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Recent advances in neuroscience have linked dynamical systems theory to cognition. The main contention is that extended cognition relies on a unitary brain-body-tool system showing the expected signatures of interaction-dominance reflected in a multifractal behavior. This might be particularly relevant when it comes to understanding how the brain is able to embody a tool to perform a task. Here we applied the multifractal formalism to the dynamics of hand movement while one was performing a computer task (the herding task) using a mouse or its own hand as a tool to move an object on the screen. We applied a focus-based multifractal detrended fluctuation analysis to acceleration time series. Then, multifractal nonlinearity was assessed by comparing original series to a finite set of surrogates obtained after Iterated Amplitude Adjusted Fourier transformation, a method that removes nonlinear multiscale dependencies while preserving the linear structure of the time series. Both hand and mouse task execution demonstrated multifractal nonlinearity, a typical form of across-scales interactivity in cognitive control. In addition, a wider multifractal spectrum was observed in mouse condition, which might highlight a richer set of interactions when the cognitive system is extended to the embodied mouse. We conclude that the emergence of multifractal nonlinearity from a brain-body-tool system pleads for recent theories of radical tool embodiment. Multifractal nonlinearity may be a promising metric to appreciate how physical objects—but also virtual tools and potentially prosthetics—are efficiently embodied by the brain.

Abstract Nanotechnologies are considered to be of growing importance to the vaccine field. Through decoration of immunogens on multivalent nanoparticles, designed nanovaccines can elicit improved humoral immunity. However, significant practical and monetary challenges in large‐scale production of nanovaccines have impeded their widespread clinical translation. Here, an alternative approach is illustrated integrating computational protein modeling and adaptive electroporation‐mediated synthetic DNA delivery, thus enabling direct in vivo production of nanovaccines. DNA‐launched nanoparticles are demonstrated displaying an HIV immunogen spontaneously self‐assembled in vivo. DNA‐launched nanovaccines induce stronger humoral responses than their monomeric counterparts in both mice and guinea pigs, and uniquely elicit CD8+ effector T‐cell immunity as compared to recombinant protein nanovaccines. Improvements in vaccine responses recapitulate when DNA‐launched nanovaccines with alternative scaffolds and decorated antigen are designed and evaluated. Finally, evaluation of functional immune responses induced by DLnanovaccines demonstrates that, in comparison to control mice or mice immunized with DNA‐encoded hemagglutinin monomer, mice immunized with a DNA‐launched hemagglutinin nanoparticle vaccine fully survive a lethal influenza challenge, and have substantially lower viral load, weight loss, and influenza‐induced lung pathology. Additional study of these next‐generation in vivo‐produced nanovaccines may offer advantages for immunization against multiple disease targets.

Integration of immune checkpoint inhibitors (ICIs) has improved the efficacy of treatment regimens for various cancers. The array of potential side effects keeps evolving and includes neurological complications. An increased risk of seizures and status epilepticus (SE) has been discussed and appears likely. In this report, we present clinical data from brain metastases patients undergoing ICI treatment revealing, for what we believe is the first time, SE as a serious adverse effect of ICI treatment. In our cohort of 3202 patients with brain metastases, we observed an increasing incidence of SE since the approval of ICIs in 2014 (16 patients in 2008–2013 vs. 36 patients in 2014–2019). Almost half of the patients treated in 2014–2019 received ICIs during the course of their disease, and in more than 80% of cases last dose of ICIs was given less than 30 days before SE. These findings suggest that ICIs may lead to an increased rate of SE in patients with brain metastases. Additional mechanistic research and prospective trials are necessary to elucidate the pathomechanism causing SE in patients treated with ICIs.

Fish spawning aggregations (FSAs) consist of the temporary gathering of a large number of fishes at a specific location to spawn. Monitoring of FSA is typically conducted by divers, but surveys are often restricted to a limited area and dependent upon sea conditions, thus our knowledge of FSA dynamics is extremely limited. Fisheries independent research strives for new technology that can help remotely and unobtrusively quantify fish biomass and abundance. Since some fish species, such as groupers, produce sounds during reproductive behaviors, Eulerian passive acoustic monitoring provides information when divers cannot access the FSA site. Fish sounds provide an innovative approach to assess fish presence and potentially their numbers during reproductive events. However, this technology is limited by the sound propagation range, hence the distance between the fish emitting sounds and the hydrophone location. As such, this Eulerian monitoring approach implicitly creates a knowledge gap about what happens beyond the range of the recorders. Furthermore, the large datasets make the detection process by human ears and eyes very tedious and inconsistent. This paper reports on two innovative approaches to overcome these limitations. To facilitate fish call detections, we have developed an algorithm based on machine learning and voice recognition methods to identify and classify the sounds known to be produced by certain species during FSA. This algorithm currently operates on a SV3 Liquid Robotics wave glider, an autonomous surface vehicle which has been fitted to accommodate a passive acoustic listening device and can cover large areas under a wide range of sea conditions. Fish sounds detections, classification results, and locations along with environmental data are transmitted in real-time enabling verification of the sites with high detections by divers or other in situ methods. Recent surveys in the US Virgin Islands with the SV3 Wave Glider are revealing for the first time the spatial and temporal distribution of fish calls surrounding known FSA sites. These findings are critical to understanding the dynamics of fish populations because calling fish were detected several kilometers away from the known FSAs. These courtship associated sounds from surrounding areas suggest that other FSAs may exist in the region.

