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Cytomegalovirus (CMV) is the most frequent cause of congenital infection worldwide, with an estimated incidence in developed countries of 0.6–0.7% of all live births. The burden of disease related to congenital CMV in substantial, as it is the leading non-genetic cause of sensorineural hearing loss and an important cause of neurodevelopmental disabilities in children. Despite its clinical significance, congenital CMV infection often goes undetected because the majority of infected infants are asymptomatic at birth and screening programs have not been substantially implemented. Other than behavioral measures, effective interventions aimed at the prevention of maternal infection and of mother-to-child transmission are lacking. Due to a convergence of recent advances in both diagnostic and therapeutic strategies in infants with congenital CMV, though, the field likely will be changing rapidly over just the next few years. Specifically, a highly-sensitive screening test with high throughput potential has been developed, and treatment of infants symptomatically infected with congenital CMV has proven to be well-tolerated and effective in improving long-term hearing and neurodevelopmental outcomes. This review highlights the clinical importance of congenital CMV infection, the developments in laboratory diagnostics, and the benefits of antiviral therapy. It also identifies the global efforts still required in the prevention of maternal infection and in the optimization of antiviral therapy to further reduce the burden of congenital CMV disease.

Abstract Background Viral loads (VLs) frequently are followed during treatment of symptomatic congenital cytomegalovirus disease, but their predictive value is unclear. Methods Post hoc analysis of 2 antiviral studies was performed. Seventy-three subjects were treated for 6 weeks and 47 subjects were treated for 6 months. Whole blood VL was determined by real-time polymerase chain reaction before and during therapy. Results Higher baseline VL was associated with central nervous system involvement (3.82 log, range 1–5.65 vs 3.32 log, range 1–5.36; P = .001), thrombocytopenia (3.68 log, range 1–5.65 vs 3.43 log, range 1–5.36; P = .03), and transaminitis at presentation (3.73 log, range 1–5.60 vs 3.39 log, range 1–5.65; P = .009), but with overlap in the amount of virus detected between groups. In subjects treated for 6 months, lower VL at presentation correlated with better hearing outcomes at 12 months, but VL breakpoints predictive of hearing loss were not identified. Sustained viral suppression during 6 months of therapy correlated with better hearing outcomes at 6, 12, and 24 months (P = .01, P = .0007, P = .04), but a majority without viral suppression still had improved hearing. Conclusions In infants with symptomatic congenital cytomegalovirus disease, higher whole blood VL before initiation of antiviral therapy has no clinically meaningful predictive value for long-term outcomes. In symptomatic congenital CMV infection, higher blood viral load before therapy correlates with thrombocytopenia, transaminitis, and CNS involvement but has little predictive value for long-term outcome. Early and sustained viral suppression during therapy may correlate with a better hearing outcome.

The detrimental effects of oxidative stress (OS) can start as early as after conception. A growing body of evidence has shown the pivotal role of OS in the development of several pathological conditions during the neonatal period, which have been therefore defined as OS-related neonatal diseases. Due to the physiological immaturity of their antioxidant defenses and to the enhanced antenatal and postnatal exposure to free radicals, preterm infants are particularly susceptible to oxidative damage, and several pathophysiological cascades involved in the development of prematurity-related complications are tightly related to OS. This narrative review aims to provide a detailed overview of the OS-related pathophysiological mechanisms that contribute to the main OS-related diseases during pregnancy and in the early postnatal period in the preterm population. Particularly, focus has been placed on pregnancy disorders typically associated with iatrogenic or spontaneous preterm birth, such as intrauterine growth restriction, pre-eclampsia, gestational diabetes, chorioamnionitis, and on specific postnatal complications for which the role of OS has been largely ascertained (e.g., respiratory distress, bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, necrotizing enterocolitis, neonatal sepsis). Knowledge of the underlying pathophysiological mechanisms may increase awareness on potential strategies aimed at preventing the development of these conditions or at reducing the ensuing clinical burden.

Background Respiratory Syncytial Virus (RSV) is the most important cause of severe respiratory infections in infants with seasonal epidemics. Environmental factors (temperature, humidity, air pollution) could influence RSV epidemics through their effects on virus activity and diffusion. Methods We conducted a retrospective study on a paediatric population who referred to our Paediatric Emergency Unit in order to analyze the correlation between weekly incidence of RSV positive cases during winter season in Bologna and meteorological factors and air pollutants concentration. Results We observed a significant correlation between the incidence of RSV infections and the mean minimum temperature registered during the same week and the previous weeks. The weekly number of RSV positive cases was also correlated to the mean PM 10 concentration of the week before. Conclusions RSV epidemic trend in Bologna (Italy) is related to the mean minimum temperature, and the mean PM 10 concentration.

Necrotizing enterocolitis (NEC) is a gut inflammatory disorder which constitutes one of the leading causes of morbidity and mortality for preterm infants. The pathophysiology of NEC is yet to be fully understood; several observational studies have led to the identification of multiple factors involved in the pathophysiology of the disease, including gut immaturity and dysbiosis of the intestinal microbiome. Given the complex interactions between microbiota, enterocytes, and immune cells, and the limited access to fetal human tissues for experimental studies, animal models have long been essential to describe NEC mechanisms. However, at present there is no animal model perfectly mimicking human NEC; furthermore, the disease mechanisms appear too complex to be studied in single-cell cultures. Thus, researchers have developed new approaches in which intestinal epithelial cells are exposed to a combination of environmental and microbial factors which can potentially trigger NEC. In addition, organoids have gained increasing attention as promising models for studying NEC development. Currently, several in vitro models have been proposed and have contributed to describe the disease in deeper detail. In this paper, we will provide an updated review of available in vitro models of NEC and an overview of current knowledge regarding its molecular underpinnings.

