Pediatric Research

Objectives: Using a nationally representative database of U.S. hospitalizations, we aimed to (1) characterize contemporary trends in hypoxic-ischemic encephalopathy (HIE) prevalence by severity, therapeutic hypothermia (TH) utilization, and associated in-hospital mortality; and (2) examine the association between TH and mortality by HIE severity and gestational age (GA), focusing on 35- and 36-weeks GA. Methods: We analyzed newborn hospitalizations from the National Inpatient Sample, 2016-2023. Unspecified, mild, moderate, and severe HIE were identified using ICD-10-CM diagnosis codes P91.60-P91.63; and 35- and 36-weeks GA using codes P07.38-P07.39. TH was identified using ICD-10-PCS codes 6A4Z0ZZ and 6A4Z1ZZ. Survey-weighted multivariable generalized linear models with marginal standardization were used to estimate adjusted mortality risk differences (RD) with surprisal (S) values, and assess whether associations between TH and mortality differed by HIE severity across GA strata. Results: Among 29,767,238 hospital discharges, HIE was identified in 66,535 neonates (2.24 per 1,000), and TH used in 19.2% of HIE cases. In-hospital mortality was 9.74% among all HIE cases and 6.65% among TH-treated neonates. From 2016-23, HIE prevalence nearly doubled (1.58 to 3.01 per 1,000; p-for-trend <0.001) and TH utilization more than doubled (0.33 to 0.74 per 1,000; p-for-trend <0.001), while TH use as a proportion of HIE remained stable (17.8%-20.8%; p-for-trend=0.39). HIE severity distribution was: mild (15%), moderate (29.4%), severe (18.3%), and unspecified (37.3%), with moderate HIE increasing over time (22.3%-33.5%). Crude mortality was consistently highest for severe HIE (range: 33.65%-35.25%). Among infants with severe HIE, TH was associated with reduced mortality overall (RD -10.12%; 95% CI -14.86, -5.39; p<0.001; S=15.12), and specifically at 36-weeks GA (RD -21.98%; 95% CI -35.85, -8.12; p=0.002; S=9.06), but not at 35-weeks (RD -1.83%; 95% CI -21.2, 17.55; p=0.86; S=0.22). Conclusions: TH was associated with mortality reduction in severe HIE overall and at 36-weeks GA, but this benefit remains uncertain at 35-weeks GA.

Objective: To identify factors associated with predischarge morbidity and mortality among small for gestational age infants. Study Design: We conducted a retrospective single-center cohort study of small for gestational age infants admitted to a level IV neonatal intensive care unit. We determined the association of clinical characteristics, congenital anomalies, and genetic disorders with the primary outcome of predischarge morbidity or mortality and characterized morbidity and mortality across congenital anomaly subgroups. Results: Among 293 small for gestational age infants, 18 (6.1%) had a genetic disorder and 103 (35.2%) had a major congenital anomaly, with congenital heart disease (CHD) representing the largest subgroup. The primary outcome of morbidity or mortality occurred in 93 infants (31.7%); 74 infants (25.3%) experienced morbidity and 19 (6.5%) died. CHD (adjusted odds ratio [aOR]: 16.5, 95% CI 6.44-45.7) and multiple congenital anomalies (aOR: 17.8, 95% CI 4.64-71.1) were found to be strongly associated with morbidity or mortality, after accounting for sex, maternal race, and intubation > 7 days. Statistically significant associations were also found with the presence of musculoskeletal anomalies as well as genetic disorders in infants without congenital anomalies, though in limited sample sizes. CHD was the largest contributor to morbidity, whereas multiple congenital anomalies accounted for the greatest proportion of mortality. Infants with abdominal wall defects and central nervous system anomalies experienced no morbidity or mortality. Conclusion: Congenital heart disease and multiple congenital anomalies were strongly associated with morbidity and mortality among SGA infants, whereas the degree of SGA alone was not. These findings suggest that risk is not explained by the degree of SGA alone and may be more strongly associated with congenital disease and other underlying factors.

