OBJECTIVE:To externally validate the Paediatric Emergency Care Applied Research Network (PECARN) rule for identifying febrile infants aged <60 days at low risk of serious bacterial infections (SBIs) and assess the utility of the rule with C reactive protein (CRP) instead of procalcitonin (PCT). METHODS:Secondary analysis of data from the Management and Outcomes of Fever in Children in Europe (MOFICHE) study (12 paediatric emergency departments in eight European countries, January 2017 to April 2018) and a Swedish study (four paediatric emergency departments, January 2014 to December 2020). Previously healthy febrile infants aged ≤60 days were included. We validated the original PECARN rule in a Swedish subcohort (2018-2020) and explored an adapted version using CRP in the full Swedish and MOFICHE cohorts. RESULTS:The Swedish subcohort (2018-2020) included 536 febrile infants with an SBI prevalence of 11%. The original PECARN rule showed a sensitivity of 96.6% (95% CI 88.1 to 99.6), specificity of 61.9% (95% CI 57.4 to 66.3), negative predictive value (NPV) of 99.3% (95% CI 97.4 to 99.8) and positive predictive value (PPV) of 23.5% (95% CI 21.4 to 25.8). The full Swedish cohort (2014-2020) included 2237 infants and the MOFICHE cohort of 512 infants with 12% and 10% SBI prevalence, respectively. Using CRP <20 mg/L instead of PCT, the adapted PECARN rule showed a sensitivity of 97.8% and NPV of 99.4% in the Swedish cohort, and sensitivity of 92.2% with an NPV of 98.3% in the MOFICHE cohort. CONCLUSIONS:The PECARN rule demonstrated high NPV (similar to the derivation cohort) and high potential in ruling out SBIs in two new European cohorts. The rule maintained good performance with CRP instead of PCT, supporting the potential use of CRP in settings where PCT is unavailable.

BACKGROUND:In children, the value of routine blood pressure measurement in first assessment at the emergency department has been questioned. This has, however, not yet been evaluated in low- and middle-income countries (LMICs) where the incidence of serious illness is high. This study assessed the predictive value of low systolic blood pressure to detect serious illness in children attending acute care settings in LMICs. METHODS:This observational study is based on data from children attending three acute care settings in The Gambia and Suriname. Hypotension was defined by age-adjusted reference values according to Advanced Paediatric Life Support (APLS) and Paediatric Advanced Life Support (PALS) cut-offs. The outcome measure was a composite marker of serious illness consisting of admission or referral to a higher level of care. A logistic regression analysis was used to evaluate the association between hypotension and serious illness for each setting separately. RESULTS:20 185 visits from Gambia rural, 398 visits from Gambia urban and 1817 visits from Suriname were included. Hypotension was present in 8.3-17.3% of visits and serious illness in 3.9-15.7%. Hypotension was not significantly associated with serious illness in Gambia urban (ORAPLS 3.2 (0.7-10.9) and ORPALS 1.4 (0.1-7.6)) and Suriname (ORAPLS 1.3 (0.9-1.9) and ORPALS 1.7 (0.9-3.2)), and with an inverse association in Gambia rural (ORAPLS 0.6 (0.5-0.7) and ORPALS 0.9 (0.5-1.4)). CONCLUSIONS:Our results do not show a significant association between hypotension and serious illness in LMICs. Our results suggest that routine blood pressure measurement does not aid in the evaluation of well-appearing children attending acute care settings in LMICs.

Objective Children with the autosomal dominant disorder Neurofibromatosis 1 (NF1) exhibit a high prevalence of both attention-deficit/hyperactivity disorder (ADHD) (up to 40%) and autism (up to 11%). The genetic mechanisms underlying these behavioral phenotypes are largely unexplored. This study examines the associations between various NF1 genotypes and NF1 behavioral phenotypes. Method A retrospective cohort study was carried out in children and adolescents with NF1 from three national referral centers for NF1 (the Netherlands, the UK and Belgium). Anonymized data was collected on five primary outcomes to characterize the behavioral phenotype in NF1: autistic traits (Social Responsiveness Scale 2 [SRS-2] Total T-score and Autism Diagnostic Observation Schedule [ADOS] Calibrated Severity Score); attention-deficit/hyperactivity disorder characteristics (Conners Inattention and Hyperactivity T-score) and global behavioral/emotional problems (Child Behavior Checklist [CBCL] Total Problems T-score). Genotypes were categorized based on three types of NF1 variant definitions: (1) coding variant type, (2) variant effect (truncating vs. non-truncating variants), and (3) the location within the gene. Results In total, 408 children and adolescents with NF1 were included, of which 187 (46%) were female. Range of median age at assessment across all outcomes was 6.0-8.4 years. Behavioral outcomes were not associated to any of the NF1 genotypes categories examined. Conclusion In this large cohort, autism traits, ADHD characteristics or global behavioral/emotional problems were not associated with NF1 variant type, effect or location. These findings indicate that the NF1 variant classes examined here do not differentially influence the NF1 behavioral phenotype, although genotype–phenotype associations at the single codon level cannot be ruled out.

