Search Results (2,141)

Pregnancies complicated by diabetes, including pregestational and gestational diabetes mellitus, are associated with increased maternal and fetal morbidity. Early identification of at-risk pregnancies is crucial for timely intervention and improved outcomes. Emerging evidence highlights the interplay of genetic predisposition, epigenetic modifications, and non-invasive biomarkers in the early detection of diabetic pregnancies. Genetic factors influencing insulin signaling, glucose metabolism, and pancreatic β-cell function may contribute to susceptibility to gestational hyperglycemia. Concurrently, epigenetic alterations, such as DNA methylation and histone modifications in maternal and placental tissues, have been linked to dysregulated metabolic pathways and adverse pregnancy outcomes. Non-invasive biomarkers, including circulating cell-free DNA and microRNAs in maternal blood, show promise for early diagnosis by offering a safer and more practical alternative to invasive testing. Integrating genetic, epigenetic, and molecular marker data could enhance risk stratification and enable personalized monitoring and management strategies. This review synthesizes current knowledge on the molecular underpinnings of diabetic pregnancies, evaluates the potential of emerging biomarkers for early diagnosis, and discusses the challenges and future perspectives for translating these findings into clinical practice. Understanding these mechanisms may pave the way for precision medicine approaches, ultimately improving maternal and neonatal outcomes in pregnancies affected by diabetes. Full article

Background/Objectives: The Bicêtre score for Vein of Galen Aneurysmal Malformation (VGAM) relies on existing end-organ damage. We hypothesized that transthoracic echocardiography (TTE) could quantify significant systemic steal in clinically stable neonates (Bicêtre score ≥ 12). This study evaluates the Aortic Flow Reversal Ratio (AoFRr) as a tool to measure this steal and predict treatment outcomes. Methods: In a single-center retrospective study of patients with VGAM, the AoFRr (the ratio of the diastolic reversal velocity time integral to the systolic forward volume time integral) was calculated via TTE in the abdominal aorta at the level of the diaphragm before and after endovascular embolization. Over the study period, the cohort underwent a total of 30 endovascular interventions and 49 TTEs. Pre-intervention AoFRr was correlated with the Bicêtre score, and post-intervention changes were analyzed for association with the need for subsequent embolizations. Results: In a cohort of 12 patients with a median Bicêtre score of 18, 83.3% had pre-intervention aortic diastolic flow reversal. The median pre-intervention AoFRr was 0.81, indicating substantial systemic steal despite clinical stability. A post-intervention AoFRr reduction of ≥85% was significantly associated with a lower likelihood of requiring re-intervention (p = 0.0253). Conclusions: The AoFRr quantifies substantial hemodynamic steal in VGAM patients who appear clinically stable by the Bicêtre score. Its reduction following embolization predicts a more favorable clinical course. The AoFRr is a valuable, non-invasive adjunct for risk stratification and may help optimize the timing of endovascular intervention. Full article

Background: Postnatal growth failure in very preterm infants remains a major concern in neonatal care and clinical management is complicated by the lack of a standardized definition. This study aims to identify risk factors for growth faltering (GF) and undernutrition (UN) at hospital discharge, defined according to the latest consensus definitions established by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Methods: We conducted a retrospective observational study of 416 preterm infants (gestational age < 32 weeks and/or birth weight < 1500 g). Growth was monitored using the Intergrowth 21st standards. In line with ESPGHAN criteria, GF was defined longitudinally as a weight for age (WFA) z-score decline ≥ 1 SD from birth, while UN was defined cross-sectionally as a WFA or length for age z-score < −2 SD at discharge. Logistic regression models were used to determine independent predictors for both growth phenotypes. Results: At discharge, the prevalence of GF and UN was 45.3% and 33.1%, respectively. In infants born without growth restriction (GR), UN was almost entirely driven by GF (89.7%). In contrast, 85.5% of infants born with GR remained undernourished at discharge. Multivariate analysis identified bronchopulmonary dysplasia and higher maximal postnatal weight loss as major independent risk factors for GF, while female sex and human milk feeding at discharge were associated with a lower risk of GF. For infants born with adequate weight, maternal hypertension, extremely low birth weight, and the co-occurrence of GF were the strongest predictors of UN. Conclusions: Nearly half of very preterm infants experience significant growth impairment before discharge. By assessing the dynamic process of GF and the static endpoint of UN, we identified distinct clinical trajectories. Standardized ESPGHAN criteria allow for the identification of high-risk “phenotypes”—particularly those with GR at birth or severe neonatal morbidity—enabling more targeted and intensive nutritional management during the critical developmental window. Full article