Background and Purpose: Neonatal hypoxia-ischemia (NHI) is a leading cause of mortality and long-term neurodevelopmental disability. Therapeutic hypothermia (TH) is currently the only established treatment for NHI; however, its efficacy remains limited, underscoring the need for adjunctive neuroprotective strategies. Lactate is now regarded as a major metabolic substrate of the brain and has previously been shown to exert neuroprotective effects following experimental NHI. We investigated whether lactate enhances hypothermia-induced neuroprotection and evaluated the optimal timing of administration and potential underlying mechanisms. Methods: Postnatal day 7 Wistar rats were subjected to NHI using the Rice-Vannucci model and treated with TH alone (2h at 32{degrees}C), sodium L-lactate alone, or combined L-lactate-TH. Animals underwent longitudinal magnetic resonance imaging (MRI) and behavioral assessments, complemented by histological, immunohistochemical, and Western blot analyses, including assessment of protein lactylation. The effect of sodium L-lactate administration timing relative to TH was also evaluated. Results: Lactate significantly enhanced the neuroprotective effects of TH, particularly when administered before hypothermia, resulting in greater lesion recovery, reduced neuroinflammation and apoptotic cell death, preserved neuronal integrity, and improved long-term motor and cognitive outcomes. Combined treatment preserved neuronal lactate transporter, prevented NHI-induced astrocytic glutamate transporter upregulation, modulated lactylation markers, supporting coordinated metabolic and epigenetic adaptations following NHI. Conclusions: Early lactate administration enhances the neuroprotective efficacy of TH following NHI. These findings identify lactate as a promising adjunct to TH and support its translational potential as a metabolic strategy to improve outcomes following NHI brain injury.

Background: Infants <30 weeks gestational age (very preterm (VPT)), are at risk of experiencing multiple serious neonatal morbidities. These morbidities impart serious biological stress, which may be reflected in dysregulated protein expression even after the morbidities have resolved. Recent studies suggest that DNA methylation-based predictors of circulating proteins may reflect the molecular effects of neonatal adversity. The objective of this study is to examine associations between DNA methylation-derived EpiScores, which are externally trained methylation signatures that proxy circulating protein levels, and neonatal morbidity burden in children born VPT. Buccal DNA methylation was obtained at NICU discharge in 537 infants from the NOVI cohort. A total of 111 EpiScores were calculated and tested for association with multimorbidity (0-1 vs. [&ge;] 2 morbidities) using adjusted linear regression models. Cross-tissue analyses in an external paired blood-buccal dataset (n=21) were used to identify EpiScores with moderate-to-strong correlations across tissues. Results: Eighteen EpiScores were nominally associated with multimorbidity (p < 0.05), with Melanoma-derived growth regulatory protein (MIA) with FDR < 0.05 (beta = 0.0023, p = 0.0004). In cross-tissue analyses, 35 EpiScores yielded r > 0.50 (p<0.05), 11 of which showed nominal associations with multimorbidity, including MIA. Overall, the morbidity-associated EpiScores reflected immune, inflammatory, metabolic, and growth-related pathways. Conclusions: Buccal DNA methylation-derived EpiScores capture biological signatures associated with neonatal morbidity burden in very preterm infants.

Introduction: The TREOCAPA (Prophylactic TREatment Of the duCtus Arteriosus in Preterm infants by Acetaminophen) trial was a pan-European, multi-centre, phase II/III trial investigating the impact of prophylactic paracetamol (also known as acetaminophen) given during the first 5 days of life for children born before 29 weeks' gestational age (GA) on survival to 36 weeks' post-menstrual age without severe neonatal morbidities. However, due to time restrictions, long-term follow-up was not planned as part of the initial trial despite recommendations for neonatal trials to include endpoints measuring efficacy after discharge from the neonatal unit and on-going debate about the long-term effects of paracetamol in the neonatal period. This protocol describes a study to follow-up participants in the TREOCAPA trial at 2 years corrected age initiated after the trial's onset. Methods and analysis: The TREOCAPA Long Term (TREOCAPA-LT) study population consists of all children included in the TREOCAPA phase III trial in centres in countries participating in the follow-up study who are aged between 23.5 and 27.5 months corrected age during the study period. Families are contacted by the clinical teams and a parent or guardian is invited to complete an internet-based (online) questionnaire. The primary outcome is cognition, as measured by the non-verbal Cognitive Scale standard score from the Parent Report of Children's Abilities-Revised (PARCA-R) questionnaire. Secondary outcomes are moderate to severe neurodevelopment, health service use and costs. Data will be analysed according to the study groups to which children were randomised in the original TREOCAPA RCT. Ethics and Dissemination: The TREOCAPA-LT protocol was first approved by ethics' committees in France (the study's sponsor) and subsequently by all participating countries. Results from TREOCAPA-LT will be published in open access journals in accordance with the funder's regulations. Registration: https://clinicaltrials.gov/study/NCT06064825

