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Respiratory syncytial virus (RSV)-mediated bronchiolitis causes a significant global health burden. Despite this, for several years, the only approved agent for RSV prophylaxis was the anti-RSV monoclonal antibody Palivizumab, reserved for a small population of infants at high risk of developing severe RSV disease. Recently, the availability and approval of nirsevimab to immunize all infants against RSV infection since their first RSV season represented a crucial paradigm shift in RSV prevention. Nirsevimab has been shown to be safe and effective (> 80%) against RSV lower respiratory tract infections (LRTIs) in all infants and children at their first season of RSV. Surveillance studies have demonstrated 90% effectiveness in reducing all-cause hospitalizations, all-cause LRTI hospitalizations, RSV-related LRTI hospitalizations, and severe RSV-related LRTIs. Moreover, the consistency and reproducibility of the beneficial outcomes coming from the prophylaxis with nirsevimab highlights its potential to deliver substantial health benefits, positioning monoclonal antibody administration as a cornerstone in the fight against RSV-related morbidity and mortality. Implementing immunization strategies for infants and children is crucial to align the international experiences and guarantee universal protection. This review provided an updated overview of the monoclonal antibody strategy for preventing RSV infection., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

Among flaviviruses, Zika virus (ZIKV) is the only arbovirus officially recognized as a teratogenic agent, as a consequence of its ability to infect and cross the placental barrier causing congenital malformation in the fetus. While many studies have focused on understanding ZIKV pathogenesis during pregnancy, the viral mechanisms affecting fetal development remain largely unclear. In this study, we investigated ZIKV virulence in placental trophoblasts, using viruses with distinct lipid profiles. Firstly, we propagated a ZIKV strain belonging to the Asian lineage in either mammalian or mosquito cells, obtaining two viral stocks, which were purified and analyzed to determine their genetic and lipid composition. Successively, we assessed the infectivity of the two stocks in placental cells using both immortalized cell lines and explants. We found that the two viral stocks displayed identical consensus sequences with homogeneous quasispecies composition. However, the lipid composition of their envelope significantly varied depending on the cell of origin, with the mammalian-derived viral stock characterized by a higher content of phosphatidylcholines compared to the virions originating from mosquito cells. Notably, ZIKV stock derived from mammalian cells showed a higher infectivity in immortalized villous trophoblasts and full-term placental explants of human origin. This increased infectivity was linked to enhanced fusion efficiency during the viral uncoating phase in trophoblast cells, as demonstrated using a lipophilic probe. Collectively, our data suggest a potential role of viral lipids as determinants of ZIKV infectivity in full-term placenta, underscoring the importance of lipidomic research in virology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: To describe the seasonal respiratory syncytial virus (RSV) burden in Italy considering the current prophylaxis strategy with palivizumab recommended only for high-risk infants (representing only 4.4% of an estimated birth cohort) and to evaluate the potential benefits of a new prophylaxis strategy targeting all infants with nirsevimab., Methods: A static decision analytic model previously used in the US was adapted to evaluate the RSV-related health and cost outcomes associated with nirsevimab versus standard of care (SoC) for the prevention of RSV medically attended lower respiratory tract infections (RSV-MA-LRTIs). Monthly probabilities of RSV infections, health events, mortality, and complications associated with RSV infections were obtained from the literature. Costs associated with each event were obtained using the available literature and through real-world data analysis of National Hospital Discharge Records., Results: For one RSV season, in the current SoC, the model estimated 216,100 RSV-MA-LRTIs, 15,121 associated complications, and 16 RSV-deaths-corresponding to an economic burden of approximately €50.5 million related to RSV-MA-LRTIs management, €10.9 million associated with potential complications due to RSV and €3 million in lost productivity due to RSV-deaths. Nirsevimab is expected to prevent 100,208 RSV-MA-LRTIs, 6,969 complications, and 6 deaths due to RSV infections, corresponding to an economic saving of about €23.3, €5, and €1.2 million, respectively., Conclusion: Nirsevimab is a new prophylaxis strategy that helps to protect all infants against RSV disease and could substantially reduce the clinical and economic burden of RSV in Italy in infants experiencing their first RSV season., (© 2025 The Authors.)

Aim: To determine whether a strength-based home-visiting program enhances parent-child interaction during the first year at home for children born extremely preterm (gestational age < 28)., Methods: A randomised controlled trial of 130 infants born extremely preterm 2018-2021 in Stockholm, allocated to either the Stockholm preterm interaction-based intervention (SPIBI) (n = 66) or an extended follow-up program (n = 64). The intervention group received ten home visits during the first year by a trained interventionist following SPIBI guidelines: an interaction-based intervention supporting sensitive parental responses to infants' signals. The primary outcome of emotional availability was assessed at 12 months corrected age (CA) using the emotional availability scales (EAS)., Results: At 1-year CA, data were collected from 115/130 (89%) of the included children. There were no significant group differences in emotional availability at 12 months CA. A secondary analysis showed an effect modifier in families with mothers self-rated as depressed at discharge, with the outcome favouring intervention in the EAS dimension of child involvement., Conclusion: The SPIBI had no significant main effect on emotional availability at 12 months CA. Children of self-reported depressed mothers displayed superior involvement behaviour in the intervention group, prompting further research on risk groups and potential modifications of post-discharge interventions., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

The use of High-Flow Nasal Cannula (HFNC) in children with bronchiolitis is globally increased in the last decade, despite the lack of evidence-based and universal guidelines to standardize their application in the clinical practice. In this systematic review, we aimed to analyse the completeness of previous studies on HFNC interventions in children with bronchiolitis using an adapted Template for Intervention Description and Replication (TIDieR) checklist. Randomized clinical trials (RCTs) and cohort studies on children younger than 2 years old with a diagnosis of bronchiolitis were included. We analysed manuscripts published between January 2010 and October 2023. An adapted TIDieR checklist based on 14 items about HFNC interventions was used to assess the completeness of the studies. A total sample of 67,324 patients was analysed in the 78 included manuscripts (21 RCTs and 57 cohort studies). Completeness of TIDieR checklist items ranged from 1% to 100%. The most reported items were related to the study rationale and the selection strategy (inclusion/exclusion criteria), identifying high quality of patients' selection in the included manuscripts. However, most of the studies did not provide separate indications for children with comorbidities. Only 23% of studies reported a complete definition and rates of treatment failure suggesting that this item needs more clarification in future studies. A minority of articles (40%) described the HFNC weaning procedures. Interestingly, most of the interventions took place in ICUs (61%), showing how, in the last decade, this location was the most cited for the use of HFNC in children with bronchiolitis., Conclusions:  Our results suggest complete reporting of our TIDieR checklist in future studies may improve the quality of the research on HFNC use in children with bronchiolitis. Our findings encourage researchers to clarify the personalization of treatment administration and to better define the criteria for treatment failure. The adoption of universal definitions in this field is needed to increase the results' comparability and create standardized protocols. Researchers may use the proposed TIDieR checklist to develop, conduct and report clinical research into HFNC and bronchiolitis as this may help to create a consensus for establishing an evidence-based protocol for HFNC., What Is Known: • High-flow nasal cannula (HFNC) is a common device used in children with bronchiolitis in the presence of respiratory distress, after the failure of standard oxygen therapy. However, no evidence-based and standardized protocol for the use of this device is globally available., What Is New: • By using an adapted Template for Intervention Description and Replication (TIDieR) checklist to review previous studies on HFNC in bronchiolitis, we found a global heterogeneity in the description of interventions with some items of the checklist poorly reported. Thus, we suggest using our TIDieR checklist for developing, conducting and reporting clinical research into HFNC and bronchiolitis as this may help to create a consensus for establishing an evidence-based protocol for HFNC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Financial disclosure: The authors have no financial relationship to disclose., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Securing sustainable access to existing antibiotics optimises agent choice for individual treatments and is crucial to curb antibiotic resistance. Access to antibiotics is often restricted in many countries, due to general market unavailability or episodic shortages. This article outlines key policy options to maintain availability of existing antibiotics and enhance antibiotic supply chain resilience focusing on the perspectives of European Union (EU) and European Economic Area (EEA) institutions and member states., Competing Interests: Competing interests: E.B. declares he has received funding from the Public Health Agency of Sweden and the Swedish Government for studies and development of incentives to improve access and R&D of antibiotics. All other authors declare no competing interests., (© 2024. The Author(s).)

