Retrospective study on neonatal seizures in a tertiary center of northern Italy after ILAE classification: Incidence, seizure type, EEG and etiology.

OBJECTIVE: We aimed to evaluate epidemiology, seizure type, EEG, and etiology of neonatal seizures (NS) in a tertiary neonatal intensive care unit. METHODS: Data on infants with a neurophysiological confirmation of NS were collected between 2009 and 2022. Seizure types and epileptic syndromes were classified by the ILAE classification and EEG by the Italian Neonatal Seizure Collaborative Network (INNESCO) score. RESULTS: Out of 91,253 neonates, 145 presented with NS; 69.7 % were born at term and 30.3 % were preterm infants. The incidence of NS in neonates born at our center was 1.2 per 1,000 live newborns (96/80697 neonates) while in the entire neonatal population admitted to our center it was 1.6 per 1,000 live births, increasing with lower preterm age. Compared to previous studies, we found a lower proportion of hypoxic-ischemic encephalopathy (HIE) (23.4 %) and a higher rate of genetic contribution (26.2 %). The infection rate was higher in preterm (31.8 %) than in full term (9.9 %) infants. Electrographic seizures were associated with acute provoked seizures (35.9 %), preterm age (52.3 %), and HIE (52.9 %). Vascular etiology was associated with focal clonic seizures (56.8 %). Non-structural neonatal genetic epilepsy was associated with sequential seizures (68.2 %), particularly KCNQ2 and SCN2A epilepsy. Background EEG was abnormal in all HIE, infections (85.7 %) and metabolic NS (83.3 %). In genetic epilepsy, background EEG depended on the epileptic syndrome: normal in 80 % of self-limited neonatal epilepsy and abnormal in 77.8 % of developmental and epileptic encephalopathy. Electroclinical seizures were associated with focal onset, while electrographic seizures correlated with a multifocal onset. CONCLUSIONS: A low incidence of HIE and a high incidence of genetic etiology were observed in our cohort of NS. Seizure type and EEG features are fundamental to address etiology.

Effect of in-line filtration in newborns: study protocol of the Intravenous Neonatal Central Access Safety (INCAS) randomized controlled trial.

BACKGROUND: Particulate contamination due to infusion therapy (administration of parenteral nutrition and medications) carries a potential health risk for infants in neonatal intensive care units (NICUs). This particulate consists of metals, drug crystals, glass fragments, or cotton fibers and can be generated by drug packaging, incomplete reconstitution, and chemical incompatibilities. In-line filters have been shown to remove micro-organisms, endotoxin, air, and particles in critically ill adults and older infants, but its benefits in newborn remain to be demonstrated. Moreover, 50% of inflammatory episodes in the setting of NICUs are blood culture-negative. These episodes could be partly related to the presence of particles in the infusion lines. METHODS: A multicenter randomized single-blind controlled trial was designed. All infants admitted to NICUs for which prolonged infusion therapy is expected will be enrolled in the study and randomized to the Filter or Control arm. All patients will be monitored until discharge, and data will be analyzed according to a "full analysis set." The primary outcome is the frequency of patients with at least one sepsis-like event, defined by any association of suspected sepsis symptoms with a level of c-reactive protein (CRP) > 5 mg/L in a negative-culture contest. The frequency of sepsis, phlebitis, luminal obstruction, and the duration of mechanical ventilation and of catheter days will be evaluated as secondary outcomes. The sample size was calculated at 368 patients per arm. DISCUSSION: This is the first multicenter randomized control trial that compares in-line filtration of parenteral nutrition and other intravenous drugs to infusion without filters. Sepsis-like events are commonly diagnosed in clinical practice and are more frequent than sepsis in a positive culture contest. The risk of these episodes in the target population is estimated at 30-35%, but this data is not confirmed in the literature. If the use of in-line filters results in a significant decrease in sepsis-like events and/or in any other complications, the use of in-line filters in all intravenous administration systems may be recommended in NICUs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05537389, registered on 12 September 2022 ( https://classic. CLINICALTRIALS: gov/ct2/show/results/NCT05537389?view=results ).

