Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus.

BACKGROUND: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. METHODS: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. RESULTS: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. CONCLUSIONS: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).

Clinical Decision Support for Improved Neonatal Care: The Development of a Machine Learning Model for the Prediction of Late-onset Sepsis and Necrotizing Enterocolitis.

OBJECTIVE: To develop an artificial intelligence-based software system for predicting late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in infants admitted to the neonatal intensive care unit (NICU). STUDY DESIGN: Single-center, retrospective cohort study, conducted in the NICU of the Antwerp University Hospital. Continuous monitoring data of 865 preterm infants born at <32 weeks gestational age, admitted to the NICU in the first week of life, were used to train an XGBoost machine learning (ML) algorithm for LOS and NEC prediction in a cross-validated setup. Afterward, the model's performance was assessed on an independent test set of 148 patients (internal validation). RESULTS: The ML model delivered hourly risk predictions with an overall sensitivity of 69% (142/206) for all LOS/NEC episodes and 81% (67/83) for severe LOS/NEC episodes. The model showed a median time gain of ≤10 hours (IQR, 3.1-21.0 hours), compared with historical clinical diagnosis. On the complete retrospective dataset, the ML model made 721 069 predictions, of which 9805 (1.3%) depicted a LOS/NEC probability of ≥0.15, resulting in a total alarm rate of <1 patient alarm-day per week. The model reached a similar performance on the internal validation set. CONCLUSIONS: Artificial intelligence technology can assist clinicians in the early detection of LOS and NEC in the NICU, which potentially can result in clinical and socioeconomic benefits. Additional studies are required to quantify further the effect of combining artificial and human intelligence on patient outcomes in the NICU.

Hair as an alternative matrix to assess exposure of premature neonates to phthalate and alternative plasticizers in the neonatal intensive care unit.

Due to adverse health effects, di-(2-ethylhexyl) phthalate (DEHP), a plasticizer used to soften plastic medical devices (PMDs), was restricted, and gradually replaced by alternative plasticizers (APs). Up to this date, urine was the sole matrix studied for plasticizer exposure in neonates hospitalized in the neonatal intensive care unit (NICU), a population highly vulnerable to toxic effects of plasticizers. The primary aim of this study was to assess simultaneous measurement of phthalate and AP metabolites in neonatal scalp hair. In addition, we aimed to use this matrix to investigate exposure of premature neonates to plasticizers during their stay in the NICU. Hair samples in this study were collected from premature neonates and their mothers included in a prospective birth cohort study in a tertiary NICU at the Antwerp University Hospital (UZA), Belgium. Samples from premature neonates (n = 45) and their mothers (n = 107) as well as from control neonates (n = 24) and mothers (n = 29) were analyzed using liquid-chromatography coupled to tandem mass spectrometry. This is the first study reporting metabolites of phthalate and alternative plasticizers in neonatal hair samples as biomarkers for exposure to these plasticizers. Results showed that hair sampled from premature neonates after a NICU stay contained significantly higher metabolite concentrations of both phthalates (DEHP, DiBP, and DnBP; 9.0-2500, 9.3-2200, and 24.7-5300 ng/g), and alternative plasticizers (DEHA, DEHT, and TOTM; 38.8-3400, 127.5-5700, and 10.8-8700 ng/g) - when compared to healthy control neonates. Besides, DEHP and DEHT metabolite concentrations were significantly higher than in hair sampled from adult populations. In addition, prolonged NICU exposure to non-invasive respiratory support devices and gastric tubes was correlated with increased concentrations in hair samples, indicating accumulation of plasticizers in this alternative matrix. In conclusion, our data indicate that preterm neonates are still highly exposed to phthalate and alternative plasticizers during NICU stay, despite the EU Medical Devices Regulation.

Functional respiratory imaging provides novel insights into the long-term respiratory sequelae of bronchopulmonary dysplasia.