Background: Vitamin B12 is essential for one-carbon metabolism, deoxyribonucleic acid (DNA) synthesis, and myelination, and inadequate maternal status during pregnancy may influence fetal growth and child neurodevelopment. Objective: To evaluate the association between maternal vitamin B12 status and perinatal and child neurodevelopmental outcomes. Methods: We conducted a systematic review and meta-analysis of observational studies and randomized clinical trials. The main outcomes were preterm birth, low birth weight, small for gestational age (SGA), and cognitive/global development. For binary outcomes, the natural logarithm of the relative risk (logRR) was the primary analytical effect measure; for neurodevelopment, Hedges g was used. Random-effects models were fitted, between-study variance was estimated by restricted maximum likelihood (REML), and inference used Knapp-Hartung (KH) adjustment. Results: For preterm birth, nine estimates yielded a pooled logRR of 0.190 (95% confidence interval [95% CI] KH: -0.046 to 0.427; p = 0.101; I2 = 19.2%). For low birth weight, nine estimates yielded a pooled logRR of 0.136 (95% CI KH: -0.013 to 0.286; p = 0.069; I2 = 4.8%). For SGA, six estimates yielded a pooled logRR of 0.047 (95% CI KH: -0.083 to 0.177; p = 0.397; I2 = 0%). Cognitive/global development, assessed in five independent studies, showed a pooled Hedges g of 0.266 (95% CI KH: 0.034 to 0.499; p = 0.034; I2 = 55.7%). Conclusions: logRR estimates for preterm birth and low birth weight were directionally compatible with higher risk among mothers with lower vitamin B12 availability, but their 95% CIs included the null. No consistent association was observed for SGA. Higher maternal vitamin B12 availability or supplementation was associated with a small favorable effect on cognitive/global development, with moderate heterogeneity.

Background: Infants with extremely low birth weight (ELBW) are at high risk for neurodevelopmental impairment, but the relationship between cerebellar structure and later developmental outcome remains incompletely defined. Methods: In this retrospective single-center study, we examined total cerebellar volume on clinically acquired brain magnetic resonance imaging (MRI) in ELBW infants while accounting for postmenstrual age (PMA) at imaging. Results: Of 65 infants screened, 42 were included. Mean gestational age at birth was 25.54 {+/-} 1.68 weeks, mean birth weight was 733.2 {+/-} 118.7 g, and mean PMA at MRI was 43.02 {+/-} 6.53 weeks (range, 31.57--68.00). Mean cerebellar volume was 22.17 {+/-} 9.63 cm. Independently adjudicated developmental outcomes comprised normal development in 16 infants, isolated or specific impairment in 12, and moderate/severe impairment in 14. Unadjusted cerebellar volumes did not differ across developmental groups (P = 0.490) or qualitative MRI categories (P = 0.875). However, the PMA-by-developmental-category interaction was significant (P = 0.002), with estimated cross-sectional slopes of 1.72, 1.56, and 0.39 cm per week, respectively. The interaction remained significant within 36--46 weeks PMA (n = 29; P = 0.011) and after adjustment for small-for-gestational-age (SGA) status. Sensitivity analyses indicated uncertainty in the stability of the interaction. Conclusions: These findings suggest that age-informed cerebellar volumetric patterns may provide developmental information not evident from average volumes alone and support prospective validation with standardized imaging and developmental assessments. As a result, cerebellar volumes obtained early in life may hold prognostic information for ELBW infants.