Sudden unexpected death in infants (SUDI) and children (SUDC) requires thorough investigation to identify causes and prevention strategies. In the Netherlands, these deaths are investigated using the standardized postmortem evaluation of sudden unexpected death in infants and children (PESUDIC) procedure. This study examines the use of various diagnostic tests within PESUDIC and their effectiveness in determining causes of death. This observational study included infants and children who died suddenly and underwent the PESUDIC procedure from 2016 to 2022. Standardized data on medical history, postmortem examinations, and diagnostic outcomes were collected. Findings were classified by consensus of two experts as “contributory” if they supported the cause of death and “decisive” if they were leading for determination. A total of 275 cases were included. Median age was 13 months (IQR 3.5–73.3). Fifty-nine percent were boys. Over 95

Angelman syndrome (AS) is a rare neurogenetic disorder. Previous studies indicate a high prevalence of autism spectrum disorder (ASD) with considerable variability. Little is known regarding the longitudinal trajectory of autistic traits. We aim to investigate autistic traits, the effect of age on these traits, and associated features in AS children. This (partly) longitudinal clinical record study at the ENCORE Expertise Center involved 107 AS children aged 2-18 with one (N = 107), two (N = 49), or three (N = 14) measurements. Autistic traits and sensory processing issues were assessed using various instruments, and DSM classifications were used descriptively. Covariates were genotype, gender, and epilepsy. Results indicate a high prevalence of autistic traits and sensory processing issues. Children with the deletion genotype exhibited more autistic traits. Autism Diagnostic Observation Schedule (ADOS) classifications indicated higher rates of ASD compared to clinician DSM classifications. Autistic traits generally remained stable over time, except that ADOS scores significantly decreased for children with the UBE3A mutation genotype, and in the social affect domain for the entire group. In conclusion, incorporating the assessment of autistic traits and sensory processing into clinical practice for AS is important to inform adaptations of the environment to meet the child's needs. Additionally, clinicians and researchers should be mindful of the potential for overestimating ASD traits in AS when relying on the ADOS. ASD diagnosis in AS should integrate multiple diagnostic instruments, diverse hetero-anamnestic sources, and multidisciplinary expert opinions.

BACKGROUND:White blood cell count (WBC) is a widely used marker for the prediction of serious bacterial infection (SBI); however, previous research has shown poor performance. This study aims to assess the value of WBC in the prediction of SBI in children at the emergency department (ED) and compare its value with C reactive protein (CRP) and absolute neutrophil count (ANC). METHODS:This study is an observational multicentre study including febrile children aged 0-18 years attending 1 of 12 EDs in 8 European countries. The association between WBC and SBI was assessed by multivariable logistic regression, adjusting for age, CRP and duration of fever. Additionally, diagnostic performance was assessed by sensitivity and specificity. Results were compared with CRP and ANC. RESULTS:We included 17 082 children with WBC measurements, of which 1854 (10.9%) had an SBI. WBC >15 had an adjusted OR of 1.9 (95% CI 1.7 to 2.1) for prediction of SBI, after adjusting for confounders. Sensitivity and specificity were 0.56 (95% CI 0.54 to 0.58) and 0.74 (0.73 to 0.75) for WBC >15, and 0.32 (0.30 to 0.34) and 0.91 (0.91 to 0.91) for WBC >20, respectively. In comparison, CRP >20 mg/L had a sensitivity of 0.87 (95% CI 0.85 to 0.88) and a specificity of 0.59 (0.58 to 059). For CRP >80 mg/L, the sensitivity was 0.55 (95% CI 0.52 to 057) and the specificity was 0.91 (0.90 to 0.91). Additionally, for ANC >10, the sensitivity was 0.55 (95% CI 0.53 to 0.58) and the specificity was 0.75 (0.75 to 0.76). The combination of WBC and CRP did not improve performance compared with CRP alone. CONCLUSION:WBC does not have diagnostic benefit in identifying children with an SBI compared with CRP and should only be measured for specific indications.

