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Objective: To investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis complex (TSC)., Methods: In this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ <80, learning disability, special schooling, or autism, aged 4-17 years, without intractable seizures to be assigned to receive everolimus or placebo. Everolimus was titrated to blood trough levels of 5-10 ng/mL. Primary outcome was full-scale IQ; secondary outcomes included autism, neuropsychological functioning, and behavioral problems., Results: Thirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect -5.6 IQ points, 95% confidence interval -12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questionnaires examining behavioral problems, social functioning, communication skills, executive functioning, sleep, quality of life, and sensory processing. All patients had adverse events. Two patients on everolimus and 2 patients on placebo discontinued treatment due to adverse events., Conclusions: Everolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC. The use of everolimus in children with TSC with the aim of improving cognitive function and behavior should not be encouraged in this age group., Clinicaltrialsgov Identifier: NCT01730209., Classification of Evidence: This study provides Class I evidence that for children with TSC, everolimus does not improve intellectual disability, autism, behavioral problems, or other neuropsychological deficits., (© 2019 American Academy of Neurology.)

Objective: To provide an overview of care in emergency departments (EDs) across Europe in order to interpret observational data and implement interventions regarding the management of febrile children., Design and Setting: An electronic questionnaire was sent to the principal investigators of an ongoing study (PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management), www.perform2020.eu) in 11 European hospitals in eight countries: Austria, Germany, Greece, Latvia, the Netherlands, Slovenia, Spain and the UK., Outcome Measures: The questionnaire covered indicators in three domains: local ED quality (supervision, guideline availability, paper vs electronic health records), organisation of healthcare (primary care, immunisation), and local factors influencing or reflecting resource use (availability of point-of-care tests, admission rates)., Results: Reported admission rates ranged from 4% to 51%. In six settings (Athens, Graz, Ljubljana, Riga, Rotterdam, Santiago de Compostela), the supervising ED physicians were general paediatricians, in two (Liverpool, London) these were paediatric emergency physicians, in two (Nijmegen, Newcastle) supervision could take place by either a general paediatrician or a general emergency physician, and in one (München) this could be either a general paediatrician or a paediatric emergency physician. The supervising physician was present on site in all settings during office hours and in five out of eleven settings during out-of-office hours. Guidelines for fever and sepsis were available in all settings; however, the type of guideline that was used differed. Primary care was available in all settings during office hours and in eight during out-of-office hours. There were differences in routine immunisations as well as in additional immunisations that were offered; immunisation rates varied between and within countries., Conclusion: Differences in local, regional and national aspects of care exist in the management of febrile children across Europe. This variability has to be considered when trying to interpret differences in the use of diagnostic tools, antibiotics and admission rates. Any future implementation of interventions or diagnostic tests will need to be aware of this European diversity., Competing Interests: Competing interests: None declared.

