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Aim: To assess the best energy intake in Parenteral Nutrition (PN) for preterm newborns, considering both possible benefits for growth and risk of complications., Methods: Quasi-experimental study comparing two cohorts of newborns, receiving Energy-Enhanced vs. Standard PN (Cohort A, from 1st January 2015 to 31 January 2016 and Cohort B from 1st February 2016 to 31 March 2017; respectively) after implementation of a change in the PN protocol. The primary outcome measure was growth at 24 months of life. The PN associated complications were also measured., Results: We enrolled 132 newborns in two Cohorts, similar for prenatal and postnatal clinical characteristics. Although, body weight and length at 24 months of life were significantly higher (p<0.05) in the Cohort A (11.1, 95% CI 10.6 to 11.6 Kg; 85.0 95% CI 83.8 to 86.2 cm) compared with Cohort B (10.4, 95% CI 9.9 to 10.9 Kg; 81.3 95% CI 79.7 to 82.8 cm), body weight and length Z-Score in the first 24 months of life were similar between the two Cohorts. The rate of PN associated complications was very high in both study Cohorts (up to 98% of enrolments). Multivariate analysis showed that length at 24 months was significantly associated with receiving standard PN (cohort A) in the first week of life and on the energy intake in the first week of life. We also found a marginally insignificant association between Cohort A assignment and body weight at 24 months of life (p = 0.060)., Conclusions: Energy-enhanced PN in early life has not significant effects on long-term growth in preterm newborns. The high prevalence of PN associated complications, poses concerns about the utility of high energy intake recommended by current guidelines for PN., Competing Interests: The authors have declared that no competing interests exist.

Epilepsy is a prevalent neurological disorder that affects approximately 1% of the global population. Approximately 30-40% of patients respond poorly to antiepileptic medications, leading to a significant negative impact on their quality of life. Closed-loop deep brain stimulation (DBS) is a promising treatment for individuals who do not respond to medical therapy. To achieve effective seizure control, algorithms play an important role in identifying relevant electrographic biomarkers from local field potentials (LFPs) to determine the optimal stimulation timing. In this regard, the detection and classification of events from ongoing brain activity, while achieving low power consumption through computationally inexpensive implementations, represents a major challenge in the field. To address this challenge, we here present two algorithms, the ZdensityRODE and the AMPDE, for identifying relevant events from LFPs by utilizing time series segmentation (TSS), which involves extracting different levels of information from the LFP and relevant events from it. The algorithms were validated validated against epileptiform activity induced by 4-aminopyridine in mouse hippocampus-cortex (CTX) slices and recorded via microelectrode array, as a case study. The ZdensityRODE algorithm showcased a precision and recall of 93% for ictal event detection and 42% precision for interictal event detection, while the AMPDE algorithm attained a precision of 96% and recall of 90% for ictal event detection and 54% precision for interictal event detection. While initially trained specifically for detecting ictal activity, these algorithms can be fine-tuned for improved interictal detection, aiming at seizure prediction. Our results suggest that these algorithms can effectively capture epileptiform activity, supporting seizure detection and, possibly, seizure prediction and control. This opens the opportunity to design new algorithms based on this approach for closed-loop stimulation devices using more elaborate decisions and more accurate clinical guidelines. [ABSTRACT FROM AUTHOR]

Re-canalization of cerebral vessels in ischemic stroke is pivotal to rescue dysfunctional brain areas that are exposed to moderate hypoxia within the penumbra from irreversible cell death. Goal of the present study was to evaluate the effect of moderate hypoxia followed by reoxygenation (MHR) on the evolution of reactive oxygen species (ROS) and blood-brain barrier (BBB) integrity in brain endothelial cells (BEC). BBB integrity was assessed in BEC in vitro and in microvessels of the guinea pig whole brain in situ preparation. Probes were exposed to MHR (2 hours 67-70 mmHg O2, 3 hours reoxygenation, BEC) or towards occlusion of the arteria cerebri media (MCAO) with or without subsequent reperfusion in the whole brain preparation. In vitro BBB integrity was evaluated using trans-endothelial electrical resistance (TEER) and transwell permeability assays. ROS in BEC were evaluated using 2',7'-dichlorodihydrofluorescein diacetate (DCF), MitoSox and immunostaining for nitrotyrosine. Tight-junction protein (TJ) integrity in BEC, stainings for nitrotyrosine and FITC-albumin extravasation in the guinea pig brain preparation were assessed by confocal microscopy. Diphenyleneiodonium (DPI) was used to investigate NADPH oxidase dependent ROS evolution and its effect on BBB parameters in BEC. MHR impaired TJ proteins zonula occludens 1 (ZO-1) and claudin 5 (Cl5), decreased TEER, and significantly increased cytosolic ROS in BEC. These events were blocked by the NADPH oxidase inhibitor DPI. MCAO with or without subsequent reoxygenation resulted in extravasation of FITC-albumin and ROS generation in the penumbra region of the guinea pig brain preparation and confirmed BBB damage. BEC integrity may be impaired through ROS in MHR on the level of TJ and the BBB is also functionally impaired in moderate hypoxic conditions followed by reperfusion in a complex guinea pig brain preparation. These findings suggest that the BBB is susceptible towards MHR and that ROS play a key role in this process.

The passage of ions across biological membranes is regulated by passive and active mechanisms. Passive ion diffusion into organs depends on the ion-pairing properties of salts present in the serum. Potassium ions could affect brain activity by crossing the blood-brain barrier (BBB) and its accumulation in the extracellular cerebral space could precipitate seizures. In the present study, we analyze passive diffusion of a series of potassium salts in the in vitro isolated guinea pig brain preparation. Different potassium counter-anions confer ion-pairing and lipophilicity properties that modulate membrane diffusion of the salt. Extracellular recordings in different cortical areas demonstrated the presence of epileptiform activities that strongly relate to anion identity, following the qualitative order of the Hofmeister series. Indeed, highly lipophilic salts that easily cross the BBB enhanced extracellular potassium concentration measured by ion-selective electrodes and were the most effective pro-epileptic species. This study constitutes a novel contribution for the understanding of the potential epileptogenicity of potassium salts and, more generally, of the role of counter-anions in the passive passage of salts through biological membranes.

Background: Tight-junction (TJ) protein degradation is a decisive step in hypoxic blood-brain barrier (BBB) breakdown in stroke. In this study we elucidated the impact of acute cerebral ischemia on TJ protein arrangement and the role of the apoptotic effector protease caspase-3 in this context., Methodology/principal Findings: We used an in vitro model of the neurovascular unit and the guinea pig whole brain preparation to analyze with immunohistochemical methods the BBB properties and neurovascular integrity. In both methodological approaches we observed rapid TJ protein disruptions after 30 min of oxygen and glucose deprivation or middle cerebral artery occlusion, which were accompanied by strong caspase-3 activation in brain endothelial cells (BEC). Surprisingly only few DNA-fragmentations were detected with TUNEL stainings in BEC. Z-DEVD-fmk, an irreversible caspase-3 inhibitor, partly blocked TJ disruptions and was protective on trans-endothelial electrical resistance., Conclusions/significance: Our data provide evidence that caspase-3 is rapidly activated during acute cerebral ischemia predominantly without triggering DNA-fragmentation in BEC. Further we detected fast TJ protein disruptions which could be partly blocked by caspase-3 inhibition with Z-DEVD-fmk. We suggest that the basis for clinically relevant BBB breakdown in form of TJ disruptions is initiated within minutes during ischemia and that caspase-3 contributes to this process.

Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca2+ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron-astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures., Competing Interests: The authors have declared that no competing interests exist.

Background: Treatment with neural stem cells represents a potential strategy to improve functional recovery of post-ischemic cerebral injury. The potential benefit of such treatment in acute phases of human ischemic stroke depends on the therapeutic viability of a systemic vascular delivery route. In spite of the large number of reports on the beneficial effects of intracerebral stem cells injection in experimental stroke, very few studies demonstrated the effectiveness of the systemic intravenous delivery approach. METODOLOGY/PRINCIPAL FINDINGS: We utilized a novel in vitro model of transient focal ischemia to analyze the brain distribution of neurosphere-derived cells (NCs) in the early 3 hours that follow transient occlusion of the medial cerebral artery (MCA). NCs obtained from newborn C57/BL6 mice are immature cells with self-renewal properties that could differentiate into neurons, astrocytes and oligodendrocytes. MCA occlusion for 30 minutes in the in vitro isolated guinea pig brain preparation was followed by arterial perfusion with 1x10(6) NCs charged with a green fluorescent dye, either immediately or 60 minutes after reperfusion onset. Changes in extracellular pH and K(+) concentration during and after MCAO were measured through ion-sensitive electrodes., Conclusion/significance: It is demonstrated that NCs injected through the vascular system do not accumulate in the ischemic core and preferentially distribute in non-ischemic areas, identified by combined electrophysiological and morphological techniques. Direct measurements of extracellular brain ions during and after MCA occlusion suggest that anoxia-induced tissue changes, such as extracellular acidosis, may prevent NCs from entering the ischemic area in our in vitro model of transitory focal ischemia and reperfusion suggesting a role played by the surrounding microenviroment in driving NCs outside the ischemic core. These findings strongly suggest that the potential beneficial effect of NCs in experimental focal brain ischemia is not strictly dependent on their homing into the ischemic region, but rather through a bystander mechanism possibly mediated by the release of neuroprotective factors in the peri-infarct region.

Background: Neurosphere-derived cells (NC), containing neural stem cells, various progenitors and more differentiated cells, were obtained from newborn C57/BL6 mice and infused in a murine model of focal ischemia with reperfusion to investigate if: 1) they decreased ischemic injury and restored brain function; 2) they induced changes in the environment in which they are infused; 3) changes in brain environment consequent to transient ischemia were relevant for NC action., Methodology/principal Findings: NC were infused intracerebroventricularly 4 h or 7 d after 30 min middle cerebral artery occlusion. In ischemic mice receiving cells at 4 h, impairment of open field performance was significantly improved and neuronal loss significantly reduced 7-14 d after ischemia compared to controls and to ischemic mice receiving cells at 7 d. Infusion of murine foetal fibroblast in the same experimental conditions was not effective. Assessment of infused cell distribution revealed that they migrated from the ventricle to the parenchyma, progressively decreased in number but they were observable up to 14 d. In mice receiving NC at 7 d and in sham-operated mice, few cells could be observed only at 24 h, indicating that the survival of these cells in brain tissue relates to the ischemic environment. The mRNA expression of trophic factors such as Insulin Growth Factor-1, Vascular Endothelial Growth Factor-A, Transforming Growth Factor-beta1, Brain Derived Neurotrophic Factor and Stromal Derived Factor-1alpha, as well as microglia/macrophage activation, increased 24 h after NC infusion in ischemic mice treated at 4 h compared to sham-operated and to mice receiving cells at 7 d., Conclusions/significance: NC reduce functional impairment and neuronal damage after ischemia/reperfusion injury. Several lines of evidence indicate that the reciprocal interaction between NC and the ischemic environment is crucial for NC protective actions. Based on these results we propose that a bystander control of the ischemic environment may be the mechanism used by NC to rapidly restore acutely injured brain function.

