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Background: Nearly 58% of very low birth weight (VLBW) infants receive at least one red blood cell transfusion, which is not without risk. Reticulocyte fluorescence (RF) indicates the degree of cell maturation. The greater the fluorescence, the greater the immaturity of the reticulocytes., Aim: To evaluate RF as a marker of reticulocyte maturity and to investigate its predictive value for transfusion requirement in VLBW infants., Methods: Complete blood count was performed at 1, 7, 14, 21, and 28 d of age in 104 VLBW infants at the University Hospital of Parma. Iron supplementation was started at 15 d of life. The infants were divided into two groups: those who required transfusion after 28 d of life. (Tr) and those who did not (NTr)., Results: Twenty-seven of 104 newborns required a red blood cell transfusion after 28 d of life (Tr group). At 14 d of life, the percentage of high fluorescence reticulocyte (HFR) was significantly higher in the r group than in infants who did not receive any transfusion (NTr groups): 18.5 vs. 5%, p = 0.002. The ROC curve (AUC 74%) revealed an HFR cut-off value of 16.5% as a predictor of the need for red blood cell (RBC) transfusion., Conclusions: Reticulocyte maturation at 14 d of life is clinically useful for estimating the qualitative impairment of erythropoiesis and predicts the risk of RBC transfusion in VLBW infants. The data suggest the need for tailored iron integration in VLBW infants to improve the quality of hematopoiesis and reduce the risk of blood transfusion., Competing Interests: Conflicts of Interest The authors declare no conflict of interest for this research article., (Copyright © 2024. Published by Elsevier Inc.)

Neonatal sepsis is a clinical syndrome mainly associated with a bacterial infection leading to severe clinical manifestations that could be associated with fatal sequalae. According to the time of onset, neonatal sepsis is categorized as early- (EOS) or late-onset sepsis (LOS). Despite blood culture being the gold standard for diagnosis, it has several limitations, and early diagnosis is not immediate. Consequently, most infants who start empirical antimicrobial therapy do not have an underlying infection. Despite stewardship programs partially reduced this negative trend, in neonatology, antibiotic overuse still persists, and it is associated with several relevant problems, the first of which is the increase in antimicrobial resistance (AMR). Starting with these considerations, we performed a narrative review to summarize the main findings and the future prospects regarding antibiotics use to treat neonatal sepsis. Because of the impact on morbidity and mortality that EOS and LOS entail, it is essential to start an effective and prompt treatment as soon as possible. The use of targeted antibiotics is peremptory as soon as the pathogen in the culture is detected. Although prompt therapy is essential, it should be better assessed whether, when and how to treat neonates with antibiotics, even those at higher risk. Considering that we are certainly in the worrying era defined as the "post-antibiotic era", it is still essential and urgent to define novel strategies for the development of antibacterial compounds with new targets or mechanisms of action. A future strategy could also be to perform well-designed studies to develop innovative algorithms for improving the etiological diagnosis of infection, allowing for more personalized use of the antibiotics to treat EOS and LOS.

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.)

Neonatal sepsis is a bacterial bloodstream infection leading to severe clinical manifestations frequently associated with death or irreversible long-term deficits. Antibiotics are the drug of choice to treat sepsis, regardless of age. In neonates, the lack of reliable criteria for a definite diagnosis and the supposition that an early antibiotic administration could reduce sepsis development in children at risk have led to a relevant antibiotic overuse for both prevention and therapy. The availability of biomarkers of neonatal sepsis that could alert the physician to an early diagnosis of neonatal sepsis could improve the short and long-term outcomes of true sepsis cases and reduce the indiscriminate and deleterious use of preventive antibiotics. The main aim of this narrative review is to summarize the main results in this regard and to detail the accuracy of currently used biomarkers for the early diagnosis of neonatal sepsis. Literature analysis showed that, despite intense research, the diagnosis of neonatal sepsis and the conduct of antibiotic therapy cannot be at present decided on the basis of a single biomarker. Given the importance of the problem and the need to reduce the abuse of antibiotics, further studies are urgently required. However, instead of looking for new biomarkers, it seems easier and more productive to test combinations of two or more of the presently available biomarkers. Moreover, studies based on omics technologies should be strongly boosted. However, while waiting for new information, the use of the clinical scores prepared by some scientific institutions could be suggested. Based on maternal risk factors and infant clinical indicators, sepsis risk can be calculated, and a significant reduction in antibiotic consumption can be obtained.

(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.

Oxygen supplementation is widely used in neonatal care, however, it can also cause toxic effects if not used properly. Therefore, it appears crucial to find a balance in oxygen administration to avoid damage as a consequence of its insufficient or excessive use. Oxygen toxicity is mainly due to the production of oxygen radicals, molecules normally produced in humans and involved in a myriad of physiological reactions. In the neonatal period, an imbalance between oxidants and antioxidant defenses, the so-called oxidative stress, might occur, causing severe pathological consequences. In this review, we focus on the mechanisms of the production of oxygen radicals and their physiological functions in determining a set of diseases grouped together as "free radical diseases in the neonate". In addition, we describe the evolution of the oxygenation target recommendations during neonatal resuscitation and post-stabilization phases with the aim to define the best oxygen administration according to the newest evidence.

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.