Objective: To assess and compare the performance of triage systems for identifying high and low-urgency patients in the emergency department (ED)., Design: Systematic review and meta-analysis., Data Sources: EMBASE, Medline OvidSP, Cochrane central, Web of science and CINAHL databases from 1980 to 2016 with the final update in December 2018., Eligibility Criteria: Studies that evaluated an emergency medical triage system, assessed validity using any reference standard as proxy for true patient urgency and were written in English. Studies conducted in low(er) income countries, based on case scenarios or involving less than 100 patients were excluded., Review Methods: Reviewers identified studies, extracted data and assessed the quality of the evidence independently and in duplicate. The Quality Assessment of studies of Diagnostic Accuracy included in Systematic Reviews -2 checklist was used to assess risk of bias. Raw data were extracted to create 2×2 tables and calculate sensitivity and specificity. ED patient volume and casemix severity of illness were investigated as determinants of triage systems' performance., Results: Sixty-six eligible studies evaluated 33 different triage systems. Comparisons were restricted to the three triage systems that had at least multiple evaluations using the same reference standard (Canadian Triage and Acuity Scale, Emergency Severity Index and Manchester Triage System). Overall, validity of each triage system to identify high and low-urgency patients was moderate to good, but performance was highly variable. In a subgroup analysis, no clear association was found between ED patient volume or casemix severity of illness and triage systems' performance., Conclusions: Established triage systems show a reasonable validity for the triage of patients at the ED, but performance varies considerably. Important research questions that remain are what determinants influence triage systems' performance and how the performance of existing triage systems can be improved., Competing Interests: Competing interests: KM-J is chair of the Manchester Triage Group., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the diagnostic value of existing clinical prediction models (CPM; ie, statistically derived) in febrile young infants at risk for serious bacterial infections., Methods: A systematic literature review identified eight CPMs for predicting serious bacterial infections in febrile children. We validated these CPMs on four validation cohorts of febrile children in Spain (age <3 months), France (age <3 months) and two cohorts in the Netherlands (age 1-3 months and >3-12 months). We evaluated the performance of the CPMs by sensitivity/specificity, area under the receiver operating characteristic curve (AUC) and calibration studies., Results: The original cohorts in which the prediction rules were developed (derivation cohorts) ranged from 381 to 15 781 children, with a prevalence of serious bacterial infections varying from 0.8% to 27% and spanned an age range of 0-16 years. All CPMs originally performed moderately to very well (AUC 0.60-0.93). The four validation cohorts included 159-2204 febrile children, with a median age range of 1.8 (1.2-2.4) months for the three cohorts <3 months and 8.4 (6.0-9.6) months for the cohort >3-12 months of age. The prevalence of serious bacterial infections varied between 15.1% and 17.2% in the three cohorts <3 months and was 9.8% for the cohort >3-12 months of age. Although discriminative values varied greatly, best performance was observed for four CPMs including clinical signs and symptoms, urine dipstick analyses and laboratory markers with AUC ranging from 0.68 to 0.94 in the three cohorts <3 months (ranges sensitivity: 0.48-0.94 and specificity: 0.71-0.97). For the >3-12 months' cohort AUC ranges from 0.80 to 0.89 (ranges sensitivity: 0.70-0.82 and specificity: 0.78-0.90). In general, the specificities exceeded sensitivities in our cohorts, in contrast to derivation cohorts with high sensitivities, although this effect was stronger in infants <3 months than in infants >3-12 months., Conclusion: We identified four CPMs, including clinical signs and symptoms, urine dipstick analysis and laboratory markers, which can aid clinicians in identifying serious bacterial infections. We suggest clinicians should use CPMs as an adjunctive clinical tool when assessing the risk of serious bacterial infections in febrile young infants., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: While fever is the main complaint among pediatric emergency services and high antibiotic prescription are observed, only a few studies have been published addressing this subject. Therefore this systematic review aims to summarize antibiotic prescriptions in febrile children at the ED and assess its determinants. Methods: We extracted studies published from 2000 to 2017 on antibiotic use in febrile children at the ED from different databases. Author, year, and country of publishing, study design, inclusion criteria, primary outcome, age, and number of children included in the study was extracted. To compare the risk-of-bias all articles were assessed using the MINORS criteria. For the final quality assessment we additionally used the sample size and the primary outcome. Results: We included 26 studies reporting on antibiotic prescription and 28 intervention studies on the effect on antibiotic prescription. In all 54 studies antibiotic prescriptions in the ED varied from 15 to 90.5%, pending on study populations and diagnosis. Respiratory tract infections were mostly studied. Pediatric emergency physicians prescribed significantly less antibiotics then general emergency physicians. Most frequent reported interventions to reduce antibiotics are delayed antibiotic prescription in acute otitis media, viral testing and guidelines. Conclusion: Evidence on antibiotic prescriptions in children with fever presenting to the ED remains inconclusive. Delayed antibiotic prescription in acute otitis media and guidelines for fever and respiratory infections can effectively reduce antibiotic prescription in the ED. The large heterogeneity of type of studies and included populations limits strict conclusions, such a gap in knowledge on the determining factors that influence antibiotic prescription in febrile children presenting to the ED remains.

