Reintroduction of Legacy Antibiotics in Neonatal Sepsis: The Special Role of Fosfomycin and Colistin.

Neonatal sepsis is a leading cause of morbidity and mortality in neonates, particularly in low- and middle-income countries. The emergence of antimicrobial resistance is a rapidly growing global problem. A significant proportion of the pathogens that commonly cause neonatal sepsis are resistant to multiple antibiotics. Therefore, for the empirical treatment of neonatal sepsis, the repurposing of older antibiotics that are effective against multidrug-resistant pathogens is being investigated. This review aims to provide an overview of current research and experience using the repurposed antibiotics colistin and fosfomycin for the empirical treatment of neonatal sepsis. Based on current knowledge, colistin and fosfomycin may be potentially helpful for the empirical treatment of sepsis in neonates due to their efficacy against a wide range of pathogens and acceptable safety profile.

Application of Advanced Molecular Methods to Study Early-Onset Neonatal Sepsis.

Early-onset sepsis (EOS) is a global health issue, considered one of the primary causes of neonatal mortality. Diagnosis of EOS is challenging because its clinical signs are nonspecific, and blood culture, which is the current gold-standard diagnostic tool, has low sensitivity. Commonly used biomarkers for sepsis diagnosis, including C-reactive protein, procalcitonin, and interleukin-6, lack specificity for infection. Due to the disadvantages of blood culture and other common biomarkers, ongoing efforts are directed towards identifying innovative molecular approaches to diagnose neonates at risk of sepsis. This review aims to gather knowledge and recent research on these emerging molecular methods. PCR-based techniques and unrestricted techniques based on 16S rRNA sequencing and 16S-23S rRNA gene interspace region sequencing offer several advantages. Despite their potential, these approaches are not able to replace blood cultures due to several limitations; however, they may prove valuable as complementary tests in neonatal sepsis diagnosis. Several microRNAs have been evaluated and have been proposed as diagnostic biomarkers in EOS. T2 magnetic resonance and bioinformatic analysis have proposed potential biomarkers of neonatal sepsis, though further studies are essential to validate these findings.

A literature review on the redundancy of additional thyroid function tests in neonates of mothers with hypothyroidism.

AIM: Newborn thyroid screening tests are carried out during the first days after birth in many parts of the world. The aim of this review was to assess whether additional thyroid function tests of neonates born to mothers with hypothyroidism are necessary to diagnose newborns with congenital hypothyroidism (CH) missed by the usual screening test. METHODS: A search in PubMed and Google Scholar databases was conducted for pertinent studies, using relevant keywords. All studies that were published in any language from 1 January 2000 to 30 June 2023 were included. Observational cohort studies were included in the analysis, while case reports and studies not referring to neonates were excluded. RESULTS: Thirteen studies were identified comprising more than 4400 infants with CH. Studies with the larger study populations recommended against additional testing in healthy infants of hypothyroid mothers. Similar were the results of some smaller retrospective studies. Few studies identified in total 16 infants with CH that were missed on neonatal screening without, though, a definite causative link between the mother's and the infant's thyroid dysfunction. CONCLUSION: Based on available data, additional thyroid function tests seem redundant in identifying undiagnosed cases of CH. Larger studies are needed to reach a definite conclusion.

Knowledge and attitudes of medical students about clinical aspects of congenital cytomegalovirus infection in newborns: A nationwide cross-sectional study in Greece.

Introduction: Cytomegalovirus (CMV) is the most frequent cause of congenital infection worldwide causing severe morbidity in newborns, infants, and children. Despite the clinical importance of congenital CMV (cCMV) infection, studies conducted so far indicate that there is limited awareness in the medical community in the field. The aim of this study was to assess Greek medical students' knowledge on cCMV infection. Methods: We performed a questionnaire-based nationwide cross-sectional study. A convenience sample of medical students from seven medical schools was enrolled. Results: Of the 562 respondents, 54,8% considered themselves undereducated on cCMV infection. However, almost half of the participants could correctly recognize some basic principles of cCMV infection including ways of transmission, diagnosis and treatment, while there were aspects of cCMV infection with knowledge deficit. The year of study had a positive impact on the level of knowledge with students of higher years of study being of more sufficient education on the specific topic. Conclusion: Overall, our study indicates a discrepancy between self-reported awareness and the level of knowledge among medical students in Greece. Further educational opportunities about cCMV should be offered, particularly in areas of the curriculum involving the care of women and children. Establishing medical students' solid background on the disease burden and educating them about preventative strategies for at-risk populations, should be the main pillars of such efforts in order to promote confidence in managing these cases in their future professional careers.