Objective: To evaluate the accuracy of a device for continuous glucose monitoring (CGM) among infants born preterm admitted to the neonatal intensive care unit., Study Design: We analyzed paired CGM sensor glucose (SG) and point-of-care blood glucose (BG) measurements collected in infants born at ≤32 weeks of gestation or with a birth weight ≤1500 g. CGM was initiated within 48 hours from birth and maintained for 5 days. BG was performed every 12 hours and used to calibrate the sensor. Measures of CGM accuracy were computed from SG and BG pairs., Results: We included 501 SG-BG paired measurements from 51 infants (age 30.5 weeks [IQR 29.0-31.0 weeks], birth weight 1400 g [IQR 1100-1500 g] with at least 24 hours of CGM data. The mean absolute relative difference (MARD) between SG and point-of-care BG measures was 7.1% [IQR 5.6-9.3], corresponding to a difference of -5.6 mg/dL [95% CI -25 to +14 mg/dl]. The median sensor use was 96 hours [IQR 72-120] with 2.0 [IQR 1.7-2.4] calibrations per day., Conclusions: Accuracy of SG measurements compared with BG measurements appears to be acceptable in a clinical study setting, with a negligible difference between SG and BG. Our data suggest that SG use may be clinically acceptable when the sensor is regularly calibrated., Competing Interests: Declaration of Competing Interest This work was supported by the Institute for Pediatric Research (IRP, Padova, Italy) Starting Grant 2020 (to A.G.), University of Padova Stars Grant 2017 C96C18001930005 (to S.B.) and the Italian Ministry of Health grant GR-RF 2019-12368539 (to A.G.). The content of this manuscript only expresses the vision and data interpretation of the Authors and no commercial partner, or third party, was involved in the study design, conduct or in the redaction and revision of the manuscript. The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The incidence of adverse short-term outcomes for infants who undergo complex congenital heart disease (CHD) surgery with cardiopulmonary bypass (CPB) is still high. Early identification and treatment of high-risk patients remain challenging, especially because clinical risk factors often fail to explain the different outcomes of this vulnerable population. Metabolomics offers insight into the phenotype of the patient and the complex interplay between the genetic substrate and the environmental influences at the time of sampling. For these reasons, it may be helpful to identify the mechanisms of physio-pathological disruptions experienced in neonates undergoing congenital heart surgery and to identify potential therapeutic targets., Methods: We conducted a systematic review ( PROSPERO : ID 565112) of studies investigating the association between targeted or untargeted metabolomic analysis of infants undergoing elective surgery with CPB for CHD and clinical outcomes. The PRISMA guidelines were followed. We searched MEDLINE via PubMed, EMBASE via Ovid, the Cochrane Central Register of Controlled Trials, the Cochrane Library, ClinicalTrials.gov and the World Health Organization's International Trials Registry and Platform., Results: Seven studies involving 509 children (aged 1 day to 21.3 months), all of whom underwent cardiac surgery requiring CPB, were included for qualitative analysis. We found associations between metabolomic profiles and various clinical outcomes, such as mortality, acute kidney injury (AKI), and neurological outcomes. Specific metabolites (mainly amino acids, their metabolic products and fatty acids) were identified as potential biomarkers for these outcomes, demonstrating the utility of metabolomics in predicting certain postoperative complications., Conclusion: The quality of the evidence was limited due to heterogeneity in study designs and small sample sizes, but the findings are promising and suggest that further research is warranted to confirm these associations., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, PROSPERO ID 565112., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Meggiolaro, Moschino, Stocchero, Giordano, Vida, Di Salvo and Baraldi.)

Background: Maintaining access to a broad range of old and new antibiotics is increasingly difficult due to supply, market, and demand issues. Next to immediate negative consequences for individual patients and healthcare systems, antibiotic unavailability can accelerate resistance development due to unmotivated use of suboptimal broad-spectrum antibiotics., Objectives: Although academics and policymakers agree that lack of access to antibiotics is a major public challenge, there are widely different situations of lack of access that are not always clearly identified. Therefore, this paper aims to clarify potential confusion by delving into four different types of lack of access, their specific causes, consequences, and potential solutions., Sources: The paper builds on a narrative review of academic and policy literature about lack of access to antibiotics and potential solutions to address it., Content: We discuss causes as well as economic and clinical consequences of four different types of antibiotic unavailability: short-term shortages, long-term shortages, deregistrations, and lack of registration. The discussion is supported by examples from Norway, Romania, and Ethiopia, three countries characterized by clearly different market sizes and ability to pay. Common causes for all types of lack access include unattractive markets, dependence on few suppliers and insufficient communication, whereas other causes are specific to one type (e.g. insufficient inventories cause short-term shortages or regulatory complexity hinders registration). Longer lack of access entails more serious clinical consequences and higher risk of resistance development, but may not correspondingly increase costs in the long-term if alternatives are identified., Implications: It is essential to understand the type of unavailability at hand because no single solution can address all types. For instance, stockpiling addresses short-term shortages, but not long-term ones or deregistrations. However, supply chain transparency and pooled procurement are remedies that support other solutions and can cope with several types of lack of access., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: We want to verify the correlation between the increasing use of novel nicotine-containing products (NNCPs) and non-nicotine delivery products (NNDPs) among young individuals and the escalating negative health consequences, necessitating their prohibition., Methods: We performed a comprehensive analysis of the most relevant literature about the utilisation of NNCPs and NNDPs among young individuals and their health effects., Results: Despite being initially seen as less harmful alternatives, for smokers aiming to quit, these products have become more popular due to misleading marketing claims. Teenagers using NNCPs and NNDPs, despite having no smoking history, are more likely to transition to tobacco smoking. Consistent use can lead to health issues like pulmonary damage, asthma, and cardiovascular and ocular problems., Conclusion: The EAP and the ECPCP endorse the WHO's appeal to outlaw these hazardous products. They urge European governments to forbid the sale of NNCPs and NNDPs to children and adolescents in order to safeguard their well-being. They also propose specific recommendations (box 4) to support this cause., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Necrotizing enterocolitis (NEC) is the most frightening gastrointestinal emergency in newborns. Despite being primarily a disease of premature infants, neonates with congenital heart disease (CHD) are at increased risk of development. Acute and chronic hemodynamic changes in this population may lead to mesenteric circulatory insufficiency., Objectives: In this narrative review, we describe monitoring tools, alone or in multimodal use, that may help in the early recognition of patients with CHD at major risk of NEC development., Methods: We focused on vital parameters, echocardiography, Doppler flowmetry, abdominal near-infrared spectroscopy (aNIRS), and abdominal ultrasound (aUS)., Results: The number of studies on this topic is small and includes a wide range of patients' ages and types of CHD. Peripheral oxygen saturation (SpO 2 ) and certain echocardiographic indices (antegrade and retrograde velocity time integral, cardiac output, etc.) do not seem to differentiate infants with further onset of NEC from those not developing it. Hypotensive events, persistent diastolic flow reversal in the descending aorta, and low mesenteric oxygen saturation (rsSO 2 ) measured by aNIRS appear to occur more frequently in infants who later develop NEC. aUS may be helpful in the diagnosis of cardiac NEC, potentially showing air contrast tracked to the right atrium in the presence of pneumatosis., Conclusions: This narrative review describes the current knowledge on bedside tools for the early prediction of cardiac NEC. Future research needs to further explore the use of easy-to-learn, reproducible instruments to assist patient status and monitor patient trends.

Background: Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal (GI) emergency in preterm neonates. Untargeted metabolomics may allow the identification of biomarkers involved in NEC pathophysiology., Methods: We conducted a prospective study including preterm infants born at < 34 gestational weeks (GWs) whose urine was longitudinally collected at birth (< 48 h, T0) and at 14 (T1) and 28 days (T2). Neonates were followed for their development of NEC, spontaneous intestinal perforation (SIP), or other GI conditions and compared to those of matched healthy controls. Urine samples were investigated by untargeted metabolomic analysis based on mass-spectrometry., Results: Thirty-five patients with NEC, 5 patients with SIP, 14 patients with other GI diseases and 113 controls were enrolled and selected for metabolomic analysis on the basis of their clinical characteristics and available samples. Considering urine samples at T0, the one-class classification approach was able to correctly classify 16/20 subjects (80%) who developed NEC, 3/3 (100%) who developed SIP and 5/7 subjects (71.4%) with other GI pathologies as not belonging to the control group. Neonates with surgical NEC had higher N-acetylaspartic acid, butyrylcarnitine and propionylcarnitine levels than did those with medical NEC. Considering the time evolution of the urinary metabolome, the NEC and control groups showed differences independently of the time point., Conclusions: The urinary metabolome is closely associated with the underlying GI disease from birth. Urinary metabolic features characterize NEC patients from healthy controls until 28 days of life. The early urinary metabolome has the potential to predict surgical NEC. Future studies are needed to validate our results., (© 2024. The Author(s).)