Objectives: First, to explore parents' views on and experiences of managing their febrile child and to assess their behaviour and needs when in search of information about fever; second, to develop and evaluate a hospital discharge information package about fever in children., Design: Mixed methods: (A) qualitative study with semistructured interviews and a focus group discussion (FGD) and (B) quantitative survey., Setting: Emergency department, non-acute hospital setting and day nursery in Rotterdam, The Netherlands., Participants: Parents of children <18 years (interviews, n=22) parents of children under 5 years (FGD (n=14), survey (n=38))., Intervention: Information package about fever in children (leaflet and website including videos)., Outcome Measures Quantitative Survey: Knowledge of fever and confidence in caring for a febrile child (Likert scale 0-5)., Results: Parents found fever mostly alarming, especially high fever. Help-seeking behaviour was based on either specific symptoms or on an undefined intuition. When parents did not feel recognised in their concern or felt criticised, anxiety increased as well as the threshold to seek healthcare for future illnesses. Information was needed, especially for situations when the general practitioner or social network were less easily available. This information should be reliable, consistent, available in multiple formats and include advice on management of fever at home and precise referral to medical services. Parents reported improved knowledge about fever (p<0.05) and mentioned improved confidence in caring for a child with fever at home after consulting the information package., Conclusion: Parents of children with a fever visiting the hospital are concerned about specific symptoms or based on an undefined intuition. Rather than telling parents that they should manage their child's illness at home, healthcare professionals should recognise parental intuition and provide clear information on alarming signs and potential diagnoses to empower parents in the management of their febrile child., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder associated with lifelong tumor growth propensity and neurocognitive impairments. Although follow-up of adults with NF1 often focuses on tumor growth, follow-up of cognitive or social problems and other NF1-related comorbidity is often not a part of standardized care. In order to provide optimal care services for these patients, we explored the care needs of adults with NF1. A qualitative study was performed using semi-structured group interviews, exploring worries and care needs in medical, psychological, and socioeconomic domains, also focusing on the transition from pediatric to adult care. Four focus groups were conducted, including young adult patients, patients over age 30, and parents of young adult patients. In total, 30 patients and 12 parents participated. Data were transcribed verbatim and analyzed by computerized thematic analysis. Themes were organized using the World Health Organization International classification of functioning, disability, and health (ICF). Results indicated many and diverse worries and care needs both during the transitional period and in adulthood in medical, mental health, and socioeconomic domains. Worries could be categorized into 13 themes. Parents reported high stress levels and difficulties with their parental role. Participants expressed the need for more information, access to NF1 experts, daily living support, care for mental health and socioeconomic participation, and closer communication between health-care providers. In conclusion, worries and needs of patients and parents underline the importance of multidisciplinary follow-up and continuity of care during and after the transitional period. Additionally, parental stress requires more attention from care providers., (© 2018 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.)

Aims: YouTube is a vast source of freely accessible user-uploaded medical information. To our knowledge no study has analysed the quality of parent-uploaded videos which depict illness in their children. We aimed to investigate the quality and quantity of videos representing two common conditions, croup and dehydration., Method: YouTube was searched using the search terms 'croup+child' and 'dehydration+child'. The first 400 videos of each search were screened. Videos created by doctors or by educational institutions were excluded. The parent-uploaded videos were analysed using the validated Medical Video Rating Scale. Each video was separately evaluated for whether it represented a good clinical example of the condition featured., Results: Out of 38 'croup' videos which met criteria, 15 were judged to be good clinical examples. Only 7 of these 15 'good clinical example' videos were also of high technical quality. Out of 28 'dehydration' videos which met the inclusion criteria, two were good clinical examples. One of these videos had good technical quality., Conclusions: There were very few videos of either condition which showed a good clinical example while also displaying high technical quality. It is extremely difficult and time consuming to isolate such examples from the mass of information available and therefore parents could be misled by apparently high technical quality videos which are not in fact good clinical examples. Healthcare professionals should be careful when discussing finding medical information on YouTube and consider creating repositories of good examples so they are able to direct parents towards more reputable resources., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Importance: Hearing loss (HL), a major cause of disability globally, negatively affects both personal and professional life., Objective: To describe the prevalence of sensorineural hearing loss (SNHL) among a population-based cohort of 9- to 11-year-old children, and to examine potential associations between purported risk factors and SNHL in early childhood., Design, Setting, and Participants: The study was among the general, nonclinical, pediatric community within the city of Rotterdam, the Netherlands, and was conducted between 2012 and 2015 as a cross-sectional assessment within the Generation R Study, a population-based longitudinal cohort study from fetal life until adulthood. Participants are children of included pregnant women in the Generation R Study with an expected delivery date between April 2002 and January 2006. They form a prenatally recruited birth cohort., Main Outcomes and Measures: Pure-tone air-conduction hearing thresholds were obtained at 0.5, 1, 2, 3, 4, 6, and 8 kHz, and tympanometry was performed in both ears. Demographic factors and parent-reported questionnaire data, including history of otitis media, were also measured., Results: A total of 5368 participants with a mean age of 9 years 9 months (interquartile range, 9 years 7 months-9 years 11 months) completed audiometry and were included in the analyses. A total of 2720 were girls (50.7%), and 3627 (67.6%) were white. Most of the participants (4426 children [82.5%]) showed normal hearing thresholds 15 dB HL or less in both ears. Within the cohort, 418 children (7.8%) were estimated to have SNHL (≥16 dB HL at low-frequency pure-tone average; average at 0.5, 1, and 2 kHz or high-frequency pure-tone average; average at 3, 4, and 6 kHz in combination with a type A tympanogram) in at least 1 ear, most often at higher frequencies. In multivariable analyses, a history of recurrent acute otitis media and lower maternal education were associated with the estimated SNHL at ages 9 to 11 years (odds ratio, 2.0 [95% CI. 1.5-2.8] and 1.4 [95% CI, 1.1-1.7], respectively)., Conclusions and Relevance: Within this cohort study in the Netherlands, 7.8% of the children ages 9 to 11 years had low-frequency or high-frequency HL of at least 16 dB HL in 1 or both ears. A history of recurrent acute otitis media and lower maternal education seem to be independent risk factors for presumed SNHL in early childhood.

