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Abstract 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.

Background: Positive effects of early nutritional strategies on neurological outcomes have been observed when nutrients were administered by the enteral route, especially during the first week of life. Evidence reports that serum neurofilament light chain (NfL), a structural protein of neurons, is a specific and reliable biomarker of neuronal damage., Objective: The present study aimed to investigate the effect of early enteral nutrition (EN) in minimizing neuroaxonal damage and assessing NfL serum levels in preterm neonates., Methods: Fifty-four preterm neonates without severe brain impairment and 20 full-term babies as controls were enrolled from the Neonatal Intensive Care Unit at the Policlinico Umberto I in Rome. We performed blood sampling at birth (day of life 0 - DoL 0) in 20 full-term newborns and in 19 pre-term infants. Furthermore, we executed blood sampling at DoL 28 in other 22 pre-term newborns who received early enteral nutrition (EN) within the third DoL (Early-EN) and in 13 other pre-term newborns who received EN after the third DoL (Late-EN)., Results: Serum levels of NfL were higher in preterm babies when compared to full-term neonates, at DoL 0 (48.81 ± 9.4 vs. 11.67 ± 1.4 pg/ml; p = 0.007). Interestingly, at DoL 28, serum NfL was significantly decreased in the Early-EN newborns compared to the Late-EN groups (15.22 ± 2.0 vs. 50.05 ± 17.9 pg/ml; p = 0.03)., Conclusions: It was shown that early enteral feeding, within the first week of life, could be a useful tool for limiting neurological impairment in pre-term neonates by restoring NfL., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Nutrition in early life has an impact on white matter (WM) development in preterm-born babies. Quantitative analysis of pixel brightness intensity (PBI) on cranial ultrasound (CUS) scans has shown a great potential in the evaluation of periventricular WM echogenicity in preterm newborns. We aimed to investigate the employment of this technique to objectively verify the effects of parenteral nutrition (PN) on periventricular WM damage in preterm infants. Prospective observational study including newborns with gestational age at birth ≤32 weeks and/or birth weight ≤1500 g who underwent CUS examination at term-equivalent age. The echogenicity of parieto-occipital periventricular WM relative to that of homolateral choroid plexus (RE CP ) was calculated on parasagittal scans by means of quantitative analysis of PBI. Its relationship with nutrient intake through enteral and parenteral routes in the first postnatal week was evaluated. The study included 42 neonates for analysis. We demonstrated that energy and protein intake administered through the parenteral route positively correlated with both right and left RE CP values (parenteral energy intake vs. right RE CP : r = 0.413, p = 0.007; parenteral energy intake vs. left RE CP : r = 0.422, p = 0.005; parenteral amino acid intake vs. right RE CP : r = 0.438, p = 0.004; parenteral amino acid intake vs. left RE CP : r = 0.446, p = 0.003). Multivariate linear regression analysis confirmed these findings. Quantitative assessment of PBI could be considered a simple, risk-free, and repeatable method to investigate the effects of PN on WM development in preterm neonates.

Importance: A multicenter randomized clinical trial (RCT) showed a lung recruitment maneuver using high-frequency oscillatory ventilation just before surfactant administration (ie, intubate-recruit-surfactant-extubate [IN-REC-SUR-E]) improved the efficacy of treatment compared with the standard intubate-surfactant-extubate (IN-SUR-E) technique without increasing the risk of adverse neonatal outcomes., Objective: To examine follow-up outcomes at corrected postnatal age (cPNA) 2 years of preterm infants previously enrolled in an RCT and treated with IN-REC-SUR-E or IN-SUR-E in 35 tertiary neonatal intensive care units., Design, Setting, and Participants: This was a follow-up study of infants recruited into the primary RCT from 2015 to 2018 at 35 tertiary neonatal intensive care units (NICUs) in Italy. Follow-up examinations included neurodevelopmental, growth, and respiratory outcomes of these children at cPNA 2 years. Participants included spontaneously breathing extremely preterm neonates (24 0/7 to 27 6/7 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 hours of life. Data were analyzed from April 2023 to January 2024., Intervention: Infants were randomly assigned (1:1) to IN-REC-SUR-E or IN-SUR-E and then followed up., Main Outcomes and Measures: The primary outcome was the occurrence of death after discharge or major disability at cPNA 2 years. Secondary outcomes were neurodevelopmental outcomes (major disability, cerebral palsy, cognitive impairment, visual deficit, or auditory deficit), anthropometric measurements (weight, length, and head circumference), and recurrent respiratory infections and hospitalizations because of respiratory causes at 2y cPNA., Results: A total of 137 extremely preterm infants (median [IQR] gestational age, 26.5 [25.3-27.5] weeks and 75 [54.7%] female), initially enrolled in the original RCT, were followed up at cPNA 2 years, including 64 infants in the IN-SUR-E group and 73 infants in the IN-REC-SUR-E group. There were no significant differences in the occurrence of death after discharge or major disability at cPNA 2 years (IN-SUR-E: 13 children [20.3%] vs IN-REC-SUR-E: 10 children [13.7%]; P = .36). There were no significant differences in incidence of disability, cerebral palsy, or cognitive impairment in the IN-REC-SUR-E group compared with the IN-SUR-E group. There were no significant differences in anthropometric measurements (weight, length, and head circumference) between groups. There were no significant differences in the incidence of recurrent respiratory infections or in hospitalizations because of respiratory causes between groups., Conclusions and Relevance: In this RCT of lung recruitment before surfactant vs standard care there were no significant differences between the 2 groups in death, neurodevelopmental outcomes, anthropometric measurements, or recurrent respiratory infections at the 2-year follow-up. These findings can aid clinicians in decision-making for the best strategy to administer surfactant, considering long-term outcomes.