While concerns about high-flow nasal cannula oxygen (HFNC) overuse and associated increased use of hospital resources are rapidly spreading, a two-tiered approach in its use is recommended by recent bronchiolitis guidelines. However, data on its effects in practice have not been reported. We aimed to analyze the trends in use of HFNC, hospitalizations, length of stay (LOS), and intensive care unit (ICU) admissions for bronchiolitis in a tertiary care center using a two-tiered HFNC approach since its introduction in practice. We retrospectively included data of children < 12 months of age who presented to the Paediatric Emergency Department (PED) and were hospitalized for bronchiolitis at our institution in the epidemic season between October 1st and April 30th during the years 2012-2023 and compared the clinical data across the years. Of the 687 hospitalized children included, 79.9% required oxygen supplementation. Use of HFNC significantly increased since its implementation (from 25% in 2012-2013 to over 60% since 2019-2020, p < 0.0001) and was most frequently administered as rescue treatment (in 57.5% of patients). There was no increased trend in ICU admissions (between 1.5% and 10.0% of hospitalizations across seasons, p = 0.40), while LOS, after increasing between 2013 and 2016 (medians between 4.0 and 5.4 days), remained stable thereafter (medians between 3.8 and 4.3 days)., Conclusions: The use of HFNC according to a two-tiered approach does not appear to be associated with an increase in ICU utilization or LOS., What Is Known: • Bronchiolitis is one of the most common reasons for hospitalization in infants. • Use high-flow nasal canulae oxygen (HFNC) has rapidly spread outside the intensive care unit (ICU) to treat infants with bronchiolitis, although increasing evidence has dampened the initial enthusiasm about their effectiveness. • Concerns nowadays are rising about HFNC overuse and associated increased use of hospital resources, including escalation of care to ICU., What Is New: • A more selective use of HFNC according to a "two-tiered approach", intended as a second-line rescue treatment in non-severely ill children who fail standard oxygen therapy, is not associated with increased ICU and length of hospital stay., (© 2024. The Author(s).)

Background: Cerebral venous thrombosis (CVT) is a cerebrovascular disorder that accounts for 20% of perinatal strokes. CVT incidence ranges from 0.67 to 1.12 per 100,000 newborns, while the incidence of "deep medullary vein thrombosis" (DMVT), a subtype of CVT, cannot be accurately estimated. This study aims to analyze the case history of CVT in the neonatal period, with a specific focus on DMVT., Materials and Methods: Newborns diagnosed with CVT, with or without DMVT, between January 2002 and April 2023, were collected using the Italian Registry of Infantile Thrombosis (RITI). Cerebral MRIs were reviewed by an expert neuroradiologist following a standardized protocol., Results: Forty-two newborns with CVT were identified, of which 27/42 (64%) had CVT, and the remaining 15/42 (36%) had DMVT (isolated DMVT in 9/15). Symptom onset occurred in the first week of life (median 8 days, IQR 4-14) with a male prevalence of 59%. The most common risk factors for CVT were complicated delivery (38%), prematurity (40%), congenital heart diseases (48%), and infections (40%). Seizures were the predominant presenting symptom in 52% of all cases. Hemorrhagic infarction was higher in cases with isolated DMVT (77%) compared to patients with CVT without DMVT (p = 0.013). Antithrombotic treatment was initiated in 36% of patients. Neurological impairment was observed in 48% of cases at discharge, while 18 out of 31 infants (58%) presented one or more neurological deficits at long term follow up.     Conclusion: DMVT occurs in over a third of neonates with CVT. Multicentric studies are essential to establish standardized protocols for therapy, neuroimaging, and follow-up in these patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Key Message: Gene silencing of BcDCL genes improves gray mold disease control in the cultivated strawberry. Gene silencing technology offers new opportunities to develop new formulations or new pathogen-resistant plants for reducing impacts of agricultural systems. Recent studies offered the proof of concept that the symptoms of gray mold can be reduced by downregulating Dicer-like 1 (DCL1) and 2 (DCL2) genes of Botrytis cinerea. In this study, we demonstrate that both solutions based on dsRNA topical treatment and in planta expression targeting BcDCL1 and BcDCL2 genes can be used to control the strawberry gray mold, the most harmful disease for different fruit crops. 50, 70 and 100 ng μL -1 of naked BcDCL1/2 dsRNA, sprayed on plants of Fragaria x ananassa cultivar Romina in the greenhouse, displayed significant reduction of susceptibility, compared to the negative controls, but to a lesser extent than the chemical fungicide. Three independent lines of Romina cultivar were confirmed for their stable expression of the hairpin gene construct that targets the Bc-DCL1 and 2 sequences (hp-Bc-DCL1/2), and for the production of hp construct-derived siRNAs, by qRT-PCR and Northern blot analyses. In vitro and in vivo detached leaves, and fruits from the hp-Bc-DCL1/2 lines showed significantly enhanced tolerance to this fungal pathogen compared to the control. This decreased susceptibility was correlated to the reduced fungal biomass and the downregulation of the Bc-DCL1 and 2 genes in B. cinerea. These results confirm the potential of both RNAi-based products and plants for protecting the cultivated strawberry from B. cinerea infection, reducing the impact of chemical pesticides on the environment and the health of consumers., (© 2024. The Author(s).)

Background: Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration., Methods: In this study, 382 infants born at 24 +0 -27 +6  weeks' gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks' postmenstrual age. The secondary outcomes are BPD at 36 weeks' postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24 +0 to 25 +6  weeks or 26 +0 to 27 +6  weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR)., Discussion: This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24 +0 -27 +6  weeks' gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks' postmenstrual age of life., Trial Registration: ClinicalTrials.gov NCT05711966. Registered on February 3, 2023., (© 2024. The Author(s).)

Nutritional intake could influence the blood glucose profile during early life of preterm infants. We investigated the impact of macronutrient intake on glycemic homeostasis using continuous glucose monitoring (CGM). We analyzed macronutrient intake in infants born ≤ 32 weeks gestational age (GA) and/or with birth weight ≤ 1500 g. CGM was started within 48 h of birth and maintained for 5 days. Mild and severe hypoglycemia were defined as sensor glucose (SG) < 72 mg/dL and <47 mg/dL, respectively, while mild and severe hyperglycemia were SG > 144 mg/dL and >180 mg/dL. Data from 30 participants were included (age 29.9 weeks (29.1; 31.2), birthweight 1230.5 g (1040.0; 1458.6)). A reduced time in mild hypoglycemia was associated to higher amino acids intake (p = 0.011) while increased exposure to hyperglycemia was observed in the presence of higher lipids intake (p = 0.031). The birthweight was the strongest predictor of neonatal glucose profile with an inverse relationship between the time spent in hyperglycemia and birthweight (p = 0.007).  Conclusions: Macronutrient intakes influence neonatal glucose profile as described by continuous glucose monitoring. CGM might contribute to adjust nutritional intakes in preterm infants. What is Known: • Parenteral nutrition may affect glucose profile during the first days of life of preterm infants. What is New: • Continuous glucose monitoring describes the relationship between daily parenteral nutrient intakes and time spent in hypo and hyperglycemic ranges., (© 2024. The Author(s).)

We analyzed and compared variations in the urinary metabolome, as well as postnatal clinical outcomes among preterm infants, based on the timing of antenatal corticosteroid (ACS) administration in response to preterm labor onset in their mothers. This was a prospective observational study held in the Neonatal Intensive Care Unit, Department of Woman's and Child's Health, Padova University Hospital (Italy). A urine sample was obtained from each patient within 24 h of birth; Mass Spectrometry-based untargeted metabolomics analysis was then conducted. We searched for any significant disparities in the metabolomic profile of preterm newborns subjected to antenatal corticosteroid (ACS) treatment at varying timings; their correlation with clinical outcomes were also evaluated. The group receiving ACS within the optimal time window (1-7 days before delivery) exhibited elevated levels of cysteine, N-acetylglutamine, propionyl carnitine and 5-hydroxyindolacetic acid, coupled with a decrease in pipecolic acid. Clinically, this group demonstrated a reduced need for invasive ventilation ( p = 0.04). In conclusion, metabolomics analysis identified several metabolites that discriminated preterm infants whose mothers received ACS within the recommended time window. Elevated levels of cysteine and 5-Hydroxyindoleacetic acid, metabolites characterized by antioxidant and anti-inflammatory properties, were observed in these infants. This metabolic profile correlated with improved respiratory outcomes, as evidenced by a reduced necessity for invasive ventilation at birth.