Abstract: Background: Children born very preterm (VPT) are at elevated risk for adverse neurobehavioral outcomes and are vulnerable to environmental exposures. We used untargeted metabolomics analysis to identify environmentally relevant metabolites associated with childhood behavioral problems and to characterize related endogenous metabolic pathways. Methods: We studied 226 children born <30 weeks gestation in a multi-site cohort study. Urine collected at age 4 was profiled using untargeted ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-HRMS). Associations between 30 exogenous environmental metabolites and behavioral problems score at age 4 were evaluated cross-sectionally using multivariable linear regression, followed by metabolome-wide association and pathway enrichment analyses. Results: Three exogenous metabolites were nominally associated with child behavior problems. Specifically, 2-(Acetylamino)-3-( henylthiol)propanoic acid was positively associated with overall ({beta}=1.42, p=0.006), externalizing ({beta}=1.50, p=0.006), and internalizing ({beta}=1.34, p=0.021) behavior problems. Diethofencarb was positively associated with overall ({beta}=0.34, p=0.018) and externalizing ({beta}=0.39, p=0.010) behavior problems, while protocatechuic acid was inversely associated with internalizing problems ({beta}=-0.68, p=0.027). No associations remained significant after false discovery rate (FDR) correction. Nevertheless, these metabolites were associated with 151, 131, and 530 endogenous metabolic features, respectively, at FDR<0.05, highlighting perturbations in lipid metabolism, mitochondrial energetics, inflammatory signaling, amino acid metabolism, and neuroactive pathways. Conclusions: Environmental metabolites associated with behavior problems were linked to broad endogenous metabolic differences relevant to neurodevelopment. These findings highlight potentially modifiable environmental influences, including exposures related to combustion-derived pollutants, pesticides, and dietary sources, that may contribute to behavioral vulnerability among children born very preterm

Objective: To investigate sex-specific associations between DNA methylation (DNAm) of neurodevelopmental, stress-response, and dopaminergic pathway genes and need for pharmacological treatment for Neonatal Opioid Withdrawal Syndrome (NOWS) among opioid-exposed newborns. Study Design: Buccal swabs were collected at birth from 181 infants in the multi-site Child and Family Study (CAFS). DNAm was measured via pyrosequencing at CpG sites within promoter regions of neurodevelopmental (BDNF), stress-response (AVP, NR3C1, OXTR, FKBP5, SLC6A4), dopaminergic (DRD2, DRD4), and opioid signaling (OPRM1) genes. Need for pharmacological treatment for NOWS was obtained from medical records. We estimated robust linear regression models to investigate sex-specific associations of DNAm and need for NOWS treatment. Estimated marginal means quantified sex-specific DNAm differences by treatment status. Results: After correction for multiple testing, five CpG sites within DRD4 were significantly associated with need for pharmacological treatment, with four sites showing higher DNAm in treated infants and one showing lower DNAm. Significant sex-specific associations were identified within DRD4 and AVP. Conclusions: Epigenetic variation across multiple biological pathways contributes to variability in NOWS severity among infants with prenatal opioid exposure. The relationship between epigenetic variation and need for NOWS treatment may vary depending on infant sex.

Background: Vitamin D modulates innate and adaptive immunity and has been investigated for preventing pediatric respiratory infections. Objective: To assess the effects of vitamin D supplementation on respiratory tract infections (RTIs), including upper RTIs, lower RTIs/recurrent pneumonia, and hospitalization/clinical severity in children and adolescents. Methods: Systematic review and random-effects meta-analysis of 16 publications, of which 13 contributed to quantitative synthesis. Twenty-four effect estimates were pooled, eight per outcome. The odds ratio (OR) was analyzed on its natural logarithmic scale (logOR), using restricted maximum likelihood (REML) estimation and Knapp-Hartung (KH) adjusted inference. Where necessary, risk ratios (RRs), hazard ratios (HRs), and incidence rate ratios (IRRs) were approximated on the logOR scale. Results: For respiratory infection/upper RTI, pooled logOR was -0.284 (KH-adjusted 95% confidence interval [CI]: -0.678 to 0.110; OR 0.753; p = 0.132; I2 = 97.2%). For lower RTI/recurrent pneumonia, logOR was -0.445 (95% CI: -0.987 to 0.097; OR 0.641; p = 0.093; I2 = 89.5%). For hospitalization/clinical severity, logOR was -0.609 (95% CI: -1.134 to -0.083; OR 0.544; p = 0.029; I2 = 78.3%). Conclusions: Pooled estimates favored supplementation in direction for all three groups, although confidence intervals included the null for the first two. Heterogeneity was substantial, and the results are limited by approximations among effect measures, clinically diverse endpoints, and potentially correlated effects from individual studies.

