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This meta-analysis assessed short-term outcomes after using human milk-derived fortifiers (HMFs) compared with bovine milk fortifiers (BMFs) in preterm infants fed an exclusive human milk (HM) diet, either mother's own milk (MOM) or donor human milk (DHM). We searched PubMed, Embase, Google Scholar, CENTRAL and CINHAL between January 2015 and August 2023 for studies reporting outcomes in infants with ≤28 weeks gestation and/or birthweight ≤ 1500 g on an exclusive human milk diet fortified with HMF versus BMF. The primary outcomes were death and NEC (stage ≥ 2). Four studies with a total of 681 infants were included. Mortality was significantly lower in infants fed with an HM-HMFs diet (four studies, 681 infants; RR = 0.50, 95% CI = 0.26–0.94; p = 0.03; I2 = 0%), NEC was similar between the two groups (four studies, 681 infants; RR = 0.48, 95% CI = 0.20–1.17; p = 0.11; I2= 39%). BPD was higher in the HM-BMFs group (four studies, 663 infants; RR = 0.83, 95% CI = 0.69–1.000; p = 0.05, I2 = 0%), although not statistically significant. No differences were found for sepsis (RR = 0.97, 95% CI = 0.66–1.42; p = 0.96; I2 = 26%) or combined ROP (four studies, 671 infants; RR = 0.64, 95% CI = 0.53–1.07; p = 0.28; I2 = 69%). An HM-HMFs diet could possibly be associated with decreased mortality with no association with NEC, BPD, sepsis, or ROP. This meta-analysis was limited by the small number of studies included. However, the results should not be refuted for this reason as they provide an impetus for subsequent clinical trials to assess the observed associations. [ABSTRACT FROM AUTHOR]

Background: International studies have reported conflicting data about the effects of COVID-19 pandemic policy measures on maternal and neonatal health. A major impact was reported on stillbirth and prematurity. The published literature suggests that the economic setting influenced the effects of imposed mitigation measures with a more severe effect in low-income countries. Objectives: Our objective is to compare pregnancy outcomes at the only tertiary Maternity Hospital in Bihor County-Romania before and during the COVID-19 pandemic. This study aims to observe and document differences in perinatal outcomes across these periods, without inferring direct causation related to the pandemic or its associated restrictions. Materials and methods: We used data from the registries of Public Health Services Bihor to conduct a retrospective cohort analysis of preterm births and stillbirths during the COVID-19 pandemic in Bihor County, Romania. Pregnancy outcomes were compared between the pandemic period (March 2020-February 2022) to the corresponding historical pre-COVID-19 period (March 2018-February 2020). Maternal socio-demographic variables and neonatal characteristics of these periods were also examined. Results: The COVID-19 pandemic period was associated with an increase in the stillbirth rate (RR: 1.53, 95% CI, 1.05-2.23). Preterm birth was significantly impacted during this period and showed changes when analyzing gestational age (RR: 0.88, 95% CI, 0.79-0.96) or birth weight (RR: 0.91, 95% CI, 0.82-1.00). The main cause of stillbirth was intrauterine asphyxia due to placental causes (67.6%) or cord pathology (12.6%), the most frequently encountered maternal pathology was cardiovascular (28.3%) or infectious (21.7%). Our study revealed no significant changes in terms of maternal and neonatal characteristics during the two-year pandemic period. Conclusions: Lockdown restrictions in Bihor County, Romania were associated with an increase in stillbirths, whilst preterm birth rate decreased. This raises concerns about whether pandemic policy measures may have led to a failure in identifying and offering proper care for pregnant women who were more likely to experience an antepartum loss. Further studies across the globe are needed in order to integrate comparable data that will help develop adequate protocols and policies for protecting maternal and child health during the next pandemic that will follow. [ABSTRACT FROM AUTHOR]

The treatment of spinal cord injury (SCI) with uncultivated human bone marrow-derived stromal cells (bmSCs) prepared by negative selection has been proposed to be therapeutically superior to treatment with stem cells that were expanded in vitro. To explore their use in clinical trials, we studied the functional effects of delayed application at 7 days after SCI by testing different doses of bmSCs. Spinal cord contusion injury was induced in adult male Wistar rats at the thoracic level T9. Human bmSCs were prepared by negative selection without expansion in vitro (NeuroCellsTM). Treatment consisted of one 150 µL injection into the cisterna magna containing 0.5 or 2.5 million fresh bmSCs or 2.5 million bmSCs. The recovery of motor functions was evaluated during a surveillance period of six weeks (6 W), during which spinal cords were assessed histologically. Treatment resulted in a significant, dose-dependent therapeutic effect on the recovery of motor performance. The histological analysis revealed a lower degree of axonal degeneration and better survival of neurons and oligodendrocytes in bmSCs treated rats. Our results support delayed intrathecal application of bmSCs prepared by negative selection without expansion in vitro as a treatment of SCI. [ABSTRACT FROM AUTHOR]

Objectives: Pain is common after craniotomy. Its incidence and predictors in developing nations are not adequately studied. We aimed to assess the incidence, predictors, and impact of acute post-operative pain after intracranial neurosurgeries. Materials and Methods: This prospective observational study was conducted in adult patients undergoing intracranial neurosurgeries. After patient consent, ethics committee approval, and study registration, we assessed the incidence of post-operative pain using numerical rating scale (NRS) score. Predictors and impact of pain on patient outcomes were also evaluated. Results: A total of 497 patients were recruited during 10-month study period. Significant (4-10 NRS score) post-operative pain at any time-point during the first 3 days after intracranial neurosurgery was reported by 65.5% (307/469) of patients. Incidence of significant pain during the 1st post-operative h, on the 1st, 2nd, and 3rd post-operative days was 20% (78/391), 50% (209/418), 38% (152/401), and 24% (86/360), respectively. Higher pre-operative NRS score and pain during the 1st h post-operatively, predicted the occurrence of pain during the first 3 days after surgery, P = 0.003 and P < 0.001, respectively. Pain was significantly associated with poor sleep quality on the first 2 post-operative nights (P < 0.001). Patient satisfaction score was higher in patients with post-operative pain, P = 0.002. Conclusion: Every two in three patients undergoing elective intracranial neurosurgery report significant pain at some point during the first 3 postoperative days. Pre-operative pain and pain during 1st post-operative h predict the occurrence of significant post-operative pain. [ABSTRACT FROM AUTHOR]

