Pathogenic G6PD variants: Different clinical pictures arise from different missense mutations in the same codon.

G6PD deficiency results from mutations in the X-linked G6PD gene. More than 200 variants are associated with enzyme deficiency: each one of them may either cause predisposition to haemolytic anaemia triggered by exogenous agents (class B variants), or may cause a chronic haemolytic disorder (class A variants). Genotype-phenotype correlations are subtle. We report a rare G6PD variant, discovered in a baby presenting with severe jaundice and haemolytic anaemia since birth: the mutation of this class A variant was found to be p.(Arg454Pro). Two variants affecting the same codon were already known: G6PD Union, p.(Arg454Cys), and G6PD Andalus, p.(Arg454His). Both these class B variants and our class A variant exhibit severe G6PD deficiency. By molecular dynamics simulations, we performed a comparative analysis of the three mutants and of the wild-type G6PD. We found that the tetrameric structure of the enzyme is not perturbed in any of the variants; instead, loss of the positively charged Arg residue causes marked variant-specific rearrangement of hydrogen bonds, and it influences interactions with the substrates G6P and NADP. These findings explain severe deficiency of enzyme activity and may account for p.(Arg454Pro) expressing a more severe clinical phenotype.

Cord blood transfusions in extremely low gestational age neonates to reduce severe retinopathy of prematurity: results of a prespecified interim analysis of the randomized BORN trial.

BACKGROUND: Preterm infants are at high risk for retinopathy of prematurity (ROP), with potential life-long visual impairment. Low fetal hemoglobin (HbF) levels predict ROP. It is unknown if preventing the HbF decrease also reduces ROP. METHODS: BORN is an ongoing multicenter double-blinded randomized controlled trial investigating whether transfusing HbF-enriched cord blood-red blood cells (CB-RBCs) instead of adult donor-RBC units (A-RBCs) reduces the incidence of severe ROP (NCT05100212). Neonates born between 24 and 27 + 6 weeks of gestation are enrolled and randomized 1:1 to receive adult donor-RBCs (A-RBCs, arm A) or allogeneic CB-RBCs (arm B) from birth to the postmenstrual age (PMA) of 31 + 6 weeks. Primary outcome is the rate of severe ROP at 40 weeks of PMA or discharge, with a sample size of 146 patients. A prespecified interim analysis was scheduled after the first 58 patients were enrolled, with the main purpose to evaluate the safety of CB-RBC transfusions. RESULTS: Results in the intention-to-treat and per-protocol analysis are reported. Twenty-eight patients were in arm A and 30 in arm B. Overall, 104 A-RBC units and 49 CB-RBC units were transfused, with a high rate of protocol deviations. A total of 336 adverse events were recorded, with similar incidence and severity in the two arms. By per-protocol analysis, patients receiving A-RBCs or both RBC types experienced more adverse events than non-transfused patients or those transfused exclusively with CB-RBCs, and suffered from more severe forms of bradycardia, pulmonary hypertension, and hemodynamically significant patent ductus arteriosus. Serum potassium, lactate, and pH were similar after CB-RBCs or A-RBCs. Fourteen patients died and 44 were evaluated for ROP. Ten of them developed severe ROP, with no differences between arms. At per-protocol analysis each A-RBC transfusion carried a relative risk for severe ROP of 1.66 (95% CI 1.06-2.20) in comparison with CB-RBCs. The area under the curve of HbF suggested that HbF decrement before 30 weeks PMA is critical for severe ROP development. Subsequent CB-RBC transfusions do not lessen the ROP risk. CONCLUSIONS: The interim analysis shows that CB-RBC transfusion strategy in preterm neonates is safe and, if early adopted, might protect them from severe ROP. TRIAL REGISTRATION: Prospectively registered at ClinicalTrials.gov on October 29, 2021. Identifier number NCT05100212.

Secondary Hirata Syndrome in a Neonate: Practical Approach and Management.

Hirata disease, also known as insulin autoimmune syndrome (IAS), is a rare cause of hypoglycemia, due to the presence of insulin autoantibodies (IAA) in the circulating blood. These antibodies are immunoglobulin G (IgG), making placental transfer to the fetus possible. To our knowledge, no reports of IAS have been previously described in the neonatal population. We present a case report of hypoglycemia due to a secondary IAS in a neonate and discuss the management and treatment of the disease.

