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Sophisticated network‐based approaches such as structural connectomics may help to detect a biomarker of mild traumatic brain injury (mTBI) in children. This study compared the structural connectome of children with mTBI or mild orthopedic injury (OI) to that of typically developing (TD) children. Children aged 8–16.99 years with mTBI (n = 83) or OI (n = 37) were recruited from the emergency department and completed 3T diffusion MRI 2–20 days postinjury. TD children (n = 39) were recruited from the community and completed diffusion MRI. Graph theory metrics were calculated for the binarized average fractional anisotropy among 90 regions. Multivariable linear regression and linear mixed effects models were used to compare groups, with covariates age, hemisphere, and sex, correcting for multiple comparisons. The two injury groups did not differ on graph theory metrics, but both differed from TD children in global metrics (local network efficiency: TD > OI, mTBI, d = 0.49; clustering coefficient: TD < OI, mTBI, d = 0.49) and regional metrics for the fusiform gyrus (lower degree centrality and nodal efficiency: TD > OI, mTBI, d = 0.80 to 0.96; characteristic path length: TD < OI, mTBI, d = −0.75 to −0.90) and in the superior and middle orbital frontal gyrus, paracentral lobule, insula, and thalamus (clustering coefficient: TD > OI, mTBI, d = 0.66 to 0.68). Both mTBI and OI demonstrated reduced global and regional network efficiency and segregation as compared to TD children. Findings suggest a general effect of childhood injury that could reflect pre‐ and postinjury factors that can alter brain structure. An OI group provides a more conservative comparison group than TD children for structural neuroimaging research in pediatric mTBI., Children with mTBI and OI demonstrated reduced global and regional network efficiency and segregation as compared to TD children. Findings suggest a general effect of childhood injury that could reflect pre‐ and postinjury factors that can alter brain structure. An OI group provides a more conservative comparison group than TD children for pediatric mTBI research.

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 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.

Background We previously conducted the Probiotic Regimen for Outpatient Gastroenteritis Utility of Treatment (PROGUT) study, which identified no improvements in children with acute gastroenteritis (AGE) administered a probiotic. However, the aforementioned study did not evaluate immunomodulatory benefits. Objectives The object of this study was to determine if stool secretory immunoglobulin A (sIgA) concentrations in children with AGE increase more among participants administered a Lactobacillus rhamnosus/helveticus probiotic compared with those administered placebo. Methods This a priori planned multicenter, randomized, double-blinded, placebo-controlled ancillary study enrolled children presenting for emergency care who received a 5-d probiotic or placebo course. Participants submitted stool specimens on days 0, 5, and 28. The primary endpoint was the change in stool sIgA concentrations on day 5 compared with baseline. Results A total of 133 (n = 66 probiotic, 67 placebo) of 886 PROGUT participants (15.0%) provided all 3 specimens. Median stool sIgA concentrations did not differ between the probiotic and placebo groups at any of the study time points: day 0 median (IQR): 1999 (768, 4071) compared with 2198 (702, 5278) (P = 0.27, Cohen's d = 0.17); day 5: 2505 (1111, 5310) compared with 3207 (982, 7080) (P = 0.19, Cohen's d = 0.16); and day 28: 1377 (697, 2248) compared with 1779 (660, 3977) (P = 0.27, Cohen's d = 0.19), respectively. When comparing measured sIgA concentrations between days 0 and 5, we found no treatment allocation effects [β: −0.24 (−0.65, 0.18); P = 0.26] or interaction between treatment and specimen collection day [β: −0.003 (−0.09, 0.09); P = 0.95]. Although stool sIgA decreased between day 5 and day 28 within both groups (P

Background There are limited treatment options that clinicians can provide to children presenting to emergency departments with vomiting secondary to acute gastroenteritis. Based on evidence of effectiveness and safety, clinicians now routinely administer ondansetron in the emergency department to promote oral rehydration therapy success. However, clinicians are also increasingly providing multiple doses of ondansetron for home use, creating unquantified cost and health system resource use implications without any evidence to support this expanding practice. Methods/design DOSE-AGE is a randomized, placebo-controlled, double-blinded, six-center, pragmatic clinical trial being conducted in six Canadian pediatric emergency departments (EDs). In September 2019 the study began recruiting children aged 6 months to 18 years with a minimum of three episodes of vomiting in the 24 h preceding enrollment, Discussion Definitive data are lacking to guide the clinical use of post-ED visit multidose ondansetron in children with acute gastroenteritis. Usage is increasing, despite the absence of supportive evidence. The incumbent additional costs associated with use, and potential side effects such as diarrhea and repeat visits, create an urgent need to evaluate the effect and safety of multiple doses of ondansetron in children focusing on post-emergency department visit and patient-centered outcomes. Trial Registration ClinicalTrials.gov: NCT03851835. Registered on 22 February 2019.