Complexity science has helped neuroscientists shed new light on brain-body coordination during movement performance and motor learning in humans. A critical intuition based on monofractal approaches has been a fractal-like coordination in the movement system, more marked in motor-skilled people. Here we aimed to show that heterogeneity in scaling exponents of movements series, literally multifractality, may reflect a special kind of interactions spanning multiple temporal scales at once, which can be grasped by a focus-based multifractal detrended fluctuation analysis. We analyzed multifractality in the variability structure of a 10-min arm cranking movement series repeated as 3 sets a day for 3 days, comparatively with their linearized (phase-randomized) surrogate series in sedentary (SED) untrained people, wheelchair athletes (WATH), and able-bodied athletes (ATH). Arm cranking exercise was chosen to minimize external variations, which tend to interfere with internal origin of variability. Participants were asked to maintain a regular effort and torque output served as the performance variable. Our first hypothesis suggests greater multiscale interactions in trained (WATH, ATH) versus untrained (SED) people, reflected in a wider range of scaling exponents characterizing movement series, providing the system with significant robustness. As a second hypothesis, we addressed a possible advantage in WATH over ATH due to greater motor skills in upper-limbs. Multifractal metrics in original and surrogate series showed ubiquitous, but different, multifractal behaviors in expert (ATH and WATH indistinctively) versus novice (SED) people. Experts exhibited high multifractality during the first execution of the task; then multifractality dropped in following repetitions. We suggest an exacerbated robustness of the movement system coordination in experts when discovering the task. Once task novelty has worn off, poor external sources of variability and limited risks of task failure have been identified, which is reflected in the narrower range of scale interactions, possibly as an energy cost effective adaptation. Multifractal corollaries of movement adaptation may be helpful in sport training and motor rehabilitation programs.

Background: Most work in endocrinology focus on the action of a single hormone, and very little on the cross-talks between two hormones. Here we characterize the nature of interactions between thyroid hormone and glucocorticoid signaling during Xenopus tropicalis metamorphosis. Methods: We used functional genomics to derive genome wide profiles of methylated DNA and measured changes of gene expression after hormonal treatments of a highly responsive tissue, tailfin. Clustering classified the data into four types of biological responses, and biological networks were modeled by system biology. Results: We found that gene expression is mostly regulated by either T3 or CORT, or their additive effect when they both regulate the same genes. A small but non-negligible fraction of genes (12%) displayed non-trivial regulations indicative of complex interactions between the signaling pathways. Strikingly, DNA methylation changes display the opposite and are dominated by cross-talks. Conclusion: Cross-talks between thyroid hormones and glucocorticoids are more complex than initially envisioned and are not limited to the simple addition of their individual effects, a statement that can be summarized with the pseudo-equation: TH ∙ GC > TH + GC. DNA methylation changes are highly dynamic and buffered from genome expression.

Inertial measurement unit sensors (IMU; i.e., accelerometer, gyroscope and magnetometer combinations) are frequently fitted to animals to better understand their activity patterns and energy expenditure. Capable of recording hundreds of data points a second, these sensors can quickly produce large datasets that require methods to automate behavioral classification. Here, we describe behaviors derived from a custom-built multi-sensor bio-logging tag attached to Atlantic Goliath grouper (Epinephelus itajara) within a simulated ecosystem. We then compared the performance of two commonly applied machine learning approaches (random forest and support vector machine) to a deep learning approach (convolutional neural network, or CNN) for classifying IMU data from this tag. CNNs are frequently used to recognize activities from IMU data obtained from humans but are less commonly considered for other animals. Thirteen behavioral classes were identified during ethogram development, nine of which were classified. For the conventional machine learning approaches, 187 summary statistics were extracted from the data, including time and frequency domain features. The CNN was fed absolute values obtained from fast Fourier transformations of the raw tri-axial accelerometer, gyroscope and magnetometer channels, with a frequency resolution of 512 data points. Five metrics were used to assess classifier performance; the deep learning approach performed better across all metrics (Sensitivity = 0.962; Specificity = 0.996; F1-score = 0.962; Matthew’s Correlation Coefficient = 0.959; Cohen’s Kappa = 0.833) than both conventional machine learning approaches. Generally, the random forest performed better than the support vector machine. In some instances, a conventional learning approach yielded a higher performance metric for particular classes (e.g., the random forest had a F1-score of 0.971 for backward swimming compared to 0.955 for the CNN). Deep learning approaches could potentially improve behavioral classification from IMU data, beyond that obtained from conventional machine learning methods.

Nucleic acid delivery: Instant, wide-ranging protection against influenza A and B A novel innoculation technique involving the injection of antibody-producing plasmid DNA has shown to be effective against influenza in mice. The flu is responsible for up to half a million deaths each year and up to five million cases of severe disease, while also posing a substantial pandemic threat, even with our current repertoire of vaccines. A team of researchers led by Sarah Elliott and David Weiner of The Wistar Institute of Anatomy and Biology, Philadelphia, developed potent plasmid-based constructs that, once injected, entered hosts’ cells and utilized cellular machinery to encode antibodies protective against a range of influenza A and B subtypes. DNA inoculation conferred acute protection from disease, with treated individuals also being immune to subsequent exposure. This approach warrants further investigation as an alternative technology for practical delivery of monoclonal antibody therapeutics.

