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Graham Thompson,1 Niranjan Kissoon2 1Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada; 2British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, CanadaBackground: Severe infection resulting in sepsis is recognized as a leading cause of morbidity and mortality worldwide. The purpose of this study is to use longitudinal, population-based data to report national-level hospital metrics, providing a current assessment of the status of sepsis hospitalizations in Canadian children.Methods: We performed an analysis of previously abstracted data from the Canadian Institute for Health Information (CIHI) Discharge Abstract Database (DAD). Children aged 0–17 years at the time of hospital admission were identified from a cohort of patients with sepsis or severe sepsis using the International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10-CA) and the Canadian Classification of Health Interventions (CCI). Descriptive population-based statistics are reported.Results: Hospitalization data for 20,130 children admitted over 5 years were reviewed. The majority of children were young, with neonates (56.3%) and infants under 2 months (18.8%) representing the majority of cases. A decline in age-adjusted hospitalization rates was demonstrated in both overall and non-severe sepsis across the study period; however, no change was demonstrated for severe sepsis. While overall in-hospital crude mortality rates did not change significantly across the study period (range 5.1%–5.4%), a significant decrease was found in children aged 3–23 months and adolescents. Multi-organ failure was reported in more than one-quarter of children with severe sepsis. Odds of mortality increased significantly with number of organs failed.Conclusion: Sepsis remains an important cause of morbidity and mortality in Canadian children, posing a significant burden on health care resources. Age continues to be associated with the incidence and severity of illness. Overall hospitalization rates have declined over time, as has mortality in severe sepsis. This report provides baseline metrics for future outcome-based research in Canada targeting prevention strategies and early diagnosis, as well as therapies preventing and managing organ failure.Keywords: septic shock, child, hospitalization, mortality, epidemiology

Importance: Appendicitis is the most common indication for urgent surgery in the pediatric population, presenting across a range of severity and with variable complications. Differentiating simple appendicitis (SA) and perforated appendicitis (PA) on presentation may help direct further diagnostic workup and appropriate therapy selection, including antibiotic choice and timing of surgery., Objective: To provide a mechanistic understanding of the differences in disease severity of appendicitis with the objective of developing improved diagnostics and treatments, specifically for the pediatric population., Design, Setting, and Participants: The Gene Expression Profiling of Pediatric Appendicitis (GEPPA) study was a single-center prospective exploratory diagnostic study with transcriptomic profiling of peripheral blood collected from a cohort of children aged 5 to 17 years with abdominal pain and suspected appendicitis between November 2016 and April 2017 at the Alberta Children's Hospital in Calgary, Alberta, Canada, with data analysis reported in August 2023. There was no patient follow-up in this study., Exposure: SA, PA, or nonappendicitis abdominal pain., Main Outcomes and Measures: Blood transcriptomics was used to develop a hypothesis of underlying mechanistic differences between SA and PA to build mechanistic hypotheses and blood-based diagnostics., Results: Seventy-one children (mean [SD] age, 11.8 [3.0] years; 48 [67.6%] male) presenting to the emergency department with abdominal pain and suspected appendicitis were investigated using whole-blood transcriptomics. A central role for immune system pathways was revealed in PA, including a dampening of major innate interferon responses. Gene expression changes in patients with PA were consistent with downregulation of immune response and inflammation pathways and shared similarities with gene expression signatures derived from patients with sepsis, including the most severe sepsis endotypes. Despite the challenges in identifying early biomarkers of severe appendicitis, a 4-gene signature that was predictive of PA compared to SA, with an accuracy of 85.7% (95% CI, 72.8-94.1) was identified., Conclusions: This study found that PA was complicated by a dysregulated immune response. This finding should inform improved diagnostics of severity, early management strategies, and prevention of further postsurgical complications.

Background: Adults aged ≥65 years, adults with certain underlying medical conditions, and persons experiencing homelessness are at increased risk for invasive pneumococcal disease (IPD). Two new pneumococcal conjugate vaccines, 15-valent pneumococcal conjugate vaccine (PCV15) and 20-valent pneumococcal conjugate vaccine (PCV20), were recently approved for use in US adults. We describe the epidemiology of IPD among Alaska adults and estimate the proportion of IPD cases potentially preventable by new vaccines., Methods: We used statewide, laboratory-based surveillance data to calculate and compare IPD incidence rates and 95% confidence intervals (CIs) among Alaska adults aged ≥18 years during 2011-2020 and estimate the proportion of IPD cases that were caused by serotypes in PCV15 and PCV20., Results: During 2011-2020, 1164 IPD cases were reported among Alaska adults for an average annual incidence of 21.3 cases per 100 000 adults per year (95% CI, 20.1-22.5). Incidence increased significantly during the study period (P < .01). IPD incidence among Alaska Native adults was 4.7 times higher than among non-Alaska Native adults (95% CI, 4.2-5.2). Among adults experiencing homelessness in Anchorage, IPD incidence was 72 times higher than in the general adult population (95% CI, 59-89). Overall, 1032 (89%) Alaska adults with IPD had an indication for pneumococcal vaccine according to updated vaccination guidelines; 456 (39%) and 700 (60%) cases were caused by serotypes in PCV15 and PCV20, respectively., Conclusions: Use of PCV15 and PCV20 could substantially reduce IPD among adults in Alaska, including Alaska Native adults and adults experiencing homelessness., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Objectives: Emergency medicine (EM) confers a high risk of burnout that may be exacerbated by the COVID-19 pandemic. We aimed to determine the longitudinal prevalence of burnout in pediatric EM (PEM) physicians/fellows working in tertiary PEM departments across Canada and its fluctuation during the pandemic., Methods: A national mixed-methods survey using a validated 2-question proxy for burnout was distributed monthly through 9 months. The primary outcome was the trajectory in probability of burnout, which was examined as both emotional exhaustion (EE) and depersonalization (DP), EE alone, and DP alone. Secondary outcomes investigated burnout and its association with demographic variables. Quantitative data were analyzed using logistic regression for primary outcomes and subanalyses for secondary outcomes. Conventional content analysis was used to analyze qualitative data and generate themes., Results: From February to October 2021, 92 of 98 respondents completed at least 1 survey, 78% completed at least 3 consecutive surveys, and 48% completed at least 6 consecutive surveys. Predicted probability of EE was bimodal with peaks in May (25%) and October (22%) 2021. Rates of DP alone or having both EE and DP were approximately 1% and stable over the study period. Mid-career physicians were at lower risk of EE (odds ratio, 0.02; 95% confidence interval, 0-0.22) compared with early-career physicians. Underlying drivers of burnout were multifaceted., Conclusions: Our study suggests that increased COVID-19 case burden was correlated with EE levels during the third and fourth waves of the pandemic. Emotional exhaustion was worsened by systemic factors, and interventions must target common themes of unsustainable workloads and overwhelming lack of control., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Tandem repeat DNA sequences constitute a significant proportion of the human genome. While previously considered to be functionally inert, these sequences are now broadly accepted as important contributors to genetic diversity. However, the polymorphic nature of these sequences can lead to expansion beyond a gene-specific threshold, causing disease. More than 50 pathogenic repeat expansions have been identified to date, many of which have been discovered in the last decade as a result of advances in sequencing technologies and associated bioinformatic tools. Commonly utilised diagnostic platforms including Sanger sequencing, capillary array electrophoresis, and Southern blot are generally low throughput and are often unable to accurately determine repeat size, composition, and epigenetic signature, which are important when characterising repeat expansions. The rapid advances in bioinformatic tools designed specifically to interrogate short-read sequencing and the development of long-read single molecule sequencing is enabling a new generation of high throughput testing for repeat expansion disorders. In this review, we discuss some of the challenges surrounding the identification and characterisation of disease-causing repeat expansions and the technological advances that are poised to translate the promise of genomic medicine to individuals and families affected by these disorders., (© 2023 The Author(s).)

