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Aim: High flow nasal cannula (HFNC) therapy is a form of respiratory support used in children with bronchiolitis. A national guideline for the use of HFNC was published in The Netherlands in 2020. We studied the implementation and use of this guideline., Methods: We performed a multicentre observational study amongst all hospitals in the North-West part of The Netherlands referring to the same paediatric intensive care unit (PICU). This study consisted of two parts: a comparison of local HFNC protocols to the national guideline and a survey about the use of HFNC amongst paediatricians in the participating centres., Results: We observed considerable variations between the local protocols and the national protocol, especially regarding criteria to initiate HFNC treatment and weaning practices. Survey results showed that expectations of HFNC widely varied, while the clinical use of HFNC deviated from both the national guideline as well as local protocols, especially for weaning practices and the use of pCO 2 as a parameter for initiation and evaluation of the effect of HFNC., Conclusion: Implementation of the national guideline for HFNC therapy in bronchiolitis was inefficacious, leading to non-uniform clinical practice., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: To investigate the long-term outcome of pediatric mild traumatic brain injury (mTBI) in terms of neurocognitive, behavioral, and school functioning and to identify clinical risk factors for adverse outcomes., Methods: This study describes the follow-up of a prospective multicenter sample of 89 children with mTBI 3.6 years postinjury and 89 neurologically healthy children matched for sex, age, and socioeconomic status. Neurodevelopmental outcomes were assessed using an intelligence test, behavioral questionnaires, computerized neurocognitive tests, and longitudinal (pre- and postinjury) standardized school performance data., Results: Children with mTBI exhibited intelligence in the average range but had more behavioral problems related to inattentiveness (P = 0.004, d = 0.47) and hyperactive impulsivity (P = 0.01, d = 0.40) and showed poorer neurocognitive performance in information processing stability (P = 0.003, d = -0.55) and Visual Working Memory (P = 0.04, d = -0.39) compared with matched peers. Longitudinal school performance data revealed poorer performance in Technical Reading up to two years postinjury (P = 0.005, d = -0.42) when compared with normative data. Clinical risk factors did not reveal predictive value for adverse outcomes in children with mTBI., Conclusions: This study indicates that children with mTBI are at risk of long-term deficits in neurocognitive and behavioral functioning, with longitudinal evidence suggesting shortfalls in school performance up to two years postinjury. Clinical risk factors do not provide a solid basis for long-term neurodevelopmental prognosis. Findings emphasize the importance of, and challenges for, early identification of children at risk for adverse neurodevelopmental outcome after mTBI., Competing Interests: Declaration of competing interest Conflicts of interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Evaluation of guidelines in actual practice is a crucial step in guideline improvement. A retrospective evaluation of the Dutch guideline for children with fever without an apparent source (FWS) showed 50% adherence in young infants. We prospectively evaluated adherence to the Dutch guideline and its impact on management in current practice. Prospective observational multicenter cross-sectional study, including children 3 days to 16 years old presented for FWS at one of seven emergency departments in participating secondary and tertiary care hospitals in the Netherlands. Adherence to the Dutch FWS guideline, adapted from the National Institute for Health and Care Excellence (NICE) guideline, was evaluated, and patterns in non-adherence and the impact of non-adherence on clinical outcomes and resource use were explored. Adherence to the guideline was 192/370 (52%). Adherence was lowest in patients categorized as high risk for severe infection (72/187, 39%), compared to the low-risk group (64/73, 88%). Differences in adherence were significant between risk categories (P < 0.001) but not between age categories. In case of non-adherence, less urinalysis, fewer bacterial cultures (blood, urine, and cerebral spinal fluid), and less empirical antibiotic treatment were performed (P < 0.050). Clinical outcomes were not significantly different between the non-adherence and the adherence group, particularly regarding missed severe infections., Conclusions: We found a high non-adherence rate of 48%, which did not lead to unfavorable clinical outcomes. This substantiates the need for a critical reevaluation of the FWS guideline and its indications for bacterial cultures, viral testing, and antibiotic treatment., What Is Known: • Despite the development of national guidelines, variation in practice is still substantial in the assessment of febrile children to distinguish severe infection from mild self-limiting disease. • Previous retrospective research suggests low adherence to national guidelines for febrile children in practice., What Is New: • In case of non-adherence to the Dutch national guideline, similar to the National Institute for Health and Care Excellence (NICE) guideline from the United Kingdom, physicians have used fewer resources than the guideline recommended without increasing missed severe infections., (© 2024. The Author(s).)

