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BackgroundEpinephrine treatment is recommended during neonatal resuscitation, if ventilation and chest compressions are ineffective. Endotracheal administration is an option, if the preferred intravenous route is unavailable. We aimed to determine the efficacy of endotracheal epinephrine for achieving return of spontaneous circulation (ROSC), and maintaining physiological stability after ROSC, at standard and higher dose, in severely asphyxiated newborn lambs.MethodsNear-term fetal lambs were instrumented for physiological monitoring, and asphyxiated until asystole. Resuscitation was commenced with ventilation and chest compressions as per ILCOR recommendations. Lambs were randomly allocated to: IV Saline placebo (5 ml/kg, n=6), IV Epinephrine (20 micrograms/kg, n=9), Standard-dose ET Epinephrine (100 micrograms/kg, n=9), and High-dose ET Epinephrine (1 mg/kg, n=9). After three allocated treatment doses, rescue IV Epinephrine was administered if ROSC had not occurred. Lambs achieving ROSC were ventilated and monitored for 60 minutes before euthanasia. Brain histology was assessed for micro-hemorrhage.ResultsROSC in response to allocated treatment (without rescue IV Epinephrine) occurred in 1/6 Saline, 9/9 IV Epinephrine, 0/9 Standard-dose ET Epinephrine, and 7/9 High-dose ET Epinephrine lambs respectively. Three Saline, six Standard-dose ET Epinephrine, and one High-dose ET Epinephrine lambs achieved ROSC after rescue IV Epinephrine. Blood pressure during CPR increased after treatment with IV Epinephrine and High-dose ET Epinephrine, but not Saline or Standard-dose ET Epinephrine.After ROSC, both ET Epinephrine groups had lower pH, higher lactate, and higher blood pressure than the IV Epinephrine group. Cortex micro-hemorrhage was more frequent in the High-dose ET Epinephrine lambs (8/8 lambs examined, versus 3/8 in IV Epinephrine lambs).ConclusionsThe currently recommended dose of ET Epinephrine was ineffective in achieving ROSC. In the absence of convincing clinical or preclinical evidence of efficacy, use of ET Epinephrine at this dose may not be appropriate.High-dose ET Epinephrine requires further evaluation before clinical translation.

Objective To evaluate COVID-19 pandemic preparedness, available resources, and guidelines for neonatal care delivery among neonatal health care providers in low- and middle-income countries (LMICs) across all continents. Study design Cross-sectional, web-based survey administered between May and June, 2020. Results Of 189 invited participants in 69 LMICs, we received 145 (77%) responses from 58 (84%) countries. The pandemic provides significant challenges to neonatal care, particularly in low-income countries. Respondents noted exacerbations of preexisting shortages in staffing, equipment, and isolation capabilities. In Sub-Saharan Africa, 9/35 (26%) respondents noted increased mortality in non-COVID-19-infected infants. Clinical practices on cord clamping, isolation, and breastfeeding varied widely, often not in line with World Health Organization guidelines. Most respondents noted family access restrictions, and limited shared decision-making. Conclusions Many LMICs face an exacerbation of preexisting resource challenges for neonatal care during the pandemic. Variable approaches to care delivery and deviations from guidelines provide opportunities for international collaborative improvement.

When analysing a large cohort of Staphylococcus haemolyticus , using whole-genome sequencing, five human isolates (four from the skin and one from a blood culture) with aberrant phenotypic and genotypic traits were identified. They were phenotypically similar with yellow colonies, nearly identical 16S rRNA gene sequences and initially speciated as S. haemolyticus based on 16S rRNA gene sequence and MALDI-TOF MS. However, compared to S. haemolyticus , these five strains demonstrate: (i) considerable phylogenetic distance with an average nucleotide identity Staphylococcus borealis sp. nov. is proposed. The novel species belong to the genus Staphylococcus and is coagulase- and oxidase-negative and catalase-positive. The type strain, 51-48T, is deposited in the Culture Collection University of Gothenburg (CCUG 73747T) and in the Spanish Type Culture Collection (CECT 30011T).

We aimed to assess the impact of POLG disease on mental health and quality of life in 15 patients using the Symptom Checklist-90-R (SCL-90-R) and Short-Form 36 Health Survey (RAND-36). We found increased scores in all nine subscales of SCL-90-R, particularly phobic anxiety, depression and somatization. Further, patients reported considerably lower scores in all RAND-36 domains. This study revealed a global decline in mental health and poor quality of life in patients with POLG disease and highlights the need for increased awareness and systematic assessment in order to improve their quality of life and mental health. © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license.

Aim - To study whether a simple targeted intervention could reduce unwarranted antibiotic treatment in near‐term and term neonates with suspected, but not confirmed early‐onset sepsis. Methods - A quality improvement initiative in three Norwegian neonatal intensive care units. The intervention included an inter‐hospital clinical practice guideline for discontinuing antibiotics after 36‐48 hours if sepsis was no longer suspected and blood cultures were negative in neonates ≥ 34+0 weeks of gestation. Two units used procalcitonin in decision‐making. We compared data 12‐14 months before and after guideline implementation. The results are presented as median with interquartile ranges. Results - A total of 284 infants (2.5% of all births ≥ 34+0 weeks of gestation) received antibiotics before and 195 (1.8%) after guideline implementation (P = .0018). The two units that used procalcitonin discontinued antibiotics earlier after guideline implementation than the unit without procalcitonin. Neonates not diagnosed with sepsis were treated 49 (31‐84) hours before and 48 (36‐72) hours after guideline implementation (P = .68). In all infants, including those diagnosed with sepsis, antibiotic treatment duration was reduced from 108 (60‐144) to 96 (48‐120) hours (P = .013). Conclusion - Antibiotic treatment duration for suspected, but not confirmed early‐onset sepsis did not change. However, treatment duration for all infants and the proportion of infants commenced on antibiotics were reduced.