Objectives: To document the level of vaccine hesitancy in caregivers' of children younger than 12 years of age over the course of the pandemic in Pediatric Emergency Departments (ED). Study design Ongoing multicenter, cross-sectional survey of caregivers presenting to 19 pediatric EDs in the USA, Canada, Israel, and Switzerland during first months of the pandemic (phase1), when vaccines were approved for adults (phase2) and most recently when vaccines were approved for children (phase3)., Results: Willingness to vaccinate rate declined over the study period (59.7%, 56.1% and 52.1% in the three phases). Caregivers who are fully vaccinated, who have higher education, and those worried their child had COVID-19 upon arrival to the ED, were more likely to plan to vaccinate in all three phases. Mothers were less likely to vaccinate early in the pandemic, but this hesitancy attenuated in later phases. Older caregivers were more willing to vaccinate, and caregivers of older children were less likely to vaccinate their children in phase 3. During the last phase, willingness to vaccinate was lowest in those who had a primary care provider but did not rely on their advice for medical decisions (34%). Those with no primary care provider and those who do and rely on their medical advice, had similar rates of willingness to vaccinate (55.1% and 52.1%, respectively)., Conclusions: COVID-19 vaccine hesitancy is widespread and growing over time, and public health measures should further try to leverage identified factors associated with hesitancy in order to enhance vaccination rates among children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Lower respiratory tract infections (LRTIs) are a leading cause of morbidity and mortality in children. The ability of healthcare providers to diagnose and prognose LRTIs in the pediatric population remains a challenge, as children can present with similar clinical features regardless of the underlying pathogen or ultimate severity. Metabolomics, the large-scale analysis of metabolites and metabolic pathways offers new tools and insights that may aid in diagnosing and predicting the outcomes of LRTIs in children. This review highlights the latest literature on the clinical utility of metabolomics in providing care for children with bronchiolitis, pneumonia, COVID-19, and sepsis. IMPACT: This article summarizes current metabolomics approaches to diagnosing and predicting the course of pediatric lower respiratory infections. This article highlights the limitations to current metabolomics research and highlights future directions for the field., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objectives: Caregiver attitudes toward mandating COVID-19 vaccines for their children are poorly understood. We aimed to determine caregiver acceptability of COVID-19 vaccine mandates for schools/daycares and assess if opposition to mandates would result in removal of children from the educational system., Study Design: Perform a cross-sectional, anonymous survey of adult caregivers with children ≤ 18 years presenting to 21 pediatric emergency departments in the United States, Canada, Israel, and Switzerland, November 1st through December 31st, 2021. The primary outcome was caregiver acceptance rates for school vaccine mandates, and the secondary outcomes included factors associated with mandate acceptance and caregiver intention to remove the child from school., Results: Of 4,393 completed surveys, 37% of caregivers were opposed to any school vaccine mandate. Caregiver acceptance was lowest for daycare settings (33%) and increased as the child's level of education increased, college (55%). 26% of caregivers report a high likelihood (score of 8-10 on 0-10 scale) to remove their child from school if the vaccine became mandatory. Child safety was caregivers' greatest concern over vaccine mandates. A multivariable model demonstrated intent to vaccinate their child for COVID-19 (OR = 8.9, 95% CI 7.3 to 10.8; P < 0.001) and prior COVID-19 vaccination for the caregiver (OR = 3.8, 95% CI 3.0 to 4.9; P < 0.001) had the greatest odds of increasing mandate acceptance for any school level., Conclusions: Many caregivers are resistant to COVID-19 vaccine mandates for schools, and acceptance varies with school level. One-fourth of caregivers plan to remove their child from the educational system if vaccines become mandated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Automated programs that carry out targeted metabolite identification and quantification using proton nuclear magnetic resonance spectra can overcome time and cost barriers that limit metabolomics use. However, their performance needs to be comparable to that of an experienced spectroscopist. A previously analyzed pediatric sepsis data set of serum samples was used to compare results generated by the automated programs rDolphin and BATMAN with the results obtained by manual profiling for 58 identified metabolites. Metabolites were selected using Student's t -tests and evaluated with several performance metrics. The manual profiling results had the highest performance metrics values, especially for sensitivity (76.9%), area under the receiver operating characteristic curve (0.90), precision (62.5%), and testing accuracy based on a neural net (88.6%). All three approaches had high specificity values (77.7-86.7%). Manual profiling by an expert spectroscopist outperformed two open-source automated programs, indicating that further development is needed to achieve acceptable performance levels.

Vaccinating children against COVID-19 is critical as a public health strategy in order to reach herd immunity and prevent illness among children and adults. The aim of the study was to identify correlation between willingness to vaccinate children under 12 years old, and vaccination rate for adult population in Canada, the United States, and Israel. This was a secondary analysis of a cross-sectional survey study (COVID-19 Parental Attitude Study) of parents of children 12 years and younger presenting to 12 pediatric emergency departments (EDs). Parental reports of willingness to vaccinate against COVID-19 when vaccines for children will be approved was correlated to country-specific rate of vaccination during December 2020-March 2021, obtained from ourworldindata.org. Logistic regression models were fit with covariates for week and the corresponding vaccine rate. A total of 720 surveys were analyzed. In Canada, administering mostly first dose to the adult population, willingness to vaccinate children was trending downward (correlation = -0.28), in the United States, it was trending upwards (correlation = 0.21) and in Israel, initially significant increase with decline shortly thereafter (correlation = 0.06). Odds of willingness to vaccinate in Canada, the United States, and Israel was OR = 0.82, 95% CI = 0.63-1.07, OR = 1.24, 95% CI = 0.99-1.56, and OR = 1.03, 95% CI = 0.95-1.12, respectively. A robust population-based vaccination program as in Israel, and to a lesser degree the United States, led to increasing willingness by parents to vaccinate their children younger than 12 years against COVID-19. In Canada, slow rate of vaccination of the adult population was associated with lower willingness to vaccinate children.

Background/aims: Despite evidence that preferential use of balanced/buffered fluids may improve outcomes compared with chloride-rich 0.9% saline, saline remains the most commonly used fluid for children with septic shock. We aim to determine if resuscitation with balanced/buffered fluids as part of usual care will improve outcomes, in part through reduced kidney injury and without an increase in adverse effects, compared to 0.9% saline for children with septic shock., Methods: The Pragmatic Pediatric Trial of Balanced versus Normal Saline Fluid in Sepsis (PRoMPT BOLUS) study is an international, open-label pragmatic interventional trial being conducted at > 40 sites in the USA, Canada, and Australia/New Zealand starting on August 25, 2020, and continuing for 5 years. Children > 6 months to < 18 years treated for suspected septic shock with abnormal perfusion in an emergency department will be randomized to receive either balanced/buffered crystalloids (intervention) or 0.9% saline (control) for initial resuscitation and maintenance fluids for up to 48 h. Eligible patients are enrolled and randomized using serially numbered, opaque envelopes concurrent with clinical care. Given the life-threatening nature of septic shock and narrow therapeutic window to start fluid resuscitation, patients may be enrolled under "exception from informed consent" in the USA or "deferred consent" in Canada and Australia/New Zealand. Other than fluid type, all decisions about timing, volume, and rate of fluid administration remain at the discretion of the treating clinicians. For pragmatic reasons, clinicians will not be blinded to study fluid type. Anticipated enrollment is 8800 patients. The primary outcome will be major adverse kidney events within 30 days (MAKE30), a composite of death, renal replacement therapy, and persistent kidney dysfunction. Additional effectiveness, safety, and biologic outcomes will also be analyzed., Discussion: PRoMPT BOLUS will provide high-quality evidence for the comparative effectiveness of buffered/balanced crystalloids versus 0.9% saline for the initial fluid management of children with suspected septic shock in emergency settings., Trial Registration: PRoMPT BOLUS was first registered at ClinicalTrials.gov ( NCT04102371 ) on September 25, 2019. Enrollment started on August 25, 2020., (© 2021. The Author(s).)