Can Postbiotics Represent a New Strategy for NEC?

Intestinal bacteria, also known as gut microbiota, are a rich ecology of microorganisms found in the human digestive tract. Extensive study has highlighted their critical relevance in preserving human health. New research has revealed that bacterial viability is not invariably necessary to induce health benefits. Postbiotics (defined soluble substances produced as a byproduct of the metabolic processes of living microbes) have thus emerged as an important topic of research. They contribute to shaping the gut microbiota, exert immune-modulation activity, and improve the integrity of the gut barrier.Alterations in preterm gut colonization associated with intestinal barrier immaturity and the increased reactivity of the intestinal mucosa to colonizing bacteria have been implicated in the pathogenesis of necrotizing enterocolitis. Postbiotics have shown promising outcomes in reducing the risk of developing NEC, lowering inflammation, encouraging the development of good bacteria, and strengthening the intestinal barrier. This is an important advancement in newborn care and highlights the potential of postbiotics to avoid severe intestinal disorders.

Early respiratory system reactance predicts respiratory outcomes in preterm infants: a retrospective, multicentre study.

OBJECTIVE: This multicenter, international, retrospective study aims to investigate whether respiratory system reactance (Xrs) assessed by respiratory oscillometry on the 7th day of life is associated with respiratory outcomes in preterm infants below 32 weeks' gestation. METHODS: Sinusoidal pressure oscillations (2-5 cmH2O peak-to-peak, 10 Hz) were superimposed on the positive end-expiratory pressure (PEEP). We assessed the association of Xrs z-score with the duration of respiratory support using linear regression and with bronchopulmonary dysplasia (BPD, according to Jensen et al. 2019) using logistic regression. We used the likelihood ratio test to evaluate whether Xrs z-score adds significantly to clinical predictors, including gestational age (GA), birth weight (BW) and the National Institute of Child Health and Human Development (NICHD) BPD prediction model. RESULTS: One hundred and thirty-seven infants (median (Q1, Q3) GA=28.43 (26.11, 30.29) weeks) were included; 44 (32%) developed BPD. Xrs z-score was significantly associated with the duration of respiratory support (R2=0.35). Xrs z-score was significantly higher in infants who developed BPD (p<0.001); the optimal cut-off value was 2.6, associated with 77% sensitivity and 80% specificity. In univariable analysis, per z-score increase in Xrs, the OR for BPD increased by 60% and the respiratory support by eight days. In multivariable analysis, Xrs z-score added significantly to the NICHD model and to GA and BW z-score to predict respiratory support duration (p=0.016 and p=0.014, respectively) and BPD development (p=0.003 and p<0.001, respectively). CONCLUSION: Xrs z-score on the 7th day after birth improves the prediction of respiratory outcome in preterm infants.

Laryngeal Mask Airway in Neonatal Resuscitation: A Survey of the Union of European Neonatal and Perinatal Societies.

INTRODUCTION: Laryngeal mask airway (LMA) use in neonatal resuscitation is limited despite existing evidence and recommendations. This survey investigated the knowledge and experience of healthcare providers on the use of the LMA and explored barriers and solutions for implementation. METHODS: This online, cross-sectional survey on LMA in neonatal resuscitation involved healthcare professionals of the Union of European Neonatal and Perinatal Societies (UENPS). RESULTS: A total of 858 healthcare professionals from 42 countries participated in the survey. Only 6% took part in an LMA-specific course. Some delivery rooms were not equipped with LMA (26.1%). LMA was mainly considered after the failure of a face mask (FM) or endotracheal tube (ET), while the first choice was limited to neonates with upper airway malformations. LMA and FM were considered easier to position but less effective than ET, while LMA was considered less invasive than ET but more invasive than FM. Participants felt less competent and experienced with LMA than FM and ET. The lack of confidence in LMA was perceived as the main barrier to its implementation in neonatal resuscitation. More training, supervision, and device availability in delivery wards were suggested as possible actions to overcome those barriers. CONCLUSION: Our survey confirms previous findings on limited knowledge, experience, and confidence with LMA, which is usually considered an option after the failure of FM/ET. Our findings highlight the need for increasing the availability of LMA in delivery wards. Moreover, increasing LMA training and having an LMA expert supervisor during clinical practice may improve the implementation of LMA use in neonatal clinical practice.