Most computational models of neurons assume constant ion concentrations, disregarding the effects of changing ion concentrations on neuronal activity. Among the models that do incorporate ion concentration dynamics, simplifications are often made that sacrifice biophysical consistency, such as neglecting the effects of ionic diffusion on electrical potentials or the effects of electric drift on ion concentrations. A subset of models with ion concentration dynamics, often referred to as electrodiffusive models, account for ion concentration dynamics in a way that ensures a biophysical consistent relationship between ion concentrations, electric charge, and electrical potentials. These models include compartmental single-cell models, geometrically explicit models, and domain-type models, but none that model neuronal network dynamics. To address this gap, we present an electrodiffusive network model with multicompartmental neurons and synaptic connections, which we believe is the first compartmentalized network model to account for intra- and extracellular ion concentration dynamics in a biophysically consistent way. The model comprises an arbitrary number of "units," each divided into three domains representing a neuron, glia, and extracellular space. Each domain is further subdivided into a somatic and dendritic layer. Unlike conventional models which focus primarily on neuronal spiking patterns, our model predicts intra- and extracellular ion concentrations (Na+, K+, Cl−, and Ca2+), electrical potentials, and volume fractions. A unique feature of the model is that it captures ephaptic effects, both electric and ionic. In this paper, we show how this leads to interesting behavior in the network. First, we demonstrate how changing ion concentrations can affect the synaptic strengths. Then, we show how ionic ephaptic coupling can lead to spontaneous firing in neurons that do not receive any synaptic or external input. Lastly, we explore the effects of having glia in the network and demonstrate how a strongly coupled glial syncytium can prevent neuronal depolarization blocks. Author summary: Neurons communicate using electrical signals called action potentials. To create these signals, sodium ions must flow into the cells and potassium ions must flow out. This transmembrane flow requires a concentration difference across the neuronal membrane, which the brain works continuously to maintain. When scientists build mathematical models of neurons, they often apply the simplifying assumption that these ion concentration differences remain constant over time. This assumption works well for many scenarios, but not all. For instance, during events like stroke or epilepsy, the ion concentrations can change dramatically, affecting how neurons behave. Moreover, recent literature suggests that changing ion concentrations also play an important role in normal brain function. To study these scenarios, we need models that can dynamically track changes in ion concentrations. The neuroscience community currently lacks a computational model describing the effects of ion concentration dynamics on neuronal networks, while maintaining a biophysical consistent relationship between ion concentrations and electrical potentials. To address the need for such a model, we have developed a neuronal network model that predicts changes in both intra- and extracellular ion concentrations, electrical potentials, and volumes in a biophysically consistent way. [ABSTRACT FROM AUTHOR]

The European Quality In Preclinical Data (EQIPD) consortium was born from the fact that publications report challenges with the robustness, rigor, and/or validity of research data, which may impact decisions about whether to proceed with further preclinical testing or to advance to clinical testing, as well as draw conclusions on the predictability of preclinical models. To address this, a consortium including multiple research laboratories from academia and industry participated in a series of electroencephalography (EEG) experiments in mice aimed to detect sources of variance and to gauge how protocol harmonisation and data analytics impact such variance. Ultimately, the goal of this first ever between-laboratory comparison of EEG recordings and analyses was to validate the principles that supposedly increase data quality, robustness, and comparability. Experiments consisted of a Localisation phase, which aimed to identify the factors that influence between-laboratory variability, a Harmonisation phase to evaluate whether harmonisation of standardized protocols and centralised processing and data analysis reduced variance, and a Ring-Testing phase to verify the ability of the harmonised protocol to generate consistent findings. Indeed, between-laboratory variability reduced from Localisation to Harmonisation and this reduction remained during the Ring-Testing phase. Results obtained in this multicentre preclinical qEEG study also confirmed the complex nature of EEG experiments starting from the surgery and data collection through data pre-processing to data analysis that ultimately influenced the results and contributed to variance in findings across laboratories. Overall, harmonisation of protocols and centralized data analysis were crucial in reducing laboratory-to-laboratory variability. To this end, it is recommended that standardized guidelines be updated and followed for collection and analysis of preclinical EEG data. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy. A major focus of human and animal studies on TLE network has been the limbic circuit. However, there is also evidence suggesting an active role of the basal ganglia in the propagation and control of temporal lobe seizures. Here, we characterize the involvement of the substantia nigra (SN) and somatosensory cortex (SI) during temporal lobe (TL) seizures induced by penicillin injection in the hippocampus (HPC) of two nonhuman primates. The seizure onset and offset patterns were manually classified and spectral power and coherence were calculated. We then compared the 3-second segments recorded in pre-ictal, onset, offset and post-ictal periods based on the seizure onset and offset patterns. Our results demonstrated an involvement of the SN and SI dependent on the seizure onset and offset pattern. We found that low amplitude fast activity (LAF) and high amplitude slow activity (HAS) onset patterns were associated with an increase in activity of the SN while the change in activity was limited to LAF seizures in the SI. However, the increase in HPC/SN coherence was specific to the farther-spreading LAF onset pattern. As for the role of the SN in seizure cessation, we observed that the coherence between the HPC/SN was reduced during burst suppression (BS) compared to other termination phases. Additionally, we found that this coherence returned to normal levels after the seizure ended, with no significant difference in post-ictal periods among the three types of seizure offsets. This study constitutes the first demonstration of TL seizures entraining the SN in the primate brain. Moreover, these findings provide evidence that this entrainment is dependent on the onset and offset pattern and support the hypothesis that the SN might play a role in the maintenance and termination of some specific temporal lobe seizure. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most common neurological disorders in children. Diagnosing epilepsy in children can be very challenging, especially as it often coexists with neurodevelopmental conditions like autism and ADHD. Functional brain networks obtained from neuroimaging and electrophysiological data in wakefulness and sleep have been shown to contain signatures of neurological disorders, and can potentially support the diagnosis and management of co-occurring neurodevelopmental conditions. In this work, we use electroencephalography (EEG) recordings from children, in restful wakefulness and sleep, to extract functional connectivity networks in different frequency bands. We explore the relationship of these networks with epilepsy diagnosis and with measures of neurodevelopmental traits, obtained from questionnaires used as screening tools for autism and ADHD. We explore differences in network markers between children with and without epilepsy in wake and sleep, and quantify the correlation between such markers and measures of neurodevelopmental traits. Our findings highlight the importance of considering the interplay between epilepsy and neurodevelopmental traits when exploring network markers of epilepsy. [ABSTRACT FROM AUTHOR]

Background: Giardiasis and zinc deficiency have been identified as serious health problems worldwide. Although Zn depletion is known to occur in giardiasis, no work has investigated whether changes occur in brain structures. Methods: Three groups of gerbils were used: control (1), orogastrically inoculated on day 3 after birth with trophozoites of two isolates of Giardia intestinalis (HGINV/WB) group (2 and 3). Estimates were made at five ages covering: establishment of infection, Giardia population growth, natural parasite clearance and a post-infection age. QuantiChrome zinc assay kit, cresyl violet staining and TUNEL technique were used. Results: A significant decrease (p<0.01) in tissue zinc was observed and persisted after infection. Cytoarchitectural changes were observed in 75% of gerbils in the HGINV or WB groups. Ectopic pyramidal neurons were found in the cornus ammonis (CA1-CA3). At 60 and 90 days of age loss of lamination was clearly visible in CA1. In the dentate gyrus (DG), thinning of the dorsal lamina and abnormal thickening of the ventral lamina were observed from 30 days of age. In the cerebellum, we found an increase (p<0.01) in the thickness of the external granular layer (EGL) at 14 days of age that persisted until day 21 (C 3 ± 0.3 μm; HGINV 37 ± 5 μm; WB 28 ± 3 μm); Purkinje cell population estimation showed a significant decrease; a large number of apoptotic somas were observed scattered in the molecular layer; in 60 and 90 days old gerbils we found granular cell heterotopia and Purkinje cell ectopia. The pattern of apoptosis was different in the cerebellum and hippocampus of parasitized gerbils. Conclusion: The morphological changes found suggest that neuronal migration is affected by zinc depletion caused by giardiasis in early postnatal life; for the first time, the link between giardiasis-zinc depletion and damaged brain structures is shown. This damage may explain the psychomotor/cognitive delay associated with giardiasis. These findings are alarming. Alterations in zinc metabolism and signalling are known to be involved in many brain disorders, including autism. Author summary: Giardia intestinalis (Syn. G. duodenalis or G. lamblia), is a protozoan flagellate that parasitizes humans and animals and is transmitted by the ingestion of food or water contaminated with cysts or via person-to-person contact. Causes diarrhoea. Affects children and adults worldwide. Giardiasis is known to have long-term effects. When giardiasis occurs in the first two years of a child's life, it is associated with stunted growth and psychomotor and cognitive retardation. Giardiasis and zinc deficiency have been identified as serious health problems worldwide. Although Zn depletion is known to occur in giardiasis, no work has investigated whether changes occur in brain structures. We modelled Giardia infection in gerbils in the first days of postnatal life and found morphological changes that suggest neuronal migration is affected by zinc depletion caused by giardiasis in early postnatal life. For the first time, the link between giardiasis-zinc depletion and damaged brain structures is shown. This damage may explain the psychomotor-cognitive delay associated with giardiasis. Alterations in zinc metabolism and signalling are known to be involved in many brain disorders, including autism. [ABSTRACT FROM AUTHOR]

