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Objectives The early detection and stratification of asphyxiated infants at higher risk for impaired neurodevelopment is challenging. S100B protein is a well-established biomarker of brain damage, but lacks conclusive validation according to the “gold standard” methodology for hypoxic-ischemic encephalopathy (HIE) prognostication, i.e. brain MRI. The aim of the present study was to investigate the predictive role of urinary S100B concentrations, assessed in a cohort of HIE infants receiving therapeutic hypothermia (TH), compared to brain MRI. Methods Assessment of urine S100B concentrations was performed by immunoluminometric assay at first void and at 4, 8, 12, 16, 20, 24, 48, 72, 96, 108 and 120-h after birth. Neurologic evaluation, routine laboratory parameters, amplitude-integrated electroencephalography, and cerebral ultrasound were performed according to standard protocols. Brain MRI was performed at 7–10 days of life. Results Overall, 74 HIE neonates receiving TH were included in the study. S100B correlated, already at first void, with the MRI patterns with higher concentrations in infants with the most severe MRI lesions. Conclusions High S100B urine levels soon after birth constitute trustable predictors of brain injury as confirmed by MRI. Results support the reliability of S100B in clinical daily practice and open the way to its inclusion in the panel of parameters used for the selection of cases suitable for TH treatment.

A possible consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the development of an exacerbated thrombophilic status, and cerebral venous thrombosis (CVT) is a rare but possible complication of SARS-CoV-2 infection reported both in adults and in children. The present case report describes the clinical course of a term neonate showing extended CVT of unclear origin, whose mother had developed SARS-CoV-2 infection during the third trimester of pregnancy. We speculate that the prothrombotic status induced by maternal SARS-CoV-2 infection may have played a pathophysiological role in the development of such severe neonatal complication. Further investigations are required to confirm such hypothesis.

BACKGROUND: The use of umbilical venous catheters (UVCs) in the perinatal period may be associated with severe complications, including the occurrence of portal vein thrombosis (PVT). AIM: To assess the incidence of UVC-related PVT in infants with postnatal age up to three months. METHODS: A systematic and comprehensive database searching (PubMed, Cochrane Library, Scopus, Web of Science) was performed for studies from 1980 to 2020 (the search was last updated on November 28, 2020). We included in the final analyses all peer-reviewed prospective cohort studies, retrospective cohort studies and case-control studies. The reference lists of included articles were hand-searched to identify additional studies of interest. Studies were considered eligible when they included infants with postnatal age up to three months with UVC-associated PVT. Incidence estimates were pooled by using random effects meta-analyses. The quality of included studies was assessed using the Newcastle-Ottawa scale. The systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. RESULTS: Overall, 16 studies were considered eligible and included in the final analyses. The data confirmed the relevant risk of UVC-related thrombosis. The mean pooled incidence of such condition was 12%, although it varied across studies (0%-49%). In 15/16 studies (94%), diagnosis of thrombosis was made accidentally during routine screening controls, whilst in 1/16 study (6%) targeted imaging assessments were carried out in neonates with clinical concerns for a thrombus. Tip position was investigated by abdominal ultrasound (US) alone in 1/16 (6%) studies, by a combination of radiography and abdominal US in 14/16 (88%) studies and by a combination of radiography, abdominal US and echocardiography in 1/16 (6%) studies. CONCLUSION: To the best of our knowledge, this is the first systematic review specifically investigating the incidence of UVC-related PVT. The use of UVCs requires a high index of suspicion, because its use is significantly associated with PVT. Well-designed prospective studies are required to assess the optimal approach to prevent UVC-related thrombosis of the portal system.

Herein, we present a newborn female with congenital vocal cord paralysis who required a tracheostomy in the neonatal period. She also presented with feeding difficulties. She was later diagnosed with a clinical picture of congenital myasthenia, associated with three variants of the MUSK gene: the 27-month follow-up was described. In particular, the c.565C>T variant is novel and has never been described in the literature; it causes the insertion of a premature stop codon (p.Arg189Ter) likely leading to a consequent formation of a truncated nonfunctioning protein. We also systematically collected and summarized information on patients’ characteristics of previous cases of congenital myasthenia with neonatal onset reported in the literature to date, and we compared them to our case. The literature reported 155 neonatal cases before our case, from 1980 to March 2022. Of 156 neonates with CMS, nine (5.8%) had vocal cord paralysis, whereas 111 (71.2%) had feeding difficulties. Ocular features were evident in 99 infants (63.5%), whereas facial-bulbar symptoms were found in 115 infants (73.7%). In one hundred sixteen infants (74.4%), limbs were involved. Respiratory problems were displayed by 97 infants (62.2%). The combination of congenital stridor, particularly in the presence of an apparently idiopathic bilateral vocal cord paralysis, and poor coordination between sucking and swallowing may indicate an underlying congenital myasthenic syndrome (CMS). Therefore, we suggest testing infants with vocal cord paralysis and feeding difficulties for MUSK and related genes to avoid a late diagnosis of CMS and improve outcomes.