Primary Subject area Emergency Medicine - Paediatric Background Many children with acute gastroenteritis (AGE) experience moderate-to-severe pain. To date, the relationship between specific enteropathogens and pain intensity in children with AGE is poorly characterized. Objectives To describe pain severity experienced by children with AGE, by enteropathogen type (i.e., bacteria, virus, co-detection) during the 24 hours prior to emergency department (ED) presentation and while in the ED. We also sought to describe analgesic medication use in AGE. Design/Methods Children 0 to under 18 years with symptoms of AGE (vomiting and/or diarrhea, less than 7 days duration) were prospectively recruited in two pediatric EDs from December 2014 to August 2018. Rectal swabs and stool specimens were analyzed with a commercial enteric panel, an in-house viral panel, and standard enteric bacterial culture. Pain severity was reported by caregivers, with input from the child whenever possible, using a validated 11-point Verbal Numerical Rating Scale from 0 (no pain) to 10 (maximum pain). Results 2686 children with AGE participated in the study. The overall maximal mean pain score was 5.50 (SD 3.00) during the 24 hours preceding the ED visit. Children with bacteria detected in their stool had a significantly higher mean pain score (difference: 1.10 [95% CI: 0.36, 1.84]) prior to ED visit and 1.32 (95% CI: 0.54, 2.10) while in the ED, compared to those with no pathogen identified. They also had significantly higher mean pain scores (difference: 1.10 [95%CI: 0.39, 1.81]) prior to ED visit and 1.44 (95%CI: 0.69, 2.20) while in the ED when compared to AGE caused by a single virus. Using a multivariable regression model, the association between pain severity and enteropathogen type was no longer demonstrated; however, longer illness duration (p=0.01), fever (p < 0.0001), increased number of diarrheal (p < 0.0001) and vomiting (p=0.03) episodes, and respiratory symptoms (p=0.03) were all associated with greater pain at home. Overall, analgesic use was low, with 41.6% (1117/2686) and 20.0% (538/2686) of participants receiving an analgesic at home and in the ED, respectively. Conclusion Enteropathogen type was not predictive of greater pain severity after adjustment for clinical symptoms (i.e., vomiting and diarrhea). The clinical constellation of symptoms accompanying any particular pathogen may differ between pathogens, and this clinical picture may play the greater role in pain experience. Analgesic use was low in children with this painful condition.

Background It is unknown if probiotics exert pathogen-specific effects in children with diarrhea secondary to acute gastroenteritis. Methods Analysis of patient-level data from 2 multicenter randomized, placebo controlled trials conducted in pediatric emergency departments in Canada and the United States. Participants were 3–48 months with >3 diarrheal episodes in the preceding 24 hours and were symptomatic for Results Pathogens were identified in specimens from 59.3% of children (928/1565). No pathogen groups were less likely to experience an MVS score ≥9 based on treatment allocation (test for interaction = 0.35). No differences between groups were identified for adenovirus (adjusted relative risk [aRR]: 1.42; 95% confidence interval [CI]: .62, 3.23), norovirus (aRR: 0.98; 95% CI: .56, 1.74), rotavirus (aRR: 0.86; 95% CI: .43, 1.71) or bacteria (aRR: 1.19; 95% CI: .41, 3.43). At pathogen-group and among individual pathogens there were no differences in diarrhea duration or the total number of diarrheal stools between treatment groups, regardless of intervention allocation or among probiotic sub-groups. Among adenovirus-infected children, those administered the L. rhamnosus R0011/L. helveticus R0052 product experienced fewer diarrheal episodes (aRR: 0.65; 95% CI: .47, .90). Conclusions Neither probiotic product resulted in less severe disease compared to placebo across a range of the most common etiologic pathogens. The preponderance of evidence does not support the notion that there are pathogen specific benefits associated with probiotic use in children with acute gastroenteritis. Clinical Trials Registration NCT01773967 and NCT01853124.

Background: Risk factors for severe outcomes of SARS-CoV-2 infection are not well established in children. We sought to describe pediatric hospital admissions associated with SARS-CoV-2 infection in Canada and identify risk factors for more severe disease. Methods: We conducted a national prospective study using the infrastructure of the Canadian Paediatric Surveillance Program (CPSP). Cases involving children who were admitted to hospital with microbiologically confirmed SARS-CoV-2 infection were reported from Apr. 8 to Dec. 31 2020, through weekly online questionnaires distributed to the CPSP network of more than 2800 pediatricians. We categorized hospital admissions as related to COVID-19, incidental, or for social or infection control reasons and determined risk factors for disease severity in hospital. Results: Among 264 hospital admissions involving children with SARS-CoV-2 infection during the 9-month study period, 150 (56.8%) admissions were related to COVID-19 and 100 (37.9%) were incidental infections (admissions for other reasons and found to be positive for SARS-CoV-2 on screening). Infants (37.3%) and adolescents (29.6%) represented most cases. Among hospital admissions related to COVID-19, 52 (34.7%) had critical disease, 42 (28.0%) of whom required any form of respiratory or hemodynamic support, and 59 (39.3%) had at least 1 underlying comorbidity. Children with obesity, chronic neurologic conditions or chronic lung disease other than asthma were more likely to have severe or critical COVID-19. Interpretation: Among children who were admitted to hospital with SARS-CoV-2 infection in Canada during the early COVID-19 pandemic period, incidental SARS-CoV-2 infection was common. In children admitted with acute COVID-19, obesity and neurologic and respiratory comorbidities were associated with more severe disease.

BACKGROUND: Between-country variation in health care resource use and its impact on outcomes in acute care settings have been challenging to disentangle from illness severity by using administrative data. METHODS: We conducted a preplanned analysis employing patient-level emergency department (ED) data from children enrolled in 2 previously conducted clinical trials. Participants aged 3 to RESULTS: In adjusted analysis, unscheduled revisits within 7 days did not differ (adjusted odds ratio [aOR]: 0.72; 95% confidence interval (CI): 0.50 to 1.02). At the index ED visit, although participants in Canada were assessed as being more dehydrated, intravenous fluids were administered more frequently in the United States (aOR: 4.6; 95% CI: 2.9 to 7.1). Intravenous fluid administration rates did not differ after enrollment (aOR: 1.4; 95% CI: 0.7 to 2.8; US cohort with Canadian as referent). Overall, intravenous rehydration was higher in the United States (aOR: 3.8; 95% CI: 2.5 to 5.7). Although hospitalization rates during the 7 days after enrollment (aOR: 1.1; 95% CI: 0.4 to 2.6) did not differ, hospitalization at the index visit was more common in the United States (3.9% vs 2.3%; aOR: 3.2; 95% CI: 1.6 to 6.8). CONCLUSIONS: Among children with gastroenteritis and similar disease severity, revisit rates were similar in our 2 study cohorts, despite lower rates of intravenous rehydration and hospitalization in Canadian-based EDs.