Objective: To determine if caregivers of children presenting to pediatric emergency departments (EDs) during the COVID-19 pandemic are delaying presenting to care for fear of contracting COVID-19., Methods: This was a pre-planned secondary analysis of a cross-sectional survey study of caregivers accompanying their children aged 0-19 years to 16 pediatric EDs in 5 countries from May to June 2020. An anonymous online survey, completed by caregivers via RedCAP, included caregiver and child demographics, presenting complaints, if they delayed presentation and whether symptoms worsened during this interval, as well as caregiver concern about the child or caregiver having COVID-19 at the time of ED visit., Results: Of 1543 caregivers completing the survey, 287 (18.6%) reported a delay in seeking ED care due to concerns of contracting COVID-19 in the hospital. Of those, 124 (43.2%) stated their child's symptoms worsened during the waiting interval. Caregiver relationship to child [mother] (OR 1.85, 95% CI 1.27-2.76), presence of chronic illness in child (OR 1.78. 95% CI 1.14-2.79), younger age of caregiver (OR 0.965, 95% CI 0.943-0.986), and caregiver concerns about lost work during the pandemic (OR 1.08, 95% CI 1.04-1.12) were independently associated with a COVID-19-related delayed presentation in multivariable regression analysis., Conclusions: Almost one in five caregivers reported delaying ED presentation for their ill or injured child specifically due to fear of contracting COVID-19 while in hospital, with mothers, younger caregivers, caregivers of children with chronic illness, and those concerned about lost work more likely to report delaying ED presentation., (© 2021. The Author(s), under exclusive licence to Canadian Association of Emergency Physicians (CAEP)/ Association Canadienne de Médecine d'Urgence (ACMU).)

Vaccines against COVID-19 are likely to be approved for children under 12 years in the near future. Understanding vaccine hesitancy in parents is essential for reaching herd immunity. A cross-sectional survey of caregivers in 12 emergency departments (ED) was undertaken in the U.S., Canada, and Israel. We compared reported willingness to vaccinate children against COVID-19 with an initial survey and post-adult COVID-19 vaccine approval. Multivariable logistic regression models were performed for all children and for those <12 years. A total of 1728 and 1041 surveys were completed in phases 1 and 2, respectively. Fewer caregivers planned to vaccinate against COVID-19 in phase 2 (64.5% and 59.7%, respectively; p = 0.002). The most significant positive predictor of willingness to vaccinate against COVID-19 was if the child was vaccinated per recommended local schedules. Fewer caregivers plan to vaccinate their children against COVID-19, despite vaccine approval for adults, compared to what was reported at the peak of the pandemic. Older caregivers who fully vaccinated their children were more likely to adopt vaccinating children. This study can inform target strategy design to implement adherence to a vaccination campaign.

While children with appendicitis often have excellent clinical outcomes, some develop life-threatening complications including sepsis and organ dysfunction requiring pediatric intensive care unit (PICU) support. Our study applied a metabolomics and inflammatory protein mediator (IPM) profiling approach to determine the bio-profiles of children who developed severe appendicitis compared with those that did not. We performed a prospective case-control study of children aged 0-17 years with a diagnosis of appendicitis. Cases had severe disease resulting in PICU admission. Primary controls had moderate appendicitis (perforation without PICU); secondary controls had mild appendicitis (non-perforated). Serum samples were analyzed using Proton Nuclear Magnetic Resonance ( 1 H NMR) Spectroscopy and Gas Chromatography-Mass Spectrometry (GC-MS); IPM analysis was performed using plasma bead-based multiplex profiling. Comparisons were made using multivariate data statistical analysis. Fifty-three children were included (15 severe, 38 non-severe). Separation between severe and moderate appendicitis demonstrated excellent sensitivity and specificity (100%, 88%; 14 compounds), separation between severe and mild appendicitis also showed excellent sensitivity and specificity (91%, 90%; 16 compounds). Biomarker patterns derived from metabolomics and IPM profiling are capable of distinguishing children with severe appendicitis from those with less severe disease. These findings provide an important first step towards developing non-invasive diagnostic tools for clinicians in early identification of children who are at a high risk of developing severe appendicitis.

Reliable and efficient diagnosis of pediatric appendicitis is essential for the establishment of a clinical management plan and improvement of patient outcomes. Current strategies used to diagnose a child presenting with a suspected appendicitis include laboratory studies, clinical scores and diagnostic imaging. Although these modalities work in conjunction with each other, one optimal diagnostic strategy has yet to be agreed upon. The recent introduction of precision medicine techniques such as genomics, transcriptomics, proteomics and metabolomics has increased both the diagnostic sensitivity and specificity of appendicitis. Using these novel strategies, the integration of precision medicine into clinical practice via point-of-care technologies is a plausible future. These technologies would assist in the screening, diagnosis and prognosis of pediatric appendicitis.

The coronavirus disease 2019 (COVID-19) pandemic has taken an unprecedented global toll and vaccination is needed to restore healthy living. Timely inclusion of children in vaccination trials is critical. We surveyed caregivers of children seeking care in 17 Emergency Departments (ED) across 6 countries during the peak of the pandemic to identify factors associated with intent to participate in COVID-19 vaccine trials. Questions about child and parent characteristics, COVID-19 expressed concerns and parental attitudes toward participation in a trial were asked.Of 2768 completed surveys, 18.4% parents stated they would enroll their child in a clinical trial for a COVID-19 vaccine and 14.4% would agree to a randomized placebo-controlled study. Factors associated with willingness to participate were parents agreeing to enroll in a COVID-19 vaccine trial themselves (Odds Ratio (OR) 32.9, 95% Confidence Interval (CI) (21.9-51.2)) having an older child (OR 1.0 (1.0-1.01)), having children who received all vaccinations based on their country schedule (OR 2.67 (1.35-5.71)) and parents with high school education or lower (OR 1.79 (1.18-2.74)). Mothers were less likely to enroll their child in a trial (OR 0.68 (0.47-0.97)). Only one fifth of families surveyed will consider enrolling their child in a vaccine trial. Parental interest in participation, history of vaccinating their child, and the child being older all are associated with parents allowing their child to participate in a COVID vaccine trial. This information may help decision-makers and researchers shape their strategies for trial design and participation engagement in upcoming COVID19 vaccination trials.