Background Temperature instability during neonatal transport contributes to adverse outcomes in preterm and low birth weight infants. Hypothermia in this population is associated with increased risk of intraventricular haemorrhage (IVH), sepsis, and death. Current transport temperature management is reactive and manually controlled. The Heating On Transport WitH prEtErm and Low birth weight neonates using Servocontrol patient temperature management system (HOTWHEELS) trial aims to determine whether automated, servo-controlled thermoregulation provides superior thermal stability compared to standard care and reduces hypothermia-associated adverse outcomes. Methods This prospective, randomised, superiority trial is conducted by the Newborn Emergency Transport Service of Western Australia. Infants with a gestational age of less than or equal to 34 weeks and/or weight of 1500 g requiring transport are randomised to serve-controlled or standard thermal care. The primary outcome is the proportion of infants with a temperature between 36.5 and 37.5 degrees Celsius on arrival at the receiving neonatal unit. Secondary outcomes include the incidence of IVH in the first 7 days, mortality before discharge, the incidence of moderate (<36.0) and severe (<35.0) hypothermia for greater than 15 minutes and the temperature change during transport. Trial registration: ANZCTR12624000503527. Impact HOTWHEELS is the first randomised trial in neonatal transport to evaluate servo-controlled temperature control. We believe the findings will inform standards of temperature control during transport for preterm and low birth weight infants.

BackgroundReactive oxygen species (ROS) overproduction, inflammatory cytokines, and plasma mediators disrupt alveolar tight junction integrity and perpetuate oxidative injury in acute respiratory distress syndrome (ARDS). Biological heterogeneity of ARDS, reflected by hyper- and hypoinflammatory subphenotypes with distinct plasma mediator profiles, may contribute to heterogeneity of treatment effect. Stem cell-derived EVs have been shown to exert regenerative and immunomodulatory effects by horizontal transfer of proteins, lipids and genetic material to injured target cells. This study investigated whether extracellular vesicles derived from bone marrow (MSC-EVs) and adipose tissue (ASC-EVs) mesenchymal stem cells restore barrier integrity and redox homeostasis, and whether efficacy differs across subphenotypes. MethodsBronchial epithelial cells (BEAS-2B), microvascular endothelial cells (HMEC-1), and small airway epithelial cells (SAEC) were challenged with plasma from patients with hyperinflammatory or hypoinflammatory ARDS subphenotypes, including those treated with venovenous ECMO. MSC-EVs or ASC-EVs were added concomitantly with plasma exposure or six hours later, at a dose of 5,000 particles/cell. After 24 h, the expression of actin and tight junction proteins, zonula occludens (ZO)-1, occludin, and vascular endothelial (VE)-cadherin, was evaluated by immunofluorescence. Oxidative stress parameters, antioxidant defenses, and antioxidant enzyme activities, were measured. ResultsPlasma from patients with the hyperinflammatory ARDS subphenotype induced marked disruption of ZO-1, occludin, and VE-cadherin expression, together with actin cytoskeletal rearrangement, across BEAS-2B, HMEC-1, and SAEC cells. Barrier disruption was accompanied by increased oxidative stress markers and altered antioxidant enzyme activity. Both MSC-EVs and ASC-EVs restored tight junction protein expression and cytoskeletal organization when administered either concurrently with ARDS plasma or 6 hours after exposure, and both effectively modulated redox parameters. Delayed administration 6 hours after injury produced greater effects for several oxidative stress endpoints, particularly in cells challenged with hypoinflammatory plasma. ConclusionARDS-associated plasma mediators induce subphenotype-dependent impairment of epithelial-endothelial barrier integrity through oxidative mechanisms. Both MSC-EVs and ASC-EVs mitigate this injury, with efficacy that varies according to ARDS subphenotype and timing of administration.

Background. Many Indian special newborn care units (SNCUs) cannot offer amplitude-integrated EEG (aEEG) or early MRI, so bedside judgement decides which newborns receive closer neurological attention. Earlier work found that asphyxiated newborns cry with a higher pitch and shorter phonation than healthy newborns, and a meta-analysis reported higher fundamental frequency, dysphonation and atypical melody in infants with neurological dysfunction, with wide differences between studies. Aim. To determine whether basic acoustic features of a smartphone-recorded pain cry (following a heel prick) can differentiate term newborns with HIE from control newborns. Also, to track changes in cry acoustics over the first 72 hours of life and evaluate their association with the clinical severity and short-term outcomes of encephalopathy. Design. A prospective, single centre diagnostic accuracy and cohort study in a tertiary SNCU. Three groups of term newborns are recorded: newborns with HIE, healthy comparators, and sick comparators who do not have HIE. Every newborn is recorded after the same stimulus, the first clinically indicated heel-prick. Newborns with HIE and sick comparators are recorded again at 24 hours, 72 hours and before discharge. A cry that is late or absent counts as a result and not as a missing value. Three clinicians blinded to group also classify the cries by listening, so the phone-based measures can be compared with the human ear. Analysis. The primary outcome is the area under the ROC curve of a logistic model with five pre-specified acoustic predictors. The target is 180 analyzable newborns (70 with HIE and 110 comparators). Reporting follows STARD and TRIPOD+AI. Relevance. In a South Asian trial, cooling did not reduce death or disability at 18 months and increased death alone. A cry tool in this setting is therefore proposed to help prioritize EEG, seizure surveillance, closer observation and referral. It is not proposed as a trigger for cooling. Keywords: neonatal encephalopathy; infant cry; acoustic analysis; smartphone; diagnostic accuracy; low-resource setting.