Synchronization is a phenomenon observed in neuronal networks involved in diverse brain activities. Neural mass models such as Wilson-Cowan (WC) and Jansen-Rit (JR) manifest synchronized states. Despite extensive research on these models over the past several decades, their potential of manifesting second-order phase transitions (SOPT) and criticality has not been sufficiently acknowledged. In this study, two networks of coupled WC and JR nodes with small-world topologies were constructed and Kuramoto order parameter (KOP) was used to quantify the amount of synchronization. In addition, we investigated the presence of SOPT using the synchronization coefficient of variation. Both networks reached high synchrony by changing the coupling weight between their nodes. Moreover, they exhibited abrupt changes in the synchronization at certain values of the control parameter not necessarily related to a phase transition. While SOPT was observed only in JR model, neither WC nor JR model showed power-law behavior. Our study further investigated the global synchronization phenomenon that is known to exist in pathological brain states, such as seizure. JR model showed global synchronization, while WC model seemed to be more suitable in producing partially synchronized patterns. [ABSTRACT FROM AUTHOR]

Background: Perinatal mortality remains a global challenge. This challenge may be worsened by the negative effects of the COVID-19 pandemic on maternal and child health. Objectives: Examine the impact of the COVID-19 pandemic on perinatal care and outcomes in the Tamale Teaching Hospital in northern Ghana. Methods: A hospital-based retrospective study was conducted in the Tamale Teaching Hospital. We compared antenatal care attendance, total deliveries, cesarean sections, and perinatal mortality before the COVID-19 pandemic (March 1, 2019 to February 28, 2020) and during the COVID-19 pandemic (March 1, 2020 to February 28, 2021). Interrupted time series analyses was performed to evaluate the impact of the COVID-19 pandemic on perinatal care and outcomes at TTH. Results: A total number of 35,350 antenatal visits and 16,786 deliveries were registered at TTH from March 2019 to February 2021. Antenatal care, early neonatal death, and emergency cesarean section showed a rapid decline after the onset of the pandemic, with a progressive recovery over the following months. The total number of deliveries and fresh stillbirths showed a step change with a marked decrease during the pandemic, while the macerated stillbirths showed a pulse change, a temporary marked decrease with a quick recovery over time. Conclusion: The COVID-19 pandemic had a negative impact on perinatal care and outcomes in our facility. Pregnancy monitoring through antenatal care should be encouraged and continued even as countries tackle the pandemic. [ABSTRACT FROM AUTHOR]

The biophysical properties of neurons not only affect how information is processed within cells, they can also impact the dynamical states of the network. Specifically, the cellular dynamics of action-potential generation have shown relevance for setting the (de)synchronisation state of the network. The dynamics of tonically spiking neurons typically fall into one of three qualitatively distinct types that arise from distinct mathematical bifurcations of voltage dynamics at the onset of spiking. Accordingly, changes in ion channel composition or even external factors, like temperature, have been demonstrated to switch network behaviour via changes in the spike onset bifurcation and hence its associated dynamical type. A thus far less addressed modulator of neuronal dynamics is cellular morphology. Based on simplified and anatomically realistic mathematical neuron models, we show here that the extent of dendritic arborisation has an influence on the neuronal dynamical spiking type and therefore on the (de)synchronisation state of the network. Specifically, larger dendritic trees prime neuronal dynamics for in-phase-synchronised or splayed-out activity in weakly coupled networks, in contrast to cells with otherwise identical properties yet smaller dendrites. Our biophysical insights hold for generic multicompartmental classes of spiking neuron models (from ball-and-stick-type to anatomically reconstructed models) and establish a connection between neuronal morphology and the susceptibility of neural tissue to synchronisation in health and disease. Author summary: Cellular morphology varies widely across different cell types and brain areas. In this study, we provide a mechanistic link between neuronal morphology and the dynamics of electrical activity arising at the network level. Based on mathematical modelling, we demonstrate that modifications of the size of dendritic arbours alone suffice to switch the behaviour of otherwise identical networks from synchronised to asynchronous activity. Specifically, neurons with larger dendritic trees tend to produce more stable phase relations of spiking across neurons. Given the generality of the approach, we provide a morphology-based hypothesis that explains the differential sensitivity of tissue to epilepsy in different brain areas and assigns relevance to cellular morphology in healthy network computation. [ABSTRACT FROM AUTHOR]

Ischemia stroke and epilepsy are two neurological diseases that have significant patient and societal burden, with similar symptoms of neurological deficits. However, the underlying mechanism of their co-morbidity are still unclear. In this study, we performed a combined analysis of six gene expression profiles (GSE58294, GSE22255, GSE143272, GSE88723, GSE163654, and GSE174574) to reveal the common mechanisms of IS and epilepsy. In the mouse datasets, 74 genes were co-upregulated and 7 genes were co-downregulated in the stroke and epilepsy groups. Further analysis revealed that the co-expressed differentially expressed genes (DEGs) were involved in negative regulation of angiogenesis and the MAPK signaling pathway, and this was verified by Gene Set Enrichment Analysis of human datasets and single cell RNA sequence of middle cerebral artery occlusion mice. In addition, combining DEGs of human and mouse, PTGS2, TMCC3, KCNJ2, and GADD45B were identified as cross species conserved hub genes. Meanwhile, molecular docking results revealed that trichostatin A and valproic acid may be potential therapeutic drugs. In conclusion, to our best knowledge, this study conducted the first comorbidity analysis of epilepsy and ischemic stroke to identify the potential common pathogenic mechanisms and drugs. The findings may provide an important reference for the further studies on post-stroke epilepsy. [ABSTRACT FROM AUTHOR]

The thalamus is a central brain structure that serves as a relay station for sensory inputs from the periphery to the cortex and regulates cortical arousal. Traditionally, it has been regarded as a passive relay that transmits information between brain regions. However, recent studies have suggested that the thalamus may also play a role in shaping functional connectivity (FC) in a task-based context. Based on this idea, we hypothesized that due to its centrality in the network and its involvement in cortical activation, the thalamus may also contribute to resting-state FC, a key neurological biomarker widely used to characterize brain function in health and disease. To investigate this hypothesis, we constructed ten in-silico brain network models based on neuroimaging data (MEG, MRI, and dwMRI), and simulated them including and excluding the thalamus. and raising the noise into thalamus to represent the afferences related to the reticular activating system (RAS) and the relay of peripheral sensory inputs. We simulated brain activity and compared the resulting FC to their empirical MEG counterparts to evaluate model's performance. Results showed that a parceled version of the thalamus with higher noise, able to drive damped cortical oscillators, enhanced the match to empirical FC. However, with an already active self-oscillatory cortex, no impact on the dynamics was observed when introducing the thalamus. We also demonstrated that the enhanced performance was not related to the structural connectivity of the thalamus, but to its higher noisy inputs. Additionally, we highlighted the relevance of a balanced signal-to-noise ratio in thalamus to allow it to propagate its own dynamics. In conclusion, our study sheds light on the role of the thalamus in shaping brain dynamics and FC in resting-state and allowed us to discuss the general role of criticality in the brain at the mesoscale level. Author summary: Synchrony between brain regions is an essential aspect of coordinated brain function and serves as a biomarker of health and disease. The thalamus, due to its centrality and widespread connectivity with the cortex, is a crucial structure that may contribute to this synchrony by allowing distant brain regions to work together. In this study, we used computational models to investigate the thalamus's role in generating brain synchrony at rest. Our findings suggest that the structural connectivity of the thalamus is not its primary contribution to brain synchrony. Instead, we found that the thalamus plays a critical role in driving cortical activity, and when it is not driving this activity, its impact on brain synchrony is null. Our study provides valuable insights into the thalamocortical network's role in shaping brain dynamics and FC in resting state, laying the groundwork for further research in this area. [ABSTRACT FROM AUTHOR]

Background: Globally, almost 15 million infants are born prematurely each year, disproportionately affecting low and middle-income countries. In the absence of mother's milk, the World Health Organization recommends using donor human milk (DHM) due to its protective effect against necrotizing enterocolitis, a life-threatening intestinal disorder. The use of DHM is increasing globally, with many low and middle-income countries integrating donor milk banks into their public health strategies to reduce neonatal mortality, yet very little is known about the nutritional composition of DHM. Additional knowledge gaps include how DHM composition is influenced by milk banking practices, and whether preterm nutrient recommendations are achieved when DHM is used with commercially available fortifiers. Methods: We designed a multi-site study with eight geographically diverse milk bank partners in high, middle, and low-income settings that will examine and compare a broad range of nutrients and bioactive factors in human milk from 600 approved milk bank donors around the world to create comprehensive, geographically diverse nutrient profiles for DHM. We will then simulate the random pooling of 2 to 10 donors to evaluate the impact of pooling as a potential strategy for milk banks to manage nutrient variability in DHM. Finally, we will evaluate whether commercially available fortifiers meet nutrient recommendations when used with DHM. Discussion: We expect that results from this study will improve nutritional care globally for the growing number of preterm infants who receive donor human milk. [ABSTRACT FROM AUTHOR]

The rate of preterm birth is increasing worldwide and preterm infants are susceptible to oral health problems. Hence, this study aimed to investigate the effect of premature birth on dietary and oral characteristics as well as dental treatment experiences of preterm infants using a nationwide cohort study. Data was retrospectively analyzed from National Health Screening Program for Infants and Children (NHSIC) of the National Health Insurance Service of Korea. 5% sample of children born between 2008 and 2012 who completed first or second infant health screening were included and divided into full-term and preterm-birth groups. Clinical data variables such as dietary habits, oral characteristics, and dental treatment experiences were investigated and comparatively analyzed. Preterm infants showed significantly lower rates of breastfeeding at 4–6 months (p<0.001), delayed start of weaning food at 9–12 months (p<0.001), higher rates of bottle feeding at 18–24 months (p<0.001), poor appetite at 30–36 months (p<0.001) and higher rates of improper swallowing and chewing function at 42–53 months (p = 0.023) than full-term infants. Preterm infants also had eating habits leading to poor oral conditions and higher percentage of absence of dental visit compared to full-term infants (p = 0.036). However, dental treatments including 1-visit pulpectomy (p = 0.007) and 2-visit pulpectomy (p = 0.042) significantly decreased when oral health screening was completed at least once. The NHSIC can be an effective policy for oral health management in preterm infants. [ABSTRACT FROM AUTHOR]