Objective: The aim was to identify whether ethnic differences in coeliac disease autoimmunity (CDA) in children at 6 years of age exist, and when present, to evaluate how these differences may be explained by sociodemographic and environmental factors., Design: This study was embedded within a multi-ethnic population-based prospective cohort study., Setting and Patients: 4442 six-year-old children born between 2002 and 2006 were included. Information on ethnicity, environmental and lifestyle characteristics was assessed by questionnaires. Ethnicity was categorised into Western (Dutch, European, Indonesian, American, Oceanian) and non-Western (Turkish, Moroccan, Cape Verdean, Antillean, Surinamese). Serum transglutaminase type 2 antibody (TG2A) levels were measured with fluorescence enzyme immunoassay. Serum IgG levels against cytomegalovirus (CMV) were measured by ELISA., Main Outcome Measures: TG2A positivity was defined as TG2A ≥7 U/mL, strong TG2A positivity as TG2A ≥10 upper limit normal (70 U/mL)., Results: Of 4442 children, 60 (1.4%) children were TG2A positive, of whom 31 were strong positive. 66% of children were Western, 33% non-Western. Western ethnicity, high socioeconomic position and daycare attendance were positively associated with strong TG2A positivity (odds ratio (OR) 6.85 (1.62 to 28.8) p<0.01, OR 3.70 (1.40 to 9.82) p<0.01, OR 3.90 (1.38 to 11.0) p=0.01 resp.), whereas CMV seropositivity was inversely related to strong TG2A positivity (OR 0.32 (0.12 to 0.84) p=0.02). Together, these factors explained up to 47% (-67 to -17; p=0.02) of the ethnic differences in TG2A positivity between Western and non-Western children., Conclusions: Ethnic differences in children with CDA are present in childhood. Socioeconomic position, daycare attendance and CMV seropositivity partly explained these differences, which may serve as targets for prevention strategies for CDA., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The EBV is known to persist in memory B cells, but it remains unclear how this affects cell numbers and humoral immunity. We here studied EBV persistence in memory B cell subsets and consequences on B cell memory in young children. EBV genome loads were quantified in 6 memory B cell subsets in EBV + adults. The effects of EBV infection on memory B cell numbers and vaccination responses were studied longitudinally in children within the Generation R population cohort between 14 mo and 6 yr of age. EBV genomes were more numerous in CD27 + IgG + , CD27 + IgA + , and CD27 - IgA + memory B cells than in IgM-only, natural effector, and CD27 - IgG + B cells. The blood counts of IgM-only, CD27 + IgA + , CD27 - IgG + , and CD27 + IgG + memory B cells were significantly lower in EBV + children than in uninfected controls at 14 mo of age-the age when these cells peak in numbers. At 6 yr, all of these memory B cell counts had normalized, as had plasma IgG levels to previous primary measles and booster tetanus vaccinations. In conclusion, EBV persists predominantly in Ig class-switched memory B cells, even when derived from T cell-independent responses (CD27 - IgA + ), and EBV infection results in a transient depletion of these cells in young children., (© Society for Leukocyte Biology.)