RATIONALE: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Lung function and imaging are classically used to assess BPD. Functional respiratory imaging (FRI) combines a structural and functional assessment of the airways and their vasculature. We aimed to assess BPD using FRI and to correlate these findings with the clinical presentation. METHODS: We included 37 adolescents with a history of preterm birth (22 BPD cases and 15 preterm controls). The study protocol included a detailed history, lung function testing and computed tomography (CT) (at total lung capacity (TLC) and functional residual capacity (FRC)) with FRI. CT images were also assessed using the Aukland scoring system. RESULTS: BPD patients had lower forced expiratory volume in 1 s to forced vital capacity ratio (p=0.02) and impaired diffusion capacity (p=0.02). Aukland CT scores were not different between the two groups. FRI analysis showed higher lobar volumes in BPD patients at FRC (p<0.01), but not at TLC. Airway resistance was significantly higher in the BPD group, especially in the distal airways. Additionally, FRI showed more air trapping in BPD patients, in contrast to findings on conventional CT images. CONCLUSION: This study is the first to use FRI in research for BPD. FRI analysis showed higher lobar volumes in BPD patients, indicating air trapping and reduced inspiratory capacity. In contrast to Aukland CT scores, FRI showed more air trapping in the BPD group, suggesting that FRI might be a more sensitive detection method. Importantly, we also showed increased distal airway resistance in BPD patients. By combining structural and functional assessment, FRI may help to better understand the long-term sequelae of BPD.

Growth and endothelial function in the first 2 years of life.

OBJECTIVE: To test the hypothesis that the inverse association between infant growth and endothelial function at 6 months would persist to 24 months and that accelerated growth would lead to an increased percent body fat, which would, in turn, impact negatively on endothelial function. STUDY DESIGN: In a prospective observational study, 104 healthy term newborns underwent anthropometry and measurements of vascular vasodilation at 0, 6, 12, and 24 months. We recorded maximum vasodilation in response to acetylcholine (endothelium-dependent) and nitroprusside (endothelium-independent) by use of laser-Doppler vascular perfusion monitoring of the forearm skin vasculature. Additional anthropometry at 1 and 3 months was collected from child welfare centers. The data were analyzed by multilevel linear regression. RESULTS: Weight gain from 0-1 month was associated inversely with maximum perfusion in response to acetylcholine at the age of 2 years (b = -8.28 perfusion units [PU] per Δ z-score, P = .03). Weight gain from 0-1 month was related positively to maximum perfusion in response to nitroprusside (b = 10.12 PU per Δ z-score, P = .04), as was birth weight (b = 8.02 PU per z-score, P = .02). Body fat percentage did not have a significant effect in any of the perfusion models and was not related to maximum perfusion at 2 years. CONCLUSION: Infant weight gain from 0-1 month is inversely related to endothelial function in healthy term infants, at least to the age of 2 years. This relationship was not explained by an increased percentage body fat.

Economic analysis comparing induction of labor and expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks (PPROMEXIL trial).

OBJECTIVE: To compare the costs of induction of labor and expectant management in women with preterm prelabor rupture of membranes (PPROM). DESIGN: Economic analysis based on a randomized clinical trial. SETTING: Obstetric departments of eight academic and 52 non-academic hospitals in the Netherlands. POPULATION: Women with PPROM near term who were not in labor 24 h after PPROM. METHODS: A cost-minimization analysis was done from a health care provider perspective, using a bottom-up approach to estimate resource utilization, valued with unit-costs reflecting actual costs. MAIN OUTCOME MEASURES: Primary health outcome was the incidence of neonatal sepsis. Direct medical costs were estimated from start of randomization to hospital discharge of mother and child. RESULTS: Induction of labor did not significantly reduce the probability of neonatal sepsis [2.6% vs. 4.1%, relative risk 0.64 (95% confidence interval 0.25-1.6)]. Mean costs per woman were €8094 for induction and €7340 for expectant management (difference €754; 95% confidence interval -335 to 1802). This difference predominantly originated in the postpartum period, where the mean costs were €5669 for induction vs. €4801 for expectant management. Delivery costs were higher in women allocated to induction than in women allocated to expectant management (€1777 vs. €1153 per woman). Antepartum costs in the expectant management group were higher because of longer antepartum maternal stays in hospital. CONCLUSIONS: In women with pregnancies complicated by PPROM near term, induction of labor does not reduce neonatal sepsis, whereas costs associated with this strategy are probably higher.

Ongoing exposure to endocrine disrupting phthalates and alternative plasticizers in neonatal intensive care unit patients.

