Significantly Longer Shedding of Norovirus Compared to Rotavirus and Adenovirus in Children with Acute Gastroenteritis.

Worldwide, acute gastroenteritis (AGE) is a major cause of morbidity and mortality in children under 5 years of age. Viruses, including norovirus, rotavirus, and enteric adenovirus, are the leading causes of pediatric AGE. In this prospective cohort study, we investigated the viral load and duration of shedding of norovirus, rotavirus, and adenovirus in stool samples collected from 173 children (median age: 15 months) with AGE who presented to emergency departments (EDs) across Canada on Day 0 (day of enrollment), and 5 and 28 days after enrollment. Quantitative RT-qPCR was performed to assess the viral load. On Day 0, norovirus viral load was significantly lower compared to that of rotavirus and adenovirus (p < 0.001). However, on Days 5 and 28, the viral load of norovirus was higher than that of adenovirus and rotavirus (p < 0.05). On Day 28, norovirus was detected in 70% (35/50) of children who submitted stool specimens, while rotavirus and adenovirus were detected in 52.4% (11/24) and 13.6% (3/22) of children (p < 0.001), respectively. Overall, in stool samples of children with AGE who presented to EDs, rotavirus and adenovirus had higher viral loads at presentation compared to norovirus; however, norovirus was shed in stool for the longest duration.

Liver transaminase concentrations in children with acute SARS-CoV-2 infection.

OBJECTIVE: To evaluate the relationship between SARS-CoV-2 infection and liver injury by comparing transaminase concentrations among children tested for SARS-CoV-2 and other respiratory viruses in pediatric emergency departments. DESIGN & METHODS: Eligible children were <18 years with suspected SARS-CoV-2, tested using molecular approaches in emergency departments between March 7, 2020, and June 15, 2021 (Pediatric Emergency Research Network), and between August 6, 2020, and February 22, 2022 (Pediatric Emergency Research Canada). We compared aspartate (AST) and alanine aminotransferase (ALT) concentrations at presentation for SARS-CoV-2 and other respiratory viruses through a multivariate linear regression model, with the natural log of serum transaminase concentrations as dependent variables. RESULTS: Of 16,892 enrolled children, 2,462 (14.6%) had transaminase concentrations measured; 4318 (25.6%) were SARS-CoV-2 positive, and 3932 (23.3%) were tested for additional respiratory viruses. Among study participants who had additional respiratory virus testing performed, the most frequently identified viruses were enterovirus/rhinovirus [8.7% (343/3,932)], respiratory syncytial virus [4.6% (181/3,932)], and adenovirus [2.6% (103/3,932)]. Transaminase concentrations were elevated in 25.6% (54/211) of children with isolated SARS-CoV-2 detection and 21.6% (117/541) of those with no virus isolated; P = 0.25. In the multivariable model, isolated SARS-CoV-2 detection was not associated with elevated ALT (adjusted geometric mean ratio (IU/L): 0.96; 95%Confidence Interval (CI): 0.84, 1.08) or AST (adjusted geometric mean ratio (IU/L): 1.03; 95%CI: 0.92, 1.16) concentrations, with negative respiratory panel as the referent group. Ninety-day follow-up was completed in 82.2% (3,550/4,318) of SARS-CoV-2 positive children; no cases of new-onset liver disease were reported. CONCLUSION: Among those tested, transaminase concentrations did not vary between SARS-CoV-2-positive children and those with a negative respiratory viral panel. In multivariate analysis, SARS-CoV-2 infection was not associated with increased initial transaminase concentrations compared to other respiratory viruses.

Intravenous ketorolac versus morphine in children presenting with suspected appendicitis: a pilot single-centre non-inferiority randomised controlled trial.