Multidisciplinary follow-up in a patient with Morgagni hernia leads to diagnosis of Marfan syndrome.

BACKGROUND: congenital diaphragmatic hernia (CDH) is a birth defect occurring in isolated or syndromic (chromosomal or monogenic) conditions. The diaphragmatic defect can be the most common one: left-sided posterolateral, named Bochdalek hernia; or it can be an anterior-retrosternal defect, named Morgagni hernia. Marfan syndrome (MFS) is a rare autosomal dominant inherited condition that affects connective tissue, caused by mutations in fibrillin-1 gene on chromosome 15. To date various types of diaphragmatic defects (about 30 types) have been reported in association with MFS, but they are heterogeneous, including CDH and paraesophageal hernia. CASE PRESENTATION: We describe the case of a child incidentally diagnosed with Morgagni hernia through a chest X-ray performed due to recurrent respiratory tract infections. Since the diagnosis of CDH, the patient underwent a clinical multidisciplinary follow-up leading to the diagnosis of MFS in accordance with revised Ghent Criteria: the child had typical clinical features and a novel heterozygous de novo single-base deletion in exon 26 of the FBN1 gene, identified by Whole-Exome Sequencing. MFS diagnosis permitted to look for cardiovascular complications and treat them, though asymptomatic, in order to prevent major cardiovascular life-threatening events. CONCLUSION: Our case shows the importance of a long-term and multidisciplinary follow-up in all children with diagnosis of CDH.

Why might cord blood be a better source of platelets for transfusion to neonates?

Thrombocytopenia (defined as a platelet count <150×109/L) is a common condition in preterm neonates and may occur in 18-35% of all infants admitted to the Neonatal Intensive Care Unit (NICU). Neonatal platelet functionality in terms of reactivity is often described as reduced compared to adults, even in healthy, term neonates. However, this platelet "hyporeactivity" does not correspond to a global functional impairment of the normal delicately balanced neonatal hemostatic system. The extent to which neonatal thrombocytopenia and platelet hyporeactivity contribute to the bleeding risk in preterm neonates remains unknown. Prophylactic platelet transfusions are often administered to them to reduce the risk of bleeding. However, recent literature indicates that adopting a higher platelet transfusion threshold than a lower one results in significantly higher death rates or major bleeding and can be harmful. Although the mechanism by which this occurs is not entirely clear, a mismatch between adult transfused platelets and the neonatal hemostatic system, as well as volume overload, are speculated to be potentially involved. Therefore, future research should consider novel transfusion products that may be more suitable for premature neonates. Blood products derived from umbilical cord blood (UCB) are promising, as they might perfectly match neonatal blood features. Here, we discuss the current knowledge about UCB-derived products, focusing on UCB-derived platelet concentrates and their potential for future clinical application. We will discuss how they may overcome the potential risks of transfusing adult-derived platelets to premature infants while maintaining efficacy.

Nasal intermittent positive pressure ventilation during less invasive surfactant administration in preterm infants: An open-label randomized controlled study.