Mycoplasma pneumoniae causes atypical pneumonia in children and young adults. Its lack of a cell wall makes it resistant to beta-lactams, which are the first-line treatment for typical pneumonia. Current diagnostic tests are time-consuming and have low specificity, leading clinicians to administer empirical antibiotics. Using a LASSO regression simulation approach and blood microarray data from 107 children with pneumonia (including 30 M. pneumoniae) we identify eight different transcriptomic signatures, ranging from 3-10 transcripts, that differentiate mycoplasma pneumonia from other bacterial/viral pneumonias with high accuracy (AUC: 0.84–0.95). Additionally, we demonstrate that existing signatures for broadly distinguishing viral/bacterial infections and viral/bacterial pneumonias are ineffective in distinguishing M. pneumoniae from viral pneumonia. The new signatures are successfully validated in an independent RNAseq cohort of children with pneumonia, demonstrating their robustness. The high sensibility of these signatures presents a valuable opportunity to guide the treatment and management of M. pneumoniae pneumonia patients. Using blood microarray data from 107 children with pneumonia, the authors here identify eight transcriptomic signatures that distinguish Mycoplasma pneumoniae pneumonia from other viral and bacterial pneumonias, paving the way for precise diagnosis and targeted treatment guidance.

Pneumonia stands as the primary cause of death among children under five, yet current diagnosis methods often result in inadequate or unnecessary treatments. Our research seeks to address this gap by identifying host transcriptomic biomarkers in the blood of children with definitive viral and bacterial pneumonia. We performed RNA sequencing on 192 prospectively collected whole blood samples, including 38 controls and 154 pneumonia cases, uncovering a 5-transcript signature (genes FAM20A, BAG3, TDRD9, MXRA7, and KLF14) that effectively distinguishes bacterial from viral pneumonia (area under the curve (AUC): 0.95 [0.88-1.00]). Initial validation using combined definitive and probable cases yielded an AUC of 0.87 [0.77-0.97], while full validation in a new prospective cohort of 32 patients achieved an AUC of 0.92 [0.83-1.00]. This robust signature holds significant potential to enhance diagnostics accuracy for pediatric pneumonia, reducing diagnostic delays and unnecessary treatments and potentially transforming clinical practice.

Objective: Studies in mouse models and human adults have shown that the intestinal microbiota composition can affect peripheral immune cells. We here examined whether the gut microbiota compositions affect B and T-cell subsets in children. Methods: The intestinal microbiota was characterized from stool samples of 344 10-year-old children from the Generation R Study by performing 16S rRNA sequencing. Bray-Curtis dissimilarity was used to cluster distinct microbiome compositions (enterotypes). B-cell and T-cell phenotypes were defined by 11-color-flow cytometry. Linear regression models with adjustment for lifestyle and child characteristics were performed to determine associations between enterotypes and immune cell numbers. Results: Three enterotypes with distinct microbiota composition were found, characterized by high abundance of Prevotella, Bacteroides and Blautia. Children with the Blautia enterotype had decreased numbers of plasmablasts, CD4+ central memory (Tcm) T cells and follicular T-helper cells (Tfh), while Th22 cells and CD4+ effector memory (Tem) T cells, CD27-IgA+ memory B cells and CD27-IgE+ memory B cells, were increased in these children. In addition, in children with the Blautia enterotype CD4+ Tcm cell numbers expressing the beta 7 integrin, which can pair with alpha 4 to mediate intestinal homing were also lower, while CD4+beta 7+ Tem cell numbers were higher than in the other enterotypes. Conclusion: The Blautia enterotype showed features beneficial for human health. Enterotypes were associated with differences in memory B- and T-cell compartments. This study is unique in the detailed analysis of the B and T-cell compartment and the intestinal microbiome in a large generic pediatric cohort, enabling correction for child and maternal covariates. These outcomes could guide further studies about the impact of intestinal microbiome intervention, for instance through diet and microbiota metabolites such as short chain fatty acid production.