OBJECTIVES: Despite a lack of evidence demonstrating superiority to non-steroidal anti-inflammatory drugs, like ketorolac, that are associated with lower risk of harms, opioids remain the most prescribed analgesic for acute abdominal pain. In this pilot trial, we will assess the feasibility of a definitive trial comparing ketorolac with morphine in children with suspected appendicitis. We hypothesise that our study will be feasible based on a 40% consent rate. METHODS AND ANALYSIS: A single-centre, non-inferiority, blinded (participant, clinician, investigators and outcome assessors), double-dummy randomised controlled trial of children aged 6-17 years presenting to a paediatric emergency department with ≤5 days of moderate to severe abdominal pain (≥5 on a Verbal Numerical Rating Scale) and are investigated for appendicitis. We will use variable randomised blocks of 4-6 and allocate participants in 1:1 ratio to receive either intravenous (IV) ketorolac 0.5 mg/kg+IV morphine placebo or IV morphine 0.1 mg/kg+IV ketorolac placebo. Analgesic co-intervention will be limited to acetaminophen (commonly used as first-line therapy). Participants in both groups will be allowed rescue therapy (morphine 0.5 mg/kg) within 60 min of our intervention. Our primary feasibility outcome is the proportion of eligible patients approached who provide informed consent and are enrolled in our trial. Our threshold for feasibility will be to achieve a ≥40% consent rate, and we will enrol 100 participants into our pilot trial. ETHICS AND DISSEMINATION: Our study has received full approval by the Hamilton integrated Research Ethics Board. We will disseminate our study findings at national and international paediatric research conferences to garner interest and engage sites for a future multicentre definitive trial. TRIAL REGISTRATION: NCT04528563, Pre-results.

Epidemiology and management of abdominal injuries in children.

BACKGROUND: Although more guideline-adherent care has been described in pediatric compared to adult trauma centers, we aimed to provide a more detailed characterization of management and resource utilization of children with intra-abdominal injury (IAI) within pediatric centers. Our primary objective was to describe the epidemiology, diagnostic evaluation, and management of children with IAI across U.S. children's hospitals. Our secondary objective was to describe the interhospital variation in surgical management of children with IAI. METHODS: We conducted a cross-sectional study of 33 hospitals in the Pediatric Health Information System. We included children aged <18 years evaluated in the emergency department from 2010 to 2019 with IAI, as defined by ICD coding, and who underwent an abdominal computed tomography (CT). Our primary outcome was abdominal surgery. We categorized IAI by organ system and described resource utilization data. We used generalized linear regression to calculate adjusted hospital-level proportions of abdominal surgery, with a random effect for hospital. RESULTS: We studied 9265 children with IAI. Median (IQR) age was 9.0 (6.0-13.0) years. Abdominal surgery was performed in 16% (n = 1479) of children, with the lowest proportion of abdominal surgery observed in children aged <5 years. Liver (38.6%) and spleen (32.1%) were the most common organs injured. A total of 3.1% of children with liver injuries and 2.8% with splenic injuries underwent abdominal surgery. Although there was variation in rates of surgery across hospitals (p < 0.001), only three of 33 hospitals had rates that were statistically different from the aggregate mean of 16%. CONCLUSIONS: Most children with IAI are managed nonoperatively, and most children's hospitals manage children with IAI similarly. These data can be used to inform future benchmarking efforts across hospitals to assess concordance with guidelines for the management of children with IAI.

Pathogen-Specific Effects of Probiotics in Children With Acute Gastroenteritis Seeking Emergency Care: A Randomized Trial.

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 <72 hours and <7 days in the Canadian and US studies, respectively. Participants received either placebo or a probiotic preparation (Canada-Lactobacillus rhamnosus R0011/Lactobacillus helveticus R0052; US-L. rhamnosus GG). The primary outcome was post-intervention moderate-to-severe disease (ie, ≥9 on the Modified Vesikari Scale [MVS] score). 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.

A Clinical Epidemiology and Molecular Attribution Evaluation of Adenoviruses in Pediatric Acute Gastroenteritis: a Case-Control Study.