Classification and Special Nutritional Needs of SGA Infants and Neonates of Multiple Pregnancies.

Data regarding the nutritional management of preterm small for gestational age (SGA) infants are scarce. In the recent report of ESPGHAN, the recommended energy for very preterm infants during hospitalization has been increased, yet this may not fit the needs of all preterm infants. It is important to distinguish fetal growth-restricted (FGR) infants from constitutional SGA infants, as well as preterm SGA from preterm AGA infants, since they may have different nutritional needs. Preterm FGR infants, and specifically infants < 29 weeks' gestation, accumulate nutrient deficits due to intrauterine malnutrition, prematurity, morbidities, delayed initiation of feeding, and feeding intolerance. Therefore, these infants may need more aggressive nutrition for optimal catch-up growth and neurologic development. However, a balance should be kept between optimal and excessive catch-up growth, since the combination of intrauterine malnutrition and excessive postnatal growth has been linked with later adverse metabolic consequences. Furthermore, multiple gestation is often complicated by FGR and prematurity. There is controversy in the definition of FGR in multiple gestations, and it should be noted that FGR in multiple gestation usually differs etiologically from FGR in singletons. The aim of this review is to summarize existing knowledge regarding the nutritional needs of preterm FGR and FGR infants of multiple gestation.

Fighting Antimicrobial Resistance in Neonatal Intensive Care Units: Rational Use of Antibiotics in Neonatal Sepsis.

Antibiotics are the most frequently prescribed drugs in neonatal intensive care units (NICUs) due to the severity of complications accompanying neonatal sepsis. However, antimicrobial drugs are often used inappropriately due to the difficulties in diagnosing sepsis in the neonatal population. The reckless use of antibiotics leads to the development of resistant strains, rendering multidrug-resistant pathogens a serious problem in NICUs and a global threat to public health. The aim of this narrative review is to provide a brief overview of neonatal sepsis and an update on the data regarding indications for antimicrobial therapy initiation, current guidance in the empirical antimicrobial selection and duration of therapy, and indications for early discontinuation.

Serum PCSK9 levels in infants with deviant birth weight: a biomarker of the lipoprotein metabolism.

OBJECTIVE: Proprotein Convertase Subtilisin/Kexin-Type 9 (PCSK9), a modulator of low-density lipoprotein (LDL) cholesterol metabolism, has been reported to be a promising biomarker for evaluating lipoprotein metabolism; however, evidence in infants is limited. In the current study, we sought to investigate potential differences in serum PCSK9 levels between infants with deviant birth weight and controls. METHODS: We enrolled 82 infants, classified into 33 small (SGA), 32 appropriate (AGA), and 17 large for gestation (LGA) infants. Serum PCSK9 was measured on routine blood analysis within the first postnatal 48 h. RESULTS: PCSK9 was significantly higher in SGA as compared to AGA and LGA infants [322 (236-431) as compared to 263 (217-302) and 218 (194-291) ng/ml respectively, p = .011]. In comparison to term AGA infants, PCSK9 was significantly elevated in preterm AGA and SGA infants. We also found a significantly higher level of PCSK9 in term female SGA infants as compared to term male SGA infants [325 (293-377) as compared to 174 (163-216) ng/ml, p = .011]. PCSK9 was significantly correlated with gestational age (R = -0.404, p < .001), birth weight (R = -0.419, p < .001), total cholesterol (R = 0.248, p = .028) and LDL cholesterol (R = 0.370, p = .001). SGA status (OR 2.56, p = .004, 95% CI 1.83-4.28) and prematurity (OR 3.10, p = .001, 95% CI 1.39-4.82) were strongly related to serum PCSK9 levels. CONCLUSION: PCSK9 levels were significantly associated with total and LDL cholesterol. Moreover, PCSK9 levels were higher in preterm and SGA infants, suggesting that PCSK9 might be a promising biomarker for evaluating infants with increased later cardiovascular risk.HighlightsWhat's already known? Proprotein Convertase Subtilisin/Kexin-Type 9 (PCSK9) is a promising biomarker for evaluating lipoprotein metabolism; however, evidence in infants is limited. Infants that were born with a deviant birth weight have a unique lipoprotein metabolism profile.What this study adds? Serum PCSK9 levels were significantly associated with total and LDL cholesterol. PCSK9 levels were higher in preterm and small for gestation infants, suggesting that PCSK9 might be a promising biomarker for evaluating infants with increased later cardiovascular risk.

