with firearm injuries. CONCLUSIONS: Mortality rate of children with firearm injury admitted to the PICU is high. Children admitted to the PICU with suicide attempt with a firearm carried the highest mortality. Further studies may help further define the epidemiology of firearm injuries in children and plan interventions to minimize these unnecessary deaths.

Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Here we show that the cell surface oncoprotein glypican 2 (GPC2) is highly expressed on multiple lethal pediatric brain tumors, including medulloblastomas, embryonal tumors with multi-layered rosettes, other CNS embryonal tumors, as well as definable subsets of highly malignant gliomas. To target GPC2 on these pediatric brain tumors with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we developed four mRNA chimeric antigen receptor (CAR) T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment. First, we validated and prioritized these CARs using in vitro cytotoxicity and T cell degranulation assays with GPC2-expressing neuroblastoma cells. Next, we expanded the testing of the two most potent GPC2-directed CAR constructs prioritized from these studies to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, locoregional delivery bi-weekly of two to four million GPC2-directed mRNA CAR T cells induced significant and sustained tumor regression in two orthotopic medulloblastoma models, and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed. Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells.One Sentence SummaryGlypican 2 is expressed on the surface of multiple pediatric brain tumors and can be successfully targeted with mRNA chimeric antigen receptor T cells.

E-consults replace “curbside” interactions, facilitate provider–specialist communication, document within the medical record, and track relative value units (RVUs). Pediatric infectious diseases (PID) E-consults commonly relate to vaccines, exposures, diagnoses, and treatments. The documented RVU effort of 197 consecutive PID E-consults was equivalent to 70 level 4 new outpatient consults.

Background:Diaphragm dysfunction following surgery for congenital heart disease is a known complication leading to delays in recovery and increased post-operative morbidity and mortality. We aimed to determine the incidence of and risk factors associated with diaphragm plication in children undergoing cardiac surgery and evaluate timing to repair and effects on hospital cost and length of stay.Methods:We conducted a multi-institutional retrospective observational cohort study. Forty-three hospitals from the Pediatric Health Information System database were included, and a total of 112,110 patients admitted between January 2004 and December 2014 were analysed.Results:Patients less than 18 years of age who underwent cardiac surgery were included. Risk Adjustment for Congenital Heart Surgery was utilized to determine procedure complexity. The overall incidence of diaphragm dysfunction was 2.2% (n = 2513 out of 112,110). Of these, 24.0% (603 patients) underwent diaphragm plication. Higher complexity cardiac surgery (Risk Adjustment for Congenital Heart Surgery 5–6) and age less than 4 weeks were associated with a higher likelihood of diaphragm plication (p-value < 0.01). Diaphragmatic plication was associated with increased hospital length of stay (p-value < 0.01) and increased medical cost.Conclusions:Diaphragm plication after surgery for congenital heart disease is associated with longer hospital length of stay and increased cost. There is a strong correlation of prolonged time to plication with increased length of stay and medical cost. The likelihood of plication increases with younger age and higher procedure complexity. Methods to improve early recognition and treatment of diaphragm dysfunction should be developed.

Background The lack of effective treatment options for Alzheimer’s disease (AD) is of momentous societal concern. Synaptic loss is the hallmark of AD that correlates best with impaired memory and occurs early in the disease process, before the onset of clinical symptoms. We have developed a small-molecule, pyridazine-based series that enhances the structure and function of both the glial processes and the synaptic boutons that form the tripartite synapse. Previously, we have shown that these pyridazine derivatives exhibit profound efficacy in an amyloid precursor protein AD model. Here, we evaluated the efficacy of an advanced compound, LDN/OSU-0215111, in rTg4510 mice—an aggressive tauopathy model. Methods rTg4510 mice were treated orally with vehicle or LDN/OSU-0215111 (10 mg/kg) daily from the early symptomatic stage (2 months old) to moderate (4 months old) and severe (8 months old) disease stages. At each time point, mice were subjected to a battery of behavioral tests to assess the activity levels and cognition. Also, tissue collections were performed on a subset of mice to analyze the tripartite synaptic changes, neurodegeneration, gliosis, and tau phosphorylation as assessed by immunohistochemistry and Western blotting. At 8 months of age, a subset of rTg4510 mice treated with compound was switched to vehicle treatment and analyzed behaviorally and biochemically 30 days after treatment cessation. Results At both the moderate and severe disease stages, compound treatment normalized cognition and behavior as well as reduced synaptic loss, neurodegeneration, tau hyperphosporylation, and neuroinflammation. Importantly, after 30 days of treatment cessation, the benefits of compound treatment were sustained, indicating disease modification. We also found that compound treatment rapidly and robustly reduced tau hyperphosphorylation/deposition possibly via the inhibition of GSK3β. Conclusions The results show that LDN/OSU-0215111 provides benefits for multiple aspects of tauopathy-dependent pathology found in Alzheimer’s disease including tripartite synapse normalization and reduction of toxic tau burden, which, in turn, likely accounted for normalized cognition and activity levels in compound-treated rTg4510 mice. This study, in combination with our previous work regarding the benefit of pyridazine derivatives against amyloid-dependent pathology, strongly supports pyridazine derivatives as a viable, clinically relevant, and disease-modifying treatment for many of the facets of Alzheimer’s disease. Electronic supplementary material The online version of this article (10.1186/s13195-019-0530-z) contains supplementary material, which is available to authorized users.

Background:Guaiac stool testing has been routinely used as a method to detect gastrointestinal complications in infants with critical congenital heart disease (CHD); however, the sensitivity and specificity have not been established.Methods:A retrospective chart review was performed investigating the presence of heme-positive stools and subsequent gastrointestinal complications as well as time to goal caloric intake and radiograph exposure.Results:The presence of heme-positive stools was not a statistically significant factor in patients with critical CHD that experienced gastrointestinal complications. Additionally, patients with heme-positive stools did undergo more abdominal X-rays than those with heme-negative stools.Conclusions:The routine use of guaiac stool testing in infants with critical CHD is not a predictor of possible gastrointestinal complications and leads to more radiograph exposure for the patient. Close clinical monitoring can be used to evaluate feeding tolerance in infants with critical CHD.