The early detection of perinatal brain damage in preterm and term newborns (i.e. intraventricular hemorrhage, periventricular leukomalacia and perinatal asphyxia) still constitute an unsolved issue. To date, despite technological improvement in standard perinatal monitoring procedures, decreasing the incidence of perinatal mortality, the perinatal morbidity pattern has a flat trend. Against this background, the measurement of brain constituents could be particularly useful in the early detection of cases at risk for short-/long-term brain injury. On this scenario, the main European and US international health-care institutions promoted perinatal clinical and experimental neuroprotection research projects aimed at validating and including a panel of biomarkers in the clinical guidelines. Although this is a promising attempt, there are several limitations that do not allow biomarkers to be included in standard monitoring procedures. The main limitations are: (i) the heterogeneity of neurological complications in the perinatal period, (ii) the small cohort sizes, (iii) the lack of multicenter investigations, (iv) the different techniques for neurobiomarkers assessment, (iv) the lack of consensus for the validation of assays in biological fluids such as urine and saliva, and (v), the lack of reference curves according to measurement technique and biological fluid. In the present review we offer an up-to-date overview of the most promising developments in the use of biomarkers in the perinatal period such as calcium binding proteins (S100B protein), vasoactive agents (adrenomedullin), brain biomarkers (activin A, neuron specific enolase, glial fibrillary acidic protein, ubiquitin carboxyl-terminal hydrolase-L1) and oxidative stress markers.

Heart rate variability (HRV) is currently considered the most valuable non-invasive test to investigate the autonomic nervous system function, based on the fact that fast fluctuations might specifically reflect changes of sympathetic and vagal activity. An association between abnormal values of HRV and brain impairment has been reported in the perinatal period, although data are still fragmentary. Considering such association, HRV has been suggested as a possible marker of brain damage also in case of hypoxic-ischemic encephalopathy following perinatal asphyxia. The aim of the present manuscript was to review systematically the current knowledge about the use of HRV as marker of cerebral injury in neonates suffering from hypoxic-ischemic encephalopathy. Findings reported in this paper were based on qualitative analysis of the reviewed data. Conclusion: A growing body of research supports the use of HRV as non-invasive, bedside tool for the monitoring of hypoxic-ischemic encephalopathy. The currently available data about the role of HRV as prognostic tool in case of hypoxic ischemic encephalopathy are promising but require further validation by future studies. What is Known: • Heart rate variability (HRV) is a non-invasive monitoring technique to assess the autonomic nervous system activity. • A correlation between abnormal HRV and cerebral injury has been reported in the perinatal period, and HRV has been suggested as possible marker of brain damage in case of hypoxic-ischemic encephalopathy. What is New: • HRV might provide precocious information about the entity of brain injury in asphyxiated neonates and be of help to design early, specific, and personalized treatments according to severity. • Further investigations are required to confirm these preliminary data.

Progressive interface failure in two-layer beams with partial shear connection is simulated. The mathematical model, based on classical beam theories and linear non-proportional interface laws, proposed previously by the authors, is considered. The related fundamental analytical solution is rewritten in vector form to facilitate the determination of the high number of arbitrary constants on which the general solution for a generic configuration of the composite beam, characterized by different regimes coexisting along the interface, depends. This is employed in the simulation of a process of progressive interface debonding as a sequence of equilibrated consecutive configurations assumed by the composite beam. Numerical analyses are finally performed to validate the solution procedure proposed.

Correction to: European Journal of Pediatrics https://doi.org/10.1007/s00431-020-03882-3

Respiratory distress syndrome (RDS) may occur in term and near-term infants because of mutations in surfactant-related genes. ATP-binding cassette A3 (ABCA3), a phospholipid carrier specifically expressed in the alveolar epithelium, is the most frequently involved protein. We report the case of a couple of late-preterm fraternal twin infants of opposite sex carrying the same compound heterozygous ABCA3 mutations, one of which has never been previously reported, with different disease severity, suggesting variable penetrance or sex-related differences. ABCA3 deficiency should be considered in term or near-term babies who develop unexplained RDS.