Studies on procalcitonin (PCT) for identifying sepsis were published as early as 1993 and since then, PCT has been the topic of over 8,500 studies. Several studies show PCT to be superior to CRP in differentiating invasive infections such as sepsis from viral infections, especially early in the disease course. However, its actual use in clinical practice is poorly documented. Our aim was to study the use of PCT in febrile children attending the ED across Europe and compare this to the use of CRP. The MOFICHE/PERFORM study, a prospective multicenter study, took place at 12 European EDs in eight countries and included febrile children < 18 years. In this secondary analysis of nine participating EDs that used PCT, descriptive analyses were performed, describing the use of PCT in all febrile children and for different age groups, foci of fever and fever duration. In total, 31,612 pediatric febrile episodes were available for analyses. Blood tests were performed in 15,812 (50.0

BACKGROUND:The number of paediatric patients visiting the ED with non-urgent problems is increasing, leading to poor patient flow and ED crowding. Fast track aims to improve the efficiency of evaluation and discharge of low acuity patients. We aimed to identify which febrile children are suitable for a fast track based on presenting symptoms and management. METHODS:This study is part of the Management and Outcome of Fever in children in Europe study, which is an observational study including routine data of febrile children <18 years attending 12 European EDs. We included febrile, low urgent children (those assigned a triage acuity of either 'standard' or 'non-urgent' using the Manchester Triage System) and defined children as suitable for fast track when they have minimal resource use and are discharged home. Presenting symptoms consisted of neurological (n=237), respiratory (n=8476), gastrointestinal (n=1953) and others (n=3473, reference group). Multivariable logistic regression analyses regarding presenting symptoms and management (laboratory blood testing, imaging and admission) were performed with adjustment for covariates: patient characteristics, referral status, previous medical care, previous antibiotic use, visiting hours and ED setting. RESULTS:We included 14 139 children with a median age of 2.7 years (IQR 1.3-5.2). The majority had respiratory symptoms (60%), viral infections (50%) and consisted of self-referrals (69%). The neurological group received imaging more often (adjusted OR (aOR) 1.8, 95% CI 1.1 to 2.9) and were admitted more frequently (aOR 1.9, 95% CI 1.4 to 2.7). The respiratory group had fewer laboratory blood tests performed (aOR 0.6, 95% CI 0.5 to 0.7), were less frequently admitted (aOR 0.6, 95% CI 0.5 to 0.7), but received imaging more often (aOR 1.8, 95% CI 1.6 to 2.0). Lastly, the gastrointestinal group had more laboratory blood tests performed (aOR 1.2. 95% CI 1.1 to 1.4) and were admitted more frequently (aOR 1.4, 95% CI 1.2 to 1.6). CONCLUSION:We determined that febrile children triaged as low urgent with respiratory symptoms were most suitable for a fast track. This study provides evidence for which children could be triaged to a fast track, potentially improving overall patient flow at the ED.

AIM:To find proof-of-principle evidence for short-term treatment with lamotrigine to improve cognitive functioning of adolescents with neurofibromatosis type 1 (NF1). METHOD:This was a double-blind, parallel-group, randomized, placebo-controlled clinical trial (the NF1-EXCEL trial: Examining the Cognitive and Electrophysiological benefit of Lamotrigine in Neurofibromatosis type 1; Clinicaltrials.gov identifier NCT02256124), with the aim of enrolling 60 adolescents with NF1 aged 12 to 17  years 6 months. The short-term study intervention was 200 mg of lamotrigine taken orally for 26 weeks. The primary outcome was performance IQ tested with the Wechsler Intelligence Scale for Children, Third Edition, complemented with secondary outcomes for visuospatial learning efficacy, visual perception, visual sustained attention, fine motor coordination, attention-deficit/hyperactivity problems, and executive functioning. RESULTS:We screened 402 adolescents with NF1, of whom 31 (eight females) entered the study. Complete-case analysis showed no effect of lamotrigine on either performance IQ (-0.23, 95% CI -6.90 to 6.44) or most secondary outcomes. Visual sustained attention showed a trend towards better performance in the lamotrigine group (-0.81, 95% CI -1.67 to 0.04). INTERPRETATION:Lamotrigine did not improve cognitive functioning in adolescents with NF1. The small treatment effects make it unlikely that a larger sample size could have changed this conclusion.