The objective of this study was to characterize the etiological role of human adenovirus (HAdV) serotypes in pediatric gastroenteritis. Using a case-control design, we compared the frequencies of HAdV serotypes between children with ≥3 episodes of vomiting or diarrhea within 24 h and <7 days of symptoms (i.e., cases) and those with no infectious symptoms (i.e., controls). Stool samples and/or rectal swabs underwent molecular serotyping with cycle threshold (Ct) values provided by multiplex real-time reverse transcription-PCR testing. Cases without respiratory symptoms were analyzed to calculate the proportion of disease attributed to individual HAdV serotypes (i.e., attributable fraction). Between December 2014 and August 2018, adenoviruses were detected in 18.8% (629/3,347) of cases and 7.2% (97/1,355) of controls, a difference of 11.6% (95% confidence interval [CI], 9.6%, 13.5%). In 96% (95% CI, 92 to 98%) of HAdV F40/41 detections, the symptoms could be attributed to the identified serotype; when serotypes C1, C2, C5, and C6 were detected, they were responsible for symptoms in 52% (95% CI, 12 to 73%). Ct values were lower among cases than among controls (P < 0.001). HAdV F40/41, C2, and C1 accounted for 59.7% (279/467), 17.6% (82/467), and 12.0% (56/467) of all typed cases, respectively. Among cases, Ct values were lower for F40/41 serotypes than for non-F40/41 serotypes (P < 0.001). HAdV F40/41 serotypes account for the majority of HAdV-positive gastroenteritis cases, and when detected, disease is almost always attributed to infection with these pathogens. Non-F40/41 HAdV species have a higher frequency of asymptomatic infection and may not necessarily explain gastroenteritis symptoms. Real-time quantitative PCR may be useful in differentiating asymptomatic shedding from active infection.

Diagnostic Test Accuracy of Commercial Tests for Detection of Shiga Toxin-Producing Escherichia coli: A Systematic Review and Meta-Analysis.

BACKGROUND: Rapid detection of Shiga toxin-producing Escherichia coli (STEC) enables appropriate monitoring and treatment. We synthesized available evidence to compare the performance of enzyme immunoassay (EIA) and PCR tests for the detection of STEC. METHODS: We searched published and gray literature for studies of STEC EIA and/or PCR diagnostic test accuracy relative to reference standards including at least one nucleic acid amplification test. Two reviewers independently screened studies, extracted data, and assessed quality with the second version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Bivariate random effects models were used to meta-analyze the clinical sensitivity and specificity of commercial EIA and PCR STEC diagnostic tests, and summary receiver operator characteristic curves were constructed. We evaluated the certainty of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We identified 43 articles reflecting 25 260 specimens. Meta-analysis of EIA and PCR accuracy included 25 and 22 articles, respectively. STEC EIA pooled sensitivity and specificity were 0.681 (95% CI, 0.571-0.773; very low certainty of evidence) and 1.00 (95% CI, 0.998-1.00; moderate certainty of evidence), respectively. STEC PCR pooled sensitivity and specificity were 1.00 (95% CI, 0.904-1.00; low certainty of evidence) and 0.999 (95% CI, 0.997-0.999; low certainty of evidence), respectively. Certainty of evidence was downgraded because of high risk of bias. CONCLUSIONS: PCR tests to identify the presence of STEC are more sensitive than EIA tests, with no meaningful loss of specificity. However, given the low certainty of evidence, our results may overestimate the difference in performance.

Low-Value Diagnostic Imaging Use in the Pediatric Emergency Department in the United States and Canada.