Persistent infections with cytomegalovirus (CMV) differentially affect the host immune phenotype in middle-aged males and females. Because CMV already impacts on T-cell memory at a young age, we studied whether these effects were modified by sex in 1,079 children with an average age of 6 years. Sex and CMV independently impacted on multiple B-cell and T-cell subsets. However, there was no significant effect of their interaction. Importantly, the effects of sex and CMV were in part explained by age and infection with other herpesviruses. Thus, immune aging is likely to be more complex, with involvement of hormonal changes with age, socioeconomic status, birth characteristics, and pathogen exposure., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Dietary patterns have been linked to obesity in adults, however, not much is known about this association in early childhood. We examined associations of different types of dietary patterns in 1-year-old children with body composition at school age in 2026 children participating in a population-based cohort study. Dietary intake at the age of 1 year was assessed with a food-frequency questionnaire. At the children's age of 6 years we measured their body composition with dual-energy X-ray absorptiometry and we calculated body mass index, fat mass index (FMI), and fat-free mass index (FFMI). Three dietary pattern approaches were used: (1) An a priori-defined diet quality score; (2) dietary patterns based on variation in food intake, derived from principal-component-analysis (PCA); and (3) dietary patterns based on variations in FMI and FFMI, derived with reduced-rank-regression (RRR). Both the a priori-defined diet score and a 'Health-conscious' PCA-pattern were characterized by a high intake of fruit, vegetables, grains, and vegetable oils, and, after adjustment for confounders, children with higher adherence to these patterns had a higher FFMI at 6 years [0.19 SD (95 % CI 0.08;0.30) per SD increase in diet score], but had no different FMI. One of the two RRR-patterns was also positively associated with FFMI and was characterized by intake of whole grains, pasta and rice, and vegetable oils. Our results suggest that different a priori- and a posteriori-derived health-conscious dietary patterns in early childhood are associated with a higher fat-free mass, but not with fat mass, in later childhood., Competing Interests: The authors declare that they have no conflict of interest.

A big drop in the number of severe infections has resulted in less experience in recognising a seriously ill child. The challenge is finding a safe and effective balance between high-quality expertise and quickly accessible care, while avoiding over-diagnosis. There are a number of tools available to aid recognition of a seriously ill child and to avoid delay in diagnostic procedures and treatment: the use of a validated paediatric triage system, validated decision rules and guidelines, listening carefully to the parents ('my child's illness is different this time'), the clinical intuition of the experienced paediatrician and the provision of good 'safety net' advice to parents concerning the alarm signals and when they should contact a care provider. Experienced paediatricians should be at the forefront in the evaluation of the acutely ill child in order to teach their younger colleagues the importance of various alarm signals and the role played by clinical intuition.

Today, in 2014, the Manchester Triage System is an evidence-based triage system for the emergency room. It has been nationally and internationally validated and is safe for children. Why use the non-validated Netherlands Triage Standard that has no specific triage that has been suitably adapted and tested for children?

Objective: Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans., Methods: We mapped a quantitative trait locus (QTL1) for hyperthermia-induced FS on mouse chromosome 1, containing the signal recognition particle 9 (Srp9) gene. Effects of differential Srp9 expression were assessed in vivo and in vitro. Hippocampal SRP9 expression and genetic association were analyzed in FS and mTLE patients., Results: Srp9 was differentially expressed between parental strains C57BL/6J and A/J. Chromosome substitution strain 1 (CSS1) mice exhibited lower FS susceptibility and Srp9 expression than C57BL/6J mice. In vivo knockdown of brain Srp9 reduced FS susceptibility. Mice with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Downregulation of neuronal Srp9 reduced surface expression of AMPA receptor subunit GluA1. mTLE patients with antecedent FS had higher SRP9 expression than patients without. SRP9 promoter SNP rs12403575(G/A) was genetically associated with FS and mTLE., Interpretation: Our findings identify SRP9 as a novel FS susceptibility gene and indicate that SRP9 conveys its effects through endoplasmic reticulum (ER)-dependent synthesis and trafficking of membrane proteins, such as glutamate receptors. Discovery of this new FS gene and mechanism may provide new leads for early diagnosis and treatment of children with complex FS at risk for mTLE.