Abstract Ethylene is a major plant hormone mediating developmental processes and stress responses to stimuli such as infection. We show here that ethylene is also produced during systemic inflammation in humans and is released in exhaled breath. Traces of ethylene were detected by laser spectroscopy both in vitro in isolated blood leukocytes exposed to bacterial lipopolysaccharide (LPS) as well as in vivo following LPS administration in healthy volunteers. Exposure to LPS triggers formation of ethylene as a product of lipid peroxidation induced by the respiratory burst. In humans, ethylene was detected prior to the increase of blood levels of inflammatory cytokines and stress-related hormones. Our results highlight that ethylene release is an early and integral component of in vivo lipid peroxidation with important clinical implications as a breath biomarker of bacterial infection.

Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2–3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period.Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the “door-to-needle” time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire.Interventions: We are applying a multi-level intervention in cooperation with three “STREAM multipliers” from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2–3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings.Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251.

Tumor budding (TB) is an important prognostic parameter in colorectal cancer (CRC) and associated with metastasis. However, the mechanisms of TB have not been fully elucidated and a major limitation is the absence of in vivo models. Here, we determine the suitability of human cell line derived xenografts (CDX) as models of TB in CRC. Pan-cytokeratin (CK)-stained next-generation Tissue Microarrays (ngTMA) of two CDX models (HT-29, n = 12 and HCT-8, n = 8) and human CRC (n = 27 high-grade and 25 low-grade budding tumors, each) were evaluated for TB. Immunohistochemistry for E-cadherin, β-catenin, Ki-67, ZEB1, and TWIST1 was performed. HT-29 and HCT-8 were predominantly high-grade and no/low-grade TB tumors, respectively. TB counts in the tumor center (intratumoral budding, ITB) were significantly higher in HT-29 CDX tumors compared to human CRC (p = 0.0099). No difference was found in TB counts at the invasion front (peritumoral budding, PTB; p=0.07). ITB and PTB were strongly correlated (r = 0.438 and r = 0.62 in CDX and human CRC, respectively). Immunohistochemistry profiles were comparable in CDX and human CRC tissues. TB in the CDX mouse models is phenotypically similar to human CRCs and highlights comparable protein profiles. The HT-29 CDX could be a suitable model for the in vivo assessment of TB.

Thyroid hormone (TH) is the most important hormone in frog metamorphosis, a developmental process which will not occur in the absence of TH but can be induced precociously by exogenous TH. However, such treatments including in-vitro TH treatments often do not replicate the events of natural metamorphosis in many organs, including lung, brain, blood, intestine, pancreas, tail, and skin. A potential explanation for the discrepancy between natural and TH-induced metamorphosis is the involvement of glucocorticoids (GCs). GCs are not able to advance development by themselves but can modulate the rate of developmental progress induced by TH via increased tissue sensitivity to TH. Global gene expression analyses and endocrine experiments suggest that GCs may also have direct actions required for completion of metamorphosis independent of their effects on TH signaling. Here, we provide a new review and analysis of the requirement and necessity of TH signaling in light of recent insights from gene knockout frogs. We also examine the independent and interactive roles GCs play in regulating morphological and molecular metamorphic events dependent upon TH.

Neutrophils kill ingested pathogens by the so-called oxidative burst, where reactive oxygen species (ROS) are produced in the lumen of phagosomes at very high rates (mM/s), although these rates can only be maintained for a short period (minutes). In contrast, dendritic cells produce ROS at much lower rates, but they can sustain production for much longer after pathogen uptake (hours). It is becoming increasingly clear that this slow but prolonged ROS production is essential for antigen cross-presentation to activate cytolytic T cells, and for shaping the repertoire of antigen fragments for presentation to helper T cells. However, despite this importance of ROS production by dendritic cells for activation of the adaptive immune system, their actual ROS production rates have never been quantified. Here, we quantified ROS production in human monocyte-derived dendritic cells by measuring the oxygen consumption rate during phagocytosis. Although a large variation in oxygen consumption and phagocytic capacity was present among individuals and cells, we estimate a ROS production rate of on average ~0.5 mM/s per phagosome. Quantitative microscopy approaches showed that ROS is produced within minutes after pathogen encounter at the nascent phagocytic cup. H2DCFDA measurements revealed that ROS production is sustained for at least ~10 h after uptake. While ROS are produced by dendritic cells at an about 10-fold lower rate than by neutrophils, the net total ROS production is approximately similar. These are the first quantitative estimates of ROS production by a cell capable of antigen cross-presentation. Our findings provide a quantitative insight in how ROS affect dendritic cell function.