Introduction: Chorioamnionitis is common in preterm birth and associated with a higher risk of intestinal inflammation and necrotizing enterocolitis. The intestinal inflammation influences the enteric nervous system development. We hypothesized that inflammation and innervation in the fetal ileum may be modified by chorioamnionitis induced by repeated challenge with lipopolysaccharide and/or preexisting Ureaplasma parvum infection at very low gestational age equivalent to 60% of term. Materials and methods: Time mated ovine fetuses were exposed by intraamniotic injections to chronic Ureaplasma parvum for 24 days and/or lipopolysaccharide for 7 days, 2 days, or 7 & 2 days before delivery at 94 +/-2 days of gestational age (term at approximately 150 days). Intestinal inflammation as well as structural changes of the enteric nervous system were assessed. Results: Lipopolysaccharide exposure increased CD3 and myeloperoxidase-positive cells (p < 0.05). Repetitive exposure to lipopolysaccharide or combined Ureaplasma parvum & lipopolysaccharide exposure increased intestinal inflammation (p < 0.05). The reduction of nuclei of neurons was most significant with repetitive lipopolysaccharide exposures but could be detected in all other intervention groups compared to the control group. Astrocyte-like glial cells increased if exposure to lipopolysaccharide was only 2 days before delivery or chronic exposure to Ureaplasma parvum existed beforehand (p < 0.05). Discussion: After exposure to chorioamnionitis induced by Ureaplasma parvum and/or lipopolysaccharide, inflammatory responses as well as structural changes of the enteric nervous system were more pronounced the longer and the more frequent the exposure to pro-inflammatory stimuli before birth. These changes may cause functional effects of clinical importance. [ABSTRACT FROM AUTHOR]

Ureaplasma species (spp.) are considered commensals of the adult genitourinary tract, but have been associated with chorioamnionitis, preterm birth, and invasive infections in neonates, including meningitis. Data on mechanisms involved in Ureaplasma-driven neuroinflammation are scarce. The present study addressed brain inflammatory responses in preterm lambs exposed to Ureaplasma parvum (UP) in utero. 7 days after intra-amniotic injection of UP (n = 10) or saline (n = 11), lambs were surgically delivered at gestational day 128–129. Expression of inflammatory markers was assessed in different brain regions using qRT-PCR and in cerebrospinal fluid (CSF) by multiplex immunoassay. CSF was analyzed for UP presence using ureB-based real-time PCR, and MRI scans documented cerebral white matter area and cortical folding. Cerebral tissue levels of atypical chemokine receptor (ACKR) 3, caspases 1-like, 2, 7, and C–X–C chemokine receptor (CXCR) 4 mRNA, as well as CSF interleukin-8 protein concentrations were significantly increased in UP-exposed lambs. UP presence in CSF was confirmed in one animal. Cortical folding and white matter area did not differ among groups. The present study confirms a role of caspases and the transmembrane receptors ACKR3 and CXCR4 in Ureaplasma-driven neuroinflammation. Enhanced caspase 1-like, 2, and 7 expression may reflect cell death. Increased ACKR3 and CXCR4 expression has been associated with inflammatory central nervous system (CNS) diseases and impaired blood–brain barrier function. According to these data and previous in vitro findings from our group, we speculate that Ureaplasma-induced caspase and receptor responses affect CNS barrier properties and thus facilitate neuroinflammation. [ABSTRACT FROM AUTHOR]

Early detection of late-onset sepsis (LOS) in preterm infants is crucial since timely treatment initiation is a key prognostic factor. We hypothesized that fecal volatile organic compounds (VOCs), reflecting microbiota composition and function, could serve as a non-invasive biomarker for preclinical pathogen-specific LOS detection. Fecal samples and clinical data of all preterm infants (≤30 weeks' gestation) admitted at nine neonatal intensive care units in the Netherlands and Belgium were collected daily. Samples from one to three days before LOS onset were analyzed by gas chromatography—ion mobility spectrometry (GC-IMS), a technique based on pattern recognition, and gas chromatography—time of flight—mass spectrometry (GC-TOF-MS), to identify unique metabolites. Fecal VOC profiles and metabolites from infants with LOS were compared with matched controls. Samples from 121 LOS infants and 121 matched controls were analyzed using GC-IMS, and from 34 LOS infants and 34 matched controls using GC-TOF-MS. Differences in fecal VOCs were most profound one and two days preceding Escherichia coli LOS (Area Under Curve; p-value: 0.73; p = 0.02, 0.83; p < 0.002, respectively) and two and three days before gram-negative LOS (0.81; p < 0.001, 0.85; p < 0.001, respectively). GC-TOF-MS identified pathogen-specific discriminative metabolites for LOS. This study underlines the potential for VOCs as a non-invasive preclinical diagnostic LOS biomarker. [ABSTRACT FROM AUTHOR]

Purpose: Opioids are the primary analgesics used in patients undergoing spine surgery. Postoperative pain is common despite their liberal use and so are opioid-associated side effects. Non-opioid analgesics are gaining popularity as alternative to opioids in spine surgery. Methods: This systematic review evaluated current evidence regarding opioid and non-opioid intraoperative analgesia and their influence on immediate postoperative pain and adverse events in spine surgery. Results: A total of 10,459 records were obtained by searching Medline, EMBASE and Web of Science databases and six randomized controlled trials were included. Differences in postoperative pain scores between opioid and non-opioid groups were not significant at 1 h: 4 studies, mean difference (MD) = 0.65 units, 95% confidence intervals (CI) [−0.12 to 1.41], p = 0.10, but favored non-opioid at 24 h after surgery: 3 studies, MD = 0.75 units, 95%CI [0.03 to 1.46], p = 0.04. The time for first postoperative analgesic requirement was shorter (MD = −45.06 min, 95%CI [−72.50 to −17.62], p = 0.001), and morphine consumption during first 24 h after surgery was higher in opioid compared to non-opioid group (MD = 4.54 mg, 95%CI [3.26 to 5.82], p < 0.00001). Adverse effects of postoperative nausea and vomiting (Relative risk (RR) = 2.15, 95%CI [1.37 to 3.38], p = 0.0009) and shivering (RR = 2.52, 95%CI [1.08 to 5.89], p = 0.03) were higher and bradycardia was lower (RR = 0.35, 95%CI [0.17 to 0.71], p = 0.004) with opioid analgesia. Conclusion: The certainty of evidence on GRADE assessment is low for studied outcomes. Available evidence supports intraoperative non-opioid analgesia for overall postoperative pain outcomes in spine surgery. More research is needed to find the best drug combination and dosing regimen. Prospero Registration: CRD42020209042. [ABSTRACT FROM AUTHOR]

Phosphodiesterase (PDE) inhibition has been identified in animal studies as a new treatment option for neonatal lung injury, and as potentially beneficial for early lung development and function. However, our group could show that the inhaled PDE4 inhibitor GSK256066 could have dose-dependent detrimental effects and promote lung inflammation in the premature lung. In this study, the effects of a high and a low dose of GSK256066 on lung function, structure and alveolar development were investigated. In a triple hit lamb model of Ureaplasma-induced chorioamnionitis, prematurity, and mechanical ventilation, 21 animals were treated as unventilated (NOVENT) or 24 h ventilated controls (Control), or with combined 24 h ventilation and low dose (iPDE1) or high dose (iPDE10) treatment with inhaled GSK 256066. We found that high doses of an inhaled PDE4 inhibitor impaired oxygenation during mechanical ventilation. In this group, the budding of secondary septae appeared to be decreased in the preterm lung, suggesting altered alveologenesis. Ventilation-induced structural and functional changes were only modestly ameliorated by a low dose of PDE4 inhibitor. In conclusion, our findings indicate the narrow therapeutic window of PDE4 inhibitors in the developing lung. [ABSTRACT FROM AUTHOR]

The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics' effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age < 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (> 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19-0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35-0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85-0.97]; p = 0.003).Conclusion: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored.What Is Known: • Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis. • The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated.What Is New: • Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged. • A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life. [ABSTRACT FROM AUTHOR]

