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Abstract Background Depending on the underlying etiology and epilepsy type, the burden of disease for patients with seizures can vary significantly. This analysis aimed to compare direct and indirect costs and quality of life (QoL) among adults with tuberous sclerosis complex (TSC) related with epilepsy, idiopathic generalized epilepsy (IGE), and focal epilepsy (FE) in Germany. Methods Questionnaire responses from 92 patients with TSC and epilepsy were matched by age and gender, with responses from 92 patients with IGE and 92 patients with FE collected in independent studies. Comparisons were made across the main QoL components, direct costs (patient visits, medication usage, medical equipment, diagnostic procedures, ancillary treatments, and transport costs), indirect costs (employment, reduced working hours, missed days), and care level costs. Results Across all three cohorts, mean total direct costs (TSC: €7602 [median €2620]; IGE: €1919 [median €446], P

Lithium is a key medication for the treatment of psychiatric disorders and is also used in various industrial applications (including battery production and recycling). Here, we review published data on the endocrine-disrupting potential of lithium, with a particular focus on the thyroid hormone system. To this end, we used PubMed and Scopus databases to search for, select and review primary research addressing human and animal health endpoints during or after lithium exposure at non-teratogenic doses. Given the key role of thyroid hormones in neurodevelopmental processes, we focused at studies of the neural effects of developmental exposure to lithium in humans and animals. Our results show that lithium meets the World Health Organization’s definition of a thyroid hormone system disruptor – particularly when used at therapeutic doses. When combined with knowledge of adverse outcome pathways linking molecular initiating events targeting thyroid function and neurodevelopmental outcomes, the neurodevelopmental data reported in animal experiments prompt us to suggest that lithium influences neurodevelopment. However, we cannot rule out the involvement of additional modes of action (i.e. unrelated to the thyroid hormone system) in the described neural effects.Given the increasing use of lithium salts in new technologies, attention must be paid to this emerging pollutant – particularly with regard to its potential effects at environmental doses on the thyroid hormone system and potential consequences on the developing nervous system.

In this paper, we present the first machine learning package developed specifically for fish calls identification within a specific range (0–500Hz) that encompasses four Caribbean grouper species: red hind (E. guttatus), Nassau (E. striatus), yellowfin (M. venenosa), and black (M. bonaci). Because of their ubiquity in the soundscape of the grouper’s habitat, squirrelfish (Holocentrus spp.) sounds along with vessel noise are also detected. In addition the model is also able to separate grouper species call types. This package called FADAR, the Fish Acoustic Detection Algorithm Research is a standalone user-friendly application developed in Matlab™. The concept of FADAR is the product of the evaluation of various deep learning architectures that have been presented in a series of published articles. FADAR is composed of a main algorithm that can detect all species calls including their call types. The architecture of this model is based on an ensemble approach where a bank of five CNNs with randomly assigned hyperparameters are used to form an ensemble of classifiers. The outputs of all five CNNs are combined by a fusion process for decision making. At the species level, the output of the multimodel is thus used to classify the calls in terms of their types. This is done by species specific deep learning models that have been thoroughly evaluated in the literature on the species concerned here, including transfer learning for red hind and yellowfin groupers and custom designed CNN for Nassau grouper, which has a greater number of known call types than the other species. FADAR was manually trained on a diversity of data that span various regions of the Caribbean Sea and also two recorder brands, hydrophone sensitivities, calibrations and sampling rates, including a mobile platform. This strategy has conferred FADAR substantive robustness to a diversity of noise level and sources that can be found in the grouper calls frequency band such as vessels and marine mammals. Performance metrics based on sensitivity (recall) and specificity showed the same performance level for both balanced and unbalanced datasets and at locations not used in the training set.

Abstract 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.

Abstract Background Epilepsy surgery is an established treatment for drug-resistant focal epilepsy (DRFE) that results in seizure freedom in about 60% of patients. Correctly identifying an epileptogenic lesion in magnetic resonance imaging (MRI) is challenging but highly relevant since it improves the likelihood of being referred for presurgical diagnosis. The epileptogenic lesion’s etiology directly relates to the surgical intervention’s indication and outcome. Therefore, it is vital to correctly identify epileptogenic lesions and their etiology presurgically. Methods We compared the final histopathological diagnoses of all patients with DRFE undergoing epilepsy surgery at our center between 2015 and 2021 with their MRI diagnoses before and after presurgical diagnosis at our epilepsy center, including MRI evaluations by expert epilepsy neuroradiologists. Additionally, we analyzed the outcome of different subgroups. Results This study included 132 patients. The discordance between histopathology and MRI diagnoses significantly decreased from 61.3% for non-expert MRI evaluations (NEMRIs) to 22.1% for epilepsy center MRI evaluations (ECMRIs; p

Today’s prediction of ocean dynamics relies on numerical models. However, numerical models are often unable to accurately model and predict real ocean dynamics, leading to a lack of fulfillment of a range of services that require reliable predictions at various temporal and spatial scales. Indeed, a numerical model cannot fully resolve all the physical processes in the ocean due to various reasons, including biases in the initial field and calculation errors in the numerical solution of the model. Thus, bias-correcting methods have become crucial to improve the dynamical accuracy of numerical model predictions. In this study, we present a machine learning-based three-dimensional velocity bias correction method derived from historical observations that applies to both hindcast and forecast. Our approach is based on the modification of an existing deep learning model, called U-Net, designed specifically for image segmentation analysis in the biomedical field. U-Net was modified to create a Transform Model that retains the temporal and spatial evolution of the differences between the model and observations to produce a correction in the form of regression weights that evolves spatially and temporally with the model both forward and backward in time, beyond the observation period. Using daily ocean current observations from a 2.5-year current meter array deployment, we show that significant bias corrections can be conducted up to 50 days pre- or post-observations. Using a 3-year-long virtual array, valid bias corrections can be conducted for up to one year.

Abstract Background Assessment of quality of life (QoL) has become an important indicator for chronic neurological diseases. While these conditions often limit personal independence and autonomy, they are also associated with treatment-related problems and reduced life expectancy. Epilepsy has a tremendous impact on the QoL of patients and their families, which is often underestimated by practitioners. The aim of this work was to identify relevant factors affecting QoL in adults with epilepsy. Methods This cross-sectional, multicenter study was conducted at four specialized epilepsy centers in Germany. Patients diagnosed with epilepsy completed a standardized questionnaire focusing on QoL and aspects of healthcare in epilepsy. Univariate regression analyses and pairwise comparisons were performed to identify variables of decreased QoL represented by the overall Quality of Life in Epilepsy Inventory (QOLIE-31) score. The variables were then considered in a multivariate regression analysis after multicollinearity analysis. Results Complete datasets for the QOLIE-31 were available for 476 patients (279 [58.6%] female, 197 [41.4%] male, mean age 40.3 years [range 18–83 years]). Multivariate regression analysis revealed significant associations between low QoL and a high score on the Liverpool Adverse Events Profile (LAEP; beta=-0.28, p