Microbiota plays a crucial role in intestinal maturation in preterm newborns. The clinical manifestation of the immaturity of the gastro-intestinal tract is called feeding intolerance (FI). This condition may resolve spontaneously or dramatically evolve into necrotizing enterocolitis. One of the most challenging tasks for the neonatologist is to identify those neonates that will develop the disease early in order to adequately provide nutrition to these patients, from the very first hours of life. A close interplay between the maturity of the gastro-intestinal tract and gut microbiota has been described; however, in preterm neonates, this relationship is still undefined. We analyzed the bacterial composition of stool samples, collected early in life, from 30 preterm newborns classified as intolerant or tolerant according to the degree of readiness of the gastro-intestinal tract to receive enteral nutrition. The Pielou evenness index was significantly increased in intolerant compared with tolerant newborns. Data corrected for confounding variables confirmed that the occurrence of gut maturation was independently influenced by Pielou evenness at birth. A lower bacterial diversity very early in life is associated with improved feeding tolerance in preterm newborns. The abundance analysis showed that neonates not ready to receive enteral nutrition for feeding intolerance show, after birth, an increased abundance of Proteobacteria , Lachnospiracae , Enterobacter and Acinetobacter . We can argue that those are the taxa that prevent the establishment of pioneer bacteria. A lower alpha-diversity, in the first days of life, may facilitate the seeding of beneficial pioneer bacteria that, in turn, drive healthy microbial colonization during neonatal life.

Autonomic symptoms may be local and general clinical manifestations of both epilepsy and migraine caused by the dysfunction of brain areas best known as the central autonomic network. Despite their prevalence, autonomic signs are often misdiagnosed and their treatment is undervalued. This review aims to describe the autonomic manifestations reported during seizures and migraineur attacks according to their presentation, focusing on the role of the central autonomic network (CAN) and on the parasympathetic outflow that often-induced cranial autonomic symptoms (CAS) during migraineur attacks. Further, our purpose is to analyze the pathophysiological meanings and whether their presence influences the prognosis and therapy of these disorders., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

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).)

Besides suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron is involved in Treg-mediated tolerance is completely unknown. Here, we showed that the transferrin receptor CD71 was upregulated on activated Tregs infiltrating human liver cancer. Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by impaired perinatal Treg expansion. CD71-null Tregs displayed decreased proliferation and tissue-Treg signature loss. In perinatal life, CD71 deficiency in Tregs triggered hepatic iron overload response, characterized by increased hepcidin transcription and iron accumulation in macrophages. Lower bacterial diversity, and reduction of beneficial species, were detected in the fecal microbiota of CD71 conditional knockout neonates. Our findings indicate that CD71-mediated iron absorption is required for Treg perinatal expansion and is related to systemic iron homeostasis and bacterial gut colonization. Therefore, we hypothesize that Tregs establish nutritional tolerance through competition for iron during bacterial colonization after birth.