A multi-step approach to overcome challenges in the management of head and neck lymphatic malformations, and response to treatment.

BACKGROUND: Lymphatic malformations are vascular developmental anomalies varying from local superficial masses to diffuse infiltrating lesions, resulting in disfigurement. Patients' outcomes range from spontaneous regression to severe sequelae notwithstanding appropriate treatment. The current classification guides, in part, clinicians through the decision-making process, prognosis prediction and choice of therapeutic strategies. Even though the understanding of molecular basis of the disease has been recently improved, a standardized management algorithm has not been reached yet. RESULTS: Here, we report our experience on five children with different lymphatic anomalies of the head and neck region treated by applying a multidisciplinary approach reaching a consensus among specialists on problem-solving and setting priorities. CONCLUSIONS: Although restitutio ad integrum was rarely achieved and the burden of care is challenging for patients, caregivers and healthcare providers, this study demonstrates how the referral to expert centres can significantly improve outcomes by alleviating parental stress and ameliorating patients' quality of life. A flow-chart is proposed to guide the multidisciplinary care of children with LMs and to encourage multidisciplinary collaborative initiatives to implement dedicated patients' pathways.

Comparison of "IN-REC-SUR-E" and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN-REC-LISA trial).

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.

Enteral nutritional strategy during therapeutic hypothermia: who? when? what?

Background: There are no guidelines regarding enteral feeding (EF) of infants with hypoxic-ischemic encephalopathy (HIE) during and shortly after therapeutic hypothermia; consequently, clinical practice is, to date, still variable. The objective of this study is to assess whether a minimal EF strategy during therapeutic hypothermia may be associated with a shorter time to full EF of infants with HIE and to identify the clinical variables that independently affect the time to full EF. Methods: A retrospective study, covering the period from 1 January 2015 to 30 June 2022 was performed at the Neonatal Intensive Care Unit of the Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, which compared infants with HIE who received minimal EF during therapeutic hypothermia with those who did not. Results: Seventy-eight infants received minimal EF during therapeutic hypothermia, while 75 did not. Infants who were fed reached full EF significantly faster than those who were not. Moreover, they received parenteral nutrition and maintained central venous lines for a shorter time. A multivariate analysis, taking into account the variable of clinical severity, confirmed that minimal EF is an independent beneficial factor for reaching full EF in a shorter time and mechanical ventilation and seizures are independent factors for a longer time to full EF. Conclusions: Minimal EF during therapeutic hypothermia is associated with a shorter time to full EF in stable infants with HIE. Further prospective studies are needed to better define the enteral nutrition strategy for infants during therapeutic hypothermia, regardless of the severity of clinical conditions.

Thymosin ß4 and ß10 Expression in Human Organs during Development: A Review.

This review summarizes the results of a series of studies performed by our group with the aim to define the expression levels of thymosin ß4 and thymosin ß10 over time, starting from fetal development to different ages after birth, in different human organs and tissues. The first section describes the proteomics investigations performed on whole saliva from preterm newborns and gingival crevicular fluid, which revealed to us the importance of these acidic peptides and their multiple functions. These findings inspired us to start an in-depth investigation mainly based on immunochemistry to establish the distribution of thymosin ß4 and thymosin ß10 in different organs from adults and fetuses at different ages (after autopsy), and therefore to obtain suggestions on the functions of ß-thymosins in health and disease. The functions of ß-thymosins emerging from these studies, for instance, those performed during carcinogenesis, add significant details that could help to resolve the nowadays so-called "ß-thymosin enigma", i.e., the potential molecular role played by these two pleiotropic peptides during human development.

Real-Time Ultrasound Tip Location Reduces Malposition and Radiation Exposure during Umbilical Venous Catheter Placement in Neonates: A Retrospective, Observational Study.