Objectives: To determine the prevalence of invasive bacterial infections (IBIs) and adverse events in afebrile infants with acute otitis media (AOM)., Methods: We conducted a 33-site cross-sectional study of afebrile infants ≤90 days of age with AOM seen in emergency departments from 2007 to 2017. Eligible infants were identified using emergency department diagnosis codes and confirmed by chart review. IBIs (bacteremia and meningitis) were determined by the growth of pathogenic bacteria in blood or cerebrospinal fluid (CSF) culture. Adverse events were defined as substantial complications resulting from or potentially associated with AOM. We used generalized linear mixed-effects models to identify factors associated with IBI diagnostic testing, controlling for site-level clustering effect., Results: Of 5270 infants screened, 1637 met study criteria. None of the 278 (0%; 95% confidence interval [CI]: 0%-1.4%) infants with blood cultures had bacteremia; 0 of 102 (0%; 95% CI: 0%-3.6%) with CSF cultures had bacterial meningitis; 2 of 645 (0.3%; 95% CI: 0.1%-1.1%) infants with 30-day follow-up had adverse events, including lymphadenitis (1) and culture-negative sepsis (1). Diagnostic testing for IBI varied across sites and by age; overall, 278 (17.0%) had blood cultures, and 102 (6.2%) had CSF cultures obtained. Compared with infants 0 to 28 days old, older infants were less likely to have blood cultures ( P < .001) or CSF cultures ( P < .001) obtained., Conclusion: Afebrile infants with clinician-diagnosed AOM have a low prevalence of IBIs and adverse events; therefore, outpatient management without diagnostic testing may be reasonable., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Objectives: To determine factors associated with parents who plan to vaccinate their children against influenza next year, especially those who did not vaccinate against influenza last year using a global survey., Study Design: A survey of caregivers accompanying their children aged 1-19 years old in 17 pediatric emergency departments in 6 countries at the peak of the coronavirus disease 2019 (COVID-19) pandemic. Anonymous online survey included caregiver and child demographic information, vaccination history and future intentions, and concern about the child and caregiver having COVID-19 at the time of emergency department visit., Results: Of 2422 surveys, 1314 (54.2%) caregivers stated they plan to vaccinate their child against influenza next year, an increase of 15.8% from the previous year. Of 1459 caregivers who did not vaccinate their children last year, 418 (28.6%) plan to do so next year. Factors predicting willingness to change and vaccinate included child's up-to-date vaccination status (aOR 2.03, 95% CI 1.29-3.32, P = .003); caregivers' influenza vaccine history (aOR 3.26, 95% CI 2.41-4.40, P < .010), and level of concern their child had COVID-19 (aOR 1.09, 95% CI 1.01-1.17, P = .022)., Conclusions: Changes in risk perception due to COVID-19, and previous vaccination, may serve to influence decision-making among caregivers regarding influenza vaccination in the coming season. To promote influenza vaccination among children, public health programs can leverage this information., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: More than 100 COVID-19 vaccine candidates are in development since the SARS-CoV-2 genetic sequence was published in January 2020. The uptake of a COVID-19 vaccine among children will be instrumental in limiting the spread of the disease as herd immunity may require vaccine coverage of up to 80% of the population. Prior history of pandemic vaccine coverage was as low as 40% among children in the United States during the 2009 H1N1 influenza pandemic., Purpose: To investigate predictors associated with global caregivers' intent to vaccinate their children against COVID-19, when the vaccine becomes available., Method: An international cross sectional survey of 1541 caregivers arriving with their children to 16 pediatric Emergency Departments (ED) across six countries from March 26 to May 31, 2020., Results: 65% (n = 1005) of caregivers reported that they intend to vaccinate their child against COVID-19, once a vaccine is available. A univariate and subsequent multivariate analysis found that increased intended uptake was associated with children that were older, children with no chronic illness, when fathers completed the survey, children up-to-date on their vaccination schedule, recent history of vaccination against influenza, and caregivers concerned their child had COVID-19 at the time of survey completion in the ED. The most common reason reported by caregivers intending to vaccinate was to protect their child (62%), and the most common reason reported by caregivers refusing vaccination was the vaccine's novelty (52%)., Conclusions: The majority of caregivers intend to vaccinate their children against COVID-19, though uptake will likely be associated with specific factors such as child and caregiver demographics and vaccination history. Public health strategies need to address barriers to uptake by providing evidence about an upcoming COVID-19 vaccine's safety and efficacy, highlighting the risks and consequences of infection in children, and educating caregivers on the role of vaccination., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: This study determined the predictors of caregivers' willingness to accept an accelerated regulatory process for the development of vaccines against coronavirus disease 2019 (COVID-19)., Methods: An international cross-sectional survey was administered to 2557 caregivers of children in 17 pediatric emergency departments (EDs) across 6 countries from March 26, 2020, to June 30, 2020. Caregivers were asked to select 1 of 4 choices with which they most agreed regarding a proposed COVID-19 vaccine-approval process, in addition to questions regarding demographic characteristics, the ED visit, and attitudes about COVID-19. Univariate analyses were conducted using the Mann-Whitney U test for comparing non-normally distributed continuous variables, an independent t test for comparing normally distributed continuous variables, and a χ 2 or Fisher exact test for categorical variables. Multivariate logistic regression analysis was used for determining independent factors associated with caregivers' willingness to accept abridged development of a COVID-19 vaccine. A P value of <0.05 was considered significant., Findings: Almost half (1101/2557; 43%) of caregivers reported that they were willing to accept less rigorous testing and postresearch approval of a new COVID-19 vaccine. Independent factors associated with caregivers' willingness to accept expedited COVID-19 vaccine research included having children who were up to date on the vaccination schedule (odds ratio [OR] = 1.72; 95% CI, 1.29-2.31), caregivers' concern about having had COVID-19 themselves at the time of survey completion in the ED (OR = 1.1; 95% CI, 1.05-1.16), and caregivers' intent to have their children vaccinated against COVID-19 if a vaccine were to become available (OR = 1.84; 95% CI, 1.54-2.21). Compared with fathers, mothers completing the survey were less likely to approve of changes in the vaccine-development process (OR = 0.641; 95% CI, 0.529-0.775)., Implications: Less than half of caregivers in this worldwide sample were willing to accept abbreviated COVID-19 vaccine testing. As a part of an effort to increase acceptance and uptake of a new vaccine, especially in order to protect children, public health strategies and individual providers should understand caregivers' attitudes toward the approval of a vaccine and consult them appropriately., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: We aimed to demonstrate the potential of precision medicine to describe the inflammatory landscape present in children with suspected appendicitis. Our primary objective was to determine levels of seven inflammatory protein mediators previously associated with intra-abdominal inflammation (C-reactive protein-CRP, procalcitonin-PCT, interleukin-6 (IL), IL-8, IL-10, monocyte chemoattractant protein-1-MCP-1, and serum amyloid A-SAA) in a cohort of children with suspected appendicitis. Subsequently, using a multiplex proteomics approach, we examined an expansive array of novel candidate cytokine and chemokines within this population., Methods: We performed a secondary analysis of targeted proteomics data from Alberta Sepsis Network studies. Plasma mediator levels, analyzed by Luminex multiplex assays, were evaluated in children aged 5-17 years with nonappendicitis abdominal pain (NAAP), acute appendicitis (AA), and nonappendicitis sepsis (NAS). We used multivariate regression analysis to evaluate the seven target proteins, followed by decision tree and heat mapping analyses for all proteins evaluated., Results: 185 children were included: 83 with NAAP, 79 AA, and 23 NAS. Plasma levels of IL-6, CRP, MCP-1, PCT, and SAA were significantly different in children with AA compared to those with NAAP ( p < 0.001). Expansive proteomic analysis demonstrated 6 patterns in inflammatory mediator profiles based on severity of illness. A decision tree incorporating the proteins CRP, ferritin, SAA, regulated on activation normal T-cell expressed and secreted (RANTES), monokine induced by gamma interferon (MIG), and PCT demonstrated excellent specificity (0.920) and negative predictive value (0.882) for children with appendicitis., Conclusions: Multiplex proteomic analyses described the inflammatory landscape of children presenting to the ED with suspected appendicitis. We have demonstrated the feasibility of this approach to identify potential novel candidate cytokines/chemokine patterns associated with a specific illness (appendicitis) amongst those with a broad ED presentation (abdominal pain). This approach can be modelled for future research initiatives in pediatric emergency medicine.

Early diagnosis and triage of sepsis improves outcomes. We aimed to identify biomarkers that may advance diagnosis and triage of pediatric sepsis. Serum and plasma samples were collected from young children (1-23 months old) with sepsis on presentation to the Pediatric Intensive Care Unit (PICU-sepsis, n = 46) or Pediatric Emergency Department (PED-sepsis, n = 58) and PED-non-sepsis patients (n = 19). Multivariate analysis was applied to distinguish between patient groups. Results were compared to our results for older children (2-17 years old). Common metabolites and protein-mediators were validated as potential biomarkers for a sepsis-triage model to differentiate PICU-sepsis from PED-sepsis in children age 1 month-17 years. Metabolomics in young children clearly separated the PICU-sepsis and PED-sepsis cohorts: sensitivity 0.71, specificity 0.93, and AUROC = 0.90 ± 0.03. Adding protein-mediators to the model did not improve performance. The seven metabolites common to the young and older children were used to create the sepsis-triage model. Validation of the sepsis-triage model resulted in sensitivity: 0.83 ± 0.02, specificity: 0.88 ± 0.05 and AUROC 0.93 ± 0.02. The metabolic-based biomarkers predicted which sepsis patients required care in a PICU versus those that could be safely cared for outside of a PICU. This has potential to inform appropriate triage of pediatric sepsis, particularly in EDs with less experience evaluating children.