Background: Antibiotic overuse in Neonatal Intensive Care Units (NICUs) is a major contributor to antimicrobial resistance and adverse neonatal outcomes. This study aims to evaluate baseline antibiotic utilization (AU), identify factors influencing variability, and assess the impact of neonatal characteristics and sepsis incidence. Methods: A multicenter retrospective analysis examined AU in seven NICUs from 2019 to 2023, involving 25,532 neonatal admissions during national antibiotic stewardship program implementation. Data encompassed neonatal clinical parameters, sepsis incidence, and AU metrics, including days of therapy (DOT) per 1000 patient-days. Statistical analyses included correlation assessments and multivariate regression to identify determinants of antibiotic use. Results: Overall, 43.8% of neonates received antimicrobials, with individual NICUs ranging from 24% to 73% (p < 0.001). Antimicrobial-exposed neonates had a mean gestational age of 35.1 weeks [SD ± 4.4] and a mean birth weight of 2360 g [SD ± 970]. Antimicrobial-exposed neonates were generally more premature [35.5 (±4.4) weeks vs. 37.5 (±2.5) weeks (p < 0.001)] and had lower mean birth weight [2360 g (±971) vs. 2817 g (±686) (p < 0.001)] compared to those not exposed to antimicrobials. Total antimicrobial days varied markedly (12,998 to 37,683 days), with DOT per 1000 patient-days ranging from 322 to 1031. Antimicrobial use for culture-negative sepsis varied widely among centers, from 23% to 71%. Antimicrobial-exposed neonates had higher all-cause mortality compared to those who did not [(7.5% vs. 3.2%), (p < 0.001)]. Multivariate analysis revealed individual NICU practice patterns remained significant predictors after adjusting for neonatal characteristics. Conclusions: Neonatal antimicrobial use varied significantly among NICUs, driven primarily by institutional practices rather than neonatal demographics. These findings provide nationally representative baseline data to inform neonatal antimicrobial stewardship interventions and offer transferable lessons for other countries seeking to optimize antibiotic use in NICUs amid rising global antimicrobial resistance. Full article

Background/Objectives: Digoxin is a cardiotonic agent with a narrow therapeutic window and a high risk of toxicity. The current clinical use is based on an empirically FDA-recommended regimen which has wide dosing ranges, introducing the risk of inappropriate dosing and related adverse events. This study aims to develop a physiologically based pharmacokinetic (PBPK) model to characterize digoxin pharmacokinetics in adult and pediatric patients with heart failure, and then to evaluate the FDA-recommended regimen. Methods: The PBPK model was initially developed in healthy adults using PK-Sim^®. Then, it was translated to adults with heart failure by incorporating disease factors. Next, it was further translated to pediatrics by scaling age-related parameters. Finally, through two-step translations, the model was used to evaluate current dosing regimens to inform safety and effectiveness based on observing predicted trough concentrations at a steady state. Results: This PBPK model has strong predicting ability, where observed concentrations and key PK metrics (C_max, AUC_0-t) were within 0.5–2.0-fold of predictions in healthy adults, adults with heart failure, neonates, and infants. The model prediction work on the evaluation of recommended dosing regimens from the FDA shows that the current regimen may not achieve the lowest boundary of the therapeutic window (0.5–2 ng/mL) in neonates (0–30 days), whereas infants (1–2 months) and children (<18 years) are generally good within it. Conclusions: This PBPK model explained major physiological and pathological contributors to differences in digoxin pharmacokinetics across populations and showed good performance in pediatric extrapolation. It also pointed out the shortage of empirical dosing regimens for such a drug with a narrow therapeutic window. The model may assist in optimizing the pediatric dosing strategies of digoxin, and suggests that current neonatal dosing regimens need refinement. Full article