Adoptive T cell therapy is a form of cellular therapy that utilizes human immune cells, often empowered by the expression of recombinant proteins, to attack selected targets present on tumor or infected cells. T cell-based immunotherapy has been progressing over the past several decades, and reached a milestone with the recent US Food and Drug Administration (FDA) approval of chimeric antigen receptor T cell therapy for relapsed and refractory leukemia and lymphoma. Although most studies have used viral vectors, a growing number of researchers have come to appreciate in vitro-transcribed (IVT) mRNA for the development, testing, and application of T cell-based immunotherapeutics. IVT mRNA offers inherent safety features, highly efficient recombinant protein translation, and the ability to control pharmacokinetic properties of the therapy. In this review, we discuss the history of IVT mRNA in adoptive T cell therapy, from tumor-infiltrating lymphocytes and T cell receptor-based therapies to chimeric antigen receptor therapy and gene-editing techniques, as well as prior and ongoing clinical trials.

Objective:To summarize risk factors for Clostridioides (formerly Clostridium) difficile infection (CDI) in hospitalized pediatric patients as determined by previous observational studies.Design:Meta-analysis and systematic review.Patients:Studies evaluating risk factors for CDI in pediatric inpatients were eligible for inclusion.Method:We systematically searched MEDLINE, Web of Science, Scopus, and EMBASE for subject headings and text words related to CDI and pediatrics from 1975 to 2017. Two of the investigators independently screened studies, extracted and compiled data, assessed study quality, and performed the meta-analysis.Results:Of the 2,033 articles screened, 14 studies reporting 10,531,669 children met the inclusion criteria. Prior antibiotic exposure (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.31–3.52) and proton pump inhibitor (PPI) use (OR, 1.33; 95% CI, 1.07–1.64) were associated with an increased risk of CDI in children. Subgroup analyses using studies reporting only adjusted results suggested that prior antibiotic exposure is not a significant risk factor for CDI. H2 receptor antagonist (H2RA) use (OR, 1.36; 95% CI, 0.31–5.98) and that female gender (OR, 0.87; 95% CI, 0.74–1.03) did not play a significant role as a risk factor for developing CDI.Conclusion:Prior antibiotic exposure appears to be an important risk factor for CDI based on the combined analysis but not significant using adjusted studies. PPI use was associated with an increased risk of CDI. Judicious and appropriate use of antibiotics and PPIs may help reduce the risk of CDI in this vulnerable population.

T cells made with messenger RNA (mRNA) encoding chimeric antigen receptor (CAR) offer a safe alternative to those transduced with viral CARs by mitigating the side effects of constitutively active T cells. Previous studies have shown that mRNA CAR T cells are transiently effective but lack persistence and potency across tumor types. It was hypothesized that the efficacy of mRNA CARs could be improved by utilizing recent advancements in RNA technology, such as incorporating a modified nucleoside, 1-methylpseudouridine, into the mRNA and applying a novel purification method using RNase III to eliminate dsRNA contaminants. T cells electroporated with nucleoside-modified and purified mRNA encoding CD19 CAR showed an initial twofold increase in CAR surface expression, as well as a twofold improvement in cytotoxic killing of leukemia cells that persisted up to 5 days. T cells generated with nucleoside-modified and purified CAR mRNA also showed reduced expression of checkpoint regulators and a differential pattern of genetic activation compared to those made with conventional mRNA. In vivo studies using a leukemia mouse model revealed that the most robust 100-fold suppression of leukemic burden was achieved using T cells electroporated with purified mRNAs, regardless of their nucleoside modification. The results provide a novel approach to generate mRNA for clinical trials, and poise mRNA CAR T cells for increased efficacy during testing as new CAR targets emerge.

Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly primarily affecting the mediastinum with high mortality rate. We present a patient with KLA and significant disease burden harboring a somatic point mutation in the Casitas B lineage lymphoma (CBL) gene. She was treated with MEK inhibition with complete resolution of symptoms, near‐complete resolution of lymphatic fluid burden, and remodeling of her lymphatic system. While patients with KLA have been reported to harbor mutations in NRAS, here we report for the first time a causative mutation in the CBL gene in a patient with KLA, successfully treated with Ras pathway inhibition., Report of a patient with the rare lymphatic anomaly, Kaposiform lymphangiomatosis (KLA). CBL proto‐oncogene mutation was identified and she was successfully treated by targeting the MAP kinase pathway.

BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) are a leading cause of health care–associated infection. Catheter insertion bundles (IBs) and maintenance bundles (MBs) have been developed to prevent CAUTIs but have not been extensively validated for use in pediatric populations. We report the CAUTI prevention efforts of a large network of children’s hospitals. METHODS: Children’s hospitals joined the Children’s Hospitals’ Solutions for Patient Safety engagement network from 2011 to 2017, using an open start time engagement approach, and elected to participate in CAUTI prevention efforts, with 26 submitting data initially and 128 at the end. CAUTI prevention recommendations were first released in May 2012, and IBs and MBs were released in May 2014. Hospitals reported on CAUTIs, patient-days, and urinary catheter-line days and tracked reliability to each bundle. For the network, run charts or control charts were used to plot CAUTI rates, urinary catheter use, and reliability to each bundle component. RESULTS: After the introduction of the pediatric CAUTI IBs and MBs, CAUTI rates across the network decreased 61.6%, from 2.55 to 0.98 infections per 1000 catheter-line days. Centerline shifts occurred both before and after the 2015 Centers for Disease Control and Prevention CAUTI definition change. Urinary catheter use rates did not decline during the intervention period. Network reliability to the IBs and MBs increased to 95.4% and 86.9%, respectively. CONCLUSIONS: IBs and MBs aimed at preventing CAUTIs were introduced across a large network of children’s hospitals. Across the network, the rate of urinary tract infections among hospitalized children with indwelling urinary catheters decreased 61.6%.

Background Epidemiological surveillance data indicate that a majority of HIV-infected in the United States (U.S.) military are African-Americans and men who have sex with men. There is limited research about barriers to HIV prevention among military service members and the unique factors that contribute to HIV stigma. Methods A convenience sample of 30 U.S. service members were recruited from an infectious disease clinic. In depth interviews were conducted and data analyzed using a thematic coding process. Results Two broad categories were identified: 1) Outcomes of HIV Stigma: Fear of Rejection, Shame, and Embarrassment; and 2) Strategies for combating stigma which include increasing HIV education and prevention resources. Military policies and institutional culture regarding sexuality were found to contribute to stigma. Conclusions Participants identified a need for HIV education and suggested individuals living with HIV serve as mentors. A peer-to-peer intervention for delivering HIV prevention education may address these needs and reduce HIV stigma.