Objectives: The suboptimal provision of analgesia to children in the emergency department (ED) is well-described. A yet unexplored barrier is caregiver or child refusal of analgesia. We sought to evaluate the frequency of caregiver/child acceptance of analgesia offered in the ED., Methods: We conducted a two-centre cross-sectional study of 743 caregivers of children 4–17 years presenting to the pediatric ED with an acutely painful condition using a survey and medical record review. The primary outcome was the proportion of children/caregiver pairs who accepted analgesia in the ED., Results: The median (IQR) age of children was 11 (7) years, and 339/743 (45.6%) were female. The overall survey response rate was 73% (743/1018). In the 24 hours preceding ED arrival, the median (IQR) maximal pain score rated by children and caregivers was 8/10 (4) and 5/10 (2), respectively, and 30.4% (226/743) of caregivers offered analgesia. In the ED, children reported a median (IQR) pain score of 8/10 (2) and 54.9% (408/743) were offered analgesia. When offered in the ED, analgesia was accepted by 91% (373/408). Overall, 55.7% (414/743) of children received some form of analgesia., Conclusions: Most caregivers/children accept analgesia when offered by ED personnel, suggesting refusal is not a major barrier to optimal management of children’s pain and highlighting the importance of ED personnel in encouraging adequate analgesia. A large proportion of children in pain are not offered analgesia by caregivers or ED personnel. Educational strategies for recognizing and treating pain should be directed at children, caregivers, and ED personnel.

Females have an overall advantage over males in resisting Gram-negative bacteremias, thus hinting at sexual dimorphism of immunity during infections. Here, through intravital microscopy, we observed a sex-biased difference in the capture of blood-borne bacteria by liver macrophages, a process that is critical for the clearance of systemic infections. Complement opsonization was indispensable for the capture of enteropathogenic Escherichia coli (EPEC) in male mice; however, a faster complement component 3-independent process involving abundant preexisting antibodies to EPEC was detected in female mice. These antibodies were elicited predominantly in female mice at puberty in response to estrogen regardless of microbiota-colonization conditions. Estrogen-driven antibodies were maternally transferrable to offspring and conferred protection during infancy. These antibodies were conserved in humans and recognized specialized oligosaccharides integrated into the bacterial lipopolysaccharide and capsule. Thus, an estrogen-driven, innate antibody-mediated immunological strategy conferred protection to females and their offspring.

Head injury accounts for 29% of all traumatic deaths in children. Sepsis is significantly associated with an increased risk of mortality in adult traumatic brain injury patients. In the pediatric population, this relationship is not well understood. The objective of this study was to compare the proportion of pediatric traumatic brain injury (TBI) patients and trauma patients without brain injury (NTBI) who developed sepsis or any infection during their index hospital admission. We performed a retrospective study of all trauma patients <18 years of age, admitted to trauma centres in Alberta, Canada from January 1, 2003 to December 31, 2012. Patients who died within 24 hrs of trauma (n = 147) and those with burns as the primary mechanism of injury (n = 53) were excluded. Hospital admission data for the remaining 2556 patients was analyzed. 1727 TBI patients and 829 NTBI patients were included. TBI was associated with lower odds of developing sepsis (OR 0.32 95% CI 0.14-0.77 p = 0.011). TBI was not found to be independently associated with developing any infectious complication after adjusting for confounding by Injury Severity Score (OR 1.25 95% CI 0.90-1.74 p = 0.180). These relationships warrant further study.

Objective: To determine parental experiences and preferences regarding the conduct of pediatric research in an emergency department (ED) setting., Methods: We conducted a cross-sectional study of parents of children ages 0 - 14 years who visited the ED of a tertiary care children's hospital. Parents completed a Web-based survey designed to assess perceptions regarding: 1) background/training of research personnel, 2) location and timing of research discussions, and 3) factors influencing their consent/refusal decision., Results: Parents totalling 339 were approached, and 227 (67%) surveys were completed. Overall, 87% (197/227; 95% confidence interval [CI] 83, 92) reported they would be comfortable being approached by a university student to discuss research. This proportion did not change when stratified by the child's gender, illness severity, or season of visit. Whereas only 37% (84/227; 95% CI 31, 43) of respondents would be comfortable being approached in the waiting room, 68% (154/227; 95% CI 62, 75) would be comfortable if approached in a separate area of the main waiting room. The majority reported comfort with follow-up via email (83%; 188/227; 95% CI 78, 88) or telephone (80%; 182/227; 95% CI 75, 85); only 51% (116/227; 95% CI 44, 57) would be comfortable with a scheduled follow-up visit in the hospital. Participants identified potential complications or side effects as the most common reason for declining consent (69%; 157/227; 95% CI 63, 75)., Conclusions: The majority of parents are comfortable being approached by trained university students, preferably in a separate area of an ED waiting room, and email and telephone follow-ups are preferred over a scheduled re-visit.

Various limitations hinder the timely and accurate diagnosis of appendicitis in pediatric patients. The present study aims to investigate the potential of metabolomics and cytokine profiling for improving the diagnosis of pediatric appendicitis. Serum and plasma samples were collected from pediatric patients for metabolic and inflammatory mediator analyses respectively. Targeted metabolic profiling was performed using Proton Nuclear Magnetic Resonance Spectroscopy and Flow Injection Analysis Mass Spectrometry/Mass Spectrometry and targeted cytokine/chemokine profiling was completed using a multiplex platform to compare children with and without appendicitis. Twenty-three children with appendicitis and 35 control children without appendicitis from the Alberta Sepsis Network pediatric cohorts were included. Metabolomic profiling revealed clear separation between the two groups with very good sensitivity (80%), specificity (97%), and AUROC (0.93 ± 0.05) values. Inflammatory mediator analysis also distinguished the two groups with high sensitivity (82%), specificity (100%), and AUROC (0.97 ± 0.02) values. A biopattern comprised of 9 metabolites and 7 inflammatory compounds was detected to be significant for the separation between appendicitis and control groups. Integration of these 16 significant compounds resulted in a combined metabolic and cytokine profile that also demonstrated strong separation between the two groups with 81% sensitivity, 100% specificity and AUROC value of 0.96 ± 0.03. The study demonstrated that metabolomics and cytokine mediator profiling is capable of distinguishing children with appendicitis from those without. These results suggest a potential new approach for improving the identification of appendicitis in children.

Multiplexed profiling approaches including various 'omics' platforms are becoming a new standard of biomarker development for disease diagnosis and prognosis. The present study applied an integrated metabolomics and cytokine profiling approach as a potential aid to the identification of pediatric appendicitis. Metabolic analysis using serum (n = 121) and urine (n = 102) samples, and cytokine analysis using plasma (n = 121) samples from children presenting to the Emergency Department with abdominal pain were performed. Comparisons between children with appendicitis vs. non-appendicitis abdominal pain, and with perforated vs. non-perforated appendicitis were made using multivariate statistics. Serum and urine biomarker patterns were statistically significantly different between groups. The combined serum metabolomics and inflammatory mediator model revealed clear separation between appendicitis and non-appendicitis abdominal pain (AUROC: 0.92 ± 0.03) as well as for perforated and non-perforated appendicitis (AUROC: 0.88 ± 0.05). Urine metabolic analysis also demonstrated distinction between the groups appendicitis and non-appendicitis abdominal pain (AUROC: 0.85 ± 0.04), and perforated and non-perforated appendicitis (AUROC: 0.98 ± 0.02). In children presenting to the Emergency Department with abdominal pain, metabolomics and inflammatory mediator profiling are capable of distinguishing children with appendicitis from those without. The approach also differentiates between severities of disease. These results provide an important first step towards a potential aid for improving appendicitis identification.

Objectives: To determine the proportion of true-positive blood culture results in children presenting to the ED with suspected appendicitis. To describe the current practice of obtaining blood cultures in children with suspected appendicitis., Methods: We performed a 2-year retrospective health record review of all children aged 2 through 17 years investigated for suspected appendicitis at a tertiary Pediatric Emergency Department. Subjects were identified by searching (a) institutional records for ICD-10-CA coding, (b) diagnostic imaging records of ultrasounds for appendicitis, and (c) surgical database records for nonincidental appendectomies. Abstracted demographic and clinical data were matched to regional laboratory services data to describe the performance and result of blood cultures., Results: Overall, 1315 children investigated for appendicitis were reviewed. Seven hundred fifty (57.0%) were girls, the average age was 11.7 years (SD, 4.0). Blood cultures were obtained in 288 (21.9%) of 1315 patients. Of the 11 (3.8%) cultures that were positive, only 1 (0.35%) was a true positive. Young age, high triage acuity, and presence of fever were associated with the acquisition of cultures (P < 0.001 for all). The proportion of children undergoing appendectomy and the negative appendectomy rate was similar between those with and without blood culture (P = 0.10 and P = 0.96, respectively)., Conclusions: True-positive blood cultures are very rare in children presenting to the ED with suspected appendicitis. Given the potential for false-positive cultures and the social/economic implications of initial testing/retesting of false positives, the use of routine blood cultures for children with suspected appendicitis is not supported.