Study objective We determine whether single-dose oral ondansetron administration to children with vomiting as a result of acute gastroenteritis without dehydration reduces administration of intravenous fluid rehydration. Methods In this 2-hospital, double-blind, placebo-controlled, emergency department–based, randomized trial conducted in Karachi Pakistan, we recruited children aged 0.5 to 5.0 years, without dehydration, who had diarrhea and greater than or equal to 1 episode of vomiting within 4 hours of arrival. Patients were randomly assigned (1:1), through an Internet-based randomization service using a stratified variable-block randomization scheme, to single-dose oral ondansetron or placebo. The primary endpoint was intravenous rehydration (administration of ≥20 mL/kg of an isotonic fluid during 4 hours) within 72 hours of randomization. Results Participant median age was 15 months (interquartile range 10 to 26) and 59.4% (372/626) were male patients. Intravenous rehydration use was 12.1% (38/314) and 11.9% (37/312) in the placebo and ondansetron groups, respectively (odds ratio 0.98; 95% confidence interval [CI] 0.60 to 1.61; difference 0.2%; 95% CI of the difference –4.9% to 5.4%). Bolus fluid administration occurred within 72 hours of randomization in 10.8% (34/314) and 10.3% (27/312) of children administered placebo and ondansetron, respectively (odds ratio 0.95; 95% CI 0.56 to 1.59). A multivariable regression model fitted with treatment group and adjusted for antiemetic administration, antibiotics, zinc prerandomization, and vomiting frequency prerandomization yielded similar results (odds ratio 0.91; 95% CI 0.55 to 1.53). There was no interaction between treatment group and age, greater than or equal to 3 stools in the preceding 24 hours, or greater than or equal to 3 vomiting episodes in the preceding 24 hours. Conclusion Oral administration of a single dose of ondansetron did not result in a reduction in intravenous rehydration use. In children without dehydration, ondansetron does not improve clinical outcomes.

IntroductionRelatively limited data are available regarding paediatric COVID-19. Although most children appear to have mild or asymptomatic infections, infants and those with comorbidities are at increased risk of experiencing more severe illness and requiring hospitalisation due to COVID-19. The recent but uncommon association of SARS-CoV-2 infection with development of a multisystem inflammatory syndrome has heightened the importance of understanding paediatric SARS-CoV-2 infection.Methods and analysisThe Paediatric Emergency Research Network-COVID-19 cohort study is a rapid, global, prospective cohort study enrolling 12 500 children who are tested for acute SARS-CoV-2 infection. 47 emergency departments across 12 countries on four continents will participate. At enrolment, regardless of SARS-CoV-2 test results, all children will have the same information collected, including clinical, epidemiological, laboratory, imaging and outcome data. Interventions and outcome data will be collected for hospitalised children. For all children, follow-up at 14 and 90 days will collect information on further medical care received, and long-term sequelae, respectively. Statistical models will be designed to identify risk factors for infection and severe outcomes.Ethics and disseminationSites will seek ethical approval locally, and informed consent will be obtained. There is no direct risk or benefit of study participation. Weekly interim analysis will allow for real-time data sharing with regional, national, and international policy makers. Harmonisation and sharing of investigation materials with WHO, will contribute to synergising global efforts for the clinical characterisation of paediatric COVID-19. Our findings will enable the implementation of countermeasures to reduce viral transmission and severe COVID-19 outcomes in children.Trial registration numberNCT04330261

It has long been accepted that Shiga toxin (Stx) only exists in Shigella dysenteriae serotype 1. However, in recent decades, the presence of Shiga toxin genes (stx) in other Shigella spp. have been reported. We screened 366 Shigella flexneri strains from Alberta, Canada (2003 to 2016) for stx and 26 positive strains were identified. These isolates are highly related with the majority originating from the Dominican Republic and three isolates with Haiti origin. Both phylogenetic and spanning tree analysis of the 26 Alberta and 29 stx positive S. flexneri originating from the U.S., France, Canada (Quebec) and Haiti suggests that there are geographic specific distribution patterns (Haiti and Dominican Republic clades). This study provides the first comprehensive whole genome based phylogenetic analysis of stx positive S. flexneri strains as well as their global transmission, which signify the public health risks of global spreading of these strains.

OBJECTIVES: The Pediatric Emergency Research Network (PERN) was launched in 2009 with the intent for existing national and regional research networks in pediatric emergency care to organize globally for the conduct of collaborative research across networks. METHODS: The Pediatric Emergency Research Network has grown from 5- to 8-member networks over the past decade. With an executive committee comprising representatives from all member networks, PERN plays a supportive and collaborative rather than governing role. The full impact of PERN's facilitation of international collaborative research, although somewhat difficult to quantify empirically, can be measured indirectly by the observed growth of the field, the nature of the increasingly challenging research questions now being addressed, and the collective capacity to generate and implement new knowledge in treating acutely ill and injured children. RESULTS: Beginning as a pandemic response with a high-quality retrospective case-controlled study of H1N1 influenza risk factors, PERN research has progressed to multiple observational studies and ongoing global randomized controlled trials. As a recent example, PERN has developed sufficient network infrastructure to enable the rapid initiation of a prospective observational study in response to the current coronavirus disease 2019 pandemic. In light of the ongoing need for translation of research knowledge into equitable clinical practice and to promote health equity, PERN is committed to a coordinated international effort to increase the uptake of evidence-based management of common and treatable acute conditions in all emergency department settings. CONCLUSIONS: The Pediatric Emergency Research Network's successes with global research, measured by prospective observational and interventional studies, mean that the network can now move to improve its ability to promote the implementation of scientific advances into everyday clinical practice. Achieving this goal will involve focus in 4 areas: (1) expanding the capacity for global randomized controlled trials; (2) deepening the focus on implementation science; (3) increasing attention to healthcare disparities and their origins, with growing momentum toward equity; and (4) expanding PERN's global reach through addition of sites and networks from resource-restricted regions. Through these actions, PERN will be able to build on successes to face the challenges ahead and meet the needs of acutely ill and injured children throughout the world.