Abstract Background Multiple studies have focused on medical and pharmacological treatments and outcome predictors of patients with status epilepticus (SE). However, a sufficient understanding of recurrent episodes of SE is lacking. Therefore, we reviewed recurrent SE episodes to investigate their clinical characteristics and outcomes in patients with relapses. Methods In this retrospective, multicenter study, we reviewed recurrent SE patient data covering 2011 to 2017 from the university hospitals of Frankfurt and Marburg, Germany. Clinical characteristics and outcome variables were compared among the first and subsequent SE episodes using a standardized form for data collection. Results We identified 120 recurrent SE episodes in 80 patients (10.2% of all 1177 episodes). The mean age at the first SE episode was 62.2 years (median 66.5; SD 19.3; range 21–91), and 42 of these patients were male (52.5%). A mean of 262.4 days passed between the first and the second episode. Tonic–clonic seizure semiology and a cerebrovascular disease etiology were predominant in initial and recurrent episodes. After subsequent episodes, patients showed increased disability as indicated by the modified Rankin Scale (mRS), and 9 out of 80 patients died during the second episode (11.3%). Increases in refractory and super-refractory SE (RSE and SRSE, respectively) were noted during the second episode, and the occurrence of a non-refractory SE (NRSE) during the first SE episode did not necessarily provide a protective marker for subsequent non-refractory episodes. An increase in the use of intravenous-available anti-seizure medication (ASM) was observed in the treatment of SE patients. Patients were discharged from hospital with a mean of 2.8 ± 1.0 ASMs after the second SE episode and 2.1 ± 1.2 ASMs after the first episode. Levetiracetam was the most common ASM used before admission and on discharge for SE patients. Conclusions This retrospective, multicenter study used the mRS to demonstrate worsened outcomes of patients at consecutive SE episodes. ASM accumulations after subsequent SE episodes were registered over the study period. The study results underline the necessity for improved clinical follow-ups and outpatient care to reduce the health care burden from recurrent SE episodes.

Thyroid hormones are involved in many biological processes such as neurogenesis, metabolism, and development. However, compounds called endocrine disruptors can alter thyroid hormone signaling and induce unwanted effects on human and ecosystems health. Regulatory tests have been developed to detect these compounds but need to be significantly improved by proposing novel endpoints and key events. The Xenopus Eleutheroembryonic Thyroid Assay (XETA, OECD test guideline no. 248) is one such test. It is based on Xenopus laevis tadpoles, a particularly sensitive model system for studying the physiology and disruption of thyroid hormone signaling: amphibian metamorphosis is a spectacular (thus easy to monitor) life cycle transition governed by thyroid hormones. With a long-term objective of providing novel molecular markers under XETA settings, we propose first to describe the differential effects of thyroid hormones on gene expression, which, surprisingly, are not known. After thyroid hormones exposure (T3 or T4), whole tadpole RNAs were subjected to transcriptomic analysis. By using standard approaches coupled to system biology, we found similar effects of the two thyroid hormones. They impact the cell cycle and promote the expression of genes involves in cell proliferation. At the level of the whole tadpole, the immune system is also a prime target of thyroid hormone action.

The presence of chemically different and compositionally varying plastics in mixed postconsumer recovered plastic (PCR) presents daunting barriers to recycling and upcycling efforts. This review systematically outlines how different processing techniques and characterization methods can be implemented to improve PCR's mechanical recycling and upcycling processes. The review further addresses the recycling challenges in the processing of mixed plastics from PCR and how their mechanical properties can be enhanced by making use of different types of compatibilizers such as copolymers, Janus nanoparticles as well as different approaches such as solid-state pulverization and microfibrillarization. In addition, the state-of-the-art applications of recycled plastics usage in automotive and construction are reviewed.

Abstract Background Large vessel occlusion (LVO) is a severe condition that carries a high risk of morbidity and mortality, underscoring the importance of effective prevention strategies. This retrospective study aimed to analyze the intake of preventive medication at the time of hospitalization in a cohort of recurrent stroke patients presenting with acute LVO. Methods The study assessed the intake of either platelet aggregation inhibitors (PAI), oral anticoagulants (OAC) or statins at admission in patients with recurrent stroke and correlated it with the final classification of LVO. The frequency of those secondary preventive medication in recurrent stroke patients was defined as primary endpoint. The Modified Rankin Scale (mRS) at discharge was used as a functional outcome and defined as a secondary outcome measure. Results This study included 866 patients who were treated for LVO between 2016 and 2020, of whom 160 (18.5%) had a recurrent ischemic stroke. OAC (25.6% vs. 14.1%, p

Continuous adaptations of the movement system to changing environments or task demands rely on superposed fractal processes exhibiting power laws, that is, multifractality. The estimators of the multifractal spectrum potentially reflect the adaptive use of perception, cognition, and action. To observe time-specific behavior in multifractal dynamics, a multiscale multifractal analysis based on DFA (MFMS-DFA) has been recently proposed and applied to cardiovascular dynamics. Here we aimed at evaluating whether MFMS-DFA allows identifying multiscale structures in the dynamics of human movements. Thirty-six (12 females) participants pedaled freely, after a metronomic initiation of the cadence at 60 rpm, against a light workload for 10 min: in reference to cycling (C), cycling while playing “Tetris” on a computer, alone (CT) or collaboratively (CTC) with another pedaling participant. Pedal revolution periods (PRP) series were examined with MFMS-DFA and compared to linearized surrogates, which attested to a presence of multifractality at almost all scales. A marked alteration in multifractality when playing Tetris was evidenced at two scales, τ ≈ 16 and τ ≈ 64 s, yet less marked at τ ≈ 16 s when playing collaboratively. Playing Tetris in collaboration attenuated these alterations, especially in the best Tetris players. This observation suggests the high sensitivity to cognitive demand of MFMS-DFA estimators, extending to the assessment of skill/demand interplay from individual behavior. So, by identifying scale-dependent multifractal structures in movement dynamics, MFMS-DFA has obvious potential for examining brain-movement coordinative structures, likely with sufficient sensitivity to find echo in diagnosing disorders and monitoring the progress of diseases that affect cognition and movement control.

Abstract Background To mitigate the potential consequences of the coronavirus disease 2019 (COVID-19) pandemic on public life, the German Federal Government and Ministry of Health enacted a strict lockdown protocol on March 16, 2020. This study aimed to evaluate the impact of the COVID-19 pandemic on physical and mental health status and the supply of medical care and medications for people with epilepsy (PWE) in Germany. Methods The Epi2020 study was a large, multicenter study focused on different healthcare aspects of adults with epilepsy. In addition to clinical and demographic characteristics, patients were asked to answer a questionnaire on the impact of the first wave of the COVID-19 pandemic between March and May 2020. Furthermore, the population-based number of epilepsy-related admissions in Hessen was evaluated for the January-June periods of 2017–2020 to detect pandemic-related changes. Results During the first wave of the pandemic, 41.6% of PWE reported a negative impact on their mental health, while only a minority reported worsening of their seizure situation. Mental and physical health were significantly more negatively affected in women than men with epilepsy and in PWE without regular employment. Moreover, difficulties in ensuring the supply of sanitary products (25.8%) and antiseizure medications (ASMs; 19.9%) affected PWE during the first lockdown; no significant difference regarding these impacts between men and women or between people with and without employment was observed. The number of epilepsy-related admissions decreased significantly during the first wave. Conclusions This analysis provides an overview of the general and medical care of epilepsy patients during the COVID-19 pandemic. PWE in our cohort frequently reported psychosocial distress during the first wave of the pandemic, with significant adverse effects on mental and physical health. Women and people without permanent jobs especially reported distress due to the pandemic. The COVID‐19 pandemic has added to the mental health burden and barriers to accessing medication and medical services, as self-reported by patients and verified in population-based data on hospital admissions. Trial registration German Clinical Trials Register (DRKS), DRKS00022024. Registered October 2, 2020, http://www.drks.de/DRKS00022024

