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The European Society for Paediatric Research (ESPR) first developed recommendations for a Neonatology specific European training curriculum in 1998, with updates in 2007 and 2021. The aim of these recommendations was to define a common, European standard of training for national educational programmes for Neonatologists. Following the Union of European Medical Specialists' (UEMS) framework of European Training Requirements (ETR), and similar to the American Board of Pediatrics (ABP) recommendations, graduates of training programmes conforming to the ETR will be eligible throughout Europe for recognition of equality of training, and with that should be enabled to freedom-of-movement. This concept also accounts for neonatal specialists. We therefore present the pan-European work on the ETR Neonatology in its third iteration (ETR III), summarising the basic requirements for contemporary training programmes, trainers, and training centres in neonatology. We highlight the European School of Neonatology (ESN) as a comprehensive online educational platform which provides the theoretical and practical background to satisfy the ETR-III. Lastly, we introduce the European Board of Neonatal & Child Health Research (EBNCHR) as a committee dedicated to gaining acceptance for the concept of harmonising education and training in Neonatology and recognising Neonatology as a Paediatric subspecialty in every European Union member state. IMPACT: Neonatology currently is not uniformly recognised as a Paediatric subspecialty throughout the 27 European countries. Hence, training in Neonatology formerly followed no commonly agreed standard throughout the European Union (EU). To ensure a minimum standard of care, an agreed minimum standard of training is required. The European Society for Paediatric Research (ESPR) has led on generating an EU-accredited, pan-European Syllabus for Neonatal training in Europe, the European Training Requirements (ETR) in Neonatology (2021). This article presents the ETR Neonatology from commissioning to accreditation and discusses means of how high-grade post-graduate education, aligned with the ETR can be achieved by practitioners., Competing Interests: Competing interests: The authors declare no competing interests. Consent for publication: All co-authors have given their consent to the final publication., (© 2025. The Author(s).)

Neonatology is a pediatric sub-discipline focused on providing care for newborn infants, including healthy newborns, those born prematurely, and those who present with illnesses or malformations requiring medical care. The European Training Requirements (ETR) in Neonatology provide a framework for standardized quality and recognition of equality of training throughout Europe. The latest ETR version was approved by the Union of European Medical Specialists (UEMS) in April 2021. Here, we present the curriculum of the European School of Neonatology Master of Advanced Studies (ESN MAS), which is based on the ETR in Neonatology and aims to provide a model for effective and standardized training and education in neonatal medicine. We review the history and theory that form the foundation of contemporary medical education and training, provide a literature review on best practices for medical training, pediatric training, and neonatology training specifically, including educational frameworks and evidence-based systems of evaluation. The ESN MAS Curriculum is then evaluated in light of these best practices to define its role in meeting the need for a standardized empirically supported neonatology training curriculum for physicians, and in the future for nurses, to improve the quality of neonatal care for all infants. IMPACT STATEMENT: A review of the neonatology training literature was conducted, which concluded that there is a need for standardized neonatology training across international contexts to keep pace with growth in the field and rapidly advancing technology. This article presents the European School of Neonatology Master of Advanced Studies in Neonatology, which is intended to provide a standardized training curriculum for pediatricians and nurses seeking sub-specialization in neonatology. The curriculum is evaluated in light of best practices in medical education, neonatology training, and adult learning theory., (© 2024. The Author(s).)

