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Abstract Background Shiga toxin-producing E. coli (STEC) infections affect children and adults worldwide, and treatment remain solely supportive. Up to 15–20% of children infected by high-risk STEC (i.e., E. coli that produce Shiga toxin 2) develop hemolytic anemia, thrombocytopenia, and kidney failure (i.e., hemolytic uremic syndrome (HUS)), over half of whom require acute dialysis and 3% die. Although no therapy is widely accepted as being able to prevent the development of HUS and its complications, several observational studies suggest that intravascular volume expansion (hyperhydration) may prevent end organ damage. A randomized trial is needed to confirm or refute this hypothesis. Methods We will conduct a pragmatic, embedded, cluster-randomized, crossover trial in 26 pediatric institutions to determine if hyperhydration, compared to conservative fluid management, improves outcomes in 1040 children with high-risk STEC infections. The primary outcome is major adverse kidney events within 30 days (MAKE30), a composite measure that includes death, initiation of new renal replacement therapy, or persistent kidney dysfunction. Secondary outcomes include life-threatening, extrarenal complications, and development of HUS. Pathway eligible children will be treated per institutional allocation to each pathway. In the hyperhydration pathway, all eligible children are hospitalized and administered 200% maintenance balanced crystalloid fluids up to targets of 10% weight gain and 20% reduction in hematocrit. Sites in the conservative fluid management pathway manage children as in- or outpatients, based on clinician preference, with the pathway focused on close laboratory monitoring, and maintenance of euvolemia. Based on historical data, we estimate that 10% of children in our conservative fluid management pathway will experience the primary outcome. With 26 clusters enrolling a mean of 40 patients each with an intraclass correlation coefficient of 0.11, we will have 90% power to detect a 5% absolute risk reduction. Discussion HUS is a devastating illness with no treatment options. This pragmatic study will determine if hyperhydration can reduce morbidity associated with HUS in children with high-risk STEC infection. Trial registration ClinicalTrials.gov NCT05219110 . Registered on February 1, 2022.

ABSTRACT Advances in diagnostic microbiology allow for the rapid identification of a broad range of enteropathogens; such knowledge can inform care and reduce testing. We conducted a randomized, unblinded trial in a tertiary-care pediatric emergency department. Participants had stool (and rectal swabs if stool was not immediately available) tested using routine microbiologic approaches or by use of a device (BioFire FilmArray gastrointestinal panel), which identifies 22 pathogens with a 1-h instrument turnaround time. Participants were 6 months to

Background Measurement of SARS-CoV-2 antibody seropositivity is important to accurately understand exposure to infection and/or vaccination in specific populations. This study aimed to estimate the serologic response to SARS-CoV-2 virus infection and vaccination in children in Calgary, Alberta over a two-year period. Methods Children with or without prior SARS-CoV-2 infections, were enrolled in Calgary, Canada in 2020. Venous blood was sampled 4 times from July 2020 to April 2022 for SARS-CoV-2 nucleocapsid and spike antibodies. Demographic and clinical information was obtained including SARS-CoV-2 testing results and vaccination records. Results 1035 children were enrolled and 88.9% completed all 4 visits; median age 9 years (IQR: 5,13); 519 (50.1%) female; and 815 (78.7%) Caucasian. Before enrolment, 118 (11.4%) had confirmed or probable SARS-CoV-2. By April 2022, 39.5% of previously uninfected participants had a SARS-CoV-2 infection. Nucleocapsid antibody seropositivity declined to 16.4% of all infected children after more than 200 days post diagnosis. Spike antibodies remained elevated in 93.6% of unvaccinated infected children after more than 200 days post diagnosis. By April 2022, 408 (95.6%) children 12 years and older had received 2 or more vaccine doses, and 241 (61.6%) 5 to 11 year-old children had received 2 vaccine doses. At that time, all 685 vaccinated children had spike antibodies, compared with 94/176 (53.4%) of unvaccinated children. Conclusions In our population, after the first peak of Omicron variant infections and introduction of COVID-19 vaccines for children, all vaccinated children, but just over one-half of unvaccinated children, had SARS-CoV-2 spike antibodies indicating infection and/or vaccination, highlighting the benefit of vaccination. It is not yet known whether a high proportion of seropositivity at the present time predicts sustained population-level protection against future SARS-CoV-2 transmission, infection or severe COVID-19 outcomes in children.