Purpose: Epileptic seizures frequently result in distinct physical injuries, fractures, traumatic brain injuries and minor trauma. The aim of this study was to retrospectively determine the frequent injury patterns due to seizure episode and to analyze consecutive acute medical care. Methods: This retrospective mono-center study was conducted at Frankfurt University Hospital, Frankfurt am Main, Germany between January 2007 and December 2017. Epilepsy patients with seizure-related fractures admitted to the emergency department were identified via a retrospective systematic query in the hospital information system using the ICD-10 German modification codes G40.0–G40.9. Patients with an unclear diagnosis of epilepsy were excluded. Sociodemographic as well as disease specific aspects were analyzed. Descriptive and Kruskal–Wallis one-way analysis of variance were used for statistical analysis. Results: A total number of 62 epilepsy patients were included. The mean age was 58.1 years. Fractures concerned the upper extremity most frequently (43.5%, n = 20), and 70.0% (14/20) were humerus fractures. Admission to intensive care unit for acute trauma care was necessary in 29.0% patients (n = 18), and surgery in 45.2% patients (n = 28). Twenty-five patients (26.6%) showed clinical or radiological signs of traumatic brain injury. Provoking factors were identified in 20 patients (32.3%), i.e., acute withdrawal or excess of alcohol (n = 15), relevant sleep deprivation (n = 2), and intoxication or withdrawal of other illegal drugs or trivial infect (n = 1 for each) and non-compliance with anti-seizure drugs (n = 1). A decreased T-score (−1.04 ± 1.15) and Z-score (−0.84 ± 0.75) compared to healthy subjects were found. Conclusion: Fractures in upper extremities, trunk and craniocerebral trauma occur frequently as seizure-induced injuries. Alcohol excess and withdrawal are important provoking factors and should be targeted with preventive measurements to avoid seizure related injuries and accidents.

Cellulose nanofibrils (CNFs) were produced from bleached eucalyptus kraft pulp using microfluidization varying the number of passes through the microfluidizer. CNFs were processed into dry films to elucidate the effect of CNFs morphology on the physical, optical and barrier properties of the films. As the number of passes through the microfluidizer increased, the fibril diameter and degree of polymerization decreased. A higher number of passes produced CNFs with smaller diameter resulting in CNF films with smaller root mean surface (RMS) roughness, higher tensile strength and Young's modulus, and higher transparency. CNF films with lower porosity had lower water vapor permeability (WVP) at 50% RH (better barrier properties), but the number of passes did not significantly affect water vapor permeability at 90% RH or oxygen permeability at 50% RH or 90% RH. Increasing the number of microfluidization passes resulted in CNF films with higher density, lower crystallinity, and higher water accessibility. The results suggest that the physical properties, such as density, of the film were more dominant for the mechanism of WVP compared with crystallinity and water accessibility. A model of water vapor transmission through the CNF film was proposed. By establishing a relationship between CNFs morphology and performance characteristics of corresponding films, especially for barrier properties, insights were obtained that would be beneficial for food packaging applications.

Abstract Background With the increasing attention for the role of General Practitioners (GPs) after cancer treatment, it is important to better understand the involvement of GPs following prostate cancer treatment. This study investigates factors associated with GP contact during follow-up of prostate cancer survivors, such as patient, treatment and symptom variables, and satisfaction with, trust in, and appraised knowledge of GPs. Methods Of 787 prostate cancer survivors diagnosed between 2007 and 2013, and selected from the Netherlands Cancer Registry, 557 (71%) responded to the invitation to complete a questionnaire. Multivariable logistic regression analyses were performed to investigate which variables were associated with GP contact during follow- up. Results In total, 200 (42%) prostate cancer survivors had contact with their GP during follow-up, and 76 (16%) survivors preferred more contact. Survivors who had an intermediate versus low educational level (OR = 2.0) were more likely to have had contact with their GP during follow-up. Survivors treated with surgery (OR = 2.8) or hormonal therapy (OR = 3.5) were also more likely to seek follow-up care from their GP compared to survivors who were treated with active surveillance. Patient reported bowel symptoms (OR = 1.4), hormonal symptoms (OR = 1.4), use of incontinence aids (OR = 1.6), and being satisfied with their GP (OR = 9.5) were also significantly associated with GP contact during follow-up. Conclusions Education, treatment, symptoms and patient satisfaction were associated with GP contact during prostate cancer follow-up. These findings highlight the potential for adverse side-effects to be managed in primary care. In light of future changes in cancer care, evaluating prostate cancer follow-up in primary care remains important.

Abstract Global surveillance has identified emerging SARS-CoV-2 variants of concern (VOC) associated with broadened host specificity, pathogenicity, and immune evasion to vaccine-induced immunity. Here we compared humoral and cellular responses against SARS-CoV-2 VOC in subjects immunized with the DNA vaccine, INO-4800. INO-4800 vaccination induced neutralizing antibodies against all variants tested, with reduced levels detected against B.1.351. IFNγ T cell responses were fully maintained against all variants tested.

The development of enzymatic browning constitutes one of the key issues in the preservation of highly perishable fresh-cut and oxygen-sensitive fruits such as avocados. This study explored the use of a packaging solution based on PLA/cellulose nanocrystal (CNC) films produced using a solvent-free cast extrusion process with strong oxygen and UV barrier properties to reduce browning in cut avocados and to prolong shelf life. Specifically, the effects of packaging material types (neat PLA vs PLA/CNC nanocomposite) and storage conditions (temperature and time) on discoloration (browning), microbial growth, and shelf life were assessed. Enzymatic browning was visually evaluated and total discoloration (ΔE*) quantified as a function of storage time and temperature to estimate the shelf life of the avocados. Compared with neat PLA, nanocomposite packaging reduced the enzymatic browning more and resulted in additional shelf life extension of 1.3 days at 23 °C and 5.4 days at 4 °C. Both PLA-based films reduced the microbial growth. The potential of sustainable and eco-friendly nanocomposite film to prolong the shelf life of food that is oxygen sensitive is clearly demonstrated.

This study addresses the challenge represented by the application of deep learning models to the prediction of ocean dynamics using datasets over a large region or with high spatial or temporal resolution In a previous study by the authors of this article, they showed that such a challenge could be met by using a divide and conquer approach. The domain was in fact split into multiple sub-regions, which were small enough to be predicted individually and in parallel with each other by a deep learning model. At each time step of the prediction process, the sub-model solutions would be merged at the boundary of each sub-region to remove discontinuities between consecutive domains in order to predict the evolution of the full domain. This approach led to the growth of non-dynamical errors that decreased the prediction skill of our model. In the study herein, we show that wavelets can be used to compress the data and reduce its dimension. Each compression level reduces by a factor of two the horizontal resolution of the dataset. We show that despite the loss of information, a level 3 compression produces an improved prediction of the ocean two-dimensional data in comparison to the divide and conquer approach. Our method is evaluated on the prediction of the sea surface height of the most energetic feature of the Gulf of Mexico, namely the Loop Current.

