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Objective: The aim of the study is to assess diagnostic performance of cardiac point-of-care ultrasound (POCUS) performed by pediatric emergency medicine (PEM) physicians in children with preexisting cardiac disease., Methods: We evaluated the use of cardiac POCUS performed by PEM physicians among a convenience sample of children with preexisting cardiac disease presenting to a tertiary care pediatric ED. We assessed patient characteristics and the indication for POCUS. The test characteristics of the sonologist interpretation for the assessment of both pericardial effusion as well as left ventricular systolic dysfunction were compared with expert POCUS review by PEM physicians with POCUS fellowship training., Results: A total of 104 children with preexisting cardiac disease underwent cardiac POCUS examinations between July 2015 and December 2017. Among children with preexisting cardiac disease, structural defects were present in 72%, acquired conditions in 22%, and arrhythmias in 13% of patients. Cardiac POCUS was most frequently obtained because of chest pain (55%), dyspnea (18%), tachycardia (17%), and syncope (10%). Cardiac POCUS interpretation compared with expert review had a sensitivity of 100% (95% confidence interval [CI], 85.7-100) for pericardial effusion and 100% (95% CI, 71.5-100) for left ventricular systolic dysfunction; specificity was 97.5% (95% CI, 91.3.1-99.7) for pericardial effusion and 98.9% (95% CI, 93.8-99.8) for left ventricular systolic dysfunction., Conclusions: Cardiac POCUS demonstrates good sensitivity and specificity in diagnosing pericardial effusion and left ventricular systolic dysfunction in children with preexisting cardiac conditions when technically adequate studies are obtained. These findings support future studies of cardiac POCUS in children with preexisting cardiac conditions presenting to the ED., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Appendiceal diameter is a primary sonographic determinant of paediatric appendicitis. We sought to determine if the diagnostic performance of outer appendiceal diameter differs based on age or with the addition of secondary sonographic findings., Methods: We retrospectively reviewed patients aged less than 19 years who presented to the Boston Children's Hospital ED and had an ultrasound (US) for the evaluation of appendicitis between November 2015 and October 2018. Our primary outcome was the presence of appendicitis. We analysed the cases to evaluate the optimal outer appendiceal diameter as a predictor for appendicitis stratified by age (<6, 6 to <11, 11 to <19 years), and with the addition of one or more secondary sonographic findings., Results: Overall, 945 patients met criteria for inclusion, of which 43.9% had appendicitis. Overall, appendiceal diameter as a continuous measure demonstrated excellent test performance across all age groups (area under the curve (AUC) >0.95) but was most predictive of appendicitis in the youngest age group (AUC=0.99 (0.98-1.00)). Although there was no significant difference in optimal diameter threshold between age groups, both 7- and 8-mm thresholds were more predictive than 6 mm across all groups (p<0.001). The addition of individual (particularly appendicolith or echogenic fat) or combinations of secondary sonographic findings increased the diagnostic value for appendicitis above diameter alone., Conclusions: Appendiceal diameter as a continuous measure was more predictive of appendicitis in the youngest group. Across all age groups, the optimal diameter threshold was 7 mm for the diagnosis of paediatric appendicitis. The addition of individual or combination secondary sonographic findings increases diagnostic performance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Foreign body ingestions are a common presentation in the emergency department (ED), particularly in young children., Objective: We sought to determine whether the COVID-19 pandemic lockdowns had an effect on the proportion of foreign body ingestions., Methods: We performed a retrospective review of the Pediatric Health Information System for patients younger than 19 years who were identified by International Classification of Diseases, Tenth Revision codes for foreign body ingestion. We analyzed patients in the following three groups: young children (younger than 5 years), school-aged children (5-12 years), and adolescents (13 years and older), using an interrupted time series analysis. Our primary outcome was the difference in proportion of foreign body ingestions. We compared 1 year after the declaration of the COVID-19 pandemic (March 13, 2020 to March 31, 2021) with the previous 3 years (March 1, 2017 to March 12, 2020)., Results: Total pediatric ED encounters decreased in the post period (p < 0.01); 4902 patients per year presented for foreign body ingestion pre-COVID-19 shutdown vs. 5235 patients per year post-COVID-19 shutdown. In all three age groups (young children, school-age children, and adolescents), there was a higher proportion of foreign body ingestions post-COVID-19 shutdown (p < 0.01, p < 0.01, and p = 0.028, respectively), driven primarily by the decrease in total ED encounters. In the youngest age group (younger than 5 years), there was also a significant increase in slope for foreign body ingestions post-COVID-19 (p = 0.010)., Conclusions: The proportion of foreign body ingestions increased after the declaration of the COVID-19 pandemic, primarily driven by an overall decrease in total ED volume., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Prescription errors are a significant cause of iatrogenic harm in the health care system. Pediatric emergency department (ED) patients are particularly vulnerable to error. We sought to decrease prescription errors in an academic pediatric ED by 20% over a 24-month period by implementing identified national best practice guidelines., Methods: From 2017 to 2019, a multidisciplinary, fellow-driven quality improvement (QI) project was conducted using the Model for Improvement. Four key drivers were identified including simplifying the electronic order entry into prescription folders, improving knowledge of dosing by indication, increasing error feedback to prescribers, and creating awareness of common prescription pitfalls. Four interventions were subsequently implemented. Outcome measures included prescription errors per 1000 prescriptions written for all medications and top 10 error-prone antibiotics. Process measures included provider awareness and use of prescription folders; the balancing measure was provider satisfaction. Differences in outcome measures were assessed by statistical process control methodology. Process and balancing measures were analyzed using 1-way analysis of variance and χ2 testing., Results: Before our interventions, 8.6 errors per 1000 prescriptions written were identified, with 62% of errors from the top 10 most error-prone antibiotics. After interventions, error rate per 1000 prescriptions decreased from 8.6 to 4.5 overall and from 20.1 to 8.8 for top 10 error-prone antibiotics. Provider awareness of prescription folders was significantly increased., Conclusion: QI efforts to implement previously defined best practices, including simplifying and standardizing computerized provider order entry (CPOE), significantly reduced prescription errors. Synergistic effect of educational and technological efforts likely contributed to the measured improvement., (Copyright © 2022 by the American Academy of Pediatrics.)