Management of suspected early-onset sepsis (EOS) is undergoing continuous evolution aiming to limit antibiotic overtreatment, yet current data on the level of overtreatment are only available for a select number of countries. This study aimed to determine antibiotic initiation and continuation rates for suspected EOS, along with the incidence of culture-proven EOS in The Netherlands. In this retrospective study from 2019 to 2021, data were collected from 15 Dutch hospitals, comprising 13 regional hospitals equipped with Level I-II facilities and 2 academic hospitals equipped with Level IV facilities. Data included birth rates, number of neonates started on antibiotics for suspected EOS, number of neonates that continued treatment beyond 48 h and number of neonates with culture-proven EOS. Additionally, blood culture results were documented. Data were analysed both collectively and separately for regional and academic hospitals. A total of 103,492 live-born neonates were included. In 4755 neonates (4.6%, 95% CI 4.5-4.7), antibiotic therapy was started for suspected EOS, and in 2399 neonates (2.3%, 95% CI 2.2-2.4), antibiotic treatment was continued beyond 48 h. Incidence of culture-proven EOS was 1.1 cases per 1000 live births (0.11%, 95% CI 0.09-0.14). Overall, for each culture-proven EOS case, 40.6 neonates were started on antibiotics and in 21.7 neonates therapy was continued. Large variations in treatment rates were observed across all hospitals, with the number of neonates initiated and continued on antibiotics per culture-proven EOS case varying from 4 to 90 and from 4 to 56, respectively. The high number of antibiotic prescriptions compared to the EOS incidence and wide variety in clinical practice among hospitals in The Netherlands underscore both the need and potential for a novel approach to the management of neonates with suspected EOS.

Early-onset sepsis (EOS) is a rare but profoundly serious bacterial infection. Neonates at risk of EOS are often treated with antibiotics. The start of empiric antibiotic therapy can successfully be reduced by the implementation of the EOS calculator. However, once started, antibiotic therapy is often continued despite a negative blood culture. To decrease the burden of antibiotic therapy, it is necessary to know whether the clinician's reasons are based on objective factors. Therefore, we performed a retrospective single-centre cohort study to identify the factors associated with prolongation of antibiotic therapy in neonates with suspected EOS but a negative blood culture. Maternal, clinical, and laboratory data of neonates with a gestational age of ≥32 weeks, admitted between January 2019 and June 2021, were collected. Among neonates with a negative blood culture, we compared neonates with prolonged (≥3 days) to neonates with discontinued (<3 days) antibiotic therapy. The clinician's reported reasons for prolonging therapy were explored. Blood cultures were positive in 4/146 (2.7%), negative in 131/146 (89.7%), and not obtained in 11/146 (7.5%) of the neonates. The incidence of EOS was 0.7 per 1000 neonates. Of the 131 neonates with a negative blood culture, 47 neonates (35.9%) received prolonged antibiotic therapy. In the prolonged group, the mean gestational age was higher (38.9 versus 36.8 weeks), and spontaneous preterm birth was less prevalent (21.3% versus 53.6%). Prolonged treatment was associated with late onset of respiratory distress, respiratory rate, hypoxia, apnoea and bradycardia, pale appearance, behavioural change, and elevated CRP levels. The most reported reasons were clinical appearance (38.3%), elevated CRP levels (36.2%), and skin colour (10.6%). Prolonging empiric antibiotic therapy despite a negative blood culture is common in suspected EOS. Clinical signs associated with prolongation are uncommon and the reported reasons for prolongation contain subjective assessments and arbitrary interpretations that are not supported by the guideline recommendations as arguments for prolonged therapy.

Background. The Dutch guideline Eating Disorders defines admission criteria for children with anorexia nervosa (AN) in need for medical stabilization and advices close monitoring to detect refeeding syndrome (RFS) in an early stage. Methods . Admission criteria, recommendations at admission, and during first week of hospitalization were evaluated in accordance to the guideline. RFS was defined as decreased electrolyte concentrations and/or clinical features. Results. 22 patients were included with a total of 50 admissions. We observed that 62% of the admitted patients met one of the admission criteria, 190/300 (63%) recommended admission examinations were performed. During admission adherence decreased, in particular daily weighing and physical examination (12% and 6%, respectively). The guideline was not fully followed in any of the patients. None of the hospitalized patients met the RFS criteria. Conclusion . Guideline adherence was moderate and can be improved by a few adaptations, which may limit unnecessary laboratory testing., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Prior studies demonstrated the neonatal early-onset sepsis (EOS) calculator's potential in drastically reducing antibiotic prescriptions, and its international adoption is increasing rapidly. To optimize the EOS calculator's impact, successful implementation is crucial. This study aimed to identify key barriers and facilitators to inform an implementation strategy. A multicenter cross-sectional survey was carried out among physicians, residents, nurses and clinical obstetricians of thirteen Dutch hospitals. Survey development was prepared through a literature search and stakeholder interviews. Data collection and analysis were based on the Consolidated Framework for Implementation Research (CFIR). A total of 465 stakeholders completed the survey. The main barriers concerned the expectance of the department's capacity problems and the issues with maternal information transfer between departments. Facilitators concerned multiple relative advantages of the EOS calculator, including stakeholder education, EOS calculator integration in the electronic health record and existing positive expectations about the safety and effectivity of the calculator. Based on these findings, tailored implementation interventions can be developed, such as identifying early adopters and champions, conducting educational meetings tailored to the target group, creating ready-to-use educational materials, integrating the EOS calculator into electronic health records, creating a culture of collective responsibility among departments and collecting data to evaluate implementation success and innovation results.