Tetrabromobisphenol A (TBBPA) is a potent flame retardant used in numerous appliances and a major pollutant in households and ecosystems. In vertebrates, it was shown to affect neurodevelopment, the hypothalamic-pituitary-gonadal axis and thyroid signaling, but its toxicity and modes of actions are still a matter of debate. The molecular phenotype resulting from exposure to TBBPA is only poorly described, especially at the level of transcriptome reprogramming, which further limits our understanding of its molecular toxicity. In this work, we combined functional genomics and system biology to provide a system-wide description of the transcriptomic alterations induced by TBBPA acting on differentiating mESCs, and provide potential new toxicity markers. We found that TBBPA-induced transcriptome reprogramming affect a large collection of genes loosely connected within the network of biological pathways, indicating widespread interferences on biological processes. We also found two hotspots of action: at the level of neuronal differentiation markers, and surprisingly, at the level of immune system functions, which has been largely overlooked until now. This effect is particularly strong, as terminal differentiation markers of both myeloid and lymphoid lineages are strongly reduced: the membrane T cell receptor (Cd79a, Cd79b), interleukin seven receptor (Il7r), macrophages cytokine receptor (Csf1r), monocyte chemokine receptor (Ccr2). Also, the high affinity IgE receptor (Fcer1g), a key mediator of allergic reactions, is strongly induced. Thus, the molecular imbalance induce by TBBPA may be stronger than initially realized.

Entropy-based and fractal-based metrics derived from heart rate variability (HRV) have enriched the way cardiovascular dynamics can be described in terms of complexity. The most commonly used multifractal testing, a method using q moments to explore a range of fractal scaling in small-sized and large-sized fluctuations, is based on detrended fluctuation analysis, which examines the power–law relationship of standard deviation with the timescale in the measured signal. A more direct testing of a multifractal structure exists based on the Shannon entropy of bin (signal subparts) proportion. This work aims to reanalyze HRV during cognitive tasks to obtain new markers of HRV complexity provided by entropy-based multifractal spectra using the method proposed by Chhabra and Jensen in 1989. Inter-beat interval durations (RR) time series were obtained in 28 students comparatively in baseline (viewing a video) and during three cognitive tasks: Stroop color and word task, stop-signal, and go/no-go. The new HRV estimators were extracted from the f/α singularity spectrum of the RR magnitude increment series, established from q-weighted stable (log–log linear) power laws, namely: (i) the whole spectrum width (MF) calculated as αmax − αmin; the specific width representing large-sized fluctuations (MFlarge) calculated as α0 − αq+; and small-sized fluctuations (MFsmall) calculated as αq− − α0. As the main results, cardiovascular dynamics during Stroop had a specific MF signature while MFlarge was rather specific to go/no-go. The way these new HRV markers could represent different aspects of a complete picture of the cognitive–autonomic interplay is discussed, based on previously used entropy- and fractal-based markers, and the introduction of distribution entropy (DistEn), as a marker recently associated specifically with complexity in the cardiovascular control.

To promote the adoption of Direct Air Capture (DAC) systems, this paper proposes and tests a photovoltaic-powered DAC system in a generic residential building located in Qatar. The proposed DAC system can efficiently reduce CO2 concentration in a living space, thus providing an incentive to individuals to adopt it. The ventilation performance of the building is determined using Computational Fluid Dynamics (CFD) simulations, undertaken with ANSYS-CFD. The CFD model was validated using microclimate-air quality dataloggers. The simulated velocity was 1.4 m/s and the measured velocity was 1.35 m/s, which corresponds to a 3.5% error. The system decarbonizes air supplied to the building by natural ventilation or ventilation according to the ASHRAE standards. Furthermore, the performance of the photovoltaic system is analyzed using the ENERGYPLUS package of the Design Builder software. We assume that 75% of CO2 is captured. In addition, a preliminary characterization of the overall system’s performance is determined. It is determined that the amount of CO2 captured by the system is 0.112 tones/year per square meter of solar panel area. A solar panel area of 19 m2 is required to decarbonize the building with natural ventilation, and 27 m2 is required in the case of ventilation according to the ASHRAE standard.

Virtual reality has obvious potential to help humans developing/recovering brain functions, which operates through modulation of multisensory inputs. Some interventions using VR rely on the need to embody a virtual avatar, which stimulates cognitive-motor adaptations. Recent research has shown that embodiment can be facilitated by synchronizing natural sensory inputs with their visual redundancy on the avatar, e.g., the user’s heartbeat flashing around its avatar (cardio-visual stimulation) or the user’s body being physically stroked while the avatar is touched in synchronized conditions (visuo-tactile stimulation). While different full-body illusions have proven obvious interest in health and disease, it is unknown to date whether individual susceptibilities to illusion are equivalent with respect to cardio-visual or visuo-tactile stimulations. In fact, a number of factors like interoception, vestibular processing, a pronounced visual dependence, a specific cognitive ability for mental rotations, or user traits and habits like empathy and video games practice may interfere with the multifaceted construct of bodily self-consciousness, the conscious experience of owning a body in space from which the world is perceived. Here, we evaluated a number of dispositions in twenty-nine young and healthy participants submitted alternatively to cardio-visual and visuo-tactile stimulations to induce full-body illusions. Three components of bodily self-consciousness consensually identified in recent research, namely self-location, perspective taking and self-identification were quantified by self-reported feeling (questionnaires), and specific VR tasks used before and after multisensory stimulations. VR tasks allowed measuring self-location in reference to a virtual ball rolling toward the participant, perspective taking through visuomotor response times when mentally rotating an avatar suddenly presented at different angles, and self-identification through heart rate dynamics in response to a threatening stimulus applied to the (embodied) avatar. Full-body illusion was evidenced by self-reported quotations of self-identification to the avatar reaching scores in agreement with the literature, lower reaction times when taking the perspective of the avatar and a marked drop in heart rate showing obvious freezing reaction changes when the user saw the avatar being pierced by a spear. Changes in bodily self-consciousness components are not significantly dependent on the type of multisensory stimulation (visuo-tactile or cardio-visual). A principal component analysis demonstrated the lack of covariation between those components, pointing to the relative independence of self-location, perspective taking and self-identification measurements. Moreover, none of these components showed significant covariations with any of the individual dispositions. These results support the hypothesis that cardio-visual and visuo-tactile stimulations affect the main components of bodily self-consciousness in an extent that, in average, is mostly independent of individual perceptive-cognitive profiles, at least in healthy young people. Although this is an important observation at group level, which indicates a similar probability of inducing embodiment with either cardio-visual or visuo-tactile stimulations in VR, these results do not discard the fact that some individuals might have higher susceptibility to specific sensory inputs, which would represent a target to adapt efficient VR stimulations.

Abstract Background Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC. Methods A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019). Results We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18–78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533–7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780–1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503–3840) among working-age individuals (

Abstract Background Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-driving factors associated with various organ manifestations in TSC patients. Methods A validated, three-month, retrospective questionnaire was administered to assess the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket, and nursing care-level costs, completed by caregivers of patients with TSC throughout Germany. Results The caregivers of 184 patients (mean age 9.8 ± 5.3 years, range 0.7–21.8 years) submitted questionnaires. The reported TSC disease manifestations included epilepsy (92%), skin disorders (86%), structural brain disorders (83%), heart and circulatory system disorders (67%), kidney and urinary tract disorders (53%), and psychiatric disorders (51%). Genetic variations in TSC2 were reported in 46% of patients, whereas 14% were reported in TSC1. Mean total direct health care costs were EUR 4949 [95% confidence interval (95% CI) EUR 4088–5863, median EUR 2062] per patient over three months. Medication costs represented the largest direct cost category (54% of total direct costs, mean EUR 2658), with mechanistic target of rapamycin (mTOR) inhibitors representing the largest share (47%, EUR 2309). The cost of anti-seizure drugs (ASDs) accounted for a mean of only EUR 260 (5%). Inpatient costs (21%, EUR 1027) and ancillary therapy costs (8%, EUR 407) were also important direct cost components. The mean nursing care-level costs were EUR 1163 (95% CI EUR 1027–1314, median EUR 1635) over three months. Total indirect costs totaled a mean of EUR 2813 (95% CI EUR 2221–3394, median EUR 215) for mothers and EUR 372 (95% CI EUR 193–586, median EUR 0) for fathers. Multiple regression analyses revealed polytherapy with two or more ASDs and the use of mTOR inhibitors as independent cost-driving factors of total direct costs. Disability and psychiatric disease were independent cost-driving factors for total indirect costs as well as for nursing care-level costs. Conclusions This study revealed substantial direct (including medication), nursing care-level, and indirect costs associated with TSC over three months, highlighting the spectrum of organ manifestations and their treatment needs in the German healthcare setting. Trial registration: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.