Introduction: Prolonged mechanical ventilation, commonly used to assist preterm newborns, increases the risk of developing bronchopulmonary dysplasia (BPD). In recent decades, studies have demonstrated that systemic corticosteroids play a significant role in the prevention and management of BPD. In this systematic review of randomized controlled trials (RCTs), we evaluated the association between the administration of systemic corticosteroids in preterm infants and its long-term outcomes, such as neurodevelopment, growth, extubation rate, and related adverse effects., Methods: We conducted an electronic search in Medline, Scopus, and PubMed using the following terms: "premature infants" and "corticosteroids." We considered all RCTs published up to June 2023 as eligible. We included all studies involving preterm newborns treated with systemic corticosteroids and excluded studies on inhaled corticosteroids., Results: A total of 39 RCTs were evaluated. The influence of steroids administered systemically during the neonatal period on long-term neurological outcomes remains unknown, with no influence observed for long-term growth. The postnatal administration of systemic corticosteroids has been found to reduce the timing of extubation and improve respiratory outcomes. Dexamethasone appears to be more effective than hydrocortisone, despite causing a higher rate of systemic hypertension and hyperglycemia. However, in the majority of RCTs analyzed, there were no differences in the adverse effects related to postnatal corticosteroid administration., Conclusion: Dexamethasone administered during the neonatal period appears to be more effective than hydrocortisone in terms of respiratory outcomes; however, caution should be taken when administering dexamethasone. Data derived from current evidence, including meta-analyses, are inconclusive on the long-term effects of the administration of systemic steroids in preterm infants or the possibility of neurodevelopmental consequences., 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. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Boscarino, Cardilli, Conti, Liguori, Repole, Parisi and Terrin.)

Background: Phthalates are a family of industrial chemicals noncovalently bonded to plastic materials to enhance flexibility and durability. These compounds are extensively used in a variety of consumer products and even in many medical devices. Newborns present a higher susceptibility to phthalates., Objective: To assess the short- and long-term health consequences of exposure to phthalates during the neonatal period., Methods: Systematic review in accordance with the PRISMA statements. Eligible articles in English language were searched in MEDLINE, Scopus, ISI Web of Science, and Ovid databases using the following terms: "phthalate", "newborn", and "neonate". Unpublished data were searched in ClinicalTrials.gov website. All in vivo studies of any design published before May 16th, 2023 and fulfilling the following criteria were included: 1) investigations in which preterm and/or term newborns underwent one or more measurement of concentrations of phthalates on biological samples taken during the neonatal period; 2) studies in which quantitative measurement of phthalates was related to any kind of health outcome. Subgroup analysis was conducted by type of outcome. The quality assessment was performed according to the criteria from the "NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies"., Results: 11,895 records were identified; finally, 5 articles were included for review. A mixture of phthalates was associated with improved performance on the NNNS summary scales of Attention, Handling, and Non-optimal reflexes before NICU discharge. At 2 months' corrected age, some phthalates were positively associated with problem-solving and gross motor abilities; increased levels of mono (2-ethylhexyl) phthalate, mono (2-ethyl-5-carboxypentyl) phthalate, and sum of di (2-ethylhexyl) phthalate (DEHP) metabolites (∑ 3 DEHP and ∑ 4 DEHP) were associated with worse fine motor performance. Furthermore, DEHP was associated with transient alteration of gut microbiota and increased IgM production after vaccine. A linear positive association between a mixture of phthalates and slope of the first growth spurt was even reported in preterm newborns. No relationship emerged between phthalates and bronchopulmonary dysplasia. Three studies out of 5 had fair quality., Conclusion: Given some methodological issues and the paucity of related studies, further investigations of flawless quality aimed at clarifying the relationship between early exposure to phthalates and health outcomes are needed., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite multifactorial pathogenesis, dysregulation of inflammatory immune response may play a crucial role in necrotizing enterocolitis (NEC). Regulatory T cells (Tregs) are involved in immune tolerance early in life. We aimed to investigate the predicting role of Tregs in developing NEC in neonates at high risk., Methods: We studied six newborns with a diagnosis of NEC (cases) in comparison with 52 controls (without NEC). We further classified controls as neonates with feeding intolerance (FI) and neonates without it (FeedTol). The rate of female and male neonates (sex defined as a biological attribute) was similar. We analyzed the blood frequency of Tregs (not overall numbers) at three time points: 0-3 (T0), 7-10 (T1), and 27-30 (T2) days after birth by flow cytometry. Neonates' sex was defined based on the inspection of external genitalia at birth., Results: We observed, at T0, a significantly lower frequency of Tregs in NEC cases (p < 0.001) compared with both FI (p < 0.01) and FeedTol controls (p < 0.01). Multivariate analysis reported that the occurrence of NEC was independently influenced by Treg frequency at birth (ß 2.98; p = 0.039)., Conclusion: Tregs frequency and features in the peripheral blood of preterm neonates, early in life, may contribute to identifying neonates at high risk of developing NEC., Impact: Regulatory T cells may play a pivotal role in regulating the immune response in early life. Reduction of Tregs in early life could predispose preterm newborns to necrotizing enterocolitis. Early markers of necrotizing enterocolitis are still lacking. We demonstrated a predicting role of assessment of regulatory T cells in the diagnosis of this gastrointestinal emergency. Early identification of newborns at high risk of necrotizing enterocolitis through measurement of regulatory T cells may guide clinicians in the management of preterm newborns in order to reduce the development of this severe condition., (© 2023. The Author(s).)