ObjectivesImpedance cardiography (ICG) is a non-invasive method for continuous cardiac output measurement and has the potential to improve monitoring and treatment of sick neonates. PhysioFlow® is a signal-morphology ICG-system showing promising results in adults with low and high cardiac output, but no data from neonates or neonatal models exist. The aim of this study was to investigate PhysioFlow® feasibility in asphyxiated newborn piglets.MethodsFifteen piglets, under continuous arterial heart rate (HR) and blood pressure (BP) monitoring, were asphyxiated until asystole. Cardiopulmonary resuscitation was performed and the piglets monitored after return of spontaneous circulation (ROSC). Arterial lactate was measured at baseline, every 5 min throughout asphyxiation, at asystole, and at 10 min and later every 30 min after ROSC. PhysioFlow® measured cardiac stroke volume (SV) and HR, and calculated cardiac index (CI) (L/m2/min). Registrations with a signal quality < 75% were excluded, and registrations recorded for 30 min from start of asphyxia analyzed. Pearson correlations were calculated for CI; and HR, mean BP and blood lactate.ResultsThe piglets were asphyxiated for median (interquartile range) 30 (20–35) min and had a lactate at asystole of 15.0 (9.1–17.0) mmol/L. Out of a total of 20.991 registrations in all animals combined, there were 10.148 (48.3%) registrations with a signal quality ≥ 75%. Signal quality ≥ 75% varied in individual piglets from 7 to 82% of registrations. We analyzed 1.254 registrations recorded 30 min from initiation of asphyxia, i.e., in piglets with brief asphyxia times, this included cardiopulmonary resuscitation and post-ROSC observation. There was a positive correlation between CI and SVI (r = 0.90, p < 0.001), and between CI and HR (r = 0.446, p < 0.001). There was no correlation between CI, or mean BP or lactate (p = 0.98 and 0.51, respectively).ConclusionAbout half of ICG-registrations in asphyxiated piglets were of good quality. However, signal quality was highly variable between piglets. In total, there was a higher proportion of reliable ICG-registrations than reported from clinical delivery room studies using electrical velocimetry. Our data are physiologically plausible and supports further research evaluating PhysioFlow® for cardiac output monitoring in perinatal asphyxia. In particular, factors influencing inter-individual variations in signal quality should be explored.

Children and adolescents with Down syndrome have a comprehensive need for follow-up in the primary and specialist healthcare services.In June 2019, we published a questionnaire on the Facebook group of the Norwegian Network for Down syndrome. The purpose was to investigate user experiences among parents of children and adolescents with Down syndrome in the age group 0-20 years, in their encounter with the healthcare services.We received 174 responses. Those most satisfied were parents of children who received follow-up for secondary diagnoses such as vision problems, heart defects and endocrine disorders. Those least satisfied were parents of children with problems associated with behaviour, sleep and puberty. Approximately 6 out of 10 parents reported no negative experiences in their encounter with the healthcare services, but 29/161 (18 %) reported that the diagnosis of Down syndrome had contributed to treatment failure by the paediatrician or in the child rehabilitation service.The study indicates a need for improved follow-up of children and adolescents with Down syndrome, both in the primary and specialist healthcare services.

We describe a newborn infant with hydrocephalus and a ventriculoperitoneal shunt infection caused by Brevibacterium casei. Essential for correct diagnosis was rapid species identification by matrix-assisted laser desorption/ionization time-of-flight, after initial report of coryneform bacteria. The patient responded well to vancomycin and rifampicin for 15 days. The shunt was not removed. Repeated cerebrospinal fluid cultures up to 4 months after therapy remained negative.

Urinary tract infections are common in children. The purpose of this study was to describe national resistance data from urinary isolates from children with a view to informing antibiotic use.We conducted an observational study based on culture responses with resistance determination in urine from the Norwegian Surveillance System for Antimicrobial Drug Resistance (NORM). All urinary isolates from children (0-17 years) in the period 2013-17 were included and compared with urinary isolates from adults. For cephalexin resistance, we used data from two Norwegian hospitals covering the period 2015-19.Of 13 211 urinary isolates included in the NORM register, 589 (4.5 %) were from children. Weighted by the number of data collection days, Escherichia coli accounted for 85.2 % of the isolates from children. For E. coli, there was a higher proportion of trimethoprim resistance in urine samples from children (27.0 %) compared to adults (22.9 %), p = 0.02. For ciprofloxacin, we found a lower resistance rate in E. coli in urine samples from children (5.7 %) compared to adults (8.7 %), p = 0.03. For other selected antibiotics, we found the following resistance rates in E. coli in children: nitrofurantoin (0.5 %), mecillinam (4.0 %), cephalexin (4.3 %), amoxicillin-clavulanic acid (7.2 %) and trimethoprim-sulfamethoxazole (24.1 %).Pivmecillinam, cephalexin and amoxicillin-clavulanic acid are relevant choices in the empirical treatment of upper urinary tract infections. Nitrofurantoin and pivmecillinam are relevant for lower urinary tract infections. Trimethoprim and trimethoprim-sulfamethoxazole should only be used after resistance determination.