Amphibian post-embryonic development and Thyroid Hormones (TH) signaling are deeply and intimately connected. In anuran amphibians, TH induce the spectacular and complex process known as metamorphosis. In paedomorphic salamanders, at similar development time, raising levels of TH fail to induce proper metamorphosis, as many “larval” tissues (e.g., gills, tailfin) are maintained. Why does the same evolutionary conserved signaling pathway leads to alternative phenotypes? We used a combination of developmental endocrinology, functional genomics and network biology to compare the transcriptional response of tailfin to TH, in the post-hatching paedormorphic Axolotl salamander and Xenopus tadpoles. We also provide a technological framework that efficiently reduces large lists of regulated genes down to a few genes of interest, which is well-suited to dissect endocrine regulations. We first show that Axolotl tailfin undergoes a strong and robust TH-dependent transcriptional response at post embryonic transition, despite the lack of visible anatomical changes. We next show that Fos and Actg1, which structure a single and dense subnetwork of cellular sensors and regulators, display opposite regulation between the two species. We finally show that TH treatments and natural variations of TH levels follow similar transcriptional dynamics. We suggest that, at the molecular level, tailfin fate correlates with the alternative transcriptional states of an fos-actg1 sub-network, which also includes transcription factors and regulators of cell fate. We propose that this subnetwork is one of the molecular switches governing the initiation of distinct TH responses, with transcriptional programs conducting alternative tailfin fate (maintenance vs. resorption) 2 weeks post-hatching.

ObjectiveMorphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population.Study designTerm and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants.Results244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, pConclusionsClearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect.Trial registrationwww.trialregister.nl NTR2529.

Recent research has clarified the existence of a networked system involving a cortical and subcortical circuitry regulating both cognition and cardiac autonomic control, which is dynamically organized as a function of cognitive demand. The main interactions span multiple temporal and spatial scales and are extensively governed by nonlinear processes. Hence, entropy and (multi)fractality in heart period time series are suitable to capture emergent behavior of the cognitive-autonomic network coordination. This study investigated how entropy and multifractal-multiscale analyses could depict specific cognitive-autonomic architectures reflected in the heart rate dynamics when students performed selective inhibition tasks. The participants (N=37) completed cognitive interference (Stroop color and word task), action cancellation (stop-signal) and action restraint (go/no-go) tasks, compared to watching a neutral movie as baseline. Entropy and fractal markers (respectively, the refined composite multiscale entropy and multifractal-multiscale detrended fluctuation analysis) outperformed other time-domain and frequency-domain markers of the heart rate variability in distinguishing cognitive tasks. Crucially, the entropy increased selectively during cognitive interference and the multifractality increased during action cancellation. An interpretative hypothesis is that cognitive interference elicited a greater richness in interactive processes that form the central autonomic network while action cancellation, which is achieved via biasing a sensorimotor network, could lead to a scale-specific heightening of multifractal behavior.

The emergence of multiple concurrent infectious diseases localized in the world creates a complex burden on global public health systems. Outbreaks of Ebola, Lassa, and Marburg viruses in overlapping regions of central and West Africa and the co-circulation of Zika, Dengue, and Chikungunya viruses in areas with A. aegypti mosquitos highlight the need for a rapidly deployable, safe, and versatile vaccine platform readily available to respond. The DNA vaccine platform stands out as such an application. Here, we present proof-of-concept studies from mice, guinea pigs, and non-human primates for two multivalent DNA vaccines delivered using in vivo electroporation (EP) targeting mosquito-borne (MMBV) and hemorrhagic fever (MHFV) viruses. Immunization with MMBV or MHFV vaccines via intradermal EP delivery generated robust cellular and humoral immune responses against all target viral antigens in all species. MMBV vaccine generated antigen-specific binding antibodies and IFNγ-secreting lymphocytes detected in NHPs up to six months post final immunization, suggesting induction of long-term immune memory. Serum from MHFV vaccinated NHPs demonstrated neutralizing activity in Ebola, Lassa, and Marburg pseudovirus assays indicating the potential to offer protection. Together, these data strongly support and demonstrate the versatility of DNA vaccines as a multivalent vaccine development platform for emerging infectious diseases.

Frogs are an ecologically diverse and phylogenetically ancient group of anuran amphibians that include important vertebrate cell and developmental model systems, notably the genus Xenopus. Here we report a high-quality reference genome sequence for the western clawed frog, Xenopus tropicalis, along with draft chromosome-scale sequences of three distantly related emerging model frog species, Eleutherodactylus coqui, Engystomops pustulosus, and Hymenochirus boettgeri. Frog chromosomes have remained remarkably stable since the Mesozoic Era, with limited Robertsonian (i.e., arm-preserving) translocations and end-to-end fusions found among the smaller chromosomes. Conservation of synteny includes conservation of centromere locations, marked by centromeric tandem repeats associated with Cenp-a binding surrounded by pericentromeric LINE/L1 elements. This work explores the structure of chromosomes across frogs, using a dense meiotic linkage map for X. tropicalis and chromatin conformation capture (Hi-C) data for all species. Abundant satellite repeats occupy the unusually long (~20 megabase) terminal regions of each chromosome that coincide with high rates of recombination. Both embryonic and differentiated cells show reproducible associations of centromeric chromatin and of telomeres, reflecting a Rabl-like configuration. Our comparative analyses reveal 13 conserved ancestral anuran chromosomes from which contemporary frog genomes were constructed.

Podosomes are adhesive cytoskeletal structures found in several cell types, but whether or how they are interconnected is not known. Here the authors demonstrate mesoscale connectivity of podosome clusters by imaging directional flow patterns of podosome components vinculin, talin and F-actin.