Background: Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease severity in adult COVID-19 is associated to the presence of anti-cytokine autoantibodies (ACAAs) against type I interferons. Similarly, ACAAs may be implicated in KD and MIS-C. Therefore, we explored the immunological response, presence of ACAAs and disease correlates in both disorders., Methods: Eighteen inflammatory plasma protein levels and seven ACAAs were measured in KD (n = 216) and MIS-C (n = 56) longitudinally by Luminex and/or ELISA. Levels (up to 1 year post-onset) of these proteins were related to clinical data and compared with healthy paediatric controls., Findings: ACAAs were found in both patient groups. The presence of ACAAs lagged behind the inflammatory plasma proteins and peaked in the subacute phase. ACAAs were mostly directed against IFN-γ (>80%) and were partially neutralising at best. KD presented with a higher variety of ACAAs than MIS-C. Increased levels of anti-IL-17A (P = 0·02) and anti-IL-22 (P = 0·01) were inversely associated with ICU admission in MIS-C. Except for CXCL10 in MIS-C (P = 0·002), inflammatory plasma proteins were elevated in both KD and MIS-C. Endothelial angiopoietin-2 levels were associated with coronary artery aneurysms in KD (P = 0·02); and sCD25 (P = 0·009), angiopoietin-2 (P = 0·001), soluble IL-33-receptor (ST2, P = 0·01) and CXCL10 (P = 0·02) with ICU admission in MIS-C., Interpretation: Markers of endothelial activation (E-selectin, angiopoietin-2), and innate and adaptive immune responses (macrophages [CD163, G-CSF], neutrophils [lipocalin-2], and T cells [IFN-γ, CXCL10, IL-6, IL-17]), are upregulated in KD and MIS-C. ACAAs were detected in both diseases and, although only partly neutralising, their transient presence and increased levels in non-ICU patients may suggest a dampening role on inflammation., Funding: The Kawasaki study is funded by the Dutch foundation Fonds Kind & Handicap and an anonymous donor. The sponsors had no role in the study design, analysis, or decision for publication., Competing Interests: Declaration of interests BK received a grant from Stichting CJ Vaillant and Innovation Impulse from the Amsterdam UMC. ET is an employee of Hycult Biotech. FLV received a HDM-FUN Horizon 2020 grant. The other authors have declared that no conflict of interest exists., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: In 2017, a new Dutch neonatal early-onset sepsis (EOS) guideline was implemented. It is an adaptation from the United Kingdom National Institute for Health and Care Excellence guideline and focuses on maternal and neonatal risk factors. We aim to assess if this guideline performs better at reducing the rate of antibiotic treatment for EOS than the old Dutch categorical EOS guideline, which focused primarily on group B streptococcus (GBS) testing and prophylaxis., Methods: We performed a single-center retrospective cohort study in the Netherlands. Data were collected from two 12-month epochs (2015 vs. 2019). Neonates were included when treated for suspected EOS or when observed for an elevated EOS risk., Results: The empirical antibiotic rate was 4.6% in both years. Prolonged antibiotic treatment (>48 u) increased from 24% in 2015 to 39% in 2019 ( P = 0.021). Adherence to the guideline decreased from 98% in 2015 to 84% in 2019 ( P < 0.001). Strict adherence in 2019 would have led to more antibiotic treatment (5.1% instead of 4.6%). The EOS incidence rate was comparable, namely 0.6% in 2015 and 0.0% in 2019 ( P = 0.480). The change in the definition of risk factors in 2019 led to less antibiotic treatment in case of a maternal fever during birth, from 48% in 2015 to 26% in 2019 ( P < 0.001)., Conclusions: The new Dutch categorical EOS guideline does not achieve its intended purpose of reducing empiric antibiotic therapy for suspected EOS. We advocate the need for a new screening strategy., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Mild traumatic brain injury (mTBI) is highly prevalent in children. Recent literature suggests that children with mTBI are at considerable risk of persisting neurocognitive deficits, threatening post-injury child development. Nevertheless, clinical tools for early identification of children at risk are currently not available. This systematic review aims to describe the available literature on neurocognitive outcome prediction models in children with mTBI. Findings are highly relevant for early identification of children at risk of persistent neurocognitive deficits, allowing targeted treatment of these children to optimize recovery. The electronic literature search was conducted in PubMed, EMBASE, CINAHL, Cochrane, PsychINFO and Web of Science on February 9, 2022. We included all studies with multi-variate models for neurocognitive outcome based on original data from only children (age <18 years) with mTBI. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, two authors independently performed data extraction and risk of bias analysis using the Prediction model Risk of Bias Assessment Tool (PROBAST). This systematic review identified eight original studies (nine articles) reporting prediction models for neurocognitive outcome, representing a total of 1033 children diagnosed with mTBI (mean age at injury = 10.5 years, 37.6% girls). Neurocognitive outcome assessment took place between 1 month and 7 years post-injury. Models were identified with significant predictive value for the following outcomes: memory, working memory, inhibition, processing speed, and general neurocognitive functioning. Prediction performance of these models varied greatly between weak and substantial ( R 2  = 10.0%-54.7%). The best performing model was based on demographic and pre-morbid risk factors in conjunction with a subacute neurocognitive screening to predict the presence of a deficit in general neurocognitive functioning at 12 months post-injury . This systematic review reflects the absence of robust prediction models for neurocognitive outcome of children with mTBI. The findings indicate that demographic factors, pre-morbid factors as well as acute and subacute clinical factors have relevance for neurocognitive outcome. Based on the available evidence, evaluation of demographic and pre-morbid risk factors in conjunction with a subacute neurocognitive screening may have the best potential to predict neurocognitive outcome in children with mTBI. The findings underline the importance of future research contributing to early identification of children at risk of persisting neurocognitive deficits.