Biophysical models of large-scale brain activity are a fundamental tool for understanding the mechanisms underlying the patterns observed with neuroimaging. These models combine a macroscopic description of the within- and between-ensemble dynamics of neurons within a single architecture. A challenge for these models is accounting for modulations of within-ensemble synchrony over time. Such modulations in local synchrony are fundamental for modeling behavioral tasks and resting-state activity. Another challenge comes from the difficulty in parametrizing large scale brain models which hinders researching principles related with between-ensembles differences. Here we derive a parsimonious large scale brain model that can describe fluctuations of local synchrony. Crucially, we do not reduce within-ensemble dynamics to macroscopic variables first, instead we consider within and between-ensemble interactions similarly while preserving their physiological differences. The dynamics of within-ensemble synchrony can be tuned with a parameter which manipulates local connectivity strength. We simulated resting-state static and time-resolved functional connectivity of alpha band envelopes in models with identical and dissimilar local connectivities. We show that functional connectivity emerges when there are high fluctuations of local and global synchrony simultaneously (i.e. metastable dynamics). We also show that for most ensembles, leaning towards local asynchrony or synchrony correlates with the functional connectivity with other ensembles, with the exception of some regions belonging to the default-mode network. [ABSTRACT FROM AUTHOR]

Introduction: Several global initiatives put parent involvement at the forefront of enabling children's well-being and development and to promote quality of care for newborns and hospitalized young children aged 0–24 months. Scanty evidence on mistreatment such as delays or neglect and poor pain management among newborns exists, with even less exploring the experience of their parents and their hospitalized young children. To address this gap, authors reviewed research on experience of care for hospitalized young children and their parents, and potential interventions that may promote positive experience of care. Methods: A scoping review of English language articles, guidelines, and reports that addressed the experiences of care for newborns and sick young children 0–24 months in health facilities was conducted. Multiple databases: PubMed, PROSPERO, COCHRANE Library and Google Scholar were included and yielded 7,784 articles. Documents published between 2009 and November 2020, in English and with evidence on interventions that addressed family involvement and partnership in care for their sick children were included. Results: The scoping review includes 68 documents across 31 countries after exclusion. Mistreatment of newborns comprises physical abuse, verbal abuse, stigma and discrimination, failure to meet professional standards, poor rapport between providers and patients, poor legal accountability, and poor bereavement and posthumous care. No literature was identified describing mistreatment of hospitalized children aged 60 days– 24 months. Key drivers of mistreatment include under-resourced health systems and poor provider attitudes. Positive experience of care was reported in contexts of good parent-provider communication. Three possible interventions on positive experience of care for hospitalized young children (0–24 months) emerged: 1) nurturing care; 2) family centered care and 3) provider and parental engagement. Communication and counseling, effective provider-parental engagement, and supportive work environments were associated with reduced anxiety and stress for parents and hospitalized young children. Few interventions focused on addressing providers' underlying attitudes and biases that influence provider behaviors, and how they affect engaging with parents. Conclusion: Limited evidence on manifestations of mistreatment, lack of respectful care, drivers of poor experience and interventions that may mitigate poor experience of care for hospitalized young children 0–24 months especially in low resource settings exists. Design and testing appropriate models that enhance socio-behavioral dimensions of care experience and promote provider-family engagement in hospitals are required. [ABSTRACT FROM AUTHOR]

Objective: Inflammation of brain structures, in particular the hippocampal formation, can induce neuronal degeneration and be associated with increased excitability manifesting as propensity for repetitive seizures. An increase in the abundance of individual proinflammatory molecules including interleukin 1 beta has been observed in brain tissue samples of patients with pharmacoresistant temporal lobe epilepsy (TLE) and corresponding animal models. The NLRP3-inflammasome, a cytosolic protein complex, acts as a key regulator in proinflammatory innate immune signalling. Upon activation, it leads to the release of interleukin 1 beta and inflammation-mediated neurodegeneration. Transient brain insults, like status epilepticus (SE), can render hippocampi chronically hyperexcitable and induce segmental neurodegeneration. The underlying mechanisms are referred to as epileptogenesis. Here, we have tested the hypothesis that distinct NLRP3-dependent transcript and protein signalling dynamics are induced by SE and whether they differ between two classical SE models. We further correlated the association of NLRP3-related transcript abundance with convulsive activity in human TLE hippocampi of patients with and without associated neurodegenerative damage. Methods: Hippocampal mRNA- and protein-expression of NLRP3 and associated signalling molecules were analysed longitudinally in pilocarpine- and kainic acid-induced SE TLE mouse models. Complementarily, we studied NLRP3 inflammasome-associated transcript patterns in epileptogenic hippocampi with different damage patterns of pharmacoresistant TLE patients that had undergone epilepsy surgery for seizure relief. Results: Pilocarpine- and kainic acid-induced SE elicit distinct hippocampal Nlrp3-associated molecular signalling. Transcriptional activation of NLRP3 pathway elements is associated with seizure activity but independent of the particular neuronal damage phenotype in KA-induced and in human TLE hippocampi. Significance: These data suggest highly dynamic inflammasome signalling in SE-induced TLE and highlight a vicious cycle associated with seizure activity. Our results provide promising perspectives for the inflammasome signalling pathway as a target for anti-epileptogenic and -convulsive therapeutic strategies. The latter may even applicable to a particularly broad spectrum of TLE patients with currently pharmacoresistant disease. [ABSTRACT FROM AUTHOR]

The mechanisms determining ictal discharge (ID) propagation are still not clear. In the present study, we aimed to examine these mechanisms in animal and mathematical models of epileptiform activity. Using double-patch and extracellular potassium ion concentration recordings in rat hippocampal-cortical slices, we observed that IDs moved at a speed of about 1 mm/s or less. The mechanisms of such slow propagation have been studied with a mathematical, conductance-based refractory density (CBRD) model that describes the GABA- and glutamatergic neuronal populations' interactions and ion dynamics in brain tissue. The modeling study reveals two main factors triggerring IDs: (i) increased interneuronal activity leading to chloride ion accumulation and a consequent depolarizing GABAergic effect and (ii) the elevation of extracellular potassium ion concentration. The local synaptic transmission followed by local potassium ion extrusion and GABA receptor-mediated chloride ion accumulation underlies the ID wavefront's propagation. In contrast, potassium ion diffusion in the extracellular space is slower and does not affect ID's speed. The short discharges, constituting the ID, propagate much faster than the ID front. The accumulation of sodium ions inside neurons due to their hyperactivity and glutamatergic currents boosts the Na+/K+ pump, which terminates the ID. Knowledge of the mechanism of ID generation and propagation contributes to the development of new treatments against epilepsy. Author summary: During an epileptic seizure, neuronal excitation spreads across the brain tissue and is accompanied by significant changes in ionic concentrations. Ictal discharge front spreads at low speeds, less than 1 mm/s. Mechanisms underlying this phenomenon are not yet well understood. We study these mechanisms using electrophysiological recordings in brain slices and computer simulations. Our detailed biophysical model describing neuronal populations' interaction, spatial propagation, and ionic dynamics reproduces the generation and propagation of spontaneously repeating ictal discharges. The simulations are consistent with our recordings of the electrical activity and the extracellular potassium ion concentration. We distinguished between the two alternative mechanisms of the ictal wavefront propagation: (i) the diffusion of potassium ions released from excited neurons, which depolarizes distant neurons and thus supports excitation, and (ii) the axonal spread of excitation followed by the local extracellular potassium ion accumulation that supports the excitation. Our simulations provide evidence in favor of the latter mechanism. Our experiment-based modeling contributes to a mathematical description of brain tissue functioning and potentially contributes to developing new treatments against epilepsy. [ABSTRACT FROM AUTHOR]

We aimed to evaluate if human milk-based fortifier (HMBF) affects human milk fat globule (MFG) size less than cow milk-based fortifier (CMBF), which may impact overall infant feeding tolerance. Measurements of donated human milk were performed before fortification as well as at 1 hour, 24 hours, and 48 hours after fortification with CMBF or HMBF. MFG size in each sample of fortified milk was measured by laser light scattering. MFG size in the fortified milks increased gradually over time. At 24 and 48 hours after fortification, MFG size in the milk with CMBF was larger than that in the milk with HMBF (4.8 ± 0.5 vs 4.3 ± 0.3 μm, p<0.01, 5.1 ± 0.7 vs 4.5 ± 0.4 μm, p = 0.03, respectively). HMBF is associated with less alteration of MFG size than CMBF. This may have an impact on feeding tolerance of very preterm infants. [ABSTRACT FROM AUTHOR]

A central question in neuroscience is how context changes perception. In the olfactory system, for example, experiments show that task demands can drive divergence and convergence of cortical odor responses, likely underpinning olfactory discrimination and generalization. Here, we propose a simple statistical mechanism for this effect based on unstructured feedback from the central brain to the olfactory bulb, which represents the context associated with an odor, and sufficiently selective cortical gating of sensory inputs. Strikingly, the model predicts that both convergence and divergence of cortical odor patterns should increase when odors are initially more similar, an effect reported in recent experiments. The theory in turn predicts reversals of these trends following experimental manipulations and in neurological conditions that increase cortical excitability. Author summary: Contextual information can powerfully influence the neural representation and perception of sensory stimuli. Here, we propose a mechanism, based on unstructured feedback from the central brain to the sensory periphery, by which similar and different contexts lead to characteristic trends in convergence and divergence of cortical odor responses that are critically dependent on threshold to firing of cortical cells. The analysis predicts specific deficits in context-driven olfactory perceptual discrimination in neurological conditions of high cortical excitability, such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Loss of function mutations of SCN1A, the gene coding for the voltage-gated sodium channel NaV1.1, cause different types of epilepsy, whereas gain of function mutations cause sporadic and familial hemiplegic migraine type 3 (FHM-3). However, it is not clear yet how these opposite effects can induce paroxysmal pathological activities involving neuronal networks' hyperexcitability that are specific of epilepsy (seizures) or migraine (cortical spreading depolarization, CSD). To better understand differential mechanisms leading to the initiation of these pathological activities, we used a two-neuron conductance-based model of interconnected GABAergic and pyramidal glutamatergic neurons, in which we incorporated ionic concentration dynamics in both neurons. We modeled FHM-3 mutations by increasing the persistent sodium current in the interneuron and epileptogenic mutations by decreasing the sodium conductance in the interneuron. Therefore, we studied both FHM-3 and epileptogenic mutations within the same framework, modifying only two parameters. In our model, the key effect of gain of function FHM-3 mutations is ion fluxes modification at each action potential (in particular the larger activation of voltage-gated potassium channels induced by the NaV1.1 gain of function), and the resulting CSD-triggering extracellular potassium accumulation, which is not caused only by modifications of firing frequency. Loss of function epileptogenic mutations, on the other hand, increase GABAergic neurons' susceptibility to depolarization block, without major modifications of firing frequency before it. Our modeling results connect qualitatively to experimental data: potassium accumulation in the case of FHM-3 mutations and facilitated depolarization block of the GABAergic neuron in the case of epileptogenic mutations. Both these effects can lead to pyramidal neuron hyperexcitability, inducing in the migraine condition depolarization block of both the GABAergic and the pyramidal neuron. Overall, our findings suggest different mechanisms of network hyperexcitability for migraine and epileptogenic NaV1.1 mutations, implying that the modifications of firing frequency may not be the only relevant pathological mechanism. Author summary: The voltage-gated sodium channel NaV1.1 is a major target of human mutations implicated in different pathologies. In particular, mutations identified in certain types of epilepsy cause loss of function of the channel, whereas mutations identified in certain types of migraine (in which spreading depolarizations of the cortical circuits of the brain are involved) cause instead gain of function. Here, we study dysfunctions induced by these differential effects in a two-neuron (GABAergic and pyramidal) conductance-based model with dynamic ion concentrations. We obtain results that can be related to experimental findings in both situations. Namely, extracellular potassium accumulation induced by the activity of the GABAergic neuron in the case of CSD, and higher propensity of the GABAergic neuron to depolarization block in the epileptogenic scenario, without significant modifications of its firing frequency prior to it. Both scenarios can induce hyperexcitability of the pyramidal neuron, leading in the migraine condition to depolarization block of both the GABAergic and the pyramidal neuron. Our results are successfully confronted to experimental data and suggest that modification of firing frequency is not the only key mechanism in these pathologies of neuronal excitability. [ABSTRACT FROM AUTHOR]