Genome sequencing studies have identified millions of somatic variants in cancer, but it remains challenging to predict the phenotypic impact of most. Experimental approaches to distinguish impactful variants often use phenotypic assays that report on predefined gene-specific functional effects in bulk cell populations. Here, we develop an approach to functionally assess variant impact in single cells by pooled Perturb-seq. We measured the impact of 200 TP53 and KRAS variants on RNA profiles in over 300,000 single lung cancer cells, and used the profiles to categorize variants into phenotypic subsets to distinguish gain-of-function, loss-of-function and dominant negative variants, which we validated by comparison with orthogonal assays. We discovered that KRAS variants did not merely fit into discrete functional categories, but spanned a continuum of gain-of-function phenotypes, and that their functional impact could not have been predicted solely by their frequency in patient cohorts. Our work provides a scalable, gene-agnostic method for coding variant impact phenotyping, with potential applications in multiple disease settings., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We established a genome-wide compendium of somatic mutation events in 3949 whole cancer genomes representing 19 tumor types. Protein-coding events captured well-established drivers. Noncoding events near tissue-specific genes, such as ALB in the liver or KLK3 in the prostate, characterized localized passenger mutation patterns and may reflect tumor-cell-of-origin imprinting. Noncoding events in regulatory promoter and enhancer regions frequently involved cancer-relevant genes such as BCL6 , FGFR2 , RAD51B , SMC6 , TERT , and XBP1 and represent possible drivers. Unlike most noncoding regulatory events, XBP1 mutations primarily accumulated outside the gene's promoter, and we validated their effect on gene expression using CRISPR-interference screening and luciferase reporter assays. Broadly, our study provides a blueprint for capturing mutation events across the entire genome to guide advances in biological discovery, therapies, and diagnostics.

Objectives: To investigate the rates of radiographic pneumonia and clinical outcomes of children with suspected pneumonia and subcentimeter, subpleural consolidations on point-of-care lung ultrasound., Study Design: We enrolled a prospective convenience sample of children aged 6 months to 18 years undergoing chest radiography (CXR) for pneumonia evaluation in a single tertiary-care pediatric emergency department. Point-of-care lung ultrasound was performed by an emergency medicine physician with subsequent expert review. We determined rates of radiographic pneumonia and clinical outcomes in the children with subcentimeter, subpleural consolidations, stratified by the presence of larger (>1 cm) sonographic consolidations. The children were followed prospectively for 2 weeks to identify a delayed diagnosis of pneumonia., Results: A total of 188 patients, with a median age of 5.8 years (IQR, 3.5-11.0 years), were evaluated. Of these patients, 62 (33%) had subcentimeter, subpleural consolidations on lung ultrasound, and 23 (37%) also had larger (>1 cm) consolidations. Patients with subcentimeter, subpleural consolidations and larger consolidations had the highest rates of definite radiographic pneumonia (61%), compared with 21% among children with isolated subcentimeter, subpleural consolidations. Overall, 23 children with isolated subcentimeter, subpleural consolidations (59%) had no evidence of pneumonia on CXR. Among 16 children with isolated subcentimeter, subpleural consolidations and not treated with antibiotics, none had a subsequent pneumonia diagnosis within the 2-week follow-up period., Conclusions: Children with subcentimeter, subpleural consolidations often had radiographic pneumonia; however, this occurred most frequently when subcentimeter, subpleural consolidations were identified in combination with larger consolidations. Isolated subcentimeter, subpleural consolidations in the absence of larger consolidations should not be viewed as synonymous with pneumonia; CXR may provide adjunctive information in these cases., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Importance: The wide variation in the accuracy and reliability of the Focused Assessment With Sonography for Trauma (FAST) and the extended FAST (E-FAST) for children after blunt abdominal trauma reflects user expertise. FAST and E-FAST that are performed by experts tend to be more complete, better quality, and more often clinically valuable., Objective: To develop definitions of a complete, high-quality, and accurate interpretation for the FAST and E-FAST in children with injury using an expert, consensus-based modified Delphi technique., Design, Setting, and