Background: Retinopathy of prematurity (ROP) is a major complication in preterm infants. We assessed if plasma levels of midregional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) serve as early markers for subsequent ROP development in preterm infants <32 weeks gestation., Methods: Prospective, two-centre, observational cohort study. MR-proANP and CT-proET1 were measured on day seven of life. Associations with ROP ≥ stage II were investigated by univariable and multivariable logistic regression models., Results: We included 224 infants born at median (IQR) 29.6 (27.1-30.8) weeks gestation and birth weight of 1160 (860-1435) g. Nineteen patients developed ROP ≥ stage II. MR-proANP and CT-proET1 levels were higher in these infants (median (IQR) 864 (659-1564) pmol/L and 348 (300-382) pmol/L, respectively) compared to infants without ROP (median (IQR) 299 (210-502) pmol/L and 196 (156-268) pmol/L, respectively; both P < 0.001). MR-proANP and CT-proET1 levels were significantly associated with ROP ≥ stage II in univariable logistic regression models and after adjusting for co-factors, including gestational age and birth weight z-score., Conclusions: MR-proANP and CT-proET1 measured on day seven of life are strongly associated with ROP ≥ stage II in very preterm infants and might improve early prediction of ROP in the future., Impact: Plasma levels of midregional pro-atrial natriuretic peptide and C-terminal pro-endothelin-1 measured on day seven of life in very preterm infants show a strong association with development of retinopathy of prematurity ≥ stage II. Both biomarkers have the potential to improve early prediction of retinopathy of prematurity. Vasoactive peptides might allow to reduce the proportion of screened infants substantially., (© 2024. The Author(s).)

Background: Perinatal arterial ischemic stroke (PAIS) is a neurologic disorder leading to long-term complications. Mesenchymal stem cells (MSCs) have emerged as a novel therapeutic agent. This systematic review aims to determine the effects of stem cell-based interventions for the treatment of PAIS in preclinical studies., Methods: We included all controlled studies on MSCs in neonatal animals with PAIS. Functional outcome was the primary outcome. The literature search was performed in February 2021., Results: In the 20 included studies, MSCs were most frequently delivered via intracerebral injection (n = 9), 3 days after the induction of PAIS (n = 8), at a dose ranging from 5 × 10 4 to 5 × 10 6 cells. The meta-analysis showed an improvement on the cylinder rearing test (MD: -10.62; 95% CI: -14.38 to -6.86) and on the water maze test (MD: 1.31 MD; 95% CI: 0.80 to 1.81) in animals treated with MSCs compared to the control group animals., Conclusion: MSCs appear to improve sensorimotor and cognitive performance in PAIS-injured animals; however, the certainty of the evidence is low. Registration of the protocol of preclinical studies, appropriate sample size calculation, rigorous randomization, and reporting of the data on animal sex and survival are warranted. PROSPERO registration number: CRD42021239642., Impact: This is the first systematic review and meta-analysis of preclinical studies investigating the effects of MSCs in an experimental model of PAIS. MSCs appear to improve sensorimotor and cognitive performance in PAIS-injured neonatal animals. The certainty of the evidence is low due to high or unclear risk of bias in most domains., (© 2022. The Author(s).)

Background: Bronchopulmonary dysplasia (BPD) is a major complication in preterm infants <32 weeks. We aimed to assess whether plasma levels of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET-1) predict respiratory morbidity., Methods: This was a prospective, two-center, observational cohort study. MR-proANP and CT-proET-1 were measured at day 7 (±2) of life. Associations with duration of supplemental oxygen and the composite outcome of moderate or severe BPD or death (BPD/death) were investigated., Results: Two hundred and twenty-nine infants <32 weeks were included (median gestational age [GA] 29.6 weeks [interquartile range 29.0-30.7], median birth weight 1150 g [IQR 840-1410]). MR-proANP and CT-proET-1 were associated with the duration of supplemental oxygen in univariable analysis (both p < 0.001) but not after adjusting for co-factors. Infants with BPD/death showed higher plasma levels of MR-proANP (623.50 pmol/L [IQR 458.50-881.38] vs. 308.35 pmol/L [IQR 216.72-538.10]; p < 0.001) and CT-proET-1 (255.40 pmol/L [IQR 202.60-311.15] vs. 198.30 pmol/L [IQR 154.70-297.95]; p = 0.015) compared to infants without BPD/death. Levels of both biomarkers were significantly associated with BPD/death in univariable models but not after adjusting for co-factors., Conclusions: MR-proANP and CT-proET-1 are associated with the duration of supplemental oxygen and the composite outcome BPD/death, but their prognostic value does not complement that of clinical risk factors., Impact: Plasma levels of MR-proANP and CT-proET-1, measured on day 7 of life (±2 days) are associated in univariable analyses with duration of supplemental oxygen and the combined outcome of BPD or death in VLGA infants. Associations between both biomarkers and respiratory morbidity do not persist in multivariable models, in particular when gestational age is included. MR-proANP and CT-proET-1 have limited additional value to predict respiratory morbidity in VLGA infants compared to clinical parameters., (© 2021. The Author(s).)