Within the computational neuroscience community, there has been a focus on simulating the electrical activity of neurons, while other components of brain tissue, such as glia cells and the extracellular space, are often neglected. Standard models of extracellular potentials are based on a combination of multicompartmental models describing neural electrodynamics and volume conductor theory. Such models cannot be used to simulate the slow components of extracellular potentials, which depend on ion concentration dynamics, and the effect that this has on extracellular diffusion potentials and glial buffering currents. We here present the electrodiffusive neuron-extracellular-glia (edNEG) model, which we believe is the first model to combine compartmental neuron modeling with an electrodiffusive framework for intra- and extracellular ion concentration dynamics in a local piece of neuro-glial brain tissue. The edNEG model (i) keeps track of all intraneuronal, intraglial, and extracellular ion concentrations and electrical potentials, (ii) accounts for action potentials and dendritic calcium spikes in neurons, (iii) contains a neuronal and glial homeostatic machinery that gives physiologically realistic ion concentration dynamics, (iv) accounts for electrodiffusive transmembrane, intracellular, and extracellular ionic movements, and (v) accounts for glial and neuronal swelling caused by osmotic transmembrane pressure gradients. The edNEG model accounts for the concentration-dependent effects on ECS potentials that the standard models neglect. Using the edNEG model, we analyze these effects by splitting the extracellular potential into three components: one due to neural sink/source configurations, one due to glial sink/source configurations, and one due to extracellular diffusive currents. Through a series of simulations, we analyze the roles played by the various components and how they interact in generating the total slow potential. We conclude that the three components are of comparable magnitude and that the stimulus conditions determine which of the components that dominate. Author summary: A common experimental method for investigating brain activity is to measure the electric potential outside neurons. These recordings usually only capture the high-frequency part of the potential while ignoring frequencies below a set cut-off between 0.1 and 1 Hz. Therefore, standard recordings cannot tell us what the slow frequency potentials might say about on-going brain activity. Most computational models are also not suited in this regard. They ignore two possibly important contributions to the slow potentials, namely the diffusion of ions in the extracellular space and a cell type called astrocytes that contribute to keeping an appropriate chemical environment for neurons. To overcome this, we here present what we call the electrodiffusive neuron-extracellular-glia model (edNEG) model for exploring the genesis of slow potentials in the brain. We use the model to study the contributions from neurons, astrocytes, and diffusive currents to the slow potentials and show that the model predicts that they are on the same order of magnitude. [ABSTRACT FROM AUTHOR]

The genetic influence in epilepsy, characterized by unprovoked and recurrent seizures, is through variants in genes critical to brain development and function. We have carried out variant calling in Mesial Temporal Lobe Epilepsy (MTLE) patients by mapping the RNA-Seq data available at SRA, NCBI, USA onto human genome assembly hg-19. We have identified 1,75,641 SNVs in patient samples. These SNVs are distributed over 14700 genes of which 655 are already known to be associated with epilepsy. Large number of variants occur in the 3'-UTR, which is one of the regions involved in the regulation of protein translation through binding of miRNAs and RNA-binding proteins (RBP). We have focused on studying the structure-function relationship of the 3'-UTR SNVs that are common to at-least 10 of the 35 patient samples. For the first time we find SNVs exclusively in the 3'-UTR of FGF12, FAR1, NAPB, SLC1A3, SLC12A6, GRIN2A, CACNB4 and FBXO28 genes. Structural modelling reveals that the variant 3'-UTR segments possess altered secondary and tertiary structures which could affect mRNA stability and binding of RBPs to form proper ribonucleoprotein (RNP) complexes. Secondly, these SNVs have either created or destroyed miRNA-binding sites, and molecular modeling reveals that, where binding sites are created, the additional miRNAs bind strongly to 3'-UTR of only variant mRNAs. These two factors affect protein production thereby creating an imbalance in the amounts of select proteins in the cell. We suggest that in the absence of missense and nonsense variants, protein-activity imbalances associated with MTLE patients can be caused through 3'-UTR variants in relevant genes by the mechanisms mentioned above. 3'-UTR SNV has already been identified as causative variant in the neurological disorder, Tourette syndrome. Inhibition of these miRNA-mRNA bindings could be a novel way of treating drug-resistant MTLE patients. We also suggest that joint occurrence of these SNVs could serve as markers for MTLE. We find, in the present study, SNV-mediated destruction of miRNA binding site in the 3'-UTR of the gene encoding glutamate receptor subunit, and, interestingly, overexpression of one of this receptor subunit is also associated with Febrile Seizures. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the emergence of seizures are one of the most important unresolved issues in epilepsy research. In this paper, we study how perturbations, exogenous or endogenous, may promote or delay seizure emergence. To this aim, due to the increasingly adopted view of epileptic dynamics in terms of slow-fast systems, we perform a theoretical analysis of the phase response of a generic relaxation oscillator. As relaxation oscillators are effectively bistable systems at the fast time scale, it is intuitive that perturbations of the non-seizing state with a suitable direction and amplitude may cause an immediate transition to seizure. By contrast, and perhaps less intuitively, smaller amplitude perturbations have been found to delay the spontaneous seizure initiation. By studying the isochrons of relaxation oscillators, we show that this is a generic phenomenon, with the size of such delay depending on the slow flow component. Therefore, depending on perturbation amplitudes, frequency and timing, a train of perturbations causes an occurrence increase, decrease or complete suppression of seizures. This dependence lends itself to analysis and mechanistic understanding through methods outlined in this paper. We illustrate this methodology by computing the isochrons, phase response curves and the response to perturbations in several epileptic models possessing different slow vector fields. While our theoretical results are applicable to any planar relaxation oscillator, in the motivating context of epilepsy they elucidate mechanisms of triggering and abating seizures, thus suggesting stimulation strategies with effects ranging from mere delaying to full suppression of seizures. Author summary: Despite its simplicity, the modelling of epileptic dynamics as a slow-fast transition between low and high activity states mediated by some slow feedback variable is a relatively novel albeit fruitful approach. This study is the first, to our knowledge, characterizing the response of such slow-fast models of epileptic brain to perturbations by computing its isochrons. Besides its numerical computation, we theoretically determine which factors shape the geometry of isochrons for planar slow-fast oscillators. As a consequence, we introduce a theoretical approach providing a clear understanding of the response of perturbations of slow-fast oscillators. Within the epilepsy context, this elucidates the origin of the contradictory role of interictal epileptiform discharges in the transition to seizure, manifested by both pro-convulsive and anti-convulsive effect depending on the amplitude, frequency and timing. More generally, this paper provides theoretical framework highlighting the role of the slow flow component on the response to perturbations in relaxation oscillators, pointing to the general phenomena in such slow-fast oscillators ubiquitous in biological systems. [ABSTRACT FROM AUTHOR]

Surgical interventions in epileptic patients aimed at the removal of the epileptogenic zone have success rates at only 60-70%. This failure can be partly attributed to the insufficient spatial sampling by the implanted intracranial electrodes during the clinical evaluation, leading to an incomplete picture of spatio-temporal seizure organization in the regions that are not directly observed. Utilizing the partial observations of the seizure spreading through the brain network, complemented by the assumption that the epileptic seizures spread along the structural connections, we infer if and when are the unobserved regions recruited in the seizure. To this end we introduce a data-driven model of seizure recruitment and propagation across a weighted network, which we invert using the Bayesian inference framework. Using a leave-one-out cross-validation scheme on a cohort of 45 patients we demonstrate that the method can improve the predictions of the states of the unobserved regions compared to an empirical estimate that does not use the structural information, yet it is on the same level as the estimate that takes the structure into account. Furthermore, a comparison with the performed surgical resection and the surgery outcome indicates a link between the inferred excitable regions and the actual epileptogenic zone. The results emphasize the importance of the structural connectome in the large-scale spatio-temporal organization of epileptic seizures and introduce a novel way to integrate the patient-specific connectome and intracranial seizure recordings in a whole-brain computational model of seizure spread. Author summary: The electrical activity of the brain during an epileptic seizure can be observed with intracranial EEG, that is electrodes implanted in the patient's brain. However, due to the practical constraints only selected brain regions can be implanted, which brings a risk that the abnormal electrical activity in some non-implanted regions is hidden from the observers. In this work we introduce a method to infer what is happening in the unobserved parts based on the incomplete observations of the epileptic seizure. The method relies on the assumption that the seizure spreads along the white-matter structural connections, and finds the explanation of the whole-brain seizure spread consistent with the data. The structural connectome can be estimated from diffusion-weighted imaging for an individual patient, therefore this way the patient-specific structural connectome is utilized to better analyze the patients' seizure recordings. [ABSTRACT FROM AUTHOR]