The fungal genus Colletotrichum includes numerous important plant pathogenic species, some of which causes fruit bitter rot as well as leaf lesions (leaf black spot) on major crops, leading to yield losses (Fu et al. 2019; Talhinhas & Baroncelli, 2023). C. acutatum was reported associated with black spot on fallen, immature fruit of pear ( Pyrus pyrifolia ) in New Zealand (Damm et al. 2012); however, to our knowledge, this species has not been reported in Italy or nowhere else. In 2022, a significant increase of anthracnose symptoms was observed on pears in Emilia-Romagna region, Italy. Symptoms, such as round brown lesions of 1 to 4 cm, appeared on more than 50% of refrigerated stored fruit. These symptoms were undetectable at the end of September 2022 and appeared after a five-month period of storage (February 2023) at 4°C (e-Xtra 1A and B). Fungal isolates were obtained from symptomatic pears after surfaces sterilization with 96% ethanol by culturing necrotic tissue pieces on Potato Dextrose Agar at 25°C in the dark (e-Xtra 1C and D). Cultures were shades of coral color, from opalescent to sunkist coral, with slight aerial mycelium becoming grey and darker with age. When observed from the reverse side, the color was pink and, with age, became coral orange to dark amaranth. Conidia observed with a light microscope appeared hyaline and fusiform, 8 to 16 × 2.5 to 4 μm, with two pointed ends or one rounded end. (e-Xtra 1E) One reference isolate, named L51, was used for molecular characterization. Total genomic DNA was extracted, and the ITS region of rDNA amplified using the universal primers ITS1 and ITS4, then sequenced. The resulting sequences were 100% identical to those of C. acutatum (NR&#95;144794.1: strain CBS 112996 ITS region; from TYPE material). Based on Damm et al. (2012), partial ACT, GAPDH, CHS and TUB2 gene sequences were also amplified and sequenced (GenBank Accession numbers: ITS: OR882016, ACT: OR882013, GAPDH: OR882011, CHS: OR882012, TUB2: OR882010), to characterize the isolates. Additionally, the multilocus phylogenetic analysis carried out with the obtained and reference sequences (Damm et al. 2012) revealed the species of analyzed isolates and confirmed the BLAST results, identifying the strain as C. acutatum (e-Xtra 1F). Koch's postulates were performed on 10 'Kaiser' pears. Surfaces sterilized fruits with 96% ethanol were subjected to wound inoculation with a conidial suspension (106 conidia ml-1) while 10 fruit were used as negative control and inoculated with sterile water. Following an incubation period of 8-14 days at 15-20°C, symptoms around the inoculation site resembled those initially observed, while the negative control showed no symptoms. Fungal colonies re-isolated from the lesions exhibited the same morphological characteristics as the original isolates. To our knowledge, this is the first report of pear bitter rot caused by C. acutatum in Italy and in Europe (Talhinhas & Baroncelli, 2023). Yet, bitter rot had not been recognized as a notable issue in pear cultivation. Nevertheless, given that pears rank as the 8th most cultivated fruit globally and economically very significant for the Emilia Romagna region in Italy the emergence of pear bitter rot caused by Colletotrichum species has the potential to evolve into a significant worldwide problem, warranting further investigation.

Background: The premature-born adult population is set to grow significantly, and prematurity has emerged as an important cardiovascular risk factor. We aimed to comprehensively assess cardiac mechanics and function in a cohort of ex-preterm preschoolers. Methods: Ex-preterm children (<30 weeks of gestation), aged 2 to 5 years, underwent transthoracic 2D, speckle-tracking, and 4D echocardiography. The findings were compared with 19 full-term children. Results: Our cohort of 38 children with prematurity history showed a normal morpho-functional echocardiographic assessment. However, compared to controls, the indexed 3D end-diastolic volumes of ventricular chambers were reduced (left ventricle 58.7 ± 11.2 vs. 67.2 ± 8.5 mL/m 2 ; right ventricle 50.3 ± 10.4 vs. 57.7 ± 11 mL/m 2 ; p = 0.02). Left ventricle global and longitudinal systolic function were worse in terms of fraction shortening (32.9% ± 6.8 vs. 36.5% ± 5.4; p = 0.05), ejection fraction (59.2% ± 4.3 vs. 62.3% ± 3.7; p = 0.003), and global longitudinal strain (-23.6% ± 2.4 vs. -25.5% ± 1.7; p = 0.003). Finally, we found a reduced left atrial strain (47.4% ± 9.7 vs. 54.9% ± 6.8; p = 0.004). Conclusions: Preschool-aged ex-preterm children exhibited smaller ventricles and subclinical impairment of left ventricle systolic and diastolic function compared to term children. Long-term follow-up is warranted to track the evolution of these findings.

Importance: Surfactant administration may be needed in late preterm through full-term neonates, but the pathophysiology of their respiratory failure can be different from that of early preterm neonates. The lung ultrasonography score (LUS) is accurate to guide surfactant replacement in early preterm neonates, but to our knowledge, it has not yet been studied in the late preterm through full-term neonatal population., Objective: To assess whether LUS is equally accurate to predict surfactant need in late preterm through full-term neonates as in early preterm neonates., Design, Setting, and Participants: This prospective, international, multicenter diagnostic study was performed between December 2022 and November 2023 in tertiary academic neonatal intensive care units in France, Italy, Spain, and the US. Late preterm through full-term neonates (≥34 weeks' gestation) with respiratory failure early after birth were enrolled., Exposure: Point-of-care lung ultrasonography to calculate the neonatal LUS (range, 0-18, with higher scores indicating worse aeration), which was registered in dedicated research databases and unavailable for clinical decision-making., Main Outcomes and Measures: The main outcomes were the area under the curve (AUC) in receiver operating characteristic analysis and derived accuracy variables, considering LUS as a replacement for other tests (ie, highest global accuracy) and as a triage test (ie, highest sensitivity). Sample size was calculated to assess noninferiority of LUS to predict surfactant need in the study population compared with neonates born more prematurely. Correlations of LUS with the ratio of hemoglobin oxygen saturation as measured by pulse oximetry (SpO2) to fraction of inspired oxygen (FiO2) and with the oxygen saturation index (OSI) were assessed., Results: A total of 157 neonates (96 [61.1%] male) were enrolled and underwent lung ultrasonography at a median of 3 hours (IQR, 2-7 hours) of life; 32 (20.4%) needed surfactant administration (pretest probability, 20%). The AUC was 0.87 (95% CI, 0.81-0.92). The highest global accuracy and sensitivity were reached for LUS values higher than 8 or 4 or lower, respectively. Subgroup analysis gave similar diagnostic accuracy in neonates born late preterm (AUC, 0.89; 95% CI, 0.81-0.97; n = 111) and early term and later (AUC, 0.84; 95% CI, 0.73-0.96; n = 46). After adjusting for gestational age, LUS was significantly correlated with SpO2:FiO2 (adjusted β, -10.4; 95% CI, -14.0 to -6.7; P < .001) and OSI (adjusted β, 0.2; 95% CI, 0.1-0.3; P < .001)., Conclusions and Relevance: In this diagnostic study of late preterm through full-term neonates with respiratory failure early after birth, LUS accuracy to predict surfactant need was not inferior to that observed in earlier preterm neonates. An LUS higher than 8 was associated with highest global accuracy (replacement test), suggesting that it can be used to guide surfactant administration. An LUS value of 4 or lower was associated with the highest sensitivity (triage test), suggesting it is unlikely for this population to need surfactant.

Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in young children and the second leading cause of infant death worldwide. While global circulation has been extensively studied for respiratory viruses such as seasonal influenza, and more recently also in great detail for SARS-CoV-2, a lack of global multi-annual sampling of complete RSV genomes limits our understanding of RSV molecular epidemiology. Here, we capitalise on the genomic surveillance by the INFORM-RSV study and apply phylodynamic approaches to uncover how selection and neutral epidemiological processes shape RSV diversity. Using complete viral genome sequences, we show similar patterns of site-specific diversifying selection among RSVA and RSVB and recover the imprint of non-neutral epidemic processes on their genealogies. Using a phylogeographic approach, we provide evidence for air travel governing the global patterns of RSVA and RSVB spread, which results in a considerable degree of phylogenetic mixing across countries. Our findings highlight the potential of systematic global RSV genomic surveillance for transforming our understanding of global RSV spread., (© 2024. The Author(s).)

Less than 2% of physicians complete a research training (PhD) after the residency with a declining trend in those pursuing a clinical scientist pathway in pediatrics. The exposure to research methodology during the clinical training may play a role in engaging the next generations of pediatric physician scientist. Herein, we describe the experience of the Padova Physician Scientist Research Training (PPSRT) of the pediatric residency program at the University of Padova. The PPSRT was addressed to residents attending PGY2 to PGY4 of the pediatric program and consisted of two cores: a general one including in person or virtual lectures about research methodology in pediatrics including design of a clinical trial, writing of a scientific paper and statistical methods, and a subspecialties core for the discussion of research challenges in each area and the scientific writing activities. The perceived barriers to a research training and an evaluation of the program were assessed by an anonymized questionnaire. Sixty-four out 150 residents registered for the research training with 62/64 completing the two cores. The major perceived barrier to research during clinical training was the absence of protected time (89%) followed by the lack of specific funds (37%). The group activities lead to the publication of 24 papers.    Conclusion: This is the first experience in the Italian pediatric training of a dedicated research program within the frame of postgraduate medical education. Our report highlights the need for protected time to promote research interest and nurture a new generation of physician scientists. What is Known: • Training to medical research is not part of residency program. • The declining trend of physician scientists might be reverted by early exposure to research methodology and challenges during residency. What is New: • An early exposure to research training during pediatric residency increases the research engagement of pediatric residents. • The lack of protected time for research is perceived as the major barrier to research training during residency., (© 2023. The Author(s).)