Abstract Background Tuberous sclerosis complex (TSC) is a monogenetic, multisystemic disease characterised by the formation of benign tumours that can affect almost all organs, caused by pathogenic variations in TSC1 or TSC2. In this multicentre study from Germany, we investigated the influence of sociodemographic, clinical, and therapeutic factors on quality of life (QoL) among individuals with TSC. Methods We assessed sociodemographic and clinical characteristics and QoL among adults with TSC throughout Germany using a validated, three-month, retrospective questionnaire. We examined predictors of health-related QoL (HRQoL) using multiple linear regression analysis and compared the QoL among patients with TSC with QoL among patients with other chronic neurological disorders. Results We enrolled 121 adults with TSC (mean age: 31.0 ± 10.5 years; range: 18–61 years, 45.5% [n = 55] women). Unemployment, a higher grade of disability, a higher number of organ manifestations, the presence of neuropsychiatric manifestations or active epilepsy, and a higher burden of therapy-related adverse events were associated with worse QoL, as measured by two QoL instruments (EuroQoL-5 dimensions [EQ-5D] and Quality of Life in Epilepsy Patients [QOLIE-31]). Neuropsychiatric and structural nervous system manifestations, the number of affected organs, and therapy-related adverse events were also associated with higher depression, as measured by the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). In multiple regression analysis, more severe therapy-related adverse events (large effect, p

The Goliath groupers are known to produce characteristic low frequency vocalizations (“calls”) during spawning aggregations and as part of territorial behavior. Acoustic monitoring for Goliath grouper calls around Florida has historically occurred between July and December to capture the spawning season, with a particular focus on August–November. Because of the unique waveform of the Goliath grouper call, we implemented a noise adaptive matched filter to automatically detect Goliath grouper calls from year-round passive acoustic recordings at two wrecks off Florida’s Gulf of Mexico coast. We investigated diel, temporal and environmental factors that could influence call rates throughout the year. Call rates peaked in August, around 0300 EST and just after the full moon. The Goliath groupers were more vocal when background noise was between 70 and 110 dB re 1 µPa. An additional smaller peak in call rates was identified in May, outside of the typical recording period, suggesting there may be other stimuli besides spawning that are eliciting high sound production in this species. Goliath grouper sound production was present year-round, indicative of consistent communication between individuals outside the spawning season.

Cardiac coherence is a state achieved when one controls their breathing rate during the so-called resonance frequency breathing. This maneuver allows respiratory-driven vagal modulations of the heart rate to superimpose with sympathetic modulations occurring at 0.1 Hz, thereby maximizing autonomous power in heart-to-brain connections. These stimulations have been shown to improve vagal regulations, which results in obvious benefits for both mental and organic health. Here, we present a device that is able to deliver visual and haptic cues, as well as HRV biofeedback information to guide the user in maintaining a 0.1 Hz breathing frequency. We explored the effectiveness of cardiac coherence in three guidance conditions: visual, haptic and visuo-haptic breathing. Thirty-two healthy students (sixteen males) were divided into three groups that experienced five minutes of either visual, haptic and visuo-haptic guided breathing at 0.1 Hz. The effects of guidance on the (adequate) breathing pattern and heart rate variability (HRV) were analyzed. The interest of introducing haptic breathing to achieve cardiac coherence was shown in the haptic and visuo-haptic groups. Especially, the P0.1 index, which indicates how the autonomous power is ‘concentrated’ at 0.1 Hz in the PSD spectrum, demonstrated the superiority of combining haptic with visual sensory inputs in potentiating cardiac coherence (0.55 ± 0.20 for visuo-haptic vs. 0.28 ± 0.14 for visual only guidance; p < 0.05) haptic-induced effectiveness could be an asset for a more efficient and time-saving practice, allowing improved health and well-being even under tight time constraints.

Abstract Daily-life behaviors strongly rely on visuomotor integration, a complex sensorimotor process with obvious plasticity. Visual-perceptive and visual-cognitive functions are degraded by neurological disorders and brain damage, but are improved by vision training, e.g. in athletes. Hence, developing tools to evaluate/improve visuomotor abilities has found echo among psychologists, neurophysiologists, clinicians and sport professionals. Here we implemented the Dynavision visuomotor reaction task in virtual reality (VR) to get a flexible tool to place high demands on visual-perceptive and visual-cognitive processes, and explore individual abilities in visuomotor integration. First, we demonstrated high test–retest reliability for the task in VR among healthy physically-active students (n = 64, 32 females). Second, the capture of head movements thanks to the VR-headset sensors provided new and reliable information on individual visual-perceptual strategies, which added significant value to explore visuomotor phenotypes. A factor analysis of mixed data and hierarchical clustering on principal components points to head movements, video-games practice and ball-tracking sports as critical cues to draw visuomotor phenotypes among our participants. We conclude that the visuomotor task in VR is a reliable, flexible and promising tool. Since VR nowadays can serve e.g. to modulate multisensorial integration by creating visual interoceptive-exteroceptive conflicts, or placing specifically designed cognitive demand, much could be learned on complex integrated visuomotor processes through VR experiments. This offers new perspectives for post brain injury risk evaluation, rehabilitation programs and visual-cognitive training.

Respiratory Syncytial virus (RSV) is a major threat to many vulnerable populations. There are currently no approved vaccines, and RSV remains a high unmet global medical need. Here we describe the employment of a novel synthetic DNA-encoded antibody technology platform to develop and deliver an engineered human DNA-encoded monoclonal antibody (dMAbTM) targeting the fusion protein (F) of RSV as a new approach to prevention or therapy of at risk populations. In in vivo models, a single administration of synthetic DNA-encoding the single-chain fragment variable-constant fragment (scFv-Fc) RSV-F dMAb resulted in robust and durable circulating levels of a functional antibody systemically and in mucosal tissue. In cotton rats, which are the gold-standard animals to model RSV infection, we observed sustained scFv-Fc RSV-F dMAb in the sera and lung-lavage samples, demonstrating the potential for both long-lasting immunity to RSV and effective biodistribution. The scFv-Fc RSV-F dMAb harbored in the sera exhibited RSV antigen-specific binding and potent viral neutralizing activity. Importantly, in vivo delivery of synthetic DNA-encoding, the scFv-Fc RSV-F dMAb protected animals against viral challenge. Our findings support the significance of dMAbs as a potential platform technology for durable protection against RSV disease.

There is currently no licensed SARS-CoV-2 vaccine. Here, the authors generate an optimized DNA vaccine candidate encoding the SARS-CoV-2 spike antigen, demonstrating induction of specific T cells and neutralizing antibody responses in mice and guinea pigs. These initial results support further development of this vaccine candidate.