Abstract 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

ABSTRACT The application of clinical diagnostics for gastroenteritis in children has implications for a broad collection of stakeholders, impacting clinical care, communicable disease control, and laboratory utilization. To support diagnostic stewardship as gastroenteritis testing options continue to advance, it is critical to understand which enteropathogens constitute priorities for testing across stakeholder groups. Using a modified Delphi technique, we elicited opinions of subject matter experts to determine clinical and public health testing priorities. There was a high level of overall agreement (≥80%) among stakeholders (final round n = 15) that testing was important for Campylobacter, Escherichia coli O157 and other Shiga toxin-producing E. coli, Salmonella, Shigella, Vibrio, Yersinia, norovirus, and rotavirus. Immunocompromised children were identified as a special population that warranted the additional testing of three to four bacterial and parasitic targets. To support these clinical and public health testing priorities, diagnostic stewardship strategies can be employed, such as educating clinicians, developing new decision support tools, and using multiplex testing in concert with selective result reporting and annotation. IMPORTANCE Children with diarrhea and vomiting who seek care can be infected with a wide variety of infectious agents. This study reports findings from a survey of clinical, public health, and laboratory subject matter experts on the infectious agents that are most important to test for. The majority agreed on the importance of testing children likely infected with several bacterial agents, as well as two common viruses. Although confirming a child is positive for a viral agent is unlikely to change clinical care, participants noted the importance of monitoring these viruses for public health purposes. To avoid over-testing children, however, these results should be used to support diagnostic stewardship strategies and design new decision support tools.

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.

ObjectiveTo estimate the proportion of SARS-CoV-2 infected children experiencing hospitalization, intensive care unit (ICU) admission, severe outcomes, and death.Data SourcesPubMed, Embase, and MedRxiv were searched for studies published between December 1, 2019 and May 28, 2021. References of relevant systematic reviews were also screened.Study SelectionWe included cohort or cross-sectional studies reporting on at least one outcome measure (i.e., hospitalization, ICU admission, severe outcomes, death) for ≥100 children ≤21 years old within 28 days of SARS-CoV-2 positivity; no language restrictions were applied.Data Extraction and SynthesisTwo independent reviewers performed data extraction and risk of bias assessment. Estimates were pooled using random effects models. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.Main Outcomes and MeasuresPercentage of SARS-CoV-2 positive children experiencing hospitalization, ICU admission, severe outcome, and death.Results118 studies representing 3,324,851 SARS-CoV-2 infected children from 68 countries were included. Community-based studies (N = 48) reported that 3.3% (95%CI: 2.7–4.0%) of children were hospitalized, 0.3% (95%CI: 0.2–0.6%) were admitted to the ICU, 0.1% (95%CI: 0.0–2.2%) experienced a “severe” outcome and 0.02% (95%CI: 0.001–0.05%) died. Hospital-based screening studies (N = 39) reported that 23.9% (95%CI: 19.0–29.2%) of children were hospitalized, 2.9% (95%CI: 2.1–3.8%) were admitted to the ICU, 1.3% (95%CI: 0.5–2.3%) experienced a severe outcome, and 0.2% (95%CI: 0.02–0.5%) died. Studies of hospitalized children (N = 31) reported that 10.1% (95%CI: 6.1–14.9%) of children required ICU admission, 4.2% (95%CI: 0.0–13.8%) had a severe outcome and 1.1% (95%CI: 0.2–2.3%) died. Low risk of bias studies, those from high-income countries, and those reporting outcomes later in the pandemic presented lower estimates. However, studies reporting outcomes after May 31, 2020, compared to earlier publications, had higher proportions of hospitalized patients requiring ICU admission and experiencing severe outcomes.Conclusion and RelevanceAmong children tested positive for SARS-CoV-2, 3.3% were hospitalized, with rates being higher early in the pandemic. Severe outcomes, ICU admission and death were uncommon, however estimates vary by study population, pandemic timing, study risk of bias, and economic status of the country.Systematic Review RegistrationPROSPERO, identifier [CRD42021260164].