INTRODUCTION: Approximately half of very preterm infants with respiratory distress syndrome (RDS) fail treatment with nasal continuous positive airway pressure (NCPAP) and need mechanical ventilation (MV). OBJECTIVES: Our aim with this study was to evaluate if nasal intermittent positive pressure ventilation (NIPPV) during less invasive surfactant treatment (LISA) can improve respiratory outcome compared with NCPAP. MATERIALS AND METHODS: We carried out an open-label randomized controlled trial at tertiary neonatal intensive care units in which infants with RDS born at 25+0-31+6 weeks of gestation between December 1, 2020 and October 31, 2022 were supported with NCPAP before and after surfactant administration and received NIPPV or NCPAP during LISA. The primary endpoint was the need for a second dose of surfactant or MV in the first 72 h of life. Other endpoints were need and duration of invasive and noninvasive respiratory supports, changes in SpO2/FiO2 ratio after LISA, and adverse effect rate. RESULTS: We enrolled 101 infants in the NIPPV group and 99 in the NCPAP group. The unadjusted odds ratio for the composite primary outcome was 0.873 (95% confidence interval: 0.456-1.671; p = .681). We found that the SpO2/FiO2 ratio was transiently higher in the LISA plus NIPPV than in the LISA plus NCPAP group, while adverse effects of LISA had similar occurrence in the two arms. CONCLUSIONS: The application of NIPPV or NCPAP during LISA in very preterm infants supported with NCPAP before and after surfactant administration had similar effects on the short-term respiratory outcome and are both safe. Our study does not support the use of NIPPV during LISA.

Clinical and economic burden of respiratory syncytial virus in children aged 0-5 years in Italy.

BACKGROUND: Respiratory syncytial virus (RSV) is among the leading causes of hospitalization due to lower respiratory tract infections (LRTIs) in children younger than 5 years worldwide and the second cause of infant death after malaria. RSV infection occurs in almost all the infants before the second year of life with variable clinical severity, often requiring medical assistance. This analysis investigated patients aged 0-5 years with RSV infection focusing on epidemiology, clinical features, and economic burden of RSV-associated hospitalizations in a setting of Italian real clinical practice. METHODS: An observational retrospective analysis was conducted on administrative databases of healthcare entities covering around 2.6 million residents of whom 120,000 health-assisted infants aged < 5 years. From 2010 to 2018, pediatric patients were included in the presence of hospitalization discharge diagnosis for RSV infections, and RSV-related acute bronchiolitis or pneumonia. Epidemiology, demographics, clinical picture and costs were evaluated in RSV-infected patients, overall and stratified by age ranges (0-1, 1-2, 2-5 years) and compared with an age-matched general population. RESULTS: Overall 1378 RSV-infected children aged 0-5 years were included. Among them, the annual incidence rate of RSV-related hospitalizations was 175-195/100,000 people, with a peak in neonates aged < 1 year (689-806/100,000). While nearly 85% of infected infants were healthy, the remaining 15% presented previous hospitalization for known RSV risk factors, like preterm birth, or congenital heart, lung, and immune diseases. The economic analysis revealed that direct healthcare costs per patient/year were markedly higher in RSV patients than in the general population (3605€ vs 344€). CONCLUSIONS: These findings derived from the real clinical practice in Italy confirmed that RSV has an important epidemiological, clinical, and economic burden among children aged 0-5 years. While the complex management of at-risk infants was confirmed, our data also highlighted the significant impact of RSV infection in infants born at term or otherwise healthy, demonstrating that all infants need protection against RSV disease, reducing then the risk of medium and long-term complications, such as wheezing and asthma.

Ototoxic and nephrotoxic drugs in neonatal intensive care units: results of a Spanish and Italian survey.