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., (© 2024. The Author(s).)

Few studies have evaluated the effect of bovine lactoferrin (bLf) on reducing respiratory infections in preschool children. This randomized controlled trial evaluated the effect of bLf in preschool children with recurrent respiratory infections. Participants were randomly assigned bLf (n = 25) or control ( n = 25). Outcomes included respiratory infection episodes (RIEs), symptom duration, school absence and medication. Fifty children aged 4.2 ± 0.1 years were included. During the active 4-month phase, median number of RIEs was reduced by 50% in the bLf group [1-episode, interquartile range (IQR): 0-2] vs. control (2, IQR: 1-3; p = 0.02). The proportion of participants with >3 RIEs was significantly lower in bLf ( n = 1, 4%) vs. control ( n = 7, 28%) with 80% lower odds of upper RIEs in the bLf arm (odds ratio: 0.20, 95% CI:0.06-0.74, p = 0.015). The duration of symptoms (3 vs. 6, p = 0.009) and days absent from school (3 vs. 6, p = 0.15) were lower in the active arm. Over the 2-month follow-up, no significant differences were observed between groups for infection episodes, symptom duration or school absence. However, bLf-treated children received significantly less corticosteroids over the entire 6-month study period (32% vs. 60%; p = 0.047). bLf supplementation significantly reduced the frequency and duration of RIEs in children with decreased corticosteroid use.

Large seasonal outbreaks of bronchiolitis put pressure on healthcare systems and particularly on intensive care units (ICUs). ICU admission is necessary to provide respiratory support to the severest cases, otherwise bronchiolitis can result in substantial mortality. ICU resources are often insufficient and there is scant evidence to guide the ICU clinical management. Most available studies do not cover the ICU-admitted cases and do not consider the associated public health issues. We review this topic through a multidisciplinary approach from both the clinical and public health perspectives, with an analysis based on pathophysiology and cost-effectiveness. We suggest ways to optimise respiratory care, minimise ICU stay, "protect" ICU beds and, whenever possible, make them available for other critically ill children. We also provide guidance on how to prepare ICUs to work under stressful conditions due to outbreaks and to reduce the risk of nosocomial cross-contamination, particularly in ICUs caring for high-risk children., Funding: None., Competing Interests: DDL has received lecture fees or research and educational support or from Chiesi Farmaceutici, Getinge, Vyaire, Radiometer, Medtronic, AstraZeneca, Boehringer Ingelheim, Airway Therapeutics, Natus, Masimo and BD. He has equity options from Ophirex ltd; he also participated to a data safety monitoring board for EXO biologics. All these were unrelated to this work and the field of bronchiolitis in general; finally, he is the Immediate Past President of the European Society for Paediatric and Neonatal Intensive Care (ESPNIC). MDN participated to the medical advisory board of Eurosets, unrelated to this work and the field of bronchiolitis in general; he is also the Secretary of ESPNIC. EB has received consultancy and lecture fees and has participated in advisory boards for AstraZeneca and Sanofi, all outside of the present work. MRG received a lecture fee from Sanofi, unrelated to this work and the field of bronchiolitis in general. The other authors have no interest to declare. This work did not receive any funding., (© 2024 The Author(s).)

The RNA-binding protein LIN28B, identified as an independent risk factor in high-risk neuroblastoma patients, is implicated in adverse treatment outcomes linked to metastasis and chemoresistance. Despite its clinical significance, the impact of LIN28B on neuroblastoma cell metabolism remains unexplored. This study employs a multi-omics approach, integrating transcriptome and metabolome data, to elucidate the global metabolic program associated with varying LIN28B expression levels over time. Our findings reveal that escalating LIN28B expression induces a significant metabolic rewiring in neuroblastoma cells. Specifically, LIN28B prompts a time-dependent increase in the release rate of metabolites related to the glutathione and aminoacyl-tRNA biosynthetic pathways, concomitant with a reduction in glucose uptake. These results underscore the pivotal role of LIN28B in governing neuroblastoma cell metabolism and suggest a potential disruption in the redox balance of LIN28B-bearing cells. This study offers valuable insights into the molecular mechanisms underlying LIN28B-associated adverse outcomes in neuroblastoma, paving the way for targeted therapeutic interventions.

Competing Interests: RB has received personal honoraria from AbbVie and Eli Lilly unrelated to the topic of this Comment. All other authors declare no competing interests.

Oxidative stress and fibrosis are important stress responses that characterize bronchopulmonary dysplasia (BPD), a disease for which only a therapy but not a cure has been developed. In this work, we investigated the effects of mesenchymal stromal cells-derived extracellular vesicles (MSC-EVs) on lung and brain compartment in an animal model of hyperoxia-induced BPD. Rat pups were intratracheally injected with MSC-EVs produced by human umbilical cord-derived MSC, following the Good Manufacturing Practice-grade (GMP-grade). After evaluating biodistribution of labelled MSC-EVs in rat pups left in normoxia and hyperoxia, oxidative stress and fibrosis investigation were performed. Oxidative stress protection by MSC-EVs treatment was proved both in lung and in brain. The lung epithelial compartment ameliorated glycosaminoglycan and surfactant protein expression in MSC-EVs-injected rat pups compared to untreated animals. Pups under hyperoxia exhibited a fibrotic phenotype in lungs shown by increased collagen deposition and also expression of profibrotic genes. Both parameters were reduced by treatment with MSC-EVs. We established an in vitro model of fibrosis and another of oxidative stress, and we proved that MSC-EVs suppressed the induction of αSMA, influencing collagen deposition and protecting from the oxidative stress. In conclusion, intratracheal administration of clinical-grade MSC-EVs protect from oxidative stress, improves pulmonary epithelial function, and counteracts the development of fibrosis. In the future, MSC-EVs could represent a new cure to prevent the development of BPD., (© The Author(s) 2023. Published by Oxford University Press.)

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., (© 2023 S. Karger AG, Basel.)