Bronchopulmonary dysplasia (BPD) still represents an important burden of neonatal care. The definition of the disease is currently undergoing several revisions, and, to date, BPD is actually defined by its treatment rather than diagnostic or clinic criteria. BPD is associated with many prenatal and postnatal risk factors, such as maternal smoking, chorioamnionitis, intrauterine growth restriction (IUGR), patent ductus arteriosus (PDA), parenteral nutrition, sepsis, and mechanical ventilation. Various experimental models have shown how these factors cause distorted alveolar and vascular growth, as well as alterations in the composition and differentiation of the mesenchymal cells of a newborn's lungs, demonstrating a multifactorial pathogenesis of the disease. In addition, inflammation and oxidative stress are the common denominators of the mechanisms that contribute to BPD development. Vascular endothelial growth factor-A (VEGFA) constitutes the most prominent and best studied candidate for vascular development. Animal models have confirmed the important regulatory roles of epithelial-expressed VEGF in lung development and function. This educational review aims to discuss the inflammatory pathways in BPD onset for preterm newborns, focusing on the role of VEGFA and providing a summary of current and emerging evidence.

The Brain is vulnerable to numerous insults that can act in the pre-, peri-, and post-natal period. There is growing evidence that demonstrate how oxidative stress (OS) could represent the final common pathway of all these insults. Fetuses and newborns are particularly vulnerable to OS due to their inability to active the antioxidant defenses. Specific molecules involved in OS could be measured in biologic fluids as early biomarkers of neonatal brain injury with an essential role in neuroprotection. Although S-100B seems to be the most studied biomarker, its use in clinical practice is limited by the complexity of brain damage etiopathogenesis and the time of blood sampling in relation to the brain injury. Reliable early specific serum markers are currently lacking in clinical practice. It is essential to determine if there are specific biomarkers that can help caregivers to monitor the progression of the disease in order to active an early neuroprotective strategy. We aimed to describe, in an educational review, the actual evidence on serum biomarkers for the early identification of newborns at a high risk of neurological diseases. To move the biomarkers from the bench to the bedside, the assays must be not only be of a high sensitivity but suitable for the very rapid processing and return of the results for the clinical practice to act on. For the best prognosis, more studies should focus on the association of these biomarkers to the type and severity of perinatal brain damage.

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.)

Objectives: We performed a systematic review to study the effect of enteral and parenteral energy intakes on neurodevelopment (NDV) and cerebral growth in preterm infants, evaluated by NDV scales, magnetic resonance imaging, and head circumference (HC)., Methods: The MEDLINE, Scopus, and ISI Web of Knowledge databases were searched, using the following medical subject headings and terms: "Premature infants," "nutrition," "brain," "nervous system/growth," and "development." A manual search of the reference lists of all eligible articles was conducted. Studies in which the intervention applied was different energy intakes in parenteral nutrition and/or enteral nutrition (EN) during the first weeks of life and NDV was investigated were included. Data regarding nutrition and NDV were collected and analyzed., Results: Thirty-five studies were included, of which 12 were randomized controlled trials (RCTs) and 23 were cohort studies. Eight RCTs and 15 cohort studies investigated NDV using NDV scales. Of these studies, two RTCs and five cohort studies found no significant difference in NDV evaluated with the Bayley scale between neonates fed high-caloric nutrition and those who received lower energy intakes during early life. In one RCT and two cohort studies was observed a positive effect of EN on NDV. Conversely, in one cohort study, a negative correlation between parenteral energy intake and NDV was described. The analysis of the data from RCTs and cohort studies showed greater HC in the groups receiving aggressive parenteral and total enhanced nutrition, respectively. However, two RCTs and one cohort study did not report any differences in terms of HC. Inconclusive results were reported by studies that investigated cerebral growth by magnetic resonance imaging. The studies observing a positive effect of enhanced nutrition on cerebral and basal ganglia growth, caudate nucleus, cerebellum, and thalami volume investigated only the influence of EN., Conclusions: The impact of energy intake during early life on NDV remains undefined. A positive impact on brain development encourages the administration of recommended energy intake, mainly by EN, and suggests a more cautious approach to enhanced nutritional strategies by the parenteral route. Further studies are advocated to elucidate the optimal nutritional intervention for preterm infants to improve NDV., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Patent ductus arteriosus is the most common cardiovascular condition in preterm infants. There is a significant uncertainty about when and how to close ductus arteriosus in preterm infants due to a high spontaneous closure rate even in very immature preterm infants. Diagnosis and management of patent ductus arteriosus remain a challenge for both neonatologists and pediatric cardiologists. Researchers have tried to define a balance between an expectant approach and active treatment in selected infants. This review aimed to focus on the pathophysiology and management of patent ductus arteriosus and to make suggestions about approaches that might eliminate the association of morbidities with patent ductus arteriosus.

Evidences demonstrated that timing of weaning influences long-term growth in full term infants. However, studies on preterm infants are still lacking, and the international guidelines are focused only on healthy full-term newborn, without consensus for preterms. We aimed at evaluating, in a cohort study, the consequences of different timing of weaning on auxological outcomes up to 12 months of corrected age in a population of neonates born with gestational age < 32 weeks or birth weight < 1500 g. We divided the enrolled neonates in two cohorts according to the timing of weaning: (i) Early Weaning: introduction of complementary food before 6 months of corrected age; (ii) Late Weaning: complementary food introduced after 6 months of corrected age. Growth parameters (weight, length, body mass index, and ponderal index) were measured at 12 months of life. The two groups were statistically comparable for baseline clinical characteristics, and differences on growth parameters were not reported between the two study groups. These results were confirmed in linear and binary logistic regression multivariate models. Timing of weaning is not related to growth of preterm newborns in the first 12 months of corrected age. Studies are needed to reach consensus for the appropriate nutritional approach for preterm babies after discharge.