IntroductionChildren and youth with mental health and addiction crises are a vulnerable patient group that often are brought to the hospital for emergency department care. We propose to evaluate the effect of a novel, acute care bundle that standardises a patient-centred approach to care.Methods and analysisTwo paediatric emergency departments in Alberta, Canada are involved in this prospective, pragmatic, 29-month interventional quasi-experimental study. The acute care bundle comprises three components, applied when appropriate: (1) assessing self-harm risk at triage using the Ask Suicide-Screening Questionnaire (ASQ) to standardise the questions administered, enabling risk stratification; (2) use of the HEADS-ED (Home, Education, Activities/peers, Drug/alcohol, Suicidality, Emotions and behaviour, Discharge Resources) to focus mental health evaluations for those who screen high risk on the ASQ; and (3) implementation of a Choice And Partnership Approach to enable shared decision making in care following the emergency department visit. The overarching goal is to deliver the right care at the right place and time for the patients. The study design involves a longitudinal collection of data 12 months before and after the introduction of the bundle and the use of quality improvement strategies such as Plan-Do-Study-Act cycles during a 5-month run-in period to test and implement changes. The primary study end-point is child/youth well-being 1 month after the emergency department visit. Secondary outcomes include family functioning, child/youth well-being at 3 and 6 months, satisfaction with emergency department care, and health system outcomes (hospital admissions, length of emergency department stays, emergency department revisits).Ethics and disseminationThe study is registered at www.ClinicalTrials.gov and has received ethics and operational approvals from study sites. The results of the study will be reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology statement. Results will be shared broadly with key policy and decision makers and disseminated in peer-reviewed academic journals and presentations at conferences.Trial registration numberNCT04292379.

Importance While intravenous magnesium decreases hospitalizations in refractory pediatric acute asthma, it is variably used because of invasiveness and safety concerns. The benefit of nebulized magnesium to prevent hospitalization is unknown. Objective To evaluate the effectiveness of nebulized magnesium in children with acute asthma remaining in moderate or severe respiratory distress after initial therapy. Design, Setting, and Participants A randomized double-blind parallel-group clinical trial from September 26, 2011, to November 19, 2019, in 7 tertiary-care pediatric emergency departments in Canada. The participants were otherwise healthy children aged 2 to 17 years with moderate to severe asthma defined by a Pediatric Respiratory Assessment Measure (PRAM) score of 5 or greater (on a 12-point scale) after a 1-hour treatment with an oral corticosteroid and 3 inhaled albuterol and ipratropium treatments. Of 5846 screened patients, 4332 were excluded for criteria, 273 declined participation, 423 otherwise excluded, 818 randomized, and 816 analyzed. Interventions Participants were randomized to 3 nebulized albuterol treatments with either magnesium sulfate (n = 410) or 5.5% saline placebo (n = 408). Main Outcomes and Measures The primary outcome was hospitalization for asthma within 24 hours. Secondary outcomes included PRAM score; respiratory rate; oxygen saturation at 60, 120, 180, and 240 minutes; blood pressure at 20, 40, 60, 120, 180, and 240 minutes; and albuterol treatments within 240 minutes. Results Among 818 randomized patients (median age, 5 years; 63% males), 816 completed the trial (409 received magnesium; 407, placebo). A total of 178 of the 409 children who received magnesium (43.5%) were hospitalized vs 194 of the 407 who received placebo (47.7%) (difference, −4.2%; absolute risk difference 95% [exact] CI, −11% to 2.8%];P = .26). There were no significant between-group differences in changes from baseline to 240 minutes in PRAM score (difference of changes, 0.14 points [95% CI, −0.23 to 0.50];P = .46); respiratory rate (0.17 breaths/min [95% CI, −1.32 to 1.67];P = .82); oxygen saturation (−0.04% [95% CI, −0.53% to 0.46%];P = .88); systolic blood pressure (0.78 mm Hg [95% CI, −1.48 to 3.03];P = .50); or mean number of additional albuterol treatments (magnesium: 1.49, placebo: 1.59; risk ratio, 0.94 [95% CI, 0.79 to 1.11];P = .47). Nausea/vomiting or sore throat/nose occurred in 17 of the 409 children who received magnesium (4%) and 5 of the 407 who received placebo (1%). Conclusions and Relevance Among children with refractory acute asthma in the emergency department, nebulized magnesium with albuterol, compared with placebo with albuterol, did not significantly decrease the hospitalization rate for asthma within 24 hours. The findings do not support use of nebulized magnesium with albuterol among children with refractory acute asthma. Trial Registration ClinicalTrials.gov Identifier:NCT01429415

OBJECTIVES: To determine if the clinical characteristics of children with gastroenteritis and influenza identified in their stool differ from those whose stool was influenza-negative. METHODS: Children

Although neonatal herpes simplex virus (HSV) causes significant morbidity, utilization of the cerebrospinal fluid (CSF) HSV polymerase chain reaction (PCR) test remains variable. Our objective was to examine the association of CSF HSV PCR testing with length of stay (LOS) in a 20-center retrospective cohort of hospitalized infants aged ≤60 days undergoing evaluation for meningitis after adjustment for patient-level factors and clustering by center. Of 20,496 eligible infants, 7,399 (36.1%) had a CSF HSV PCR test performed, and 46 (0.6% of those tested) had a positive test. Infants who had a CSF HSV PCR test performed had a 23% longer hospital LOS (incident rate ratio 1.23; 95% CI: 1.14-1.33). Targeted CSF HSV PCR testing may mitigate the impact on LOS for low-risk infants.