The bile acid tauroursodeoxycholic acid (TUDCA) reduces cell death under oxidative stress and inflammation. Implants of bone marrow-derived stromal cells (bmSC) are currently under investigation in clinical trials of spinal cord injury (SCI). Since cell death of injected bmSC limits the efficacy of this treatment, the cytoprotective effect of TUDCA may enhance its benefit. We therefore studied the therapeutic effect of TUDCA and its use as a combinatorial treatment with human bmSC in a rat model of SCI. A spinal cord contusion injury was induced at thoracic level T9. Treatment consisted of i.p. injections of TUDCA alone or in combination with one injection of human bmSC into the cisterna magna. The recovery of motor functions was assessed during a surveillance period of six weeks. Biochemical and histological analysis of spinal cord tissue confirmed the anti-inflammatory activity of TUDCA. Treatment improved the recovery of autonomic bladder control and had a positive effect on motor functions in the subacute phase, however, benefits were only transient, such that no significant differences between vehicle and TUDCA-treated animals were observed 1–6 weeks after the lesion. Combinatorial treatment with TUDCA and bmSC failed to have an additional effect compared to treatment with bmSC only. Our data do not support the use of TUDCA as a treatment of SCI. [ABSTRACT FROM AUTHOR]

Inflammation of the chorion and/or amnion during pregnancy is called chorioamnionitis. Acute chorioamnionitis is implicated in approximately 40% of preterm births and has wide-ranging implications for the mother, fetus, and newborn. Large disease burden and lack of therapeutic approaches drive the discovery programs to define and test targets to tackle chorioamnionitis. Central to the advancement of these studies is the use of animal models. These models are necessary to deepen our understanding of basic mechanisms of host-pathogen interactions central to chorioamnionitis disease pathogenesis. Models of chorioamnionitis have been developed in numerous species, including mice, rabbits, sheep, and non-human primates. The various models present an array of strategies for initiating an inflammatory response and unique opportunities for studying its downstream consequences for mother, fetus, or newborn. In this review, we present a discussion of the key features of human chorioamnionitis followed by evaluation of currently available animal models in light of these features and consideration of how these models can be best applied to tackle outstanding questions in the field. [ABSTRACT FROM AUTHOR]

Background The role of intestinal microbiota in the pathogenesis of late-onset sepsis (LOS) in preterm infants is largely unexplored but could provide opportunities for microbiota-targeted preventive and therapeutic strategies. We hypothesized that microbiota composition changes before the onset of sepsis, with causative bacteria that are isolated later in blood culture. Methods This multicenter case-control study included preterm infants born under 30 weeks of gestation. Fecal samples collected from the 5 days preceding LOS diagnosis were analyzed using a molecular microbiota detection technique. LOS cases were subdivided into 3 groups: gram-negative, gram-positive, and coagulase-negative S taphylococci (CoNS). Results Forty LOS cases and 40 matched controls were included. In gram-negative LOS, the causative pathogen could be identified in at least 1 of the fecal samples collected 3 days prior to LOS onset in all cases, whereas in all matched controls, this pathogen was absent (P =.015). The abundance of these pathogens increased from 3 days before clinical onset. In gram-negative and gram-positive LOS (except CoNS) combined, the causative pathogen could be identified in at least 1 fecal sample collected 3 days prior to LOS onset in 92% of the fecal samples, whereas these pathogens were present in 33% of the control samples (P =.004). Overall, LOS (expect CoNS) could be predicted 1 day prior to clinical onset with an area under the curve of 0.78. Conclusions Profound preclinical microbial alterations underline that gut microbiota is involved in the pathogenesis of LOS and has the potential as an early noninvasive biomarker. [ABSTRACT FROM AUTHOR]

Chorioamnionitis, inflammation of fetal membranes, is an important cause of preterm birth and a risk factor for the development of adverse neonatal outcomes including sepsis and intestinal pathologies. Intestinal bile acids (BAs) accumulation and hepatic cytokine production are involved in adverse intestinal outcomes. These findings triggered us to study the liver and enterohepatic circulation (EHC) following intra-amniotic (IA) lipopolysaccharide (LPS) exposure. An ovine chorioamnionitis model was used in which circulatory cytokines and outcomes of the liver and EHC of preterm lambs were longitudinally assessed following IA administration of 10 mg LPS at 5, 12 or 24h or 2, 4, 8 or 15d before preterm birth. Hepatic inflammation was observed, characterized by increased hepatic cytokine mRNA levels (5h – 2d post IA LPS exposure) and increased erythropoietic clusters (at 8 and 15 days post IA LPS exposure). Besides, 12h after IA LPS exposure, plasma BA levels were increased, whereas gene expression levels of several hepatic BA transporters were decreased. Initial EHC alterations normalized over time. Concluding, IA LPS exposure induces significant time-dependent changes in the fetal liver and EHC. These chorioamnionitis induced changes have potential postnatal consequences and the duration of IA LPS exposure might be essential herein. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is one of the most common and lethal gastrointestinal diseases in preterm infants. Early recognition of infants in need for surgical intervention might enable early intervention. In this multicenter case-control study, performed in nine neonatal intensive care units, preterm born infants (< 30 weeks of gestation) diagnosed with NEC (stage ≥ IIA) between October 2014 and August 2017 were divided into two groups: (1) medical (conservative treatment) and (2) surgical NEC (sNEC). Perinatal, clinical, and laboratory parameters were collected daily up to clinical onset of NEC. Univariate and multivariate logistic regression analyses were applied to identify potential predictors for sNEC. In total, 73 preterm infants with NEC (41 surgical and 32 medical NEC) were included. A low gestational age (p value, adjusted odds ratio [95%CI]; 0.001, 0.91 [0.86–0.96]), no maternal corticosteroid administration (0.025, 0.19 [0.04–0.82]), early onset of NEC (0.003, 0.85 [0.77–0.95]), low serum bicarbonate (0.009, 0.85 [0.76–0.96]), and a hemodynamically significant patent ductus arteriosus for which ibuprofen was administered (0.003, 7.60 [2.03–28.47]) were identified as independent risk factors for sNEC. Conclusions: Our findings may support the clinician to identify infants with increased risk for sNEC, which may facilitate early decisive management and consequently could result in improved prognosis. What is Known: • In 27–52% of the infants with NEC, a surgical intervention is indicated during its disease course. • Absolute indication for surgical intervention is bowel perforation, whereas fixed bowel loop or clinical deterioration highly suggestive of bowel perforation or necrosi, is a relative indication. What is New: • Lower gestational age, early clinical onset, and no maternal corticosteroids administration are predictors for surgical NEC. • Low serum bicarbonate in the 3 days prior clinical onset and patent ductus arteriosus for which ibuprofen was administered predict surgical NEC. [ABSTRACT FROM AUTHOR]