IMPORTANCE: Diagnostic imaging overuse in children evaluated in emergency departments (EDs) is a potential target for reducing low-value care. Variation in practice patterns across Canada and the United States stemming from organization of care, payment structures, and medicolegal environments may lead to differences in imaging overuse between countries. OBJECTIVE: To compare overall and low-value use of diagnostic imaging across pediatric ED visits in Ontario, Canada, and the United States. DESIGN, SETTING, AND PARTICIPANTS: This study used administrative health databases from 4 pediatric EDs in Ontario and 26 in the United States in calendar years 2006 through 2016. Individuals 18 years and younger who were discharged from the ED, including after visits for diagnoses in which imaging is not routinely recommended (eg, asthma, bronchiolitis, abdominal pain, constipation, concussion, febrile convulsion, seizure, and headache) were included. Data analysis occurred from April 2018 to October 2018. EXPOSURES: Diagnostic imaging use. MAIN OUTCOME AND MEASURES: Overall and condition-specific low-value imaging use. Three-day and 7-day rates of hospital admission and those admissions resulting in intensive care, surgery, or in-hospital mortality were assessed as balancing measures. RESULTS: A total of 1 783 752 visits in Ontario and 21 807 332 visits in the United States were analyzed. Compared with visits in the United States, those in Canada had lower overall use of head computed tomography (Canada, 22 942 [1.3%] vs the United States, 753 270 [3.5%]; P < .001), abdomen computed tomography (5626 [0.3%] vs 211 018 [1.0%]; P < .001), chest radiographic imaging (208 843 [11.7%] vs 3 408 540 [15.6%]; P < .001), and abdominal radiographic imaging (77 147 [4.3%] vs 3 607 141 [16.5%]; P < .001). Low-value imaging use was lower in Canada than the United States for multiple indications, including abdominal radiographic images for constipation (absolute difference, 23.7% [95% CI, 23.2%-24.3%]) and abdominal pain (20.6% [95% CI, 20.3%-21.0%]) and head computed tomographic scans for concussion (22.9% [95% CI, 22.3%-23.4%]). Abdominal computed tomographic use for constipation and abdominal pain, although low overall, were approximately 10-fold higher in the United States (0.1% [95% CI, 0.1%-0.2%] vs 1.2% [95% CI, 1.2%-1.2%]) and abdominal pain (0.8% [95% CI, 0.7%-0.9%] vs 7.0% [95% CI, 6.9%-7.1%]). Rates of 3-day and 7-day post-ED adverse outcomes were similar. CONCLUSIONS AND RELEVANCE: Low-value imaging rates were lower in pediatric EDs in Ontario compared with the United States, particularly those involving ionizing radiation. Lower use of imaging in Canada was not associated with higher rates of adverse outcomes, suggesting that usage may be safely reduced in the United States.

Performance of commercial tests for molecular detection of Shiga toxin-producing Escherichia coli (STEC): a systematic review and meta-analysis protocol.

INTRODUCTION: Rapid detection of Shiga toxin-producing Escherichia 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 ANALYSIS: The 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 DISSEMINATION: Ethics 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 NUMBER: CRD42018099119.

Diagnostic Interpretation Guidance for Pediatric Enteric Pathogens: A Modified Delphi Consensus Process.

BACKGROUND: We sought to develop diagnostic test guidance definitions for pediatric enteric infections to facilitate the interpretation of positive test results in the era of multianalyte molecular diagnostic test platforms. METHODS: We employed a systematic, two-phase, modified Delphi consensus process consisting of three web-based surveys and an expert panel face-to-face meeting. In phase 1, we surveyed an advisory panel of North American experts to select pathogens requiring diagnostic test guidance definition development. In phase 2, we convened a 14-member expert panel to develop, refine, and select the final definitions through two web-based questionnaires interspersed with a face-to-face meeting. Both questionnaires asked panelists to rate the degree to which they agreed that if the definition is met the pathogen is likely to be causative of clinical illness. RESULTS: The advisory panel survey identified 19 pathogens requiring definitions. In the expert panel premeeting survey, 13 of the 19 definitions evaluated were rated as being highly likely ("agree" or "strongly agree") to be responsible for acute gastroenteritis symptoms by ≥67% of respondent panel members. The definitions for the remaining six pathogens (Aeromonas, Clostridium difficile, Edwardsiella, nonenteric adenovirus, astrovirus, and Entamoeba histolytica) were indeterminate. After the expert panel meeting, only two of the modified definitions, C. difficile and E. histolytica/dispar, failed to achieve the a priori specified threshold of ≥67% agreement. CONCLUSIONS: We developed diagnostic test guidance definitions to assist healthcare providers for 17 enteric pathogens. We identified two pathogens that require further research and definition development.