Early recognition of children at risk of serious illness is essential in preventing morbidity and mortality, particularly in low- and middle-income countries (LMICs). This study aimed to validate the Emergency Department-Paediatric Early Warning Score (ED-PEWS) for use in acute care settings in LMICs. This observational study is based on previously collected clinical data from consecutive children attending four diverse settings in LMICs. Inclusion criteria and study periods (2010-2021) varied. We simulated the ED-PEWS, consisting of patient age, consciousness, work of breathing, respiratory rate, oxygen saturation, heart rate, and capillary refill time, based on the first available parameters. Discrimination was assessed by the area under the curve (AUC), sensitivity and specificity (previously defined cut-offs < 6 and ≥ 15). The outcome measure was for each setting a composite marker of high urgency. 41,917 visits from Gambia rural, 501 visits from Gambia urban, 2,608 visits from Suriname, and 1,682 visits from Tanzania were included. The proportion of high urgency was variable (range 4.6% to 24.9%). Performance ranged from AUC 0.80 (95%CI 0.70-0.89) in Gambia urban to 0.62 (95%CI 0.55-0.67) in Tanzania. The low-urgency cut-off showed a high sensitivity in all settings ranging from 0.83 (95%CI 0.81-0.84) to 1.00 (95%CI 0.97-1.00). The high-urgency cut-off showed a specificity ranging from 0.71 (95%CI 0.66-0.75) to 0.97 (95%CI 0.97-0.97). The ED-PEWS has a moderate to good performance for the recognition of high urgency children in these LMIC settings. The performance appears to have potential in improving the identification of high urgency children in LMICs.

Background Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children’s functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials. Aim Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype. Methods The study sample consisted of 28 children with AS aged 2–18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored. Results Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD). Conclusions Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition. Trial registration Registered d.d. 23-04-2020 under number ‘NL8550’ in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075

BACKGROUND:Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing.METHODS:Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final "bacterial" or "viral" phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification.RESULTS:Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/β-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the "Watch" category.CONCLUSIONS:Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship.

Objectives: The COVID-19 pandemic and subsequent rise of multisystem inflammatory syndrome in children have raised interest in high-sensitivity troponin (hs-TnT) and N-terminal probrain natriuretic peptide (NT-proBNP) because these have been found to be elevated in many cases of multisystem inflammatory syndrome in children. Our aim was to study hs-TnT and NT-proBNP concentrations in febrile children not affected by COVID-19. Methods: We retrospectively measured cardiac markers, hs-TnT, and NT-proBNP in leftover blood samples of febrile children (0-18 years) diagnosed and treated in a single-center emergency department (ED) (N = 67) and pediatric intensive care unit (PICU) (N = 19) that participated in a multicenter, prospective study of infection biomarkers (PERFORM). Results: Concentrations of hs-TnT, median 1.8 ng/L (interquartile range [IQR], 0.0-15.1), and NT-proBNP, 194 pg/mL (IQR, 54.9-706), were higher in febrile children than in controls (N = 25, hs-TnT 0.0 [IQR, 0-0]; NT-proBNP 56.3 [IQR, 29.7-109], both P < 0.001), whereas PICU patients had higher concentrations (hs-TnT 15.1 [IQR, 10.3-102] and NT-proBNP 828 [IQR, 657-4712], both P < 0.001) than ED patients (hs-TnT 0 [IQR, 0-7.4] and NT-proBNP 104 [IQR, 39.5-363]). No differences were found between viral and bacterial infections. Highest concentrations were found in children with either comorbidity predisposing to elevated concentrations (eg, chronic cardiac or renal disease) or children with critical illness or multiorgan failure such as those with septic shock. Conclusions: Concentrations of hs-TnT and NT-proBNP are often elevated in febrile children with different causes of fever. Concentrations were higher in children admitted to the PICU than in children attending the ED, and seem to reflect disease severity rather than the underlying cause of fever.