Importance: Although several studies have provided information on short-term clinical outcomes in children with perinatal exposure to SARS-CoV-2, data on the immune response in the first months of life among newborns exposed to the virus in utero are lacking., Objective: To characterize systemic and mucosal antibody production during the first 2 months of life among infants who were born to mothers infected with SARS-CoV-2., Design, Setting, and Participants: This prospective cohort study enrolled 28 pregnant women who tested positive for SARS-CoV-2 infection and who gave birth at Policlinico Umberto I in Rome, Italy, from November 2020 to May 2021, and their newborns. Maternal and neonatal systemic immune responses were investigated by detecting spike-specific antibodies in serum, and the mucosal immune response was assessed by measuring specific antibodies in maternal breastmilk and infant saliva 48 hours after delivery and 2 months later., Exposures: Maternal infection with SARS-CoV-2 in late pregnancy., Main Outcomes and Measures: The systemic immune response was evaluated by the detection of SARS-CoV-2 IgG and IgA antibodies and receptor binding domain-specific IgM antibodies in maternal and neonatal serum. The mucosal immune response was assessed by measuring spike-specific antibodies in breastmilk and in infant saliva, and the presence of antigen-antibody spike IgA immune complexes was investigated in breastmilk samples. All antibodies were detected using an enzyme-linked immunosorbent assay., Results: In total, 28 mother-infant dyads (mean [SD] maternal age, 31.8 [6.4] years; mean [SD] gestational age, 38.1 [2.3] weeks; 18 [60%] male infants) were enrolled at delivery, and 21 dyads completed the study at 2 months' follow-up. Because maternal infection was recent in all cases, transplacental transfer of virus spike-specific IgG antibodies occurred in only 1 infant. One case of potential vertical transmission and 1 case of horizontal infection were observed. Virus spike protein-specific salivary IgA antibodies were significantly increased (P = .01) in infants fed breastmilk (0.99 arbitrary units [AU]; IQR, 0.39-1.68 AU) vs infants fed an exclusive formula diet (0.16 AU; IQR, 0.02-0.83 AU). Maternal milk contained IgA spike immune complexes at 48 hours (0.53 AU; IQR, 0.25-0.39 AU) and at 2 months (0.09 AU; IQR, 0.03-0.17 AU) and may have functioned as specific stimuli for the infant mucosal immune response., Conclusions and Relevance: In this cohort study, SARS-CoV-2 spike-specific IgA antibodies were detected in infant saliva, which may partly explain why newborns are resistant to SARS-CoV-2 infection. Mothers infected in the peripartum period appear to not only passively protect the newborn via breastmilk secretory IgA but also actively stimulate and train the neonatal immune system via breastmilk immune complexes.

(1) Background: The tolerance of preterm newborns for the high nutritional intakes given by parenteral nutrition (PN) is still debated because of the risk of metabolic complications. Despite enteral nutrition (EN) being the preferred route of nutrition, an exclusive enteral feeding is not always possible, as in preterm newborns, the gut is immature and less tolerant of EN. We aimed to study the impact of a minimal enteral feeding (MEF) on the possible early metabolic complications of PN in a cohort of preterms with gestational age at birth GA ≤ 29 + 6/7 weeks of postmenstrual age. (2) Methods: We divided the study sample in two cohorts: 1) Late-Feeding (cohort 1), newborns who received MEF starting from the 8th day of age, and (2) Early-Feeding (cohort 2), newborns who received MEF, consisting of the administration of at least 4-5 mL/kg/day by the enteral route, in the first 7 days of age. The primary outcome of the study was the rate of at least one metabolic complication, including hyperglycemia, hypertriglyceridemia, or metabolic acidosis. (3) Results: We enrolled 80 newborns (Late-Feeding cohort 51 vs. Early-Feeding cohort 29). The rate of all metabolic complications was statistically higher in the Late-Feeding cohort compared to the Early-Feeding cohort. Binary logistic regression analysis showed that late administration of MEF negatively influenced the rate of all metabolic complications. (4) Conclusions: Early minimal administration of EN is associated with less frequent PN-related metabolic side effects and a higher rate of survival in critically ill newborns.

(1) Background: Preterm birth exposes the infant to the known risk factors for atopic diseases. We aimed to study the neonatal risk factors and to describe the clinical manifestations of atopy, including the march of symptoms, in a cohort of preschool children born preterm. (2) Methods: We enrolled neonates with gestational age < 32 weeks or birth weight < 1500 g. We classified patients in cases and controls according to the presence of at least one atopic manifestation. (3) Results: We observed 72 cases and 93 controls. Multivariate models showed that the administration of more than one cycle of antibiotics (B 0.902, p = 0.026) and gestational diabetes (B 1.207, p = 0.035) influence the risk of atopy in babies born preterm. In addition, risk of atopic dermatitis was influenced by gestational age < 29 weeks (B -1.710, p = 0.025) and gestational diabetes (B 1.275, p = 0.027). The risk of wheeze was associated with familiarity for asthma (B 1.392, p = 0.022) and the administration of more than one cycle of antibiotics (B 0.969, p = 0.025). We observed a significant reduction in the rate of atopic manifestation after 2 years of life (33.9% vs. 23.8%, p < 0.05). (4) Conclusions: Modifiable (gestational diabetes, antibiotics use) and unmodifiable (familiarity for asthma) conditions influence the risk of atopy in babies born preterm. Extreme prematurity reduces the risk of atopic dermatitis. Preterm babies showed a peculiar atopic march.