Despite considerable appeal, the growing appreciation of biosignals complexity reflects that system complexity needs additional support. A dynamically coordinated network of neurovisceral integration has been described that links prefrontal-subcortical inhibitory circuits to vagally-mediated heart rate variability. Chronic stress is known to alter network interactions by impairing amygdala functional connectivity. HRV-biofeedback training can counteract stress defects. We hypothesized the great value of an entropy-based approach of beat-to-beat biosignals to illustrate how HRVB training restores neurovisceral complexity, which should be reflected in signal complexity. In thirteen moderately-stressed participants, we obtained vagal tone markers and psychological indexes (state anxiety, cognitive workload, and Perceived Stress Scale) before and after five-weeks of daily HRVB training, at rest and during stressful cognitive tasking. Refined Composite Multiscale Entropy (RCMSE) was computed over short time scales as a marker of signal complexity. Heightened vagal tone at rest and during stressful tasking illustrates training benefits in the brain-to-heart circuitry. The entropy index reached the highest significance levels in both variance and ROC curves analyses. Restored vagal activity at rest correlated with gain in entropy. We conclude that HRVB training is efficient in restoring healthy neurovisceral complexity and stress defense, which is reflected in HRV signal complexity. The very mechanisms that are involved in system complexity remain to be elucidated, despite abundant literature existing on the role played by amygdala in brain interconnections.

Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.

Introduction: This study was designed to evaluate risk factors and incidence of epilepsy-related injuries and accidents (ERIA) at an outpatient clinic of a German epilepsy center providing healthcare to a mixed urban and rural population of over one million inhabitants.Methods: Data acquisition was performed between 10/2013 and 09/2014 using a validated patient questionnaire on socioeconomic status, course of epilepsy, quality of life (QoL), depression, injuries and accidents associated with seizures or inadequate periictal patterns of behavior concerning a period of 3 months. Univariate analysis, multiple testing and regression analysis were performed to identify possible variables associated with ERIA.Results: A total of 292 patients (mean age 40.8 years, range 18–86; 55% female) were enrolled and analyzed. Focal epilepsy was diagnosed in 75% of the patients. The majority was on an antiepileptic drug (AEDs) polytherapy (mean number of AEDs: 1.65). Overall, 41 patients (14.0%) suffered from epilepsy-related injuries and accidents in a 3-month period. Besides lacerations (n = 18, 6.2%), abrasions and bruises (n = 9, 3.1%), fractures (n = 6, 2.2%) and burns (n = 3, 1.0%), 17 mild injuries (5.8%) were reported. In 20 (6.8% of the total cohort) cases, urgent medical treatment with hospitalization was necessary. Epilepsy-related injuries and accidents were related to active epilepsy, occurrence of generalized tonic-clonic seizures (GTCS) and drug-refractory course as well as reported ictal falls, ictal loss of consciousness and abnormal peri-ictal behavior in the medical history. In addition, patients with ERIA had significantly higher depression rates and lower QoL.Conclusion: ERIA and their consequences should be given more attention and standardized assessment for ERIA should be performed in every outpatient visit.

In coral reef ecosystems, mesophotic coral habitat (>30 m to the end of the photic zone) are extensions of shallow reefs and contribute to the persistence of coral reef populations. In the North West Gulf of Mexico (NW GOM), the Flower Garden Banks National Marine Sanctuary (FGBNMS) is an isolated reef ecosystem comprising contiguous shallow and mesophotic reefs habitats on two central banks along the margin of the continental shelf. A future expansion of the sanctuary is proposed to include additional mesophotic banks and aims at building a network of protected areas in the NW GOM to ensure the persistence of the coral reef populations inhabiting the sanctuary. To evaluate the feasibility of this expansion and investigate the overall dynamics of coral species in the region, we studied the patterns of larval connectivity of Montastraea cavernosa, a common depth generalist coral species, using a larval dispersal modeling approach. Our results highlighted larval exports from the NW GOM banks to the northeastern and southwestern GOM, larval connectivity between all banks investigated in this study, and the potential for exporting larvae from mesophotic to shallower reefs. Our study associated with Studivan and Voss (2018; associate manuscript) demonstrates the relevance of combining modeling and genetic methods to consider both demographic and genetic timescales for the evaluation of the connectivity dynamics of marine populations. In the case of the NW GOM, both studies support the future management plan for expanding FGBNMS.

BackgroundHypoxic–ischemic encephalopathy following perinatal asphyxia is a leading cause of neonatal death and disability worldwide. Treatment with therapeutic hypothermia reduced adverse outcomes from 60 to 45%. Additional strategies are urgently needed to further improve the outcome for these neonates. Inhibition of nitric oxide synthase (NOS) is a potential neuroprotective target. This article reviews the evidence of neuroprotection by nitric oxide (NO) synthesis inhibition in animal models.MethodsLiterature search using the EMBASE, Medline, Cochrane, and PubMed databases. Studies comparing NOS inhibition to placebo, with neuroprotective outcome measures, in relevant animal models were included. Methodologic quality of the included studies was assessed.Results26 studies were included using non-selective or selective NOS inhibition in rat, piglet, sheep, or rabbit animal models. A large variety in outcome measures was reported. Outcome measures were grouped as histological, biological, or neurobehavioral. Both non-selective and selective inhibitors show neuroprotective properties in one or more outcome measures. Methodologic quality was either low or moderate for all studies.ConclusionInhibition of NO synthesis is a promising strategy for additional neuroprotection. In humans, intervention can only take place after the onset of the hypoxic–ischemic event. Therefore, combined inhibition of neuronal and inducible NOS seems the most likely candidate for human clinical trials. Future studies should determine its safety and effectiveness in neonates, as well as a potential sex-specific neuroprotective effect. Researchers should strive to improve methodologic quality of animal intervention studies by using a systematic approach in conducting and reporting of these studies.