Due to endocrine disrupting effects, di-(2-ethylhexyl) phthalate (DEHP), a plasticizer used to soften plastic medical devices, was restricted in the EU Medical Devices Regulation (EU MDR 2017/745) and gradually replaced by alternative plasticizers. Neonates hospitalized in the neonatal intensive care unit (NICU) are vulnerable to toxic effects of plasticizers. From June 2020 to August 2022, urine samples (n = 1070) were repeatedly collected from premature neonates (n = 132, 4-10 samples per patient) born at <31 weeks gestational age and/or <1500 g birth weight in the Antwerp University Hospital, Belgium. Term control neonates (n = 21, 1 sample per patient) were included from the maternity ward. Phthalate and alternative plasticizers' metabolites were analyzed using liquid-chromatography coupled to tandem mass spectrometry. Phthalate metabolites were detected in almost all urine samples. Metabolites of alternative plasticizers, di-(2-ethylhexyl)-adipate (DEHA), di-(2-ethylhexyl)-terephthalate (DEHT) and cyclohexane-1,2-dicarboxylic-di-isononyl-ester (DINCH), had detection frequencies ranging 30-95 %. Urinary phthalate metabolite concentrations were significantly higher in premature compared to control neonates (p = 0.023). NICU exposure to respiratory support devices and blood products showed increased phthalate metabolite concentrations (p < 0.001). Phthalate exposure increased from birth until four weeks postnatally. The estimated phthalate intake exceeded animal-derived no-effect-levels (DNEL) in 10 % of samples, with maximum values reaching 24 times the DNEL. 29 % of premature neonates had at least once an estimated phthalate intake above the DNEL. Preterm neonates are still exposed to phthalates during NICU stay, despite the EU Medical Devices Regulation. NICU exposure to alternative plasticizers is increasing, though currently not regulated, with insufficient knowledge on their hazard profile.

Neonatal exposure to phthalate and alternative plasticizers via parenteral nutrition.

Di-(2-ethylhexyl) phthalate (DEHP), a plasticizer used to soften plastic medical devices (PMDs), was restricted in PMDs due to adverse health effects, being gradually replaced by alternative plasticizers (APs). Parenteral nutrition (PN), essential in the care for premature neonates in the neonatal intensive care unit, is stored in plastic storage bags and administered intravenously through plastic infusion circuits. We investigated to which extent PN contributes to current phthalate and AP exposure in premature neonates. First, we showed that DEHP and several APs are present in relevant amounts in PMDs used for neonatal PN administration. Secondly, ex vivo experiments mimicking clinical PN administration showed that lipid emulsions contained significant concentrations of DEHP and several APs (ATBC, TOTM, DEHT & DEHA), while hardly any plasticizers were detected in non-lipid solutions. ATBC leached from infusion circuits, while lipid emulsions were the major source for DEHP, TOTM, DEHT, and DEHA. PN administration resulted in estimated daily exposures of 13.9 µg/kg/d DEHP and 95.7 µg/kg/d ATBC in premature neonates, below their respective reference doses. Our data indicate that premature neonates requiring PN are still exposed to DEHP, as well as to a range of APs, making it a target for reduction of harmful plasticizer exposure.

Development of a neonatal Göttingen Minipig model for dose precision in perinatal asphyxia: technical opportunities, challenges, and potential further steps.

Animal models provide useful information on mechanisms in human disease conditions, but also on exploring (patho)physiological factors affecting pharmacokinetics, safety, and efficacy of drugs in development. Also, in pediatric patients, nonclinical data can be critical for better understanding the disease conditions and developing new drug therapies in this age category. For perinatal asphyxia (PA), a condition defined by oxygen deprivation in the perinatal period and possibly resulting in hypoxic ischemic encephalopathy (HIE) or even death, therapeutic hypothermia (TH) together with symptomatic drug therapy, is the standard approach to reduce death and permanent brain damage in these patients. The impact of the systemic hypoxia during PA and/or TH on drug disposition is largely unknown and an animal model can provide useful information on these covariates that cannot be assessed separately in patients. The conventional pig is proven to be a good translational model for PA, but pharmaceutical companies do not use it to develop new drug therapies. As the Göttingen Minipig is the commonly used pig strain in nonclinical drug development, the aim of this project was to develop this animal model for dose precision in PA. This experiment consisted of the instrumentation of 24 healthy male Göttingen Minipigs, within 24 h of partus, weighing approximately 600 g, to allow the mechanical ventilation and the multiple vascular catheters inserted for maintenance infusion, drug administration and blood sampling. After premedication and induction of anesthesia, an experimental protocol of hypoxia was performed, by decreasing the inspiratory oxygen fraction (FiO2) at 15%, using nitrogen gas. Blood gas analysis was used as an essential tool to evaluate oxygenation and to determine the duration of the systemic hypoxic insult to approximately 1 h. The human clinical situation was mimicked for the first 24 h after birth in case of PA, by administering four compounds (midazolam, phenobarbital, topiramate and fentanyl), frequently used in a neonatal intensive care unit (NICU). This project aimed to develop the first neonatal Göttingen Minipig model for dose precision in PA, allowing to separately study the effect of systemic hypoxia versus TH on drug disposition. Furthermore, this study showed that several techniques that were thought to be challenging or even impossible in these very small animals, such as endotracheal intubation and catheterization of several veins, are feasible by trained personnel. This is relevant information for laboratories using the neonatal Göttingen Minipig for other disease conditions or drug safety testing.

