Zinc metabolism and its role in immunity status in subjects with trisomy 21: chromosomal dosage effect.

Introduction: Trisomy 21 (T21), which causes Down syndrome (DS), is the most common chromosomal aneuploidy in humankind and includes different clinical comorbidities, among which the alteration of the immune system has a heavy impact on patient's lives. A molecule with an important role in immune response is zinc and it is known that its concentration is significantly lower in children with T21. Different hypotheses were made about this metabolic alteration and one of the reasons might be the overexpression of superoxide dismutase 1 (SOD1) gene, as zinc is part of the SOD1 active enzymatic center. Methods: The aim of our work is to explore if there is a linear correlation between zinc level and immune cell levels measured in a total of 217 blood samples from subjects with T21. Furthermore, transcriptome map analyses were performed using Transcriptome Mapper (TRAM) software to investigate whether a difference in gene expression is detectable between subjects with T21 and euploid control group in tissues and cells involved in the immune response such as lymphoblastoid cells, thymus and white blood cells. Results: Our results have confirmed the literature data stating that the blood zinc level in subjects with T21 is lower compared to the general population; in addition, we report that the T21/control zinc concentration ratio is 2:3, consistent with a chromosomal dosage effect due to the presence of three copies of chromosome 21. The transcriptome map analyses showed an alteration of some gene's expression which might explain low levels of zinc in the blood. Discussion: Our data suggest that zinc level is not associated with the levels of immunity cells or proteins analyzed themselves and rather the main role of this ion might be played in altering immune cell function.

Impact of a newly established expert clinical pharmacological advice programme based on therapeutic drug monitoring results in tailoring antimicrobial therapy hospital-wide in a tertiary university hospital: Findings after the first year of implementation.

OBJECTIVES: Therapeutic drug monitoring (TDM) may be helpful in tailoring antimicrobial treatment, and expert interpretation of the results may make it more clinically useful. METHODS: This study aimed to assess retrospectively the first-year impact (July 2021 to June 2022) of a newly established expert clinical pharmacological advice (ECPA) programme based on TDM results in tailoring therapy with 18 antimicrobials hospital-wide in a tertiary university hospital. All patients having ≥1 ECPA were grouped in five cohorts [haematology, intensive care unit (ICU), paediatrics, medical wards and surgical wards]. Four indicators of performance were identified: total ECPAs; total ECPAs recommending dosing adjustments/total ECPAs both at first and at subsequent assessments; and turnaround time (TAT) of ECPAs, defined as optimal (<12 h), quasi-optimal (12-24 h), acceptable (24-48 h) or suboptimal (>48 h). RESULTS: A total of 8484 ECPAs were provided for tailoring treatment in 2961 patients, mostly admitted in the ICU (34.1%) and medical wards (32.0%). The proportion of ECPAs recommending dosing adjustments was >40% at first assessment (40.9% haematology; 62.9% ICU; 53.9% paediatrics; 59.1% medical wards; and 59.7% surgical wards), and decreased consistently at subsequent TDM assessments (20.7% haematology; 40.6% ICU; 37.4% paediatrics; 32.9% medical wards; and 29.2% surgical wards). The overall median TAT of the ECPAs was optimal (8.11 h). CONCLUSION: The TDM-guided ECPA programme was successful in tailoring treatment with a wide panel of antimicrobials hospital-wide. Expert interpretation by medical clinical pharmacologists, short TATs, and strict interaction with infectious diseases consultants and clinicians were crucial in achieving this.

Down Syndrome: how to communicate the diagnosis.

Communicating the diagnosis of Down Syndrome to a couple of parents is never easy, whether before or after birth. As doctors, we must certainly rely on our own relational skills, but it is also necessary to be confident in some general indications, which are often overlooked in the strict hospital routine. This article is intended as a summary of the main articles published on this subject in the international literature, collecting and summarising the most important indications that have emerged in years of medical practice all over the world as well as in our personal experience. The diffusion of these guidelines is essential to help the doctor in this difficult task, on which there is often little training, and above all to guarantee to the parents the least traumatic communication possible.