Diverse indicators of postural control in Humans have been explored for decades, mostly based on the trajectory of the center-of-pressure. Classical approaches focus on variability, based on the notion that if a posture is too variable, the subject is not stable. Going deeper, an improved understanding of underlying physiology has been gained from studying variability in different frequency ranges, pointing to specific short-loops (proprioception), and long-loops (visuo-vestibular) in neural control. More recently, fractal analyses have proliferated and become useful additional metrics of postural control. They allowed identifying two scaling phenomena, respectively in short and long timescales. Here, we show that one of the most widely used methods for fractal analysis, Detrended Fluctuation Analysis, could be enhanced to account for scalings on specific frequency ranges. By computing and filtering a bank of synthetic fractal signals, we established how scaling analysis can be focused on specific frequency components. We called the obtained method Frequency-specific Fractal Analysis (FsFA) and used it to associate the two scaling phenomena of postural control to proprioceptive-based control loop and visuo-vestibular based control loop. After that, convincing arguments of method validity came from an application on the study of unaltered vs. altered postural control in athletes. Overall, the analysis suggests that at least two timescales contribute to postural control: a velocity-based control in short timescales relying on proprioceptive sensors, and a position-based control in longer timescales with visuo-vestibular sensors, which is a brand-new vision of postural control. Frequency-specific scaling exponents are promising markers of control strategies in Humans.

INTRODUCTION:Heart rate variability biofeedback (HRV-BFB) training, a method whereby one controls an unusually low breathing rate to reach cardiac coherence, has been shown to reduce anxiety and improve cardiac autonomic markers in diseased people, but much less is known about HRV-BFB benefits in healthy people. Here we investigated potential benefits in young competitors experiencing stress during university examinations as well as persistence of benefits after HRV-BFB training cessation. METHODS:A group of sports students (n = 12) practiced 5-min HRV-BFB training twice a day for 5-weeks using URGOfeel® (URGOTECH) and was compared to a control group (n = 6). University examinations occurred immediately after HRV-BFB training (Exam1), then 12-weeks later (Exam2). Anxiety markers and cardiac autonomic markers were assessed at baseline, Exam1 and Exam2. Principal Component Analyses (PCA) that combined all these markers were computed at Exam1 and Exam2 to emphasize covariations. RESULTS:At Exam 1, immediately after HRV-BFB training cessation, the experimental group demonstrated greater autonomic markers but similar states of anxiety when compared to the Control group. Twelve weeks later at Exam2, autonomic markers were greater and anxiety scores were lesser among the experimental group. PCA highlighted covariations only within cardiac autonomic markers at Exam1. Rather, variations in cardiac markers were associated with anxiety markers at Exam2. CONCLUSION:Short sessions of HRV-BFB training for a brief period of 5 weeks bring substantial benefits to autonomic markers and anxiety levels in young competitors. Here beneficial effects persisted for 12 weeks. Dissociated profiles of anxiety and cardiac autonomic adaptations shed new light on the role of the amygdala in heart-brain interactions after cardiac coherence training.

In this study, banana petiole-based cellulose nanofibril (CNF) films treated with graphene oxide (GO) were prepared and evaluated by means of Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), dynamic mechanical analysis (DMA), and thermogravimetric analysis (TGA). Tensile strengths (TS), dynamic mechanical properties, and thermal stabilities of the films were affected positively when the GO loading was less than 4.4 wt%. From these results, FTIR spectra, and SEM analyses, a strong coupling between the GO and the cellulose matrix could be concluded at lower GO loadings. The TGA and DMA results also suggested that the CNF film treated with 4.4 wt% GO had more char residue, better thermal stability, higher storage modulus, and higher retention ratio when compared to that without treatment. This work provides a new approach for more effective utilization of banana petiole as a feedstock for CNF and GO/CNF composites.

Arrhythmogenic cardiomyopathy (AC) is a rare mostly hereditary disease, in which fibro-fatty tissue replaces cardiomyocytes. Typically, the first alterations of the disease can be encountered in the epicardium of the right ventricle in adolescent patients. From there, the disease usually progresses over time. Besides the development of heart failure, the clinical significance of the disease is determined by the predisposition to potentially lethal ventricular arrhythmias. Hence, a majority of patients with AC require an implantable cardioverter-defibrillator (ICD) to be protected from sudden cardiac death. A recently developed alternative to transvenous systems are subcutaneous ICDs (S-ICD), associated with a lower risk of device-related complications such as endocarditis since no foreign material is implanted within the heart and vascular system. In this report, we describe and discuss our experience with the implantation of a S-ICD in a patient with AC, who had low QRS voltage and persistent atrial fibrillation precluding successful S-ICD implantation, as well as the challenges encountered during subsequent transvenous lead implantation.

Lacosamide (LCM) is approved for anticonvulsive treatment in focal epilepsy and exhibits its function through the slow inactivation of voltage-gated sodium channels (VGSCs). LCM shows comparable efficacy with other antiepileptic drugs (AEDs) licensed in the last decade: in three randomized placebo-controlled trials, significant median seizure reduction rates of 35.2% for 200 mg/day, 36.4–39% for 400 mg/day and 37.8–40% for 600 mg/day were reported. Likewise, 50% responder rates were 38.3–41.1% for 400 mg/day and 38.1–41.2% for 600 mg/day. Similar rates were reported in post-marketing studies. The main adverse events (AEs) are dizziness, abnormal vision, diplopia and ataxia. Overall, LCM is well tolerated and has no clinically-relevant drug–drug interactions. Due to the drug’s intravenous availability, its use in status epilepticus (SE) is increasing, and the available data are promising.