Are the current feeding volumes adequate for the growth of very preterm neonates?

Postnatal growth failure, a common problem in very preterm neonates associated with adverse neurodevelopmental outcome, has recently been shown not to be inevitable. There is a wide discussion regarding feeding practices of very preterm neonates, specifically regarding feeding volumes and nutrients supply to avoid postnatal growth failure. Current guidelines recommend an energy intake of 115­140 kcal /kg per d with a considerably higher upper limit of 160 kcal/kg per d. The feeding volume corresponding to this energy supply is not higher than 200 ml/kg in most cases. From the other side, randomised and observational studies used higher feeding volumes, and these were associated with better weight gain and growth, while no complications were noted. Taking into account the above, nutritional practices should be individualised in each very and extremely preterm infant trying to reduce postnatal growth failure, pointing out that available data are inconclusive regarding the effect of high-volume feeds on growth. Large clinical trials are necessary to conclude in the best feeding practices of very preterm neonates.

Psychometric properties of the Greek versions of the Pandemic-Related Pregnancy Stress Scale and the Pandemic-Related Postpartum Stress Scale and associated risk factors during the second year of the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has affected perinatal mental health. Reliable tools are needed to assess perinatal stress during pandemic situations. AIMS: To assess the psychometric properties of the Greek versions of the Pandemic-Related Pregnancy Stress Scale (PREPS) and the Pandemic-Related Postpartum Stress Scale (PREPS-PP) and to explore the associations between women's characteristics and perinatal stress during the second pandemic wave. METHODS: The PREPS and PREPS-PP were completed by 264 pregnant and 188 postpartum women, respectively, who also completed the State-Trait Anxiety Inventory (STAI) and the Edinburgh Perinatal Depression Scale (EPDS). RESULTS: The internal consistency was similar for PREPS and PREPS-PP. It was good for preparedness stress (a = 0.77 and α = 0.71, respectively) and infection stress (α = 0.83 for both scales) but low for positive appraisal (α = 0.46 and α = 0.41, respectively). Of the pregnant women, 55.33% and 55.27%, respectively, reported scores of ≥40 on STAI-S and STAI-T, and the respective percentages for the postpartum women were 47.34% and 46.80%. In addition, 14.39% of the pregnant women and 20.74% of the postpartum women scored ≥13 on the EPDS. Higher preparedness stress on PREPS and PREPS-PP was associated with primiparity (P = 0.022 and P = 0.021, respectively) and disrupted perinatal care (P = 0.069 and P = 0.007, respectively). In postpartum women, higher infection stress was associated with chronic disease (P = 0.037), primiparity (P = 0.02) and perceived risk of infection (P = 0.065). Higher score on infection stress was associated with disrupted perinatal care in both groups (P = 0.107 and P = 0.010, respectively). CONCLUSIONS: The Greek versions of PREPS and PREPS-PP are valid tools for the assessment of women at risk of perinatal stress during a health crisis.

Antibiotic Resistance and Biofilm Infections in the NICUs and Methods to Combat It.