The extraction of electrophysiological features that reliably forecast the occurrence of seizures is one of the most challenging goals in epilepsy research. Among possible approaches to tackle this problem is the use of active probing paradigms in which responses to stimuli are used to detect underlying system changes leading up to seizures. This work evaluates the theoretical and mechanistic underpinnings of this strategy using two coupled populations of the well-studied Wendling neural mass model. Different model settings are evaluated, shifting parameters (excitability, slow inhibition, or inter-population coupling gains) from normal towards ictal states while probing stimuli are applied every 2 seconds to the input of either one or both populations. The correlation between the extracted features and the ictogenic parameter shifting indicates if the impending transition to the ictal state may be identified in advance. Results show that not only can the response to the probing stimuli forecast seizures but this is true regardless of the altered ictogenic parameter. That is, similar feature changes are highlighted by probing stimuli responses in advance of the seizure including: increased response variance and lag-1 autocorrelation, decreased skewness, and increased mutual information between the outputs of both model subsets. These changes were mostly restricted to the stimulated population, showing a local effect of this perturbational approach. The transition latencies from normal activity to sustained discharges of spikes were not affected, suggesting that stimuli had no pro-ictal effects. However, stimuli were found to elicit interictal-like spikes just before the transition to the ictal state. Furthermore, the observed feature changes highlighted by probing the neuronal populations may reflect the phenomenon of critical slowing down, where increased recovery times from perturbations may signal the loss of a systems' resilience and are common hallmarks of an impending critical transition. These results provide more evidence that active probing approaches highlight information about underlying system changes involved in ictogenesis and may be able to play a role in assisting seizure forecasting methods which can be incorporated into early-warning systems that ultimately enable closing the loop for targeted seizure-controlling interventions. Author summary: Epilepsy is characterized by spontaneous and recurrent seizures. Developing a method to forecast the occurrence of these events would ease part of the burden to patients by providing warning systems and identifying critical periods for closed-loop seizure suppressing methods. However, this task is far from trivial and doing this in a clinical setting has been a challenge that is not yet solved. A possible way to achieve this is by using active probing paradigms, in which stimuli are used to highlight otherwise hidden changes in brain dynamics that may lead to seizures. In this work, this approach is tested in a computational model with two coupled neuronal populations. Active probing responses highlighted underlying model parameter changes that led neuronal activity closer to seizures, something that was not detected with the passive observation in most evaluated model settings. Observed feature changes revealed higher excitability, longer recovery times from stimuli, and increased synchrony between populations as the threshold to seizure-like activity approached. This indicates that low frequency stimuli may be used to reveal early-warning signs and assist in seizure forecasting methods. [ABSTRACT FROM AUTHOR]

Epilepsy is a dynamic and complex neurological disease affecting about 1% of the worldwide population, among which 30% of the patients are drug-resistant. Epilepsy is characterized by recurrent episodes of paroxysmal neural discharges (the so-called seizures), which manifest themselves through a large-amplitude rhythmic activity observed in depth-EEG recordings, in particular in local field potentials (LFPs). The signature characterizing the transition to seizures involves complex oscillatory patterns, which could serve as a marker to prevent seizure initiation by triggering appropriate therapeutic neurostimulation methods. To investigate such protocols, neurophysiological lumped-parameter models at the mesoscopic scale, namely neural mass models, are powerful tools that not only mimic the LFP signals but also give insights on the neural mechanisms related to different stages of seizures. Here, we analyze the multiple time-scale dynamics of a neural mass model and explain the underlying structure of the complex oscillations observed before seizure initiation. We investigate population-specific effects of the stimulation and the dependence of stimulation parameters on synaptic timescales. In particular, we show that intermediate stimulation frequencies (>20 Hz) can abort seizures if the timescale difference is pronounced. Those results have the potential in the design of therapeutic brain stimulation protocols based on the neurophysiological properties of tissue. Author summary: Epilepsy is a complex disease affecting 1% of the worldwide population of which 30% of the patients are drug-resistant and seeking for alternative therapeutic methods, such as neurostimulation. Epileptic seizures can be hallmarked by preceding pre-ictal phases which are a possible window of opportunity to trigger electrical stimulation with the objective to prevent seizure initiation. Biophysiological models are an appropriate framework to understand underlying dynamics and transitions between different epileptogenic phases. In this study, we consider a typical pre-ictal regime with complex bursting-type oscillations, which can be accurately reproduced by a neural mass model. By analyzing the multiple time-scaled structure of the model, we identify the key role of the subpopulations of GABAergic interneurons. We show that appropriate brain stimulation targeting GABAergic interneurons is able to abort pre-ictal bursting, thus preventing seizures to develop. [ABSTRACT FROM AUTHOR]

Background: Youth continue to fall victim to sexual and reproductive health problems. Despite, reproductive health needs of youth had been supported by different organizations, utilization of those services is low. All efforts have not been felt across the Ethiopian learning institutions as is evidenced by persistent reproductive health problems. Therefore, this study aimed to assess the magnitude of youth friendly sexual and reproductive health service utilization and associated factors among high and preparatory school youths in Debre Tabor town, Northwest Ethiopia. Methods: An institution based cross- sectional study was conducted from March 1 to 28, 2016. The data were collected using a pre-tested and structured self-administered questionnaire. Multistage cluster sampling method was used to select the study participants. The data were entered into Epi-data version 4.2.0.0 and analyzed using SPSS version 20. Binary logistics regression was used for analysis. Odds ratio along with 95%CI was estimated to measure the strength of the association. Level of statistical significance was declared at p value ≤0.05. Results: Overall utilization of reproductive health service was 28.8%. Being male (AOR = 1.54, 95% CI: 1.05, 2.25), prior discussion on reproductive health issues (AOR = 6.33, 95% CI: 4.22, 9.51), and previous sexual intercourse within the past one year (AOR = 1.95, 95% CI: 1.10, 3.44) were significantly associated with youth friendly health service utilization. Conclusions: Youth friendly health service utilization among high school and preparatory students in Debre Tabor town was low. Ensuring gender empowerment and advocating sexual and reproductive service discussion among themselves and with others might be important in improving reproductive health utilization and health. Future researcher should address segment of population who does not enter school. [ABSTRACT FROM AUTHOR]

Neonatal vitamin D deficiency is common and is associated with development of pulmonary disease in children and adults. While the role of vitamin D in normal lung development is well established, the association between vitamin D deficiency and bronchopulmonary dysplasia (BPD) remains unclear. The present meta-analysis was conducted to evaluate the relationship between vitamin D and BPD. We identified relevant studies (n = 8) using the PubMed, EMBASE, Cochrane Library, and KoreaMed databases and applied the Newcastle–Ottawa Scale to assess the methodological components of each study, and used I2 statistic to evaluate heterogeneity. Comprehensive Meta-Analysis software version 3.3 was used for the statistical analysis. A total of 909 infants were included, of whom 251 (27.6%) were diagnosed with BPD. We found that both vitamin D deficiency at birth (four studies; OR 2.405; 95% CI 1.269 to 4.560; p = 0.007) and low levels of vitamin D at birth (four studies; standardized mean difference -1.463; 95% CI -2.900 to -0.027; p = 0.046) were associated with BPD. The compiled data suggest that antenatal vitamin D deficiency and low vitamin D levels are associated with neonatal BPD. [ABSTRACT FROM AUTHOR]

Background: Human breast milk (BM) fortification is required to feed preterm newborns with less than 32 weeks of gestation. However, addition of fortifiers increases osmolarity and osmolarity values higher than 450 mOsm/kg may be related to gastrointestinal pathology. Hence, fortifier selection and dosage are key to achieve optimal feeding. Objectives: To compare the effect on osmolality of adding different fortifications, including recently developed formulations, to BM and to study evolution of osmolarity over time in supplemented BM. Methods: Frozen mature BM from 10 healthy mothers of premature newborns was fortified with each of the following human milk fortifiers (HMF): AlmirónFortifier®, NANFM85®, or PreNANFM85®. In addition, fortified BMs were modified with one of the following nutritional supplements (NS): Duocal MCT®, Nutricia® AminoAcids Mix, or Maxijul®. Osmolality of BM alone, fortified and/or supplemented was measured at 1 and 22 hours after their preparation. All samples were kept at 4°C throughout the study. Results: Osmolality of BM alone was close to 300 mOsm/kg and did not change over 22 hours. When equicaloric amounts of HMF AlmirónFortifier®, NANFM85®, and PreNANFM85® were added to BM, osmolality increased roughly to 480 mOsm/kg with the first two fortifiers and only to 433±6 mOsm/kg with the third one. Upon addition of any of four different NSs to BM modified with AlmirónFortifier® and NANFM85®, osmolality reached values greater than 520 mOsm/kg, while osmolality of PreNANFM85® with two out of the four NSs remained below 490 mOsm/kg. NSs supplementing carbohydrates and hydrolysed proteins resulted into a higher increase of BM osmolarity. Osmolality increased significantly with time and, after 22h, only BM modified with PreNANFM85® remained below 450 mOsm/kg. Conclusions: Upon addition of the HMFs tested, BM osmolality increases significantly and keeps raising over time. All HMFs but the recently developed PreNAN FM85® at 4% exceed the AAP recommended threshold for osmolarity of 450 mOsm/kg. Addition of NSs to PreNAN FM85® at 4% significantly increases osmolality above 450 mOsm/Kg. Thus, using PreNAN FM85® at 5% may be preferable to adding nutritional supplements since nutritional recommendations by the ESPGHAN are reached with a lower increase in osmolality. [ABSTRACT FROM AUTHOR]