Philippe Caillet,1,2 Marie Laurent,1,2 Sylvie Bastuji-Garin,1,3,4 Evelyne Liuu,2 Stephane Culine,5 Jean-Leon Lagrange,6 Florence Canoui-Poitrine,1,2,3,* Elena Paillaud1,2,* 1Laboratoire d’Investigation Clinique (LIC), Faculté de Medecine, Université Paris Est Créteil (UPEC), Créteil, Paris, 2Unité de Coordination d’Onco-Gériatrie, Département de Médecine Interne et Gériatrie, Hôpital Henri-Mondor, Assistance Publique – Hopitaux de Paris (AP-HP), Créteil, 3Service de Santé Publique, Hôpital Henri-Mondor, AP-HP, Créteil, 4Unité de Recherche Clinique, Hôpital Henri-Mondor, AP-HP, Créteil, 5Service d’Oncologie Médicale, Hôpital Saint-Louis, AP-HP, Paris, 6Service de Radiotherapie, Hôpital Henri-Mondor, AP-HP, Créteil, France*These authors contributed equally to this workBackground: Cancer is common in older patients, who raise specific treatment challenges due to aging-related, organ-specific physiologic changes and the presence in most cases of comorbidities capable of affecting treatment tolerance and outcomes. Identifying comorbid conditions and physiologic changes due to aging allows oncologists to better assess the risk/benefit ratio and to adjust the treatment accordingly. Conducting a Comprehensive Geriatric Assessment (CGA) is one approach developed for this purpose. We reviewed the evidence on the usefulness of CGA for assessing health problems and predicting cancer treatment outcomes, functional decline, morbidity, and mortality in older patients with solid malignancies. Methods: We searched Medline for articles published in English between January 1, 2000 and April 14, 2014, and reporting prospective observational or interventional studies of CGA feasibility or effectiveness in patients aged ≥65 years with solid malignancies. We identified studies with at least 100 patients, a multivariate analysis, and assessments of at least five of the following CGA domains: nutrition, cognition, mood, functional status, mobility and falls, polypharmacy, comorbidities, and social environment.Results: All types of CGA identified a large number of unrecognized health problems capable of interfering with cancer treatment. CGA results influenced 21%–49% of treatment decisions. All CGA domains were associated with chemotoxicity or survival in at least one study. The abnormalities that most often predicted mortality and chemotoxicity were functional impairment, malnutrition, and comorbidities.Conclusion: The CGA uncovers numerous health problems in elderly patients with cancer and can affect treatment decisions. Functional impairment, malnutrition, and comorbidities are independently associated with chemotoxicity and/or survival. Only three randomized published studies evaluated the effectiveness of CGA-linked interventions. Further research into the effectiveness of the CGA in improving patient outcomes is needed. Keywords: cancer, geriatric assessment, elderly, mortality, chemotoxicity, outcomes

In humans, physiological systems involved in maintaining stable conditions for health and well-being are complex, encompassing multiple interactions within and between system components. This complexity is mirrored in the temporal structure of the variability of output signals. Entropy has been recognized as a good marker of systems complexity, notably when calculated from heart rate and postural dynamics. A degraded entropy is generally associated with frailty, aging, impairments or diseases. In contrast, high entropy has been associated with the elevated capacity to adjust to an ever-changing environment, but the link is unknown between entropy and the capacity to cope with cognitive tasks in a healthy young to middle-aged population. Here, we addressed classic markers (time and frequency domains) and refined composite multiscale entropy (MSE) markers (after pre-processing) of heart rate and postural sway time series in 34 participants during quiet versus cognitive task conditions. Recordings lasted 10 min for heart rate and 51.2 s for upright standing, providing time series lengths of 500–600 and 2048 samples, respectively. The main finding was that entropy increased during cognitive tasks. This highlights the possible links between our entropy measures and the systems complexity that probably facilitates a control remodeling and a flexible adaptability in our healthy participants. We conclude that entropy is a reliable marker of neurophysiological complexity and adaptability in autonomic and somatic systems.

Cancer transformation involves reprograming of mitochondrial function to avert cell death mechanisms, monopolize energy metabolism, accelerate mitotic proliferation, and promote metastasis. Mitochondrial ion channels are emerging as promising therapeutic targets mainly because of their connection to metabolic and apoptotic functions. This mini-review discusses how mitochondrial channels might be associated with cancer transformation; and expands on the possible involvement of the mitochondrial protein import complexes in such pathophysiological process.