Induction of labor versus expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks: a randomized controlled trial.

BACKGROUND: At present, there is insufficient evidence to guide appropriate management of women with preterm prelabor rupture of membranes (PPROM) near term. METHODS AND FINDINGS: We conducted an open-label randomized controlled trial in 60 hospitals in The Netherlands, which included non-laboring women with >24 h of PPROM between 34(+0) and 37(+0) wk of gestation. Participants were randomly allocated in a 1:1 ratio to induction of labor (IoL) or expectant management (EM) using block randomization. The main outcome was neonatal sepsis. Secondary outcomes included mode of delivery, respiratory distress syndrome (RDS), and chorioamnionitis. Patients and caregivers were not blinded to randomization status. We updated a prior meta-analysis on the effect of both interventions on neonatal sepsis, RDS, and cesarean section rate. From 1 January 2007 to 9 September 2009, 776 patients in 60 hospitals were eligible for the study, of which 536 patients were randomized. Four patients were excluded after randomization. We allocated 266 women (268 neonates) to IoL and 266 women (270 neonates) to EM. Neonatal sepsis occurred in seven (2.6%) newborns of women in the IoL group and in 11 (4.1%) neonates in the EM group (relative risk [RR] 0.64; 95% confidence interval [CI] 0.25 to 1.6). RDS was seen in 21 (7.8%, IoL) versus 17 neonates (6.3%, EM) (RR 1.3; 95% CI 0.67 to 2.3), and a cesarean section was performed in 36 (13%, IoL) versus 37 (14%, EM) women (RR 0.98; 95% CI 0.64 to 1.50). The risk for chorioamnionitis was reduced in the IoL group. No serious adverse events were reported. Updating an existing meta-analysis with our trial results (the only eligible trial for the update) indicated RRs of 1.06 (95% CI 0.64 to 1.76) for neonatal sepsis (eight trials, 1,230 neonates) and 1.27 (95% CI 0.98 to 1.65) for cesarean section (eight trials, 1,222 women) for IoL compared with EM. CONCLUSIONS: In women whose pregnancy is complicated by late PPROM, neither our trial nor the updated meta-analysis indicates that IoL substantially improves pregnancy outcomes compared with EM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29313500

Management of late-preterm premature rupture of membranes: the PPROMEXIL-2 trial.

OBJECTIVE: The evidence for the management of near term prelabor rupture of membranes is poor. From January 2007 until September 2009, we performed the PPROM Expectant Management versus Induction of Labor (PPROMEXIL) trial. In this trial, we showed that in women with preterm prelabor rupture of membranes (PPROM), the incidence of neonatal sepsis was low, and the induction of labor (IoL) did not reduce this risk. Because the PPROMEXIL trial was underpowered and because of a lower-than-expected incidence of neonatal sepsis, we performed a second trial (PPROMEXIL-2), aiming to randomize 200 patients to improve the evidence in near-term PPROM. STUDY DESIGN: In a nationwide multicenter study, nonlaboring women with PPROM between 34 and 37 weeks' gestational age were eligible for inclusion. Patients were randomized to IoL or expectant management (EM). The primary outcome measure was neonatal sepsis. RESULTS: From December 2009 until January 2011, we randomized 100 women to IoL and 95 to EM. Neonatal sepsis was seen in 3 neonates (3.0%) in the IoL-group versus 4 neonates (4.1%) in the EM group (relative risk, 0.74; 95% confidence interval, 0.17-3.2). One of the sepsis cases in the IoL group resulted in neonatal death because of asphyxia. There were no significant differences in secondary outcomes. CONCLUSION: The risk of neonatal sepsis after PPROM near term is low. Induction of labor does not reduce this risk.