Neonates face heightened susceptibility to drug toxicity, often exposed to off-label medications with dosages extrapolated from adult or pediatric studies. Premature infants in Neonatal Intensive Care Units (NICUs) are particularly at risk due to underdeveloped pharmacokinetics and exposure to multiple drugs. The study aimed to survey commonly used medications with a higher risk of ototoxicity and nephrotoxicity in Spanish and Italian neonatal units. A prospective cross-sectional study was conducted in Italian and Spanish neonatal units using a web-based survey with 43 questions. A modified Delphi method involved experts refining the survey through online consensus. Ethical approval was obtained, and responses were collected from January to July 2023. The survey covered various aspects, including drug-related ototoxic and nephrotoxic management, hearing screening, and therapeutic drug monitoring. Responses from 131 participants (35.9% from Spain and 64.1% from Italy) revealed awareness of drug toxicity risks. Varied practices were observed in hearing screening protocols, and a high prevalence of ototoxic and nephrotoxic drug use, including aminoglycosides (100%), vancomycin (70.2%), loop diuretics (63.4%), and ibuprofen (62.6%). Discrepancies existed in guideline availability and adherence, with differences between Italy and Spain in therapeutic drug monitoring practices. CONCLUSIONS: The study underscores the need for clinical guidelines and uniform practices in managing ototoxic and nephrotoxic drugs in neonatal units. Awareness is high, but inconsistencies in practices indicate a necessity for standardization, including the implementation of therapeutic drug monitoring and the involvement of clinical pharmacologists. Addressing these issues is crucial for optimizing neonatal care in Southern Europe. WHAT IS KNOWN: • Neonates in intensive care face a high risk of nephrotoxicity and ototoxicity from drugs like aminoglycosides, vancomycin, loop diuretics, and ibuprofen. • Therapeutic drug monitoring is key for managing these risks, optimizing dosing for efficacy and minimizing side effects. WHAT IS NEW: • NICUs in Spain and Italy show high drug toxicity awareness but differ in ototoxic/nephrotoxic drug management. • Urgent need for standard guidelines and practices to address nephrotoxic risks from aminoglycosides, vancomycin, loop diuretics, and ibuprofen.

Enterovirus and parechovirus meningoencephalitis in infants: A ten-year prospective observational study in a neonatal intensive care unit.

BACKGROUND: Non-polio enteroviruses (EV) and human parechoviruses (HPeV) are known etiological agents of meningoencephalitis in neonates. However, reports of neuroradiological findings and neurodevelopmental outcomes in this population are scarce. OBJECTIVES: to describe clinical characteristics, neuroradiological findings and, in a subset of patients, neurodevelopmental outcomes in a cohort of infants with EV or HPeV meningoencephalitis within 60 days of life. STUDY DESIGN: clinical/laboratory data, neuroradiological findings (cranial ultrasound, cUS, brain magnetic resonance imaging, MRI), and neurodevelopmental outcomes assessed by Ages and Stages Questionnaires - third edition were prospectively collected. RESULTS: overall, 32 infants with EV (21, 67.8 %) or HPeV (11, 28.2 %) meningoencephalitis were enrolled. Infants with HPeV (73 %: type 3 HPeV) presented more frequently with seizures (18.2 % vs. 0, p value=0.03), lymphopenia (1120 vs. 2170 cells/mm3, p = 0.02), focal anomalies at electroencephalography (EEG) (63.6 vs. 23.8 %, p = 0.03), and pathological findings at MRI (72.7 % vs. 15.8 %, p value=0.004) compared to those affected by EV. cUS was not significantly altered in any of the enrolled infants. All infants with EV meningoencephalitis evaluated at 12-24 months and at 30-48 months were normal. Two out of the 7 infants with HPeV meningoencephalitis showed some concerns in gross motor (1/7, 14.3 %) or in problem solving (1/7, 14.3 %) function at 30-48 months of age. CONCLUSIONS: In our cohort, neonates infected by HPeV had more severe clinical manifestations, more alterations at brain MRI, and some signs of long-term neurodevelopmental delay. Our data highlight the heterogeneity of manifestations in infants with EV or HPeV meningoencephalitis, and the need for long-term follow-up of those infected by HPeV in the neonatal period.

Circulating hematopoietic stem/progenitor cell subsets contribute to human hematopoietic homeostasis.