Participants: This consensus-based qualitative study was conducted between May 1 to June 30, 2021. It used a scoping review and iterative Delphi technique and involved 2 rounds of online surveys and a live webinar to achieve consensus among a 26-member panel. This panel consisted of international experts in pediatric emergency point-of-care ultrasonography., Main Outcomes and Measures: Definitions of complete, high-quality, and accurate FAST and E-FAST studies for children after injury., Results: Of the 29 invited pediatric FAST experts, 26 (15 men [58%]) agreed to participate in the panel. All 26 panelists completed the 2 rounds of surveys, and 24 (92%) participated in the live and asynchronous online discussions. Consensus was reached on FAST and E-FAST study definitions, and the panelists rated these 5 anatomic views as important and appropriate for a complete FAST: right upper-quadrant abdominal view, left upper-quadrant abdominal view, suprapubic views (transverse and sagittal), and subxiphoid cardiac view. For E-FAST, the same FAST anatomic views with the addition of the lung or pneumothorax view were deemed appropriate and important. In addition, the panelists rated a total of 32 landmarks as important for assessing completeness. Similarly, the panelists rated 14 statements on quality and 20 statements on accurate interpretation as appropriate., Conclusions and Relevance: This qualitative study generated definitions for complete FAST and E-FAST studies with high image quality and accurate interpretation in children with injury. These definitions are similar to those in adults with injury and may be used for future education, quality assurance, and research. Future research may focus on interpretation of trace volumes of abdominal free fluid and the use of serial FAST.

Objectives: We sought to describe the test characteristics of cardiac point-of-care ultrasound (POCUS) performed by pediatric emergency medicine (PEM) physicians after structured cardiac POCUS training., Methods: We evaluated the use of clinically indicated cardiac POCUS by PEM physicians in a single tertiary care pediatric emergency department after implementation of a focused cardiac POCUS training curriculum. The test characteristics of the sonologist interpretation were compared with expert POCUS review, by PEM physicians who have completed PEM POCUS fellowship training, for the assessment of both pericardial effusion and left ventricular systolic dysfunction., Results: A total of 1241 cardiac POCUS examinations were performed between July 2015 and December 2017, of which 456 were clinically indicated and underwent expert POCUS review and comprised the study sample. These examinations were performed by 33 different PEM attending sonologists. Chest pain (52%), dyspnea (20%), and tachycardia (18%) were the most common indications for cardiac POCUS. Prevalence of pericardial effusion and global systolic dysfunction based on expert POCUS review were 11% (48/443) and 4% (16/435), respectively. Real-time cardiac POCUS interpretation had a sensitivity and specificity of 100% and 99.5%, respectively, for both pericardial effusion and left ventricular systolic dysfunction when compared with expert POCUS review., Conclusions: Cardiac POCUS is both sensitive and specific for identifying pericardial effusion and left ventricular systolic dysfunction when performed by PEM attendings with focused training., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine. To assess how CHK1 inhibition-induced ERK activation promotes PDAC survival, we perform a CRISPR-Cas9 loss-of-function screen targeting direct/indirect ERK substrates and identify RIF1. A key component of non-homologous end joining repair, RIF1 suppression sensitizes PDAC cells to CHK1 inhibition-mediated apoptotic growth suppression. Furthermore, ERK inhibition alone decreases RIF1 expression and phenocopies RIF1 depletion. We conclude that concurrent DDR suppression enhances the efficacy of ERK and/or autophagy inhibitors in KRAS mutant PDAC., Competing Interests: Declaration of interests C.J.D. is a consultant/advisory board member for Anchiano Therapeutics, Deciphera Pharmaceuticals, Mirati Therapeutics, and Revolution Medicines. C.J.D. has received research funding support from SpringWorks Therapeutics, Mirati Therapeutics, and Deciphera Pharmaceuticals and has consulted for Ribometrix, Sanofi, Jazz Therapeutics, Turning Point Therapeutics, and Eli Lilly. A.D.C. has consulted for Eli Lilly and Mirati Therapeutics. E.F.P. and M.P. receive royalties from Avant Diagnostics. E.F.P. is a consultant to and shareholder in Avant Diagnostics, Inc., and Perthera, Inc., and received funding support from Mirati Therapeutics, Genentech, Inc., and Abbvie, Inc., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)