INTRODUCTION: The umbilical venous catheter is a vital access device in neonatal intensive care units for preterm and critically ill infants. Correct positioning is crucial, as malpositioning can lead to severe complications. According to international guidelines, the position of the umbilical venous catheter tip must be assessed in real time; traditionally, the catheter is visualized with a thoracoabdominal X-ray, but one of the most effective and safest methods is therefore real-time ultrasound. METHODS: This study compares real-time ultrasound and traditional X-ray methods for assessing umbilical venous catheter tip location in 461 cases. The rate of tip malposition was analyzed retrospectively. The secondary aim was to assess indwelling time of umbilical venous catheters and reasons of removal. RESULTS: Real-time ultrasound tip location, found to be more reliable and efficient, demonstrated a significantly lower incidence of primary malpositioning compared to X-ray assessments (9.6 vs. 75.9%). The study also highlighted the association of real-time ultrasound with reduced catheter manipulation, fewer radiographs, and higher indwelling times of umbilical venous catheter. The multiple logistic regression showed a high probability of the central safe position of the umbilical venous catheter tip using real-time ultrasound tip location (odds ratio 29.5, 95% confidence interval: 17.4-49.4). CONCLUSION: The findings support the adoption of real-time ultrasound in clinical settings to enhance umbilical venous catheter placement accuracy and minimize associated risks. A minimal training investment is needed to attain the proficiency to visualize the umbilical venous catheters, offering a substantial advantage in terms of both cost-effectiveness for the procedure and enhanced patient safety.

Diagnostic Accuracy of Lung Ultrasound in Neonatal Diseases: A Systematized Review.

Background: Respiratory problems are frequent in newborns, and are mainly studied with chest X-rays, whereas CT scans are usually needed for the evaluation of rare malformations and diseases. Lung ultrasound (LUS] has been proposed as an alternative method of diagnosing a variety of respiratory conditions. In recent years, there has been a rapid increase in LUS studies, thanks to the ability of LUS to rapidly exclude complications and significantly reduce radiation exposure in this fragile population. We aimed to summarize the current knowledge about LUS. Methods: A literature search was conducted on the Medline and Cochrane databases using appropriate terms. The inclusion criteria were: English language and human species. Exclusion criteria were: non-English language, animal species, case reports, case series, non-systematic reviews, and editorials. Results: The search returned 360 results. No Cochrane reviews were found. Titles and abstracts were screened, and 37 were finally considered. Studies concerning the use of lung ultrasound for the following conditions were presented: neonatal respiratory distress syndrome, transient tachypnea of the newborn, pneumothorax, pulmonary hemorrhage, pneumonia, bronchopulmonary dysplasia, and prediction of extubation success. Conclusions: We discussed the utility of LUS for the diagnosis and treatment of neonatal diseases according to the most recent literature.

Potential pathogenetic role of a novel ABCC8 missense variant on both transient neonatal diabetes mellitus and fetal growth restriction: a case report.

BACKGROUND: The diagnosis of neonatal diabetes can be problematic in preterm infants with fetal growth restriction (FGR). Growth restricted fetuses may have impaired insulin production and secretion; low birthweight infants may have a reduced response to insulin. We report a novel missense ABCC8 variant associated with a clinical phenotype compatible with transient neonatal diabetes mellitus (TNDM) in a fetal growth restricted preterm infant. METHODS AND RESULTS: A preterm growth restricted infant experienced hyperglycemia from the first day of life, requiring insulin therapy on the 13th and 15th day of life and leading to the diagnosis of TNDM. Glycemic values normalized from the 35th day of life onwards. Genetic screening was performed by next generation sequencing, using a Clinical Exon panel of 4800 genes, filtered for those associated with the clinical presentation and by means of methylation-specific multiplex ligation-dependent probe amplification analysis to identify chromosomal aberrations at 6q24. Genetic tests excluded defects at 6q24 and were negative for KCNJ11, SLC2A2 (GLUT-2) and HNF1B, but revealed the presence of the heterozygous missense variant c.2959T > C (p.Ser987Pro) in ABCC8 gene. The presence of the variant was excluded in parents' DNA and the proband variant was then considered de novo. CONCLUSIONS: In our infant, the persistence of hyperglycemia beyond 3 weeks of life led us to the diagnosis of TNDM and to hypothesize a possible genetic cause. The genetic variant we found could be, most likely, the main cause of both FGR and TNDM.

Current management of surgical neonates: is it optimal or do we need to improve? A national survey of the Italian Society of Neonatology.