Recent clinical trials of as-needed fixed-dose combination of inhaled corticosteroid (ICS)/formoterol have provided new evidence that may warrant a reconsideration of current practice. A Task Force was set up by the European Respiratory Society to provide evidence-based recommendations on the use of as-needed ICS/formoterol as treatment for mild asthma. The Task Force defined two questions that were assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. The Task Force utilised the outcomes to develop recommendations for a pragmatic guideline for everyday clinical practice. The Task Force suggests that adults with mild asthma use as-needed ICS/formoterol instead of regular ICS maintenance treatment plus as-needed short-acting β 2 -antagonist (SABA) and that adolescents with mild asthma use either as-needed ICS/formoterol or ICS maintenance treatment plus as-needed SABA (conditional recommendation; low certainty of evidence). The recommendation for adults places a relatively higher value on the reduction of systemic corticosteroid use and the outcomes related to exacerbations, and a relatively lower value on the small differences in asthma control. Either treatment option is suggested for adolescent patients as the balance is very close and data more limited. The Task Force recommends that adult and adolescent patients with mild asthma use as-needed ICS/formoterol instead of as-needed SABA (strong recommendation; low certainty of evidence). This recommendation is based on the benefit of as-needed ICS/formoterol in mild asthma on several outcomes and the risks related to as-needed SABA in the absence of anti-inflammatory treatment. The implementation of this recommendation is hampered in countries (including European Union countries) where as-needed ICS/formoterol is not approved for mild asthma., Competing Interests: Conflict of interest: A. Papi reports grants from Chiesi, AstraZeneca, GSK, Sanofi and Agenzia Italiana del Farmaco (AIFA), consulting fees from Chiesi, AstraZeneca, GSK, Novartis, Sanofi, Avillion and Elpen Pharmaceutica, lecture honoraria from Chiesi, AstraZeneca, GSK, Menarini, Novartis, Zambon, Munidpharma, Sanofi, Edmond Pharma, IQVIA, Avillion and Elpen Pharmaceuticals, and advisory board participation with Chiesi, AstraZeneca, GSK, MSD, Novartis, Sanofi, IQVIA, Avillion and Elpen Pharmaceuticals, outside the submitted work. I. Agache reports lecture honoraria from Stallergennes, Pfizer and Sanofi, and advisory board participation with Pfizer, outside the submitted work. E. Baraldi reports lecture honoraria from AstraZeneca and Sanofi, outside the submitted work. R. Beasley reports grants from AstraZeneca, Genentech and Health Research Council New Zealand, consulting fees, lecture honoraria, travel support and advisory board participation with AstraZeneca, Cipla, Avillion, Health Research Council New Zealand, CSL Seqirus and Teva, outside the submitted work; R. Beasley is also chair of the Asthma and Respiratory Foundation NZ adolescent and adult asthma guidelines, member of the GOLD Board, and consultant for GINA. G. Brusselle reports lecture honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Merck, Sharp & Dohme and Sanofi, outside the submitted work. C. Coleman is an employee of the European Lung Foundation. M. Gaga reports a role as Alternate Minister of Health, Greece, outside the submitted work. E. Melén has received consulting fees from ALK, AstraZeneca, Chiesi, Novartis and Sanofi, outside the submitted work. I.D. Pavord reports speaker fees from Aerocrine AB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi and Teva, consultant fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi, Teva, Circassia, Dey Pharma, Genentech, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, RespiVert and Schering-Plough, payments for organisation of educational events from AstraZeneca, GSK, Regeneron Pharmaceuticals, Inc., Sanofi and Teva, international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Regeneron Pharmaceuticals, Inc., Sanofi, Teva and Napp Pharmaceuticals, and research grants from Chiesi, outside the submitted work. D. Peñate Gómez works as PMO Analyst at Asthma and Lung UK. A. Spanevello reports lecture honoraria, travel support and advisory board participation with Chiesi, AstraZeneca and GSK, outside the submitted work. T. Tonia acts as ERS methodologist. F. Schleich reports grants from GSK, AstraZeneca and Chiesi, lecture honoraria from GSK, AstraZeneca, Chiesi and Teva, and advisory board participation with GSK and AstraZeneca, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Competing Interests: DDL received consultancy and lecture fees from Chiesi Farmaceutici, Getinge, Vyaire, Radiometer, Medtronic, Astra Zeneca, Boehringer Ingelheim, Airway Therapeutics, Natus, Masimo; he also has equity options from Ophirex ltd. All these were unrelated to the present work and to nirsevimab and the universal RSV immunisation. MSL received consultancy and lecture fees from Medtronic, Astra Zeneca, and Sanofi, all outside of the present work and unrelated to nirsevimab and the universal RSV immunisation. EB received consultancy and lecture fees and participated to advisory boards for Astra-Zeneca and Sanofi, all outside of the present work. LB is the founding chairman of the ReSViNET Foundation. He has not received any personal benefit. His institution has conversely received research grants from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD and MeMed Diagnostics, GSK and Novavax, Julius Clinical. His institution also received consultancy and invited lecture fees by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, Astrazeneca, MSD, Sanofi and Janssen. All these were unrelated to the present work. KS has no conflict of interest to declare. This work did not receive any funding.

Low-field (LF) benchtop NMR is a new family of instruments available on the market, promising for fast metabolic fingerprinting and targeted quantification of specific metabolites despite a lack of sensitivity and resolution with respect to high-field (HF) instruments. In the present study, we evaluated the possibility to use the urinary metabolic fingerprint generated using a benchtop LF NMR instrument for an early detection of sepsis in preterm newborns, considering a cohort of neonates previously investigated by untargeted metabolomics based on Mass Spectrometry (MS). The classifier obtained behaved similarly to that based on MS, even if different classes of metabolites were taken into account. Indeed, investigating the regions of interest mainly related to the development of sepsis by a HF NMR instrument, we discovered a set of relevant metabolites associated to sepsis. The set included metabolites that were not detected by MS, but that were reported as relevant in other published studies. Moreover, a strong correlation between LF and HF NMR spectra was observed. The high reproducibility of the NMR spectra, the interpretability of the fingerprint in terms of metabolites and the ease of use make LF benchtop NMR instruments promising in discovering early-onset sepsis., Competing Interests: The authors declare no conflict of interest. Claire Cannet, Claudia Napoli and Elena Demetrio are employees of Bruker. The paper reflects the views of the scientists, and not the company.

Since the last Italian cost-utility assessment of palivizumab in 2009, new data on the burden of respiratory syncytial virus (RSV) and an International Risk Scoring Tool (IRST) have become available. The objective of this study was to provide an up-to-date cost-utility assessment of palivizumab versus no prophylaxis for the prevention of severe RSV infection in otherwise healthy Italian infants born at 29-31 weeks' gestational age (wGA) infants and those 32-35wGA infants categorized as either moderate- or high-risk of RSV-hospitalization (RSVH) by the IRST. A decision tree was constructed in which infants received palivizumab or no prophylaxis and then could experience: i) RSVH; ii) emergency room medically-attended RSV-infection (MARI); or, iii) remain uninfected/non-medically attended. RSVH cases that required intensive care unit admission could die (0.43%). Respiratory morbidity was considered in all surviving infants up to 18 years of age. Hospitalization rates were derived from Italian data combined with efficacy from the IMpact-RSV trial. Palivizumab costs were calculated from vial prices (50mg: €490.37 100mg: €814.34) and Italian birth statistics combined with a growth algorithm. A lifetime horizon and healthcare and societal costs were included. The incremental cost-utility ratio (ICUR) was €14814 per quality-adjusted life year (QALY) gained in the whole population (mean: €15430; probability of ICUR being <€40000: 0.90). The equivalent ICURs were €15139 per QALY gained (€15915; 0.89) for 29-31wGA infants and €14719 per QALY gained (€15230; 0.89) for 32-35wGA infants. The model was most sensitive to rates of long-term sequelae, utility scores, palivizumab cost, and palivizumab efficacy. Palivizumab remained cost-effective in all scenario analyses, including a scenario wherein RSVH infants received palivizumab without a reduction in long-term sequelae and experienced a 6-year duration of respiratory morbidity (ICUR: €27948 per QALY gained). In conclusion, palivizumab remains cost-effective versus no prophylaxis in otherwise healthy Italian preterm infants born 29-35wGA. The IRST can help guide cost-effective use of palivizumab in 32-35wGA infants., Competing Interests: BP, EB, PM, ML, XCE have received research funding and/or compensation as advisor/lecturer from AstraZeneca and/or Sanofi and/or Pfizer outside the scope of this study. BRG, IK, JF, and RR employers have received payment from AstraZeneca for work on various projects. JET has nothing to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Keary et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Sparse metanephrines reference intervals in pediatric populations are available and different study designs and technologies/ assays used in these studies lead to hardly transferable data from a laboratory to another. The aim of this study was to update pediatric reference intervals of total fractionated metanephrines in spot urine samples, using a commercial extraction kit run on a specific high-pressure liquid chromatograph coupled with an electrochemical detector., Methods: Four hundred and fifty-two spot pediatric urinary samples previously submitted to urinalysis were consecutively included in the study with the exclusion of children's samples with diagnosis or clinical suspicion of paraganglioma/pheochromocytoma, kidney diseases and arterial hypertension. Urinary metanephrine, normetanephrine and 3-methoxytyramine were extracted with ClinRep ® HPLC Complete kit and run on HPLC Prominence liquid chromatograph LC-20AT (Shimadzu Italia S.r.l. Milan, Italy) coupled with Decade II electrochemical detector (Antec Scientific, Zoeterwoude, the Nederlands, provided by Alfatech S.r.l., Genoa, Italy). Results were expressed as the ratio analyte-to-creatinine., Results: Any of the three analytes required a repartition by gender (metanephrine P=0.27; normetanephrine P=0.90 and 3-methoxytyramine P=0.18). A significant statistically inversely proportional relation with age was found for metanephrine (P<0.0001; ρ=-0.72), normetanephrine (P<0.0001; ρ=-0.75) and 3-methoxytyramine (P<0.0001; ρ=-0.83). Reference intervals were calculated as function of age., Conclusions: This study provides pediatric reference intervals for urinary fractionated total metanephrines in spot urine calibrated on a specific instrumentation and extraction commercial kit.