Congenital cytomegalovirus (CMV) infection is the main cause of non-hereditary sensorineural hearing loss (SNHL). In order to shed light on SNHL pathophysiology, we examined the auditory pathway in CMV-infected fetuses; the temporal lobe, in particular the auditory cortex, and the inner ear. We investigated both inner ears and temporal lobes of 20 human CMV-infected fetuses at 21 weeks of gestation. As a negative group, five fetuses from spontaneous miscarriages without CMV infection were studied. Inner ears and temporal lobes were histologically examined, immunohistochemistry for CMV and CMV-PCR were performed. On the auditory cortex, we evaluated the local microglial reaction to the infection. CMV-positive cells were found in 14/20 brains and the damage was classified as severe, moderate, or mild, according to histological features. Fetuses with severe brain damage had a statistically higher temporal lobe viral load and a higher number of activated microglial cells in the auditory cortex compared to fetuses with mild brain damage (p: 0.01; p: 0.01). In the inner ears, the marginal cells of the stria vascularis were the most CMV positive. In our study, CMV affected the auditory pathway, suggesting a tropism for this route. In addition, in the auditory cortex, microglial activation may favor further tissue damage contributing to hearing loss.

BackgroundThe thermal servo-controlled systems are routinely used in neonatal intensive care units (NICUs) to accurately manage patient temperature, but their role during the immediate postnatal phase has not been previously assessed.ObjectiveTo compare two modalities of thermal management (with and without the use of a servo-controlled system) immediately after birth.Study design and settingMulticentre, unblinded, randomised trial conducted 15 Italian tertiary hospitals.ParticipantsInfants with estimated birth weight <1500 g and/or gestational age <30+6 weeks.InterventionThermal management with or without a thermal servo-controlled system during stabilisation in the delivery room.Primary outcomeProportion of normothermia at NICU admission (axillary temperature 36.5°C–37.5°C).ResultsAt NICU admission, normothermia was achieved in 89/225 neonates (39.6%) with the thermal servo-controlled system and 95/225 neonates (42.2%) without the thermal servo-controlled system (risk ratio 0.94, 95% CI 0.75 to 1.17). Thermal servo-controlled system was associated with increased mild hypothermia (36°C–36.4°C) (risk ratio 1.48, 95% CI 1.09 to 2.01).ConclusionsIn very low birthweight infants, thermal management with the servo-controlled system conferred no advantage in maintaining normothermia at NICU admission, while it was associated with increased mild hypothermia. Thermal management of preterm infants immediately after birth remains a challenge.Trial registration number NCT03844204

Abstract Background Sensorineural hearing loss (SNHL) and neurodevelopmental (ND) outcomes are favorably impacted by antiviral therapy in infants with symptomatic cCMV disease. We correlated blood VL before and during therapy with clinical findings at presentation and follow-up in this population. Methods Post-hoc analysis of two clinical trials conducted by the CASG from 2002 to 2013 evaluating valganciclovir therapy. 120 subjects (73 treated × 6 weeks, 47 treated × 6 months) were included. Whole blood VL was determined by real-time PCR at a central laboratory before therapy (baseline, BL) and periodically for 6 months. Results In subjects treated for 6 months, increases in BL VL correlated with decreased probability of better hearing outcomes at 12 months (Figure 1), but clinically meaningful VL thresholds that predict SNHL were not identified (Table 1). Subjects treated for 6 weeks had no correlation between BL VL and SNHL. No correlation was found between BL VL and Bayley ND testing at 12 and 24 months for subjects receiving either treatment duration. Subjects treated for 6 months who achieved and sustained VL suppression (<2.5 log) between treatment day 14 and month 4 had better hearing outcomes at 6, 12, and 24 months (89% vs. 56%, P = 0.01; 100% vs. 63%, P = 0.0007; 94% vs. 68%, P = 0.04), but 56%–68% of subjects not achieving suppression still had improved hearing. Higher BL VL correlated with BL CNS involvement, thrombocytopenia, and transaminase elevation for subjects receiving either treatment duration, but with substantial overlap in quantity of virus detected (Figure 2). Subjects with >3 symptoms of congenital CMV at presentation had higher BL VL than subjects with ≤3 symptoms (3.75 log, range 1.00–5.65, vs. 3.38 log, range 1.00–5.36; P = 0.005). Conclusion Blood VL at BL and during therapy has little clinically meaningful predictive value for long-term outcomes in symptomatic congenital CMV. Table 1 Hearing outcome BL VL (log genome equivalent/ml) Improved/protected (no.) Others (no.) P-value Negative predictive value (CI) Positive predictive value (CI) 12 months >3 43 20 0.10 93 (79–100) 32 (20–43) ≤3 13 1 >4.5 8 9 0.01 80 (70–90) 53 (29–77) ≤4.5 48 12 24 months >3 42 14 0.72 83 (62–100) 25 (14–36) ≤3 10 2 >4.5 10 5 0.32 79 (68–90) 33 (9–57) ≤4.5 42 11 Figure 1 Figure 2 Disclosures J. Englund, Gilead: Consultant and Investigator, Research support; Chimerix: Investigator, Research support; Alios: Investigator, Research support; Novavax: Investigator, Research support; MedImmune: Investigator, Research support; GlaxoSmithKline: Investigator, Research support