PURPOSE: Few guidelines exist for the perioperative management (PM) of neonates with surgical conditions (SC). This study examined the current neonatal PM in Italy. METHODS: We invited 51 neonatal intensive care units with pediatric surgery in their institution to participate in a web-based survey. The themes included (1) the involvement of the neonatologist during the PM; (2) the spread of bedside surgery (BS); (3) the critical issues concerning the neonatal PM in operating rooms (OR) and the actions aimed at improving the PM. RESULTS: Response rate was 82.4%. The neonatologist is involved during the intraoperative management in 42.9% of the responding centers (RC) and only when the surgery is performed at the patient's bedside in 50.0% of RCs. BS is reserved for extremely preterm (62.5%) or clinically unstable (57.5%) infants, and the main barrier to its implementation is the surgical-anesthesiology team's preference to perform surgery in a standard OR (77.5%). Care protocols for specific SC are available only in 42.9% of RCs. CONCLUSION: Some critical issues emerged from this survey: the neonatologist involvement in PM, the spread of BS, and the availability of specific care protocols need to be implemented to optimize the care of this fragile category of patients.

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

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

Diaphragm atrophy during invasive mechanical ventilation is related to extubation failure in preterm infants: An ultrasound study.

BACKGROUND: Diaphragm dysfunction is associated with poor outcomes in critically ill patients. Ventilator-induced diaphragmatic dysfunction (VIDD), including diaphragm atrophy (DA), is poorly studied in newborns. We aimed to assess VIDD and its associations in newborns. METHODS: Single-center prospective study. Diaphragm thickness was measured at end-inspiration (TDI) and end-expiration (TDE) on the right midaxillary line. DA was defined as decrease in TDE ≥ 10%. Daily measurements were recorded in preterm newborns on invasive mechanical ventilation (IMV) for ≥2 days. Clinical characteristics of patients and extubation failure were recorded. Univariate analysis, logistic regression, and mixed models were performed to describe VIDD and associated factors. RESULTS: We studied 17 patients (median gestational age 270/7 weeks) and 22 IMV cycles (median duration 9 days). Median TDE decreased from 0.118 cm (interquartile range [IQR] 0.094-0.165) on the first IMV day to 0.104 cm (IQR 0.083-0.120) on the last IMV day (p = .092). DA occurred in 11 IMV cycles (50%) from 10 infants early during IMV (median: second IMV day). Mean airway pressure (MAP) and lung ultrasound score (LUS) on the first IMV day were significantly higher in patients who developed DA. DA was more frequent in patients with extubation failure than in those with extubation success within 7 days (83.3 vs. 33.3%, p = .038). CONCLUSIONS: DA, significantly associated with extubation failure, occurred in 58.8% of the study infants on IMV. Higher MAP and LUS at IMV start were associated with DA. Our results suggest a potential role of diaphragm ultrasound to assess DA and predict extubation failure in clinical practice.

Neonatal hypoglycemia and neurodevelopmental outcomes: Yesterday, today, tomorrow.

Neonatal hypoglycemia is a major source of concern for pediatricians since it has commonly been related to poor neurodevelopmental outcomes. Diagnosis is challenging, considering the different operational thresholds provided by each guideline. Screening of infants at risk plays a crucial role, considering that most hypoglycemic infants show no clinical signs. New opportunities for prevention and treatment are provided by the use of oral dextrose gel. Continuous glucose monitoring systems could be a feasible tool in the next future. Furthermore, there is still limited evidence to underpin the current clinical practice of administering, in case of hypoglycemia, an intravenous "mini-bolus" of 10% dextrose before starting a continuous dextrose infusion. This brief review provides an overview of the latest advances in this field and neurodevelopmental outcomes according to different approaches.   Conclusion: To adequately define if a more permissive approach is risk-free for neurodevelopmental outcomes, more research on continuous glucose monitoring and long-term follow-up is still needed. What is Known: • Neonatal hypoglycemia (NH) is a well-known cause of brain injury that could be prevented to avoid neurodevelopmental impairment. • Diagnosis is challenging, considering the different suggested operational thresholds for NH (<36, <40, <45, <47 or <50 mg/dl). What is New: • A 36 mg/dl threshold seems to be not associated with a worse psychomotor development at 18 months of life when compared to the "traditional" threshold (47 mg/dl). • Further studies on long-term neurodevelopmental outcomes are required before suggesting a more permissive management of NH.