Purpose: It is important to advise parents when to consult a doctor when their child has fever. To provide evidence-based, safety-net advice for young febrile children, we studied the risk of complications, the occurrence of alarm symptoms, the duration of fever., Methods: In a 7-day prospective follow-up study, we included 463 consecutive children aged 3 months to 6 years who presented with fever at a general practitioner out-of-hours service. We excluded 43 children with complicated illnesses at presentation. In a structured assessment, the duration of fever before presentation was noted and a physical examination was performed. Parents reported alarming symptoms and rectal temperature in a diary for 1 week. The total duration of fever included its duration before presentation. Median duration of fever was estimated using the Kaplan-Meier test., Results: During follow-up, 3.2% of the children with uncomplicated illness at presentation developed a complicated illness. The presence of alarming symptoms dropped from 79.3% at day 2 of the fever episode to 36.7% at day 9. The estimated median duration of the total fever episode was 4.0 days (95% confidence interval, 3.6-4.4)., Conclusions: In children with uncomplicated illnesses, the daily occurrence of alarming symptoms reported by parents was high. The median duration of fever was 4 days. The predictive value of alarming symptoms reported by parents for complicated illness should be reconsidered.

Objective: To derive, cross validate, and externally validate a clinical prediction model that assesses the risks of different serious bacterial infections in children with fever at the emergency department., Design: Prospective observational diagnostic study., Setting: Three paediatric emergency care units: two in the Netherlands and one in the United Kingdom., Participants: Children with fever, aged 1 month to 15 years, at three paediatric emergency care units: Rotterdam (n=1750) and the Hague (n=967), the Netherlands, and Coventry (n=487), United Kingdom. A prediction model was constructed using multivariable polytomous logistic regression analysis and included the predefined predictor variables age, duration of fever, tachycardia, temperature, tachypnoea, ill appearance, chest wall retractions, prolonged capillary refill time (>3 seconds), oxygen saturation <94%, and C reactive protein., Main Outcome Measures: Pneumonia, other serious bacterial infections (SBIs, including septicaemia/meningitis, urinary tract infections, and others), and no SBIs., Results: Oxygen saturation <94% and presence of tachypnoea were important predictors of pneumonia. A raised C reactive protein level predicted the presence of both pneumonia and other SBIs, whereas chest wall retractions and oxygen saturation <94% were useful to rule out the presence of other SBIs. Discriminative ability (C statistic) to predict pneumonia was 0.81 (95% confidence interval 0.73 to 0.88); for other SBIs this was even better: 0.86 (0.79 to 0.92). Risk thresholds of 10% or more were useful to identify children with serious bacterial infections; risk thresholds less than 2.5% were useful to rule out the presence of serious bacterial infections. External validation showed good discrimination for the prediction of pneumonia (0.81, 0.69 to 0.93); discriminative ability for the prediction of other SBIs was lower (0.69, 0.53 to 0.86)., Conclusion: A validated prediction model, including clinical signs, symptoms, and C reactive protein level, was useful for estimating the likelihood of pneumonia and other SBIs in children with fever, such as septicaemia/meningitis and urinary tract infections.

A 15-year-old girl presented with fever and pain in her legs. A viral infection was suspected, but within 24 hours she became confused and developed meningeal signs, based on which she was diagnosed as having meningitis. Within a few hours a 6-month-old boy developed fever, a grey colour, bulging fontanel, cold hands and feet, and was groaning. He too appeared to have meningitis. It is important to recognize this serious infection in children with fever, since delay of diagnosis and treatment may result in serious complications. Recognition is difficult because of non-specific symptoms on presentation and a lack of alarm symptoms early in the course of the disease. Alarm symptoms of serious infection in children are cyanosis, rapid breathing, decreased capillary refill, petechial rash, meningeal signs, leg pain and decreased consciousness. If serious infection is uncertain in a child with fever, parents should be advised on the potential course of the disease, the alarm symptoms and the need to seek medical help in time.