Aim To explore and compare expired CO2 (ECO2) and heart rate (HR), during newborn resuscitation with bag-mask ventilation, as predictors of 24-h outcome. Methods Observational study from March 2013 to June 2017 in a rural Tanzanian hospital. Side-stream measures of ECO2, ventilation parameters, HR, clinical information, and 24-h outcome were recorded in live born bag-mask ventilated newborns with initial HR < 120 bpm. We analysed the data using logistic regression models and compared areas under the receiver operating curves (AUC) for ECO2 and HR within three selected time intervals after onset of ventilation (0–30 s, 30.1–60 s and 60.1–300 s). Results Among 434 included newborns (median birth weight 3100 g), 378 were alive at 24 h, 56 had died. Both ECO2 and HR were independently significant predictors of 24-h outcome, with no differences in AUCs. In the first 60 s of ventilation, ECO2 added extra predictive information compared to HR alone. After 60 s, ECO2 lost significance when adjusted for HR. In 70% of newborns with initial ECO2

Background Urinary tract infections are common in children. The purpose of this study was to describe national resistance data from urinary isolates from children with a view to informing antibiotic use. Method We conducted an observational study based on culture responses with resistance determination in urine from the Norwegian Surveillance System for Antimicrobial Drug Resistance (NORM). All urinary isolates from children (0-17 years) in the period 2013-17 were included and compared with urinary isolates from adults. For cephalexin resistance, we used data from two Norwegian hospitals covering the period 2015-19. Results Of 13 211 urinary isolates included in the NORM register, 589 (4.5 %) were from children. Weighted by the number of data collection days, Escherichia coli accounted for 85.2 % of the isolates from children. For E. coli, there was a higher proportion of trimethoprim resistance in urine samples from children (27.0 %) compared to adults (22.9 %), p = 0.02. For ciprofloxacin, we found a lower resistance rate in E. coli in urine samples from children (5.7 %) compared to adults (8.7 %), p = 0.03. For other selected antibiotics, we found the following resistance rates in E. coli in children: nitrofurantoin (0.5 %), mecillinam (4.0 %), cephalexin (4.3 %), amoxicillin-clavulanic acid (7.2 %) and trimethoprim-sulfamethoxazole (24.1 %). Interpretation Pivmecillinam, cephalexin and amoxicillin-clavulanic acid are relevant choices in the empirical treatment of upper urinary tract infections. Nitrofurantoin and pivmecillinam are relevant for lower urinary tract infections. Trimethoprim and trimethoprim-sulfamethoxazole should only be used after resistance determination.

Background Children and adolescents with Down syndrome have a comprehensive need for follow-up in the primary and specialist healthcare services. Material and method In June 2019, we published a questionnaire on the Facebook group of the Norwegian Network for Down syndrome. The purpose was to investigate user experiences among parents of children and adolescents with Down syndrome in the age group 0-20 years, in their encounter with the healthcare services. Results We received 174 responses. Those most satisfied were parents of children who received follow-up for secondary diagnoses such as vision problems, heart defects and endocrine disorders. Those least satisfied were parents of children with problems associated with behaviour, sleep and puberty. Approximately 6 out of 10 parents reported no negative experiences in their encounter with the healthcare services, but 29/161 (18 %) reported that the diagnosis of Down syndrome had contributed to treatment failure by the paediatrician or in the child rehabilitation service. Interpretation The study indicates a need for improved follow-up of children and adolescents with Down syndrome, both in the primary and specialist healthcare services.

BACKGROUND: International guidelines for resuscitation recommend using positive end-expiratory pressure (PEEP) during ventilation of preterm newborns. Reliable PEEP-valves for self-inflating bags have been lacking, and effects of PEEP during resuscitation of term newborns are insufficiently studied. The objective was to determine if adding a new PEEP valve to the bag-mask during resuscitation of term and near-term newborns could improve heart rate response. METHODS: This randomized controlled trial was performed at Haydom Lutheran Hospital in Tanzania (September 2016 to June 2018). Helping Babies Breathe–trained midwives performed newborn resuscitation using self-inflating bags with or without a new, integrated PEEP valve. All live-born newborns who received bag-mask ventilation at birth were eligible. Heart rate response measured by ECG was the primary outcome, and clinical outcome and ventilation data were recorded. RESULTS: Among 417 included newborns (median birth weight 3200 g), 206 were ventilated without and 211 with PEEP. We found no difference in heart rate response. Median (interquartile range) measured PEEP in the PEEP group was 4.7 (2.0–5.6) millibar. The PEEP group received lower tidal volumes (4.9 [1.9–8.2] vs 6.3 [3.9–10.5] mL/kg; P = .02) and had borderline lower expired CO2 (2.9 [1.5–4.3] vs 3.3 [1.9–5.0] %; P = .05). Twenty four-hour mortality was 9% in both groups. CONCLUSIONS: We found no evidence for improved heart rate response during bag-mask ventilation with PEEP compared with no PEEP. The PEEP valve delivered a median PEEP within the intended range. The findings do not support routine use of PEEP during resuscitation of newborns around term.