Non-cystic white matter (WM) injury has become prevalent among preterm newborns and is associated with long-term neurodevelopmental impairment. Magnetic resonance is the gold-standard for diagnosis; however, cranial ultrasound (CUS) is more easily available but limited by subjective interpretation of images. To overcome this problem, we enrolled in a prospective observational study, patients with gestational age at birth < 32 weeks with normal CUS scans or grade 1 WM injury. Patients underwent CUS examinations at 0-7 days of life (T 0 ), 14-35 days of life (T 1 ), 37 0/7 -41 6/7  weeks' postmenstrual age (T 2 ), and 42 0/7 -52 0/7  weeks' postmenstrual age (T 3 ). The echogenicity of parieto-occipital periventricular WM relative to that of homolateral choroid plexus (RE CP ) was calculated on parasagittal scans by means of pixel brightness intensity and its relationship with Bayley-III assessment at 12 months' corrected age was evaluated. We demonstrated that: (1) Left RE CP values at T 1 negatively correlated with cognitive composite scores; (2) Right RE CP values at T 2 and T 3 negatively correlated with language composite scores; (3) Left RE CP values at T 1 and T 2 negatively correlated with motor composite scores. Thus, this technique may be used as screening method to early identify patients at risk of neurodevelopmental issues and promptly initiate preventive and therapeutic interventions., (© 2023. Springer Nature Limited.)

(1) Background: An increased protein intake via parenteral nutrition (PN) in early life is associated with an improvement of the nitrogen balance in preterm newborns. However, the role of energy intake on amino acid (AA) utilization provided by PN remains to be defined. We investigated the effects of energy intake on blood AA levels and profiles. (2) Methods: Quasi-experimental study including preterm very low birth weight newborns who received an energy enhanced PN (Cohort A) or an energy standard PN (Cohort B), with a similar protein amount in the first week of life. Blood AA levels were measured between three and seven days of life (T0) and at fifteen days of life (T1) and compared between the two study cohorts. (3) Results: AA levels of 40 newborns from each group were analyzed. No difference was found for total essential and non-essential blood AA concentration at T0 between the two study cohorts. At T1, we found a significantly higher blood concentration of leucine, isoleucine and proline, and a significantly lower concentration of tyrosine in Cohort B. However, multivariate analysis did not confirm this result. (4) Conclusions: An enhanced PN protocol in terms of energy but not of protein did not influence AA levels and profiles. Considering the high risk of side effects, we suggest exercising caution when administering high energy intake via PN in the first week of life.

The relationship between migraines and allergies is controversial. Though they are epidemiologically linked, the underlying pathophysiological connection between them remains unclear. Migraines and allergic disorders have various underlying genetic and biological causes. As per the literature, these conditions are epidemiologically linked, and some common pathophysiological pathways have been hypothesized. The histaminergic system may be the clue to understanding the correlation among these diseases. As a neurotransmitter in the central nervous system with a vasodilatory effect, histamine has a well-documented influence on the allergic response and could be involved in the pathophysiology of migraines. Histamine may influence hypothalamic activity, which may play a major role in migraines or may simply influence their severity. In both cases, antihistamine drugs could prove useful. This review examines whether the histaminergic system, particularly H3 and H4 receptors, may provide a mechanistic link between the pathophysiology of migraines and allergic disorders, two common and debilitating conditions. Identifying their connection could help identify novel therapeutic strategies.