Current guidelines for preterm newborns recommend high energy nutrition soon after birth in order to limit growth retardation. However, long-term effects of this nutritional approach are still debated, and it has been demonstrated that cerebral growth depends on protein intake in early life. A negative impact of early high energy intake by parenteral nutrition (PN) has been reported for patients in critically ill conditions, observed in intensive care unit. We aimed at evaluating the impact of energy intake on cerebral growth in preterm neonates early in life. We included preterm newborns with gestational age < 32 weeks or birth weight (BW) < 1500 g. Measurement of cerebral structures was performed by cranial Ultrasonography (cUS) between 3 and 7 days of life (DOL, T0) and at 28 DOL (T1). We evaluated the relation between energy intake and cerebral growth in the first 28 DOL. We observed in 109 preterm newborns a significant (p < 0.05) negative correlation between energy intake received by PN and right caudate head growth (r = - 0.243*) and a positive correlation between total energy intake and transverse cerebellum diameter (r = 0.254*). Multivariate analysis showed that energy intake administered by enteral nutrition (EN), independently increased growth of left caudate head (β = 0.227*) and height cerebellar vermis (β = 0.415*), while PN independently affected growth of both right and left caudate head (β = - 0.164* and β = - 0.228*, respectively) and cerebellum transverse diameter (β = - 0.849*). The route of energy administration may exert different effects on cerebral growth in early life. High energy intake administered through EN seems to be positively correlated to cerebral growth; conversely, PN energy intake results in a poorer cerebral growth evaluated with cUS., (© 2021. The Author(s).)

Objectives: Preterm births are at higher risk for neurodevelopment (NDV) disabilities. To limit long-term consequences, guidelines recommend aggressive parenteral nutrition (PN) soon after birth. The aim of this study was to examine the effects of energy-enhanced PN in the first week of life on long-term NDV in preterm neonates., Methods: We compared two cohorts of newborns (group A: energy-enhanced PN and group B: energy-standard PN) with different energy intake in the first 7 d of life (DoL) given by PN with the same protein amount, to study the influences of an energy-enhanced PN on NDV at 24 mo of life evaluated with the Bayley Scale of Infant Development-III edition., Results: We analyzed 51 newborns (A: n = 24 versus B: n = 27). The two cohorts were similar in baseline characteristics (gestational age group A 29 wk, 95% confidence interval [CI], 28-30 wk versus group B 29 wk, 95% CI, 28-30 wk; birth weight A: 1214 g, 95% CI, 1062-1365 g versus B 1215 g, 95% CI, 1068-1363 g; boys A 62.5% versus B 55.6%). Infants in cohort B showed significantly (P < 0.05) better gross motor, total scaled, and total composite motor scores (A: 8 (1) versus B 9 (2); A 17 (4) versus B 19 (5); A 91 (12) versus B 97 (15); respectively). Cohort A showed a higher percentage of infants with delayed socioemotional competence (A 30.4% versus B 7.7%, P < 0.05). No differences were found in growth parameters at 24 mo of life. Linear regression analysis showed that socioemotional competence and motor score were negatively associated with energy intake of the first 7 DoL given by PN., Conclusions: A more aggressive PN strategy results in lower motor score and socioemotional competence performance at 24 mo of life. More caution might be advocated for an energy-enhanced PN protocol, particularly in neonates with lower birth weight, for long-term NDV in preterm neonates., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: An early diagnosis of necrotizing enterocolitis (NEC), a major gastrointestinal emergency in preterm newborns, is crucial to improve diagnostic approach and prognosis. We evaluated whether fecal high-mobility group box protein 1 (HMGB1) may early identify preterms at risk of developing NEC. Materials and Methods: A case-control study including neonates admitted at the Neonatal Intensive Care Unit (NICU) of the Sapienza University Hospital "Umberto I" in Rome, from July 2015 to December 2016. Stool samples obtained from cases (preterm newborns with NEC) and controls (newborns without NEC) were collected at the enrolment (T0) and within 7-14 days after the first sample collection (T1). HMGB1, extracted and measured with western blot, was reported as densitometry units (DUS). Results: HMGB1 levels in 30 cases ( n = 28-Bell stage 1, n = 2 Bell stage 2) were higher [T0: 21,462 DUS (95% CI, 16,370-26,553 DUS)-T1: 17,533 DUS (95% CI, 13,052-22,014 DUS)] than in 30 preterm controls [T0: 9,446 DUS (95% CI, 6,147-12,746 DUS)-T1: 9,261 DUS (95% CI, 5,126-13,396 DUS), p < 0.001). Preterm newborns showed significant higher levels of HMGB1 (15,690 DUS (95% CI, 11,929-19,451 DUS)] in comparison with 30 full-term neonates with birth weight >2,500 g [6,599 DUS (95% CI, 3,141-10,058 DUS), p = 0.003]. Multivariate analysis showed that the risk of NEC was significantly ( p = 0.012) related to the HMGB1 fecal levels at T0. Conclusions: We suggest fecal HMGB1 as a reliable marker of early NEC in preterm neonates. This study supports further investigation on the role of fecal HMGB1 assessment in managing preterm newborns at risk of NEC. Further studies are advocated to evaluate diagnostic accuracy of this marker in more severe forms of the disease., 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 © 2021 Vitali, Terrin, Palone, Laudadio, Cucchiara, Boscarino, Di Chiara and Stronati.)