Objectives: Children with suspected appendicitis are at risk for suboptimal pain management. We sought to describe pain management patterns for suspected appendicitis across Canadian pediatric emergency departments (PEDs)., Methods: A retrospective medical record review was undertaken at 12 Canadian PEDs. Children ages 3 to 17 years who were admitted to the hospital in February or October 2010 with suspected appendicitis were included. Patients were excluded if partially assessed or treated at another hospital. Data were abstracted using a study-specific, standardized electronic data extraction tool. The primary outcome was the proportion of children who received analgesia while in the emergency department (ED). Secondary outcomes included the proportion of children receiving intravenous (IV) morphine and the timing of analgesic provision., Results: A total of 619 health records were abstracted; mean (SD) patient age was 11.4 (3.5) years. Sixty-one percent (381/616) of patients received analgesia in the ED; 42.8% (264/616) received IV morphine. Other analgesic agents provided included oral acetaminophen (23.5% [145/616]) and oral ibuprofen (5.8% [36/616]). The median (IQR) initial dose of IV morphine was 0.06 (0.04, 0.09) mg/kg. The median (IQR) time from triage to the initial dose of analgesia was 196 (101, 309.5) minutes. Forty-three percent (117/269) of children receiving analgesia received the initial dose following surgical consultation; 43.7% (121/277) received their first analgesic after abdominal ultrasound was performed., Conclusions: Suboptimal and delayed analgesia remains a significant issue for children with suspected appendicitis in Canadian PEDs. This suggests a role for multidimensional knowledge translation interventions and care protocols to improve timely access to analgesia.

Background: Ondansetron is often used in the emergency department (ED) to promote oral rehydration in children with acute gastroenteritis (AGE), yet medication solutions administered orally may be poorly tolerated in this population., Objectives: We compared the tolerability of ondansetron oral dissolve tab (ODT) to oral solution (OS) in children presenting to the ED with AGE., Methods: Using alternate-day controlled clinical trial design, children aged 3 months to 10 years received either ondansetron ODT or OS. Our primary outcome was early vomiting (within 15 min of drug administration). The secondary outcome was intravenous (i.v.) fluid administration., Results: There were 462/534 eligible children who met study criteria. Demographics, severity, and duration of illness were similar between groups. Using intention-to-treat analysis, early vomiting occurred in 8/209 ODT vs. 19/253 OS children (3.8% vs. 7.5%; odds ratio [OR] 0.49; 95% confidence interval [CI] 0.18-1.21). Using as-treated analysis, 6/222 (2.7%) children receiving ODT experienced early vomiting, compared with 21/221 (9.5%) of the OS group (OR 0.26; 95% CI 0.09-0.70). The proportion of children discharged without i.v. fluids was not different (intention-to-treat: ODT = 91.4% (191/209), OS = 94.1% (238/253), OR 1.49, 95% CI 0.69-3.28; as-treated: ODT = 92.3% (205/222), OS = 93.2% (206/221), OR 0.88, 95% CI 0.40-1.93)., Conclusions: Using a conservative intention-to-treat analysis, we found that children presenting to an ED with AGE did not have statistically less early vomiting with ondansetron ODT as compared with OS. However, our as-treated analysis demonstrates that children receiving ondansetron ODT experienced early vomiting approximately one-third as often as those receiving OS. The rate of i.v. fluid administration was no different between groups regardless of the type of analysis used., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Evidence exists that analgesics are underutilized, delayed, and insufficiently dosed for emergency department (ED) patients with acute abdominal pain. For physicians practicing in a Canadian paediatric ED setting, we (1) explored theoretical practice variation in the provision of analgesia to children with acute abdominal pain; (2) identified reasons for withholding analgesia; and (3) evaluated the relationship between providing analgesia and surgical consultation., Methods: Physician members of Paediatric Emergency Research Canada (PERC) were prospectively surveyed and presented with three scenarios of undifferentiated acute abdominal pain to assess management. A modified Dillman's Tailored Design method was used to distribute the survey from June to July 2014., Results: Overall response rate was 74.5% (149/200); 51.7% of respondents were female and mean age was 44 (SD 8.4) years. The reported rates of providing analgesia for case scenarios representative of renal colic, appendicitis, and intussusception, were 100%, 92.1%, and 83.4%, respectively, while rates of providing intravenous opioids were 85.2%, 58.6%, and 12.4%, respectively. In all 60 responses where the respondent indicated they would obtain a surgical consultation, analgesia would be provided. In the 35 responses where analgesia would be withheld, 21 (60%) believed pain was not severe enough, while 5 (14.3%) indicated it would obscure a surgical condition., Conclusions: Pediatric emergency physicians self-reported rates of providing analgesia for acute abdominal pain scenarios were higher than previously reported, and appeared unrelated to request for surgical consultation. However, an unwillingness to provide opioid analgesia, belief that analgesia can obscure a surgical condition, and failure to take self-reported pain at face value remain, suggesting that the need exists for further knowledge translation efforts.

Background: Despite the poor independent test characteristics of the white blood cell count (WBC) and neutrophil count (NC) in identifying appendicitis, common clinical decision supports including the Pediatric Appendicitis Score (PAS) and Alvarado Score (AS), require the WBC and NC values. Moreover, blood tests cause discomfort/pain to children and require time for processing results. Scores based on clinical information alone may be of benefit in the pediatric population. The objective of our study was to determine the test characteristics of the PAS and the AS with and without laboratory investigations (mPAS, mAS respectively) as well as the Lintula Score., Methods: A prospective cohort study of children aged 5-17 years presenting to a pediatric ED with suspected appendicitis. Clinical care of the patient was left to the managing physician. At risk for appendicitis was defined by PAS ≥6; AS ≥5; LS ≥16, as originally described; modified cutoffs were defined as mPAS ≥4; mAS ≥4. Appendicitis was defined as acute inflammation, rupture or abscess of the appendix on pathologic evaluation. Test characteristics for each of the 5 scores were calculated., Results: Of the 180 eligible children, 102 (56.7 %) were female. The average age was 11.2 years (SD 3.1). Appendectomy was performed in 58 (32.2 %) of children, 55 (94.8 %) were positive. For the PAS and mPAS, sensitivity and negative predictive values were similar (80.0 %, 86.4 % vs 87.3 %, 85.1 % respectively). For the AS and mAS, sensitivity and negative predictive values were also similar (85.5 %, 87.1 % vs 83.6 %, 83.3 % respectively). Specificities in the PAS, mPAS, AS and mAS were low (56.0 %, 32.0 %, 43.2 %, 63.0 % respectively). Test characteristics of the LS were poor (59.3 %, 79.2 %, 55.2 %, 81.8 %)., Conclusions: A modified Alvarado and PAS can be used to screen for children at low risk of appendicitis who may be carefully observed at home without the need for laboratory investigation. Translation to primary care settings should evaluate generalizability and determine impact on referral patterns.