Background Although oral rehydration therapy is recommended for children with acute gastroenteritis (AGE) with none to some dehydration, intravenous (IV) rehydration is still commonly administered to these children in high-income countries. IV rehydration is associated with pain, anxiety, and emergency department (ED) revisits in children with AGE. Objectives We sought to better understand the factors associated with IV rehydration in children with AGE in order to inform knowledge translation strategies. Design/Methods This was a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN) randomized, controlled trials of oral probiotics in children with AGE-associated diarrhea. Eligible children were aged 3–48 months and reported >3 watery stools in a 24-hour period. The primary outcome was administration of IV rehydration at the index ED visit. We used mixed-effects logistic regression model to explore univariable and multivariable relationships between IV rehydration and a prioririsk factors. Results From the parent study sample of 1848 participants, 1846 had data available for analysis: mean (SD) age of 19.1 ± 11.4 months, 45.4% females. 70.2% (1292/1840) vomited within 24 hours of the index ED visit and 34.1% (629/1846) received ondansetron in the ED. 13.0% (240/1846) were administered IV rehydration at the index ED visit, and 3.6% (67/1842) were hospitalized. Multivariable predictors of IV rehydration were Clinical Dehydration Scale (CDS) score [compared to none: mild to moderate (OR: 8.1, CI: 5.5–11.8); severe (OR: 45.9, 95% CI: 20.1–104.7), P Conclusion Higher CDS scores, antiemetic use, previous healthcare visits and country were independent predictors of IV rehydration which was also associated with increased ED revisits. Knowledge translation focused on optimizing the use of antiemetics (i.e. for those with dehydration) and reducing the geographic variation in IV rehydration use may improve the ED experience and reduce ED-revisits.

Background Shiga toxin–producing Escherichia coli (STEC) infections are leading causes of pediatric acute renal failure. Identifying hemolytic uremic syndrome (HUS) risk factors is needed to guide care. Methods We conducted a multicenter, historical cohort study to identify features associated with development of HUS (primary outcome) and need for renal replacement therapy (RRT) (secondary outcome) in STEC-infected children without HUS at initial presentation. Children aged Results Of 927 STEC-infected children, 41 (4.4%) had HUS at presentation; of the remaining 886, 126 (14.2%) developed HUS. Predictors (all shown as odds ratio [OR] with 95% confidence interval [CI]) of HUS included younger age (0.77 [.69–.85] per year), leukocyte count ≥13.0 × 103/μL (2.54 [1.42–4.54]), higher hematocrit (1.83 [1.21–2.77] per 5% increase) and serum creatinine (10.82 [1.49–78.69] per 1 mg/dL increase), platelet count Conclusions The complex nature of STEC infection renders predicting its course a challenge. Risk factors we identified highlight the importance of avoiding dehydration and performing close clinical and laboratory monitoring.

IntroductionRapid detection of Shiga toxin-producingEscherichia coli(STEC) enables appropriate treatment. Numerous commercially available molecular tests exist, but they vary in clinical performance. This systematic review aims to synthesise available evidence to compare the clinical performance of enzyme immunoassay (EIA) and nucleic acid amplification tests (NAATs) for the detection of STEC.Methods and analysisThe following databases will be searched employing a standardised search strategy: Medline, Embase, Cochrane CENTRAL Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed, Scopus and Web of Science. Grey literature will be searched under advice from a medical librarian. Independent reviewers will screen titles, abstracts and full texts of retrieved studies for relevant studies. Data will be extracted independently by two reviewers, using a piloted template. Quality Assessment of Diagnostic Accuracy Studies-2 will be employed to assess the risk of bias of individual studies, and the quality of evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. A bivariate random-effects model will be used to meta-analyse the sensitivity and specificity of commercial STEC diagnostic tests, and a hierarchical summary receiver operator characteristic curve will be constructed. Studies of single test accuracy of EIA and NAATs and studies of comparative accuracy will be analysed separately.Ethics and disseminationEthics approval was not required for this systematic review and meta-analysis. Findings will be disseminated in conferences, through a peer-reviewed journal and via personal interactions with relevant stakeholders.PROSPERO registration numberCRD42018099119.

Background The ability to identify bacterial pathogens that necessitate specific clinical management or public health action in children with acute gastroenteritis is crucial to patient care and public health. However, existing stool-testing guidelines offer inconsistent recommendations, and their performance characteristics are unknown. We evaluated 6 leading gastroenteritis guidelines (eg, those of the Centers for Disease Control and Prevention and Infectious Disease Society of America) that recommend when to test children’s stool for bacterial enteropathogens. Methods Via 2 emergency departments in Alberta, Canada, we enrolled 2447 children Results Outcome data were available for 2391 (97.7%) participants, and 6% (144/2391) of participants tested positive for a bacterial enteropathogen. Guideline sensitivity ranged from 25.8% (95% confidence interval [CI] 18.7–33.0%) to 66.9% (95% CI 59.3–74.6%), and varied for individual pathogens. Guideline specificity for all bacterial enteropathogens ranged from 63.6% (95% CI 61.6–65.6%) to 96.5% (95% CI 95.7–97.2%). Conclusions No guideline provided optimally balanced performance. The most sensitive guidelines missed one-third of cases and would drastically increase testing volumes. The most specific guidelines missed almost 75% of cases.

OBJECTIVE: To determine if treatment failure varies based on ROME III classification and adherence to guideline congruent therapy among children diagnosed in an emergency department with functional constipation. METHODS: Children aged 1 month to 18 years who were diagnosed with constipation in a paediatric emergency department underwent chart review and 7-day phone follow-up to complete the ROME III questionnaire, confirm treatments administered, and assess treatment failure. Participants were classified according to the ROME III criteria as having functional constipation (FC) or irritable bowel syndrome – constipation (IBS-C) subtype. The primary outcome was treatment failure defined as ≥ 2 of the following: 1) presenting symptom persistence; 2) < 1 bowel movement every other day; 3) pain/difficulty passing stools; and 4) abdominal pain between bowel movements. RESULTS: Five hundred and thirteen children completed follow-up; 40% (204/513) had FC, 23% (118/513) IBS-C, and 37% (191/513) did not meet either criteria. Treatment failure rates in children who received guideline congruent treatment were 28% (38/135) among those classified as FC and 43% (37/86) among those with IBS-C; P=0.02, a difference of 15% (95% confidence interval [CI]: 0.02, 0.27). On regression analysis, ROME III classification was not an independent predictor of treatment failure (odds ratio [OR]: 1.56 [95% CI: 0.97, 2.51]). At 7-day follow up, pain in between bowel movements was present in 22% (44/204) in FC patients versus 45% (53/118) of IBS-C patients; P=0.001. CONCLUSIONS: Treatment failure rates in children who receive guideline congruent therapy are higher among those with IBS-C, however, after adjustment for known confounders the relationship was not statistically significant.