Introduction: Neonatal sepsis is a leading cause of infant mortality worldwide with non-specific and varied presentation. We aimed to catalogue the current definitions of neonatal sepsis in published randomised controlled trials (RCTs)., Method: A systematic search of the Embase and Cochrane databases was performed for RCTs which explicitly stated a definition for neonatal sepsis. Definitions were sub-divided into five primary criteria for infection (culture, laboratory findings, clinical signs, radiological evidence and risk factors) and stratified by qualifiers (early/late-onset and likelihood of sepsis)., Results: Of 668 papers screened, 80 RCTs were included and 128 individual definitions identified. The single most common definition was neonatal sepsis defined by blood culture alone (n = 35), followed by culture and clinical signs (n = 29), and then laboratory tests/clinical signs (n = 25). Blood culture featured in 83 definitions, laboratory testing featured in 48 definitions while clinical signs and radiology featured in 80 and 8 definitions, respectively., Discussion: A diverse range of definitions of neonatal sepsis are used and based on microbiological culture, laboratory tests and clinical signs in contrast to adult and paediatric sepsis which use organ dysfunction. An international consensus-based definition of neonatal sepsis could allow meta-analysis and translate results to improve outcomes., (© 2021. The Author(s).)

The difficulty in recognizing early-onset neonatal sepsis (EONS) in a timely manner due to non-specific symptoms and the limitations of diagnostic tests, combined with the risk of serious consequences if EONS is not treated in a timely manner, has resulted in a low threshold for starting empirical antibiotic treatment. New guideline strategies, such as the neonatal sepsis calculator, have been proven to reduce the antibiotic burden related to EONS, but lack sensitivity for detecting EONS. In this review, the potential of novel, targeted preventive and diagnostic methods for EONS is discussed from three different perspectives: maternal, umbilical cord and newborn perspectives. Promising strategies from the maternal perspective include Group B Streptococcus (GBS) prevention, exploring the virulence factors of GBS, maternal immunization and antepartum biomarkers. The diagnostic methods obtained from the umbilical cord are preliminary but promising. Finally, promising fields from the newborn perspective include biomarkers, new microbiological techniques and clinical prediction and monitoring strategies. Consensus on the definition of EONS and the standardization of research on novel diagnostic biomarkers are crucial for future implementation and to reduce current antibiotic overexposure in newborns.