Infants Born Following SARS-CoV-2 Infection in Pregnancy.

OBJECTIVES: To evaluate outcomes of neonates born to mothers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy, the dynamics of placental transfer of maternal antibodies, and its persistence during infancy. METHODS: Cohort study enrolling neonates born to mothers with SARS-CoV-2 infection in pregnancy. All infants were evaluated at birth. Those born to women with infection onset within 2 weeks before delivery were excluded from further analyses. Remaining infants underwent cerebral and abdominal ultrasound, fundoscopy evaluation, and were enrolled in a 12 month follow-up. Qualitative immunoglobulin G (IgG)/immunoglobulin M and quantitative IgG to S1/S2 subunits of spike protein were assessed in mother-neonate dyads within 48 hours postdelivery and during follow-up. RESULTS: Between April 2020 and April 2021, 130 of 2745 (4.7%) neonates were born to mothers with SARS-CoV-2 infection in pregnancy, with 106 of 130 infections diagnosed before 2 weeks before delivery. Rates of preterm and cesarean delivery were comparable between women with and without infection (6% vs 8%, P = .57; 22% vs 32%, P = .06). No clinical or instrumental abnormalities were detected at birth or during follow-up. There was a positive correlation between maternal and neonatal SARS-CoV-2 IgG levels (r = 0.81, P < .001). Transplacental transfer ratio was higher after second-trimester maternal infections as compared with first and third trimester (P = .03). SARS-CoV-2 IgG level progressively decreased in all infants, with 89 of 92 (97%) infants seronegative at 6 months of age. CONCLUSIONS: Clinical outcomes were favorable in all infants. Matching peak IgG level after infection and higher IgG transplacental transfer might result in the most durable neonatal passive immunity.

A Proof of Concept of the Role of TDM-Based Clinical Pharmacological Advices in Optimizing Antimicrobial Therapy on Real-Time in Different Paediatric Settings.

Introduction: Antimicrobial treatment is quite common among hospitalized children. The dynamic age-associated physiological variations coupled with the pathophysiological alterations caused by underlying illness and potential drug-drug interactions makes the implementation of appropriate antimicrobial dosing extremely challenging among paediatrics. Therapeutic drug monitoring (TDM) may represent a valuable tool for assisting clinicians in optimizing antimicrobial exposure. Clinical pharmacological advice (CPA) is an approach based on the correct interpretation of the TDM result by the MD Clinical Pharmacologist in relation to specific underlying conditions, namely the antimicrobial susceptibility of the clinical isolate, the site of infection, the pathophysiological characteristics of the patient and/or the drug-drug interactions of cotreatments. The aim of this study was to assess the role of TDM-based CPAs in providing useful recommendations for the real-time personalization of antimicrobial dosing regimens in various paediatric settings. Materials and methods: Paediatric patients who were admitted to different settings of the IRCCS Azienda Ospedaliero-Universitaria of Bologna, Italy (paediatric intensive care unit [ICU], paediatric onco-haematology, neonatology, and emergency paediatric ward), between January 2021 and June 2021 and who received TDM-based CPAs on real-time for personalization of antimicrobial therapy were retrospectively assessed. Demographic and clinical features, CPAs delivered in relation to different settings and antimicrobials, and type of dosing adjustments were extracted. Two indicators of performance were identified. The number of dosing adjustments provided over the total number of delivered CPAs. The turnaround time (TAT) of CPAs according to a predefined scale (optimal, <12 h; quasi-optimal, between 12-24 h; acceptable, between 24-48 h; suboptimal, >48 h). Results: Overall, 247 CPAs were delivered to 53 paediatric patients (mean 4.7 ± 3.7 CPAs/patient). Most were delivered to onco-haematological patients (39.6%) and to ICU patients (35.8%), and concerned mainly isavuconazole (19.0%) and voriconazole (17.8%). Overall, CPAs suggested dosing adjustments in 37.7% of cases (24.3% increases and 13.4% decreases). Median TAT was 7.5 h (IQR 6.1-8.8 h). Overall, CPAs TAT was optimal in 91.5% of cases, and suboptimal in only 0.8% of cases. Discussion: Our study provides a proof of concept of the helpful role that TDM-based real-time CPAs may have in optimizing antimicrobial exposure in different challenging paediatric scenarios.