BACKGROUND: Although neonatal herpes simplex virus (HSV) is a potentially devastating infection requiring prompt evaluation and treatment, large-scale assessments of the frequency in potentially infected infants have not been performed. METHODS: We performed a retrospective cross-sectional study of infants ≤60 days old who had cerebrospinal fluid culture testing performed in 1 of 23 participating North American emergency departments. HSV infection was defined by a positive HSV polymerase chain reaction or viral culture. The primary outcome was the proportion of encounters in which HSV infection was identified. Secondary outcomes included frequency of central nervous system (CNS) and disseminated HSV, and HSV testing and treatment patterns. RESULTS: Of 26 533 eligible encounters, 112 infants had HSV identified (0.42%, 95% confidence interval [CI]: 0.35%–0.51%). Of these, 90 (80.4%) occurred in weeks 1 to 4, 10 (8.9%) in weeks 5 to 6, and 12 (10.7%) in weeks 7 to 9. The median age of HSV-infected infants was 14 days (interquartile range: 9–24 days). HSV infection was more common in 0 to 28-day-old infants compared with 29- to 60-day-old infants (odds ratio 3.9; 95% CI: 2.4–6.2). Sixty-eight (0.26%, 95% CI: 0.21%–0.33%) had CNS or disseminated HSV. The proportion of infants tested for HSV (35%; range 14%–72%) and to whom acyclovir was administered (23%; range 4%–53%) varied widely across sites. CONCLUSIONS: An HSV infection was uncommon in young infants evaluated for CNS infection, particularly in the second month of life. Evidence-based approaches to the evaluation for HSV in young infants are needed.

Introduction Paediatric mild traumatic brain injury (mTBI) is a public health burden. Clinicians urgently need evidence-based guidance to manage mTBI, but gold standards for diagnosing and predicting the outcomes of mTBI are lacking. The objective of the Advancing Concussion Assessment in Pediatrics (A-CAP) study is to assess a broad pool of neurobiological and psychosocial markers to examine associations with postinjury outcomes in a large sample of children with either mTBI or orthopaedic injury (OI), with the goal of improving the diagnosis and prognostication of outcomes of paediatric mTBI. Methods and analysis A-CAP is a prospective, longitudinal cohort study of children aged 8.00–16.99 years with either mTBI or OI, recruited during acute emergency department (ED) visits at five sites from the Pediatric Emergency Research Canada network. Injury information is collected in the ED; follow-up assessments at 10 days and 3 and 6 months postinjury measure a variety of neurobiological and psychosocial markers, covariates/confounders and outcomes. Weekly postconcussive symptom ratings are obtained electronically. Recruitment began in September 2016 and will occur for approximately 24 months. Analyses will test the major hypotheses that neurobiological and psychosocial markers can: (1) differentiate mTBI from OI and (2) predict outcomes of mTBI. Models initially will focus within domains (eg, genes, imaging biomarkers, psychosocial markers), followed by multivariable modelling across domains. The planned sample size (700 mTBI, 300 OI) provides adequate statistical power and allows for internal cross-validation of some analyses. Ethics and dissemination The ethics boards at all participating institutions have approved the study and all participants and their parents will provide informed consent or assent. Dissemination will follow an integrated knowledge translation plan, with study findings presented at scientific conferences and in multiple manuscripts in peer-reviewed journals.

Background Little is known about the association between specific enteropathogens and disease severity in outpatient children with acute gastroenteritis. Recent advances in diagnostics enabling the rapid and simultaneous detection of common enteropathogens have become readily available. While such knowledge can be used to optimize therapy it also has the potential to predict disease severity. Such knowledge can aid clinical decision making, can clarify guidance and expectations provided to families, and can guide public health policy. Methods We conducted a prospective cohort study of children with acute gastroenteritis who were brought for emergency department care. The primary outcome measure was the 20-point Modified Vesikari Scale (MVS) score calculated from symptom onset until day14 of follow-up (total MVS score). Stool and/or rectal swab specimens were collected and analyzed for 18 unique pathogens by molecular diagnostic assays (in-house 5 virus panel, Luminex xTAG Gastrointestinal Pathogen Panel) and/or bacterial culture. An enteropathogen was deemed to be present if a candidate pathogen was identified in the rectal swab or stool specimens by any testing method. Binary logistic regression was performed to assess the association between pathogens (including all pathogens as present or not) and disease severity with the dependent variable being the total MVS score categorized as severe (11–20 points) vs.. non-severe (0–10 points). Results The mean total MVS score (SD) was 12.8 (3.2) and 73.0% (807/1102) of participants experienced severe disease. A pathogen was identified in 72.8% (802/1102) of study participants. Rotavirus, norovirus GII and adenovirus were identified in 26.6% (293/1102), 23.0% (253/1102) and 16.0% (176/1102) of participants respectively. After adjusting for other pathogens significant predictors of severe disease were: rotavirus (OR=8.0; 95% CI: 4.8, 13.2), Salmonella (OR=5.4; 95% CI: 1.2, 24.4), adenovirus (OR=2.1; 95% CI: 1.3, 3.3), and norovirus GII (OR=1.8; 95% CI: 1.3, 2.6). Clostridium difficile (OR=1.6; 95% CI: 0.96, 2.6) and Aeromonas (OR=0.97; 95% CI: 0.2, 4.7) were not significantly associated with severe disease. Conclusion In children with acute gastroenteritis, the enteropathogens associated with severe disease included rotavirus, Salmonella, adenovirus and norovirus GII. Disclosures All authors: No reported disclosures.