The COVID-19 pandemic may have had an impact on healthcare-associated infection (HAI) rates. In this study, we analyzed the occurrence of HAIs in a neonatal intensive care unit (NICU) of the Umberto I teaching hospital in Rome before and during the pandemic. All infants admitted from 1 March 2018 to 28 February 2022 were included and were divided into four groups according to their admission date: two groups before the pandemic (periods I and II) and two during the pandemic (periods III and IV). The association between risk factors and time-to-first event was analyzed using a multivariable Cox regression model. Over the four-year period, a total of 503 infants were included, and 36 infections were recorded. After adjusting for mechanical ventilation, birth weight, sex, type of delivery, respiratory distress syndrome, and previous use of netilmicin and fluconazole, the multivariable analysis confirmed that being hospitalized during the pandemic periods (III and IV) was the main risk factor for HAI acquisition. Furthermore, a change in the etiology of these infections was observed across the study periods. Together, these findings suggest that patient management during the pandemic was suboptimal and that HAI surveillance protocols should be implemented in the NICU setting promptly.

Background: Preterm birth and subsequent NICU admission can be a traumatic experience for parents who may subsequently develop post-traumatic stress (PTS) disorder (PTSD). Given that developmental issues are common among children of parents with PTSD, interventions for prevention and treatment are essential., Objective: To assess the most effective non-pharmacological interventions to prevent and/or treat PTS symptoms in parents of preterm newborns., Methods: Systematic review performed in accordance with the PRISMA statements. Eligible articles in English language were searched in MEDLINE, Scopus, and ISI Web of Science databases using the following medical subject headings and terms: "stress disorder, post-traumatic," "parents," "mothers," "fathers," "infant, newborn," "intensive care units, neonatal," and "premature birth." The terms "preterm birth" and "preterm delivery" were also used. Unpublished data were searched in ClinicalTrials.gov website. All intervention studies published until September 9th, 2022 and including parents of newborns with gestational age at birth (GA b ) <37 weeks which underwent ≥1 non-pharmaceutical interventions for prevention and/or treatment of PTS symptoms related to preterm birth were included. Subgroup analyses were conducted by type of intervention. The quality assessment was performed according to the criteria from the RoB-2 and the "NIH Quality Assessment Tool for Before-After studies.", Results: Sixteen thousand six hundred twenty-eight records were identified; finally, 15 articles (1,009 mothers, 44 fathers of infants with GA b  ≤ 36 6/7 weeks) were included for review. A good standard of NICU care (effective as sole intervention: 2/3 studies) and education about PTSD (effective in association with other interventions: 7/8 studies) could be offered to all parents of preterm newborns. The 6-session Treatment Manual is a complex intervention which revealed itself to be effective in one study with low risk of bias. However, the effectiveness of interventions still remains to be definitively established. Interventions could start within 4 weeks after birth and last 2-4 weeks., Conclusion: There is a wide range of interventions targeting PTS symptoms after preterm birth. However, further studies of good quality are needed to better define the effectiveness of each intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Laccetta, Di Chiara, De Nardo and Terrin.)

Hyperglycemia (HG) is an independent risk factor of mortality and morbidity in very low birth weight newborns (VLBW). Achievement of high nutritional intakes in the first days of life (DoL) by parenteral nutrition (PN) increases the risk of HG. We aim to assess if a delayed achievement of the PN macronutrient target dose could reduce the occurrence of HG in VLBW. We enrolled 353 VLBW neonates in a randomized controlled clinical trial comparing two PN protocols that differed in the timing of energy and amino acid target dose achievement: (1) early target dose achievement (energy within 4-5 DoL; amino acids within 3-4 DoL) vs. (2) late target dose achievement (energy within 10-12 DoL; amino acids within 5-7 DoL). The primary outcome was the occurrence of HG during the first week of life. An additional endpoint was long-term body growth. We observed a significant difference in the rate of HG between the two groups (30.7% vs. 12.2%, p = 0.003). Significant differences were observed in terms of body growth at 12 months of life between the two groups (weight Z-Score: -0.86 vs. 0.22, p = 0.025; length: -1.29 vs. 0.55, p < 0.001). Delayed achievement of energy and amino acid intake may be useful to reduce the risk of HG along with an increase of growth parameters in VLBW neonates.