Arnaud Cavailles,1 Boris Melloni,2 Stéphane Motola,3 Florent Dayde,3 Marie Laurent,3 Katell Le Lay,4 Didier Caumette,5 Laura Luciani,4 Pierre Louis Lleu,6 Geoffrey Berthon,7 Thomas Flament8 1Service de Pneumologie, Institut du Thorax, CHU de Nantes, Nantes, France; 2Service de Pneumologie, CHU Dupuytren, Limoges, France; 3HEVA, Lyon, France; 4HEOR/RWE, Boehringer Ingelheim, Paris, France; 5Institutional and Hospital Partnership, Boehringer Ingelheim, Paris, France; 6Medical Affairs, Boehringer Ingelheim, Paris, France; 7CHRU Tours, Tours, France; 8Service de Pneumologie, CHRU Bretonneau, Tours, FranceCorrespondence: Marie Laurent 186 Avenue Thiers, Lyon 69006, FranceTel +33 4 72 74 25 60Email mlaurent@hevaweb.comPurpose: To characterise patients with chronic obstructive pulmonary disease (COPD) who are rehospitalised for an acute exacerbation, to estimate the cost of these hospitalisations, to characterise high risk patient sub groups and to identify factors potentially associated with the risk of rehospitalisation.Patients and Methods: This was a retrospective study using the French National Hospital Discharge Database. All patients aged ≥ 40 years hospitalised for an acute exacerbation of COPD between 2015 and 2016 were identified and followed for six months. Patients with at least one rehospitalisation for acute exacerbation of COPD constituted the rehospitalisation analysis population. A machine learning model was built to study the factors associated with the risk of rehospitalisation using decision tree analysis. A direct cost analysis was performed from the perspective of national health insurance.Results: A total of 143,006 eligible patients were hospitalised for an acute exacerbation of COPD (AECOPD) in 2015– 2016 (mean age: 74 years; 62.1% men). 25,090 (18.8%) were rehospitalised for another exacerbation within six months. In this study, 8.5% of patients died during or immediately following the index hospitalisation and 10.5% died during or immediately after rehospitalisation (p < 0.001). The specific cost of these rehospitalisations was € 5304. The overall total cost per patient of all AECOPD-related stays was € 9623, being significantly higher in patients who were rehospitalised (€ 16,275) compared to those who were not (€ 8208). In decision tree analysis, the most important driver of rehospitalisation was hospitalisation in the previous two years (contributing 85% of the information).Conclusion: Rehospitalisations for acute exacerbations of COPD carry a high epidemiological and economic burden. Since hospitalisation for an acute exacerbation is the most important determinant of future rehospitalisations, management of COPD needs to focus on interventions aimed at decreasing the rehospitalisation risk of in order to lower the burden of disease.Keywords: comorbidity, rehospitalisation, decision tree analysis, cost

ObjectiveTo assess predictive factors for poststroke pneumonia (PSP) in patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) of the anterior circulation, with special regard to the impact of intravenous thrombolysis (IVT) and endovascular treatment (EVT) on the risk of PSP. As a secondary goal, the validity of the A2DS2, PNEUMONIA, and ISAN scores in LVO will be determined.MethodsAnalysis was based on consecutive data for the years 2017 to 2019 from the prospective inpatient stroke registry covering the entire federal state of Hesse, Germany, using the Kruskal-Wallis test and binary logistic regression.ResultsData from 4,281 patients with LVO were included in the analysis (54.8% female, median age = 78 years, range = 18–102), of whom 66.4% (n = 2,843) received recanalization therapy (RCT). In total, 19.4% (n = 832) of all LVO patients developed PSP. Development of PSP was associated with an increase in overall in-hospital mortality of 32.1% compared with LVO patients without PSP (16.4%; p < 0.001). Incidence of PSP was increased in 2132 patients with either EVT (n = 928; 25.9% PSP incidence) or combined EVT plus IVT (n = 1,204; 24.1%), compared with 2,149 patients with IVT alone (n = 711; 15.2%) or conservative treatment only (n = 1,438; 13.5%; p < 0.001). Multivariate analysis identified EVT (OR 1.5) and combined EVT plus IVT (OR 1.5) as significant independent risk factors for PSP. Furthermore, male sex (OR 1.9), age ≥ 65 years (OR 1.7), dysphagia (OR 3.2) as well as impaired consciousness at arrival (OR 1.7) and the comorbidities diabetes (OR 1.4) and atrial fibrillation (OR 1.3) were significantly associated risk factors (each p < 0.001). Minor stroke (NIHSS ≤ 4) was associated with a significant lower risk of PSP (OR 0.5). Performance of risk stratification scores varied between A2DS2 (96.1% sensitivity, 20.7% specificity), PNEUMONIA (78.2% sensitivity and 45.1% specificity) and ISAN score (98.0% sensitivity, 20.0% specificity).ConclusionNearly one in five stroke patients with LVO develops PSP during acute care. This risk of PSP is further increased if an EVT is performed. Other predictive factors are consistent with those previously described for all AIS patients. Available risk stratification scores proved to be sensitive tools in LVO patients but lack specificity.

Biophysical models are a powerful tool for assessing population connectivity of marine organisms that broadcast spawn. Albula vulpes is a species of bonefish that is an economically and culturally important sportfish found throughout the Caribbean and that exhibits genetic connectivity among geographically distant populations. We created ontogenetically relevant biophysical models for bonefish larval dispersal based upon multiple observed spawning events in Abaco, The Bahamas in 2013, 2018, and 2019. Biological parameterizations were informed through active acoustic telemetry, CTD casts, captive larval rearing, and field collections of related albulids and anguillids. Ocean conditions were derived from the Regional Navy Coastal Ocean Model American Seas dataset. Each spawning event was simulated 100 times using the program Ichthyop. Ten-thousand particles were released at observed and putative spawning locations and were allowed to disperse for the full 71-day pelagic larval duration for A. vulpes. Settlement densities in defined settlement zones were assessed along with interactions with oceanographic features. The prevailing Northern dispersal paradigm exhibited strong connectivity with Grand Bahama, the Berry Islands, Andros, and self-recruitment to lower and upper Abaco. Ephemeral gyres and flow direction within Northwest and Northeast Providence Channels were shown to have important roles in larval retention to the Bahamian Archipelago. Larval development environments for larvae settling upon different islands showed few differences and dispersal was closely associated with the thermocline. Settlement patterns informed the suggestion for expansion of conservation parks in Grand Bahama, Abaco, and Andros, and the creation of a parks in Eleuthera and the Berry Islands to protect fisheries. Further observation of spawning events and the creation of biophysical models will help to maximize protection for bonefish spawning locations and nursery habitat, and may help to predict year-class strength for bonefish stocks throughout the Greater Caribbean.

Post-embryonic acute developmental processes mainly allow the transition from one life stage in a specific ecological niche to the next life stage in a different ecological niche. Metamorphosis, an emblematic type of these post-embryonic developmental processes, has occurred repeatedly and independently in various phylogenetic groups throughout metazoan evolution, such as in cnidarian, insects, molluscs, tunicates, or vertebrates. This review will focus on metamorphoses and developmental transitions in vertebrates, including typical larval metamorphosis in anuran amphibians, larval and secondary metamorphoses in teleost fishes, egg hatching in sauropsids and birth in mammals. Two neuroendocrine axes, the hypothalamic-pituitary-thyroid and the hypothalamic-pituitary-adrenal/interrenal axes, are central players in the regulation of these life transitions. The review will address the molecular and functional evolution of these axes and their interactions. Mechanisms of integration of internal and environmental cues, and activation of these neuroendocrine axes represent key questions in an “eco-evo-devo” perspective of metamorphosis. The roles played by developmental transitions in the innovation, adaptation, and plasticity of life cycles throughout vertebrates will be discussed. In the current context of global climate change and habitat destruction, the review will also address the impact of environmental factors, such as global warming and endocrine disruptors on hypothalamic-pituitary-thyroid and hypothalamic-pituitary-adrenal/interrenal axes, and regulation of developmental transitions.