ABSTRACT: In physiological conditions, few circulating hematopoietic stem/progenitor cells (cHSPCs) are present in the peripheral blood, but their contribution to human hematopoiesis remain unsolved. By integrating advanced immunophenotyping, single-cell transcriptional and functional profiling, and integration site (IS) clonal tracking, we unveiled the biological properties and the transcriptional features of human cHSPC subpopulations in relationship to their bone marrow (BM) counterpart. We found that cHSPCs reduced in cell count over aging and are enriched for primitive, lymphoid, and erythroid subpopulations, showing preactivated transcriptional and functional state. Moreover, cHSPCs have low expression of multiple BM-retention molecules but maintain their homing potential after xenotransplantation. By generating a comprehensive human organ-resident HSPC data set based on single-cell RNA sequencing data, we detected organ-specific seeding properties of the distinct trafficking HSPC subpopulations. Notably, circulating multi-lymphoid progenitors are primed for seeding the thymus and actively contribute to T-cell production. Human clonal tracking data from patients receiving gene therapy (GT) also showed that cHSPCs connect distant BM niches and participate in steady-state hematopoietic production, with primitive cHSPCs having the highest recirculation capability to travel in and out of the BM. Finally, in case of hematopoietic impairment, cHSPCs composition reflects the BM-HSPC content and might represent a biomarker of the BM state for clinical and research purposes. Overall, our comprehensive work unveiled fundamental insights into the in vivo dynamics of human HSPC trafficking and its role in sustaining hematopoietic homeostasis. GT patients' clinical trials were registered at ClinicalTrials.gov (NCT01515462 and NCT03837483) and EudraCT (2009-017346-32 and 2018-003842-18).

A Survey of the Union of European Neonatal and Perinatal Societies on Neonatal Respiratory Care in Neonatal Intensive Care Units.

(1) Background: Our survey aimed to gather information on respiratory care in Neonatal Intensive Care Units (NICUs) in the European and Mediterranean region. (2) Methods: Cross-sectional electronic survey. An 89-item questionnaire focusing on the current modes, devices, and strategies employed in neonatal units in the domain of respiratory care was sent to directors/heads of 528 NICUs. The adherence to the "European consensus guidelines on the management of respiratory distress syndrome" was assessed for comparison. (3) Results: The response rate was 75% (397/528 units). In most Delivery Rooms (DRs), full resuscitation is given from 22 to 23 weeks gestational age. A T-piece device with facial masks or short binasal prongs are commonly used for respiratory stabilization. Initial FiO2 is set as per guidelines. Most units use heated humidified gases to prevent heat loss. SpO2 and ECG monitoring are largely performed. Surfactant in the DR is preferentially given through Intubation-Surfactant-Extubation (INSURE) or Less-Invasive-Surfactant-Administration (LISA) techniques. DR caffeine is widespread. In the NICUs, most of the non-invasive modes used are nasal CPAP and nasal intermittent positive-pressure ventilation. Volume-targeted, synchronized intermittent positive-pressure ventilation is the preferred invasive mode to treat acute respiratory distress. Pulmonary recruitment maneuvers are common approaches. During NICU stay, surfactant administration is primarily guided by FiO2 and SpO2/FiO2 ratio, and it is mostly performed through LISA or INSURE. Steroids are used to facilitate extubation and prevent bronchopulmonary dysplasia. (4) Conclusions: Overall, clinical practices are in line with the 2022 European Guidelines, but there are some divergences. These data will allow stakeholders to make comparisons and to identify opportunities for improvement.

Congenital diaphragmatic hernia: automatic lung and liver MRI segmentation with nnU-Net, reproducibility of pyradiomics features, and a machine learning application for the classification of liver herniation.