The purpose of this quantitative, quasi-experimental study was to analyze whether the education of radiology personnel mandated by the American Registry of Radiologic Technologists (ARRT) affects the quality of care delivered to radiology patients. One area of radiology quality of care was focused on the findings presented in this study: radiation dosage. Three groups of study participants were used. The participants were chosen and divided into groups based on their radiology background, non-radiology medical background, or lack of medical background. All study participants were required to complete an assessment asking participants what radiation dosage and shields they would use for a standard set of radiographic examinations. A training video was shown to those participants with no radiology background prior to the assessment. The data provided by each group was compared to determine similarities and variances between the groups and ANOVA calculations were completed. Differences were found between the assessments completed by members of all three groups. The results support the perception that ARRT-mandated education does affect radiation dosage chosen in the care of radiology patients.

Increased antimicrobial resistance to Salmonella species threatens successful treatment of typhoid and other infectious diseases. Consequently, rare complications arising from incompletely treated typhoid could increase in frequency. We describe a case of enteric encephalopathy caused by Salmonella enterica serovar Typhi and the utility of adjunct treatment with corticosteroids.

PALB2 (partner and localizer of BRCA2) gene encodes a protein that colocalizes with BRCA2 in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. PALB2 plays a critical role in maintaining genome integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. It has a known loss-of-function disease mechanism. Biallelic PALB2 pathogenic variants have been described in autosomal recessive Fanconi anemia. Heterozygous pathogenic variants in PALB2 are associated with increased risk for female and male breast cancer and pancreatic cancer (Science 324: 217; Cancer Res 71: 2222–2229; N Engl J Med 371: 497–506). Heterozygous germline PALB2 mutations have also been observed in patients with medulloblastoma (Lancet Oncol 19: 785–798). However, PALB2-related cancer predisposition to high-grade gliomas has not been reported. Here we report a germline PALB2 pathogenic variant (c.509_510delGA, p.Arg170Ilefs*14, NM_024675.3) found in a pediatric patient with high-grade glioma. This variant was first identified by tumor sequencing using the Children's Hospital of Philadelphia (CHOP) Comprehensive Solid Tumor Panel and then confirmed to be a germline change using the CHOP Comprehensive Hereditary Cancer Panel on DNA from a blood sample of this patient. Parental studies showed that this variant was paternally inherited. Further studies are needed to illustrate if pathogenic variants in PALB2 convey increased risk to developing brain tumor. This case also highlights the potential of identifying germline mutation through tumor sequencing.

Background aims: Manufacturing of potent chimeric antigen receptor (CAR) T cells requires phenotypically naive and early memory T cells. We hypothesized lymphatic fluid collected from the thoracic duct of children would serve as a unique reservoir for early T cells, which could then be used for CAR T-cell therapy. Methods: We evaluated lymphatic fluid collected from 25 pediatric patients undergoing thoracic duct cannulation for other clinical indications. Results: Lymphatic fluid in the thoracic duct was rich in T cells, with higher percentage of naive and stem central memory T-cell subsets compared with paired blood samples. T cells from lymphatic fluid showed decreased negative checkpoint regulators on the surface and increased rapid expansion with bead activation. Creation of CD19-directed CAR T cells from blood and lymphatic T cells showed similar lentiviral transduction properties, but CAR T cells generated from lymphatic fluid produced superior cytotoxicity in a murine leukemia model because they were able to achieve equivalent tumor eradication at lower doses. Conclusions: These results are the first characterization of T cells from the thoracic duct of pediatric patients and suggest an alternative approach for manufacturing of cellular therapy that will improve both expansion and cytotoxic effect.

Following preclinical optimization of B7-H3-specific CAR T cells against pediatric brain tumor models, we opened BrainChild-03 (NCT04185038), a phase 1 clinical trial of repeatedly dosed, outpatient, locoregional B7-H3-specific CAR T cells for children with recurrent/refractory central nervous system (CNS) tumors or diffuse intrinsic pontine glioma (DIPG). Here, we report the interim findings from patients enrolled on Arm C, dedicated to DIPG. The primary endpoints are feasibility and safety, with secondary endpoints of disease response. We utilize second-generation CAR T cells with a 4-1BB costimulatory domain and a methotrexate-resistant human DHFR mutein (huDHFRFS; L22F,F31S), allowing for methotrexate selection. We do not deliver conditioning chemotherapy. The first three evaluable patients with DIPG all met feasibility for generating a balanced CD4:CD8 CAR T cell product, with 3.85x109 CAR T cells generated for S005, 4.29x109 for S008, and 2.45x109 for S012, allowing for greater than 6 months of biweekly dosing for each patient. All subjects were treated at Dose Level 1 (1x107 CAR T cells). S005 received 10 doses before clinical progression greater than 2 years from diagnosis, S008 has received 10 doses and continues on therapy with decreased tumor volume, and S012 has received 5 doses and continues on study with stable disease. There have been no dose limiting toxicities (DLT). 3/3 patients exhibited post infusion fever, headache, and elevated serum CRP but no evidence of cytokine release syndrome (CRS) or systemic CAR T cells. 0/3 patients required PICU admissions. In the cerebrospinal fluid (CSF), 2/3 patients have had elevations of cytokines such as CXCL10 and CCL2, as well as circulating CSF CAR T cells. Advanced serial patient CSF proteomic and transcriptomic profiling are underway. Ultimately, this report provides preliminary evidence that outpatient locoregional B7-H3 CAR T cells for children with DIPG may be feasible and tolerable.