Neuroprem 2: An Italian Study of Neurodevelopmental Outcomes of Very Low Birth Weight Infants.

Background: Despite the increased survival of preterm newborns worldwide, the risk of neurodevelopmental disabilities remains high. Analyzing the outcomes of the preterm population can identify risk factors and enable specific early interventions. Aims: Neuroprem is a prospective cohort study of very low birth weight (VLBW) infants that aims to evaluate the neurodevelopmental outcomes and risk factors for severe functional disability at 2 years of corrected age. Methods: Nine Italian neonatal intensive care units participated in the network. The Griffiths Mental Developmental Scales (GMDS-R) or the Bayley Scales of Infant and Toddler Development (BSDI III) and a neuro-functional evaluation (according to the International Classification of Disability and Health and Neuro-Functional Assessment, or NFA ICF-CY) were administered to VLBW infants at 24 months of corrected age. The primary outcome measure was severe functional disability, defined as cerebral palsy, bilateral blindness, deafness, an NFA ICF-CY of >2, a BSDI III cognitive composite score of <2 SD, or a GMDS-R global quotient score of <2 SD. Perinatal risk factors for severe functional disability were assessed through multivariate logistic regression analysis. Results: Among 502 VLBW survivors who completed the 24-month follow-up, 48 (9.6%) presented severe functional disability, of whom 27 had cerebral palsy (5.4%). Rates of severe functional disability and cerebral palsy were higher in neonates with a lower gestational age (p < 0.001). Overall, 147 infants (29.3%) were referred to neuromotor intervention. In the multivariate regression model, gestational age at birth OR 0.79; 95% CI 0.67-0.90; p = 0.001) and periventricular-intraventricular hemorrhage (OR 2.51; 95% CI 1.19-5.26; p = 0.015) were significantly associated with severe functional disability. Conclusion: Neuroprem 2 provides updated information on the neurodevelopmental outcomes of VLBW infants in a large Italian cohort. The overall rate of neurodevelopmental disabilities was quite lower than reported in the previous literature. These data indicate the need for structured follow-up programs from a national neonatal network perspective.

Neuroprem: the Neuro-developmental outcome of very low birth weight infants in an Italian region.

INTRODUCTION: The survival of preterm babies has increased worldwide, but the risk of neuro-developmental disabilities remains high, which is of concern to both the public and professionals. The early identification of children at risk of neuro-developmental disabilities may increase access to intervention, potentially influencing the outcome. AIMS: Neuroprem is an area-based prospective cohort study on the neuro-developmental outcome of very low birth weight (VLBW) infants that aims to define severe functional disability at 2 years of age. METHODS: Surviving VLBW infants from an Italian network of 7 neonatal intensive care units (NICUs) were assessed for 24 months through the Griffiths Mental Developmental Scales (GMDS-R) or the Bayley Scales of Infant and Toddler Development (BSDI III) and neuro-functional evaluation according to the International Classification of Disability and Health (ICF-CY). The primary outcome measure was severe functional disability at 2 years of age, defined as cerebral palsy, a BSDI III cognitive composite score < 2 standard deviation (SD) or a GMDS-R global quotients score < 2 SD, bilateral blindness or deafness. RESULTS: Among 211 surviving VLBW infants, 153 completed follow-up at 24 months (72.5%). Thirteen patients (8.5%) developed a severe functional disability, of whom 7 presented with cerebral palsy (overall rate of 4.5%). Patients with cerebral palsy were all classified with ICF-CY scores of 3 or 4. BSDI III composite scores and GMDS-R subscales were significantly correlated with ICF-CY scores (p < 0.01). CONCLUSION: Neuroprem represents an Italian network of NICUs aiming to work together to ensure preterm neuro-developmental assessment. This study updates information on VLBW outcomes in an Italian region, showing a rate of cerebral palsy and major developmental disabilities in line with or even lower than those of similar international studies. Therefore, Neuroprem provides encouraging data on VLBW neurological outcomes and supports the implementation of a preterm follow-up programme from a national network perspective.