Background: Nirsevimab is an extended half-life monoclonal antibody to the respiratory syncytial virus (RSV) fusion protein that has been developed to protect infants for an entire RSV season. Previous studies have shown that the nirsevimab binding site is highly conserved. However, investigations of the geotemporal evolution of potential escape variants in recent (ie, 2015-2021) RSV seasons have been minimal. Here, we examine prospective RSV surveillance data to assess the geotemporal prevalence of RSV A and B, and functionally characterise the effect of the nirsevimab binding-site substitutions identified between 2015 and 2021., Methods: We assessed the geotemporal prevalence of RSV A and B and nirsevimab binding-site conservation between 2015 and 2021 from three prospective RSV molecular surveillance studies (the US-based OUTSMART-RSV, the global INFORM-RSV, and a pilot study in South Africa). Nirsevimab binding-site substitutions were assessed in an RSV microneutralisation susceptibility assay. We contextualised our findings by assessing fusion-protein sequence diversity from 1956 to 2021 relative to other respiratory-virus envelope glycoproteins using RSV fusion protein sequences published in NCBI GenBank., Findings: We identified 5675 RSV A and RSV B fusion protein sequences (2875 RSV A and 2800 RSV B) from the three surveillance studies (2015-2021). Nearly all (25 [100%] of 25 positions of RSV A fusion proteins and 22 [88%] of 25 positions of RSV B fusion proteins) amino acids within the nirsevimab binding site remained highly conserved between 2015 and 2021. A highly prevalent (ie, >40·0% of all sequences) nirsevimab binding-site Ile206Met:Gln209Arg RSV B polymorphism arose between 2016 and 2021. Nirsevimab neutralised a diverse set of recombinant RSV viruses, including new variants containing binding-site substitutions. RSV B variants with reduced susceptibility to nirsevimab neutralisation were detected at low frequencies (ie, prevalence <1·0%) between 2015 and 2021. We used 3626 RSV fusion-protein sequences published in NCBI GenBank between 1956 and 2021 (2024 RSV and 1602 RSV B) to show that the RSV fusion protein had lower genetic diversity than influenza haemagglutinin and SARS-CoV-2 spike proteins., Interpretation: The nirsevimab binding site was highly conserved between 1956 and 2021. Nirsevimab escape variants were rare and have not increased over time., Funding: AstraZeneca and Sanofi., Competing Interests: Declaration of interests DW, CM, BA, AAA, TB, VG, EJK, KMT, and MTE are current employees of and hold stock or stock options in AstraZeneca. MEA and DET are former employees of and hold stock or stock options in AstraZeneca. EB has received honoraria from AstraZeneca and Sanofi for lectures, presentations, speaker bureaus, manuscript writing, or educational events. TH has participated in Data Safety Monitoring Boards and ad-hoc advisory boards for Sanofi, Data Safety Monitoring Boards for Enanta, and ad-hoc advisory boards for Janssen and has received honoraria from Janssen and Merck, Sharp & Dohme (MSD) for lectures at academic meetings. CK has received honoraria from F Hoffmann-La Roche for lectures. FM-T's research activities are supported by grants from Instituto de Salud Carlos III (grant numbers: PI16/01569, PI19/01090, PI22/00406, and CB21/06/00103), GEN-COVID (grant number: IN845D 2020/23), and Grupos de Referencia Competitiva (grant number: IIN607A2021/05), and he has received additional grants to his institution from AstraZeneca and Sanofi; he also received honoraria from GlaxoSmithKline, Pfizer, Sanofi Pasteur, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as speaker in congresses outside the scope of the submitted work, in addition to travel support from GlaxoSmithKline, MSD, Pfizer, and Sanofi. FM-T has also participated in advisory boards for Pfizer, MSD, Sanofi, and GlaxoSmithKline, and in Data Safety Monitoring Boards for Biofabri; is a member of The European Technical Advisory Group of Experts—WHO Europe and the Spanish Paediatric Infectious Diseases Society; and has also acted as principal investigator in randomised controlled trials for AstraZeneca, Biofabri Seqirus, GlaxoSmithKline, Janssen, MSD, Novavax, Novartis, Pfizer, Roche, Regeneron, and Sanofi Pasteur with honoraria paid to his institution. MCN has received grants from the Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials, Pfizer, and Sanofi Pasteur; honoraria from Sanofi for lectures presentations, speakers' bureaus, manuscript writing or educational events; payment for expert testimony from Pfizer and Sanofi Pasteur; and is a board member for Gavi vaccine alliance. JMP has received payments to his institution from the Canadian Paediatric Review and Yearly RSV Coordinators Workshop and is an unpaid co-chair of the Ontario Immunization Advisory Committee. PR has received investigator-initiated research grants to his institution from MSD and has received institutional funding from GlaxoSmithKline for local and international lectures and from AstraZeneca, GlaxoSmithKline, MSD, Sanofi, and Pfizer for participation in advisory boards. RTS has received payment or honoraria for lectures for AstraZeneca, Pfizer, and Sanofi Pasteur. CV has received payment or honoraria for lectures from AstraZeneca. LJB has not received personal fees or other personal benefits from pharmaceutical companies. His institution, University Medical Center Utrecht (UMCU), has received major funding (>€100 000 per industrial partner) from AbbVie, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics for investigator-initiated studies. UMCU has received major funding for the RSV-GOLD study from the Bill & Melinda Gates Foundation. UMCU has received major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GlaxoSmithKline, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi Pasteur. UMCU has received major funding by Julius Clinical for participating in clinical studies sponsored by AstraZeneca and Pfizer. UMCU has received minor funding (€1 000–25 000 per industrial partner) for consultation and invited lectures by AbbVie, AstraZeneca, Ablynx, Bavaria Nordic, MabXience, GlaxoSmithKline, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Genzyme, and Janssen. LJB is the founding chairman of the ReSViNET Foundation. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Digital mental health represents a way to increase access to evidence-based psychological support. However, the implementation of digital mental health in routine health care practice is limited, with few studies focusing on implementation. Accordingly, there is a need to better understand the barriers to and facilitators of implementing digital mental health. Existing studies have mainly focused on the viewpoints of patients and health professionals. Currently, there are few studies about barriers and facilitators from the perspective of primary care decision makers, that is, the persons responsible for deciding whether a given digital mental health intervention should be implemented in a primary care organization., Objective: The objectives were to identify and describe barriers to and facilitators of the implementation of digital mental health as perceived by primary care decision makers, evaluate the relative importance of different barriers and facilitators, and compare barriers and facilitators reported by primary care decision makers who have versus have not implemented digital mental health interventions., Methods: A web-based self-report survey was conducted with primary care decision makers responsible for the implementation of digital mental health in primary care organizations in Sweden. Answers to 2 open-ended questions about barriers and facilitators were analyzed through summative and deductive content analysis., Results: The survey was completed by 284 primary care decision makers-59 (20.8%) decision makers representing implementers (ie, organizations that offered digital mental health interventions) and 225 (79.2%) respondents representing nonimplementers (ie, organizations that did not offer digital mental health interventions). Overall, 90% (53/59) of the implementers and 98.7% (222/225) of the nonimplementers identified barriers, and 97% (57/59) of the implementers and 93.3% (210/225) of the nonimplementers identified facilitators. Altogether, 29 barriers and 20 facilitators of implementation were identified related to guidelines; patients; health professionals; incentives and resources; capacity for organizational change; and social, political, and legal factors. The most prevalent barriers were related to incentives and resources, whereas the most prevalent facilitators were related to the capacity for organizational change., Conclusions: A number of barriers and facilitators were identified that could influence the implementation of digital mental health from the perspective of primary care decision makers. Implementers and nonimplementers identified many common barriers and facilitators, but they differ in terms of certain barriers and facilitators. Common and differing barriers and facilitators identified by implementers and nonimplementers may be important to address when planning for the implementation of digital mental health interventions. For instance, financial incentives and disincentives (eg, increased costs) are the most frequently mentioned barrier and facilitator, respectively, by nonimplementers, but not by implementers. One way to facilitate implementation could be to provide more information to nonimplementers about the actual costs related to the implementation of digital mental health., (©Anders Brantnell, Serdar Temiz, Enrico Baraldi, Joanne Woodford, Louise von Essen. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 26.06.2023.)

Background: Evidence-based data on treatment of neonatal status epilepticus (SE) are scarce. We aimed to collect data on the efficacy and safety of ketamine for the treatment of neonatal SE and to assess its possible role in the treatment of neonatal SE., Methods: We described a novel case and conducted a systematic literature review on neonatal SE treated with ketamine. The search was carried out in Pubmed, Cochrane, Clinical Trial Gov, Scopus and Web of Science., Results: Seven published cases of neonatal SE treated with ketamine were identified and analyzed together with our novel case. Seizures typically presented during the first 24 h of life (6/8). Seizures were resistant to a mean of five antiseizure medications. Ketamine, a NMDA receptor antagonist, appeared to be safe and effective in all neonates treated. Neurologic sequelae including hypotonia and spasticity were reported for 4/5 of the surviving children (5/8). 3/5 of them were seizure free at 1-17 months of life., Discussion: Neonatal brain is more susceptible to seizures due to a shift towards increased excitation because of a paradoxical excitatory effect of GABA, a greater density of NMDA receptors and higher extracellular concentrations of glutamate. Status epilepticus and neonatal encephalopathy could further enhance these mechanisms, providing a rationale for the use of ketamine in this setting., Conclusions: Ketamine in the treatment of neonatal SE showed a promising efficacy and safety profile. However, further in-depth studies and clinical trials on larger populations are needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Pin, Leonardi, Nosadini, Cavicchiolo, Guariento, Zarpellon, Perilongo, Raffagnato, Toldo, Baraldi and Sartori.)