Background: Recommended vaccinations are the cheapest and most effective measure to reduce the risk of transmission and related complications, especially in high-risk healthcare settings. This study aimed to evaluate the knowledge, attitudes and behaviours of HCWs in relation to national recommendations. Methods: A transversal study was conducted through administration of a questionnaire by personal interview. The following care units were involved: Paediatric, Neonatal, Cardiac Surgery and General Intensive Care Units and Infectious Diseases Unit. Results: The study sample comprised 308 HCWs. Half the sample were aware of the vaccination recommendations, with occupation and age found to be predictive factors (OR = 9.38, 95%CI: 2.07−42.41; OR = 0.36, 95%CI: 0.22−0.60). A higher percentage defined the diseases as a risk for their patients’ health, although this perception was lower in the over-40 age group. In several cases, there were statistically significant differences between the care units (p < 0.001). Around three-quarters of the sample agreed that vaccination should be mandatory; willingness to undergo a future booster vaccination was statistically correlated with the variables of age and care unit (p < 0.001, p = 0.03). Conclusion: The protection of health in the workplace can be achieved through some strategic actions, such as the implementation of educational strategies, and protocols for the monitoring of immunocompetence and the improvement of vaccination.

To assess the diagnostic utility of proton ( 1 H) magnetic resonance spectroscopy in early diagnosis of neurodevelopmental impairment in preterm newborns. Systematic review performed in compliance with the PRISMA statements. Eligible articles were searched in MEDLINE, Scopus, and ISI Web of Science databases using the following medical subject headings and terms: "magnetic resonance spectroscopy," "infant," and "newborn." Studies of any design published until 20 December 2021 and fulfilling the following criteria were selected: (1) studies including newborns with gestational age at birth <37 weeks which underwent at least one 1H-MRS scan within 52 weeks' postmenstrual age and neurodevelopmental assessment within 4 years of age; (2) studies in which preterm newborns with congenital infections, genetic disorders, and brain congenital anomalies were clearly excluded. Data regarding the relationship between metabolite ratios in basal ganglia, thalamus, and white matter, and neurodevelopment were analysed. The quality assessment of included studies was performed according to the criteria from the QUADAS-2. N-acetylaspartate (NAA)/choline (Cho) was the most studied metabolite ratio. Lower NAA/Cho ratio in basal ganglia and thalamus was associated with adverse motor, cognitive, and language outcomes, and worse global neurodevelopment. Lower NAA/Cho ratio in white matter was associated with cognitive impairment. However, some associations came from single studies or were discordant among studies. The quality of included studies was low. 1 H-MRS could be a promising tool for early diagnosis of neurodevelopmental impairment. However, further studies of good quality are needed to define the relationship between metabolite ratios and neurodevelopment.

Eosinophilic esophagitis (EoE) is an immune-mediated condition characterized by symptoms of esophageal dysfunction and an eosinophilic inflammation of the esophagus. 1 Swallowed topical steroids represent one of the possible strategies for inducing and maintaining remission in EoE. 2 To date, a validated maintenance strategy has yet to be defined, especially in children. The available evidence suggests decreasing the dose after a successful induction therapy. 3 No study has reported the efficacy of a continuous progressive dose reduction; thus, it is unknown if all patients need to use the same dosages and for how long. 4,5 ., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Preterm birth and admission to the neonatal intensive care unit (NICU) could induce post-traumatic stress disorder (PTSD). PTSD is an important factor to focus on, as it is associated with parental mental health difficulties and with changes in caregiving quality such as increased intrusiveness, reduced sensitivity, and increased attachment insecurity for the child., Aims: We aimed to study the main risk factors, in the early life of newborns, and preventive measures for PTSD in parents of neonates hospitalized in the NICU., Methods: We included parents of preterm newborns, consecutively admitted to the NICU of the University La Sapienza of Rome. The presence of PTSD following preterm birth and NICU admission was assessed using the Clinician-administered PTSD scale (CAPS) at enrollment and at 28-30 days following NICU admission or the moment of discharge. We also evaluated the Family Environment Scale which measures the social environment of all types of families; the Parental Stressor Scale which measures parental anxiety and stress; the Spielberger State-Trait Anxiety Inventory consisting of two parts measuring the State (response to present situation) and Trait (pre-disposition to be anxious) anxieties separately, and the Beck Depression Inventory Second Edition assessing depressive symptoms., Results: We found, in a multivariate analysis, that the gestational age of newborns admitted to NICU significantly (β = 2.678; p = 0.040) influences the occurrence of PTSD. We found that the cases showed significantly (β = 2.443; p = 0.020) more pathological Parental Stressor Scale sights and sounds scores compared to controls. The early Kangaroo-Care (KC) significantly (β = -2.619; p = 0.015) reduces the occurrence of PTSD., Conclusion: Post-traumatic stress disorder in parents of preterm newborns is a pathological condition that should be properly managed, in the very first days after birth. The NICU environment represents a main risk factor for PTSD, whereas KC has been demonstrated to have a protective role in the occurrence of PTSD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Di Chiara, Laccetta, Gangi, De Santis, Spiriti, Attenni, Bertolaso, Boscarino, De Nardo, Ciambra, Parisi and Terrin.)