Although "late preterm" (LP) newborns (33-36 weeks of gestational age) represent more than 70% of all preterm labors, little is known about the relation between certain risk factors and developmental outcomes in LP compared to "very preterm" (≤32 weeks) children (VP). This study investigates: (1) LP and VP infants' development at 12 months of corrected age (CA) using the Bayley Scales of Infant Development - 3rd Edition (BSID-III); (2) correlation between BSID-III performances and maternal stress (using Parenting Stress Index-Short Form, PSI-SF) among LP and VP at 12 months CA; and (3) the link between known neonatal and demographic risk factors and developmental outcomes of LP and VP infants. For both LP and VP infants the Mean Cognitive (LP: 102.69±7.68; VP: 103.63±10.68), Language (LP: 96.23±10.08; VP: 99.10±10.37) and Motor (LP: 91.11±10.33; VP: 93.85±10.17) composite scores were in the normal range, without significant differences between the groups. Correlations between PSI-SF and BSID-III showed that in the VP group (but not LP), Language score was negatively related to the PSI-SF 'Difficult Child' scale (r=-.34, p

Objectives – To investigate the dose of enoxaparin required in neonates to achieve target therapeutic ranges of anti factor Xa 48 hours after starting therapy, and compare this dose to recommended guideline dosages for neonates. Methods – We retrospectively reviewed 19 records of newborns who received enoxaparin at different doses for the treatment of thrombosis and evaluated how many among them reached the target anti-factor Xa level after 48 hours. Results – Only 1/5 neonates (20%) treated with 150 UI/kg twice a day, but 100% (6/6) of those treated with 175 UI/kg twice a day reached therapeutic levels of anti-factor Xa at 48 hours. Of the 8 neonates treated with lower starting doses none reached the therapeutic range after 48 hours and these required the highest number of dose changes. Conclusions – Our results reinforce the need to increase in neonates the dosage of enoxaparin suggested in published guidelines, in order to shorten the time-delay in achieving a therapeutic level of anti-factor Xa, and also reducing the number of blood tests necessary for dosing anti-factor Xa.

The studies carried out to develop a robust crystallization method for the substituted piperazinyl-quinoline (1) a compound potentially active in the treatment of depression, are described in this contribution. These studies include the control of a solvate that could have potentially formed in the crystallization process. The principles of quality by design (QbD) were applied to generate the process understanding and to define the control strategy for the control of the formation of the solvate during the crystallization. The application of process analytical technology (PAT) tools was key in achieving the desired process control.

Although relatively rare, thromboembolic events are a major complication of invasive procedures, mainly vascular catheterization, required for the survival of neonates admitted to the neonatal intensive care unit. Sometimes symptoms may be ambiguous and the diagnosis may not be immediate. The clinical relevance of polymorphism of methilene tetrahydrofolate reductase (MTHFR) gene heterozigosity and of omocystein level in the genesis of these thromboembolic events are poorly understood. We report two cases of thrombosis of the abdominal aorta, mimicking aortic coarctation, in two neonates, successfully treated at diagnosis with 170 UI/Kg of low molecular weight heparin (LMWH) twice daily, without side effects. Screening for prothrombotic defects revealed the heterozygosity for MTHFR C677T in both neonates and low omocystein level in one of them. We suggest that in newborns vascular thrombosis should be considered in the differential diagnosis of acute disorders of blood circulation at birth and familial thrombophilia should be investigated. LMWH therapy with a dose of 170 UI/Kg twice daily usually allows vascular recanalization, without side effects.

Therapeutic hypothermia (TH) started within six hours from birth has been shown to improve neurodevelopmental outcomes in newborns with moderate-to-severe hypoxic-ischemic encephalopathy.Twenty-nine consecutive newborns treated with whole body cooling at the Bambino Gesú Children's Hospital between March 2011 and December 2012 were included in this study. All infants were out-born neonates. Passive cooling was always started at the birth center and continued during transportation. Pre- and post-transport risk index of physiological stability (TRIPS) scores were calculated for each patient to evaluate the impact of the transportation. Magnetic resonance imaging (MRI) was performed within 10 days of life to investigate the presence of brain injury.Among the 26 survivors, 14 had no detectable lesions and 12 presented with brain injury on MRI. Four babies presented with cerebral bleeding. Babies with cerebral hemorrhage had a worse pre-transport TRIPS score, but among these neonates no worsening between pre and post-transport score was registered.The presence of cerebral hemorrhagic lesions seemed to be related to the initial clinical conditions of the baby rather than to the transport itself. Our data confirm that TH performed in an out-born center is efficient and safe.