Background It is important to understand the diagnostic accuracy of syndromic multiplex panels such as the Luminex xTAG® Gastrointestinal Pathogen Panel (GPP) as they are increasingly employed as routine diagnostic tests in laboratories worldwide. Recent evaluations in our laboratory identified lower detection rates of norovirus genogroup II (NoV GII) using the GPP as compared with our lab-developed RT-qPCR Gastroenteritis Virus Panel (GVP). This study is to characterize the NoV strains in samples with discordant NoV GII test results between GPP and GVP and determine the sensitivity of the two assays for specific NoV GII genotypes. Methods We genotyped all NoV GII strains with discordant test result in stool samples or rectal swabs collected prospectively from a cohort of children with acute gastroenteritis between December 2014 and July 2016. The sensitivity of GVP and GPP for NoV GII were compared by analyzing GVP threshold cycle (Ct) and using ten-fold serial dilutions of positive samples of various NoV GII genotypes. Results All discordant samples (11%; 63/607) tested positive for NoV GII by GVP but negative by GPP. Thirty-five percent (22/63) were successfully genotyped; 64% (14/22) of those were NoV GII genotype 2 (GII.2). The median Ct value of concordant positive was lower than those with discordant results (19.8 vs.. 33.7 respectively; P < 0.0001). GVP was 10-fold and at least 10,000-fold more sensitive than GPP in detecting NoV GII.3 and GII.2, respectively, but has similar sensitivity for NoV GII.4. The GII.2 variants with discordant test results differed genetically from the concordant GII.2 variants. Conclusion GPP has suboptimal sensitivity to detect NoV GII.2 and its use may lead to an underestimation of NoV disease burden with some cases not being detected. Disclosures All authors: No reported disclosures.

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer disease (AD) and likely contributes to neuropathology through various pathways. Here we report that the intracellular trafficking of apoE4 is impaired in Neuro-2a cells and primary neurons, as shown by measuring fluorescence recovery after photobleaching. In Neuro-2a cells, more apoE4 than apoE3 molecules remained immobilized in the endoplasmic reticulum (ER) and the Golgi apparatus, and the lateral motility of apoE4 was significantly lower in the Golgi apparatus (but not in the ER) than that of apoE3. Likewise, the immobile fraction was larger, and the lateral motility was lower for apoE4 than apoE3 in mouse primary hippocampal neurons. ApoE4 with the R61T mutation, which abolishes apoE4 domain interaction, was less immobilized, and its lateral motility was comparable with that of apoE3. The trafficking impairment of apoE4 was also rescued by disrupting domain interaction with the small-molecule structure correctors GIND25 and PH002. PH002 also rescued apoE4-induced impairments of neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons. ApoE4 did not affect trafficking of amyloid precursor protein, another AD-related protein, through the secretory pathway. Thus, domain interaction renders more newly synthesized apoE4 molecules immobile and slows their trafficking along the secretory pathway. Correcting the pathological structure of apoE4 by disrupting domain interaction is a potential therapeutic approach to treat or prevent AD related to apoE4.

Apolipoprotein (apo) E4 is the major genetic risk factor for late-onset Alzheimer disease (AD). ApoE4 assumes a pathological conformation through an intramolecular interaction mediated by Arg-61 in the amino-terminal domain and Glu-255 in the carboxyl-terminal domain, referred to as apoE4 domain interaction. Because AD is associated with mitochondrial dysfunction, we examined the effect of apoE4 domain interaction on mitochondrial respiratory function. Steady-state amounts of mitochondrial respiratory complexes were examined in neurons cultured from brain cortices of neuron-specific enolase promoter-driven apoE3 (NSE-apoE3) or apoE4 (NSE-apoE4) transgenic mice. All subunits of mitochondrial respiratory complexes assessed were significantly lower in NSE-apoE4 neurons compared with NSE-apoE3 neurons. However, no significant differences in levels of mitochondrial complexes were detected between astrocytes expressing different apoE isoforms driven by the glial fibrillary acidic protein promoter, leading to our conclusion that the effect of apoE4 is neuron specific. In neuroblastoma Neuro-2A (N2A) cells, apoE4 expression reduced the levels of mitochondrial respiratory complexes I, IV, and V. Complex IV enzymatic activity was also decreased, lowering mitochondrial respiratory capacity. Mutant apoE4 (apoE4-Thr-61) lacking domain interaction did not induce mitochondrial dysfunction in N2A cells, indicating that the effect is specific to apoE4-expressing cells and dependent on domain interaction. Consistent with this finding, treatment of apoE4-expressing N2A cells with a small molecule that disrupts apoE4 domain interaction restored mitochondrial respiratory complex IV levels. These results suggest that pharmacological intervention with small molecules that disrupt apoE4 domain interaction is a potential therapeutic approach for apoE4-carrying AD subjects.