Identification of Enteric Viruses in Oral Swabs from Children with Acute Gastroenteritis.

Stool is the diagnostic specimen of choice to identify enteropathogens in pediatric gastroenteritis. However, stool collection is challenging and its diagnostic characteristics in patients with isolated vomiting are unknown. Therefore, we evaluated if oral swabs are a suitable alternative specimen to stools. In total, 738 oral swabs and 577 stool specimens were collected from 738 children with vomiting and/or diarrhea. All specimens were tested by a laboratory-developed quantitative RT-PCR Gastroenteritis Virus Panel; 150 oral swabs and 577 stool specimens were tested by the commercial gastroenteritis pathogen panel. The Gastroenteritis Virus Panel identified adenovirus (n = 38), norovirus (n = 21), and rotavirus (n = 16) commonly in oral swabs. In stool specimens, rotavirus (n = 139), norovirus (n = 86), and adenovirus (n = 69) were detected commonly. Compared with stool specimens, the specificity of oral swabs was 99% (95% CI, 96%-100%); the sensitivity of oral swabs was 18% (95% CI, 14%-22%) for the detection of enteric viruses. The Gastrointestinal Pathogen Panel identified enteric bacteria and parasites in stool but not in oral swabs. Given the lower sensitivity of oral swabs, stool remains a preferable specimen to detect enteric viruses. However, with their high specificity, oral swabs can be considered as a suitable specimen if stool specimens are unavailable. Nevertheless, negative oral swabs require a confirmative test of stool specimens.

Emergency Department Use of Computed Tomography for Children with Ventricular Shunts.

OBJECTIVES: To quantify rates and variation in emergency department (ED) cranial computed tomography (CT) utilization in children with ventricular shunts, estimate radiation exposure, and evaluate the association between CT utilization and shunt revision. STUDY DESIGN: Retrospective longitudinal cohort study of ED visits from 2003-2013 in children 0-18 years old with initial shunt placement in 2003. Data were examined from 31 hospitals in the Pediatric Health Information System. Main outcomes were cranial CT performed during an ED visit, estimated cumulative effective radiation dose, and shunt revision within 7 days. Multivariable regression modeled the relationship between patient- and hospital-level covariates and CT utilization. RESULTS: The 1319 children with initial shunt placed in 2003 experienced 6636 ED visits during the subsequent decade. A cranial CT was obtained in 49.4% of all ED visits; 19.9% of ED visits with CT were associated with a shunt revision. Approximately 6% of patients received ≥10 CTs, accounting for 37.2% of all ED visits with a CT. The mean number of CTs per patient varied nearly 20-fold across hospitals; the individual hospital accounted for the most variation in CT utilization. The median (IQR) cumulative effective radiation dose was 7.2 millisieverts (3.6-14.0) overall, and 33.4 millisieverts (27.2-43.8) among patients receiving ≥10 CTs. CONCLUSIONS: A CT scan was obtained in half of ED visits for children with a ventricular shunt, with wide variability in utilization by hospitals. Strategies are needed to identify children at risk of shunt malfunction to reduce variability in CT utilization and radiation exposure in the ED.

Radiation exposure from imaging tests in pediatric emergency medicine: a survey of physician knowledge and risk disclosure practices.