Diffuse intrinsic pontine glioma (DIPG) continues to carry a dismal prognosis despite a growing understanding of its epigenetic regulation. While generally reclassified as diffuse midline glioma, H3 K27M-mutant (DMG), a subgroup of DIPGs do not harbor the classic histone mutation, with a further subset exhibiting a hypermutant phenotype. To evaluate whether hypermutant DIPG shares transcriptional vulnerabilities with H3K27M-mutant DMG, we screened a biopsy-derived treatment-naive PMS2 mutant DIPG model (PBT-24FH) for sensitivity to a panel of HDAC inhibitors (HDACi). In vitro evaluation of cell viability revealed the low nanomolar IC50 of quisinostat (50nM) and romidepsin (2nM). Dose-dependent increases in H3 acetylation and c-PARP were confirmed by western blot. Despite romidepsin’s superior potency in vitro, quisinostat demonstrated greater efficacy in an in vivo PBT-24FH flank study. 42 days following drug initiation, quisinostat-treated mice displayed dramatic tumor regression (mean volume= 33mm3, n= 7) compared to mice treated with romidepsin (mean volume= 669mm3, n= 7)(p= 0.005), or vehicle (mean volume= 990mm3, n= 6)(p< 0.001). Immunohistochemistry of quisinostat-treated tumors revealed few residual tumor cells displaying a low proliferative index. To evaluate cross-resistance, romidepsin-treated mice (mean volume= 1158mm3, n= 2) were switched to quisinostat treatment and displayed swift tumor regression (mean volume after 25 days of quisinostat= 419mm3), emphasizing quisinostat’s in vivo cytotoxic effect against both large tumors and tumors previously treated by another HDACi. To evaluate quisinostat’s effect on other hypermutant tumors, we tested HCT-116, a colon cancer cell line bearing a biallelic MLH1 deletion and observed similar cytotoxicity. We also aim to repeat these studies utilizing additional pediatric hypermutant high grade glioma models. Transcriptomic and proteomic investigations are underway to identify the mechanism of action underlying quisinostat-induced cytotoxicity. Ultimately, we are the first to demonstrate in vivo efficacy of the HDACi quisinostat against hypermutant DIPG, supporting further investigation and clinical advancement.

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor with a median survival of one year. Recently Mount et al (Nat Med 2018) discovered the disialoganglioside GD2 is present at high levels on the surface of DIPG and can be targeted using GD2-directed CAR T cells. However, permanently expressed CAR T cells created by lentiviral transduction resulted in a significant number of deaths from tumor swelling with uncontrolled T cell proliferation. We hypothesized that using mRNA to create transient GD2-directed CAR T cells delivered locally with repeated dosing would result in a safer yet equally effective way to treat DIPG using CAR T cell therapy. In vitro studies using mRNA GD2-directed CAR T cells resulted in robust tumor cytotoxicity and T cell degranulation across a panel of six DIPG cell lines. Using an orthotopic murine model of SU-DIPGXIIIP*, an extremely aggressive model, we delivered of a single dose of two million mRNA GD2-directed CAR T cells locoregionally to the pons via stereotactic injection. The mRNA GD2-directed CAR T cells resulted in no toxic deaths of the mice. In addition, a single dose of mRNA CAR T cells targeting GD2 prolonged survival of the mice by a median of six days (p

Glypican 2 (GPC2) is a cell-surface oncoprotein initially identified in neuroblastoma, retinoblastoma, and medulloblastoma as an ideal target for immunotherapy (Cancer Cell, 2017). Here we evaluated GPC2 expression across the spectrum of pediatric brain tumors using RNA sequencing from specimens in the Children’s Brain Tumor Network (CBTN). High GPC2 expression, defined as >10 FPKM, was found in 100% of embryonal tumors with multilayered rosettes (ETMRs) (n=6), 95% of medulloblastomas (n=122), 86% of other embryonal tumors (n=21), 50% of choroid plexus carcinomas (n=4), 42% of high grade gliomas (HGG) (n=117), and 37% of diffuse midline gliomas (DMG) (n=65). Within medulloblastoma subtypes, group 4 tumors had the highest expression, and within the HGG tumor cohort H3.3 G34 mutated gliomas had the highest GPC2 expression. High GPC2 protein expression was validated with medulloblastoma and HGG/DMG primary tumors and cell lines using IHC, Western blot, and flow cytometry. We next developed two potent CAR T cell constructs using the D3 specific scFv directed against GPC2 for testing in brain tumor models. GPC2-directed CAR T cells were tested in vitro against medulloblastoma and HGG cells lines, and in vivo using two patient-derived medulloblastoma xenograft models: Rcmb28 (group 3) and 7316-4509 (group 4). GPC2-directed mRNA CAR T cells induced significant GPC2-specific cell death in medulloblastoma and HGG cellular models with concomitant T cell degranulation compared to CD19-directed mRNA CAR T cells. In vivo, GPC2-directed mRNA CAR T cells delivered locoregionally induced significant tumor regression measured by bioluminescence after 4–6 intratumoral infusions of 4 x 106 CAR T cells (p

In-stent restenosis remains an important clinical problem in the era of drug eluting stents. Development of clinical gene therapy protocols for the prevention and treatment of in-stent restenosis is hampered by the lack of adequate local delivery systems. Herein we describe a novel stent-based gene delivery platform capable of providing local arterial gene transfer with adeno-associated viral (AAV) vectors. This system exploits the natural affinity of protein G (PrG) to bind to the Fc region of mammalian IgG, making PrG a universal adaptor for surface immobilization of vector-capturing antibodies (Ab). Our results: 1) demonstrate the feasibility of reversible immobilization of AAV2 vectors using vector tethering by AAV2-specific Ab appended to the stent surface through covalently attached PrG, 2) show sustained release kinetics of PrG/Ab-immobilized AAV2 vector particles into simulated physiological medium in vitro and site-specific transduction of cultured cells, 3) provide evidence of long-term (12 weeks) arterial expression of luciferase with PrG/Ab-tethered AAV2Luc, and 4) show anti-proliferative activity and anti-restenotic efficacy of stent-immobilized AAV2iNOS in the rat carotid artery model of stent angioplasty.