The analysis of large, multisite neuroimaging datasets provides a promising means for robust characterization of brain networks that can reduce false positives and improve reproducibility. However, the use of different MRI scanners introduces variability to the data. Managing those sources of variability is increasingly important for the generation of accurate group-level inferences. ComBat is one of the most promising tools for multisite (multiscanner) harmonization of structural neuroimaging data, but no study has examined its application to graph theory metrics derived from the structural brain connectome. The present work evaluates the use of ComBat for multisite harmonization in the context of structural network analysis of diffusion-weighted scans from the Advancing Concussion Assessment in Pediatrics (A-CAP) study. Scans were acquired on six different scanners from 484 children aged 8.00–16.99 years [Mean = 12.37 ± 2.34 years; 289 (59.7%) Male] ~10 days following mild traumatic brain injury (n = 313) or orthopedic injury (n = 171). Whole brain deterministic diffusion tensor tractography was conducted and used to construct a 90 x 90 weighted (average fractional anisotropy) adjacency matrix for each scan. ComBat harmonization was applied separately at one of two different stages during data processing, either on the (i) weighted adjacency matrices (matrix harmonization) or (ii) global network metrics derived using unharmonized weighted adjacency matrices (parameter harmonization). Global network metrics based on unharmonized adjacency matrices and each harmonization approach were derived. Robust scanner effects were found for unharmonized metrics. Some scanner effects remained significant for matrix harmonized metrics, but effect sizes were less robust. Parameter harmonized metrics did not differ by scanner. Intraclass correlations (ICC) indicated good to excellent within-scanner consistency between metrics calculated before and after both harmonization approaches. Age correlated with unharmonized network metrics, but was more strongly correlated with network metrics based on both harmonization approaches. Parameter harmonization successfully controlled for scanner variability while preserving network topology and connectivity weights, indicating that harmonization of global network parameters based on unharmonized adjacency matrices may provide optimal results. The current work supports the use of ComBat for removing multiscanner effects on global network topology.

Compositional analysis of the intestinal microbiome in pre-schoolers is understudied. Effects of probiotics on the gut microbiota were evaluated in children under 4-years-old presenting to an emergency department with acute gastroenteritis. Included were 70 study participants (n=32 placebo, n=38 probiotics) with stool specimens at baseline (day 0), day 5, and after a washout period (day 28). Microbiota composition and deduced functions were profiled using 16S ribosomal RNA sequencing and predictive metagenomics, respectively. Probiotics were detected at day 5 of administration but otherwise had no discernable effects, whereas detection of bacterial infection (P

Abstract Background Acute gastroenteritis is a leading cause of emergency department visits and hospitalizations among children in North America. Oral-rehydration therapy is recommended for children with mild-to-moderate dehydration, but children who present with vomiting are frequently offered intravenous rehydration in the emergency department (ED). Recent studies have demonstrated that the anti-emetic ondansetron can reduce vomiting, intravenous rehydration, and hospitalization when administered in the ED to children with dehydration. However, there is little evidence of additional benefit from prescribing ondansetron beyond the initial ED dose. Moreover, repeat dosing may increase the frequency of diarrhea. Despite the lack of evidence and potential adverse side effects, many physicians across North America provide multiple doses of ondansetron to be taken following ED disposition. Thus, the Multi-Dose Oral Ondansetron for Pediatric Gastroenteritis (DOSE-AGE) trial will evaluate the effectiveness of prescribing multiple doses of ondansetron to treat acute gastroenteritis-associated vomiting. This article specifies the statistical analysis plan (SAP) for the DOSE-AGE trial and was submitted before the outcomes of the study were available for analysis. Methods/design The DOSE-AGE study is a phase III, 6-center, placebo-controlled, double-blind, parallel design randomized controlled trial designed to determine whether participants who are prescribed multiple doses of oral ondansetron to administer, as needed, following their ED visit have a lower incidence of experiencing moderate-to-severe gastroenteritis, as measured by the Modified Vesikari Scale score, compared with a placebo. To assess safety, the DOSE-AGE trial will investigate the frequency and maximum number of diarrheal episodes following ED disposition, and the occurrence of palpitations, pre-syncope/syncope, chest pain, arrhythmias, and serious adverse events. For the secondary outcomes, the DOSE-AGE trial will investigate the individual elements of the Modified Vesikari Scale score and caregiver satisfaction with the therapy. Discussion The DOSE-AGE trial will provide evidence on the effectiveness of multiple doses of oral ondansetron, taken as needed, following an initial ED dose in children with acute gastroenteritis-associated vomiting. The data from the DOSE-AGE trial will be analyzed using this SAP. This will reduce the risk of producing data-driven results and bias in our reported outcomes. The DOSE-AGE study was registered on ClinicalTrials.gov on February 22, 2019. Trial registration ClinicalTrials.gov NCT03851835 . Registered on 22 February 2019.