Abstract Objective: Examine whether prenatal adversity is associated with Neonatal Opioid Withdrawal Syndrome (NOWS) severity and the need for pharmacological treatment in infants with prenatal opioid exposure. Study Design: Prospective cohort study of 235 infants from a multi-center study of infants with prenatal opioid exposure. Maternal factors were assessed using the electronic medical record and maternal questionnaires. Latent Class Analysis (LCA) was used to derive mutually exclusive prenatal adversity groups. Results: A 3-class LCA solution provided the best fit to the data and showed 3 distinct groups: one low adversity group (Class 3, 38.7%) and 2 high adversity groups. Infants born to mothers with elevated demographic, medical, polysubstance, and mental health risk factors (Class 1, 31.9%) were more likely to require pharmacological treatment for NOWS (OR=7.70, 95% CI: 3.65-17.14) and had higher NOWS severity, as indexed by longer length of stay ({beta} = 6.08, 95% CI: 4.09-8.07), and higher maximum Finnegan scores ({beta} = 2.62, 95% CI: 1.49-3.76). Infants born to mothers with elevated medical and polysubstance risk factors (Class 2, 29.4%) were also more likely to receive pharmacological treatment for NOWS (OR=3.22, 95% CI: 1.56-6.78) and had higher NOWS severity, as indexed by higher likelihood of receiving adjunctive medication (OR=3.62, 95% CI: 1.11-12.99). Conclusion: Maternal sociodemographic, mental health, substance use, and medical adversity may serve as an early marker of NOWS severity and may aid in the prediction of which neonates will require pharmacological treatment for NOWS. Early identification of infants at high risk for NOWS could lead to earlier treatment and the potential to reduce NOWS severity, length of stay, and associated healthcare costs.

Background Neonatal sepsis remains a major cause of neonatal morbidity and mortality, particularly in low- and middle-income countries. Its management is increasingly complicated by antimicrobial resistance (AMR), while limited facility-specific data on causative bacterial pathogens and susceptibility patterns often necessitate empirical antibiotic treatment. This study assessed the prevalence of neonatal sepsis, bacterial pathogens and antimicrobial resistance patterns, and maternal, neonatal and clinical factors associated with neonatal sepsis among neonates admitted to the Neonatal Intensive Care Unit (NICU) at Livingstone University Teaching Hospital (LUTH), Zambia. Methods A retrospective cross-sectional record review was conducted among neonates admitted to the NICU at LUTH from 2020 to 2025. A total of 150 neonatal records were analysed. Neonatal, maternal, clinical, blood culture and antimicrobial susceptibility data were analysed using descriptive statistics, chi-square tests and logistic regression. Missing information was treated as missing and was not imputed; denominators were reported according to the records available for each analysis. Results Neonatal sepsis was identified in 52/150 neonates, giving a prevalence of 34.7% (95% CI: 27.5%-42.6%). Among the 52 sepsis cases, 20 had positive blood cultures, corresponding to a culture positivity rate of 38.5% (95% CI: 26.5%-52.0%); this represented 13.3% of the full study sample. Maternal fever during labour (aOR=6.822; 95% CI: 2.032-22.905; p=0.002) and caesarean delivery (aOR=2.245; 95% CI: 1.050-4.801; p=0.037) were independently associated with neonatal sepsis, while increasing birth weight was protective (aOR=0.891 per 100 g; 95% CI: 0.817-0.973; p=0.010). Escherichia coli was the most frequent isolate (5/20; 25.0%), followed by Klebsiella pneumoniae (4/20; 20.0%) and Staphylococcus aureus (4/20; 20.0%). Resistance was highest to ampicillin (15/19; 78.9%), followed by gentamicin and ceftriaxone (10/19; 52.6% each), while all 19 isolates tested against meropenem were susceptible. Conclusion The findings indicate that empirical management of neonatal sepsis at LUTH should be informed by local microbiological surveillance rather than reliance on historical first-line susceptibility assumptions. Routine blood culture and susceptibility testing, a regularly updated facility antibiogram, strengthened infection prevention and antimicrobial stewardship are required to improve treatment decisions and preserve effective antibiotics. Interpretation should consider the retrospective single-centre design, incomplete routine records and the small number of culture-positive isolates.