The response of multilayered plates with imperfectly bonded interfaces and delaminations to quasi static and dynamic loadings is conveniently studied by assuming the displacements as two length-scales fields, given by global displacements, which are continuous in the thickness, and local perturbations or enrichments, which account for the multilayered structure and the jumps at the interfaces. The a priori imposition of interfacial continuity conditions then leads to a homogenized field defined by the global variables only. The number of displacement unknowns is independent of the number of layers and is equal to five or six, for sliding or mixed mode interfaces, respectively. Dynamic equilibrium equations are derived using variational principles. This effective idea, which was originally proposed in the zigzag theories for fully bonded plates, was first applied to plates with imperfect interfaces by Cheng et al. (J Appl Mech, 63:1019–1026, 1996), Schmidt and Librescu (Nova J Math Game Theory Algebra, 5:131–147, 1996), and Di Sciuva (AIAA J, 35(11):1753–1759, 1997). These pioneering models, as all subsequent models which extend the theories to various problems, suffer from a common omission in the treatment of the interfacial energy in the derivation of the equilibrium equations, which leads to solutions which are accurate only for fully bonded/debonded plates. In this paper a linear, first order model which resolves the inaccuracy and extends the theories to more general interfacial traction laws is presented along with the corrected formulations of the original models. The formulations are validated using exact 2D elasticity solutions for multilayered plates in cylindrical bending.

Respiratory distress syndrome (RDS) may occur in term and near-term infants because of mutations in surfactant-related genes. ATP-binding cassette A3 (ABCA3), a phospholipid carrier specifically expressed in the alveolar epithelium, is the most frequently involved protein. We report the case of a couple of late-preterm fraternal twin infants of opposite sex carrying the same compound heterozygous ABCA3 mutations, one of which has never been previously reported, with different disease severity, suggesting variable penetrance or sex-related differences. ABCA3 deficiency should be considered in term or near-term babies who develop unexplained RDS.

In multilayered systems with interfacial imperfections, such as imperfect bonding of the layers or delaminations, or where the plies are separated by thin interlayers allowing relative motion, the displacement field is highly discontinuous in the thickness, with a characteristic zig-zag pattern and interfacial jumps. Stresses also have large variations, especially for highly deformable interlayers or fully debonded layers. These effects cannot be captured using classical, first- or higher-order single-layer theories. A mechanical model is formulated for the solution of multilayered beams/wide plates with an arbitrary number of imperfect interfaces/delaminations loaded dynamically. The formulation is in the framework of the discrete-layer approach and the interfaces are described through affine traction laws which relate interfacial tractions and relative displacements. Homogenization and variational techniques define novel equilibrium equations depending on only four generalized displacement functions. Comparison with 2D elasticity solutions shows that complex discontinuous fields in thick, highly-anisotropic plates with an arbitrary number of sliding-interfaces are accurately predicted. The approach extends the range of problems which can be solved analytically compared to discrete-layer models where the unknowns depend on the number of layers/interfaces. The affine traction laws describe arbitrary branches of piecewise linear functions approximating nonlinear traction laws to represent different interfacial mechanisms.

A new formulation to analyze two-layer beams with interlayer slip is proposed. Each layer is modeled as a linearly elastic Timoshenko beam. The connection between the layers is assumed to be perfect in the transverse direction while imperfect in the longitudinal one (only interlayer slips are allowed). The interface behavior in the longitudinal direction is described through a linear non proportional relationship relating tangential reactions transmitted between the two layers and slips. The problem is then solved analytically and a novel closed form solution is obtained. Explicit expressions for all static and kinematic variables are derived. This analytical solution is shown to be employed in the analysis of composite beams for different boundary and loading conditions generating interfacial tractions that induce an irreversible process of progressive debonding at the interface. Some numerical examples are considered and a parametric analysis performed to investigate the influence of the interface behavior on the response of the composite beam when the layers are still elastic.

The influence of skin imperfections, in the form of delamination damage or thickness variations, on the indentation collapse mechanism in composite sandwich beams with compressive yielding cores is studied using the models of non-prismatic beam and beam-column resting on a nonlinear Winkler foundation. Upper and lower threshold solutions are derived for the indentation response and collapse load and the transition between the two limits is defined as a function of size, magnitude and position of the imperfections. In beams where global bending effects are not negligible, the collapse load is limited from above by the indentation collapse load of beams with rigid-plastic cores and the face wrinkling collapse load of beams with elastic cores; the transition between the two limits is controlled by material/structure properties and the magnitude of the imperfections. Characteristic lengths, which depend on material and geometrical properties, define the minimum size of the imperfections with the strongest effect on the solution and the minimum distance between load and imperfections with no effect on the solution.