Prenatal assessment of lung size and liver position is essential to stratify congenital diaphragmatic hernia (CDH) fetuses in risk categories, guiding counseling, and patient management. Manual segmentation on fetal MRI provides a quantitative estimation of total lung volume and liver herniation. However, it is time-consuming and operator-dependent. In this study, we utilized a publicly available deep learning (DL) segmentation system (nnU-Net) to automatically contour CDH-affected fetal lungs and liver on MRI sections. Concordance between automatic and manual segmentation was assessed by calculating the Jaccard coefficient. Pyradiomics standard features were then extracted from both manually and automatically segmented regions. The reproducibility of features between the two groups was evaluated through the Wilcoxon rank-sum test and intraclass correlation coefficients (ICCs). We finally tested the reliability of the automatic-segmentation approach by building a ML classifier system for the prediction of liver herniation based on support vector machines (SVM) and trained on shape features computed both in the manual and nnU-Net-segmented organs. We compared the area under the classifier receiver operating characteristic curve (AUC) in the two cases. Pyradiomics features calculated in the manual ROIs were partly reproducible by the same features calculated in nnU-Net segmented ROIs and, when used in the ML procedure, to predict liver herniation (both AUC around 0.85).          Conclusion: Our results suggest that automatic MRI segmentation is feasible, with good reproducibility of pyradiomics features, and that a ML system for liver herniation prediction offers good reliability.          Trial registration: https://clinicaltrials.gov/ct2/show/NCT04609163?term=NCT04609163&draw=2&rank=1 ; Clinical Trial Identification no. NCT04609163. What is Known: • Magnetic resonance imaging (MRI) is crucial for prenatal congenital diaphragmatic hernia (CDH) assessment. It enables the quantification of the total lung volume and the extent of liver herniation, which are essential for stratifying the severity of CDH, guiding counseling, and patient management. • The manual segmentation of MRI scans is a time-consuming process that is heavily reliant upon the skill set of the operator. What is New: • MRI lung and liver automatic segmentation using the deep learning nnU-Net system is feasible, with good Jaccard coefficient values and satisfactory reproducibility of pyradiomics features compared to manual results. • A feasible ML system for predicting liver herniation could improve prenatal assessments and CDH patient management.

Long-lasting effects of COVID-19 pandemic on hospitalizations and severity of bronchiolitis.

Bronchiolitis is a common cause of hospitalization in infants. The long-lasting impact of hygiene and social behavior changes during the pandemic on this disease is debated. We investigated the prevalence of hospitalized cases, clinical severity, and underlying risk factors before and during pandemic. The study was conducted in 27 hospitals in Italy and included infants hospitalized for bronchiolitis during the following four periods: July 2018-March 2019, July 2020-March 2021, July 2021-March 2022, and July 2022-March 2023. Data on demographics, neonatal gestational age, breastfeeding history, underlying chronic diseases, presence of older siblings, etiologic agents, clinical course and outcome were collected. A total of 5330 patients were included in the study. Compared to 2018-19 (n = 1618), the number of hospitalizations decreased in 2020-21 (n = 121). A gradual increase was observed in 2021-22 (n = 1577) and 2022-23 (n = 2014). A higher disease severity (need and length of O2-supplementation, need for non-invasive ventilation, hospital stay) occurred in the 2021-22 and, especially, the 2022-23 periods compared to 2018-19. This tendency persisted after adjusting for risk factors associated with bronchiolitis severity.   Conclusions: Compared to adults, COVID-19 in infants is often asymptomatic or mildly symptomatic and rarely results in hospitalization. This study indicates that the pandemic has indirectly induced an increased burden of bronchiolitis among hospitalized infants. This shift, which is not explained by the recognized risk factors, suggests the existence of higher infant vulnerability during the last two seasons. What is known: • The pandemic led to a change in epidemiology of respiratory diseases • Large data on severity of bronchiolitis and underlying risk factors before and during COVID-19 pandemic are scarce What is new: • Compared to pre-pandemic period, hospitalizations for bronchiolitis decreased in 2020-21 and gradually increased in 2021-22 and 2022-23 • Compared to pre-pandemic period, higher disease burden occurred in 2021-22 and, especially, in 2022-23. This tendency persisted after adjusting for risk factors associated with bronchiolitis severity • The interplay among viruses, preventive measures, and the infant health deserves to be further investigated.

A Case of Enterococcal Patent Ductus Arteriosus-associated Endarteritis in a Preterm Neonate.

INTRODUCTION: The persistent patency of the ductus arteriosus frequently occurs in premature neonates and can cause infective endocarditis (IE) or ductal endarteritis (DE) during sepsis. Even though neonatal IE and DE are believed to be a rare eventuality, their incidence has been increasing in the last decades due to the improved survival of even more preterm babies, favored by highly invasive procedures and therapies. In parallel, antimicrobial resistance is another rising problem in neonatal intensive care units, which frequently compels to treat infections with broad-spectrum or last generation antibiotics. CASE PRESENTATION: We report the case of a preterm neonate affected by patent ductus arteriosus-associated DE that followed an episode of sepsis caused by a high-level aminoglycoside-resistant enterococcus. The neonate was successfully treated with the synergistic combination of ampicillin and cefotaxime. DISCUSSION: IE and patent ductus arteriosus-associated DE are rising inside neonatal intensive care units and neonatologists should be aware of these conditions. Enterococcal IE and patent ductus arteriosus-associated DE sustained by high-level aminoglycoside-resistant strains can be successfully treated with the synergistic combination of ampicillin and cefotaxime even in preterm neonates.