Background: Understanding fetal brain responses to hypoxia-ischemia is of growing interest, as it remains unclear to what extent these responses differ from those of newborns and whether developmental adaptations during gestation contribute to such differences. Materials and methods: Using a combination of broadband near-infrared spectroscopy (bNIRS) and diffuse correlation spectroscopy (DCS), we measured brain microvascular oxygen saturation (StO2), total hemoglobin concentration (THC), relative cerebral blood flow (rCBF), and the oxidation state of cytochrome c oxidase (oxCCO) during an acute ischemic challenge in the brains of five rabbit fetuses in utero. Simultaneous measurements were acquired from four control fetuses located in the contralateral uterine horn. Results: During the hypoxia-ischemia phase, we observed a rapid reduction of CBF (47% +/- 29%) and StO2, (from 64.7% +/- 1.5% at baseline to 40.6% +/- 2.0%) together with an increase of oxCCO (3.7 uM +/- 0.5 uM). Conclusion: The simultaneous increase in oxCCO and decrease in rCBF and StO2 during hypoxia-ischemia reveals a cerebral response pattern that differs from that commonly reported in the newborn brain. These findings support the hypothesis that unique developmental adaptations influence fetal cerebral metabolism during hypoxic-ischemic stress.

OBJECTIVE: Sepsis-associated encephalopathy (SAE) and sepsis-associated delirium (SAD) lack confirmatory laboratory tests or biomarkers. We evaluated whether the Th17/interleukin (IL)-17 axis or neuroglial-injury biomarkers reflect acute brain dysfunction beyond systemic inflammation and whether biomarker profiles differ between these phenotypes. DATA SOURCES: EMBASE, MEDLINE/PubMed, and the Cochrane Library from inception to August 1, 2026, supplemented by backward and forward citation searching, following PRISMA 2020. STUDY SELECTION: Observational studies of adults with sepsis classified by SAE or SAD status and reporting circulating biomarker concentrations by neurological group or biomarker-outcome associations. Eighteen studies (2,388 participants; 1,863 with sepsis) were included. DATA EXTRACTION: Two reviewers independently extracted study, phenotype, assay, and outcome data. Risk of bias was assessed with the Newcastle-Ottawa Scale and certainty with GRADE. DATA SYNTHESIS: Random-effects models pooled standardized mean differences (SMDs) separately against non-septic and septic controls and odds ratios (ORs) for biomarker-outcome associations. IL-6 was the only mediator elevated in both comparative frameworks and associated with outcomes (non-septic controls: SMD, 0.54 [0.25-0.82]; septic controls: SMD, 1.05 [0.51-1.59]; OR, 1.85 [1.50-2.29]). S100B, neuron-specific enolase, IL-10, tumor necrosis factor; and interferon-gamma; were elevated versus septic controls, whereas IL-17 was modestly elevated only versus non-septic controls (SMD, 0.37 [0.01-0.73]). The IL-6 septic-control effect was concentrated in SAE (p<0.0001) and remained robust in leave-one-out and risk-of-bias sensitivity analyses. Certainty was low to very low, and all 14 computable prediction intervals included the null. CONCLUSIONS: IL-6 emerges as the leading circulating candidate biomarker of sepsis-associated brain dysfunction, while S100B and NSE capture neuroglial injury beyond sepsis. Current evidence does not establish a discriminating role for the Th17 axis. Future studies require standardized neurological phenotyping and appropriately matched septic controls to establish diagnostic value.