Controversy exists in clinical practice regarding optimal initial enteral feeding (EF) for moderately premature and low birth weight (BW) infants. We included 96 infants stratified into 3 groups (I: 1600-1799 g [n = 22]; II: 1800-1999 g [n = 42]; III: 2000-2200 g [n = 32]). The protocol recommended starting with minimal EF (MEF) in infants weighing <1800 g. On the first day of life, 5% of the infants in group I did not follow the protocol mandating MEF, but started with exclusive EF instead, compared to 36% and 44% of the infants in groups II and III, respectively. The median number of days until exclusive EF was achieved was 5 days longer for infants receiving MEF than for infants who had received normal portions of EF from birth onward. We observed no significant differences in feeding-related complications. We advocate omitting MEF in moderately premature infants with a BW of 1600 g or higher., Competing Interests: Guarantor: F.B.P. The other authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: Newborns are at risk for early-onset sepsis (EOS). In the Netherlands, EOS affects less than 0.2% of newborns, but approximately 5% are treated with empirical antibiotics. These numbers form an example of overtreatment in countries using risk-factor based guidelines for administrating antibiotics. An alternative to these guidelines is the EOS calculator, a tool that calculates an individual EOS risk and provides management recommendation. However, validation outside the North-American setting is limited, especially for safety outcomes. We aim to investigate whether EOS calculator use can safely reduce antibiotic exposure in newborns with suspected EOS compared with the Dutch guideline., Methods and Analysis: This protocol describes a cluster randomised controlled trial assessing whether EOS calculator use is non-inferior regarding safety, and superior regarding limiting overtreatment, compared with the Dutch guideline. We will include newborns born at ≥34 weeks' gestation, with at least one risk factor consistent with EOS within 24 hours after birth. After 1:1 randomisation, the 10 participating Dutch hospitals will use either the Dutch guideline or the EOS calculator as standard of care for all newborns at risk for EOS. In total, 1830 newborns will be recruited. The coprimary non-inferiority outcome will be the presence of at least one of four predefined safety criteria. The coprimary superiority outcome will be the proportion of participants starting antibiotic therapy for suspected and, or proven EOS within 24 hours after birth. Secondary outcomes will be the total duration of antibiotic therapy, the percentage of antibiotic therapy started between 24 and 72 hours after birth, and parent-reported quality of life. Analyses will be performed both as intention to treat and per protocol., Ethics and Dissemination: This trial has been approved by the Medical Ethics Committee of the Amsterdam UMC (NL78203.018.21). Results will be presented in peer-reviewed journals and at international conferences., Trial Registration Number: NCT05274776., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Fever without a source (FWS) in children poses a diagnostic challenge. To distinguish a self-limiting infection from a serious infection, multiple guidelines have been developed to aid physicians in the management of FWS. Currently, there is no comparison of existing FWS guidelines., Methods: This comparative review describes consistencies and differences in guideline definitions and diagnostic and therapeutic recommendations. A literature search was performed to include secondary care FWS guidelines of high-income countries, composed by national or regional pediatric or emergency care associations, available in English or Dutch., Results: Ten guidelines of five high-income countries were included, with varying age ranges of children with FWS. In children younger than one month with FWS, the majority of the guidelines recommended laboratory testing, blood and urine culturing and antibiotic treatment irrespective of the clinical condition of the patient. Recommendations for blood culture and antibiotic treatment varied for children aged 1-3 months. In children aged above three months, urine culture recommendations were inconsistent, while all guidelines consistently recommended cerebral spinal fluid testing and antibiotic treatment exclusively for children with a high risk of serious infection., Conclusions: We found these guidelines broadly consistent, especially for children with FWS younger than one month. Guideline variation was seen most in the targeted age ranges and in recommendations for children aged 1-3 months and above three months of age. The findings of the current study can assist in harmonizing guideline development and future research for the management of children with FWS., (© 2022. The Author(s).)

Background: Procedural sedation and analgesia (PSA) and peripheral nerve blocks (NBs) are techniques to manage pain and facilitate reduction of dislocated joints or fractures. However, it is unclear if either approach provides any distinct advantage in the emergency department (ED). The aim of this systematic review is to compare these 2 techniques on pain scores, adverse events, patient satisfaction, and length of stay (LOS) in the ED., Methods: We performed an electronic search of MEDLINE, EMBASE, and the Cochrane Library, and references were hand-searched. Randomized controlled trials (RCTs) comparing PSA with NBs for orthopedic reductions in the ED were included. Outcomes of interest included pain scores, adverse events, patient satisfaction, and LOS in the ED. A total of 2 reviewers independently screened abstracts and extracted data into a standardized form. The Cochrane risk-of-bias tool was used to evaluate study quality. The Grading of Recommendation Assessment Development and Evaluation approach was used to assess the certainty and strength of the evidence. Data on pain scores were pooled using a random-effects model and are reported as standardized mean differences (SMDs) with 95% confidence intervals (CIs)., Results: A total of 6 RCTs (n = 256) were included in a qualitative review, and 4 RCTs (n = 101) were included in the meta-analysis. There was no significant difference in pain scores between the PSA and NB groups ( P  = 0.47; SMD, 0.45; 95% CI, -0.78 to 1.69; I 2  = 0.94). There were less adverse events in the NB group (0%-3.3%) compared