Background and Clinical Significance: Annular pancreas is a rare congenital anomaly in which pancreatic tissue partially or completely encircles the duodenum, potentially causing duodenal obstruction. Clinical presentation varies from asymptomatic cases to persistent vomiting, feeding intolerance, and failure to thrive, often leading to delayed diagnosis. Case Presentation: We report a 2-year and 10-month-old girl with a long-standing history of intermittent, recurrent vomiting since the neonatal period, without growth impairment or other alarming symptoms. Initial imaging suggested proximal duodenal dilation, with suspicion for superior mesenteric artery (SMA) syndrome. Endoscopy revealed mechanical obstruction at the second portion of the duodenum. Contrast-enhanced CT confirmed annular pancreas partially encircling the duodenum. The patient underwent duodeno-duodenostomy with an uneventful postoperative course and complete resolution of symptoms. This case illustrates the diagnostic challenges of annular pancreas in older children with atypical presentations. Multimodal imaging is crucial for accurate diagnosis. Surgical bypass remains the definitive treatment, offering excellent long-term outcomes. Conclusions: Persistent or recurrent vomiting in children, even without classic signs such as bilious vomiting or failure to thrive, should prompt consideration of annular pancreas. Early recognition and timely surgical intervention can prevent prolonged morbidity and ensure normal growth and development. Full article

Aims: The aim of this study was to evaluate clinical outcomes and identify predictors of mortality in preterm infants with respiratory distress syndrome (RDS) treated in a tertiary Pediatric Intensive Care Unit (PICU). Methods: This retrospective study included 86 preterm infants diagnosed with RDS and treated between January 2015 and December 2024. Clinical data were extracted from medical records and included demographic and anthropometric parameters, perinatal history, associated neonatal diagnoses, ventilation type and duration, surfactant administration, use of inotropes and antibiotics, cranial ultrasound findings, and PICU length of stay. Results: Mortality was 18.6%, with the highest rates observed in extremely preterm infants (<28 weeks) and those with extremely low birth weight (<1000 g). Several clinical variables were significantly associated with survival: gestational age, birth weight, birth length, and Apgar scores at 1 and 10 min (all p ≤ 0.005). In multivariable logistic regression, each additional week of gestation (OR 0.72, 95% CI 0.59–0.87), higher birth weight (OR 0.998, 95% CI 0.997–0.999), and higher Apgar scores (OR 0.69 at 1 min; OR 0.60 at 10 min) were significantly associated with survival. Ventilation was required in 97.7% of infants, and outcomes differed significantly by ventilation modality (p = 0.021), with the lowest mortality observed in those treated with combined invasive and non-invasive ventilation. Resuscitation (p < 0.001) and inotropic support (p < 0.001) were strongly associated with death. Length of PICU stay and duration of ventilation were significantly shorter in non-survivors (p < 0.05). Surfactant therapy was used in 79.1% of infants but was not significantly associated with survival. Conclusions: Gestational age, birth weight, and early postnatal condition were the strongest predictors of survival in preterm infants with RDS. Non-invasive and combined ventilation were associated with better outcomes, whereas the need for resuscitation and inotropes indicated markedly higher mortality. These results highlight the importance of early stabilization and optimized respiratory support in improving outcomes. Full article