Structural connectomics provides a means of characterising white matter (WM) network organisation using diffusion MRI (dMRI), but reconstructing neonatal structural connectomes remains challenging due to the immature and heterogeneous nature of the developing brain. Although recent neonatal studies have increasingly adopted approaches beyond conventional diffusion tensor imaging (DTI), there remains scope to incorporate more advanced tractography and streamline post-processing approaches within neonatal pipelines. Here, we propose a neonatal structural connectome pipeline integrating surface-based anatomical constraints, ensemble tractography, hierarchical anatomical refinement of pathways (HARP) filtering, and spherical-deconvolution informed filtering (SIFT2) reweighting. We acquired 3T MRI data from 300 neonates (185 preterm, 115 term-born) to assess the impact of pipeline configuration on network organisation. Mean gestational age (GA) at birth was 29.31 (23.43-32.86) weeks in preterm infants and 39.52 (37.00-42.43) weeks in term infants. At scan, mean GA was 40.85 (36.29-49.00) weeks in preterm infants and 42.06 (38.29-48.00) weeks in term infants. Four connectome variants were generated: raw surfaced-based tractograms, HARP-filtered, SIFT2-weighted, and combined HARP+SIFT2. Pipeline performance was primarily evaluated using an existing brain age prediction model: connectome-based predictive model (CPM) and our derived connectomes to estimate GA at scan in term and preterm infants. In addition, global graph theoretical metric analyses were conducted to provide a complementary assessment of pipeline configuration differences in network organisation. In total, seven graph theoretical metrics were calculated and evaluated: global efficiency, local efficiency, transitivity, modularity, assortativity, degree variance and statistical complexity. Across all configurations, connectomes supported accurate brain age prediction, with mean absolute errors (MAE) of 0.76-0.79 weeks in term infants and 1.00-1.06 weeks in preterm infants. Prediction error and brain age gap variability were greater in preterm than term infants across configurations, with HARP+SIFT2 achieving the lowest preterm MAE (1.00 weeks) and brain age gap (BAG) variability (SD = 1.38 weeks). However, differences in prediction performance across configurations were minimal, suggesting limited influence of pipeline choice on brain age prediction. However, analysis of global network metrics demonstrated that pipeline choice significantly influenced downstream measures of network organisation, with HARP+SIFT2 being the only configuration to identify significant preterm vs. term differences across all seven metrics examined. These findings demonstrate the importance of considering tractography and streamline-processing choices when constructing neonatal structural connectomes and provide a framework for more anatomically informed investigation of early brain development.

Introduction: With global warming, heatwaves are increasing in severity, affecting species worldwide. Recent studies show associations between heat exposure in pregnancy and adverse birth outcomes such as preterm birth, low birthweight and stillbirth across multiple species. This suggests potentially conserved mechanisms such as maternal inflammation, dehydration and changes in placental physiology in response to heat exposure. Moreover, the gestational timing of antenatal heat likely impacts the type and severity of outcome, yet this is not fully understood. Methods: We conducted a scoping review of studies on heat exposure and pregnancy outcomes in humans and other animals, to identify common mechanisms and temporal dynamics of effects. Temperature-, trimester- and species- specific patterns were reviewed across 197 studies and ten species (human, cow, sheep, pig, goat, rat, mouse, guinea pig, lizard and rabbit). Results: Qualitative trends indicate that high temperatures are associated with adverse birth outcomes. In particular, third trimester exposure increases risk of preterm birth and low birthweight. Many studies emphasise placental involvement in adverse outcomes and point to potential aberrations in placental physiology or cortisol signaling pathways. Conclusions: Overall, literature presents that heat exposure increases risk of adverse birth outcomes across studies, and taxa. Understanding the relationship between heat exposure and adverse birth outcomes, as well as the mechanisms and timing, is vital for informing public health policies and creating mitigating strategies for expecting mothers.

Introduction: Fighting the ventilator (FV) is characterized by a patients active counteraction of respiratory gas flow across multiple breaths during mechanical ventilation. An effective ventilation is prevented during such episodes. The objective of this exploratory study was to evaluate clinicians knowledge, perception and agreement regarding this condition. Methods: In a cross-sectional online survey, medical professionals with experience in intensive care medicine (mostly neonatal and pediatric patients) responded to 11 questions covering various clinical aspects of FV. Results: All respondents were familiar with the phenomenon and assessed it to be clinically relevant. Neonates were perceived to be predominantly affected. Promoting factors of FV included inadequate sedation and ventilation-associated factors. In clinical practice, the participants identified FV by clinical evaluation, analysis of ventilator waveforms and capnography and used both pharmacological and non-pharmacological intervention strategies. There was no consensus concerning the English terminology of the condition. Only few respondents were familiar with local guidelines to manage FV. Conclusion: Although there was consensus on the relevance of FV, diagnostics and management strategies were highly heterogeneous. Many participants agreed that poor patient-ventilator synchrony was an important cause of FV. Future work should focus on characterizing and generating evidence on FV.