Summary: Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a dramatic global impact on public health and social and economic infrastructures. Here, we assess the immunogenicity and anamnestic protective efficacy in rhesus macaques of an intradermal (i.d.)-delivered SARS-CoV-2 spike DNA vaccine, INO-4800, currently being evaluated in clinical trials. Vaccination with INO-4800 induced T cell responses and induced spike antigen and RBD binding antibodies with ADCP and ADCD activity. Sera from the animals neutralized both the D614 and G614 SARS-CoV-2 pseudotype viruses. Several months after vaccination, animals were challenged with SARS-CoV-2 resulting in rapid recall of anti-SARS-CoV-2 spike protein T cell and neutralizing antibody responses. These responses were associated with lower viral loads in the lung. These studies support the immune impact of INO-4800 for inducing both humoral and cellular arms of the adaptive immune system, which are likely important for providing durable protection against COVID-19 disease.

Recent evidence available in the literature has highlighted that the high-energy consumption rate associated with air conditioning leads to the undesired “overcooling” condition in arid-climate regions. To this end, this study quantified the effects of increasing the cooling setpoint temperature on reducing energy consumption and CO2 emissions to mitigate overcooling. DesignBuilder software was used to simulate the performance of a generic building operating under the currently adopted ASHRAE HVAC criteria. It was found that increasing the cooling setpoint temperature by 1 °C will increase the operative temperature by approximately 0.25 °C and reduce the annual cooling electricity consumption required for each 1 m2 of an occupied area by approximately 8 kWh/year. This accounts for a reduction of 8% in cooling energy consumption compared to the ASHRAE cooling setpoint (i.e., t_s = 26 °C) and a reduction in the annual CO2 emission rate to roughly 4.8 kg/m2 °C. The largest reduction in cooling energy consumption and CO2 emissions was found to occur in October, with reduced rates of approximately–1.3 kWh/m2 °C and −0.8 kg/m2 °C, respectively.

Beyond apparent simplicity, visuomotor dexterity actually requires the coordination of multiple interactions across a complex system that links the brain, the body and the environment. Recent research suggests that a better understanding of how perceptive, cognitive and motor activities cohere to form executive control could be gained from multifractal formalisms applied to movement behavior. Rather than a central executive “talking” to encapsuled components, the multifractal intuition suggests that eye-hand coordination arises from multiplicative cascade dynamics across temporal scales of activity within the whole system, which is reflected in movement time series. Here we examined hand movements of sport students performing a visuomotor task in virtual reality (VR). The task involved hitting spatially arranged targets that lit up on a virtual board under critical time pressure. Three conditions were compared where the visual search field changed: whole board (Standard), half-board lower view field (LVF) and upper view field (UVF). Densely sampled (90 Hz) time series of hand motions captured by VR controllers were analyzed by a focus-based multifractal detrended fluctuation analysis (DFA). Multiplicative rather than additive interactions across temporal scales were evidenced by testing comparatively phase-randomized surrogates of experimental series, which confirmed nonlinear processes. As main results, it was demonstrated that: (i) the degree of multifractality in hand motion behavior was minimal in LVF, a familiar visual search field where subjects correlatively reached their best visuomotor response times (RTs); (ii) multifractality increased in the less familiar UVF, but interestingly only for the non-dominant hand; and (iii) multifractality increased further in Standard, for both hands indifferently; in Standard, the maximal expansion of the visual search field imposed the highest demand as evidenced by the worst visuomotor RTs. Our observations advocate for visuomotor dexterity best described by multiplicative cascades dynamics and a system-wide distributed control rather than a central executive. More importantly, multifractal metrics obtained from hand movements behavior, beyond the confines of the brain, offer a window on the fine organization of control architecture, with high sensitivity to hand-related control behavior under specific constraints. Appealing applications may be found in movement learning/rehabilitation, e.g., in hemineglect people, stroke patients, maturing children or athletes.

Abstract Objective We sought to evaluate the efficacy and tolerability of intranasal midazolam (in‐MDZ) as first‐line inhospital therapy in patients with status epilepticus (SE) during continuous EEG recording. Methods Data on medical history, etiology and semiology of SE, anticonvulsive medication usage, efficacy and safety of in‐MDZ were retrospectively reviewed between 2015 and 2018. Time to end of SE regarding the administration of in‐MDZ and ß‐band effects were analyzed on EEG and with frequency analysis. Results In total, 42 patients (mean age: 52.7 ± 22.7 years; 23 females) were treated with a median dose of 5 mg of in‐MDZ (range: 2.5–15 mg, mean: 6.4 mg, SD: 2.6) for SE. The majority of the patients suffered from nonconvulsive SE (n = 24; 55.8%). In total, 24 (57.1%) patients were responders, as SE stopped following the administration of in‐MDZ without any other drugs being given. On average, SE ceased on EEG at 05:05 (minutes:seconds) after the application of in‐MDZ (median: 04:56; range: 00:29–14:53; SD:03:13). Frequency analysis showed an increased ß‐band on EEG after the application of in‐MDZ at 04:07 on average (median: 03:50; range: 02:20–05:40; SD: 01:09). Adverse events were recorded in six patients (14.3%), with nasal irritations present in five (11.9%) and prolonged sedation occurring in one (2.6%) patient. Conclusions This pharmaco‐EEG–based study showed that in‐MDZ is effective and well‐tolerated for the acute treatment of SE. EEG and clinical effects of in‐MDZ administration occurred within 04:07 and 5:05 on average. Intranasal midazolam appears to be an easily applicable and rapidly effective alternative to buccal or intramuscular application as first‐line treatment if an intravenous route is not available.

Lassa virus (LASV) is a hemorrhagic fever virus of the Arenaviridae family with high rates of mortality and co-morbidities, including chronic seizures and permanent bilateral or unilateral deafness. LASV is endemic in West Africa and Lassa fever accounts for 10–16% of hospitalizations annually in parts of Sierra Leone and Liberia according to the CDC. An ongoing outbreak in Nigeria has resulted in 144 deaths in 568 cases confirmed as LASV as of November 2018, with many more suspected, highlighting the urgent need for a vaccine to prevent this severe disease. We previously reported on a DNA vaccine encoding a codon-optimized LASV glycoprotein precursor gene, pLASV-GPC, which completely protects Guinea pigs and nonhuman primates (NHPs) against viremia, clinical disease, and death following lethal LASV challenge. Herein we report on the immunogenicity profile of the LASV DNA vaccine in protected NHPs. Antigen-specific binding antibodies were generated in 100% (6/6) NHPs after two immunizations with pLASV-GPC. These antibodies bound predominantly to the assembled LASV glycoprotein complex and had robust neutralizing activity in a pseudovirus assay. pLASV-GPC DNA-immunized NHPs (5/6) also developed T cell responses as measured by IFNγ ELISpot assay. These results revealed that the pLASV-GPC DNA vaccine is capable of generating functional, LASV-specific T cell and antibody responses, and the assays developed in this study will provide a framework to identify correlates of protection and characterize immune responses in future clinical trials.