Genome-wide functional analyses require high-resolution genome assembly and annotation. We applied ChIA-PET to analyze gene regulatory networks, including 3D chromosome interactions, underlying thyroid hormone (TH) signaling in the frog Xenopus tropicalis. As the available versions of Xenopus tropicalis assembly and annotation lacked the resolution required for ChIA-PET we improve the genome assembly version 4.1 and annotations using data derived from the paired end tag (PET) sequencing technologies and approaches (e.g., DNA-PET [gPET], RNA-PET etc.). The large insert (~10 Kb, ~17 Kb) paired end DNA-PET with high throughput NGS sequencing not only significantly improved genome assembly quality, but also strongly reduced genome "fragmentation", reducing total scaffold numbers by ~60%. Next, RNA-PET technology, designed and developed for the detection of full-length transcripts and fusion mRNA in whole transcriptome studies (ENCODE consortia), was applied to capture the 5' and 3' ends of transcripts. These amendments in assembly and annotation were essential prerequisites for the ChIA-PET analysis of TH transcription regulation. Their application revealed complex regulatory configurations of target genes and the structures of the regulatory networks underlying physiological responses. Our work allowed us to improve the quality of Xenopus tropicalis genomic resources, reaching the standard required for ChIA-PET analysis of transcriptional networks. We consider that the workflow proposed offers useful conceptual and methodological guidance and can readily be applied to other non-conventional models that have low-resolution genome data.

BACKGROUND:[18F]-fluorodeoxyglucose (FDG) has been suggested for the clinical and experimental imaging of inflammatory atherosclerotic lesions. Significant FDG uptake in brown adipose tissue (BAT) has been observed both in humans and mice. The objective of the present study was to investigate the influence of periaortic BAT on apolipoprotein E-deficient (apoE-/-) mouse atherosclerotic lesion imaging with FDG. METHODS:ApoE-/- mice (36 ± 2 weeks-old) were injected with FDG (12 ± 2 MBq). Control animals (Group A, n = 7) were injected conscious and kept awake at room temperature (24°C) throughout the accumulation period. In order to minimize tracer activity in periaortic BAT, Group B (n = 7) and C (n = 6) animals were injected under anaesthesia at 37°C and Group C animals were additionally pre-treated with propranolol. PET/CT acquisitions were performed prior to animal euthanasia and ex vivo analysis of FDG biodistribution. RESULTS:Autoradiographic imaging indicated higher FDG uptake in atherosclerotic lesions than in the normal aortic wall (all groups, P

Hypothermia is ineffective in 45% of neonates with hypoxic-ischemic encephalopathy. Xenon has additive neuroprotective properties, but is expensive, and its application complicated. Argon gas is cheaper, easier to apply, and also has neuroprotective properties in experimental settings. The aim was to explore the safety of argon ventilation in newborn piglets.Eight newborn piglets (weight 1.4-3.0 kg) were used. Heart rate, blood pressure, regional cerebral saturation, and electrocortical brain activity were measured continuously. All experiments had a 30 min. baseline period, followed by three 60 min. periods of argon ventilation alternated with 30 min argon washout periods. Two animals were ventilated with increasing concentrations of argon (1h 30%, 1 h 50%, and 1 h 80%), two were subjected to 60 min. hypoxia (FiO2 0.08) before commencing 50% argon ventilation, and two animals received hypothermia following hypoxia as well as 50% argon ventilation. Two animals served as home cage controls and were terminated immediately.Argon ventilation did not result in a significant change of heart rate (mean ± s.d. -3.5 ± 3.6 bpm), blood pressure (-0.60 ± 1.11 mmHg), cerebral oxygen saturation (0.3 ± 0.9%), electrocortical brain activity (-0.4 ± 0.7 µV), or blood gas values. Argon ventilation resulted in elevated argon concentrations compared to the home cage controls (34.5, 25.4, and 22.4 vs. 7.3 µl/ml).Ventilation with up to 80% argon during normoxia, and 50% argon after hypoxia did not affect heart rate, blood pressure, cerebral saturation and electrocortical brain activity. Clinical safety studies of argon ventilation in humans seem justified.

C23H27NO3, monoclinic, P1211 (no. 4), a = 8.669(3) Å, b = 22.880(5)Å, c = 10.220(3)Å, β = 96.04(2)°, V = 2015.9Å3, Z = 4, Rgt(F) = 0.039, wRref(F2) = 0.106, T = 125 K.

INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetically transmitted disease prone to ventricular arrhythmias. We therefore investigated the clinical, echocardiographical and electrophysiological predictors of appropriate implantable cardioverter defibrillator (ICD) therapy in patients with ARVC. METHODS: A retrospective analysis was performed in 26 patients (median age of 40 years at diagnosis, 21 males and 5 females) with ARVC who underwent ICD implantation. RESULTS: Over a median (range) follow-up period of 10 (2.7, 37) years, appropriate ICD therapy for ventricular arrhythmias was documented in 12 (46%) out of 26 patients. In all patients with appropriate ICD therapy the ICD was originally inserted for secondary prevention. Median time from ICD implantation to ICD therapy was 9 months (range 3.6, 54 months). History of heart failure was a significant predictor of appropriate ICD therapy (p = 0.033). Left ventricular disease involvement (p = 0.059) and age at implantation (p = 0.063) were borderline significant predictors. Patients with syncope at time of diagnosis were significantly less likely to receive ICD therapy (p = 0.02). Invasive electrophysiological testing was not significantly associated with appropriate ICD therapy. CONCLUSION: In our cohort of patients with ARVC, history of heart failure was a significant predictor of appropriate ICD therapy, whereas left ventricular involvement and age at time of ICD implantation were of borderline significance. These predictors should be tested in larger prospective cohorts to optimize ICD therapy in this rare cardiomyopathy.