Introduction: Parenteral nutrition (PN) may have detrimental effects on neurodevelopment in preterm newborns. Moreover, enteral nutrition (EN) seems to be protective. To understand the mechanisms of how neurological development can be influenced by the route of administration of nutritional intake, we investigated the relationship between the serum levels of the nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and nutritional intake received in early life by preterm newborns., Materials and Methods: Specimens of blood were obtained at 28 days of life (DOL) for NGF/BDNF determination in neonates <32 weeks of gestation and/or with birth weight <1,500 g, consecutively observed in the neonatal intensive care unit. We analyzed the relation between amino acid content and energy intake and NGF/BDNF measurements at 28 DOL. PN protein intake was referred to as the total amounts of amino acid intake received daily., Results: We enrolled 20 newborns (gestational age 30.45 ± 1.76 weeks, birth weight 1,340 ± 352.63 g). Serum NGF value at 28 DOL was positively correlated with enteral protein and energy intake ( r = 0.767; r = 0.746, p < 0.001), whereas, negatively correlated with parenteral amino acid and energy intake ( r = -0.652, p < 0.001; r = -0.466, p < 0.05). Similar significant correlations were described between BDNF level at 28 DOL and enteral energy intake ( r = 0.493, p < 0.05). Multivariate regression analysis showed that NGF level at 28 DOL depends on enteral protein and energy intake administrated in the 1st week of life., Conclusion: Neurotrophin values varied according to the route of nutrition administration in preterm newborns. NGF/BDNF serum levels are influenced positively and negatively by EN and PN, respectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 De Nardo, Petrella, Di Chiara, Di Mario, Deli, Travaglia, Baldini, Russo, Parisi, Fiore and Terrin.)