Children and adolescents are at lower risk of disease caused by SARS-CoV-2. We describe the incidence of confirmed infection and hospitalisation of children and adolescents under the age of 20 in Norway, and specifically among those with underlying conditions.The Norwegian Directorate of Health has collaborated with the Norwegian Institute of Public Health on the establishment of a data extraction system to monitor the coronavirus outbreak. Data from the specialist health service (Norwegian Patient Registry, NPR), and the primary health service (Norwegian Registry for Primary Health Care, NRPHC) are linked to data on positive SARS-CoV-2 tests from the Surveillance System for Communicable Diseases (MSIS). This covers all persons living in Norway as of 1 March 2020, with data on confirmed infection up to and including 13 May 2020 and on hospitalisations up to and including 30 April 2020.Of 8 125 persons with confirmed SARS-CoV-2 in the whole population, 493 (6.1 %) were under 20 years old. The median age of the under-20s was 15 years, and 252 (51 %) were girls. 3 % were hospitalised. No deaths were registered among patients aged under 20 in Norway. We found a somewhat larger share with confirmed SARS-CoV-2 in the group with diseases of the neuromuscular system.Few children and adolescents have had SARS-CoV-2 confirmed, and only a very few have been hospitalised. Underlying conditions may result in a lower threshold for testing, and hence a higher incidence of confirmed infection in this group, although higher risk cannot be excluded.

Background To date, few data on paediatric COVID-19 have been published, and most reports originate from China. This study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across Europe to inform physicians and health-care service planning during the ongoing pandemic. Methods This multicentre cohort study involved 82 participating health-care institutions across 25 European countries, using a well established research network—the Paediatric Tuberculosis Network European Trials Group (ptbnet)—that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. We included all individuals aged 18 years or younger with confirmed SARS-CoV-2 infection, detected at any anatomical site by RT-PCR, between April 1 and April 24, 2020, during the initial peak of the European COVID-19 pandemic. We explored factors associated with need for intensive care unit (ICU) admission and initiation of drug treatment for COVID-19 using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with ICU admission. Findings 582 individuals with PCR-confirmed SARS-CoV-2 infection were included, with a median age of 5·0 years (IQR 0·5–12·0) and a sex ratio of 1·15 males per female. 145 (25%) had pre-existing medical conditions. 363 (62%) individuals were admitted to hospital. 48 (8%) individuals required ICU admission, 25 (4%) mechanical ventilation (median duration 7 days, IQR 2–11, range 1–34), 19 (3%) inotropic support, and one ( Interpretation COVID-19 is generally a mild disease in children, including infants. However, a small proportion develop severe disease requiring ICU admission and prolonged ventilation, although fatal outcome is overall rare. The data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed. Funding ptbnet is supported by Deutsche Gesellschaft für Internationale Zusammenarbeit.

BACKGROUND Suspected early-onset sepsis (EOS) results in antibiotic treatment of a substantial number of neonates who are uninfected. We evaluated if an approach using serial physical examinations (SPEs) can reduce antibiotic exposure for suspected EOS in term neonates during the first 3 days of life, without affecting safety. METHODS Within a quality-improvement framework, SPEs for 24-48 hours for neonates with suspected EOS was implemented in the neonatal intensive care unit, Stavanger, Norway. The proportion of neonates ≥37 weeks gestation exposed to antibiotics, antibiotic therapy-days and the safety outcome time from birth to start antibiotics were compared between a baseline period (April 2014-February 2016), when a risk factor based approach was used, and a post-SPE-implementation period (January 2017-November 2018). RESULTS We included all term live born neonates (n = 17,242) in the 2 periods. There was a 57% relative reduction in neonates exposed to antibiotics; 2.9% in the baseline and 1.3% in the post-implementation period, P < 0.001. There was a 60% relative reduction in mean antibiotic therapy-days/1000 patient-days; from 320 to 129, P < 0.001, and a 50% relative reduction in time to initiate antibiotics in suspected EOS-cases, from median (interquartile range) 14 (5-28) to 7 (3-17) hours, P = 0.003. The incidence of culture-positive EOS remained unchanged. There were no infection-attributable deaths. CONCLUSIONS Implementing SPE to guide empiric antibiotic therapy in term neonates with suspected EOS more than halved the burden of antibiotic exposure, without delay of antibiotic treatment of infected neonates or increased sepsis-related mortality.

Objectives To systematically review and meta-analyse the relationship between antibiotic exposure in neonates and the following early adverse outcomes: necrotizing enterocolitis (NEC), invasive fungal infections (IFIs) and/or death. Methods Data sources were PubMed, Embase, Medline and the Cochrane Database (to December 2016), supplemented by manual searches of reference lists. Randomized controlled trials (RCTs) and observational studies were included if they provided data on different categories of antibiotic exposures (yes versus no, long versus short duration, and/or broad- versus narrow-spectrum regimens) and the risk of developing NEC, IFI and/or death in the neonatal period. Two reviewers extracted data and evaluated the risk of bias using the Cochrane Handbook, adapted to include observational studies. When appropriate, meta-analyses were conducted using the random-effect model. Results We identified 9 RCTs and 38 observational studies. The quality of the majority of studies was poor to moderate. There was a significant association between prolonged antibiotic exposure and an increased risk of NEC in five observational studies (5003 participants) and/or risk of death in five observational studies (13 534 participants). Eleven of 15 studies with data on broad- versus narrow-spectrum regimens reported an increased risk of IFI after broad-spectrum antibiotic exposure, in particular with third-generation cephalosporins and carbapenems. Meta-analysis was limited by few and old RCTs, insufficient sample sizes and diversity of antibiotic exposure and outcomes reported. Conclusions Prolonged antibiotic exposure in uninfected preterm infants is associated with an increased risk of NEC and/or death, and broad-spectrum antibiotic exposure is associated with an increased risk of IFI.