Stephen Freedman and colleagues performed a cost analysis of the routine administration of ondansetron in both the United States and Canada and show that its routine administration to eligible children in such settings could provide substantial benefit., Background The use of antiemetics for children with vomiting is one of the most controversial decisions in the treatment of gastroenteritis in developed countries. Ondansetron, a selective serotonin receptor antagonist, has been found to be effective in improving the success of oral rehydration therapy. However, North American and European clinical practice guidelines continue to recommend against its use, stating that evidence of cost savings would be required to support ondansetron administration. Thus, an economic analysis of the emergency department administration of ondansetron was conducted. The primary objective was to conduct a cost analysis of the routine administration of ondansetron in both the United States and Canada. Methods and Findings A cost analysis evaluated oral ondansetron administration to children presenting to emergency departments with vomiting and dehydration secondary to gastroenteritis from a societal and health care payer's perspective in both the US and Canada. A decision tree was developed that incorporated the frequency of vomiting, intravenous insertion, hospitalization, and emergency department revisits. Estimates of the monetary costs associated with ondansetron use, intravenous rehydration, and hospitalization were derived from administrative databases or emergency department use. The economic burden in children administered ondansetron plus oral rehydration therapy was compared to those not administered ondansetron employing deterministic and probabilistic simulations. We estimated the costs or savings to society and health care payers associated with the routine administration of ondansetron. Sensitivity analyses considered variations in costs, treatment effects, and exchange rates. In the US the administration of ondansetron to eligible children would prevent approximately 29,246 intravenous insertions and 7,220 hospitalizations annually. At the current average wholesale price, its routine administration to eligible children would annually save society US$65.6 million (US$49.1–US$81.1) and health care payers US$61.1 million (US$46.2–US$76.3). In Canada the administration of ondansetron to eligible children would prevent 4,065 intravenous insertions and 1,003 hospitalizations annually. Its routine administration would annually save society CDN$1.72 million (CDN$1.15–CDN$1.89) and the health care system CDN$1.18 million (CDN$0.88–CDN$1.41). Conclusions In countries where intravenous rehydration is often employed, the emergency department administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis results in significant monetary savings compared to a no-ondansetron policy. Please see later in the article for the Editors' Summary, Editors' Summary Background Although many episodes of gastroenteritis in children are mild and can be managed with oral fluids, including oral rehydration therapy (ORT), some cases are severe enough to require hospital admission for intravenous fluids. Administration of an antiemetic (a drug that reduces nausea and sickness) can be clinically effective, especially ondansetron, (a drug that belongs to a class of drugs known as selective serotonin receptor antagonists), which is safer than other antiemetics, such as promethazine and prochlorperazine, and in which there is good evidence to support its effectiveness in improving the success of ORT in children with gastroenteritis. Furthermore, studies have shown that administration of ondansetron decreases the risk of further vomiting, and hence the need for intravenous rehydration, and immediate hospital admission. However, despite the proven clinical benefits of ondansetron, clinical practice guidelines continue to recommend against the use of antiemetics in gastroenteritis because the evidence of cost savings is not yet clear. Last year, the UK's National Institute for Health and Clinical Excellence recommended that such a cost analysis should be a key research priority in pediatric gastroenteritis. Why Was This Study Done? This study—which is an economic analysis—was conducted in response to the various calls for the need to demonstrate the cost effectiveness of ondansetron in the management of pediatric gastroenteritis. What Did the Researchers Do and Find? The researchers analysed the costs of the administration of oral ondansetron in both the US and Canada, if routinely given to children with gastroenteritis-induced vomiting and dehydration in the emergency department setting. In addition, the researchers calculated the incremental cost of ondansetron per quality-adjusted life-year (QALY) gained from a health care perspective, compared to a regimen without ondansetron administration. The authors conducted a particular type of statistical analysis, known as decision tree analysis, to compare the two treatment options—administering ondansetron and not administering ondansetron in addition to ORT, with the clinical outcomes (further vomiting, intravenous rehydration, and hospitalization) determined on the basis of the documented efficacy of ondansetron. In addition, the researchers conducted their analyses from both the societal perspective (which included all costs, both direct—the resources required to produce a service; and indirect—productivity costs) and the health care payer's perspective. The US and Canada use similar medical resources, management programs, and treatment guidelines, but as prices differ dramatically (for example, the cost of hospitalization in the US is 8-fold higher than that in Canada), the researchers conducted a separate analysis for each country. On the basis of data from the US, the researchers found that the administration of ondansetron to eligible children would prevent approximately 29,246 intravenous insertions and 7,220 hospitalizations every year with an annual saving of US$65.6 million to society and US$61.1 million to payers of health care costs if this drug was given routinely. When using Canadian data, the researchers found that the administration of ondansetron to eligible children would prevent 4,065 intravenous insertions and 1,003 hospitalizations every year, with an annual saving of CDN$1.72 million to society and CDN$1.18 million to payers of health care costs if this drug was given routinely. What Do These Findings Mean? The results of this study show that the emergency department administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis results in significant monetary savings from both societal and health care perspectives compared to a policy that does not include ondansetron administration. Furthermore, the societal savings are probably an underestimate because in their model, the researchers assumed that only 10% of children with gastroenteritis presenting to an emergency department would meet eligibility criteria (in reality, this proportion would likely be higher). In addition, the researchers did not include estimates for ondansetron administration in the clinic or private office setting, as although such use is common, no estimates of eligibility and efficacy were available. Therefore, in addition to being clinically beneficial, the administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis is also economically advantageous. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000350. Patient UK and the US National Institutes of Health provide information for patients on ondansetron Patient UK provides information on gastroenteritis in children BBC Health also provides general information on gastroenteritis The Centers for Disease Control and Prevention contains a report on managing acute gastroenteritis among children

Alzheimer's disease neuropathology is characterized by key features that include the deposition of the amyloid beta peptide (Abeta) into plaques, the formation of neurofibrillary tangles, and the loss of neurons and synapses in specific brain regions. The loss of synapses, and particularly the associated presynaptic vesicle protein synaptophysin in the hippocampus and association cortices, has been widely reported to be one of the most robust correlates of Alzheimer's disease-associated cognitive decline. The beta-amyloid hypothesis supports the idea that Abeta is the cause of these pathologies. However, the hypothesis is still controversial, in part because the direct role of Abeta in synaptic degeneration awaits confirmation. In this study, we show that Abeta reduction by active or passive Abeta immunization protects against the progressive loss of synaptophysin in the hippocampal molecular layer and frontal neocortex of a transgenic mouse model of Alzheimer's disease. These results, substantiated by quantitative electron microscopic analysis of synaptic densities, strongly support a direct causative role of Abeta in the synaptic degeneration seen in Alzheimer's disease and strengthen the potential of Abeta immunotherapy as a treatment approach for this disease.