Objectives: Advanced nursing directives (ANDs) empower nursing staff to provide advanced levels of care before physician assessment. The objectives of this study were (1) to determine whether an AND for right lower quadrant (RLQ) pain could identify children who required any further investigation to diagnose appendicitis and (2) to determine whether children meeting AND criteria had better emergency department (ED) flow metrics compared with those who did not meet the criteria., Methods: Health records of children aged 3 to 17 years presenting to the ED with abdominal pain who were managed using the departmental AND for RLQ pain were reviewed. Primary outcomes included (1) the proportion of patients requiring further investigation to diagnose appendicitis and (2) the time interval from triage to blood draw. Secondary outcomes included additional ED flow metrics, perforation rate, and negative appendectomy rate., Results: An AND was completed for 210 children. Those who met the AND criteria were more likely to undergo further investigation to rule out appendicitis than those who did not meet the criteria (92/137 [67.2%] vs 32/73 [43.8%]; odds ratio [OR], 2.62; 95% confidence interval [CI], 1.40-4.90). Time to blood draw was significantly lower for those children meeting the AND criteria (74 vs 162 minutes, P < 0.001) as was time to hospital admission (271 vs 395 minutes, P = 0.008) and appendectomy (498 vs 602 minutes, P = 0.015). The negative appendectomy rate was 8.6% (5/58) for children meeting the AND criteria and 9.1% (2/22) for those not meeting the criteria (OR, 0.94; 95% CI, 0.14-10.67); the perforation rate was 29.3% (17/58) and 4.5% (1/22), respectively (OR, 8.17; 95% CI, 1.17-380.86)., Conclusions: Children presenting to the ED with RLQ pain who meet the AND criteria are more likely to require further investigation to rule out appendicitis and have better department flow metrics than those who do not meet the criteria. Our results provide further evidence of the utility of ANDs in the ED.

Background: Pediatric sepsis remains a leading cause of morbidity and mortality. Understanding current practice patterns and challenges is essential to inform future research and education strategies., Objective: Our aim was to describe the practice patterns of pediatric emergency physicians (PEPs) in the recognition and management of sepsis in children and to identify perceived priorities for future research and education., Methods: We conducted a cross-sectional, internet-based survey of members of the American Academy of Pediatrics, Section on Emergency Medicine and Pediatric Emergency Research Canada. The survey was internally derived, externally validated, and distributed using a modified Dillman methodology. Rank scores (RS) were calculated for responses using Likert-assigned frequency values., Results: Tachycardia, mental-status changes, and abnormal temperature (RS = 83.7, 80.6, and 79.6) were the highest ranked clinical measures for diagnosing sepsis; white blood cell count, lactate, and band count (RS = 73.5, 70.9, and 69.1) were the highest ranked laboratory investigations. The resuscitation fluid of choice (85.5%) was normal saline. Dopamine was the first-line vasoactive medication (VAM) for cold (57.1%) and warm (42.2%) shock with epinephrine (18.5%) and norepinephrine (25.1%) as second-line VAMs (cold and warm, respectively). Steroid administration increased with complexity of presentation (all-comers 3.8%, VAM-resistant shock 54.5%, chronic steroid users 72.0%). Local ED-specific clinical pathways, national emergency department (ED)-specific guidelines, and identification of clinical biomarkers were described as future priorities., Conclusions: While practice variability exists among clinicians, PEPs continue to rely heavily on clinical metrics for recognizing sepsis. Improved recognition through clinical biomarkers and standardization of care were perceived as priorities. Our results provide a strong framework to guide future research and education strategies in pediatric sepsis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: The first steps in goal-directed therapy for sepsis are early diagnosis followed by appropriate triage. These steps are usually left to the physician's judgment, as there is no accepted biomarker available. We aimed to determine biomarker phenotypes that differentiate children with sepsis who require intensive care from those who do not., Methods: We conducted a prospective, observational nested cohort study at two pediatric intensive care units (PICUs) and one pediatric emergency department (ED). Children ages 2-17 years presenting to the PICU or ED with sepsis or presenting for procedural sedation to the ED were enrolled. We used the judgment of regional pediatric ED and PICU attending physicians as the standard to determine triage location (PICU or ED). We performed metabolic and inflammatory protein mediator profiling with serum and plasma samples, respectively, collected upon presentation, followed by multivariate statistical analysis., Results: Ninety-four PICU sepsis, 81 ED sepsis, and 63 ED control patients were included. Metabolomic profiling revealed clear separation of groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.89, area under the receiver operating characteristic curve (AUROC) of 0.96 (standard deviation [SD] 0.01), and predictive ability (Q(2)) of 0.60. Protein mediator profiling also showed clear separation of the groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.78 and AUROC of 0.88 (SD 0.03). Combining metabolomic and protein mediator profiling improved the model (Q(2) =0.62), differentiating PICU sepsis from ED sepsis with accuracy of 0.87 and AUROC of 0.95 (SD 0.01). Separation of PICU sepsis or ED sepsis from ED controls was even more accurate. Prespecified age subgroups (2-5 years old and 6-17 years old) improved model accuracy minimally. Seventeen metabolites or protein mediators accounted for separation of PICU sepsis and ED sepsis with 95% confidence., Conclusions: In children ages 2-17 years, combining metabolomic and inflammatory protein mediator profiling early after presentation may differentiate children with sepsis requiring care in a PICU from children with or without sepsis safely cared for outside a PICU. This may aid in making triage decisions, particularly in an ED without pediatric expertise. This finding requires validation in an independent cohort.

Objectives: The objective was to characterize the variations in practice in the diagnosis and management of children admitted to hospitals from Canadian pediatric emergency departments (EDs) with suspected appendicitis, specifically the timing of surgical intervention, ED investigations, and management strategies., Methods: Twelve sites participated in this retrospective health record review. Children aged 3 to 17 years admitted to the hospital with suspected appendicitis were eligible. Site-specific demographics, investigations, and interventions performed were recorded and compared. Factors associated with after-hours surgery were determined using generalized estimating equations logistic regression., Results: Of the 619 children meeting eligibility criteria, surgical intervention was performed in 547 (88%). After-hours surgery occurred in 76 of the 547 children, with significant variation across sites (13.9%, 95% confidence interval = 7.1% to 21.6%, p < 0.001). The overall perforation rate was 17.4% (95 of 547), and the negative appendectomy rate was 6.8% (37 of 547), varying across sites (p = 0.004 and p = 0.036, respectively). Use of inflammatory markers (p < 0.001), blood cultures (p < 0.001), ultrasound (p = 0.001), and computed tomography (p = 0.001) also varied by site. ED administration of narcotic analgesia and antibiotics varied across sites (p < 0.001 and p = 0.001, respectively), as did the type of surgical approach (p < 0.001). After-hours triage had a significant inverse association with after-hours surgery (p = 0.014)., Conclusions: Across Canadian pediatric EDs, there exists significant variation in the diagnosis and management of children with suspected appendicitis. These results indicate that the best diagnostic and management strategies remain unclear and support the need for future prospective, multicenter studies to identify strategies associated with optimal patient outcomes., (© 2015 by the Society for Academic Emergency Medicine.)

Cell segmentation and counting is often required in disciplines such as biological research and medical diagnosis. Manual counting, although still employed, suffers from being time consuming and sometimes unreliable. As a result, several automated cell segmentation and counting methods have been developed. A main component of automated cell counting algorithms is the image segmentation technique employed. Several such techniques were investigated and implemented in the present study. The segmentation and counting was performed on antibody stained brain tissue sections that were magnified by a factor of 40. Commonly used methods such as the circular Hough transform and watershed segmentation were analysed. These tests were found to over-segment and therefore over-count samples. Consequently, a novel cell segmentation and counting algorithm was developed and employed. The algorithm was found to be in almost perfect agreement with the average of four manual counters, with an intraclass correlation coefficient (ICC) of 0.8., (© 2014 Wiley Periodicals, Inc.)