Introduction: Child abuse is a serious problem worldwide and can be difficult to detect. Although children who experience the consequences of abuse will probably be treated at an emergency department, detection rates of child abuse at emergency departments remain low., Objective: To identify effective interventions applied at emergency departments that significantly increase the detection rate of confirmed cases of child abuse., Design: This review was carried out according to the Cochrane Handbook. Two reviewers individually searched PubMed, the Cochrane Library, EMBASE, Web of Science and CINAHL for papers that met the inclusion criteria., Results: Fifteen papers describing interventions were selected and reviewed; four of these were finally included and assessed for quality. In these studies the intervention consisted of a checklist of indicators of risk for child abuse. After implementation, the rate of detected cases of suspected child abuse increased by 180% (weighted mean in three studies). The number of confirmed cases of child abuse, reported in two out of four studies, showed no significant increase., Conclusions: Interventions at emergency departments to increase the detection rate of cases of confirmed child abuse are scarce in the literature. Past study numbers and methodology have been inadequate to show conclusive evidence on effectiveness.

Intrauterine growth restriction has been linked to infant behavioral problems. While typically only birth weight is examined, here the authors assessed fetal circulatory redistribution, also called the "brain-sparing effect," which is a fetal adaptive reaction to placental insufficiency. They aimed to investigate whether fetal circulatory redistribution protects against behavioral problems. Within the Generation R Study (Rotterdam, the Netherlands, 2003-2007), fetal circulation variables for the umbilical artery and the middle and anterior cerebral arteries were assessed with Doppler ultrasound in late pregnancy. Ratios between placental resistance and cerebral resistance were related to behavioral problems, as measured by the Child Behavior Checklist, in 935 toddlers aged 18 months. The umbilical/anterior cerebral ratio was associated with the Total Problems summary score from the Child Behavior Checklist (per standard-deviation increase, odds ratio = 1.2, 95% confidence interval: 1.0, 1.5). Children with higher umbilical/anterior cerebral ratios had higher risks of internalizing problems, emotional reactivity, somatic complaints, and attention problems. A high umbilical/middle cerebral ratio was related to higher scores on the Internalizing and Somatic Complaints scales. The authors conclude that infants with circulatory redistribution in gestation are more likely to have behavioral problems. This suggests that "brain-sparing" does not completely spare the brain and indicates underlying pathology with consequences for later behavior.

Objective: To validate use of the Manchester triage system in paediatric emergency care., Design: Prospective observational study., Setting: Emergency departments of a university hospital and a teaching hospital in the Netherlands, 2006-7., Participants: 17,600 children (aged <16) visiting an emergency department over 13 months (university hospital) and seven months (teaching hospital)., Intervention: Nurses triaged 16,735/17,600 patients (95%) using a computerised Manchester triage system, which calculated urgency levels from the selection of discriminators embedded in flowcharts for presenting problems. Nurses over-ruled the urgency level in 1714 (10%) children, who were excluded from analysis. Complete data for the reference standard were unavailable in 1467 (9%) children leaving 13,554 patients for analysis., Main Outcome Measures: Urgency according to the Manchester triage system compared with a predefined and independently assessed reference standard for five urgency levels. This reference standard was based on a combination of vital signs at presentation, potentially life threatening conditions, diagnostic resources, therapeutic interventions, and follow-up. Sensitivity, specificity, and likelihood ratios for high urgency (immediate and very urgent) and 95% confidence intervals for subgroups based on age, use of flowcharts, and discriminators., Results: The Manchester urgency level agreed with the reference standard in 4582 of 13,554 (34%) children; 7311 (54%) were over-triaged and 1661 (12%) under-triaged. The likelihood ratio was 3.0 (95% confidence interval 2.8 to 3.2) for high urgency and 0.5 (0.4 to 0.5) for low urgency; though the likelihood ratios were lower for those presenting with a medical problem (2.3 (2.2 to 2.5) v 12.0 (7.8 to 18.0) for trauma) and in younger children (2.4 (1.9 to 2.9) at 0-2 months [corrected] v 5.4 (4.5 to 6.5) at 8-16 years)., Conclusions: The Manchester triage system has moderate validity in paediatric emergency care. It errs on the safe side, with much more over-triage than under-triage compared with an independent reference standard for urgency. Triage of patients with a medical problem or in younger children is particularly difficult.