Here, the authors report the results of a randomized, placebo controlled trial of children with acute gastroenteritis who were treated with a probiotic and find no virus-specific beneficial effects attributable to the probiotic, either in reducing clinical symptoms or clearance of viral nucleic acid from stool specimens.

Abstract 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,

Detection of Clostridioides difficile toxins in patients with gastroenteritis has increasingly been accomplished through the use of enteric multiplex syndromic panels. Comparisons of the performance of these panels to both direct-from-stool (DFS) and culture-enriched stools followed by polymerase chain reaction (PCR) methods in pediatric populations are limited. Here, we compare the performance of the Luminex xTAG® Gastrointestinal Pathogen Panel (GPP) to our DFS in-house real-time PCR (DFS RT-PCR) assay for the detection of C. difficile toxin gene, tcdB, using 2641 stool specimens collected from children enrolled in the Alberta Provincial Pediatric EnTeric Infection Team (APPETITE) study in Alberta, Canada. We used culture enrichment followed by in-house RT-PCR to resolve discordant results between the two assays. We found excellent agreement (k = 0.89) between the GPP and our DFS RT-PCR assay: the positive percent agreement between the two assays was 97%, and the negative percent agreement was 99%. GPP, a multi-analyte platform can easily be implemented into a routine diagnostic laboratory for detecting enteric pathogens including C. difficile.

Introduction Relatively 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 analysis The 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 dissemination Sites 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 number NCT04330261

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.

Objective: To determine the stability of children's retrospective ratings of pre-injury levels of symptoms over time following concussion.Methods: Children and adolescents (n = 3,063) between the ages of 5–17 diagnosed with a concussion by their treating pediatric emergency department (PED) physician within 48 h of injury completed the Post-Concussion Symptom Inventory (PCSI) at the PED and at 1, 2, 4, 8, and 12-weeks post-injury. At each time point, participants retrospectively recalled their pre-injury levels of post-injury symptoms. The PCSI has three age-appropriate versions for children aged 5–7 (PCSI-SR5), 8–12 (PCSI-SR8), and 13–18 (PCSI-SR13). Total scale, subscales (physical, cognitive, emotional, and sleep), and individual items from the PCSI were analyzed for stability using Gini's mean difference (GMD).Results: The mean GMD for total score was 0.31 (95% CI = 0.28, 0.34) for the PCSI-SR5, 0.19 (95% CI = 0.18, 0.20) for the PCSI-SR8, and 0.17 (95% CI = 0.16, 0.18) for the PCSI-SR13. Subscales ranged from mean GMD 0.18 (physical) to 0.31 (emotional) for the PCSI-SR8 and 0.16 (physical) to 0.31 (fatigue) for the PCSI-SR13. At the item-level, mean GMD ranged from 0.13 to 0.60 on the PCSI-SR5, 0.08 to 0.59 on the PCSI-SR8, and 0.11 to 0.41 on the PCSI-SR13.Conclusions: Children and adolescents recall their retrospective pre-injury symptom ratings with good-to-perfect stability over the first 3-months following their concussion. Although some individual items underperformed, variability was reduced as items were combined at the subscale and full-scale level. There is limited benefit gained from collecting multiple pre-injury symptom queries.Clinical Trial Registration: Clinicaltrials.gov through the US National Institute of Health/National Library of Medicine. (NCT01873287; http://clinicaltrials.gov/ct2/show/NCT01873287).

Norovirus is a major pathogen identified in children with acute gastroenteritis (AGE), little is known about the strain’s diversity and their clinical severity. Stool and/or rectal swabs were collected from children ≤18 years of age recruited at emergency departments (ED), and a provincial nursing advice phone line due to AGE symptoms in the province of Alberta, Canada between December 2014 and August 2018. Specimens were tested using a reverse transcription real time PCR and genotyped by Sanger sequencing. The Modified Vesikari Scale score (MVS) was used to evaluate the disease severity. The objectives are to identify the Genogroup and Genotype distribution and to compare illness severity between the GI and GII genogroups and to complete further analyses comparing the GII genotypes identified. GII.4 was the genotype most commonly identified. Children with GII.4 had higher MVS scores (12.0 (10.0, 14.0; p = 0.002)) and more prolonged diarrheal (5 days (3.0, 7.8)) and vomiting (3.2 days (1.7, 5.3; p < 0.001)) durations compared to other non GII.4 strains. The predominant strain varied by year with GII.4 Sydney[P31] predominant in 2014/15, GII.4 Sydney[P16] in 2015/16 and 2017/18, and GII.3[P12] in 2016/17. Genogroup II norovirus strains predominated in children with AGE with variance between years; clinical severity associated with different strains varied with episodes being most severe among GII.4 infected children.