Determinants of infant growth in four age windows: a twin study.

OBJECTIVE: To identify determinants of growth during infancy. STUDY DESIGN: The sample included 424 twin pairs from the East Flanders Prospective Twin Survey. Multilevel regression analysis was performed and intrapair growth correlations were calculated. The main outcome measure was growth, measured in g/kg/d (0-1 month) or in change in weight z-score (0-6, 6-12 and 12-24 months). RESULTS: Growth during infancy was associated with birth weight and gestational age. One z-score increase in birth weight resulted in -1.77 g/kg/d less growth from 0-1 month (P < .0001). The effect size decreased with age until -0.02 (P = .70) z-scores less growth from 12 to 24 months. Corresponding numbers for one z-score increase in gestational age decreased from 0.78 (P = .001) to 0.06 (P = .40). From 12 to 24 months, paternal height had a significant positive effect. The difference in growth similarity within the twin pair between monozygotic and dizygotic twins increased from non-significant from 0 to 1 month (P = .49) to a monozygotic:dizygotic ratio approximating 2:1 from 12 to 24 months (P = .002). CONCLUSION: From 0 to 1 month, environmental factors are most important for growth, whereas genetic factors become more important over time. This is a first step in identifying age windows for future counseling and interventions on the effects of accelerated growth.

Multi-centre, randomised non-inferiority trial of early treatment versus expectant management of patent ductus arteriosus in preterm infants (the BeNeDuctus trial): statistical analysis plan.

BACKGROUND: Controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome. In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy. METHODS/DESIGN: The BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24-72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent. The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data. TRIAL REGISTRATION: ClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial Registry, sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28.

Machine Learning to Support Hemodynamic Intervention in the Neonatal Intensive Care Unit.

Hemodynamic support in neonatal intensive care is directed at maintaining cardiovascular wellbeing. At present, monitoring of vital signs plays an essential role in augmenting care in a reactive manner. By applying machine learning techniques, a model can be trained to learn patterns in time series data, allowing the detection of adverse outcomes before they become clinically apparent. In this review we provide an overview of the different machine learning techniques that have been used to develop models in hemodynamic care for newborn infants. We focus on their potential benefits, research pitfalls, and challenges related to their implementation in clinical care.

The Neonatal and Juvenile Pig in Pediatric Drug Discovery and Development.

Pharmacotherapy in pediatric patients is challenging in view of the maturation of organ systems and processes that affect pharmacokinetics and pharmacodynamics. Especially for the youngest age groups and for pediatric-only indications, neonatal and juvenile animal models can be useful to assess drug safety and to better understand the mechanisms of diseases or conditions. In this respect, the use of neonatal and juvenile pigs in the field of pediatric drug discovery and development is promising, although still limited at this point. This review summarizes the comparative postnatal development of pigs and humans and discusses the advantages of the juvenile pig in view of developmental pharmacology, pediatric diseases, drug discovery and drug safety testing. Furthermore, limitations and unexplored aspects of this large animal model are covered. At this point in time, the potential of the neonatal and juvenile pig as nonclinical safety models for pediatric drug development is underexplored.

Flexible spike timing of layer 5 neurons during dynamic beta oscillation shifts in rat prefrontal cortex.

Human brain oscillations occur in different frequency bands that have been linked to different behaviours and cognitive processes. Even within specific frequency bands such as the beta- (14-30 Hz) or gamma-band (30-100 Hz), oscillations fluctuate in frequency and amplitude. Such frequency fluctuations most probably reflect changing states of neuronal network activity, as brain oscillations arise from the correlated synchronized activity of large numbers of neurons. However, the neuronal mechanisms governing the dynamic nature of amplitude and frequency fluctuations within frequency bands remain elusive. Here we show that in acute slices of rat prefrontal cortex (PFC), carbachol-induced oscillations in the beta-band show frequency and amplitude fluctuations. Fast and slow non-harmonic frequencies are distributed differentially over superficial and deep cortical layers, with fast frequencies being present in layer 3, while layer 6 only showed slow oscillation frequencies. Layer 5 pyramidal cells and interneurons experience both fast and slow frequencies and they time their spiking with respect to the dominant frequency. Frequency and phase information is encoded and relayed in the layer 5 network through timed excitatory and inhibitory synaptic transmission. Our data indicate that frequency fluctuations in the beta-band reflect synchronized activity in different cortical subnetworks, that both influence spike timing of output layer 5 neurons. Thus, amplitude and frequency fluctuations within frequency bands may reflect activity in distinct cortical neuronal subnetworks that may process information in a parallel fashion.