SummaryBackground During the Fall of 2014, numerous children were hospitalized with asthma or respiratory distress related to Enterovirus D68 (EV-D68). A large proportion initially tested positive for rhinovirus. During this period our laboratory noted a cross-reactivity between EV-D68 and the rhinovirus component of the GenMark multiplex respiratory viral panel. Many other laboratories used assays not designed to distinguish these Picornoviridae. Methods To compare the presentation and outcomes of patients with rhinovirus and EV-D68, 103 GenMark rhinovirus positive nasopharyngeal swabs from hospitalized children were retested for EV-D68. Results EV-D68 positive patients versus EV-D68 negative patients were more likely to have a history of asthma (33.3% vs. 11.0%, P = 0.02) and to present with acute respiratory illness (66.7% vs. 40.2%, P = 0.048), especially status asthmaticus (47.6% vs. 2.4%, P

Background: Catheter-associated urinary tract infections (CAUTIs) are a leading cause of healthcare-associated infection. Catheter insertion and maintenance bundles have been developed to prevent CAUTIs, but they have not been extensively validated for use in pediatric populations. We report the CAUTI prevention efforts of a large network of children’s hospitals. Methods: Children’s hospitals joined the Solution for Patient Safety (SPS) safety engagement network from 2011 through 2017 and elected to participate in CAUTI prevention efforts, with 26 hospitals submitting data initially and 128 participating by the end. CAUTI prevention recommendations were first released in May 2012, and insertion and maintenance bundles were released in May 2014 (Table 1). Hospitals reported on CAUTIs, patient days, urinary catheter line days (CLD), and they tracked reliability to each bundle. For the network, control charts were used to plot CAUTI rates, urinary catheter utilization, and reliability to each bundle component. Results: Following the introduction of the pediatric CAUTI insertion and maintenance bundles, CAUTI rates across the network decreased 61.6%, from 2.55 to 0.98 infections per 1,000 CLD (Fig. 1). Centerline shifts occurred both before and after the 2015 CDC CAUTI definition change, which may also have contributed to a centerline shift. Urinary catheter utilization rates did not decline during the intervention period. Network reliability to the insertion and maintenance bundles increased to 95.4% and 86.9%, respectively. Conclusions: Insertion and maintenance bundles aimed at preventing CAUTIs were introduced across a large network of children’s hospitals. Across the network, the rate of urinary tract infections among hospitalized children with indwelling urinary catheters decreased 61.6%.Funding: NoneDisclosures: None

The field of cancer immunotherapy has progressed at an accelerated rate over the past decade. Pediatric brain tumors thus far have presented a formidable challenge for immunotherapy development, given their typically low mutational burden, location behind the blood–brain barrier in a unique tumor microenvironment, and intratumoral heterogeneity. Despite these challenges, recent developments in the field have resulted in exciting preclinical evidence for various immunotherapies and multiple clinical trials. This work reviews the history and advances in active immunotherapy, checkpoint blockade, and adoptive T-cell therapy for pediatric brain tumors, including ongoing clinical trials.

Sclerosing epithelioid fibrosarcoma (SEF) is an uncommon neoplasm that rarely presents in bone. It is characterized by epithelioid cells arranged in nests and single-file cords within a sclerotic stromal background which may mimic neoplastic bone. SEF harbors an EWSR1 translocation, which may complicate its distinction from Ewing sarcoma in cases with histomorphologic overlap. We present a diagnostically challenging case of SEF in the mandible of a 16-year-old girl. Our experience highlights the lack of specificity of traditional morphology and EWSR1 break-apart fluorescent in situ hybridization. Open-ended RNA-based fusion gene testing coupled with MUC4 immunohistochemistry aided the eventual diagnosis in this case. Herein, we report the third case of SEF with EWSR1-CREB3L3 translocation and show that this fusion leads to aberrant upregulation of the phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway in heterologous cell models.

BACKGROUND AND OBJECTIVES: Respiratory tract infections (RTIs) are a common reason for direct-to-consumer (DTC) telemedicine consultation. Antibiotic prescribing during video-only DTC telemedicine encounters was explored for pediatric RTIs. METHODS: Encounter data were obtained from a nationwide DTC telemedicine platform. Mixed-effects regression was used to assess variation in antibiotic receipt by patient and physician factors as well as the association between antibiotic receipt and visit length or patient satisfaction. RESULTS: Of 12 842 RTI encounters with 560 physicians, antibiotics were prescribed in 55%. The provider was more likely to receive a 5-star rating from the parent when an antibiotic was prescribed (93.4% vs 80.8%). A 5-star rating was associated with a prescription for an antibiotic (odds ratio [OR] 3.38; 95% confidence interval [CI] 2.84 to 4.02), an antiviral (OR 2.56; 95% CI 1.81 to 3.64), or a nonantibiotic (OR 1.93; 95% CI 1.58 to 2.36). Visit length was associated with higher odds of a 5-star rating only when no antibiotic was prescribed (OR 1.03 per 6 seconds; 95% CI 1.01 to 1.06). Compared with nonpediatricians, pediatric providers were less likely to prescribe antibiotics (OR 0.44; 95% CI 0.29 to 0.68); however, pediatricians received higher encounter satisfaction ratings (OR 1.50; 95% CI 1.11 to 2.03). CONCLUSIONS: During DTC telemedicine consultations for RTIs, pediatric patients were frequently prescribed antibiotics, which correlated with visit satisfaction. Although pediatricians prescribed antibiotics at a lower rate than other physicians, their satisfaction scores were higher. Further work is required to ensure that antibiotic use during DTC telemedicine encounters is guideline concordant.

Botulism in children can have severe complications necessitating intensive care. The current literature lacks data of children with botulism requiring critical care. We aim to describe the outcomes of pediatric botulism in the pediatric intensive care unit (PICU). Retrospective cohort data from Virtual Pediatric Systems (VPS, LLC, Los Angeles, California), from 2009 to 2016 including all PICU admissions among children with botulism, were analyzed. Characteristics and outcomes were compared with similar studies. A total of 380 children were identified over 8 years. Our cohort had the shortest length of stay (median 4.6 days), the smallest percent requiring mechanical ventilation (40%), and the highest median age (120 days) amongst comparable studies. Length of mechanical ventilation and PICU stay has decreased among children with botulism. Advances in PICU care may have contributed to these improved outcomes.

Tuberculosis (TB) in the health care worker demands orchestrated efforts from health care institutions to promptly identify cases and address community risk. We describe a pediatric intensive care unit nurse with latent TB infection who developed hemoptysis and a lung infiltrate concerning for active TB. Her evaluation and contact investigation were facilitated by our institution's command center. Although TB was ultimately ruled out, this case tested our team-based care in response to a suspected high-consequence pathogen.

We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection.

Low serum selenium or selenoprotein P (SePP) levels have been repetitively observed in severe sepsis. The role of SePP in sepsis is incompletely characterized. To test the hypothesis that lipopolysaccharide (LPS) interacts with SePP, we investigated the interaction between LPS and the histidine-rich (His-rich) regions of SePP. We demonstrate that both purified SePP and synthetic peptides corresponding to the His-rich motifs neutralized LPS. In addition, we used a hepatocyte model to study the fate of SePP in response to LPS or endoplasmic reticulum (ER) stress. Our findings indicate that ER stress increases the cellular level of SePP and promotes its nuclear localization.