(1) Background: Recent evidence reported a reduced tolerance of macronutrient parenteral intakes in subjects in critically ill conditions. We designed a prospective cohort study to evaluate the effects of hyperglycemia (HG) related to parenteral nutrition (PN) on neurodevelopment (NDV) in survived preterm newborns. (2) Methods: Enrolled newborns with gestational age < 32 weeks or birth weight < 1500 g, were divided in two cohorts: (A) exposed to moderate or severe HG (glucose blood level > 180 mg/dL) in the first week of life; (B) not exposed to HG. We considered as the primary outcome the rate of preterm newborns survived without NDV delay at 24 months of life, evaluated with Bayley Scales of Infants Development III edition. (3) Results: We analyzed 108 (A 32 vs. B 76) at 24 months of life. Newborns in cohort A showed a higher rate of cognitive and motor delay (A 44% vs. B 22 %, p = 0.024; A 38% vs. B 8%, p < 0.001). When adjusting for background characteristics, HG remained a risk factor for motor delay. (4) Conclusions: High nutritional intakes through PN soon after birth increase the risk of HG. The consequences of this severe metabolic complication affect long-term NDV and survival in preterm newborns.

We have analyzed in a retrospective study of consecutive diabetic patients affected by no-option critical limb ischemia (CLI) the efficacy of the dermal substitute Integra Dermal Regeneration Template for treatment of complicated foot lesions. The primary end point was limb salvage and 1-year amputation-free survival. The secondary end point was healing time of surgical site. Between October 2014 and October 2017, 1024 patients with diabetic foot ulcer (DFU) and CLI were admitted. In 84 patients (8.2%), there was a failure in distal revascularization with a persistent CLI after the procedure. Despite the persistent CLI, a group of 26 patients of this cohort obtained complete wound healing. Among them, 13 patients were treated with surgical debridement or open amputations and application of dermal substitute Integra Dermal Regeneration Template and the other 13 patients were treated without any dermal substitute. The Integra group healed within a mean time of 83.5 days, and the control group healed within a mean of 139 days ( P = .028). No major amputation was carried out at 1-year follow-up in the Integra group versus 15% in the control group. A conservative foot surgery or an approach with minor amputation in diabetic patients with no-option CLI may achieve limb salvage. The use of Integra Dermal Regeneration Template in patients with DFU and no-option CLI may be a useful option in a limb salvage program.

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues its spread all over the world, data on perinatal management of the maternal-infant dyad are urgent. We performed an observational study to describe the effects of the early separation of the maternal-infant dyad, in case of maternal SARS-CoV-2 infection. We reported the medical records for 37 neonates born to 37 SARS-CoV-2 positive mothers in a setting of separation of the dyad after birth. Data on neonatal infection, clinical condition, and breastfeeding rate were recorded until the first month of life. No maternal deaths were recorded; 37.8% of women had at least one pregnancy-related complication. We reported a high adherence to recommended safety measures after discharged with 84.8% of the mothers using at least one personal protective device and 51.5% using all the protective devices. We reported one case of vertical transmission and no cases of horizontal transmission. However, the separation of the dyad had a negative impact on breastfeeding because only 23.5% of the newborns received exclusively human milk during the first month of life. Despite early separation of the dyad protecting the newborns from possible horizontal transmission of SARS-CoV-2, it negatively affects breastfeeding during the first months of life.

(1) Background: Hypertriglyceridemia (HiTG) is a metabolic complication of intravenous lipid emulsions (ILEs) infusion. We aimed to evaluate the influence of HiTG on the respiratory outcome of preterm babies; (2) Methods: We enrolled, in a case-control study, newborns with gestational age <32 weeks or birth weight <1500 g, over a 3-year period. They were divided into cases and controls; cases were defined by the detection of HiTG defined as serum triglycerides (TG) value >150 mg/dL; (3) Results: We enrolled 40 cases and 105 controls. Cases had an increased incidence of bronchopulmonary dysplasia (30.0% vs. 14.3%, p < 0.05) and longer duration of invasive mechanical ventilation (7 days, 95% CI 4-10 days vs. 4 days, 95% CI 1-7 days, p < 0.01) compared to controls. Multivariate analysis confirmed that HiTG independently influenced the duration of invasive mechanical ventilation, also in the subgroups with gestational age ≤28 + 6/7 weeks or birth weight ≤1000 g; (4) Conclusion: Newborns with HiTG related to ILEs had a longer duration of invasive mechanical ventilation. Temporary suspension or reduction in ILEs in the case of HiTG is associated with an improvement of respiratory outcome.