Enteral Nutrition Tolerance And REspiratory Support (ENTARES) Study in preterm infants: study protocol for a randomized controlled trial.

BACKGROUND: Respiratory distress syndrome (RDS) and feeding intolerance are common conditions in preterm infants and among the major causes of neonatal mortality and morbidity. For many years, preterm infants with RDS have been treated with mechanical ventilation, increasing risks of acute lung injury and bronchopulmonary dysplasia. In recent years non-invasive ventilation techniques have been developed. Showing similar efficacy and risk of bronchopulmonary dysplasia, nasal continuous positive airway pressure (NCPAP) and heated humidified high-flow nasal cannula (HHHFNC) have become the most widespread techniques in neonatal intensive care units. However, their impact on nutrition, particularly on feeding tolerance and risk of complications, is still unknown in preterm infants. The aim of the study is to evaluate the impact of NCPAP vs HHHFNC on enteral feeding and to identify the most suitable technique for preterm infants with RDS. METHODS: A multicenter randomized single-blind controlled trial was designed. All preterm infants with a gestational age of 25-29 weeks treated with NCPAP or HHHFNC for RDS and demonstrating stability for at least 48 h along with the compliance with inclusion criteria (age less than 7 days, need for non-invasive respiratory support, suitability to start enteral feeding) will be enrolled in the study and randomized to the NCPAP or HHHFNC arm. All patients will be monitored until discharge, and data will be analyzed according to an intention-to-treat model. The primary outcome is the time to reach full enteral feeding, while parameters of respiratory support, feeding tolerance, and overall health status will be evaluated as secondary outcomes. The sample size was calculated at 141 patients per arm. DISCUSSION: The identification of the most suitable technique (NCPAP vs HHHFNC) for preterm infants with feeding intolerance could reduce gastrointestinal complications, improve growth, and reduce hospital length of stay, thus improving clinical outcomes and reducing health costs. The evaluation of the timing of oral feeding could be useful in understanding the influence that these techniques could have on the development of sucking-swallow coordination. Moreover, the evaluation of the response to NCPAP and HHHFNC could clarify their efficacy as a treatment for RDS in extremely preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03548324 . Registered on 7 June 2018.

Nevirapine prophylaxis to prevent HIV-1 mother-to-child transmission: pharmacokinetic considerations in preterm infants.

Prophylaxis with zidovudine and 3 doses of nevirapine (NVP) is recommended for infants born to HIV-1 infected untreated mothers to prevent HIV-1 mother-to-child transmission. However little is known about NVP pharmacokinetics in neonates, mostly in preterm infants. We performed therapeutic monitoring of NVP plasma concentrations in a 32-week preterm HIV-1 exposed infant born to an infected untreated mother. With the recommended regimen, an intense NVP exposure was observed, with NVP plasma levels exceeding the target concentration by up to 40 times, suggesting that when a laboratory assessment of NVP plasma concentrations is available, it may be useful to monitor and optimize drug exposure.

Contribution of a Comparative Western Blot Method to Early Postnatal Diagnosis of Congenital Syphilis.