The presence of advanced practice providers has become increasingly common in many ICUs. The ideal staffing model for units that contain both advanced practice providers and physician trainees has not been described. The objectives of this study were to evaluate ICU staffing models that include physician trainees and advanced practice providers and their effects on patient outcomes, resident and fellow education, and training experience. A second aim was to assess strategies to promote collaboration between team members.PubMed, CINAHL, OVID MEDLINE, and Cochrane Review from 2002 to 2015.Experimental study designs conducted in an ICU setting.Two reviewers screened articles for eligibility and independently abstracted data using the identified search terms.We found 21 articles describing ICU team structure and outcomes. Four articles were found describing the impact of advanced practice providers on resident or fellow education. Two articles were found discussing strategies to promote collaboration between advanced practice providers and critical care fellows or residents.Several articles were identified describing the utilization of advanced practice providers in the ICU and the impact of models of care on patient outcomes. Limited data exist describing the impact of advanced practice providers on resident and fellow education and training experience. In addition, there are minimal data describing methods to enhance collaboration between providers. Future research should focus on determining the optimal ICU team structure to improve patient outcomes, education of trainees, and job satisfaction of team members and methods to promote collaboration between advanced practice providers and physicians in training.

Proteasome inhibitors have garnered interest as novel chemotherapeutic agents based on their ability to inhibit the growth of cancer cells by altering the balance of intracellular proteins. Initial clinical trials of this drug class focused on bortezomib, a reversible inhibitor of the 20S proteasome, with promising results for the treatment of adult hematologic malignancies, including multiple myeloma and non-Hodgkin lymphoma.This article will review the use of bortezomib and other proteasome inhibitors in both adult and pediatric populations, with a focus on their use in pediatrics. Expert commentary: Bortezomib moved into the pediatric oncology arena with encouraging results in multiple early phase trials for relapsed acute lymphoblastic leukemia and acute myeloid leukemia. Bortezomib is also being studied in the treatment of non-malignant disorders, including antibody-mediated allograft rejection, graft-versus-host disease, and autoimmune cytopenias. The numerous applications of bortezomib have inspired the development of second-generation proteasome inhibitors.

Background/Objective The impact of family composition on glycemic control in children with type 1 diabetes remains unclear. We sought to evaluate the relationship between health insurance coverage, family composition, and insulin management, and assess their impact on glycemic control in a pediatric type 1 diabetes population. Methods A retrospective chart review was completed for patients seen in the Pediatric Endocrinology Clinic at the University of Louisville in 2012. Results The analysis included 729 patients with type 1 diabetes; 268 (37%) had public insurance while 461(63%) had private insurance. Compared with publicly insured patients, privately insured patients had higher rates of intensive insulin management with multiple daily injections (MDI) plans or pump devices (88 vs. 83.2%, p = 0.066) and lower HbA1c levels [8.57 vs. 9.39% (70 vs. 79 mmol/mol), p

Gulf War illness is associated with a combination of exposure to war-related chemical agents and traumatic stress. Currently, there are no effective treatments, and the pathophysiology remains elusive. Neurological problems are among the most commonly reported symptoms. In this study, we investigated the glutamatergic system in the hippocampi of mice exposed to war-related chemical agents and stress. Mice developed Gulf War illness-like symptoms, including mood deficits, cognitive impairments, and fatigue. They exhibited the following pathological changes in hippocampi: elevated extracellular glutamate levels, impaired glutamatergic synapses, astrocyte atrophy, loss of interneurons, and decreased neurogenesis. LDN/OSU-215111 is a small-molecule that can strengthen the structure and function of both the astrocytic processes and the glutamatergic synapses that together form the tripartite synapses. We found that LDN/OSU-215111 effectively prevented the development of mood and cognitive deficits in mice when treatment was implemented immediately following the exposure. Moreover, when symptoms were already present, LDN/OSU-215111 still significantly ameliorated these deficits; impressively, benefits were sustained one month after treatment cessation, indicating disease modification. LDN/OSU-215111 effectively normalized hippocampal pathological changes. Overall, this study provides strong evidence that restoration of tripartite glutamatergic synapses by LDN/OSU-215111 is a potential therapy for Gulf War illness., Highlights • Exposure to Gulf War-related agents and stress causes long-term hippocampal glutamatergic synapses impairment. • LDN/OSU-215111, a small-molecule that enhances tripartite synapses, normalizes hippocampal deficits in a mouse model of GWI. • LDN/OSU-215111 effectively ameliorates mood deficits, cognitive impairments, and fatigue in a mouse model of GWI.

Highlights • Two infants treated for syphilis born to at risk mothers who were not rescreened at delivery are described. • Screening for syphilis at the first prenatal visit is the standard of care but may fail to detect late term acquisition of maternal infection. • In high risk populations, rescreening for syphilis should be performed during pregnancy both early in the third trimester and again at delivery. • Early maternal syphilis may be recognized using the treponemal first reverse-screening algorithm., Two infants treated for syphilis born to at risk mothers who screened negative at their first prenatal visit but were not rescreened at delivery are described. The first presented with classic, but unrecognized, features of congenital syphilis. In the second case, possible early maternal syphilis was diagnosed soon after delivery using the treponemal first reverse-screening algorithm. Although the child’s physical exam was normal and the maternal rapid plasma reagin (RPR) negative, the child was treated for syphilis because maternal confirmatory treponemal tests suggested recent seroconversion. Given the re-emergence of congenital syphilis, our report aims to demonstrate the importance of rescreening women at increased risk and improve awareness of common manifestations of the syphilis disease in the newborn. For women at increased risk, repeat syphilis testing early in the third trimester and again at delivery in communities and populations with a high prevalence of syphilis is recommended.