Observational studies demonstrating reduced rates of infections, necrotizing enterocolitis (NEC), and mortality in preterm infants fed their own mother's milk, as opposed to formula, have prompted endeavors to achieve similar effects with the right choice of food and food additives. In a systematic review of meta-analyses and randomized controlled trials (RCTs), we considered nutritional interventions aimed at reducing the rates of infections, NEC, or mortality in very preterm infants. The overall effects of particular interventions were presented as risk ratios with 95% confidence intervals. In RCTs, pasteurized human donor milk, as opposed to formula, reduced NEC but not infections or mortality. No differences emerged between infants receiving human or bovine milk-based fortifiers. Pooled data of small trials and a recent large RCT suggested that bovine lactoferrin reduced rates of fungal sepsis without impact on other infections, NEC, or mortality. Pooled data of RCTs assessing the use of prebiotic oligosaccharides found reduced infection but not mortality. Enteral L-glutamine (six RCTs) lowered infection rates, and enteral L-arginine (three RCTs) reduced NEC. A meta-analysis sensitivity approach found multiple-strain (but not single-strain) probiotics to be highly effective in reducing NEC and mortality. Thus, selected food components may help to improve outcomes in preterm infants.

Background: Machine learning models may enhance the early detection of clinically relevant hyperbilirubinemia based on patient information available in every hospital., Methods: We conducted a longitudinal study on preterm and term born neonates with serial measurements of total serum bilirubin in the first two weeks of life. An ensemble, that combines a logistic regression with a random forest classifier, was trained to discriminate between the two classes phototherapy treatment vs. no treatment., Results: Of 362 neonates included in this study, 98 had a phototherapy treatment, which our model was able to predict up to 48 h in advance with an area under the ROC-curve of 95.20%. From a set of 44 variables, including potential laboratory and clinical confounders, a subset of just four (bilirubin, weight, gestational age, hours since birth) suffices for a strong predictive performance. The resulting early phototherapy prediction tool (EPPT) is provided as an open web application., Conclusion: Early detection of clinically relevant hyperbilirubinemia can be enhanced by the application of machine learning. Existing guidelines can be further improved to optimize timing of bilirubin measurements to avoid toxic hyperbilirubinemia in high-risk patients while minimizing unneeded measurements in neonates who are at low risk.

Vaginal birth prepares the fetus for postnatal life. It confers respiratory, cardiovascular and homeostatic advantages to the newborn infant compared with elective cesarean section, and is reported to provide neonatal analgesia. We hypothesize that infants born by vaginal delivery will show lower noxious-evoked brain activity a few hours after birth compared to those born by elective cesarean section. In the first few hours of neonatal life, we record electrophysiological measures of noxious-evoked brain activity following the application of a mildly noxious experimental stimulus in 41 infants born by either vaginal delivery or by elective cesarean section. We demonstrate that noxious-evoked brain activity is related to the mode of delivery and significantly lower in infants born by vaginal delivery compared with those born by elective cesarean section. Furthermore, we found that the magnitude of noxious-evoked brain activity is inversely correlated with fetal copeptin production, a surrogate marker of vasopressin, and dependent on the experience of birth-related distress. This suggests that nociceptive sensitivity in the first few hours of postnatal life is influenced by birth experience and endogenous hormonal production.