Serology has a pivotal role in the diagnosis of congenital syphilis (CS), but problems arise because of the passive transfer of IgG antibodies across the placenta. The aim of this study was to assess the diagnostic value of a comparative Western blot (WB) method finalized to match the IgG immunological profiles of mothers and their own babies at birth in order to differentiate between passively transmitted maternal antibodies and antibodies synthesized by the infants against Treponema pallidum Thirty infants born to mothers with unknown or inadequate treatment for syphilis were entered in a retrospective study, conducted at St. Orsola-Malpighi Hospital, Bologna, Italy. All of the infants underwent clinical, instrumental, and laboratory examinations, including IgM WB testing. For the retrospective study, an IgG WB assay was performed by blotting T. pallidum antigens onto nitrocellulose sheets and incubating the strips with serum specimens from mother-child pairs. CS was diagnosed in 11 out of the 30 enrolled infants; 9/11 cases received the definitive diagnosis within the first week of life, whereas the remaining two were diagnosed later because of increasing serological test titers. The use of the comparative IgG WB testing performed with serum samples from mother-child pairs allowed a correct CS diagnosis in 10/11 cases. The CS diagnosis was improved by a strategy combining comparative IgG WB results with IgM WB results, leading to a sensitivity of 100%. The comparative IgG WB test is thus a welcome addition to the conventional laboratory methods used for CS diagnosis, allowing identification and adequate treatment of infected infants and avoiding unnecessary therapy of uninfected newborns.

Evaluation of the effects of intrapartum antibiotic prophylaxis on newborn intestinal microbiota using a sequencing approach targeted to multi hypervariable 16S rDNA regions.

Different factors are known to influence the early gut colonization in newborns, among them the perinatal use of antibiotics. On the other hand, the effect on the baby of the administration of antibiotics to the mother during labor, referred to as intrapartum antibiotic prophylaxis (IAP), has received less attention, although routinely used in group B Streptococcus positive women to prevent the infection in newborns. In this work, the fecal microbiota of neonates born to mothers receiving IAP and of control subjects were compared taking advantage for the first time of high-throughput DNA sequencing technology. Seven different 16S rDNA hypervariable regions (V2, V3, V4, V6 + V7, V8, and V9) were amplified and sequenced using the Ion Torrent Personal Genome Machine. The results obtained showed significant differences in the microbial composition of newborns born to mothers who had received IAP, with a lower abundance of Actinobacteria and Bacteroidetes as well as an overrepresentation of Proteobacteria. Considering that the seven hypervariable regions showed different discriminant ability in the taxonomic identification, further analyses were performed on the V4 region evidencing in IAP infants a reduced microbial richness and biodiversity, as well as a lower number of bacterial families with a predominance of Enterobacteriaceae members. In addition, this analysis pointed out a significant reduction in Bifidobacterium spp. strains. The reduced abundance of these beneficial microorganisms, together with the increased amount of potentially pathogenic bacteria, may suggest that IAP infants are more exposed to gastrointestinal or generally health disorders later in age.

Influence of intrapartum antibiotic prophylaxis against group B Streptococcus on the early newborn gut composition and evaluation of the anti-Streptococcus activity of Bifidobacterium strains.

Several factors are known to influence the early colonization of the gut in newborns. Among them, the use of antibiotics on the mother during labor, referred to as intrapartum antibiotic prophylaxis (IAP), has scarcely been investigated, although this practice is routinely used in group B Streptococcus (GBS)-positive women. This work is therefore aimed at verifying whether IAP can influence the main microbial groups of the newborn gut microbiota at an early stage of microbial establishment. Fifty-two newborns were recruited: 26 born by mothers negative to GBS (control group) and 26 by mothers positive to GBS and subjected to IAP with ampicillin (IAP group). Selected microbial groups (Lactobacillus spp., Bidobacterium spp., Bacteroides fragilis, Clostridium difficile, and Escherichia coli) were quantified with real-time PCR on DNA extracted from newborn feces. Further analysis was performed within the Bidobacterium genus by using DGGE after amplification with genus-specific primers. Results obtained showed a significant decrease of the bifidobacteria counts after antibiotic treatment of the mother. Bifidobacteria were found to be affected by IAP not only quantitatively but also qualitatively. In fact, IAP determined a decrement in the frequency of Bidobacterium breve, Bidobacterium bifidum, and Bidobacterium dentium with respect to the control group. Moreover, this study has preliminarily evaluated that some bifidobacterial strains, previously selected for use in infants, have antibacterial properties against GBS and are therefore potential candidates for being applied as probiotics for the prevention of GBS infections.