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.

BackgroundAcute gastroenteritis (AGE) causing dehydration with or without dysnatremias is a common childhood health challenge. While it is accepted that oral rehydration therapy is preferred, clinical factors or parent and healthcare provider preferences may lead to intravenous rehydration (IVR). Isotonic solutions are increasingly recommended in most scenarios requiring IVR. Nevertheless, children with AGE, having ongoing losses of water and electrolytes, represent a unique population.ObjectivesTo evaluate the association between acquired dysnatremias and IVR in children with AGE.MethodsA systematic search of MEDLINE database was conducted through September 14, 2016. Observational studies and clinical trials conducted in high-income countries were included. The Grades of Recommendation, Assessment, Development, and Evaluation approach was used to evaluate the overall quality of evidence for each outcome.Results603 papers were identified of which 6 were included (3 randomized controlled trials and 3 observational studies). Pooling of patient data was not possible due to significantly different interventions or exposures. Single studies results demonstrated that within 24 h, administration of isotonic saline was not associated with a significant decline in serum sodium while hypotonic solutions (0.2–0.45% saline) were associated, in one study, with mean serum sodium declines from 1.3 mEq/L (139.2, SD 2.9–137.9, SD 2.5) in 133 young infants (aged 1–28 months), to 5.7 (SD 3.1) mEq/L in a subgroup of 18 older children (age mean 5.8, SD 2.7 years). Both isotonic and hypotonic saline were shown to be associated with improvement of baseline hyponatremia in different studies. Baseline hypernatremia was corrected within 4–24 h in 81/83 (99.6%) children using hypotonic saline IVR.ConclusionThere is a paucity of publications assessing the risk for acquired dysnatremias associated with IVR in children with AGE. Current high-quality evidence suggests that, short-term use of isotonic solutions is safe and effective in most children with AGE; hypotonic solutions may also be appropriate in some subpopulations, however, the quality of available evidence is low to very low. Further research investigating outcomes associated with IVR use beyond 24 h focusing on specific age groups is required.

Escherichia coli O157:H7 is the predominant cause of diarrhea-associated hemolytic uremic syndrome (HUS) worldwide. Its cardinal virulence traits are Shiga toxins, which are encoded by stx genes, the most common of which are stx1a, stx2a, and stx2c. The toxins these genes encode differ in their in vitro and experimental phenotypes, but the human population-level impact of these differences is poorly understood. Using Shiga toxin-encoding bacteriophage insertion typing and real-time polymerase chain reaction, we genotyped isolates from 936 E. coli O157:H7 cases and verified HUS status via chart review. We compared the HUS risk between isolates with stx2a and those with stx2a and another gene and estimated additive interaction of the stx genes. Adjusted for age and symptoms, the HUS incidence of E. coli O157:H7 containing stx2a alone was 4.4% greater (95% confidence interval (CI) −0.3%, 9.1%) than when it occurred with stx1a. When stx1a and stx2a occur together, the risk of HUS was 27.1% lower (95% CI −87.8%, −2.3%) than would be expected if interaction were not present. At the population level, temporal or geographic shifts toward these genotypes should be monitored, and stx genotype may be an important consideration in clinically predicting HUS among E. coli O157:H7 cases.

An expert panel exercise was conducted to assess feasibility and potential effectiveness of 10 emerging health interventions against childhood diarrhoea. Twelve international experts were invited to take part in a CHNRI priority setting process. This group used 12 different criteria relevant to successful development and implementation of the emerging interventions, nine of which were retained in the final analysis. They showed most collective optimism towards developing household or community-level water treatment, followed by sustainable, affordable latrine options; those two emerging interventions were followed by antibiotic therapy of Cryptosporidium diarrhoea, and oral or transcutaneous enteric vaccine development.