Neonatal sepsis is an important cause of neonatal morbidity and mortality. A significant proportion of bacteria causing neonatal sepsis is resistant to multiple antibiotics, not only to the usual empirical first-line regimens, but also to second- and third-line antibiotics in many neonatal intensive care units (NICUs). NICUs have unique antimicrobial stewardship goals. Apart from antimicrobial resistance, NICUs have to deal with another problem, namely biofilm infections, since neonates often have central and peripheral lines, tracheal tubes and other foreign bodies for a prolonged duration. The aim of this review is to describe traditional and novel ways to fight antibiotic-resistant bacteria and biofilm infections in NICUs. The topics discussed will include prevention and control of the spread of infection in NICUs, as well as the wise use of antimicrobial therapy and ways to fight biofilm infections.

The role of serum vitamin 25(OH)D concentration in the Covid-19 pandemic in children.

The ongoing Coronavirus disease 19 (Covid-19) pandemic and associated mortality in children led to an effort to address risk factors and develop protective measures. Observational studies in adults showed that vitamin D deficiency is associated with Covid-19 severity. The aim of this review was to summarise data regarding the role of serum vitamin 25(OH)D concentration in the severity of Covid-19 and the associated multisystem inflammatory syndrome in children (MIS-C). Many studies noted lower concentrations of vitamin 25(OH)D in children with Covid-19 compared with healthy controls; however, studies that assessed vitamin 25(OH)D suboptimal concentrations as a risk factor for Covid-19 severity were scarce. There was no high-quality evidence that vitamin 25(OH)D concentrations are associated with Covid-19 severity. Similarly, for MIS-C, a few studies with a small number of patients found that vitamin D deficiency was associated with more severe MIS-C. Vitamin D has many immunomodulatory actions and is consumed in the immunomodulatory cells, especially in infections such as the Covid-19 which is associated with increased inflammation and cytokine storm. Therefore, decreased concentrations of plasma vitamin 25(OH)D have been proposed to be the result of vitamin use by immunomodulatory cells in severe Covid-19, rather than a predisposing factor. In conclusion, the available data cannot prove that vitamin D deficiency is a risk factor for severe Covid-19 disease. More studies, of prospective design, are needed to investigate the role of this marker independently of other risk factors.

The trends for the "trend toward significance" in the pediatric literature.

Purpose This study is to examine whether the term "trend toward statistical significance" is used to describe statistically nonsignificant results in biomedical literature. We examined articles published in five high-impact pediatric journals, including The Lancet Child & Adolescent Health, The Journal of Pediatrics, Early Human Development, Frontiers in Pediatrics, and BMC Pediatrics to identify manuscripts where a "trend" was used to describe a statistically nonsignificant result, from January 2020 to December 2021, and, furthermore, for The Journal of Pediatrics, Early Human Development, and BMC Pediatrics from January 2010 to December 2011. We detected that a "trend toward significance" was used to describe a statistically nonsignificant result at least once in 146 articles (2.7%) during the period between 2020 and 2021 and in 97 articles (4.0%) during the period between 2010 and 2011. We found no significant difference in the proportion of published articles with inappropriate use of "trend" across journals belonging to the first quartile of impact compared to the second quartile or across journals publishing under the subscription model or open access policy compared to journals publishing solely under the open access policy, in any period. The overall proportion of the inappropriate use of "trend" declined significantly between 2010 and 2011 to 2020 and 2021 (p = 0.002, RR 0.66 95% CI 0.51-0.86). CONCLUSION: "Trend" statements were sporadically used to describe statistically nonsignificant results across pediatric literature. The inappropriate use of "trend" to describe almost significant differences could be misleading, and "trend" should be reserved only when a specific statistical test for trend has been performed, or in relation to appropriate scientific definitions. WHAT IS KNOWN: •Previously, researchers have reported inappropriate use of "trend" in articles across anaesthesia or major oncology journals. •In many cases, hypothesized results that are close but not lower than the statistical significance threshold are emphasized as "almost" significant. WHAT IS NEW: •"Trend" statements were sporadically used to describe statistically nonsignificant results across pediatric literature. •Inappropriate use of  "trend" was similar in journals with a subscription model compared to those having an open access policy and decreased within a 10-year period.

Biomarkers of cardiovascular disease risk in the neonatal population.