Aim This study compared the management and outcomes of early-onset neonatal sepsis (EONS) in two tertiary neonatal units in Denmark and Norway. Methods We retrospectively studied all infants diagnosed with EONS between April 2010 and March 2013 and managed at Odense University Hospital, Denmark, and the University Hospital of North Norway, Norway. Clinical and laboratory data were collected from patient records. Results We identified 137 EONS cases in Denmark and 101 in Norway. There were 35 culture-confirmed EONS cases: 16% of the Danish cases and 13% of the Norwegian cases. Staphylococcus aureus was the most frequently detected pathogen in 11 cases (31%), followed by Group B streptococci in nine (26%) and Escherichia coli in six (17%). In 85% of the 238 cases, the empiric therapy comprised gentamicin and a beta-lactam, namely ampicillin in Denmark and benzylpenicillin in Norway. Patients with positive blood cultures had higher C-reactive protein levels than patients with negative blood cultures and higher sepsis-attributable mortality. Lumbar punctures were performed more frequently in Denmark. Conclusion There were marginal differences in the management of EONS between units in Denmark and Norway, mainly in their choice of antibiotics and the use of lumbar punctures. Staphylococcus aureus was the most common pathogen.

Staphylococcus haemolyticus is a skin commensal gaining increased attention as an emerging pathogen of nosocomial infections. However, knowledge about the transition from a commensal to an invasive lifestyle remains sparse and there is a paucity of studies comparing pathogenicity traits between commensal and clinical isolates. In this study, we used a pan-genomic approach to identify factors important for infection and hospital adaptation by exploring the genomic variability of 123 clinical isolates and 46 commensal S. haemolyticus isolates. Phylogenetic reconstruction grouped the 169 isolates into six clades with a distinct distribution of clinical and commensal isolates in the different clades. Phenotypically, multi-drug antibiotic resistance was detected in 108/123 (88%) of the clinical isolates and 5/46 (11%) of the commensal isolates (p < 0.05). In the clinical isolates, we commonly identified a homolog of the serine-rich repeat glycoproteins sraP. Additionally, three novel capsular polysaccharide operons were detected, with a potential role in S. haemolyticus virulence. Clinical S. haemolyticus isolates showed specific signatures associated with successful hospital adaption. Biofilm forming S. haemolyticus isolates that are resistant to oxacillin (mecA) and aminoglycosides (aacA-aphD) are most likely invasive isolates whereas absence of these traits strongly indicates a commensal isolate. We conclude that our data show a clear segregation of isolates of commensal origin, and specific genetic signatures distinguishing the clinical isolates from the commensal isolates. The widespread use of antimicrobial agents has probably promoted the development of successful hospital adapted clones of S. haemolyticus clones through acquisition of mobile genetic elements or beneficial point mutations and rearrangements in surface associated genes.

Staphylococcus haemolyticus is a skin commensal gaining increased attention as an emerging pathogen of nosocomial infections. However, knowledge about the transition from a commensal to an invasive lifestyle remains sparse and there is a paucity of studies comparing pathogenicity traits between commensal and clinical isolates. In this study, we used a pan-genomic approach to identify factors important for infection and hospital adaptation by exploring the genomic variability of 123 clinical isolates and 46 commensal S. haemolyticus isolates. Phylogenetic reconstruction grouped the 169 isolates into six clades with a distinct distribution of clinical and commensal isolates in the different clades. Phenotypically, multi-drug antibiotic resistance was detected in 108/123 (88%) of the clinical isolates and 5/46 (11%) of the commensal isolates (p < 0.05). In the clinical isolates, we commonly identified a homolog of the serine-rich repeat glycoproteins sraP. Additionally, three novel capsular polysaccharide operons were detected, with a potential role in S. haemolyticus virulence. Clinical S. haemolyticus isolates showed specific signatures associated with successful hospital adaption. Biofilm forming S. haemolyticus isolates that are resistant to oxacillin (mecA) and aminoglycosides (aacA-aphD) are most likely invasive isolates whereas absence of these traits strongly indicates a commensal isolate. We conclude that our data show a clear segregation of isolates of commensal origin, and specific genetic signatures distinguishing the clinical isolates from the commensal isolates. The widespread use of antimicrobial agents has probably promoted the development of successful hospital adapted clones of S. haemolyticus clones through acquisition of mobile genetic elements or beneficial point mutations and rearrangements in surface associated genes.

Objectives Extended high frequency (EHF) audiometry is the recommended method for monitoring oxotoxic hearing loss in children. This study aims to provide high quality reference audiological data for the EHF range in healthy children. Methods Participants were 126 healthy schoolchildren between 6 and 14 years of age. All participants were term born with normal birthweight, had not suffered severe neonatal illness and had no history of middle ear disease. Results The averaged mean (SD) hearing threshold for the EHF 9, 10, 11.2, 12.5, 14 and 16 kHz was −0.4 (6.0) dB HL. The lowest mean hearing thresholds were observed at 14 kHz with −4.2 (8.7) dB and at 16 kHz with −6.4 (12.1) dB HL. We found significantly lower thresholds at 16 kHz for children aged 6–9 years (−8.7 dB HL) compared to age 10–14 years (−3.9 db HL), p 0.042. For both age groups the inter-subject variability increased in the highest frequencies. We found no significant differences in mean hearing thresholds between right and left ears at any frequency, and no gender differences in the EHF range. Conclusion Our findings support that decreased hearing sensitivity in the EHF's may start around or even before the age of 10 years. In order to use EHF audiometry for ototoxic monitoring in children, we suggest to establish an international reference standard for hearing levels in children under the age of 18. Specific references for different age groups are needed as hearing in the EHF range appears to gradually deteriorate from an early age. Clinical trial registration NCT03253614.