Objective. Presence of a patent ductus arteriosus (PDA) in neonates is assessed by echocardiography. Echocardiographic assessment has disadvantages, primarily its discontinuous nature. We hypothesize that the continuously measured ratio of arterial blood pressures (ABP) at the borders of a window surrounding the systolic peak ratio discriminates non-PDA from PDA patients. Approach. Preterm infants (gestational age <32 weeks) with and without PDA were included. Patients were divided into controls (n = 8) and PDA patients (n = 22), the latter with a subset of patients with closed PDA after three doses Ibuprofen (n = 10). For each patient, a six-hour ABP segment from 12 AM to 6 AM on the day of echocardiographic assessment patency or closure of the DA was selected. The mean ratio of the ABP values a samples before and p samples after the systolic peak (RABP) was calculated for each segment. If RABP < 1, the patient was predicted to have a PDA. The a and p with the least misclassifications were selected (−64 and +104 ms). Main results.RABP was significantly lower in PDA patients (median 0.95, IQR 0.06) compared to controls (median 1.05, IQR 0.10; p = 0.0024). RABP correctly predicted 19 out of 22 patients (86.4%) and six out of eight controls (75%). RABP increased after closure in nine out of 10 patients (median 1.01, IQR 0.04; p = 0. 0182). Significance.RABP may discriminate preterm PDA patients from non-PDA patients and can be calculated continuously from clinical data measured during standard of care. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome (ARDS) can have various causes. The study objective was to investigate whether different pathophysiologic models of ARDS would show different respiratory, cardiovascular and inflammatory outcomes.Methods: We performed a prospective, randomized study in 27 ventilated ewes inducing ARDS using three different techniques to mimic the pulmonary causes of ARDS (ARDSp): warm saline lavage (n = 6), intratracheal hydrochloric acid (HCl; n = 6), intratracheal albumin (n = 10), and one technique to mimic an extrapulmonary cause of ARDS (ARDSexp): intravenous lipopolysaccharide (LPS iv; n = 5). ARDS was defined when PaO2 was < 15 kPa (112 mmHg) when ventilated with PEEP 10 cm H2O and FiO2 = 1.0. The effects on gas exchange were investigated by calculating the oxygenation index (OI) and the ventilation efficacy index (VEI) every 30 min for a period of 4 h. Post mortem lung lavage was performed to obtain broncho-alveolar lavage fluid (BALF) to assess lung injury and inflammation. Lung injury and inflammation were assessed by measuring the total number and differentiation of leukocytes, the concentration of protein and disaturated phospholipids, and interleukine-6 and -8 in the BALF. Histology of the lung was evaluated by measuring the mean alveolar size, alveolar wall thickness and the lung injury score system by Matute-Bello et al., as markers of lung injury. The concentration of interleukin-6 was determined in plasma, as a marker of systematic inflammation.Results: The OI and VEI were most affected in the LPS iv group and thereafter the HCl group, after meeting the ARDS criteria. Diastolic blood pressure was lowest in the LPS iv group. There were no significant differences found in the total number and differentiation of leukocytes, the concentration of protein and disaturated phospholipids, or interleukin-8 in the BALF, histology of the lung and the lung injury score. IL-6 in BALF and plasma was highest in the LPS iv group, but no significant differences were found between the other groups. It took a significantly longer period of time to meet the ARDS criteria in the LPS iv group.Conclusions: The LPS model caused the most severe pulmonary and cardiovascular insufficiency. Surprisingly, there were limited significant differences in lung injury and inflammatory markers, despite the different pathophysiological models, when the clinical definition of ARDS was applied. [ABSTRACT FROM AUTHOR]

Chorioamnionitis (CA) is considered a key risk factor for very preterm birth and for developing early onset sepsis (EOS) in preterm infants, but recent data suggest that CA might be protective against late onset sepsis (LOS). We performed a systematic review and meta-analysis of studies exploring the association between CA and sepsis. A comprehensive literature search was performed in PubMed/MEDLINE and EMBASE, from their inception to December 1, 2018. A random-effects model was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Sources of heterogeneity were analyzed by subgroup and meta-regression analyses. The following categories of sepsis were analyzed: EOS, LOS, unspecified onset sepsis (UOS), culture-proven, and clinical sepsis. CA was subdivided into clinical and histological chorioamnionitis. Funisitis was also analyzed. We found 3,768 potentially relevant studies, of which 107 met the inclusion criteria (387,321 infants; 44,414 cases of CA). Meta-analysis showed an association between any CA and any EOS (OR 4.29, CI 3.63–5.06), any LOS (OR 1.29, CI 1.11–1.54), and any UOS (OR 1.59, CI 1.11–1.54). Subgroup analysis showed that CA was associated with culture-proven EOS (OR 4.69, CI 3.91–5.56), clinical EOS (OR 3.58, CI 1.90–6.76), and culture-proven LOS (OR 1.31, CI 1.12–1.53), but not with clinical LOS (OR 1.52, CI 0.78–2.96). The presence of funisitis did not increase the risk of either EOS or LOS when compared with CA without funisitis. CA-exposed infants had lower gestational age (−1.11 weeks, CI −1.37 to −0.84) than the infants not exposed to CA. Meta-regression analysis showed that the lower gestational age of the CA group correlated with the association between CA and LOS but not with the association between CA and EOS. In conclusion, our data suggest that the positive association between chorioamnionitis and LOS may be modulated by the effect of chorioamnionitis on gestational age. [ABSTRACT FROM AUTHOR]

Aims: Mutations in DNA/RNA‐binding factor (fused‐in‐sarcoma) FUS and superoxide dismutase‐1 (SOD‐1) cause amyotrophic lateral sclerosis (ALS). They were reproduced in SOD‐1‐G93A (SOD‐1) and new FUS[1‐359]‐transgenic (FUS‐tg) mice, where inflammation contributes to disease progression. The effects of standard disease therapy and anti‐inflammatory treatments were investigated using these mutants. Methods: FUS‐tg mice or controls received either vehicle, or standard ALS treatment riluzole (8 mg/kg/day), or anti‐inflammatory drug a selective blocker of cyclooxygenase‐2 celecoxib (30 mg/kg/day) for six weeks, or a single intracerebroventricular (i.c.v.) infusion of Neuro‐Cells (a preparation of 1.39 × 106 mesenchymal and hemopoietic human stem cells, containing 5 × 105 of CD34+ cells), which showed anti‐inflammatory properties. SOD‐1 mice received i.c.v.‐administration of Neuro‐Cells or vehicle. Results: All FUS‐tg‐treated animals displayed less marked reductions in weight gain, food/water intake, and motor deficits than FUS‐tg‐vehicle‐treated mice. Neuro‐Cell‐treated mutants had reduced muscle atrophy and lumbar motor neuron degeneration. This group but not celecoxib‐FUS‐tg‐treated mice had ameliorated motor performance and lumbar expression of microglial activation marker, ionized calcium‐binding adapter molecule‐1 (Iba‐1), and glycogen‐synthase‐kinase‐3ß (GSK‐3ß). The Neuro‐Cells‐treated‐SOD‐1 mice showed better motor functions than vehicle‐treated‐SOD‐1 group. Conclusion: The neuropathology in FUS‐tg mice is sensitive to standard ALS treatments and Neuro‐Cells infusion. The latter improves motor outcomes in two ALS models possibly by suppressing microglial activation. [ABSTRACT FROM AUTHOR]