Background: Nutritional supplements may improve short-term growth of infants born small (preterm or small for gestational age), but there are few data on long-term effects and concerns that body composition may be adversely affected. Effects also may differ between girls and boys. Our systematic review and meta-analysis assessed the effects of macronutrient supplements for infants born small on later growth.Methods and Findings: We searched OvidMedline, Embase, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews from inception to January 30, 2020, and controlled-trials.com, clinicaltrials.gov, and anzctr.org.au on January 30, 2020. Randomised or quasirandomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born small and growth was assessed after discharge. Primary outcome was body mass index (BMI) in childhood. Data were pooled using random-effect models. Outcomes were evaluated in toddlers (< 3 years), childhood (3 to 8 years), adolescence (9 to 18 years), and adulthood (>18 years). Forty randomised and 2 quasirandomised trials of variable methodological quality with 4,352 infants were included. Supplementation did not alter BMI in childhood (7 trials, 1,136 children; mean difference [MD] -0.10 kg/m2, [95% confidence interval (CI) -0.37 to 0.16], p = 0.45). In toddlers, supplementation increased weight (31 trials, 2,924 toddlers; MD 0.16 kg, [0.01 to 0.30], p = 0.03) and length/height (30 trials, 2,889 toddlers; MD 0.44 cm, [0.10 to 0.77], p = 0.01), but not head circumference (29 trials, 2,797 toddlers; MD 0.15 cm, [-0.03 to 0.33], p = 0.10). In childhood, there were no significant differences between groups in height (7 trials, 1,136 children; MD 0.22 cm, [-0.48 to 0.92], p = 0.54) or lean mass (3 trials, 354 children; MD -0.07 kg, [-0.98 to 0.85], p = 0.88), although supplemented children appeared to have higher fat mass (2 trials, 201 children; MD 0.79 kg, [0.19 to 1.38], p = 0.01). In adolescence, there were no significant differences between groups in BMI (2 trials, 216 adolescents; MD -0.48 kg/m2, [-2.05 to 1.08], p = 0.60), height (2 trials, 216 adolescents; MD -0.55 cm, [-2.95 to 1.86], p = 0.65), or fat mass (2 trials, 216 adolescents; MD -1.3 5 kg, [-5.76 to 3.06], p = 0.55). In adulthood, there also were no significant differences between groups in weight z-score (2 trials, 199 adults; MD -0.11, [-0.72 to 0.50], p = 0.73) and height z-score (2 trials, 199 adults; MD -0.07, [-0.36 to 0.22], p = 0.62). In subgroup analysis, supplementation was associated with increased length/height in toddler boys (2 trials, 173 boys; MD 1.66 cm, [0.75 to 2.58], p = 0.0003), but not girls (2 trials, 159 girls; MD 0.15 cm, [-0.71 to 1.01], p = 0.74). Limitations include considerable unexplained heterogeneity, low to very low quality of evidence, and possible bias due to low or unbalanced followup.Conclusions: In this systematic review and meta-analysis, we found no evidence that early macronutrient supplementation for infants born small altered BMI in childhood. Although supplements appeared to increase weight and length in toddlers, effects were inconsistent and unlikely to be clinically significant. Limited data suggested that supplementation increased fat mass in childhood, but these effects did not persist in later life. PROSPERO registration: CRD42019126918. [ABSTRACT FROM AUTHOR]

The mechanisms of epileptic discharge generation and spread are not yet fully known. A recently proposed simple biophysical model of interictal and ictal discharges, Epileptor-2, reproduces well the main features of neuronal excitation and ionic dynamics during discharge generation. In order to distinguish between two hypothesized mechanisms of discharge propagation, we extend the model to the case of two-dimensional propagation along the cortical neural tissue. The first mechanism is based on extracellular potassium diffusion, and the second is the propagation of spikes and postsynaptic signals along axons and dendrites. Our simulations show that potassium diffusion is too slow to reproduce an experimentally observed speed of ictal wavefront propagation (tenths of mm/s). By contrast, the synaptic mechanism predicts well the speed and synchronization of the pre-ictal bursts before the ictal front and the afterdischarges in the ictal core. Though this fact diminishes the role of diffusion and electrodiffusion, the model nevertheless highlights the role of potassium extrusion during neuronal excitation, which provides a positive feedback that changes at the ictal wavefront the balance of excitation versus inhibition in favor of excitation. This finding may help to find a target for a treatment to prevent seizure propagation. [ABSTRACT FROM AUTHOR]

The temporal and spectral characteristics of tonic-clonic seizures are investigated using a neural field model of the corticothalamic system in the presence of a temporally varying connection strength between the cerebral cortex and thalamus. Increasing connection strength drives the system into ∼ 10 Hz seizure oscillations once a threshold is passed and a subcritical Hopf bifurcation occurs. In this study, the spectral and temporal characteristics of tonic-clonic seizures are explored as functions of the relevant properties of physiological connection strengths, such as maximum strength, time above threshold, and the ramp rate at which the strength increases or decreases. Analysis shows that the seizure onset time decreases with the maximum connection strength and time above threshold, but increases with the ramp rate. Seizure duration and offset time increase with maximum connection strength, time above threshold, and rate of change. Spectral analysis reveals that the power of nonlinear harmonics and the duration of the oscillations increase as the maximum connection strength and the time above threshold increase. A secondary limit cycle at ∼ 18 Hz, termed a saddle-cycle, is also seen during seizure onset and becomes more prominent and robust with increasing ramp rate. If the time above the threshold is too small, the system does not reach the 10 Hz limit cycle, and only exhibits 18 Hz saddle-cycle oscillations. It is also seen that the time to reach the saturated large amplitude limit-cycle seizure oscillation from both the instability threshold and from the end of the saddle-cycle oscillations is inversely proportional to the square root of the ramp rate. [ABSTRACT FROM AUTHOR]

Background: Breast milk is the optimal choice for feeding premature babies. However, the prevalence rate of extrauterine growth restriction in preterm infants remains high. Objectives: The purpose of this study was to analyze the macronutrients present in human milk and the correlation with the growth of in-hospital preterm infants. Methods: This prospective study is based on data from 99 in-hospital preterm infants younger than 37 weeks of gestational age on an exclusively human milk diet. Infants who had previously received parenteral nutrition were eligible, but they had to have reached full enteral feeding at the time that the samples were taken. A total of 3282 samples of raw human milk or donor pasteurized milk were collected. The levels of lactose, protein, fat, and energy in the samples were measured using a Miris human milk analyzer. The primary outcome was weight growth velocity (g/kg/day) which was obtained using two-point approach. Results: The mean (±standard deviation) macronutrient composition per 100 mL of milk was 7.2 (±0.3) g of lactose, 1.1 (±0.2) g of true protein, 3.5 (±0.9) g of fat, and 66.9 (±6.5) kcal of energy. The protein concentration in human milk had a positive, significant correlation with body weight gain, with a coefficient of 0.41 (p < 0.001). After adjusting for gestational age, postmenstrual age, small-for-gestational age, intraventricular hemorrhage, patent ductus arteriosus or congestive heart failure, duration of total parenteral nutrition support, bottle feeding or use of orogastric tube, and ventilator support, total daily protein intake was associated with body weight growth (p < 0.001). Conclusion: Both the protein concentration in human milk and the daily total protein intake had a positive correlation with the body weight gain of premature infants. Routine analysis of breast milk and individualized fortification might be indicated to optimize the growth of preterm infants. [ABSTRACT FROM AUTHOR]

Objective: To clarify the complex mechanism underlying epileptogeneis, a novel animal model was generated. Methods: In our previous research, we have generated a melanocyte-lineage mTOR hyperactivation mouse model (Mitf-M-Cre Tsc2 KO mice; cKO mice) to investigate mTOR pathway in melanogenesis regulation, markedly reduced skin pigmentation was observed. Very unexpectedly, spontaneous recurrent epilepsy was also developed in this mouse model. Results: Compared with control littermates, no change was found in either brain size or brain mass in cKO mice. Hematoxylin staining revealed no obvious aberrant histologic features in the whole brains of cKO mice. Histoimmunofluorescence staining and electron microscopy examination revealed markedly increased mTOR signaling and hyperproliferation of mitochondria in cKO mice, especially in the hippocampus. Furthermore, rapamycin treatment reversed these abnormalities. Conclusions: This study suggests that our melanocyte-lineage mTOR hyperactivation mouse is a novel animal model of epilepsy, which may promote the progress of both epilepsy and neurophysiology research. [ABSTRACT FROM AUTHOR]

The aim of this retrospective study was to explore the risk factors and clinical characteristics related to neonatal fulminant necrotizing enterocolitis (NEC). From 1 November 2007 to 31 October 2017, 352 neonates who were diagnosed with NEC (Bell stage ≥ΠB) and admitted to the Children's Hospital of Chongqing Medical University were enrolled. Among these patients, 112 (31.82%) cases fulfilled the definition of fulminant NEC, and 62.5% (70/112) of fulminant cases presented a poor prognosis. All the survivors in the fulminant NEC group underwent surgery. Those in the fulminant NEC group were more likely to have the following clinical features: sepsis preceding NEC (P<0.001), abdominal distention (P<0.001), bowel sound disappearance (P = 0.001), leukopenia or neutropenia (P<0.001), C-reactive protein (CRP) <10 mg/L (P = 0.003), procalcitonin (PCT) < 2 μg/L (P<0.001), pH ≤7.2 (P<0.001), and radiographic evidence of pneumoperitoneum (P<0.001) or seroperitoneum on ultrasonography (P = 0.017). In conclusion, fulminant NEC is characterized by urgent onset and prompt deterioration, potentially resulting in death. The lack of unique characteristics makes it difficult to recognize by medical caregivers. Close observation, early detection and timely surgical intervention may improve the prognosis. [ABSTRACT FROM AUTHOR]

Epilepsy is a significant contributor to worldwide disability. In epilepsy, disability can be broadly divided into two components: ictal (pertaining to the burden of unpredictable seizures and associated medical complications including death) and interictal (pertaining to more pervasive debilitating changes in cognitive and emotional behavior). In this study, we objectively and noninvasively appraise aspects of ictal and interictal behavior in mice using instrumented home-cage chambers designed to assay kinematic and appetitive behavioral measures. Through daily intraperitoneal injections of the chemoconvulsant pentylenetetrazole (PTZ) applied to C57BL/6J mice, we coordinately measure how "behavioral severity" (complex dynamic changes in movement and sheltering behavior) and convulsive severity (latency and occurrence of convulsive seizures) evolve or kindle with repeated injections. By closely studying long epochs between PTZ injections, we identify an interictal syndrome of nocturnal hypoactivity and increased sheltering behavior which remits with the cessation of seizure induction. We observe elements of this interictal behavioral syndrome in seizure-prone DBA/2J mice and in mice with a pathogenic Scn1a mutation (modeling Dravet syndrome). Through analyzing their responses to PTZ, we illustrate how convulsive severity and "behavioral" severity are distinct and independent aspects of the overall severity of a PTZ-induced seizure. Our results illustrate the utility of an ethologically centered automated approach to quantitatively appraise murine expressions of disability in mouse models of seizures and epilepsy. In doing so, this study highlights the very unique psychopharmacological profile of PTZ. [ABSTRACT FROM AUTHOR]