Umbilical cord care can be a stressful practice for parents. Complications of cord care can increase neonatal morbidity and mortality. The extracts of Arnica montana (AM) have been reported to possess antibacterial, anti-inflammatory, antifungal, and immunomodulatory activities. We aim to demonstrate the efficacy of AM on cord detachment and parents' stress level induced by cord medication in healthy full-term newborns. We enrolled full-term infants with a birth weight ≥ 2500 g in healthy conditions. Cord stumps of infants in the PRE-group were cleaned and dried, while cord stumps of infants in the POST-group were cleaned, dried, and medicated with a natural topic dermo-protective powder containing AM. After discharge, we interviewed parents on the stump status during follow-up visits in a pediatric office at 7 and 14 days of life, or by phone calls after follow-up visits. Long-rank test showed that time of cord separation of newborns in the PRE-group was significantly higher compared to that in the POST-group (p < 0.001). Parents of newborns in the PRE-group were significantly more stressed during cord medication compared to parents in the POST-group (2.0 (1.2 to 2.1) vs 1.0 (0.8 to 1.3), p = 0.011). Multivariate analysis showed a significantly linear relation with group assignment for cord separation (p < 0.001) and parents' stress during the medication (p = 0.033).Conclusion: The use of a natural topic dermo-protective powder containing AM reduces the time of cord separation, improves parents' stress level, and reduces the risk of complications. What is Known: • Cord stump care can be a stressful practice for parents. • Antiseptic treatment recommended for cord care could be associated with side effects such as burning and sensitization. What is New: • The medication of cord stump with a natural topic dermo-protective powder containing Arnica montana reduces time of cord detachment and of complication such as redness', bleeding, or secretions. • The use of Arnica montana for cord medication may have a positive impact on the family, reducing parents' stress, and the use of other medications.

Introduction: Association between persistency of a patent ductus arteriosus (PDA) and morbidity in preterm newborns is still controversial. We aimed to investigate the relation between PDA and morbidity in a large retrospective study., Methods: A case-control study including neonates consecutively admitted to the Neonatal Intensive Care Unit (NICU), with gestational age (GA) < 32 weeks or body birth weight (BW) < 1500 g, over a 5-year period. Newborns were divided into Cases and Controls, according with the presence or absence of a hemodynamically significant PDA (hs-PDA)., Results: We enrolled 85 Cases and 193 Controls. Subjects with hs-PDA had significantly (p < 0.001) lower GA (26.7 w, 95%CI 27.1-28.0 vs. 30.1 w, 95%CI 29.7-30.4), BW (1024 g, 95% CI 952-1097 vs. 1310 g 95%CI 1263-1358) and an increased morbidity (60.0% vs. 18.7%). In a sub-group of extremely preterm newborns (GA ≤ 28 weeks and BW ≤ 1000 g), the rate of bronchopulmonary dysplasia (BPD) was significantly increased in Cases (31.7%) compared with Controls (5.9%, p = 0.033). Multivariate analysis showed that morbidity significantly depended on hs-PDA, GA and BW, and that, in extremely preterms, the hs-PDA represented an independent risk factor for BPD., Conclusions: Occurrence of the main morbidities of prematurity depended by hs-PDA, in association with GA, BW, and use of prenatal steroids. In extremely premature babies, hs-PDA is a risk factor for BPD, one of the most important morbidity of prematurity, independently by other confounding variables.

Introduction: Echocardiography (ECHO) with color flow Doppler is considered as the gold standard to identify a hemodynamic patent ductus arteriosus (hs-PDA). However, the optimal diagnostic and therapeutic management for newborns with hs-PDA is still controversial. We aimed to investigate two clinical strategies: (1) targeted treatment based on ECHO criteria and (2) treatment based on ECHO criteria in addition to clinical signs and symptoms. Materials and Methods: This is a cohort study including all neonates consecutively admitted in the Neonatal Intensive Care Unit of University La Sapienza in Rome, with gestational age <32 weeks or body birth weight <1,500 g and with a diagnosis of hs-PDA as confirmed by ECHO evaluation performed within 72 h of life. We classified the babies in two cohorts: (A) pharmacological treatment immediately after ECHO screening and (B) pharmacological therapy for PDA was administered when the relevance of a hs-PDA was associated with clinical signs of hemodynamic instability. Results: We considered as primary outcome newborns who survived without any morbidities (A: 48.1% vs. B: 22.2%, p = 0.022). In particular, we found that the rate of intraventricular hemorrhage stage ≥2 was increased in cohort B (A: 3.7% vs. B 24.4%, p = 0.020). A multivariate analysis showed that assignment to cohort A independently influences the primary outcome. Conclusions: Adopting an hs-PDA management option based on ECHO-directed therapy regardless of symptoms may reduce the morbidity and improve the survival of very low birth weight infants., 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 © 2020 Terrin, Di Chiara, Boscarino, Versacci, Di Donato, Giancotti, Pacelli, Faccioli, Onestà, Corso, Ticchiarelli and De Curtis.)