Background: Chorioamnionitis, inflammation of the fetal membranes during pregnancy, is often caused by intra-amniotic (IA) infection with single or multiple microbes. Chorioamnionitis can be either acute or chronic and is associated with adverse postnatal outcomes of the intestine, including necrotizing enterocolitis (NEC). Neonates with NEC have structural and functional damage to the intestinal mucosa and the enteric nervous system (ENS), with loss of enteric neurons and glial cells. Yet, the impact of acute, chronic, or repetitive antenatal inflammatory stimuli on the development of the intestinal mucosa and ENS has not been studied. The aim of this study was therefore to investigate the effect of acute, chronic, and repetitive microbial exposure on the intestinal mucosa, submucosa and ENS in premature lambs. Materials and Methods: A sheep model of pregnancy was used in which the ileal mucosa, submucosa, and ENS were assessed following IA exposure to lipopolysaccharide (LPS) for 2 or 7 days (acute), Ureaplasma parvum (UP) for 42 days (chronic), or repetitive microbial exposure (42 days UP with 2 or 7 days LPS). Results: IA LPS exposure for 7 days or IA UP exposure for 42 days caused intestinal injury and inflammation in the mucosal and submucosal layers of the gut. Repetitive microbial exposure did not further aggravate injury of the terminal ileum. Chronic IA UP exposure caused significant structural ENS alterations characterized by loss of PGP9.5 and S100β immunoreactivity, whereas these changes were not found after re-exposure of chronic UP-exposed fetuses to LPS for 2 or 7 days. Conclusion: The in utero loss of PGP9.5 and S100β immunoreactivity following chronic UP exposure corresponds with intestinal changes in neonates with NEC and may therefore form a novel mechanistic explanation for the association of chorioamnionitis and NEC. [ABSTRACT FROM AUTHOR]

With the current practice of therapeutic hypothermia for neonatal encephalopathy, disability rates and the severity spectrum of cerebral palsy are reduced. Nevertheless, safe and effective adjunct therapies are needed to optimize outcomes. This study's objective was to assess if 18 mg/kg melatonin given rapidly over 2 h at 1 h after hypoxia-ischemia with cooling from 1–13 h was safe, achieved therapeutic levels within 3 h and augmented hypothermic neuroprotection. Following hypoxia-ischemia, 20 newborn piglets were randomized to: (i) Cooling 1–13 h (HT; n = 6); (ii) HT+ 2.5% ethanol vehicle (HT+V; n = 7); (iii) HT + Melatonin (HT+M; n = 7). Intensive care was maintained for 48 h; aEEG was acquired throughout, brain MRS acquired at 24 and 48 h and cell death (TUNEL) evaluated at 48 h. There were no differences for insult severity. Core temperature was higher in HT group for first hour after HI. Comparing HT+M to HT, aEEG scores recovered more quickly by 19 h (p < 0.05); comparing HT+V to HT, aEEG recovered from 31 h (p < 0.05). Brain phosphocreatine/inorganic phosphate and NTP/exchangeable phosphate were higher at 48 h in HT+M versus HT (p = 0.036, p = 0.049 respectively). Including both 24 h and 48 h measurements, the rise in Lactate/N-acetyl aspartate was reduced in white (p = 0.030) and grey matter (p = 0.038) after HI. Reduced overall TUNEL positive cells were observed in HT+M (47.1 cells/mm2) compared to HT (123.8 cells/mm2) (p = 0.0003) and HT+V (97.5 cells/mm2) compared to HT (p = 0.012). Localized protection was seen in white matter for HT+M versus HT (p = 0.036) and internal capsule for HT+M compared to HT (p = 0.001) and HT+V versus HT (p = 0.006). Therapeutic melatonin levels (15–30mg/l) were achieved at 2 h and were neuroprotective following HI, but ethanol vehicle was partially protective. [ABSTRACT FROM AUTHOR]

Background: Spinal cord injury (SCI) is a highly debilitating pathology without curative treatment. One of the most promising disease modifying strategies consists in the implantation of stem cells to reduce inflammation and promote neural regeneration. In the present study we tested a new human bone marrow-derived stromal cell preparation (bmSC) as a therapy of SCI. Methods: Spinal cord contusion injury was induced in adult male rats at thoracic level T9/T10 using the Infinite Horizon impactor. One hour after lesion the animals were treated with a sub-occipital injection of human bmSC into the cisterna magna. No immune suppression was used. One dose of bmSC consisted, on average, of 2.3 million non-manipulated cells in 100 μL suspension, which was processed out of fresh human bone marrow from the iliac crest of healthy volunteers. Treatment efficacy was compared with intraperitoneal injections of methylprednisolone (MP) and saline. The recovery of motor functions was assessed during a surveillance period of nine weeks. Adverse events as well as general health, weight and urodynamic functions were monitored daily. After this time, the animals were perfused, and the spinal cord tissue was investigated histologically. Results: Rats treated with bmSC did not reject the human implants and showed no sign of sickness behavior or neuropathic pain. Compared to MP treatment, animals displayed better recovery of their SCI-induced motor deficits. There were no significant differences in the recovery of bladder control between groups. Histological analysis at ten weeks after SCI revealed no differences in tissue sparing and astrogliosis, however, bmSC treatment was accompanied with reduced axonal degeneration in the dorsal ascending fiber tracts, lower Iba1-immunoreactivity (IR) close to the lesion site and reduced apoptosis in the ventral grey matter. Neuroinflammation, as evidenced by CD68-IR, was significantly reduced in the MP-treated group. Conclusions: Human bmSC that were prepared by negative selection without expansion in culture have neuroprotective properties after SCI. Given the effect size on motor function, implantation in the acute phase was not sufficient to induce spinal cord repair. Due to their immune modulatory properties, allogeneic implants of bmSC can be used in combinatorial therapies of SCI. [ABSTRACT FROM AUTHOR]

Introduction Periconception obesity is associated with a higher risk for adverse perinatal outcomes such as gestational diabetes mellitus, preeclampsia, large for gestational age, operative delivery and preterm birth. Lifestyle interventions during pregnancy have resulted in insufficient effects on reducing these perinatal complications. A few reasons for this disappointing effect can be suggested: (1) the time period during pregnancy for improvement of developmental circumstances is too short; (2) the periconception period in which complications originate is not included; and (3) lifestyle interventions may not have been sufficiently multidisciplinary and customised. A preconception lifestyle intervention might be more effective to reduce perinatal complications. Therefore, the aim of the Towards Prepared mums study is to evaluate the effect of a lifestyle intervention starting prior to conception on lifestyle behaviour change. Methods and analysis This protocol outlines a non-blinded, randomised controlled trial. One hundred and twelve women (18–40 years of age) with overweight or obesity (body mass index≥25.0 kg/m²) who plan to conceive within 1 year will be randomised to either the intervention or care as usual group. The intervention group will receive a multidisciplinary, customised lifestyle intervention stimulating physical activity, a healthy diet and smoking cessation, if applicable. The lifestyle intervention and monitoring will take place until 12 months postpartum. The primary outcome is difference in weight in kg from baseline to 6 weeks postpartum. Secondary outcomes are gestational weight gain, postpartum weight retention, smoking cessation, dietary and physical activity habits. Furthermore, exploratory outcomes include body composition, cardiometabolic alterations, time to pregnancy, need for assisted reproductive technologies, perinatal complications of mother and child, and lung function of the child. Vaginal and oral swabs, samples of faeces, breast milk, placenta and cord blood will be stored for evaluation of microbial flora, epigenetic markers and breast milk composition. Furthermore, a cost-effectiveness analysis will take place. Ethics and dissemination Ethical approval was obtained from the Medical Ethical Committee of Maastricht University Medical Centre+ (NL52452.068.15/ METC152026). Knowledge derived from this study will be made available by publications in international peer-reviewed scientific journals and will be presented at (inter) national scientific conferences. A dissemination plan for regional and national implementation of the intervention is developed. [ABSTRACT FROM AUTHOR]