with the PSA group (0%-20%; n = 256). LOS times were consistently shorter in the NB group (n = 215). Patient satisfaction was comparable in both groups (n = 196)., Conclusion: Based on the available evidence, NBs performed by emergency physicians are as effective as PSA in managing pain during orthopedic reductions in the ED. NBs are associated with fewer adverse events and shorter LOS in the ED. The quality of evidence is low., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Background: Early onset neonatal sepsis (EONS) and late onset neonatal sepsis (LONS) are important causes of neonatal mortality and morbidity. A pressing need for reliable and detailed data of low- and middle-income countries exists. This study aimed to describe the incidence and outcome of neonatal sepsis in the only tertiary hospital of Suriname, a middle-income country in South America., Methods: Infants born at the Academic Hospital of Paramaribo from May 2017 through December 2018 were prospectively included at birth. Perinatal data, duration of antibiotic treatment, blood culture results and mortality data were gathered. Neonatal sepsis was defined as positive blood culture with a pathogenic microorganism within the first 28 days of life., Results: Of the 2190 infants included, 483 (22%) were admitted to neonatal (intensive) care. The incidence of EONS was 2.1 (95% CI: 0.9-5) per 1000 live births, with no deaths. Antibiotics for suspected EONS were administrated to 189 (8.6%) infants, of whom 155 (82%) were born prematurely. The incidence of LONS cases was 145 (95% CI: 114-176) per 1000 admissions. Gramnegative bacteria accounted for 70% (48 out of 70) of causative organisms. Seventeen deaths were directly caused by sepsis (35 per 1000 admissions)., Conclusions: Findings from this tertiary center birth cohort study in a middle-income setting indicate EONS incidence and outcomes comparable to high-income settings, whereas LONS is a more prevalent and significant challenge with a predominance of gram-negative bacteria, and high mortality., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: As SARS-CoV-2 will likely continue to circulate, low-impact methods become more relevant to monitor antibody-mediated immunity. Saliva sampling could provide a non-invasive method with reduced impact on children. Studies reporting on the differences between systemic and mucosal humoral immunity to SARS-CoV-2 are inconsistent in adults and scarce in children. These differences may be further unraveled by exploring associations to demographic and clinical variables., Methods: To evaluate the use of saliva antibody assays, we performed a cross-sectional cohort study by collecting serum and saliva of 223 children attending medical services in the Netherlands (irrespective of SARS-CoV-2 exposure, symptoms or vaccination) from May to October 2021. With a Luminex and a Wantai assay, we measured prevalence of SARS-CoV-2 spike (S), receptor binding domain (RBD) and nucleocapsid-specific IgG and IgA in serum and saliva and explored associations with demographic variables., Findings: The S-specific IgG prevalence was higher in serum 39% (95% CI 32 - 45%) than in saliva 30% (95% CI 24 - 36%) (P ≤ 0.003). Twenty-seven percent (55/205) of children were S-specific IgG positive in serum and saliva, 12% (25/205) were only positive in serum and 3% (6/205) only in saliva. Vaccinated children showed a higher concordance between serum and saliva than infected children. Odds for saliva S-specific IgG positivity were higher in girls compared to boys (aOR 2.63, P = 0.012). Moreover, immunocompromised children showed lower odds for S- and RBD-specific IgG in both serum and saliva compared to healthy children (aOR 0.23 - 0.25, P ≤ 0.050)., Conclusions: We showed that saliva-based antibody assays can be useful for identifying SARS-CoV-2 humoral immunity in a non-invasive manner, and that IgG prevalence may be affected by sex and immunocompromisation. Differences between infection and vaccination, between sexes and between immunocompromised and healthy children should be further investigated and considered when choosing systemic or mucosal antibody measurement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Keuning, Grobben, Bijlsma, Anker, Berman-de Jong, Cohen, Felderhof, de Groen, de Groof, Rijpert, van Eijk, Tejjani, van Rijswijk, Steenhuis, Rispens, Plötz, van Gils and Pajkrt.)

Currently, in young children with minor traumatic head injuries (MTHI) classified as intermediate risk (IR), PECARN recommends clinical observation over computer tomography (CT) scan depending on provider comfort, although both options being possible. In this study, we describe clinicians' choice and which factors were associated with this decision. This was a planned sub-study of a prospective multicenter observational study that enrolled 1006 children younger than 18 years with MTHI who presented to six emergency departments in The Netherlands. Of those, 280 children classified as IR group fulfilling one or more minor criteria, leaving the clinician with the choice between clinical observation and a CT scan. In our cohort, 228/280 (81%) children were admitted for clinical observation, 15/280 (5.4%) received a CT scan, 6/280 (2.1%) received a CT scan and were admitted for observation, and 31/280 (11%) children were discharged from the emergency department without any intervention. Three objective factors were associated with a CT scan, namely age above 2 years, the presence of any loss of consciousness (LOC), and presentation on weekend days., Conclusion: In children with MTHI in an IR group, clinicians prefer clinical observation above performing a CT scan. Older age, day of presentation, and any loss of consciousness are factors associated with a CT scan., What Is Known: • Clinical decision rules have been developed in the management of children of different risk groups with minor traumatic head injury (MTHI). • According to the Dutch national, clinical decision rules in children under 6 years of age up to 50% of children classify as intermediate risk (IR) and clinicians may choose between clinical observation and computed tomography (CT)., What Is New: • In this IR group, clinical observation is chosen in 81% children with MTHI. • In the subgroup where clinicians performed a CT scan, children were older and presented more frequently on a weekend day, and more frequently consciousness was lost., (© 2022. The Author(s).)