The consistently high prevalence of cardiovascular disease (CVD) has urged the need for punctual and effective prevention. Extended research on this specific area has demonstrated the influence of fetal and neonatal periods on the risk of developing CVD in adulthood. Thus, the role of traditional and novel biological markers to the effective screening of CVD among the neonatal population is widely investigated. The objective of the present narrative review is to examine those neonatal biomarkers that may play a role in the development of CVD, to exhibit scientific data that appertain to their association with various perinatal conditions leading to CVD predisposition, and their potential role on prediction and prevention strategies. Multiple biomarkers, traditional and novel, have been mined across the studied literature. Adiposity, insulin resistance, altered lipid profile, inflammation, and endothelial dysfunction seem among the headliners of CVD. Even though various novel molecules have been studied, their clinical utility remains controversial. Therefore, it is quite important for the scientific community to find elements with strong predictive value and practical clinical use.

Gaucher Disease Type 2 Manifested as Hemophagocytic Lymphohistiocytosis in a Neonate in the COVID-19 Era.

BACKGROUND: A term neonate presented with persistent severe thrombocytopenia, elevated liver enzymes, conjugated hyperbilirubinemia, hepatosplenomegaly, and mild hypotonia. OBSERVATIONS: A thorough workup for infections, congenital thrombocytopenias, and neonatal malignancies was negative. Because of increased anti-SARS-CoV-2 IgG antibodies after maternal COVID-19, multisystem inflammatory syndrome of neonates was considered and intravenous immunoglobulin was administered. The clinical condition of the neonate deteriorated and due to laboratory evidence of hyperinflammation, hemophagocytic lymphohistiocytosis was suspected, and treatment with etoposide and dexamethasone was initiated with temporary stabilization. Gaucher disease type 2 was eventually diagnosed. CONCLUSION: Gaucher disease can rarely present in neonates as hemophagocytic lymphohistiocytosis.

A Narrative Review of the Ocular Manifestations in Noonan Syndrome.

PURPOSE: The purpose of this review is to provide an update on ophthalmological manifestations of Noonan Syndrome (NS). Emerging evidence has suggested that NS patients may present with a wide spectrum of ocular characteristics. Detailed investigation of genotype has revealed the diversity of related gene mutations. The potential association of genetic basis with clinical expressivity of phenotype remains a challenging aspect of this issue. METHODS: A literature search was performed in PubMed; we have analyzed prospective and retrospective cohort studies, case reports, and reference lists of retrieved articles until February 2021. We identified all papers referring to NS ocular manifestations referring to genotype and phenotype characteristics. RESULTS: A comprehensive update on ocular manifestations of NS patients indicates significant evidence for variability of genotype and phenotype features. Ophthalmologic features of NS are characterized by a wide spectrum of abnormalities; external ocular malformations, distortions of refraction, alignment, motilily, anterior and posterior ocular segment and visual impairment. Currently, a variety of pathogenic mutations in patients with NS have been investigated, while the nature of the genetic variants may determine expressivity. Albeit it remains a clinical diagnosis with variation in the progress of each NS phenotype. Although the available evidence that is needed to establish genotype-phenotype correlation as predicting factor in clinical practice is limited, it could aid risk assessment and patient management. CONCLUSION: A review of the existing literature sheds light on the ocular characteristics of NS. The current article discusses notable aspects of key publications on the topic, highlights the importance of the potential genotype-phenotype correlation in clinical practice, and proposes the need for further future research.

Gastric Volume Changes in Preterm Neonates during Intermittent and Continuous Feeding-GRV and Feeding Mode in Preterm Neonates.