The conclusion of our recent paper that performance of the STAN device in clinical practice is potentially limited by high false-negative and high false-positive STAN-event rates and loss of ST waveform assessment capacity during severe hypoxemia, evoked comments by Kjellmer, Lindecrantz and Rosén. These comments can be summarized as follows: 1) STAN analysis is based on a unipolar lead but the authors used a negative aVF lead, and they did not validate this methodology; 2) The fetuses used in the study were too young to display the signals that the authors were trying to detect. In response to these comments we now provide both a theoretical and an experimental underpinning of our approach. In an in vivo experiment in human we placed several electrodes over the head (simulating different places of a scalp electrode), simultaneously recorded Einthoven lead I and II, and constructed −aVF from these two frontal leads. Irrespective of scalp electrode placement, the correlation between any of unipolar scalp electrode-derived signals and constructed–aVF was excellent (≥ 0.92). In response to the second comment we refer to a study which demonstrated that umbilical cord occlusion resulted in rapid increase in T/QRS ratio that coincided with initial hypertension and bradycardia at all gestational ages which were tested from 0.6–0.8 gestation. The animals of our study were in this gestational range and, hence, our experimental setup can be used to assess STAN’s quality to detect fetal hypoxia. In conclusion, we have clearly demonstrated the appropriateness of using–aVF as a proxy for a scalp electrode-derived signal in STAN in these preterm lambs. Investigation why STAN could not detect relevant ST-changes and instead produced erroneous alarms in our experimental setup is hampered by the fact that the exact STAN algorithm (signal processing and analysis) is not in the public domain. [ABSTRACT FROM AUTHOR]

This study compares the performance of pediatricians and anesthetists in neonatal and pediatric endotracheal intubations (ETI) during simulated settings. Participants completed a questionnaire and performed an ETI scenario on a neonatal and a child manikin. The procedures were recorded with head cameras and cameras attached to standard laryngoscope blades. The outcomes were successful intubation, time to successful intubation, number of attempts, complications, total performance score, end-assessment rating, and an assessment whether the participant was sufficiently able to perform an ETI. Fifty-two pediatricians and 52 anesthetists were included. For the neonatal ETI, the rate of successful intubation was in favor of anesthetists although not significant. Anesthetists performed significantly better in all other outcomes. Of the pediatricians, 65% was rated sufficiently adept to perform a neonatal ETI vs 100% of the anesthetists. Pediatricians (29%) overestimated while anesthetists (33%) underestimated their performance in neonatal ETI. For the pediatric ETI, all outcomes were significantly better for anesthetists. Only 15% of all pediatricians were considered sufficiently able to perform pediatric ETI vs 94% of the anesthetists.Conclusion: Anesthetists are far more adept in performing ETI in neonates and children compared with pediatricians in a simulated setting. Complications are expected to occur less frequently and less seriously when anesthetists perform ETI. What is Known: • Endotracheal intubation (ETI) performed by inexperienced care providers can lead to unsuccessful and/or prolonged intubation attempts. This can cause complications such as hypoxemia, trauma to the oropharynx and larynx, and prolonged interruption of resuscitation, which results in a high morbidity/mortality. • Fifty to 60 real-life ETI procedures are needed before ETI can be performed with a 90% success rate. Despite this, 18% of providers still require some assistance even after performing 80 intubations. Skill fade will occur if there is too little exposure. What is New: • This study shows that, on both neonatal and child manikins, anesthetists perform better in ETI compared with pediatricians. Besides this, complications are expected to occur less frequently and less seriously when anesthetists are performing the ETIs on neonates and children. • In those countries where there are no clear interprofessional agreements made in general hospitals on who will perform ETI on neonates and children in acute care settings, these agreements are urgently necessary. [ABSTRACT FROM AUTHOR]

Background: Late-onset sepsis (LOS) in preterm infants is a leading cause of mortality and morbidity. Timely recognition and initiation of antibiotics are important factors for improved outcomes. Identification of risk factors could allow selection of infants at an increased risk for LOS. Objectives: The aim was to identify risk factors for LOS. Methods: In this multicenter case-control study, preterm infants born at ≤30 weeks of gestation were included at 9 neonatal intensive care units. Detailed demographical and clinical data were collected daily up to day 28 postnatally. Clinical and demographic risk factors were identified using univariate and multivariate regression analyses in a 1: 1 matched case-control cohort. Results: In total, 755 infants were included, including 194 LOS cases (41 gram-negative cases, 152 gram-positive cases, and 1 fungus). In the case-control cohort, every additional day of parenteral feeding increased the risk for LOS (adjusted OR = 1.29; 95% CI 1.07–1.55; p = 0.006), whereas antibiotics administration decreased this risk (OR = 0.08; 95% CI 0.01–0.88; p = 0.039). These findings could largely be attributed to specific LOS-causative pathogens, since these predictive factors could be identified for gram-positive, but not for gram-negative, LOS cases. Specifically cephalosporins administration prior to clinical onset was inversely related to coagulase-negative staphylococcus LOS (CoNS-LOS) development. Formula feeding was an independent risk factor for development of CoNS-LOS (OR = 3.779; 95% CI 1.257–11.363; p = 0.018). Conclusion: The length of parenteral feeding was associated with LOS, whereas breastmilk administration was protective against CoNS-LOS. A rapid advancement of enteral feeding, preferably with breastmilk, may proportionally reduce the number of parenteral feeding days and consequently the risk for LOS. [ABSTRACT FROM AUTHOR]

Objective: Pulse transit time (PTT) refers to the time it takes a pulse wave to travel between two arterial sites. PTT can be estimated, amongst others, using the electrocardiogram (ECG) and photoplethysmogram (PPG). Because we observed a sawtooth artifact in the PTT while using standard patient monitoring equipment for ECG and PPG, we explored the reasons for this artifact. Methods: PPG and ECG were simulated at a heartrate of both 100 and 160 beats per minute while using a Masimo PPG post-processing module and a Philips patient monitor setup at the neonatal intensive care unit. Two different post-processing modules were used. PTT was defined as the difference between the R-peak in the ECG and the point of 50% increase in the PPG. Results: A sawtooth artifact was seen in all simulations. Both length (59.2 to 72.4 s) and amplitude (30.8 to 36.0 ms) of the sawtooth were dependent on the post-processing module used. Furthermore, the absolute PTT value differed up to 250 ms depending on post-processing module and heart rate. The sawtooth occurred because the PPG wave continuously showed a minimal prolongation during the length of the sawtooth, followed by a sudden shortening. Both artifacts were generated in the post-processing module containing Masimo algorithms. Conclusion: Post-processing of the PPG signal in the Masimo module of the Philips patient monitor introduces a sawtooth in PPG and derived PTT. This sawtooth, together with a large module-dependent absolute difference in PTT, renders the thus-derived PTT insufficient for clinical purposes. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is a relatively common disease in very-low-birth-weight infants and is associated with high mortality and morbidity. In survivors, neurodevelopmental impairment is frequently seen. The exact etiology remains largely to be elucidated, but microbiota are considered to play a major role in the development of NEC. Furthermore, emerging evidence exists that the microbiota is also of importance in brain function and development. Therefore, microbiota characterization has not only potential as a diagnostic or even preventive tool to predict NEC, but may also serve as a biomarker to monitor and possibly even as a target to manipulate brain development. Analysis of fecal volatile organic compounds, which shape the volatile metabolome and reflect microbiota function and host interaction, has been shown to be of interest in the diagnosis of NEC and late-onset sepsis. In this review, we discuss evidence of the role of the complex interplay between microbiota, NEC, and brain development, including the brain-gut axis in preterm infants. [ABSTRACT FROM AUTHOR]