OBJECTIVE:To investigate a dose-response relationship between the magnitude of decrease in pediatric respiratory tract infections (RTIs) during the 2020 implementation of nonpharmaceutical interventions (NPIs) and the increase thereafter during NPI lifting. STUDY DESIGN:We conducted an interrupted, time-series analysis based on a multinational surveillance system. All patients <16 years of age coming to medical attention with various symptoms and signs of RTI at 25 pediatric emergency departments from 13 European countries between January 2018 and June 2022 were included. We used generalized additive models to correlate the magnitude of decrease of each RTI during NPI (such as social distancing) implementation and its subsequent increase during NPI lifting. Urinary tract infections served as control outcome. RESULTS:In total, 528 055 patients were included. We observed reductions in cases during the NPI period, from -76% (95% CI -113 to -53 in pneumonia) to -65% (95% CI -100 to -39 for tonsillitis/pharyngitis), followed by strong increases during NPI lifting, from +83% (95% CI 29-150 for tonsillitis/pharyngitis) to +329% (95% CI 149-517 for bronchiolitis). For each RTI, we found a significant association between the magnitude of decrease during NPI implementation and the increase during NPI lifting. Urinary tract infection cases remained stable. CONCLUSIONS:The magnitude of increase in RTI observed after NPI lifting was directly correlated to the magnitude of case reduction during NPI implementation, suggesting a "dose-response" relationship from an "immune debt" phenomenon. The likely rebound in RTIs should be expected when implementing and lifting NPI in the future.

BackgroundGlobally, the COVID-19 pandemic had a huge impact on patients and healthcare systems. A decline in paediatric visits to healthcare settings was observed, which might have been due to lower incidence of injury and infectious illness, changes in healthcare services and parental concern. The aim of our study was to examine parental experiences of help-seeking for, and care of, a sick or injured child during COVID-19 lockdown periods in five European countries with different healthcare systems in place.MethodsAn online survey for parents with a child with any kind or illness of injury during COVID-19 lockdowns was circulated through social media in five European countries: Italy, Spain, Sweden, the Netherlands, and the United Kingdom. Parents living in one of these countries with self-identification of a sick or injured child during COVID-19 lockdown periods were eligible to fill in the survey. Descriptive statistics were used for the level of restrictions per country, children's characteristics, family characteristics and reported help-seeking behaviour of parents prior to the lockdown and their real experience during the lockdown. The free text data was subjected to thematic analysis.ResultsThe survey was fully completed by 598 parents, ranging from 50 to 198 parents per country, during varying lockdown periods from March 2020 until May 2022. Parents who completed the survey were not deterred from seeking medical help for their sick or injured child during the COVID-19 pandemic. This finding was comparable in five European countries with different healthcare systems in place. Thematic analysis identified three main areas: parental experiences of access to healthcare, changes in parents' help-seeking behaviours for a sick or injured child during lockdowns, and the impact of caring for a sick or injured child during the lockdowns. Parents reported limited access to non-urgent care services and were anxious about either their child or themselves catching COVID-19.ConclusionThis insight into parental perspectives of help-seeking behaviour and care for a sick or injured child during COVID-19 lockdowns could inform future strategies to improve access to healthcare, and to provide parents with adequate information concerning when and where to seek help and support during pandemics.

Angelman syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromosome 15q11.2q13 caused by a deletion, uniparental paternal disomy (UPD), imprinting center disorder (ICD), or pathological variant of the UBE3A gene. AS is characterized by developmental delay, epilepsy, and lack of speech. Although fractures are observed frequently in our clinical practice, there are few studies on bone health in AS. The aim of this study is to investigate bone health in children with AS. In this prospective cohort study, we describe bone health in 91 children with AS visiting the ENCORE Expertise Center for AS between April 2010 and December 2021. Bone health was assessed with the bone health index (BHI) in standard deviation score (SDS) measured by digital radiogrammetry of the left hand using BoneXpert software. Risk factors analyzed were age, sex, genetic subtype, epilepsy, anti-seizure medication use, mobility, body mass index (BMI), and onset of puberty. Children with AS had a mean BHI of −1.77 SDS (SD 1.4). A significantly lower BHI was found in children with a deletion (−2.24 SDS) versus non-deletion (−1.02 SDS). Other factors associated with reduced BHI-SDS were inability to walk and late onset of puberty. Children with a history of one or more fractures (22%) had a significantly lower BHI than children without fractures (−2.60 vs −1.56 SDS). Longitudinal analysis showed a significant decrease in BHI-SDS with age in all genetic subtypes. Conclusions : Children with AS have a reduced bone health. Risk factors are deletion genotype, no independent walking, and late onset of puberty. Bone health decreased significantly with age. What is Known: • Children with neurological disorders often have a low bone health and higher risk of fractures. • Little is known about bone health in children with Angelman syndrome (AS). What is New: • Children with AS showed a reduced bone health and this was significantly associated with having a deletion, not being able to walk independently, and late onset of puberty. • Longitudinal analysis showed a significant decrease in bone health as children got older.