Introduction Anaphylaxis is a severe, potentially fatal multiorgan system manifestation of an allergic reaction. The highest incidence of anaphylaxis is in children and adolescents. Biphasic anaphylaxis (BA) is defined as the recurrence of allergic symptoms after resolution of an initial reaction. It has been reported to occur in 10%–20% of cases within 1–48 hours from the onset of the initial reaction. The dilemma for physicians is determining which patients with resolved anaphylaxis should be observed for BA and for how long. Guidelines for duration of postanaphylaxis monitoring vary, are based on limited evidence and can have unintended negative impacts on patient safety, quality of life and healthcare resources. The objectives of this study are to derive a prognostic model for BA and to develop a risk-scoring system that informs disposition decisions of children who present to emergency departments (ED) with anaphylaxis.Methods and analysis This prospective multicentre cohort study will enrol 1682 patients from seven paediatric EDs that are members of the Paediatric Emergency Research Canada network. We will enrol patients younger than 18 years of age with an allergic reaction meeting anaphylaxis diagnostic criteria. Trained ED research assistants will screen, obtain consent and prospectively collect study data. Research assistants will follow patients during their ED visit and ascertain, in conjunction with the medical team, if the patient develops BA. A standardised follow-up survey conducted following study enrolment will determine if a biphasic reaction occurred after ED disposition. Model development will conform to the broad principles of the PROGRESS (Prognosis Research Strategy) framework and reporting will follow the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis Statement.Ethics and dissemination Ethics approval has been received from all participating centres. Our dissemination plan focuses on informing clinicians, policy makers and parents of the results through publication in peer-reviewed journals and broadcasting on multiple media platforms.Trial registration number NCT05135377.

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.

[This corrects the article DOI: 10.1371/journal.pone.0128754.].

Gastroenteritis remains a leading cause of childhood morbidity.Because prior reviews have focused on isolated symptoms and studies conducted in developing countries, this study focused on interventions commonly considered for use in developed countries. Intervention specific, patient-centered outcomes were selected.MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, trial registries, grey literature, and scientific meetings.Randomized controlled trials, conducted in developed countries, of children aged

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.

Given the lack of evidence regarding effective pharmacological and non-pharmacological interventions for pediatric mild traumatic brain injury (mTBI) and the resultant lack of treatment recommendations reflected in consensus guidelines, variation in the management of pediatric mTBI is to be expected. We therefore surveyed practitioners across 15 centers in the United States and Canada who care for children with pediatric mTBI to evaluate common-practice variation in the management of pediatric mTBI. The survey, developed by a panel of pediatric mTBI experts, consisted of a 10-item survey instrument regarding providers' perception of common pediatric mTBI symptoms and mTBI interventions. Surveys were distributed electronically to a convenience sample of local experts at each center. Frequencies and percentages (with confidence intervals [CI]) were determined for survey responses. One hundred and seven respondents (71% response rate) included specialists in pediatric Emergency Medicine, Sports Medicine, Neurology, Neurosurgery, Neuropsychology, Neuropsychiatry, Physical and Occupational Therapy, Physiatry/Rehabilitation, and General Pediatrics. Respondents rated headache as the most prevalently reported symptom after pediatric mTBI, followed by cognitive problems, dizziness, and irritability. Of the 65 (61%; [95% CI: 51,70]) respondents able to prescribe medications, non-steroidal anti-inflammatory medications (55%; [95% CI: 42,68]) and acetaminophen (59%; [95% CI: 46,71]) were most commonly recommended. One in five respondents reported prescribing amitriptyline for headache management after pediatric mTBI, whereas topiramate (8%; [95% CI: 3,17]) was less commonly reported. For cognitive problems, methylphenidate (11%; [95% CI: 4,21]) was used more commonly than amantadine (2%; [95% CI: 0,8]). The most common non-pharmacological interventions were rest ("always" or "often" recommended by 83% [95% CI: 63,92] of the 107 respondents), exercise (59%; [95%CI: 49,69]), vestibular therapy (42% [95%CI: 33,53]) and cervical spine exercises (29% [95%CI: 21,39]). Self-reported utilization for common pediatric mTBI interventions varied widely across our Canadian and United States consortium. Future effectiveness studies for pediatric mTBI are urgently needed to advance the evidence-based care.