Background: Approximately 90% of the children with chronic abdominal pain are diagnosed as having functional abdominal pain disorder (FAPD). The Dutch guideline "functional abdominal pain" provides a stepwise approach to treat FAPD. The aim of this survey was twofold first, to determine adherence to the Dutch guideline, and second to determine current management of FAPDs in clinical practice., Methods: A multicenter survey was designed. The survey was sent to pediatricians and pediatric residents in December 2020. The study ran from October 2020 until March 2021. Participants in ten hospitals in the western region of The Netherlands were invited to complete this survey. Respondents who indicated not to treat children with FAPDs or respondents who completed less than 3 steps of the survey were excluded., Results: In total, 85/174 (48.9%) respondents completed the survey. We included 80 respondents, 68 pediatricians and 12 pediatric residents, for analysis. Overall, self-reported guideline adherence was 85%. Self-reported adherence was higher than actual adherence. Only 50% of all respondents followed the first three steps of the guideline. The reported non-pharmacological and pharmacological treatments were diverse and varied between different age groups. The average follow-up duration was between 2 and 6 months, and the most regularly used outcome measures were attendance at school, quality of life, and adequate pain relief/reassurance., Conclusion: We reportedly observed a large variation in the management of children with FAPDs, due to low guideline adherence among clinicians. Improved guideline adherence may be accomplished by updating the guideline with specific recommendations per subtype, follow-up and outcome measures as well measures to improve guideline implementation., (© 2022. The Author(s).)

Background: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs., Study Design: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier., Results: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random., Conclusions: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The lack of a consensus definition of neonatal sepsis and a core outcome set (COS) proves a substantial impediment to research that influences policy and practice relevant to key stakeholders, patients and parents., Methods: A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the included studies, the described outcomes were extracted in accordance with the provisions of the Core Outcome Measures in Effectiveness Trials (COMET) handbook and registered., Results: Among 884 abstracts identified, 90 randomised controlled trials (RCTs) were included in this review. Only 30 manuscripts explicitly stated the primary and/or secondary outcomes. A total of 88 distinct outcomes were recorded across all 90 studies included. These were then assigned to seven different domains in line with the taxonomy for classification proposed by the COMET initiative. The most frequently reported outcome was survival with 74% (n = 67) of the studies reporting an outcome within this domain., Conclusions: This systematic review constitutes one of the initial phases in the protocol for developing a COS in neonatal sepsis. The paucity of standardised outcome reporting in neonatal sepsis hinders comparison and synthesis of data. The final phase will involve a Delphi Survey to generate a COS in neonatal sepsis by consensus recommendation., Impact: This systematic review identified a wide variation of outcomes reported among published RCTs on the management of neonatal sepsis. The paucity of standardised outcome reporting hinders comparison and synthesis of data and future meta-analyses with conclusive recommendations on the management of neonatal sepsis are unlikely. The final phase will involve a Delphi Survey to determine a COS by consensus recommendation with input from all relevant stakeholders., (© 2022. The Author(s).)

Broad-spectrum antibiotics for suspected early-onset neonatal sepsis (sEONS) may have pronounced effects on gut microbiome development and selection of antimicrobial resistance when administered in the first week of life, during the assembly phase of the neonatal microbiome. Here, 147 infants born at ≥36 weeks of gestational age, requiring broad-spectrum antibiotics for treatment of sEONS in their first week of life were randomized 1:1:1 to receive three commonly prescribed intravenous antibiotic combinations, namely penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime (ZEBRA study, Trial Register NL4882). Average antibiotic treatment duration was 48 hours. A subset of 80 non-antibiotic treated infants from a healthy birth cohort served as controls (MUIS study, Trial Register NL3821). Rectal swabs and/or faeces were collected before and immediately after treatment, and at 1, 4 and 12 months of life. Microbiota were characterized by 16S rRNA-based sequencing and a panel of 31 antimicrobial resistance genes was tested using targeted qPCR. Confirmatory shotgun metagenomic sequencing was executed on a subset of samples. The overall gut microbial community composition and antimicrobial resistance gene profile majorly shift directly following treatment (R 2  = 9.5%, adjusted p-value = 0.001 and R 2  = 7.5%, adjusted p-value = 0.001, respectively) and normalize over 12 months (R 2  = 1.1%, adjusted p-value = 0.03 and R 2  = 0.6%, adjusted p-value = 0.23, respectively). We find a decreased abundance of Bifidobacterium spp. and increased abundance of Klebsiella and Enterococcus spp. in the antibiotic treated infants compared to controls. Amoxicillin + cefotaxime shows the largest effects on both microbial community composition and antimicrobial resistance gene profile, whereas penicillin + gentamicin exhibits the least effects. These data suggest that the choice of empirical antibiotics is relevant for adverse ecological side-effects., (© 2022. The Author(s).)