Objectives: The objective was to review the clinical outcomes of children with suspected appendicitis after an ultrasound (US) examination fails to fully visualize the appendix, the diagnostic characteristics of US in children with suspected appendicitis, and the predictive value of secondary signs of appendicitis when the appendix is not fully visualized., Methods: This was a retrospective health record review of children aged 3 to 17 years presenting to a tertiary pediatric emergency department (ED) with suspected appendicitis. Descriptive statistics and diagnostic test characteristics are reported., Results: Overall, 968 children had US. The appendix was fully visualized in 442 cases (45.7%), and 526 (54.3%) children had incompletely visualized appendices. The disposition of those with incompletely visualized appendices were as follows: 59.1% were discharged home, 10.5% went directly to the operating room, and 30.4% were admitted to the hospital for further observation. Of those discharged home based on clinical findings after incompletely visualized appendices, fewer than 0.3% ended up having appendicitis. Ultimately 15.6% of children with incompletely visualized appendices had pathology-confirmed appendicitis. The sensitivity and specificity of US for children with fully visualized appendices were 99.5% (95% confidence interval [CI] = 96.7% to 100%) and 81.3% (95% CI = 75.2% to 86.2%), respectively. The sensitivity and specificity for the presence of any secondary sign in diagnosing appendicitis were 40.2% (95% CI = 29.6% to 51.7%) and 90.6% (95% CI = 87.5% to 93.2%), respectively., Conclusions: Children with incompletely visualized appendices on US can be safely discharged home based on clinical findings with an acceptable rate of missed appendicitis. Children with nonreassuring clinical examinations following incompletely visualized appendices on US may benefit from further imaging studies prior to appendectomy, to reduce the rate of negative appendectomy. While the presence of secondary signs of inflammation can be used to rule in appendicitis, statistical strength to rule out appendicitis in the absence of secondary signs is insufficient., (© 2014 by the Society for Academic Emergency Medicine.)

In an effort to improve the quality and flow of care provided to children presenting to the emergency department the implementation of nurse-initiated protocols is on the rise. We review the current literature on nurse-initiated protocols, validated emergency department clinical scoring systems, and the merging of the two to create Advanced Nursing Directives (ANDs). The process of developing a clinical pathway for children presenting to our pediatric emergency department (PED) with suspected appendicitis will be used to demonstrate the successful integration of validated clinical scoring systems into practice through the use of Advanced Nursing Directives. Finally, examples of 2 other Advanced Nursing Directives for common clinical PED presentations will be provided.

In response to a clinical safety review, we have implemented an AND to empower our pediatric emergency nurses to identify and initiate care directives for children with suspected appendicitis. Future quality assessment and research studies will focus on the accuracy of the AND in predicting which children will have imaging studies or an appendectomy as well as the impact of the AND on key pediatric ED flow measures.

During development, serotonin (5-HT) accumulates in thalamic, noradrenergic, and auditory brainstem neurons that are non-serotonergic in the adult. As demonstrated in somatosensory thalamocortical projections, this accumulation of 5-HT is necessary for the precise organization of afferent terminal arborizations. Accumulation of 5-HT in the auditory brainstem appears to be most robust in the lateral superior olive (LSO) and as demonstrated in the MAO-A knockout mouse, is present at birth and begins to taper off at postnatal day 7 (P7). During the same developmental period, 5-HT-positive terminal endings in the inferior colliculus (IC) have been reported to be more numerous than in the adult [O. Cases, C. Lebrand, B. Giros, T. Vitalis, E. De Maeyer, M. Caron, D. Price, P. Gaspar, I. Seif, Plasma membrane transporters of serotonin, dopamine and norepinephrine mediate serotonin accumulation in atypical locations in the developing brain of monoamine oxidase A knock-outs, J. Neurosci. 18 (1998) 6914-6927]. It has been hypothesized that the serotonergic terminal fibers in the IC belong to neurons whose cell bodies reside in the LSO. Here, we provide evidence based on morphological and tract-tracing data that LSO neurons containing serotonin in the perinatal mouse, project to the IC. These data suggest that, similar to thalamocortical projections in other sensory systems, 5-HT may play a role in regulating development of LSO terminal arbors in the IC.

During the same postnatal period of development when their terminal projection patterns in the midbrain are maturing, lateral superior olivary (LSO) neurons are immunoreactive for serotonin (5-HT). As there is no evidence that LSO neurons synthesize 5-HT, it is likely that they accumulate 5-HT via the 5-HT transporter. To determine if the 5-HT transporter is responsible for 5-HT inside postnatal mouse LSO neurons, pups (postnatal ages 5-6) were treated with fluoxetine and LSO neurons examined for 5-HT. We also evaluated whether LSO neurons containing 5-HT expressed the 5-HT transporter. To further rule out any potential synthesis of 5-HT, brainstem sections of mice at postnatal ages when 5-HT staining is the most robust were stained for the rate-limiting enzyme in the synthesis of 5-HT, tryptophan hydroxylase. Fluoxetine treatment reduced or in most cases, completely eliminated the number of neurons in the LSO stained for 5-HT. Postnatal LSO neurons containing 5-HT were immunoreactive for the 5-HT transporter; in older animals in which 5-HT was no longer observed in the LSO neurons, 5-HT transporter expression was similarly absent. Further, LSO neurons in mice at any age did not stain for tryptophan hydroxylase. These results indicate that LSO neurons express the functional 5-HT transporter to internalize 5-HT; this mechanism may serve to regulate extracellular 5-HT levels during maturation of their terminal endings in the inferior colliculus.

The cochlear nucleus is well known as an obligatory relay center for primary auditory nerve fibers. Perhaps not so well known is the neural input to the cochlear nucleus from cells containing serotonin that reside near the midline in the midbrain raphe region. Although the specific locations of the main, if not sole, sources of serotonin within the dorsal cochlear nucleus subdivision are known to be the dorsal and median raphe nuclei, sources of serotonin located within other cochlear nucleus subdivisions are not currently known. Anterograde tract tracing was used to label fibers originating from the dorsal and median raphe nuclei while fluorescence immunohistochemistry was used to simultaneously label specific serotonin fibers in cat. Biotinylated dextran amine was injected into the dorsal and median raphe nuclei and was visualized with Texas Red, while serotonin was visualized with fluorescein. Thus, double-labeled fibers were unequivocally identified as serotoninergic and originating from one of the labeled neurons within the dorsal and median raphe nuclei. Double-labeled fiber segments, typically of fine caliber with oval varicosities, were observed in many areas of the cochlear nucleus. They were found in the molecular layer of the dorsal cochlear nucleus, in the small cell cap region, and in the granule cell and external regions of the cochlear nuclei, bilaterally, of all cats. However, the density of these double-labeled fiber segments varied considerably depending upon the exact region in which they were found. Fiber segments were most dense in the dorsal cochlear nucleus (especially in the molecular layer) and the large spherical cell area of the anteroventral cochlear nucleus; they were moderately dense in the small cell cap region; and fiber segments were least dense in the octopus and multipolar cell regions of the posteroventral cochlear nucleus. Because of the presence of labeled fiber segments in subdivisions of the cochlear nucleus other than the dorsal cochlear nucleus, we concluded that the serotoninergic projection pattern to the cochlear nucleus is divergent and non-specific. Double-labeled fiber segments were also present, but sparse, in the superior olive, localized mainly in periolivary regions; this indicated that the divergence of dorsal and median raphe neurons that extends throughout regions of the cochlear nucleus also extended well beyond the cochlear nucleus to include at least the superior olivary complex as well.

Gentamicin (4%) was injected intratympanically into the middle ear of guinea pigs and the effects on the brainstem evaluated 28 days later by immunohistochemistry with an antibody against glial fibrillary acidic protein to detect astrocytes, and by cytochrome oxidase staining to detect metabolic activity. Astrocytes were observed in the cochlear nucleus indicating the possible presence of anterograde degeneration. Deficiencies in the intensity of cytochrome oxidase staining up to the level of the superior olivary complex indicated the presence of abnormal metabolic activity. Both of these observations support the conclusion that a single intratympanic injection of gentamicin may lead to neuronal degeneration along the central auditory pathway., (Copyright 1998 Elsevier Science B.V.)

Body movement of guinea pigs was measured using a force platform at various times before and after unilateral end organ ablation and before and after sham surgery. Both spontaneous and drop-evoked movement patterns differed in the same animal after vestibular ablation and from control animals that received sham lesions. Whereas measures of eye nystagmus disappeared by 48 h postablation, measures of body movement indicated persistent differences even at 72 h. We conclude that the force platform can differentiate between movement patterns of normal and vestibular-lesioned animals and, in fact, measures a vestibular deficiency that is independent of eye nystagmus. The force platform appears to be a useful addition to evaluate vestibular deficits as well as to detect any benefits of pharmacological or surgical therapies.