Disease modeling has become challenging in the context of amyotrophic lateral sclerosis (ALS), as obtaining viable spinal motor neurons from postmortem patient tissue is an unlikely possibility. Limitations in the animal models due to their phylogenetic distance from human species hamper the success of translating possible findings into therapeutic options. Accordingly, there is a need for developing humanized models as a lead towards identifying successful therapeutic possibilities. In this study, human embryonic stem cells—BJNHem20—were differentiated into motor neurons expressing HB9, Islet1, and choline acetyl transferase using retinoic acid and purmorphamine. These motor neurons discharged spontaneous action potentials with two different frequencies (< 5 and > 5 Hz), and majority of them were principal neurons firing with < 5 Hz. Exposure to cerebrospinal fluid from ALS patients for 48 h induced several degenerative changes in the motor neurons as follows: cytoplasmic changes such as beading of neurites and vacuolation; morphological alterations, viz., dilation and vacuolation of mitochondria, curled and closed Golgi architecture, dilated endoplasmic reticulum, and chromatin condensation in the nucleus; lowered activity of different mitochondrial complex enzymes; reduced expression of brain-derived neurotrophic factor; up-regulated neurofilament phosphorylation and hyperexcitability represented by increased number of spikes. All these changes along with the enhanced expression of pro-apoptotic proteins—Bax and caspase 9—culminated in the death of motor neurons. [ABSTRACT FROM AUTHOR]

Importance: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking.Objective: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants.Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017.Interventions: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190).Main Outcomes and Measures: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age.Results: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%).Conclusions and Relevance: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication.Trial Registration: Netherlands National Trial Register Identifier: NTR2768. [ABSTRACT FROM AUTHOR]

Background The intestinal microbiota has increasingly been considered to play a role in the etiology of late-onset sepsis (LOS). We hypothesize that early alterations in fecal volatile organic compounds (VOCs), reflecting intestinal microbiota composition and function, allow for discrimination between infants developing LOS and controls in a preclinical stage. Methods In 9 neonatal intensive care units in the Netherlands and Belgium, fecal samples of preterm infants born at a gestational age ≤30 weeks were collected daily, up to the postnatal age of 28 days. Fecal VOC were measured by high-field asymmetric waveform ion mobility spectrometry (FAIMS). VOC profiles of LOS infants, up to 3 days prior to clinical LOS onset, were compared with profiles from matched controls. Results In total, 843 preterm born infants (gestational age ≤30 weeks) were included. From 127 LOS cases and 127 matched controls, fecal samples were analyzed by means of FAIMS. Fecal VOCs allowed for preclinical discrimination between LOS and control infants. Focusing on individual pathogens, fecal VOCs differed significantly between LOS cases and controls at all predefined time points. Highest accuracy rates were obtained for sepsis caused by Escherichia coli, followed by sepsis caused by Staphylococcus aureus and Staphylococcus epidermidis. Conclusions Fecal VOC analysis allowed for preclinical discrimination between infants developing LOS and matched controls. Early detection of LOS may provide clinicians a window of opportunity for timely initiation of individualized therapeutic strategies aimed at prevention of sepsis, possibly improving LOS-related morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: The identification of independent clinical risk factors for necrotizing enterocolitis (NEC) may contribute to early selection of infants at risk, allowing for the development of targeted strategies aimed at the prevention of NEC. Objective: The objective of this study was to identify independent risk factors contributing to the development of NEC in a large multicenter cohort. Methods: This prospective cohort study was performed in 9 neonatal intensive care units. Infants born at a gestational age ≤30 weeks were included. Demographic and clinical data were collected daily until day 28 postnatally. Factors predictive of the development of NEC were identified using univariate and multivariable analyses in a 1: 5 matched case-control cohort. Results: In total, 843 infants (56 NEC cases) were included in this study. In the case-control cohort, univariate analysis identified sepsis prior to the onset of NEC and formula feeding to be associated with an increased risk of developing NEC, whereas the administration of antibiotics directly postpartum was inversely associated with NEC. In a multivariable logistic regression model, enteral feeding type and the number of days parenterally fed remained statistically significantly associated with NEC, whereas the administration of antibiotics directly after birth was associated with a lower risk of developing NEC. Conclusions: Formula feeding and prolonged (duration of) parenteral feeding were associated with an increased risk of NEC. Contrary to expectations, the initiation of treatment with antibiotics within 24 h after birth was inversely associated with NEC. [ABSTRACT FROM AUTHOR]

Background and Objectives: Several mechanisms have been proposed for the sudden unexpected death in epilepsy patients, such as cardiac arrhythmias, a decrease in heart rate variability and the use of anti-epileptic drugs (AEDs). Although carbamazepine is commonly used as an AED, the exact working mechanism of this drug as well as its effect on the heart are not completely understood. The aim of this study was to determine whether chronic carbamazepine therapy in patients with focal seizures and impaired awareness has an effect on the electrocardiogram (ECG).Subjects and Methods: This cross-sectional study included 36 patients with focal seizures and impaired awareness treated for 12-32 months with carbamazepine monotherapy and 38 healthy volunteers. A 5-min modified three-electrode chest lead ECG with lead II configuration was recorded using LabChart 7 ECG software module at 1000-Hz sampling frequency. All data analysis was performed using custom-made Matlab 2015b scripts. ECGs of patients and controls were compared with respect to heart rate, time intervals and measures of short- and long-term variation.Results: There were no significant differences in heart rate and ECG time intervals between the patient and control groups. Measures on short- and long-term variability also did not show any significant group differences.Conclusion: Our study shows that chronic use of carbamazepine as monotherapy does not have any significant effects on ECG time intervals or measures of short- and long-term variability. [ABSTRACT FROM AUTHOR]