Amnioinfusion Compared With No Intervention in Women With Second-Trimester Rupture of Membranes: A Randomized Controlled Trial.

OBJECTIVE: To assess the effectiveness of amnioinfusion in women with second-trimester preterm prelabor rupture of membranes. METHODS: We performed a nationwide, multicenter, open-label, randomized controlled trial, the PPROM: Expectant Management versus Induction of Labor-III (PPROMEXIL-III) trial, in women with singleton pregnancies and preterm prelabor rupture of membranes at 16 0/7 to 24 0/7 weeks of gestation with oligohydramnios (single deepest pocket less than 20 mm). Participants were allocated to transabdominal amnioinfusion or no intervention in a one-to-one ratio by a web-based system. If the single deepest pocket was less than 20 mm on follow-up visits, amnioinfusion was repeated weekly until 28 0/7 weeks of gestation. The primary outcome was perinatal mortality. We needed 56 women to show a reduction in perinatal mortality from 70% to 35% (ß error 0.20, two-sided α error 0.05). RESULTS: Between June 15, 2012, and January 13, 2016, we randomized 28 women to amnioinfusion and 28 to no intervention. One woman was enrolled before the trial registration date (June 19, 2012). Perinatal mortality rates were 18 of 28 (64%) in the amnioinfusion group vs 21 of 28 (75%) in the no intervention group (relative risk 0.86, 95% CI 0.60-1.22, P=.39). CONCLUSION: In women with second-trimester preterm prelabor rupture of membranes and oligohydramnios, we found no reduction in perinatal mortality after amnioinfusion. CLINICAL TRIAL REGISTRATION: NTR Dutch Trial Register, NTR3492.

Anticipatory reward signals in ventral striatal neurons of behaving rats.

It has been proposed that the striatum plays a crucial role in learning to select appropriate actions, optimizing rewards according to the principles of 'Actor-Critic' models of trial-and-error learning. The ventral striatum (VS), as Critic, would employ a temporal difference (TD) learning algorithm to predict rewards and drive dopaminergic neurons. This study examined this model's adequacy for VS responses to multiple rewards in rats. The respective arms of a plus-maze provided rewards of varying magnitudes; multiple rewards were provided at 1-s intervals while the rat stood still. Neurons discharged phasically prior to each reward, during both initial approach and immobile waiting, demonstrating that this signal is predictive and not simply motor-related. In different neurons, responses could be greater for early, middle or late droplets in the sequence. Strikingly, this activity often reappeared after the final reward, as if in anticipation of yet another. In contrast, previous TD learning models show decremental reward-prediction profiles during reward consumption due to a temporal-order signal introduced to reproduce accurate timing in dopaminergic reward-prediction error signals. To resolve this inconsistency in a biologically plausible manner, we adapted the TD learning model such that input information is nonhomogeneously distributed among different neurons. By suppressing reward temporal-order signals and varying richness of spatial and visual input information, the model reproduced the experimental data. This validates the feasibility of a TD-learning architecture where different groups of neurons participate in solving the task based on varied input information.

Neural coding of reward magnitude in the orbitofrontal cortex of the rat during a five-odor olfactory discrimination task.

The orbitofrontal cortex (OBFc) has been suggested to code the motivational value of environmental stimuli and to use this information for the flexible guidance of goal-directed behavior. To examine whether information regarding reward prediction is quantitatively represented in the rat OBFc, neural activity was recorded during an olfactory discrimination "go"/"no-go" task in which five different odor stimuli were predictive for various amounts of reward or an aversive reinforcer. Neural correlates related to both actual and expected reward magnitude were observed. Responses related to reward expectation occurred during the execution of the behavioral response toward the reward site and within a waiting period prior to reinforcement delivery. About one-half of these neurons demonstrated differential firing toward the different reward sizes. These data provide new and strong evidence that reward expectancy, regardless of reward magnitude, is coded by neurons of the rat OBFc, and are indicative for representation of quantitative information concerning expected reward. Moreover, neural correlates of reward expectancy appear to be distributed across both motor and nonmotor phases of the task.