Monogenic diabetes (MD) is a rare and heterogeneous group of disorders caused by genetic variants in genes involved in glucose metabolism. Among many MD genes, the insulin gene (INS) deserves special attention, as its variants are responsible for both permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM), as well as a form of MODY (maturity-onset diabetes of the young)—INS-MODY. The aim of the study was to perform a clinical and molecular analysis of patients focused on the evaluation of INS gene variants identified during molecular testing in patients referred with suspected MD, and to assess the prediction of their impact on protein structure using in silico methods. Between 2017 and 2024, 1043 unrelated probands were tested using targeted next-generation sequencing (tNGS) panels. Three pathogenic or likely pathogenic variants in the INS gene were identified in three unrelated families, indicating that this gene accounts for 0.38% of MD cases. This allowed for the diagnosis of PNDM in two patients with diabetes diagnosed within the first four months of life and INS-MODY in a patient with diabetes since the age of 16. Moreover, in the patient with PNDM and the INS:c.T104C variant, additional disorders were identified in the form of intrauterine growth restriction (IUGR) and neurological disorders. Importantly, two of the identified genetic variants, c.C103G and c.G3C, have not previously been described in the literature. Furthermore, in silico analysis of the variants at the protein level, i.e., investigation of mutations at the 35th residue, indicated that symptom severity correlates with the extent of structural changes in insulin. The results obtained broaden the spectrum of causative variants of the INS gene, but also emphasize the clinical significance of these variants in patients with various forms of diabetes, pointing to the key role of comprehensive genetic testing in enabling accurate diagnosis and targeted treatment of patients. Full article

Background/Objectives: Preterm birth remains a major cause of neonatal morbidity and mortality, particularly in multiple pregnancies and in cases of cervical shortening. While cervical cerclage is established in singleton pregnancies, its efficacy in multiple gestations remains uncertain. This study compares pregnancy and neonatal outcomes following second-trimester cerclage in singleton and multiple pregnancies with a short cervix. Methods: In this retrospective cohort study, 96 women underwent second-trimester cerclage at a tertiary perinatal center between 2020 and 2024. All had a cervical length ≤ 25 mm or prolapsed membranes without infection or premature rupture. Primary outcomes included term delivery rate, gestational age, mode of delivery, and neonatal outcomes; secondary outcomes comprised surgical complications and rehospitalization, defined as the need for renewed inpatient care due to threatened preterm labor or procedure-related complications. Results: In total, 79 singleton and 17 multiple pregnancies were analyzed. Term delivery occurred more often in singletons (54%) than multiples (18%, p = 0.006). Mean gestational age at birth was 258 ± 25 days in singletons versus 228 ± 28 days in multiples (p < 0.001). Birth weight was significantly lower in multiples (1985 g vs. 2943 g; p < 0.001), and neonatal infections were more frequent (53% vs. 26%; p = 0.008). Caesarean delivery was more common in multiples (82% vs. 33%; p < 0.001). Apart from increased postoperative contractions in multiples (24% vs. 5%; p = 0.031), complication rates and rehospitalization (27% vs. 29%; p = 0.8) were similar. Conclusions: Second-trimester cerclage is less effective in preventing preterm birth in multiple pregnancies compared to singleton pregnancies; however, it appears to be associated with a stabilizing clinical course and may facilitate outpatient management in selected high-risk cases. These findings support individualized counseling and shared decision-making, particularly in multifetal gestations. Full article

The closure of rural maternity units in hospitals across the United States contributes to health inequities; however, little is known about the effects of reopening maternity services in this context. We conducted a mixed-methods study to characterize labor and delivery outcomes and patient experiences associated with the reopening of a rural Level 1 Maternity Care Center (MCC) at a critical access hospital. We compared clinical outcomes and distance to care for patients who gave birth at the rural MCC in the three years after its opening with outcomes from a similar low-risk and geographically located sample who gave birth at a large suburban academic medical center in the same hospital system in the three years before the MCC reopened. We also conducted in-depth interviews with patients who gave birth at the MCC. Labor and delivery outcomes were similar across both groups, with significantly more care provided by family physicians and midwives and lower neonatal intensive care unit use at the MCC. The opening of the MCC halved the distance patients traveled to give birth, and patients reported high rates of satisfaction. Rural maternity care centers can improve access to quality care closer to home using a resource-appropriate model. Full article