Cytokine-based diagnostic assays are increasingly used in research and clinical practice. Assays developed for adults such as the interferon-gamma release assay for tuberculosis show inferior performance in children. Limited evidence suggests that release of cytokines is influenced by age but normal ranges of cytokines in children are lacking. Whole blood of healthy children (0-12 years) undergoing elective/diagnostic procedures was stimulated with SEB, PHA, Candida albicans for 24 hours or left unstimulated. Concentrations of eight cytokines were measured by multiplex bead-based immunoassays and associations with age and other factors quantified by regression analysis. 271 children (median age 5.2 years) were included. In unstimulated samples IL-1ra, IP-10 and TNF-α concentrations decreased by up to -60% with age. Following antigen stimulation, an age-associated increase (ranging from +90% to +500%) was observed for all cytokines except IL-1ra (significant for IL-4, IFN-γ and TNF-α). Inter-individual variability in cytokine concentrations was large with a coefficient of variation ranging from 42% to 1412%. Despite inter-individual variation age was identified as a strong influencing factor of cytokine concentrations. Age-specific normal values need to be considered for cytokine-based diagnostic purposes. These results are relevant for development of novel cytokine-based diagnostic assays and for optimal dosing of therapeutic agents targeting cytokines.

Introduction: Adrenomedullin (ADM) is one of the strongest endogenous vasodilating hormones. Its stable by-product midregional-proADM (MR-proADM) is an established indicator of systemic infection and cardiovascular compromise in adult patients., Methods: A prospective cross-sectional study was performed to investigate the perinatal factors affecting MR-proADM plasma concentrations in 328 newborn infants with a gestational age (GA) between 24 and 41 wk., Results: Blood samples were obtained in 270 infants from umbilical veins (with additional 108 paired samples from umbilical arteries), and at 2-3 d of life in 183 infants. Paired venous and arterial umbilical cord MR-proADM concentrations were closely related (Spearman's rank order correlation coefficient (R(s)) = 0.825, P < 0.001). MR-proADM concentrations at birth and at 2-3 d were inversely related to GA (R(s) = -0.403 and R(s) = -0.541, respectively) and birth weight (BW; R(s) = -0.421 and R(s) = -0.530, respectively; all P < 0.001). On stepwise regression analysis, clinical chorioamnionitis and umbilical arterial blood base excess retained a significant impact on MR-proADM cord venous blood concentrations. At 2-3 d of life, histologic chorioamnionitis and GA at delivery were significantly associated with MR-proADM levels., Discussion: As compared with adults, MR-proADM concentrations are elevated in neonates, especially those born very preterm. Immaturity and infection, which both feature low systemic vascular resistance, are related to increased MR-proADM concentrations.

Hypoxia and other adverse conditions are commonly encountered by rapidly growing cells. The RNA-binding protein RBM3 (RNA-binding motif protein 3), which is transcriptionally induced by low temperature and hypoxia, has recently been implicated in survival of colon cancer cells by mechanisms involving cyclooxygenase-2 (COX-2) signaling. Immunohistochemically, we found strong RBM3 expression in a variety of malignant and proliferating tissues but low expression in resting and terminally differentiated cells. RBM3 expression in fibroblasts and human embryonal kidney (HEK293) cells subjected to serum deprivation or contact inhibition closely paralleled proliferation rates, assessed by real-time RT-PCR and immunoblotting. siRNA-mediated RBM3 knockdown reduced cell viability and finally led to cell death, which did not involve caspase-3-mediated apoptosis, cell cycle arrest, or COX-2 regulation. In contrast, RBM3 over-expression rescued cells from death under serum starvation. This was associated with increased translation rates, as measured by C serine and H phenylalanine incorporation. Together, RBM3 is a critical factor providing cellular survival advantages in an adverse microenvironment presumably by restoring translation efficacy.