Purpose: To compare clinical response of intermittent bolus versus continuous infusion neostigmine for acute colonic pseudo-obstruction (ACPO). Acute colonic pseudo-obstruction occurs due to reduced colonic parasympathetic activity. Neostigmine is an acetylcholinesterase inhibitor that increases frequency of smooth muscle contraction by increasing acetylcholine at autonomic nervous system synapses. Although these administration modalities have been studied separately, they have never been compared. Methods: This retrospective study compared bolus versus continuous infusion neostigmine for ACPO. The primary outcome was initial clinical response, defined as bowel movement (BM) within 4 hours of bolus dose or 24 hours of initiation of continuous infusion. Secondary outcomes included time to BM, bowel diameter reduction at 24 hours, incidence of bradycardia, additional neostigmine requirements, and need for colonic decompression or surgical intervention. Results: Seventy-five patients were included (bolus n = 37; infusion n = 38). Median total 24-hour neostigmine dose was 2.0 mg (interquartile range [IQR]: 2.0-2.6) with bolus and 9.6 mg (IQR: 6.3-9.6) with continuous infusion. Initial clinical response was similar (infusion 81.6% vs bolus 62.2%, P = .06), but continuous infusion was associated with greater bowel diameter reduction (73.7% vs 40.5%, P = .004). Bolus administration had shorter time to BM (1.4 vs 3.5 hours, P = .0478) and increased need for colonic decompression (67.6% vs 39.5%, P = .0148). Bolus dosing was associated with less bradycardia (13.5% vs 39.5%, P = 0.011), with no difference in atropine usage (10.8% vs 5.3%, P = .43). Conclusion: Initial clinical response was similar between groups; however, continuous infusion neostigmine was associated with greater bowel diameter reduction at 24 hours. Bolus administration resulted in less bradycardia; however, given the lack of difference in atropine use, clinical significance is unknown. This study is the first to compare bolus versus continuous infusion neostigmine for ACPO. Further studies are needed to confirm findings.

Factors favoring blood stream infections associated with gastrointestinal mucosa versus skin organisms were explored. An observed difference was attributable to bacteremia from oral flora in patients with acute myelogenous leukemia or mucositis. Our data do not support the conclusion that isolation of enteric Gram-negatives is unrelated to the central catheter.Infect Control Hosp Epidemiol 2015;00(0): 1–4

Immunotherapy for the treatment of cancer has advanced at a tremendous pace over the last decade. In this review, we provide an overview of recent progress in immunotherapy for the treatment of leukemia, focusing on antibody-drug conjugates (ADC), bi-specific T-cell engagers (BiTE), and chimeric antigen receptor (CAR) T cells.Ongoing clinical trials of CAR T cells directed against CD19 have produced complete remission rates as high as 93%, prompting global multicenter phase 2 trials and the first FDA approval of a CAR T-cell therapy. Insights into cytokine release syndrome, a toxicity of CAR T-cell therapy, and the cause for relapse after CAR T-cell therapy are evolving. The bispecific antibody blinatumomab and the ADCs inotuzumab and gemtuzumab have also recently received FDA approval for ALL and AML, respectively, moving these agents into a more prominent role in the relapse setting.The use of immunotherapy for leukemia has been successful in creating durable remissions for multiply relapsed and refractory patients who previously had little chance of cure. The ongoing clinical and preclinical work continues to advance our understanding of these immune-based therapies, and will shape the next generation of clinical trials.

Purpose Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is being recognized with increasing frequency among children. Given the paucity of evidence to guide the critical care management of these complex patients, we provide a comprehensive review of the literature with pooled analysis of published case reports and case series. Methods We performed a comprehensive literature search using PubMed, Scopus, EMBASE, and Web of Science for relevant published studies. The literature search was conducted using the terms NMDA, anti-NMDA, Anti-N-methyl-d-aspartate, pediatric encephalitis, and anti-NMDAR and included articles published between 2005 and May 1, 2016. Results Forty-eight references met inclusion criteria accounting for 373 cases. For first-line treatments, 335 (89.8%) received high-dose corticosteroids, 296 received intravenous immunoglobulin (79.3%), and 116 (31%) received therapeutic plasma exchange. In these, 187 children (50.1%) had a full recovery with only minor deficits, 174 patients (46.7%) had partial recovery with major deficits, and 12 children died. In addition, 14 patients were reported to require mechanical ventilation. Conclusion Anti-NMDA encephalitis is a formidable disease with great variation in clinical presentation and response to treatment. With early recognition of this second most common cause of pediatric encephalitis, a multidisciplinary approach by physicians may provide earlier access to first- and second-line therapies. Future studies are needed to examine the efficacy of these current therapeutic strategies on long-term morbidity.

The objective of this work was to investigate the mechanisms of hepatobiliary toxicity caused by thienopyrimidone MCHR1 antagonists using BMS-773174 as a tool molecule. Co-administration of the pan CYP inhibitor 1-aminobenzotriazole with BMS-773174 prevented hepatobiliary damage, and direct delivery of the diol metabolite BMS-769750 caused hepatobiliary toxicity, identifying the diol and possibly its downstream hydroxyacid (BMS-800754) metabolite as the toxic species. Rat liver gene expression revealed treatment-related changes in hepatic transporters and induction of oval cell-specific genes including deleted malignant tumor 1 (Dmbt1). The metabolites did not alter hepatic transporter activities, suggesting that transporter-mediated cholestasis was not involved. Because injury to biliary epithelium can result in adaptive hyperplasia, rat biliary epithelial cells (BECs) were isolated and exposed to the oxidative metabolites. BMS-769750 was cytotoxic to BECs, but not rat hepatocytes, suggesting a role of the diol in biliary epithelial injury. BMS-800754 was cytotoxic to rat hepatocytes therefore its contribution to hepatocyte injury in rats is a possibility. Induction of Dmbt1 in rat BECs was investigated because of its role in hepatic progenitor cell differentiation/proliferation during injury. Dmbt1 mRNA was induced by BMS-769750, but not BMS-800754 in BECs; this induction and cellular injury was confirmed with diol metabolites formed by other compounds with the same hepatobiliary liability. In conclusion, hepatobiliary injury by thienopyrimidinone MCHR1 antagonists was driven through a CYP-mediated bioactivation pathway. Induction of Dmbt1 mRNA coupled with cellular injury suggests that injury of biliary epithelium may be the first step toward an adaptive proliferative response causing BDH by these compounds.