Background Allergic diseases are common chronic diseases in children and adolescents, but limited epidemiological data are available during transition into adulthood. Nasal Staphylococcus aureus carriage has been linked to increased prevalence of allergic disease. The objective of this study was to define the prevalence of allergic diseases in adolescents above the Arctic Circle in Northern Norway and to study the associations of S. aureus carriage with allergic diseases. Methods A school-based cohort in late adolescence (18-19 years) was invited to participate in a cross-sectional study on lifestyle and health, and 868 attended (71.9%). Self-reported allergic disease and severity of eczema were assessed by Mechanisms of the Development of Allergy and Patient-Oriented Eczema Measure questionnaires. Participants were tested with spirometry and exhaled nitric oxide (FeNO) and swabbed for bacterial culture from nose and eczematous skin. Results We found asthma, eczema, allergic rhinitis (AR), and nasal S. aureus carriage among 11.9%, 10.4%, 26.0%, and 51.3% of the participants, respectively, and 10.2% had allergic multimorbidity. Lifetime prevalence for any allergic disease was 45.1%. Reduced lung function and increased FeNO were found in 11.6% and 22.1% in participants with asthma, respectively. Nasal S. aureus carriage was associated with eczema, severe asthma, and severe AR. FeNO > 25 ppb was associated with both asthma and nasal S. aureus carriage. Conclusion Asthma, eczema, and AR are common among adolescents above the Arctic Circle in Norway. Allergic disease is associated with S. aureus carriage, but its role in the pathogenesis and severity is not established.

Background Sepsis is a leading cause of neonatal morbidity and mortality. Clinical suspicion may lead to overuse of antibiotics. The objective of this study was to assess the epidemiology of early-onset sepsis (EOS) and antibiotic exposure during the first week of life in Norwegian term infants. Methods This is a nationwide population-based study from the Norwegian Neonatal Network. During the 3-year study period (2009-2011), 20 of Norway's 21 neonatal units prospectively collected data. Among 168,877 live-born (LB) term infants born during the study period, 10,175 (6.0%) infants were hospitalized in the first week of life and included in the study. Results There were 91 cases of culture-confirmed EOS (0.54 per 1000 LB) and 1447 cases classified as culture-negative EOS (8.57 per 1000 LB). The majority of culture-confirmed EOS cases were caused by Gram-positives (83/91; 91%), most commonly group B streptococci (0.31 per 1000 LB). Intravenous antibiotics were administered to 3964 infants; 39% of all admissions and 2.3% of all LB term infants. Empiric therapy consisted of an aminoglycoside and either benzylpenicillin or ampicillin in 95% of the cases. The median (interquartile range) treatment duration was 8 (7-10) days for culture-confirmed EOS and 6 (5-7) days for culture-negative EOS. There was 1 EOS-attributable death (group B streptococcal EOS) during the study period. Conclusions In this registry-based study, the incidence of culture-confirmed EOS was in line with previous international reports and the mortality was very low. A large proportion of infants without infection were treated with antibiotics. Measures should be taken to spare neonates unnecessary antibiotic treatment.

The following article, Klingenberg, C., Kornelisse, R.F., Buonocore, G., Maier, R.F. & Stocker, M. (2018). Culture-negative early-onset neonatal sepsis - at the crossroad between efficient sepsis care and antimicrobial stewardship. Frontiers in pediatrics, 6, 285, can be accessed at https://doi.org/10.3389/fped.2018.00285. Sepsis is a leading cause of mortality and morbidity in neonates. Presenting clinical symptoms are unspecific. Sensitivity and positive predictive value of biomarkers at onset of symptoms are suboptimal. Clinical suspicion therefore frequently leads to empirical antibiotic therapy in uninfected infants. The incidence of culture confirmed early-onset sepsis is rather low, around 0.4–0.8/1000 term infants in high-income countries. Six to 16 times more infants receive therapy for culture-negative sepsis in the absence of a positive blood culture. Thus, culture-negative sepsis contributes to high antibiotic consumption in neonatal units. Antibiotics may be life-saving for the few infants who are truly infected. However, overuse of broad-spectrum antibiotics increases colonization with antibiotic resistant bacteria. Antibiotic therapy also induces perturbations of the non-resilient early life microbiota with potentially long lasting negative impact on the individual‘s own health. Currently there is no uniform consensus definition for neonatal sepsis. This leads to variations in management. Two factors may reduce the number of culture-negative sepsis cases. First, obtaining adequate blood cultures (0.5–1 mL) at symptom onset is mandatory. Unless there is a strong clinical or biochemical indication to prolong antibiotics physician need to trust the culture results and to stop antibiotics for suspected sepsis within 36–48 h. Secondly, an international robust and pragmatic neonatal sepsis definition is urgently needed. Neonatal sepsis is a dynamic condition. Rigorous evaluation of clinical symptoms (“organ dysfunction”) over 36–48 h in combination with appropriately selected biomarkers (“dysregulated host response”) may be used to support or refute a sepsis diagnosis.