Neonatal outcomes and follow-up of children born to women with pregnancy-associated cancer: a prospective observational study.

BACKGROUND: During the last decade, there has been a growing number of cases of children born from pregnancy-associated cancer (PAC), however there are currently insufficient data on the follow up to be observed in this category of newborns. Objective of the study was to evaluate the neonatal outcomes of infants born to mother with PAC, the potential adverse effect of chemotherapy during pregnancy and the risk of metastasis to the fetus. METHODS: Maternal clinical data and neonatal outcomes of child born to mothers diagnosed with PAC were collected; infants were divided into those were and were not exposed to chemotherapy during fetal life and their outcomes were compered. RESULTS: A total of 37 newborn infants from 36 women with PAC were analyzed. Preterm delivery occurred in 83.8% of the cases. No significant differences in neonatal outcomes were found between infants who were and were not exposed to chemotherapy during pregnancy. The median follow-up period was 12 months. CONCLUSIONS: PAC treatment during the second or third trimester does not seem to be dangerous for the fetus, however infants born from PAC must be carefully evaluated for to rule out the consequences of chemotherapy and exclude the presence of metastasis. Long-term follow-up, especially in children exposed to chemotherapy, should be encouraged to obtain relevant data on long-term toxicity.

Can the CHOP-INTEND be used as An Outcome Measure in the First Months of Age? Implications for Clinical Trials and Real World Data.

BACKGROUND: The CHOP-INTEND is an established outcome measure used to assess motor function in young and weak SMA patients previously validated in type I infants older than 3 months. OBJECTIVE: The aim of our study was to assess the maturation of the CHOP-INTEND scores in a group of healthy infants, establishing which items of the scale can be reliably used in individuals younger than 3 months. METHODS: This is a prospective observational study. The whole cohort was divided into 5 age groups. Each of the 16 CHOP-INTEND items was analyzed looking at the frequency distribution of the scores in each age subgroup. An item was considered developmentally appropriate when > 85% of the infants achieved a full score. RESULTS: our study includes 61 assessments collected < 2 weeks, 25 at 2-4 weeks, 20 at 5-8 weeks, 25 at 9-12 weeks and 20 at 13-17 weeks. Eight of the 16 items were developmentally appropriate already in the first week and another by the end of the first month. The remaining 7 items had more variable responses in the first three months and full scores were consistently achieved only after the third month. CONCLUSIONS: Our findings suggest that the CHOP-INTEND can be used before the age of 3 months, but the results should be interpreted with caution, considering which items are developmentally appropriate at the time of testing. This will also help to establish whether the changes observed following early treatments are a sign of efficacy or at least partly reflect maturational aspects.

Psychological factors and barriers to donating and receiving milk from human milk banks: A review.

Human milk banks (HMBs), established in the early 20th century, aimed to provide safe breast milk for infants with challenges obtaining it. The spread of infections since the 1980s resulted in strict regulations and screening in HMBs, to ensure the safety of donated milk. Several social and personal factors discourage mothers from practicing breastfeeding, making donated milk a viable alternative because of its protective and immunity-enhancing properties. However, psychological barriers can affect the decision to donate or receive donated milk. To identify psychological factors related to donating and receiving human milk from HMBs, we searched PubMed to identify studies reporting psychological factors in donating and receiving milk and excluding studies not reporting psychological factors. The search identified 28 articles meeting the inclusion criteria. Eligible studies from various countries spanned from 1995 to 2023 and focused on psychological factors influencing milk donation and receiving. Most studies were descriptive-qualitative. Factors facilitating or hindering milk donation and reception included perceptions, psychological aspects, and previous experiences. Positive factors for donors included the desire to help other mothers, support from health care professionals, and personal well-being. Negative factors included breast milk exclusivity and discomfort caused by health checks. For recipients, awareness of donated milk benefits was a positive factor, whereas fear regarding safety was negative. The altruistic motivation to help other mothers drove many women to donate. Proper awareness and support from health care professionals and families can help women understand the value of milk donation and support their personal and identity reintegration, especially in cases of the loss of a child.