External Validation of a Multivariate Model for Targeted Surfactant Replacement.

INTRODUCTION: Early targeted surfactant therapy for preterm infants is recommended but the best criteria to personalize treatment are unclear. We validate a previously published multivariate prognostic model based on gestational age (GA), lung ultrasound score (LUS), and oxygen saturation to inspire oxygen fraction ratio (SatO2/FiO2) using an independent data set. METHODS: Pragmatic, observational study in 10 Italian and Spanish NICUs, including preterm babies (250 and 336 weeks divided into 3 GA intervals) with clinical signs of respiratory distress syndrome and stabilized on CPAP. LUS and SatO2/FiO2 were collected soon after stabilization. Their prognostic accuracy was evaluated on the subsequent surfactant administration by a rigorously masked physician. RESULTS: One hundred seventy-five infants were included in the study. Surfactant was given to 74% infants born at 25-27 weeks, 38.5% at 28-30 weeks, and 26.5% at 31-33 weeks. The calibration curve comparing the validation and the development populations showed significant overlap with an intercept = 0.08, 95% CI (-0.34; 0.5) and a slope = 1.53, 95% CI (1.07-1.98). The validation cohort had a high predictive accuracy. Its ROC curve showed an AUC = 0.95, 95% CI (0.91-0.99) with sensitivity = 0.93, 95% CI (0.83-0.98), specificity = 0.81, 95% CI (0.73-0.88), PPV = 0.76, 95% CI (0.65-0.84), NPV = 0.95, 95% CI (0.88-0.98). LUS ≥9 demonstrated the highest sensitivity (0.91, 95% CI [0.82-0.97]) and specificity = 0.81, 95% CI (0.72-0.88) as individual predictor. LUS and SatO2/FiO2 prognostic performances varied with GA. CONCLUSION: We validated a prognostic model based on LUS and Sat/FiO2 to facilitate early, customized surfactant administration that may improve respiratory management of preterm neonates.

Estimation of the reference values and decision limits for growth hormone in newborns using dried blood spots.

OBJECTIVES: Severe deficiency of growth hormone (GHD) of the newborn is a rare but potentially life-threatening disease. GH measured during the first week of life, using dried blood spots (DBS), may offer several advantages. Aim of the study was to estimate the reference values for GH in newborns by a new analytical method using DBS. METHODS: Using a new developed analytical method, GH was estimated from DBS of 1,036 healthy newborns attending the Neonatology Unit of Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan in the period July-October 2021. Reference values for GH deficiency were estimated by the Harrell-Davis bootstrap method, with 90 %CI calculated by the bias-corrected and accelerated bootstrap method. RESULTS: All GH measurements required 33 analytical sessions (8 months) with a CV% for calibration curve slopes equal to 6.9 %. Intermediate precision evaluated by measurement of low (3 µg/L) and high (10 µg/L) quality controls was, respectively, 14 and 6.5 %. GH reference values, estimated at percentiles 1.0st, 2.5th and 5.0th, and their 90 %CI, were, respectively, 4.5 µg/L (90 %CI 3.8-5.1), 5.9 µg/L (90 %CI 5.4-6.4) and 7.0 µg/L (90 %CI 6.7-7.3). GH levels were not associated with sex, standard deviation scores, birth weight, gestational age, type of delivery or mother's variables (age, smoking habit, gestational diabetes). CONCLUSIONS: Validation data suggest that this method can be used to measured GH in newborns using DBS. The reference values estimated in this study are in accordance with previous published works using ELISA and may help confirming the clinical suspicion of neonatal GHD.