Chest compressions (CC) and adrenaline administration are recommended in asphyxiated newborns with persistent bradycardia despite effective ventilation. The effects of CC on cerebral blood flow in newborns at birth are unknown. Our aim was to determine the effects of CC, with or without adrenaline administration, on the return of spontaneous circulation, carotid blood flow (CBF), and carotid arterial pressure (CAP) in asphyxiated near-term lambs.Asphyxia was induced in near-term lambs by clamping the umbilical cord and delaying ventilation onset until spontaneous circulation ceased. Lambs were then resuscitated by positive pressure ventilation along with CC followed by adrenaline administration. CAP and CBF were continuously recorded.Mean CAP did not increase significantly during CC and only increased following adrenaline administration. CC did not increase mean CBF but increased CBF amplitude due to increased peak flow and the onset of retrograde flow during diastole. Adrenaline increased mean CBF from 1 ± 2 to 15 ± 5 ml/kg/min and abolished retrograde diastolic CBF, leading to the return in spontaneous circulation.We conclude that CC with adrenaline administration was required to increase CBF and restore spontaneous circulation in asphyxiated lambs. Low CBF and retrograde diastolic CBF during CC indicate hypoperfusion to the brain.

Background Mitochondria play an important role in iron metabolism and haematopoietic cell homeostasis. Recent studies in mice showed that a mutation in the catalytic subunit of polymerase gamma (POLG) was associated with haematopoietic dysfunction including anaemia. The aim of this study was to analyse the frequency of anaemia in a large cohort of patients with POLG related disease. Methods We conducted a multi-national, retrospective study of 61 patients with confirmed, pathogenic biallelic POLG mutations from six centres, four in Norway and two in the United Kingdom. Clinical, laboratory and genetic data were collected using a structured questionnaire. Anaemia was defined as an abnormally low haemoglobin value adjusted for age and sex. Univariate survival analysis was performed using log-rank test to compare differences in survival time between categories. Results Anaemia occurred in 67% (41/61) of patients and in 23% (14/61) it was already present at clinical presentation. The frequency of anaemia in patients with early onset disease including Alpers syndrome and myocerebrohepatopathy spectrum (MCHS) was high (72%) and 35% (8/23) of these had anaemia at presentation. Survival analysis showed that the presence of anaemia was associated with a significantly worse survival (P = 0.004). Conclusion Our study reveals that anaemia can be a feature of POLG-related disease. Further, we show that its presence is associated with significantly worse prognosis either because anaemia itself is impacting survival or because it reflects the presence of more serious disease. In either case, our data suggests anaemia is a marker for negative prognosis.

Bifidobacteria are commensals that colonize the orogastrointestinal tract and rarely cause invasive human infections. However, an increasing number of bifidobacterial blood culture isolates has lately been observed in Norway. In order to investigate the pathogenicity of the Bifidobacterium species responsible for bacteremia, we studied Bifidobacterium isolates from 15 patients for whom cultures of blood obtained from 2013 to 2015 were positive. We collected clinical data and analyzed phenotypic and genotypic antibiotic susceptibility. All isolates (11 Bifidobacterium longum , 2 B. breve , and 2 B. animalis isolates) were subjected to whole-genome sequencing. The 15 patients were predominantly in the extreme lower or upper age spectrum, many were severely immunocompromised, and 11 of 15 had gastrointestinal tract-related conditions. In two elderly patients, the Bifidobacterium bacteremia caused a sepsis-like picture, interpreted as the cause of death. Most bifidobacterial isolates had low MICs (≤0.5 mg/liter) to beta-lactam antibiotics, vancomycin, and clindamycin and relatively high MICs to ciprofloxacin and metronidazole. We performed a pangenomic comparison of invasive and noninvasive B. longum isolates based on 65 sequences available from GenBank and the sequences of 11 blood culture isolates from this study. Functional annotation identified unique genes among both invasive and noninvasive isolates of Bifidobacterium . Phylogenetic clusters of invasive isolates were identified for a subset of the B. longum subsp. longum isolates. However, there was no difference in the number of putative virulence genes between invasive and noninvasive isolates. In conclusion, Bifidobacterium has an invasive potential in the immunocompromised host and may cause a sepsis-like picture. Using comparative genomics, we could not delineate specific pathogenicity traits characterizing invasive isolates.

Dosing regimens often recommend lower gentamicin doses in neonates (3–5 mg/kg) than in older children (7 mg/kg or more) despite the higher volume of distribution in neonates. We studied an extended-interval high-dose (6 mg/kg) gentamicin regimen in a single tertiary neonatal unit from 2004–2012. During the first week of life, dosing interval was 24 h for term infants, 36 h for preterm infants with gestational age (GA) 29–36 weeks and 48 h for preterm infants with GA

Objective To compare patient comfort in preterm infants treated with heated humidified high flow nasal cannulae (HHHFNC) versus nasal continuous positive airway pressure (NCPAP). Design Randomised cross-over trial (2×24 h). Setting Single tertiary neonatal unit. Patients 20 infants less than 34 weeks postmenstrual age treated with NCPAP due to mild respiratory illness. Interventions After parental consent, infants were randomised to 24 h of treatment with NCPAP or HHHFNC followed by 24 h of the alternate therapy. Main outcome measures Primary outcome was patient comfort assessed by the EDIN (neonatal pain and discomfort) scale. Secondary outcomes were respiratory parameters (respiratory rate, FiO 2 , SpO 2 , TcPCO 2 ), ambient noise, salivary cortisol and parental assessments of their child. Results We found no differences between HHHFNC and NCPAP in mean cumulative EDIN score (10.7 vs 11.1, p=0.25) or ambient noise (70 vs 74 dBa, p=0.18). Parents assessed HHHFNC treatment as significantly better in the three domains, 1) child satisfied, 2) parental contact and interaction and 3) possibility to take part in care. Mean respiratory rate over 24 h was lower during HHHFNC than CPAP (41 vs 46, p=0.001). Other respiratory parameters were similar. Conclusions Using EDIN scale, we found no difference in patient comfort with HHHFNC versus NCPAP. However, parents preferred HHHFNC, and during HHHFNC respiratory rate was lower than during NCPAP. ClinicalTrials.gov, number NCT01526226.