Background: The pathobiological mechanisms associated with perinatal asphyxia and hypoxic-ischemic encephalopathy are complex and poorly understood. The metabolic effects of therapeutic hypothermia have been partially explored., Methods: We conducted a single-center longitudinal study to investigate the metabolic effects of perinatal asphyxia and hypoxic-ischemic encephalopathy on the urinary metabolome of a group of 12 asphyctic infants over time compared to 22 matched healthy newborns, using untargeted metabolomics based on mass spectrometry., Findings: Over-representation pathway analysis identified the steroidogenesis pathway as being significantly disrupted, with reduced steroid levels in the first three days of life despite treatment with hypothermia. Comparison with matched healthy newborns showed that the urinary steroid content was lower in asphyctic infants before hypothermia. The lysine degradation and carnitine synthesis pathways were also significantly affected., Interpretation: Steroidogenesis is significantly disrupted in asphyctic infants compared to healthy newborns. Given how neurosteroids are involved in neuromodulation and neuroprotection, translational research is warranted on the potential role of neurosteroid-based intervention in asphyctic infants., Funding: None., Competing Interests: Declaration of interests The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Bronchiolitis is the most common lower respiratory tract infection (LRTI) in children and is mainly caused by the Respiratory Syncytial Virus (RSV). Bronchiolitis presents seasonally and lasts about five months, usually between October to March, with peaks of hospitalizations between December and February, in the Northern Hemisphere. The burden of bronchiolitis and RSV in primary care is not well understood., Materials and Methods: This retrospective analysis used data from Pedianet, a comprehensive paediatric primary care database of 161 family paediatricians in Italy. We evaluated the incidence rates (IR) of all-cause bronchiolitis (ICD9-CM codes 466.1, 466.11 or 466.19), all-cause LRTIs, RSV-bronchiolitis and RSV-LRTIs in children from 0 to 24 months of age, between January 2012 to December 2019. The role of prematurity (<37 weeks of gestational age) as a bronchiolitis risk factor was evaluated and expressed as odds ratio., Results: Of the 108,960 children included in the study cohort, 7,956 episodes of bronchiolitis and 37,827 episodes of LRTIs were recorded for an IR of 47 and 221 × 1,000 person-years, respectively. IRs did not vary significantly throughout the eight years of RSV seasons considered, showing a seasonality usually lasting five months, between October and March, while the peak of incidence was between December and February. Bronchiolitis and LRTI IRs were higher during the RSV season, between October and March, regardless of the month of birth, with bronchiolitis IR being higher in children aged ≤12 months. Only 2.3% of bronchiolitis and LRTI were coded as RSV-related. Prematurity and comorbidity increased the risk of bronchiolitis; however, 92% of cases happened in children born at term, and 97% happened in children with no comorbidities or otherwise healthy., Conclusions: Our results confirm that all children aged ≤24 months are at risk of bronchiolitis and LRTI during the RSV season, regardless of the month of birth, gestational age or underlying health conditions. The IRs of bronchiolitis and LRTI RSV-related are underestimated due to the poor outpatient epidemiological and virological surveillance. Strengthening the surveillance system at the paediatric outpatient level, as well as at the inpatient level, is needed to unveil the actual burden of RSV-bronchiolitis and RSV-LRTI, as well as to evaluate the effectiveness of new preventive strategies for anti-RSV., Competing Interests: MB, LB and SP are employees of Sanofi and may hold shares. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Barbieri, Cavagnis, Scamarcia, Cantarutti, Bertizzolo, Bangert, Parisi, Cantarutti, Baraldi, Giaquinto and Baldo.)

Objectives: Antibacterial drug discovery activities are essential for filling clinical pipelines with promising clinical candidates. Little information is available about the challenges and shortcomings of small companies and academic institutions in performing these important discovery tasks., Methods: We performed a content analysis of 463 reviewer comments on 91 funding applications of antibacterial drug discovery projects submitted to two major global funders between 2016 and 2020 that had not proceeded further in the selection process. This quality assessment was complemented with the inputs (via e-mail) from a panel involving six antibiotic research and development (R&D) experts with long-standing expertise and experience in antibiotic drug discovery., Results: Common critical comments of reviewers are grouped into three main categories: scientific and technical shortcomings, unclear potential societal impact, and insufficient capability and expertise of the project team regarding the R&D process. Insufficient characterization of in vitro activity and/or testing of the hits/leads and insufficient antibacterial activity were the most common critical comments. Other areas of concern were insufficient or lack of differentiation from available drugs or projects with a long R&D history, and the research team's insufficient knowledge of a structured streamlined R&D process as reflected in severe gaps in the expertise of the R&D team. Little appreciation for the problem of the emergence of target-based resistance, especially in single-target approaches, and little awareness of toxicological issues, including approaches with historical liabilities were also commonly mentioned. The shortcomings identified through the analysis of funding applications are echoed by the results of the expert panel., Discussion: Our analysis identified an urgent need of strengthening the support for antibacterial drug discovery teams to help more projects reach such a quality to be eligible for global funders and private investors., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The biochemical variations occurring in intrauterine growth restriction (IUGR), when a fetus is unable to achieve its genetically determined potential, are not fully understood. The aim of this study is to compare the urinary metabolomic profile between IUGR and non-IUGR very preterm infants to investigate the biochemical adaptations of neonates affected by early-onset-restricted intrauterine growth., Methods: Neonates born <32 weeks of gestation admitted to neonatal intensive care unit (NICU) were enrolled in this prospective matched case-control study. IUGR was diagnosed by an obstetric ultra-sonographer and all relevant clinical data during NICU stay were captured. For each subject, a urine sample was collected within 48 h of life and underwent untargeted metabolomic analysis using mass spectrometry ultra-performance liquid chromatography. Data were analyzed using multivariate and univariate statistical analyses., Results: Among 83 enrolled infants, 15 IUGR neonates were matched with 19 non-IUGR controls. Untargeted metabolomic revealed evident clustering of IUGR neonates versus controls showing derangements of pathways related to tryptophan and histidine metabolism and aminoacyl-tRNA and steroid hormones biosynthesis., Conclusions: Neonates with IUGR showed a distinctive urinary metabolic profile at birth. Although results are preliminary, metabolomics is proving to be a promising tool to explore biochemical pathways involved in this disease., Impact: Very preterm infants with intrauterine growth restriction (IUGR) have a distinctive urinary metabolic profile at birth. Metabolism of glucocorticoids, sexual hormones biosynthesis, tryptophan-kynurenine, and methionine-cysteine pathways seem to operate differently in this sub-group of neonates. This is the first metabolomic study investigating adaptations exclusively in extremely and very preterm infants affected by early-onset IUGR. New knowledge on metabolic derangements in IUGR may pave the ways to further, more tailored research from a perspective of personalized medicine., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

More and more very low birth weight (VLBW) infants around the world survive nowadays, with consequently larger numbers of children developing prematurity-related morbidities, especially bronchopulmonary dysplasia (BPD). BPD is a multifactorial disease and its rising incidence in recent years means that general pediatricians are much more likely to encounter a child born extremely preterm, possibly with BPD, in their clinical practice. Short- and long-term sequelae in VLBW patients may affect not only pulmonary function (principally characterized by an obstructive pattern), but also other aspect including the neurological (neurodevelopmental and neuropsychiatric disorders), the sensorial (earing and visual impairment), the cardiological (systemic and pulmonary hypertension, reduced exercise tolerance and ischemic heart disease in adult age), nutritional (feeding difficulties and nutritional deficits), and auxological (extrauterine growth restriction). For the most premature infants at least, a multidisciplinary follow-up is warranted after discharge from the neonatal intensive care unit in order to optimize their respiratory and neurocognitive potential, and prevent respiratory infections, nutritional deficiencies or cardiovascular impairments.  Conclusion: The aim of this review is to summarize the main characteristics of preterm and BPD infants, providing the general pediatrician with practical information regarding these patients' multidisciplinary complex follow-up. We explore the current evidence on respiratory outcomes and their management that actually does not have a definitive available option. We also discuss the available investigations, treatments, and strategies for prevention and prophylaxis to improve the non-respiratory outcomes and the quality of life for these children and their families, a critical aspect not always considered. This comprehensive approach, added to the increased needs of a VLBW subjects, is obviously related to very high health-related costs that should be beared in mind. What is Known: • Every day, a general pediatrician is more likely to encounter a former very low birth weight infant. • Very low birth weight and prematurity are frequently related not only with worse respiratory outcomes, but also with neurological, sensorial, cardiovascular, renal, and nutritional issues. What is New: • This review provides to the general pediatrician a comprehensive approach for the follow-up of former premature very low birth weight children, with information to improve the quality of life of this special population., (© 2023. The Author(s).)