Background Cardiorespiratory stabilization is recommended before surgical repair of congenital diaphragmatic hernia (CDH) because surgery may induce a transitory deterioration of chest compliance and gas exchange. It is not known if surgical intervention can affect cerebral circulation and oxygenation. Aim The aim of the study was to assess noninvasively, by near-infrared spectroscopy, the possible changes in cerebral hemodynamics and oxygenation associated with surgical repair of CDH. Subjects Twenty-five newborns with severe CDH (birth weight, 3057 ± 354 g; gestational age, 37.8 ± 1.8 weeks; male/female newborns, 15/10; left/right CDH, 19/6) were sedated, paralyzed, and mechanically ventilated by conventional gentle ventilation and surgically corrected at a median age of 2.7 days (min-max, 2-14 days) after cardiorespiratory stabilization. Methods Heart rate (HR [beats per minute]), preductal transcutaneous oxygen saturation (tcSao 2 [%]), carbon dioxide tension (tcPco 2 [Torr]), and mean arterial blood pressure (mm Hg) were continuously monitored. Inspired fractional oxygen concentration (Fio 2 ) was adjusted to maintain and preductal tcSao 2 of greater than 80%, whereas the ventilator's settings were kept unchanged throughout the surgical procedure. Cerebral hemodynamics was assessed by near-infrared spectroscopy (NIRO 300, Hamamatsu Photonics, Japan), recording continuously and noninvasively the relative changes in concentration of oxygenated ( Δ O 2 Hb [ μ mol/L]), deoxygenated ( Δ HHb [ μ mol/L]), and total ( Δ tHb [ μ mol/L]) hemoglobin; the tissue oxygenation index (TOI [%]) was also calculated (TOI = O 2 Hb/O 2 Hb + HHb). Total hemoglobin concentration is considered to be representative of cerebral blood volume. Arterial blood gases were also measured at the beginning ( T 1 ) and at the end of surgery ( T 2 ). For all measurements, results at T 1 and at T 2 , as well as the differences between T 1 and T 2 , have been expressed as means or medians and SDs or 95% confidence intervals or ranges. The differences between T 1 and T 2 were considered statistically significant for a P value of less than .05 by the Student t test for paired values. Results At T 1 , mean tcSao 2 % was 94.1 % (SD, 4.6) with a Fio 2 of 0.25 (SD, 0.1); at T 2 , to obtain similar values of tcSao 2 (93.4%; SD, 4.4), it was necessary to increase the Fio 2 to 0.37 (SD, 0.14; P T 1 was 149.5 beats per minute (SD, 9.1) and increased significantly ( P T 2 (165.2 beats per minute; SD, 14.2). Mean arterial blood pressure was 54.7 mm Hg (SD, 7.7) at T 1 and did not change appreciably at T 2 (55.6 mm Hg; SD, 8.1). Moreover, tcPco 2 did not change significantly during the procedure (mean tcPco 2 = 49.9 Torr [SD, 12.8] at T 1 and 57.3 mm Hg [SD, 17.9] at T 2 ). O 2 Hb and tHb decreased ( P P Δ [SD]: Δ O 2 Hb= −10.9 μ mol/L [9.7], Δ tHb = −7.5 μ mol/L [11.7], and Δ HHb = −3.5 μ mol/L [6.8]). Mean TOI was 70% at T 1 (normal values >60%) and decreased significantly at T 2 (mean Δ TOI = −6.1% [SD, 10.6]). In all infants, the greatest changes occurred when the viscera were positioned into the abdomen. Conclusions Notwithstanding the initial cardiorespiratory stabilization, surgical repair of CDH was associated with a rise in HR and oxygen requirement and a drop in cerebral tHb and O 2 Hb, suggesting a reduction in cerebral blood volume and oxygenation. These events were probably due to the combined effects of an increase in right to left shunting (as indicated by the increased oxygen requirement) and a decrease in venous return (possibly due to compression of the inferior vena cava by the viscera positioned into the abdomen). These preliminary results reinforce the importance of achieving a good cardiorespiratory stability before undertaking surgical correction of CDH to minimize the possible interference of the procedure with cerebral circulation and oxygenation.

60 Birthweight and Mcgoon Index Predict Outcome in Newborn Infants with Congenital Diaphragmatic Hernia (CDH).

202 Cerebral Haemodynamics and Lung Mechanics in Preterm Infants During Synchronized Intermittent Mandatory Ventilation (SIMV) and Synchronized Intermittent Positive Pressure Ventilation (SIPPV), with and Without Volume Guaranteed (VG)