Emerging coronaviruses from zoonotic reservoirs, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been associated with human-to-human transmission and significant morbidity and mortality. Here, we study both intradermal and intramuscular 2-dose delivery regimens of an advanced synthetic DNA vaccine candidate encoding a full-length MERS-CoV spike (S) protein, which induced potent binding and neutralizing antibodies as well as cellular immune responses in rhesus macaques. In a MERS-CoV challenge, all immunized rhesus macaques exhibited reduced clinical symptoms, lowered viral lung load, and decreased severity of pathological signs of disease compared with controls. Intradermal vaccination was dose sparing and more effective in this model at protecting animals from disease. The data support the further study of this vaccine for preventing MERS-CoV infection and transmission, including investigation of such vaccines and simplified delivery routes against emerging coronaviruses.

There is some evidence that an improved understanding of executive control in the human movement system could be gained from explorations based on scale-free, fractal analysis of cyclic motor time series. Such analyses capture non-linear fractal dynamics in temporal fluctuations of motor instances that are believed to reflect how executive control enlist a coordination of multiple interactions across temporal scales between the brain, the body and the task environment, an essential architecture for adaptation. Here by recruiting elite rugby players with high motor skills and submitting them to the execution of rhythmic motor tasks involving legs and arms concurrently, the main attempt was to build on the multifractal formalism of movement control to show a marginal need of effective adaptation in concurrent tasks, and a preserved adaptability despite complexified motor execution. The present study applied a multifractal analytical approach to experimental time series and added surrogate data testing based on shuffled, ARFIMA, Davies&Harte and phase-randomized surrogates, for assessing scale-free behavior in repeated motor time series obtained while combining cycling with finger tapping and with circling. Single-tasking was analyzed comparatively. A focus-based multifractal-DFA approach provided Hurst exponents (H) of individual time series over a range of statistical moments H(q), q = [−15 15]. H(2) quantified monofractality and H(-15)-H(15) provided an index of multifractality. Despite concurrent tasking, participants showed great capacity to keep the target rhythm. Surrogate data testing showed reasonable reliability in using multifractal formalism to decipher movement control behavior. The global (i.e., monofractal) behavior in single-tasks did not change when adapting to dual-task. Multifractality dominated in cycling and did not change when cycling was challenged by upper limb movements. Likewise, tapping and circling behaviors were preserved despite concurrent cycling. It is concluded that the coordinated executive control when adapting to dual-motor tasking is not modified in people having developed great motor skills through physical training. Executive control likely emerged from multiplicative interactions across temporal scales which puts emphasis on multifractal approaches of the movement system to get critical cues on adaptation. Extending such analyses to less skilled people is appealing in the context of exploring healthy and diseased movement systems.

Background: A vaccine against SARS-CoV-2 is of high urgency. Here the safety and immunogenicity induced by a DNA vaccine (INO-4800) targeting the full length spike antigen of SARS-CoV-2 are described. Methods: INO-4800 was evaluated in two groups of 20 participants, receiving either 1.0 mg or 2.0 mg of vaccine intradermally followed by CELLECTRA® EP at 0 and 4 weeks. Thirty-nine subjects completed both doses; one subject in the 2.0 mg group discontinued trial participation prior to receiving the second dose. ClinicalTrials.gov identifier: NCT04336410. Findings: The median age was 34.5, 55% (22/40) were men and 82.5% (33/40) white. Through week 8, only 6 related Grade 1 adverse events in 5 subjects were observed. None of these increased in frequency with the second administration. No serious adverse events were reported. All 38 subjects evaluable for immunogenicity had cellular and/or humoral immune responses following the second dose of INO-4800. By week 6, 95% (36/38) of the participants seroconverted based on their responses by generating binding (ELISA) and/or neutralizing antibodies (PRNT IC50), with responder geometric mean binding antibody titers of 655.5 [95% CI (255.6, 1681.0)] and 994.2 [95% CI (395.3, 2500.3)] in the 1.0 mg and 2.0 mg groups, respectively. For neutralizing antibody, 78% (14/18) and 84% (16/19) generated a response with corresponding geometric mean titers of 102.3 [95% CI (37.4, 280.3)] and 63.5 [95% CI (39.6, 101.8)], in the respective groups. By week 8, 74% (14/19) and 100% (19/19) of subjects generated T cell responses by IFN-ɣ ELISpot assay with the median SFU per 106 PBMC of 46 [95% CI (21.1, 142.2)] and 71 [95% CI (32.2, 194.4)] in the 1.0 mg and 2.0 mg groups, respectively. Flow cytometry demonstrated a T cell response, dominated by CD8+ T cells co-producing IFN-ɣ and TNF-α, without increase in IL-4. Interpretation: INO-4800 demonstrated excellent safety and tolerability and was immunogenic in 100% (38/38) of the vaccinated subjects by eliciting either or both humoral or cellular immune responses. Funding: Coalition for Epidemic Preparedness Innovations (CEPI).

Research on sensorimotor rhythms (SMR) based on neurofeedback (NFb) emphasizes improvements in selective attention associated with SMR amplification. However, the long-term training proposed in most studies posed the question of acceptability, which led to the evaluation of the potential of a single NFb session. Based on cognitive and autonomic controls interfering with attention processes, we hypothesized changes in selective attention after a single SMR-NFb session, along with changes in brain–heart interplay, which are reflected in the multifractality of heartbeat dynamics. Here, young healthy participants (n = 35, 20 females, 21 ± 3 years) were randomly assigned either to a control group (Ctrl) watching a movie or to a neurofeedback (NFb) group performing a single session of SMR-NFb. A headset with EEG electrodes (positioned on C3 and C4) connected to a smartphone app served to guide and to evaluate NFb training efficacy. A Stroop task was performed for 8 min by each group before and after the intervention (movie vs. SMR-NFb) while collecting heart rate variability and C4-EEG for 20 min. When compared to Ctrl, the NFb group exhibited better Stroop performance, especially when facing incongruent trials. The multifractality and NFb training efficacy were identified as strong predictors of the gain in global Stroop performance, while multifractality was the only predictor regarding incongruent trials. We conclude that a single session of SMR-NFb improves selective attention in healthy individuals through the specific reorganization of brain–heart interplay, which is reflected in multifractal heartbeat dynamics.

In multicellular organisms, development is based in part on the integration of communication systems. Two neuroendocrine axes, the hypothalamic–pituitary–thyroid and the hypothalamic–pituitary–adrenal/interrenal axes, are central players in orchestrating body morphogenesis. In all vertebrates, the hypothalamic–pituitary–thyroid axis controls thyroid hormone production and release, whereas the hypothalamic–pituitary–adrenal/interrenal axis regulates the production and release of corticosteroids. One of the most salient effects of thyroid hormones and corticosteroids in post-embryonic developmental processes is their critical role in metamorphosis in anuran amphibians. Metamorphosis involves modifications to the morphological and biochemical characteristics of all larval tissues to enable the transition from one life stage to the next life stage that coincides with an ecological niche switch. This transition in amphibians is an example of a widespread phenomenon among vertebrates, where thyroid hormones and corticosteroids coordinate a post-embryonic developmental transition. The review addresses the functions and interactions of thyroid hormone and corticosteroid signaling in amphibian development (metamorphosis) as well as the developmental roles of these two pathways in vertebrate evolution.