Introduction: To limit extrauterine growth restriction, recent guidelines on nutrition of preterm neonates recommended high protein intake since the first day of life (DOL). The impact of this nutritional strategy on the brain is still controversial. We aimed to evaluate the effects of protein intake on early cerebral growth in very low birth weight newborns. Materials and Methods: We performed serial cranial ultrasound (cUS) scans at 3-7 DOL and at 28 DOL in very low birth weight newborns consecutively observed in the neonatal intensive care unit. We analyzed the relation between protein intake and cerebral measurements at 28 DOL performed by cUS. Results: We enrolled 100 newborns (gestational age 29 ± 2 weeks, birth weight 1,274 ± 363 g). A significant ( p < 0.05) positive correlation between enteral protein intake and biparietal diameter ( r = 0.490 ** ), occipital-frontal diameter ( r = 0.608 ** ), corpus callosum (length r = 0.293 * , genu r = 0.301 * ), caudate head (right r = 0.528 ** , left r = 0.364 ** ), and cerebellum (transverse diameter r = 0.440 ** , vermis height r = 0.356 ** , vermis width r = 0.377 ** ) was observed at 28 DOL. Conversely, we found a significant negative correlation of protein intake given by parenteral nutrition (PN) with biparietal diameter ( r = -0.524 ** ), occipital-frontal diameter ( r = -0.568 ** ), body of corpus callosum ( r = -0.276 * ), caudate head (right r = -0.613 ** , left r = -0.444 ** ), and cerebellum (transverse diameter r = -0.403 ** , vermis height r = -0.274 * , vermis width r = -0.462 ** ) at 28 DOL. Multivariate regression analysis showed that measurements of occipital-frontal diameter, caudate head, and cerebellar vermis at 28 DOL depend positively on protein enteral intake ( r = 0.402 * , r = 0.305 * , and r = 0.271 * ) and negatively by protein parenteral intake ( r = -0.278 * , r = -0.488 * , and r = -0.342 * ). Conclusion: Brain development in neonatal life depends on early protein intake. High protein intake affects cerebral structures' measurements of preterm newborn when administered by PN. Positive impact on brain development encourages the administration of recommended protein intake mainly by enteral nutrition., (Copyright © 2020 Terrin, De Nardo, Boscarino, Di Chiara, Cellitti, Ciccarelli, Gasparini, Parisi, Urna, Ronchi, Russo, Sabatini and De Curtis.)

Aim: To assess the best energy intake in Parenteral Nutrition (PN) for preterm newborns, considering both possible benefits for growth and risk of complications., Methods: Quasi-experimental study comparing two cohorts of newborns, receiving Energy-Enhanced vs. Standard PN (Cohort A, from 1st January 2015 to 31 January 2016 and Cohort B from 1st February 2016 to 31 March 2017; respectively) after implementation of a change in the PN protocol. The primary outcome measure was growth at 24 months of life. The PN associated complications were also measured., Results: We enrolled 132 newborns in two Cohorts, similar for prenatal and postnatal clinical characteristics. Although, body weight and length at 24 months of life were significantly higher (p<0.05) in the Cohort A (11.1, 95% CI 10.6 to 11.6 Kg; 85.0 95% CI 83.8 to 86.2 cm) compared with Cohort B (10.4, 95% CI 9.9 to 10.9 Kg; 81.3 95% CI 79.7 to 82.8 cm), body weight and length Z-Score in the first 24 months of life were similar between the two Cohorts. The rate of PN associated complications was very high in both study Cohorts (up to 98% of enrolments). Multivariate analysis showed that length at 24 months was significantly associated with receiving standard PN (cohort A) in the first week of life and on the energy intake in the first week of life. We also found a marginally insignificant association between Cohort A assignment and body weight at 24 months of life (p = 0.060)., Conclusions: Energy-enhanced PN in early life has not significant effects on long-term growth in preterm newborns. The high prevalence of PN associated complications, poses concerns about the utility of high energy intake recommended by current guidelines for PN., Competing Interests: The authors have declared that no competing interests exist.

(1) Background: Zinc is a key element for protein synthesis in preterm newborns. Early aggressive nutrition, promoting protein synthesis, may increase zinc consumption; (2) Methods: We performed a prospective observational study, to assess the relationship between early macronutrients intake and serum zinc levels, in preterm newborns with Gestational Age (GA) of 24-35 weeks, consecutively observed in Neonatal Intensive Care Unit (NICU). (3) Results: We enrolled 130 newborns (GA 31.5 ± 2.8). A significant negative correlation between serum zinc level at 28 days of life and energy (r -0.587, p < 0.001) and protein intake (r -0.556, p < 0.001) in the first week of life was observed. Linear regression analysis showed that zinc levels depended on energy (β -0.650; p < 0.001) and protein (β -0.669; p < 0.001) intake given through parenteral nutrition (PN) in the first week of life; (4) Conclusions: zinc status of preterm neonates was influenced by early protein and energy intake. An additional zinc supplementation should be considered when high protein and energy intake are received by preterm newborns in the first week of life.