Background: The early-onset sepsis calculator (EOSC) reduces unnecessary antibiotic treatment in newborns. However, its performance in identifying cases with early-onset disease (EOD) is unclear. We compared the sensitivity of the EOSC to the current Dutch and National Institute for Health and Care Excellence (NICE) guidelines when applied to a cohort of newborns with culture-positive early-onset sepsis and meningitis., Methods: Culture-positive Streptococcus agalactiae (GBS) and Escherichia coli ( E. coli ) sepsis and meningitis patients ≤3 days old with a gestational age ≥34 weeks, identified between 1/1/2018 and 31/1/2021 in a Dutch prospective nationwide cohort study were included. Cases were identified by treating physicians and microbiological surveillance. Primary outcome was the proportion of patients that would have been treated according to the EOSC, the Dutch, and the NICE EOD prevention guidelines. Differences between proportions were analysed using McNemar's test., Findings: We included 81 GBS and 7 E. coli EOD cases. At 4 h after birth, the EOSC would have recommended antibiotic treatment in 32 (36%) patients, compared to 44 (50%) by the Dutch ( p <0·01) and 48 (55%) by the NICE guideline ( p <0·01). The EOSC would have initially recommended routine care for 52% of patients compared to 31% and 30% for the Dutch and NICE guidelines ( p <0·01). At 24 h after birth, the EOSC would have recommended antibiotic treatment in 54 (61%) infants compared to 64 (73%) by the Dutch ( p  = 0·02) and 63 (72%) by the NICE guidelines ( p  = 0·06)., Interpretation: The sensitivity of the EOSC in identifying cases of EOD is lower compared to both Dutch and NICE guidelines, especially directly after birth. The EOSC relies more on clinical symptoms and results in less overtreatment of healthy newborns at the cost of later antibiotic treatment in initially well-appearing EOD patients., Funding: This work was supported by grants received from Netherlands Organization for Health Research and Development (ZonMw; NWO-Vidi-Grant (grant number 917·17·308); NWO-Vici-Grant (grant number 918·19·627)), the Academic Medical Centre (AMC Innovative Impulse Grant) and Steun Emma Foundation Grant., Competing Interests: MCB participates on the Advisory Board for the ENCEPH-IG trial. All the other authors declare no conflicts., (© 2021 The Author(s).)

The SARS-CoV-2 pandemic has had a significant impact worldwide, particularly in middle- and low-income countries. While this impact has been well-recognized in certain age groups, the effects, both direct and indirect, on the neonatal population remain largely unknown. There are placental changes associated, though the contributions to maternal and fetal illness have not been fully determined. The rate of premature delivery has increased and SARS-CoV-2 infection is proportionately higher in premature neonates, which appears to be related to premature delivery for maternal reasons rather than an increase in spontaneous preterm labor. There is much room for expansion, including long-term data on outcomes for affected babies. Though uncommon, there has been evidence of adverse events in neonates, including Multisystem Inflammatory Syndrome in Children, associated with COVID-19 (MIS-C). There are recommendations for reduction of viral transmission to neonates, though more research is required to determine the role of passive immunization of the fetus via maternal vaccination. There is now considerable evidence suggesting that the severe visitation restrictions implemented early in the pandemic have negatively impacted the care of the neonate and the experiences of both parents and healthcare professionals alike. Ongoing collaboration is required to determine the full impact, and guidelines for future management. IMPACT: Comprehensive review of current available evidence related to impact of the COVID-19 pandemic on neonates, effects on their health, impact on their quality of care and indirect influences on their clinical course, including comparisons with other age groups. Reference to current evidence for maternal experience of infection and how it impacts the fetus and then neonate. Outline of the need for ongoing research, including specific areas in which there are significant gaps in knowledge., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Evidence shows that activation of pulmonary vascular endothelium and neutrophils are involved in the pathophysiology of acute bronchiolitis. We hypothesized that levels of markers of endothelial activation and leukocyte counts are associated with requirement and duration of respiratory support., Methods: Thirty-four infants with bronchiolitis and eight controls were included. Nasopharyngeal swabs and blood samples were taken at admission. Serum levels of Angiopoietin (Ang)-1, Ang-2, sP-selectin, sE-selectin, vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), and leukocyte counts were measured. For univariate analysis, bronchiolitis cases were grouped into two groups, namely those not requiring and those requiring any form of respiratory support. To control for known risk factors for poor outcome (i.e., age, prematurity, and congenital heart disease), and for days post symptom onset, linear regression analysis was performed with duration of any type of respiratory support in days., Results: Ang-2 levels, Ang-2/Ang-1 ratios, sE-selectin levels, immature neutrophil count, and neutrophil/lymphocyte ratio (NLR) were higher in acute bronchiolitis versus controls. Ang-2, and NLR levels were significantly higher, and lymphocyte counts significantly lower, in infants that required respiratory support versus those that did not. Ang-2 levels (β: .32, 95% confidence interval [CI]: 0.19-1.19) and NLR (β: .68, 95% CI: 0.17-1.19) were positive predictors for the duration of respiratory support., Conclusions: Markers of endothelial and neutrophil activation are associated with respiratory support for acute bronchiolitis. Admission Ang-2 levels and NLR may be promising markers to determine requirement of respiratory support and deserve further study., (© 2021 Wiley Periodicals LLC.)