Background: Cyclic Vomiting Syndrome (CVS) is a rare functional gastrointestinal disorder, which has a considerable burden on quality of life of both children and their family. Aim of the study was to evaluate the diagnostic modalities and therapeutic approach to CVS among Italian tertiary care centers and the differences according to subspecialties, as well as to explore whether potential predictive factors associated with either a poor outcome or a response to a specific treatment., Methods: Cross-sectional multicenter web-based survey involving members of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP)., Results: A total of 67 responses were received and analyzed. Most of the respondent units cared for less than 20 patients. More than half of the patients were referred after 3 to 5 episodes, and a quarter after 5 attacks. We report different diagnostic approaches among Italian clinicians, which was particularly evident when comparing gastroenterologists and neurologists. Moreover, our survey demonstrated a predilection of certain drugs during emetic phase according to specific clinic, which reflects the cultural background of physicians., Conclusion: In conclusion, our survey highlights poor consensus amongst clinicians in our country in the diagnosis and the management of children with CVS, raising the need for a national consensus guideline in order to standardize the practice., (© 2022. The Author(s).)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with adverse maternal and neonatal outcomes, yet uptake of SARS-CoV-2 vaccines during pregnancy and lactation has been slow. As a result, millions of pregnant and lactating women and their infants remain susceptible to the virus., Methods: We measured spike-specific immunoglobulin G (anti-S IgG) and immunoglobulin A (anti-S IgA) in serum and breastmilk (BM) samples from 3 prospective mother-infant cohorts recruited in 2 academic medical centers. The primary aim was to determine the impact of maternal SARS-CoV-2 immunization vs infection and their timing on systemic and mucosal immunity., Results: The study included 28 mothers infected with SARS-CoV-2 in late pregnancy (INF), 11 uninfected mothers who received 2 doses of the BNT162b2 vaccine in the latter half of pregnancy (VAX-P), and 12 uninfected mothers who received 2 doses of BNT162b2 during lactation. VAX dyads had significantly higher serum anti-S IgG compared to INF dyads (P < .0001), whereas INF mothers had higher BM:serum anti-S IgA ratios compared to VAX mothers (P = .0001). Median IgG placental transfer ratios were significantly higher in VAX-P compared to INF mothers (P < .0001). There was a significant positive correlation between maternal and neonatal serum anti-S IgG after vaccination (r = 0.68, P = .013), but not infection., Conclusions: BNT161b2 vaccination in late pregnancy or lactation enhances systemic immunity through serum anti-S immunoglobulin, while SARS-CoV-2 infection induces mucosal over systemic immunity more efficiently through BM immunoglobulin production. Next-generation vaccines boosting mucosal immunity could provide additional protection to the mother-infant dyad. Future studies should focus on identifying the optimal timing of primary and/or booster maternal vaccination for maximal benefit., Competing Interests: Potential conflicts of interest . V. P. participated in a lecture on coronavirus disease 2019 vaccination in children (with honorarium made to their university), and also participated in the National Greek Advisory Committee for Immunization Practices. C. P. was a steering committee member for clinical trials MN42988 and MN42989 by La Roche Ltd. A. A. received an National Institute of Allergy and Infectious Diseases (NIAID) Development of Sample Sparing Assays (DSSA) for Monitoring Immune Responses Infrastructure & Opportunity Fund (IOF) Award grant for Comprehensive Analysis of the Neonatal Immune System via High-Throughout Proteomics; and honorarium for an invited review article on neonatal vaccination. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hypokalemic periodic paralysis is a rare neuromuscular genetic disorder due to defect of ion channels and subsequent function impairment. It belongs to a periodic paralyses group including hyperkalemic periodic paralysis (HEKPP), hypokalemic periodic paralysis (HOKPP) and Andersen-Tawil syndrome (ATS). Clinical presentations are mostly characterized by episodes of flaccid generalized weakness with transient hypo- or hyperkalemia., Case Presentation: A teenage boy presented to Emergency Department (ED) for acute weakness and no story of neurological disease, during the anamnestic interview he revealed that he had a carbohydrates-rich meal the previous evening. Through a focused diagnostic work-up the most frequent and dangerous causes of paralysis were excluded, but low serum potassium concentration and positive family history for periodic paralyses raised the diagnostic suspicion of HOKPP. After the acute management in ED, he was admitted to Pediatric Department where a potassium integration was started and the patient was counselled about avoiding daily life triggers. He was discharged in few days. Unfortunately, he presented again because of a new paralytic attack due to a sugar-rich food binge the previous evening. Again, he was admitted and treated by potassium integration. This time he was strongly made aware of the risks he may face in case of poor adherence to therapy or behavioral rules. Currently, after 15 months, the boy is fine and no new flare-ups are reported., Conclusion: HOKPP is a rare disease but symptoms can have a remarkable impact on patients' quality of life and can interfere with employment and educational opportunities. The treatment aims to minimize the paralysis attacks by restoring normal potassium level in order to reduce muscle excitability but it seems clear that a strong education of the patient about identification and avoidance triggering factors is essential to guarantee a benign clinical course. In our work we discuss the typical clinical presentation of these patients focusing on the key points of the diagnosis and on the challenges of therapeutic management especially in adolescence. A brief discussion of the most recent knowledge regarding this clinical condition follows., (© 2022. The Author(s).)

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- CoV-2) represents an emerging infection that is spreading around the world. Among susceptible patients, pregnant women are more likely to develop serious complications and negative obstetric outcomes. Vertical transmission constitutes a debating issue which has not been completely understood. This review aims at describing the currently available evidence on SARS-CoV2 vertical transmission. We carried out a computerized literature search in the Cochrane Library, PubMed, Scopus and Web of Science, selecting the most relevant studies on vertical transmission from the outbreak onset until February 2022. The analysis of the available literature identifies the presence of SARS-CoV2 genome in different biological specimens, confirming the hypothesis that a transplacental infection can occur. In spite of the high number of infected people around the world, mother-to-child infections have been infrequently reported but it can be observed under certain biologic conditions. A deep knowledge of the underlying mechanisms of SARS-CoV2 vertical transmission is of paramount importance for planning an adequate management for the affected mothers and newborns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sessa, Anastasi, Brandolino, Brunelli, Di Pietro, Filardo, Masciullo, Terrin, Viscardi and Porpora.)