BACKGROUND: Disclosing potential future malignancy risks from diagnostic tests that expose children to ionizing radiation in the emergency department may be challenging. OBJECTIVES: We determined the proportion of pediatric emergency medicine (PEM) physicians who are aware of current malignancy risk estimates associated with head computed tomography (CT). We also examined reported risk and strategy disclosure practice patterns. METHODS: We conducted an online survey of members of a national Canadian PEM physician association using a modified Dillman's technique. RESULTS: Of 156 eligible participants, 126 (80.8%) responded to the survey. Of the 126 respondents, 124 (98.4%; 95% confidence interval [CI] 96.2-100) reported that there is a potential malignancy risk associated with head CT, and 46 (36.5%; 95% CI 28.1-44.9) correctly identified the best current estimate of this risk. The majority, 68.8% (95% CI 60.7-76.9), reported disclosing these possible risks "most of the time/almost always." Although some physicians reported varying their strategy with the clinical scenario, the most frequently selected disclosure strategies were a comparison with chest radiographs and everyday risks. Frequently cited barriers to informed risk-benefit discussions were concerns that parents will worry excessively about cancer (27.8%), discussions during the treatment of a critically ill child (23.8%), and a concern that parents may not want the test (15.9%). CONCLUSIONS: Approximately one-third of pediatric emergency physicians were able to identify the best available estimate of the malignancy risk from a head CT. Although there are some barriers, many PEM physicians report regularly participating in risk-benefit disclosures.

Parental knowledge of potential cancer risks from exposure to computed tomography.

OBJECTIVE: Computed tomography (CT) imaging of children is increasing in emergent settings without an understanding of parental knowledge of potential cancer risks. In children with head injuries, our primary objective was to determine the proportion of parents who were aware of the potential of CT to increase a child's lifetime risk of malignancy. We also examined willingness to proceed with recommended CT after risk disclosure and preference to be informed of potential risks. METHODS: This was a prospective cross-sectional survey of parents whose children presented to a tertiary care pediatric emergency department with a head injury. Survey questions were derived and validated by using expert opinion, available literature, and pre- and pilot testing of questions with the target audience. RESULTS: Of the 742 enrolled parents, 454 (61.2%) were female and 594 (80.0%) were aged 31 to 50 years. Importantly, 357 (46.8%) were aware of the potential for an increased lifetime malignancy risk from CT. Before risk estimate provision, the proportion of parents "very willing/willing" to proceed with head CT was 90.4%; after disclosure, willingness decreased to 69.6% (P < .0001), and 42 (5.6%) would refuse the CT. Of note, 673 (90.3%) wished to be informed of potential malignancy risks. CONCLUSIONS: Approximately half of the participating parents were aware of the potential increased lifetime malignancy risk associated with head CT imaging. Willingness to proceed with CT testing was reduced after risk disclosure but was a significant barrier for a small minority of parents. Most parents wanted to be informed of potential malignancy risks before proceeding with imaging.

Rapid versus standard intravenous rehydration in paediatric gastroenteritis: pragmatic blinded randomised clinical trial.

OBJECTIVE: To determine if rapid rather than standard intravenous rehydration results in improved hydration and clinical outcomes when administered to children with gastroenteritis. DESIGN: Single centre, two arm, parallel randomised pragmatic controlled trial. Blocked randomisation stratified by site. Participants, caregivers, outcome assessors, investigators, and statisticians were blinded to the treatment assignment. SETTING: Paediatric emergency department in a tertiary care centre in Toronto, Canada. PARTICIPANTS: 226 children aged 3 months to 11 years; complete follow-up was obtained on 223 (99%). Eligible children were aged over 90 days, had a diagnosis of dehydration secondary to gastroenteritis, had not responded to oral rehydration, and had been prescribed intravenous rehydration. Children were excluded if they weighed less than 5 kg or more than 33 kg, required fluid restriction, had a suspected surgical condition, or had an insurmountable language barrier. Children were also excluded if they had a history of a chronic systemic disease, abdominal surgery, bilious or bloody vomit, hypotension, or hypoglycaemia or hyperglycaemia. INTERVENTIONS: Rapid (60 mL/kg) or standard (20 mL/kg) rehydration with 0.9% saline over an hour; subsequent fluids administered according to protocol. PRIMARY OUTCOME: clinical rehydration, assessed with a validated scale, two hours after the start of treatment. SECONDARY OUTCOMES: prolonged treatment, mean clinical dehydration scores over the four hour study period, time to discharge, repeat visits to emergency department, adequate oral intake, and physician's comfort with discharge. Data from all randomised patients were included in an intention to treat analysis. RESULTS: 114 patients were randomised to rapid rehydration and 112 to standard. One child was withdrawn because of severe hyponatraemia at baseline. There was no evidence of a difference between the rapid and standard rehydration groups in the proportions of participants who were rehydrated at two hours (41/114 (36%) v 33/112 (30%); difference 6.5% (95% confidence interval -5.7% to 18.7%; P=0.32). The results did not change after adjustment for weight, baseline dehydration score, and baseline pH (odds ratio 1.8, 0.90 to 3.5; P=0.10). The rates of prolonged treatment were similar (52% rapid v 43% standard; difference 8.9%, 21% to -5%; P=0.19). Although dehydration scores were similar throughout the study period (P=0.96), the median time to discharge was longer in the rapid group (6.3 v 5.0 hours; P=0.03). CONCLUSIONS: There are no relevant clinical benefits from the administration of rapid rather than standard intravenous rehydration to haemodynamically stable children deemed to require intravenous rehydration. Trail registration Clinical Trials NCT00392145.

Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors.

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 E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease.

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.

Pediatric myocarditis: emergency department clinical findings and diagnostic evaluation.

OBJECTIVE: The goal was to determine, in children with myocarditis, the frequency of various presenting symptoms and the sensitivity of clinical and laboratory investigations routinely available in the emergency department. METHODS: We performed a retrospective review of all patients < 18 years of age who were diagnosed as having myocarditis at our institution between May 2000 and May 2006 and who initially presented to an emergency department. Patients were categorized as having definite myocarditis (positive endomyocardial biopsy results) or probable myocarditis (diagnosis assigned by a pediatric cardiologist on the basis of history, physical examination, and investigation results in the absence of an endomyocardial biopsy or in the presence of negative biopsy results). All patients were assigned a predominant category of symptoms at presentation on the basis of criteria defined a priori. RESULTS: There were 16 cases of definite myocarditis and 15 cases of probable myocarditis. The age distribution was nonnormal, with peaks among children < or = 3 years and > or = 16 years of age. Of 14 patients who were seen by a physician before being diagnosed with myocarditis, 57% were originally diagnosed as having pneumonia or asthma. Thirty-two percent of patients presented with predominantly respiratory symptoms, 29% had cardiac symptoms, and 6% had gastrointestinal symptoms. Although evidence of cardiac dysfunction was frequently present in the form of respiratory distress, only a minority of children had evidence of hepatomegaly or abnormal cardiac examination results. The sensitivities of electrocardiograms and chest radiographs as screening tests were 93% and 55%, respectively. Among laboratory tests studied, aspartate aminotransferase measurement was the most sensitive (sensitivity: 85%). CONCLUSIONS: Children with myocarditis present with symptoms that can be mistaken for other types of illnesses; respiratory presentations were most common. When clinical suspicion of myocarditis exists, chest radiography alone is an insufficient screening test. All children should undergo electrocardiography. Aspartate aminotransferase testing may be a useful adjunctive investigation.

Transient bulging fontanelle after vaccination: case report and review of the vaccine adverse event reporting system.

OBJECTIVE: To describe the features of transient bulging fontanelle (TBF) after vaccination. STUDY DESIGN: We searched the Vaccine Adverse Event Reporting System database for reports describing bulging fontanelle. We defined a definite TBF case as a patient with a bulging fontanelle, normal neuroimaging and cerebrospinal fluid analysis, and absence of a depressed level of consciousness, focal neurologic findings, or identified cause. Follow-up had to reveal normal development. Probable cases lacked either lumbar puncture or neuroimaging or both but met all other criteria. RESULTS: We identified 18 patients with definite or probable TBF. The median age at presentation was 4.5 months, interval from vaccination to symptom onset was 18 hours, and time to resolution was 3 days. Fifteen children were febrile. CONCLUSIONS: We cannot conclude that vaccines cause TBF. Further controlled studies are necessary. Even if further research verifies TBF as a rare side effect, immunization benefits would still vastly outweigh this hypothetical risk. However, confirmation of a vaccine association could modify the management of infants who develop TBF after immunizations.

Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer's disease.

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.