Mammarenaviruses (MaAv) cause persistent infection in their natural rodent hosts across the world and, via zoonotic events, can cause severe disease in humans. Thus, the MaAv Lassa virus (LASV) in Western Africa and the Junin virus (JUNV) in the Argentinean Pampas cause hemorrhagic fever diseases with significant case fatality rates in their endemic regions. In addition, the globally distributed MaAv lymphocytic choriomeningitis virus (LCMV) is an underrecognized human pathogen of clinical significance capable of causing devastating infections in neonates and immunocompromised individuals. Despite their impact on human health, there are currently no FDA-approved vaccines or specific antiviral treatments for MaAv infections. Existing anti-MaAv therapies are limited to the off-label use of ribavirin, whose efficacy remains controversial; hence, the development of novel therapeutics to combat human pathogenic MaAv is vital. We employed a high-throughput cell-based infection assay to screen the Pandemic Response Box, a collection of 400 diverse compounds with established antimicrobial activity, for MaAv inhibitors. We identified Ro-24-7429, an antagonist of the HIV-1 Tat protein and RUNX family transcription factor 1 inhibitor; WO 2006118607 A2, a dihydroorotate dehydrogenase inhibitor; and verdinexor, a novel selective inhibitor of nuclear export (SINE) targeting the XPO1/CRM1, as potent anti-MaAv compounds. Consistent with their distinct validated targets, verdinexor and WO 2006118607 A2 exhibited very strong synergistic antiviral activity when used in combination therapy. Our findings pave the way for the development of verdinexor as a potent host-directed antiviral against MaAv, which could be integrated into the development of combination therapy with direct- or host-acting antivirals to combat human pathogenic MaAv. Full article

(1) Background: Neonatal sepsis continues to be one of the leading causes of mortality and morbidity, particularly in underdeveloped countries. We aimed to compare laboratory parameters between clinical early-onset sepsis (clinEOS) and NNNon-clinEOS groups and to evaluate the association between TLR2-Arg753Gln, TLR4-Asp299Gly, IL6-174G/C, and IL10-1082G/A gene single-nucleotide polymorphisms and clinical EOS susceptibility in preterm newborns. (2) Materials and Methods: Genotyping of the TLR2, TLR4, IL6, and IL10 polymorphisms was performed in 36 preterm neonates with polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (RFLP). Logistic regression analysis was used to test the associations between the studied gene polymorphisms and EOS susceptibility. (3) Results: Statistically significant differences in gestational age and birth weight were observed between the two groups, with preterm neonates with clinical EOS having a lower mean gestational age (mean (SD): 29.4 (2.8) weeks vs. 32.6 (1.1); p = 0.00002) and a lower mean birth weight (1342.1 (446.5) gr. Vs. 1984 (376.9)) than preterm neonates without clinical EOS. C-reactive protein (CRP) values measured on the first day significantly increased in the clinEOS group compared with the non-clinEOS group (median, 95% CI: 0.80 [0.40, 1.15] vs. 0.30 [0.02, 0.50]). The mean number of neutrophils significantly decreased in the preterm neonates with clinical EOS (mean difference: 17.3%; 95% CI: [4.0%, 30.5%]; p = 0.0126) and non-clinEOS group (mean difference: 20.8%; 95% CI: [1.8%, 39.9%]; p = 0.0354) between the first and seventh hospitalization days. In the dominant model, the A/G + A/A variant genotype of the IL10-1082G/A polymorphism significantly increased the odds of clinical EOS compared with the GG genotype (OR = 5.25; p = 0.0322), but the gestational-age-group adjusted model yielded p = 0.0752. (4) Conclusions: The results of the current study suggest that IL10-1082G/A gene polymorphism is a significant risk factor for clinical early-onset sepsis development in preterm neonates, but there was no evidence of a gestational age-group independent direct effect of IL10-1082G/A gene polymorphism on clinical EOS susceptibility. The results should be considered as exploratory. Full article