Background: The current exploratory study was aimed at estimating measures of blood pressure variability (BPV) and baroreflex sensitivity (BRS) in a healthy population in the Indian sub-continent. Methods: One hundred and forty-two healthy subjects were recruited for the study. Blood pressure (BP) was recorded continuously for 15 min using the Finometer (Finapres Medical Systems, The Netherlands). For offline analysis, Nevrokard cardiovascular parameter analysis (CVPA) software (version 2.1.0) was used for BPV analysis. BRS was determined by spectral and sequence methods. One-way ANOVA and Bonferroni's test were used to compare parameters. Pearson's correlation coefficient was employed to look for possible associations between age and other continuous variables. Results: Out of 196 screened volunteers, 54 were excluded and 142 subjects were grouped based on ages as 10-19 years (group 1), 20-29 years (group 2), 30-39 years (group 3), 40-49 years (group 4), and 50-59 years (group 5). Within groups, body mass index (BMI, p = 0.000) and BP (systolic and diastolic) were significantly different. Post hoc analysis showed mean blood pressure (MBP) and diastolic blood pressure (DBP) differing significantly between groups 1 and 4 (p < 0.05 for both) along with other cardiovascular parameters. Age correlated positively with BMI and all parameters of BP. Significant gender differences were observed for stroke volume, cardiac output, up BRS, total BRS, peripheral resistance (PR), and aortic impedance. Conclusions: Our study has provided reference values for BPV and BRS in an Indian population. It also indicates age-related neurocardiac imbalance and possible utility of these tests for screening at the start of neurocardiac damage in a healthy population. [ABSTRACT FROM AUTHOR]

Background: Antenatal corticosteroids (ACS) improve preterm neonatal outcomes. However, uncertainty remains regarding the safety of ACS exposure for the developing fetus, particularly its neurosensory development. Objectives: We investigated the effect of single and multiple ACS exposures on auditory nerve development in an ovine model of pregnancy. Methods: Ewes with a single fetus (gestational age [GA] 100 days) received an intramuscular injection of 150 mg medroxyprogesterone-acetate, followed by intramuscular (i) betamethasone (0.5 mg/kg) on days 104, 111, and 118 GA; (ii) betamethasone on day 104 and saline on days 111 and 118 GA; or (iii) saline on days 104, 111, and 118 GA, with delivery on day 125 GA. Transmission electron microscope images of lamb auditory nerve preparations were digitally analyzed to determine auditory nerve morphology and myelination. Results: Relative to the control, mean auditory nerve myelin area was significantly increased in the multiple-treatment group (p < 0.001), but not in the single-treatment group. Increased myelin thickness was significantly changed only in a subgroup analysis for those axons with myelin thickness greater than the median value (p < 0.001). Morphological assessments showed that the increased myelin area was due to an increased likelihood of decompacted areas (p = 0.005; OR = 2.14, 95% CI 1.26–3.63; 31.6 vs. 18.2% in controls) and irregular myelin deposition (p = 0.001; OR = 5.91, 95% CI 2.16–16.19; 49.0 vs. 16.8% in controls) in the myelin sheath. Conclusions: In preterm sheep, ACS exposure increased auditory nerve myelin area, potentially due to disruption of normal myelin deposition. [ABSTRACT FROM AUTHOR]

Introduction: The inconclusive clinical results for ST-waveform analysis (STAN) in detecting fetal hypoxemia may be caused by the signal processing of the STAN-device itself. We assessed the performance of a clinical STAN device in signal processing and in detecting hypoxemia in a fetal sheep model exposed to prolonged umbilical cord occlusion (UCO). Methods: Eight fetal lambs were exposed to 25 minutes of UCO. ECG recordings were analyzed during a baseline period and during UCO. STAN-event rates and timing of episodic T/QRS rise, baseline T/QRS rise and the occurrence of biphasic ST-waveforms, as well as signal loss, were assessed. Results: During baseline conditions of normoxemia, a median of 40 (IQR, 25–70) STAN-events per minute were detected, compared to 10 (IQR, 2–22) during UCO. During UCO STAN-events were detected in five subjects within 10 minutes and in six subjects after 18 minutes, respectively. Two subjects did not generate any STAN-event during UCO. Biphasic ST event rate was reduced during UCO (median 0, IQR 0–5), compared to baseline (median 32, IQR, 6–55). ST-waveforms could not be assessed in 62% of the recording time during UCO, despite a good quality of the ECG signal. Conclusions: The STAN device showed limitations in detecting hypoxemia in fetal sheep after prolonged UCO. The STAN device produced high false positive event rates during baseline and did not detect T/QRS changes adequately after prolonged fetal hypoxemia. During 14% of baseline and 62% of the UCO period, the STAN-device could not process the ECG signal, despite its good quality. Resolving these issues may improve the clinical performance of the STAN device. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is the most common complication after preterm birth. Pasteurized donor human milk (DHM) has increasingly become the standard of care for very preterm infants over the use of preterm formula (PF) if the mother's own milk (MOM) is unavailable. Studies have reported beneficial effects of DHM on BPD. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies on the effects of DHM on BPD and other respiratory outcomes. Eighteen studies met the inclusion criteria. Meta-analysis of RCTs could not demonstrate that supplementation of MOM with DHM reduced BPD when compared to PF (three studies, risk ratio (RR) 0.89,95% confidence interval (CI) 0.60-1.32). However, meta-analysis of observational studies showed that DHM supplementation reduced BPD (8 studies, RR 0.78, 95% CI 0.67-0.90). An exclusive human milk diet reduced the risk of BPD, compared to a diet with PF and/or bovine milk-based fortifier (three studies, RR 0.80, 95% CI 0.68-0.95). Feeding raw MOM, compared to feeding pasteurized MOM, protected against BPD (two studies, RR 0.77,95% CI 0.62-0.96). In conclusion, our data suggest that DHM protects against BPD in very preterm infants. [ABSTRACT FROM AUTHOR]

Chorioamnionitis is associated with adverse neurodevelopmental outcomes in preterm infants. Ureaplasma spp. are the microorganisms most frequently isolated from the amniotic fluid of women diagnosed with chorioamnionitis. However, controversy remains concerning the role of Ureaplasma spp. in the pathogenesis of neonatal brain injury. We hypothesize that reexposure to an inflammatory trigger during the perinatal period might be responsible for the variation in brain outcomes of preterms following Ureaplasma -- driven chorioamnionitis. To investigate these clinical scenarios, we performed a detailed multimodal study in which ovine neurodevelopmental outcomes were assessed following chronic intra-amniotic Ureaplasma parvum (UP) infection either alone or combined with subsequent lipopolysaccharide (LPS) exposure. We show that chronic intra-amniotic UP exposure during the second trimester provoked a decrease in astrocytes, increased oligodendrocyte numbers, and elevated 5-methylcytosine levels. In contrast, short-term LPS exposure before preterm birth induced increased microglial activation, myelin loss, elevation of 5-hydroxymethylcytosine levels, and lipid profile changes. These LPS-induced changes were prevented by chronic preexposure to UP (pre-conditioning). These data indicate that chronic UP exposure has dual effects on preterm brain development in utero. On the one hand, prolonged UP exposure causes detrimental cerebral changes that may predispose to adverse postnatal clinical outcomes. On the other, chronic intra-amniotic UP exposure preconditions the brain against a second inflammatory hit. This study demonstrates that microbial interactions and the timing and duration of the inflammatory insults determine the effects on the fetal brain. Therefore, this study helps to understand the complex and diverse postnatal neurological outcomes following UP driven chorioamnionitis. [ABSTRACT FROM AUTHOR]