Background Curbside consultation is a ubiquitous practice within the medical field informally providing advice to community providers. The electronic consult (E-Consult) allows direct provider-to-provider communication between the primary care provider (PCP) and specialists using a secure electronic platform while documenting these interactions within the patient’s medical record (EMR). They offer PCP’s a forum for asking nonurgent questions. For the specialist, it allows review of the EMR, reduces medical liability of the curbside consult and provides a mechanism for generating RVUs. This service was implemented in our healthcare network (of over 300 pediatricians and pediatric specialists who see more than 500,000 pediatric visits each year) in April 2018. Our aim was to review and analyze the E-consults provided by the Pediatric Infectious Diseases (PID) service. Methods Cross-sectional study of E-consults performed by the PID from April 11 -2018-April 22 2019. Clinical queries were categorized by type and tabulated. Consult Billing was as following: Level 1=5 minutes (min); Level 2 =10min; Level 3= 15 minutes; Level 4= 25 minutes. RVU values were institutionally derived and assigned. Results We performed 171 E- consults with an average of 13 per month (range 3–18) generated from 59 providers (52 (88%) physicians and 7 (12%) certified nurse practitioners). Common reasons for the E-consult included: vaccine questions (25.7%), diagnosis questions (21.6%), exposure questions (20.4%) and treatment recommendations (10.5%). Of vaccine questions, 43% related to vaccine schedules /boosters, 13% vaccines for travel and 11.3% vaccines for the immunocompromised host. Consultation in the PID clinic was recommended for 25.7% patients, 9% requiring urgent evaluation. Of the 171 E-consults, 12.2% were evaluated in the PID clinic and 5% by another specialty. Billing was performed for 168 of the E consults= 9 level 1, 35 level 2, 83 level 3 and 41 level 4 generating 161 RVUs (equivalent to 53 level 4 new outpatient visits at our institution). Conclusion E-consults are an alternative to informal curbside consults for nonurgent clinical queries. Encounters are documented in the EMR and professional effort devoted to the task is tracked providing an additional source of RVU generation for the PID physician. Disclosures All authors: No reported disclosures.

Background Respiratory tract infections (RTIs) are a common reason for direct-to-consumer (DTC) telemedicine consultation. Antibiotic prescribing during video-only DTC telemedicine consults was explored for pediatric RTIs, focusing on correlates with visit duration and patient satisfaction. Methods Data on pediatric (age less than 19 years) RTI consults were obtained from a large DTC nationwide telemedicine platform and included patient, physician, and encounter characteristics. Mixed-effects regression was used to assess variation in antibiotic receipt by patient and physician factors, as well as the association between antibiotic receipt and visit length or patient satisfaction. Results Of 12,842 RTI visits with 560 physicians, 55% of patients received an antibiotic prescription. Antibiotic prescribing rates among telemedicine providers were high: sinusitis (92.1%), otitis media (96.0%), pharyngitis (76.7%), and bronchitis/bronchiolitis (62.0%). A provider was more likely to receive a 5-star satisfaction rating from the parent when the child was provided a prescription for an antibiotic (OR 3.38; 95% CI 2.84–4.02), an antiviral (OR 2.56; 95% CI 1.81–3.64) or a nonantibiotic (OR 1.93; 95% CI 1.58–2.36). Visit length (mean 6.4 minute) was associated with higher satisfaction only when no antibiotic was prescribed (OR 1.03 per 6 seconds; 95% CI 1.01–1.06). Compared with nonpediatricians, pediatric providers were less likely to prescribe antibiotics (OR 0.44; 95% CI 0.29–0.68); however, patients of pediatricians were more likely to be highly satisfied (OR 1.50; 95% CI 1.11–2.03). Conclusion During DTC telemedicine video consultations for RTIs, pediatric patients were frequently prescribed antibiotics, which correlated with visit satisfaction. Although pediatricians prescribed antibiotics at a lower rate than other physicians, their satisfaction scores were higher. Especially problematic, adherence to guideline-concordant criteria for diagnosing acute otitis media and streptococcal pharyngitis, which, respectively, require otoscopy and throat culture, is not possible during a video-only telemedicine consult. High rates of antibiotic prescribing to children with RTIs suggest a need for antimicrobial stewardship efforts during video-only telemedicine consultation. Disclosures All Authors: No reported Disclosures.

The recent identification of glypican-2 (GPC2) as a cell surface oncoprotein in neuroblastoma, high grade glioma (HGG), and medulloblastoma provides the opportunity for the development of targeted immunotherapy. We hypothesized that chimeric antigen receptor (CAR) T cell therapy directed against GPC2 could be achieved using in vitro transcribed mRNA, allowing for rapid and safe iterative trials to test novel CAR constructs. We created mRNA encoding four different CAR proteins using a GPC2-specific scFv paired with 4-1BB and CD3ζ co-stimulatory domains, with varied heavy and light chain orientation and linker length between chains. After electroporation of CAR encoding mRNA into human T cells, we evaluated for CAR persistence, markers of T cell exhaustion, and cellular cytotoxicity against four primary and two isogenic neuroblastoma cell lines and three primary HGG cell lines. All four constructs showed >80% CAR expression and GPC2-specific binding by flow cytometry. CAR molecules in the light-to-heavy (V(L)-V(H)) configuration showed persistence on the surface over seven days and increased cytotoxicity compared to heavy-to-light (V(H)-V(L)) configuration. V(H)-V(L) configuration with a long linker provided the weakest cytotoxic effect, and evaluation of negative checkpoint regulators revealed the highest expression of PD1 and Lag3 (62% vs. 17–40% in other constructs, p

Background The Korean regulatory framework of nursing licensure reflects that of the USA, but its content differs in some of the powers related to quality assurance. Aim This article compares regulatory quality indicators and describes core standards in nursing regulations that are related to both initial licensure and discipline for three groups: the National Council of State Boards of Nursing, the North Carolina and the South of Korea. Methods A descriptive, comparative law design is used to examine the differences and similarities in the quality indicators and core standards found in three documents: the National Council of State Boards of Nursing Model Act, the North Carolina Nursing Practice Act and the Korean Medical Service Act for registered nurses. Results The findings indicate that ten quality indicators and two standards appear in study objects. Although most of the quality indicators are common to all documents, some differences are found in terms of the scope of criminal background checks and the range of grounds for disciplinary action. Limitations These findings cannot be generalized in the USA because although the North Carolina nursing act was selected as an example of US nursing laws, nursing laws differ somewhat across states. Conclusions This comparative study shows a clear opportunity to develop indicators that acknowledge the important areas of competence and good moral character and how they can improve patient safety in Korea. Implications for nursing and health policy This study provides recommendations for Korean nursing legislative redesign and pointers for other jurisdictions to consider.