Background: We aimed to evaluate gastric volume changes during intermittent milk feeds (IMF) and continuous milk feeds (CMF) in very premature neonates (VPN), with gastric residual volume (GRV) based on antral cross-sectional area (ACSA) measurements and to examine if there were differences in GRV between the two feeding methods. Methods: A randomized prospective clinical trial with crossover design was conducted in 31 preterm neonates (gestational age < 30 weeks). Gastric volume was assessed twice in each neonate (during IMF and CMF feeding), at 7 specific time points during a 2-h observation period by measuring ACSA changes via the ultrasound (U/S) method. Results: There was a significantly different pattern of gastric volume changes between the two feeding methods. GRV, expressed as the median percentage of ACSA measurement at 120 min relative to the higher ACSA measurement during IMF, was found to be 3% (range 0-25%) for IMF and 50% (range 15-80%) for CMF. Neonates fed with IMF had a shorter mean gastric emptying time compared to those fed with CMF (p = 0.0032). No signs of feeding intolerance were recorded in either group during the period of observation. Conclusions: Our results showed that gastric volume changes and gastric emptying time in VPN, based on ACSA measurement changes, depend on the milk feeding method. No gastrointestinal complications/adverse events were noted with GRV up to 80% with CMF.

Caffeine and Gastric Emptying Time in Very Preterm Neonates.

BACKGROUND: Caffeine has been commonly used for prevention and treatment of apnea-related symptoms in premature infants. However, its side effects have not been thoroughly studied. We investigated whether caffeine affects gastric motility in very-preterm (VP) neonates. METHODS: The study is a randomized crossover clinical trial. Twenty-two neonates with mean birth weight (BW) (standard deviation-SD) 1077 (229) g and mean gestational age (GA) (SD) 28.6 (2.1) weeks were recruited. Each neonate had its gastric emptying time checked twice with ultrasound assessment of changes in antral cross sectional area (ACSA). All neonates were sequentially allocated to the caffeine group (A) and the control group (B). Complications from the gastrointestinal tract were documented throughout the study. RESULTS: Statistically significant difference was found with regards to the gastric emptying time [median, (range)] between caffeine and control group (p = 0.040). Additionally, in the neonates with BW 1000-1500 g and GA ≥ 28 weeks, the gastric emptying time (minutes) was significantly longer during caffeine treatment [44.5 (36-68.2)] and [40 (34.5-66.5)] respectively, as compared to the gastric emptying time during no caffeine treatment [27 (24.2-30)] (p = 0.002) and [27 (24.5-30)] (p = 0.001). The incidence of gastrointestinal (GI) complications was significantly greater in neonates receiving caffeine [6 (27.%)] as compared with those without caffeine treatment [1 (4.6%)] (p = 0.039). CONCLUSIONS: During caffeine treatment, a significantly delayed gastric emptying time was noted in all study neonates, especially in these with BW 1000-1500 g and those with GA ≥ 28 weeks. Further larger studies are necessary in order to confirm this interesting finding.

Safety of medical interventions in children versus adults.

OBJECTIVE: Compare the risk of harm from pharmacologic interventions in pediatric versus adult randomized controlled trials (RCTs). METHODS: We used systematic reviews from the Cochrane Database of Systematic Reviews. We considered separately 7 categories of harms/harm-related end points: severe harms, withdrawals due to harms, any harm, organ system-level harms, specific harms, withdrawals for any reason, and mortality. Systematic reviews with quantitative synthesis from at least 1 adult and 1 pediatric RCT for any of those end points were eligible. We calculated the summary odds ratio (experimental versus control intervention) in adult and pediatric trials/meta-analysis; the relative odds ratio (ROR) in adults versus children per meta-analysis; and the summary ROR (sROR) across all meta-analyses for each end point. ROR <1 means that the experimental intervention fared worse in children than adults. RESULTS: We identified 176 meta-analyses for 52 types of harms/harm-related end points with 669 adult and 184 pediatric RCTs. Of those, 165 had sufficient data for ROR estimation. sRORs showed statistically significant discrepancy between adults and children only for headache (sROR 0.82; 95% confidence interval 0.70-0.96). Nominally significant discrepancies for specific harms were identified in 12 of 165 meta-analyses (RORs <1 in 7, ROR >1 in 5). In 36% of meta-analyses, the ROR estimates suggested twofold or greater differences between children and adults, and the 95% confidence intervals could exclude twofold differences only in 18% of meta-analyses. CONCLUSIONS: Available evidence on harms/harm-related end points from pharmacologic interventions has large uncertainty. Extrapolation of evidence from adults to children may be tenuous. Some clinically important discrepancies were identified.