Objective : To describe the characteristics, the management and the outcome of a consecutive series of patients with diabetic foot lesions (DF) and no-option critical limb ischemia (CLI) treated with a multidimensional, interdisciplinary approach in a dedicated center. Research Design and Methods : The prospective database of the Diabetic Foot Unit of the Maria Cecilia Hospital (Cotignola, Italy) collects medical history, risk factors, chemistry values, angiographic data, characteristic of foot lesions, medical and surgical therapies of all patients admitted with a diagnosis of DF and CLI. All patients were followed-up for at least 1 year and/or total recovery. The primary endpoint was 1-year amputation-free survival (AFS), secondary endpoints were limb salvage and survival. Results : Between October 2014 and October 2017, 1024 patients with DF and CLI were admitted to the center. Eighty-four of them (8.2%) fulfilled the criteria for no-option CLI. At 1 year, AFS, limb salvage, and survival rates were 34%, 34%, and 83%, respectively. Lesions located proximal to the Lisfranc joint were associated with major amputation (HR 2.1 [1.2-3.6]). One-year survival of patients treated with minor procedures was significantly higher compared to patients treated with major amputation (96% vs 76%, log-rank p = 0.019). Major amputation was independently associated with mortality (HR 7.83 [1.02-59.89]). Conclusions : The application of dedicated and standardized strategies permitted limb salvage in one-third of patients with no-option CLI. Patients with stable lesions limited to the forefoot and without ischaemic pain had a greater probability to successfully receive conservative treatments. Limb salvage was associated with subsequent higher one-year survival., (© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Diabetic hindfoot ulcers, complicated by osteomyelitis, are associated with a high risk of major amputation. Partial calcanectomy, preceded by an effective management of the infection and of the eventual peripheral artery disease, can be considered as valid therapeutic option. We have evaluated a therapeutic protocol for diabetic hindfoot ulcers complicated by osteomyelitis, which, besides an adequate surgical debridement, considers a reconstructive pathway assisted by the positioning of a circular external fixator. We made a prospective study of a cohort of diabetic patients affected by heel ulcer complicated by osteomyelitis. All patients underwent open partial calcanectomy associated with the positioning of a circular external frame specifically designed for hindfoot stabilization and offloading. A reconstructive procedure was implemented starting with the application of negative pressure wound therapy and coverage with dermal substitute and split thickness skin grafting. From November 2014 to November 2015, 18 consecutive patients were enrolled. Mean follow-up period was 212.3 ± 64.0 days. Healing was achieved in 18 (100%) patients. The mean healing time was 69.0 ± 64.0 days. No major amputation had to be performed during the follow-up. Open partial calcanectomy associated with external fixation and skin reconstruction was as efficient as limb salvage in patients with infected lesions of the hindfoot complicated by calcaneal osteomyelitis.

Aims: Charcot neuropathic osteoarthropathy (CN) represents a complication for diabetic patients which involves a progressive alteration of the osteoarticular apparatus with high risk of amputation. The aim of the study was to assess whether the localization of CN and the extent or grading of the osteomyelitis have an influence on the rate of limb salvage and the time to recovery., Methods: We treated a diabetic population affected by CN complicated by ulceration and widespread osteomyelitic involvement. All patients were treated surgically to eliminate infected tissues, stabilize and correct the bone deformities. Histopathological and microbiological analyses were carried out on the bone specimens., Results: Thirty-three patients affected by CN complicated by large osteomyelitic involvement of midfoot and/or ankle were treated between January 2010 and May 2014. The mean follow-up was 409,35 ± 154,06 days. Thirty patients had complete recovery (90.91%) at the end of follow-up. No difference in limb salvage rate and time to recovery was observed when stratifying the population according to CN localization, extent and grading of osteomyelitis., Conclusions: In this cohort prospective study we observed a high percentage of limb salvage in patients affected by CN complicated by diffuse midfoot/hindfoot osteomyelitis. The localization of Charcot deformity and the extent/stage of osteomyelitis did not change the rate of limb salvage., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Paragangliomas (PGL) are rare lesions of the neuroendocrine system; in the neck, they usually affect the carotid glomus (carotid body tumours-CBT). This retrospective analysis reports our experience in management of these lesions in patients treated by surgical resection. Between 2000 and 2014, 33 patients were surgically treated at our institution, obtaining a series of 44 cervical PGLs. Tumour characteristics, family history, diagnostic procedures, surgical treatment, short- and long-term outcomes were reviewed. A female prevalence was found (76% of cases). Familial cases occurred in 9 patients (20%); 6 presented with bilateral lesions and 1 had multiple paragangliomas. Lymph node metastasis was not found in any patient. All lesions were classified into three groups according to the latero-lateral diameter. Complete resection of the PGL was performed in all patients. Mortality was null; transitory cranial nerve deficit occurred in 20% of cases with permanent palsy in 6.7%. No perioperative stroke/TIA were observed. Surgical resection of PGL should be considered as the only therapeutic option because it can ensure complete removal of the disease. Patients with bilateral lesions and positive family history should be referred for genetic analysis. Preoperative planning of the surgical procedure by integrated diagnostic imaging and a full mastery of vascular surgery techniques are mandatory to minimise the risk of the most common postoperative complications. Long-term follow-up is recommended, particularly in patients with familial disease or sporadic lesions treated in an advanced stage.

The age effect on the kinetics of piroxicam at the steady-state after oral administration of piroxicam beta-cyclodextrin was evaluated. The mean plasma concentration of piroxicam at the steady-state was significantly higher in elderly subjects (9.30 +/- 0.69 micrograms/ml mean +/- s.e.) than in younger adults (6.24 +/- 0.58 micrograms/ml mean +/- s.e.). Even though the distribution volume tended to be lower in elderly subjects (106.37 ml/kg), it did not show substantial differences in the two groups whereas the correlation between clearance and age was significant (p less than 0.05). It is therefore confirmed that piroxicam beta-cyclodextrin has the same pharmacokinetic behaviour at the steady-state in elderly subjects, as the active principle in a non-complexed form.