RESULTS Fifty (96 %) of the maternity units returned a completed questionnaire. Twelve units (24 %) reported early clamping of the umbilical cord of term newborns delivered at term, and 38 (76 %) reported to practise late clamping. Nineteen maternity units (38 %) followed written routines for cord clamping of term neonates, and among these, early cord clamping was practised in nine (47 %). In the 31 maternity units that had no written routines, early cord clamping was practised in three (10 %). Twenty-seven of the maternity units reported that the child is placed on the maternal abdomen prior to clamping the cord, 14 reported that the child commonly is held below the introitus prior to cord clamping, and the rest did not report any consistent practice. INTERPRETATION There is wide variation in the practice for umbilical cord clamping in Norwegian maternity units, many of which have no written guidelines. We argue that national guidelines for umbilical cord clamping of neonates should be established.

OBJECTIVE: To determine 1-year survival and major neonatal morbidities (intracranial hemorrhage grade >2, cystic periventricular leukomalacia, retinopathy of prematurity grade >2, necrotizing enterocolitis, severe bronchopulmonary dysplasia) among extremely preterm infants in Norway in 2013–2014, and to compare the results to the first Norwegian Extreme Prematurity Study 1999–2000 and similar contemporary European population-based studies. METHODS: Population-based study of all infants born at 22 through 26 weeks’ gestation in Norway in 2013–2014. Prospectively collected data were obtained by linking data in the Norwegian Neonatal Network to the Medical Birth Registry of Norway. RESULTS: Of 420 infants (incidence 3.5 per 1000 births), 145 were stillborn (34.5%), 275 were live-born (82.3% of the 334 fetuses alive at admission for obstetrical care), and 251 (91.3% of live-born infants) were admitted to a neonatal unit. The survival among live-born infants was 18% at 22 weeks, 29% at 23 weeks, 56% at 24 weeks, 84% at 25 weeks and 90% at 26 weeks (for each week increment in gestational age: odds ratio 3.3; 95% confidence interval, 2.4–4.4). Among infants surviving to 1 year of age, major neonatal morbidity was diagnosed in 55%. Decreasing gestational age was moderately associated with rates of major morbidity (odds ratio 1.6; 95% confidence interval, 1.2–2.2). CONCLUSIONS: Compared to the previous 1999–2000 cohort, the rate of stillbirth before admission to an obstetrical unit increased, whereas the survival rate among live born infants was similar in our 2013–2014 cohort. Neonatal morbidity rates remain high among extremely preterm infants.

PurposeMutations in POLG, the most common single-gene cause of inherited mitochondrial disease, are diagnostically challenging owing to clinical heterogeneity and overlap between syndromes. We aimed to improve the clinical recognition of POLG-related disorders in the pediatric population.MethodsWe performed a multinational, phenotype: genotype study using patients from three centers, two Norwegian and one from the United Kingdom. Patients with age at onset12 years and confirmed pathogenic biallelic POLG mutations were considered eligible.ResultsA total of 27 patients were identified with a median age at onset of 11 months (range 0.6-80.4). The majority presented with global developmental delay (n=24/24, 100%), hypotonia (n=22/23, 96%) and faltering growth (n=24/27, 89%). Epilepsy was common, but notably absent in patients with the myocerebrohepatopathy spectrum phenotype. We identified two novel POLG gene mutations.ConclusionOur data suggest that POLG-related disease should be suspected in any child presenting with diffuse neurological symptoms. Full POLG sequencing is recommended since targeted screening may miss mutations. Finally, we simplify the classification of POLG-related disease in children using epilepsy as the crucial defining element; we show that Alpers and myocerebrohepatopathy spectrum follow different outcomes and that they manifest different degrees of respiratory chain dysfunction.

Staphylococcus epidermidis (SE) is an important cause of late-onset sepsis in neonates. SE frequently produces a polysaccharide intercellular adhesin (PIA) biofilm, important in the pathogenesis of these infections. Little is known about how the neonatal innate immune system reacts to SE biofilm–associated infections. Our hypothesis was that SE biofilms induce a lower complement activation in neonates as compared with adults. Cord blood from term infants (n = 15) and blood from adults (n = 6) were studied in an ex vivo whole-blood sepsis model. A PIA biofilm–producing strain (SE1457) and its isogenic mutant (M10), producing a non-PIA biofilm, were used. Both SE biofilms induced stronger complement activation in adult than in cord blood (P ≤ 0.033). We found lower levels of antibodies toward both PIA (P = 0.002) and the whole bacterium (P = 0.001) in cord vs. adult blood. By contrast, the interleukin-8 (IL-8) and IL-6 secretion were higher in cord than in adult blood (P ≤ 0.002). The PIA biofilm induced stronger complement activation than the non-PIA biofilm. We conclude that the neonatal complement system exhibits a maturational deficiency. This may reduce the ability of neonates to combat biofilm-associated SE infections.