Background/Objectives: Neonatal Intensive Care Units (NICUs) constitute a highly complex clinical environment characterized by patient fragility and frequent ethically sensitive decisions. To date, systematic studies investigating how Italian NICUs address these challenges and what forms of ethics support are effectively available are lacking. The aim of this study is therefore to assess how ethical issues are managed in Italian NICUs, with particular attention to the availability, use, and perceived usefulness of clinical ethics support in everyday practice. Methods: A 25-item questionnaire was developed by adapting an existing tool for investigating clinical ethics activities to the neonatal context. Following expert review by the GIBCE (Gruppo Interdisciplinare di Bioetica Clinica e Consulenza Etica in ambito sanitario), the final instrument covered four areas (general data, experience with ethical dilemmas, tools and procedures, opinions and training needs). A manual web search identified all Italian NICUs and their clinical directors, who were asked to disseminate the survey among staff. Participation was voluntary and anonymous. Data collection was conducted via Google Forms and analyzed through qualitative thematic analysis. Results: A total of 217 questionnaires were collected. The most frequent ethical dilemmas concern quality of life with anticipated multiple or severe disabilities (72.4%) and decisions to withdraw or withhold life-sustaining treatments (64.5%). Major challenges include fear of medico-legal repercussions (57.6%) and communication divergences between physicians and nurses (49.8%). More than half of respondents (52.1%) reported no formal training in clinical ethics, and 68.7% had never developed a Shared Care Plan (Shared Document for healthcare ethics planning) as defined by the Italian Law 219/2017. Conclusions: Findings highlight marked fragmentation in ethical practices across Italian NICUs. On this basis, establishing structured and accessible CEC services could help promote consistency, reinforce shared ethical standards, and support transparent and equitable decision-making in critical neonatal care. Full article

Bovine Respiratory Disease (BRD) represents one of the largest causes of economic loss and animal morbidity in the global cattle industry, second only to neonatal diarrhea. Its etiology is complex, originating from a multifactorial combination of host susceptibility, environmental stressors, viral infections, and secondary bacterial pathogens. Although viruses are often the initial cause of disease, suppressing the host’s respiratory defense mechanisms, most of the severe pneumonic damage and clinical signs can be attributed to bacterial infections. This review provides an overview of the primary bacterial agents identified within the BRD complex, including Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis. We discuss their role as commensals that then become opportunistic pathogens, and further how they interact in a synergistic relationship with a primary viral insult, leading to the resulting pathogenesis and the development of pneumonia. This manuscript discusses in further detail some of the challenges in BRD management, such as the limitations of current diagnostic methodologies, overreliance on antimicrobial therapy, and the growing concern of antimicrobial resistance. Lastly, the need for integrated approaches in management, better husbandry and biosecurity, coupled with the development of novel therapeutic alternatives, is underlined as a means of assuring a sustainable control of this serious syndrome. Full article

Background: Red cell distribution width (RDW) and the RDW-to-platelet ratio (RPR) have emerged as readily available hematologic markers reflecting systemic inflammation in neonates with hypoxic–ischemic encephalopathy (HIE); however, their early postnatal trajectories across the clinical spectrum of HIE remain insufficiently characterized. Methods: This retrospective cohort study included 229 term or near-term infants diagnosed with HIE. Among them, 166 infants received therapeutic hypothermia, whereas 63 infants who did not undergo cooling served as the reference group. RDW and RPR values were measured at birth and at 72 h of life (after completion of cooling in the hypothermia group). Results: In the reference group, RDW values significantly decreased at 72 h, reflecting normal postnatal hematologic adaptation. In contrast, the hypothermia group demonstrated a blunted decline, with RDW levels remaining relatively stable over the first 72 h, consistent with a blunted early postnatal RDW decline. RPR values showed a mild, non-significant upward trend during the first 72 h of life; however, exploratory analyses suggested an association between higher RPR levels and increasing HIE severity. Conclusions: Across the spectrum of hypoxic–ischemic encephalopathy, RDW demonstrated a blunted postnatal decline, whereas RPR showed a mild, non-significant increase during the early neonatal period. These readily available hematologic markers may provide complementary insights into early systemic inflammatory and hematologic responses in HIE. Prospective multicenter studies are needed to determine their prognostic value and relationship with clinical and neurodevelopmental outcomes. Full article