Background: Increasingly studies show that immigrants have different perinatal health outcomes compared to native-born women. Nevertheless, we lack a detailed examination of the combined effects of maternal immigrant trajectory and socioeconomic status on perinatal outcomes. Our objective was to analyze the influence of time since naturalization on low birth weight and maternal socioeconomic status in Belgium. Methods: The data came from the linkage between the Brussels birth and death registers, the national register of migrant trajectories and the social security register for the years 2004–2010. We used logistic regression to estimate the odds ratios of the associations between low birth weight (LBW) and time since naturalization, by nationality groups, taking into account socioeconomic status (SES), parity and maternal age. Results: Data relate to all singleton births to Belgian, Maghrebi, Sub-Saharan African and Turkish women (n = 76 312). The results show an U-shaped of LBW according to time since naturalization for all migrant groups. LBW declines for women naturalized since less than one year and increases significantly thereafter (p<0.0001). In parallel, we observe an increase of SES among all migrant groups. Compared to Belgians, we found a lower risk of LBW among women from Maghreb (p<0.0001) and this protection is maintained even after 10 years since naturalization. In contrast, the risk of LBW for Sub-Saharan African and Turkish mothers is lower than for Belgians after one year of naturalization but similar to that of Belgians after 10 years of naturalization. Conclusion: Our results show that, despite an improvement of their SES, LBW increases among Maghrebi, Sub-Saharan African and Turkish women with time since naturalization. Mothers from Maghreb have lower rates of LBW compared to Belgians and maintain their protection even after more than 10 years of having acquired the Belgian nationality. Additional studies need to be carried out in order to gain a better understanding of the association between migration trajectories, SES and perinatal health of immigrants. [ABSTRACT FROM AUTHOR]

Background: Different methods are used to assess the growth of preterm infants during neonatal hospital stay. The primary objective was to compare two methods for assessing growth velocity: g/kg/d according to the Patel exponential model (EM) and change in weight z-score (ZS) according to Fenton curves. The secondary objective was to highlight factors influencing the level of agreement between the two methods. Methods: Preterm infants born before 33 weeks were included. Growth velocity was computed by EM and ZS methods and linear regression was used to predict what growth velocity by EM method would be obtained using the ZS method. Differences between EM growth velocity and EM growth velocity predicted by ZS method were then used to assess the level of agreement between the two methods. A difference between -2 and +2 g/kg/day was considered as fair agreement, greater than ± 4 g/kg/day as poor agreement, and as disagreement otherwise. Results: Among the 3954 children included, we observe a fair agreement in 2471 children (62.5%), a poor agreement in 1278 (32.3%) and a disagreement in 205 children (5.2%). Birth weight and gestational age explained 31% and 25%, respectively, of the variance in the difference between the two methods. Conclusions: In more than a third of enrolled children, the two methods for measuring growth velocity disagreed substantially. As variation of weight Z-score takes into account infant gestational age and gender, it could be more suitable to analyze a population of preterm infants with a wide range of gestational age. [ABSTRACT FROM AUTHOR]

Neural systems are organized in a modular way, serving multiple functionalities. This multiplicity requires that both positive (e.g. excitatory, phase-coherent) and negative (e.g. inhibitory, phase-opposing) interactions take place across brain modules. Unfortunately, most methods to detect modules from time series either neglect or convert to positive, any measured negative correlation. This may leave a significant part of the sign-dependent functional structure undetected. Here we present a novel method, based on random matrix theory, for the identification of sign-dependent modules in the brain. Our method filters out both local (unit-specific) noise and global (system-wide) dependencies that typically obfuscate the presence of such structure. The method is guaranteed to identify an optimally contrasted functional ‘signature’, i.e. a partition into modules that are positively correlated internally and negatively correlated across. The method is purely data-driven, does not use any arbitrary threshold or network projection, and outputs only statistically significant structure. In measurements of neuronal gene expression in the biological clock of mice, the method systematically uncovers two otherwise undetectable, negatively correlated modules whose relative size and mutual interaction strength are found to depend on photoperiod. [ABSTRACT FROM AUTHOR]

Background: The use of histamine-2 receptor antagonists (H2RA) in neonates is still debated because of possible risk of infection, necrotizing enterocolitis (NEC) and increased mortality. Aim: To review whether the use of H2RA in neonates admitted to neonatal intensive care units (NICU) is associated with infection, NEC or mortality. Materials and method: We performed a systematic search in PubMed, Web of Science and SCOPUS databases using the terms “histamine-2 receptor antagonists”, “infection”, “necrotizing enterocolitis”, “mortality”, “neonates” and related terms to identify studies published up to April 30, 2017. We included studies conducted in hospitalized neonates and exposed to H2RA. The primary outcomes were infection, NEC and mortality. We included reports of infections with clinical signs and positive culture, and NEC according to Bell stages (stage ≥II) based on standardised clinical and radiologic criteria. Among 1,144 studies identified, 10 fulfilled the selection criteria. Information extracted included study design, sample size and number of participants, along with the outcomes of interest. We conducted a meta-analysis of adjusted data and pooled estimates of infection, NEC and mortality are reported as odds ratios (OR) and 95% confidence intervals (95%CI). Results: Ten studies were analysed. There were substantial associations between H2RA and infection (pooled OR: 2.09; 95%CI: 1.35–3.24; P = 0.001) and NEC (pooled OR: 2.81, 95%CI: 1.19–6.64; P = 0.02) but not with the mortality risk (pooled OR: 1.76; 95%CI: 0.50–6.16; P: 0.38). Conclusion: Current evidence suggests that H2RA is associated with an increased risk of infection and NEC, but not with mortality in neonates admitted to NICU. The use of H2RA in neonates must be stringently considered when necessary. [ABSTRACT FROM AUTHOR]

Despite big experimental data on the phenomena and mechanisms of the generation of ictal and interictal discharges (IDs and IIDs), mathematical models that can describe the synaptic interactions of neurons and the ionic dynamics in biophysical detail are not well-established. Based on experimental recordings of combined hippocampal-entorhinal cortex slices from rats in a high-potassium and a low-magnesium solution containing 4-aminopyridine as well as previous observations of similar experimental models, this type of mathematical model has been developed. The model describes neuronal excitation through the application of the conductance-based refractory density approach for three neuronal populations: two populations of glutamatergic neurons with hyperpolarizing and depolarizing GABAergic synapses and one GABAergic population. The ionic dynamics account for the contributions of voltage-gated and synaptic channels, active and passive transporters, and diffusion. The relatively slow dynamics of potassium, chloride, and sodium ion concentrations determine the transitions from pure GABAergic IIDs to IDs and GABA-glutamatergic IIDs. The model reproduces different types of IIDs, including those initiated by interneurons; repetitive IDs; tonic and bursting modes of an ID composed of clustered IID-like events. The simulations revealed contributions from different ionic channels to the ion concentration dynamics before and during ID generation. The proposed model is a step forward to an optimal mathematical description of the mechanisms of epileptic discharges. [ABSTRACT FROM AUTHOR]

Background: Births by cesarean section (CS) usually require longer recovery time, and as a result women remain hospitalized longer following CS than vaginal delivery (VD). A number of strategies have been proposed to reduce avoidable health care costs associated with childbirth. Among these, the containment of length of hospital stay (LoS) has been identified as an important quality indicator of obstetric care and performance efficiency of maternity centres. Since improvement of obstetric care at hospital level needs quantitative evidence, we compared the maternity services of an Italian region on LoS post CS. Methods: We conducted a population-based study in Friuli Venezia Giulia (FVG), a region of North-Eastern Italy, collecting data from all its 12 maternity centres (coded from A to K) during 2005–2015. We fitted a multivariable logistic regression using LoS as a binary outcome, higher/lower than the international early discharge (ED) cutoffs for CS (4 days), controlling for hospitals as well as several factors related to the clinical conditions of the mothers and the newborn, the obstetric history and socio-demographic background. Results were expressed as adjusted odds ratios (aOR) with 95% confidence interval (95%CI). Population attributable risks (PARs) were also calculated as proportional variation of LoS>ED for each hospital in the ideal scenario of having the same performance as centre J (the reference) during calendar year 2015. Results were expressed as PAR with 95%CI. Differences in mean LoS were also investigated with a multivariable linear regression model including the same explanatory factors of the above multiple logistic regression. Results were expressed as adjusted regression coefficients (aRC) with 95%CI. Results: Although decreasing over the years (5.0 ± 1.7 days in 2005 vs. 4.4 ± 1.7 days in 2015), the pooled mean LoS in the whole FVG during these 11 years was still 4.7 ± 1.7 days, higher than respective international ED benchmark. The significant decreasing trend of LoS>ED over time in FVG (aOR = 0.89; 95%CI: 0.88; 0.90) was marginal as compared to the variability of LoS>ED observed among the various maternity services. Regardless it was expressed as aRC or aOR, LoS after CS was lowest in hospital C, highest in hospital D and intermediate in centres I, K, G, F, A, H, E, B and J (in descending order). The aOR of LoS being longer than ED ranged from 1.63 (95%CI:1.46; 1.81) in hospital B up to 32.09 (95%CI: 25.68; 40.10) in facility D. When hospitals were ranked by PAR the same pattern was found, even if restricting the analysis to low risk pregnancies. Conclusions: Although significantly decreasing over time, the mean LoS in FVG during 2005–2015 was 4.7 days, higher than the international threshold recommended for CS. There was substantial variability in LoS by facility centre, suggesting that internal organizational processes of single hospitals should be improved by enforcing standardized guidelines and using audits, economic incentives and penalties if need be. [ABSTRACT FROM AUTHOR]

Information transmission in the human brain is a fundamentally dynamic network process. In partial epilepsy, this process is perturbed and highly synchronous seizures originate in a local network, the so-called epileptogenic zone (EZ), before recruiting other close or distant brain regions. We studied patient-specific brain network models of 15 drug-resistant epilepsy patients with implanted stereotactic electroencephalography (SEEG) electrodes. Each personalized brain model was derived from structural data of magnetic resonance imaging (MRI) and diffusion tensor weighted imaging (DTI), comprising 88 nodes equipped with region specific neural mass models capable of demonstrating a range of epileptiform discharges. Each patient’s virtual brain was further personalized through the integration of the clinically hypothesized EZ. Subsequent simulations and connectivity modulations were performed and uncovered a finite repertoire of seizure propagation patterns. Across patients, we found that (i) patient-specific network connectivity is predictive for the subsequent seizure propagation pattern; (ii) seizure propagation is characterized by a systematic sequence of brain states; (iii) propagation can be controlled by an optimal intervention on the connectivity matrix; (iv) the degree of invasiveness can be significantly reduced via the proposed seizure control as compared to traditional resective surgery. To stop seizures, neurosurgeons typically resect the EZ completely. We showed that stability analysis of the network dynamics, employing structural and dynamical information, estimates reliably the spatiotemporal properties of seizure propagation. This suggests novel less invasive paradigms of surgical interventions to treat and manage partial epilepsy. [ABSTRACT FROM AUTHOR]