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An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed. PopPK analyses were used to determine a product's optimal posology to target predefined steady-state FIX activity trough levels in a hypothetical population of 10,000 people with severe HB. Model-derived optimal posologies were compared across several parameters including trough levels, proportion of patients per regimen and consumption, considering 64 hypothetical patient scenarios of different FIX trough level targets and ages. Results indicated a marked difference between FIX products estimated to achieve target trough levels, consumption and dosing frequencies. rIX-FP was associated with higher trough levels than rFIX and rFIXFc, at a lower weekly dose and administration frequency, across all age groups. N9-GP use in adolescents and adults was associated with lower consumption compared with rIX-FP. Insights from this study may be utilized by clinicians to inform decision-making, by considering the model-generated estimated optimal posologies alongside multiple clinical factors and patient preferences. [ABSTRACT FROM AUTHOR]

Rapid eye movement sleep (REMS) is increasingly suggested as a discriminant sleep state for subtle signs of age-related neurodegeneration. While REMS expression is under strong circadian control and circadian dysregulation increases with age, the association between brain aging and circadian REMS regulation has not yet been assessed. Here, we measure the circadian amplitude of REMS through a 40-h in-lab multiple nap protocol in controlled laboratory conditions, and brain microstructural integrity with quantitative multi-parameter mapping (MPM) imaging in 86 older individuals. We show that reduced circadian REMS amplitude is related to lower magnetization transfer saturation (MTsat), longitudinal relaxation rate (R1) and effective transverse relaxation rate (R2*) values in several white matter regions mostly located around the lateral ventricles, and with lower R1 values in grey matter clusters encompassing the hippocampus, parahippocampus, thalamus and hypothalamus. Our results further highlight the importance of considering circadian regulation for understanding the association between sleep and brain structure in older individuals. This study highlights the circadian regulation of rapid eye movement sleep as a neurophysiological correlate of subtle brain microstructural changes in key brain regions sensitive to aging and involved in sleep-wake regulation. [ABSTRACT FROM AUTHOR]

Recently, new constitutive tensile models for describing the post-cracking behaviour of fibre reinforced concrete for different performance classes were developed by the author(s). The models are based on test data on notched beams with macro fibres, including one type of glass fibres and two polypropylene fibres. Nowadays, a wide range of macro fibres for reinforcing concrete mixtures is available. The objective of this paper is thus to examine whether the newly developed models are applicable for other FRC mixtures. For this purpose, the experimental results of 236 three-point bending tests on notched beams, obtained from Vrijdaghs et al. and the international company Bekaert, are compared with the model predictions. The results indicate that the proposed model for performance class a & b and class c exhibit a higher accuracy at CMOD1 than the model in MC10 and EC2 (next version). However, further optimization is required at CMOD3 for the model of performance class a & b and class d. A strong correlation is also found between the experimental fR1-values, as well as the fR3-values, and the predicted compression zone height of the beam cross-section at midspan by use of those new constitutive models. Moreover, this paper also proposes a modification to the model of Oettel et al. for better estimating the residual flexural tensile strength of FRC mixtures with 4D Dramix fibres. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS) have been associated with a risk of accelerated cognitive decline or conversion to dementia of the Alzheimer's Disease (AD) type. Moreover, the NPS were also associated with higher AD biomarkers (brain tau and amyloid burden) even in non-demented patients. But the effect of the relationship between NPS and biomarkers on cognitive decline has not yet been studied. This work aims to assess the relationship between longitudinal cognitive changes and NPS, specifically depression and anxiety, in association with AD biomarkers in healthy middle-aged to older participants. The cohort consisted of 101 healthy participants aged 50–70 years, 66 of whom had neuropsychological assessments of memory, executive functions, and global cognition at a 2-year follow-up. At baseline, NPS were assessed using the Beck Depression and Anxiety Inventories while brain tau and amyloid loads were measured using positron emission topography. For tau burden, THK5351 uptake is used as a proxy of tau and neuroinflammation. Participants, declining or remaining stable at follow-up, were categorized into groups for each cognitive domain. Group classification was investigated using binary logistic regressions based on combined AD biomarkers and the two NPS. The results showed that an association between anxiety and prefrontal amyloid burden significantly classified episodic memory decline, while the classification of global cognitive decline involved temporal and occipital amyloid burden but not NPS. Moreover, depression together with prefrontal and hippocampal tau burden were associated with a decline in memory. The classification of participants based on executive decline was related to depression and mainly prefrontal tau burden. These findings suggest that the combination of NPS and brain biomarkers of AD predicts the occurrence of cognitive decline in aging. [ABSTRACT FROM AUTHOR]

The growing field of historical game studies (which studies the intersection of history and video games) has often described video games with historical settings as virtual museums, based on their potential to allow players to move through a historical game space and/or interact with historical artefacts. The present article investigates how these insights may be applied to mythological video games (i.e. those that represent and simulate a storyworld known from or inspired by mythological traditions). Specifically, this article argues (1) that through the collection, combination, and presentation of different myths, mythological video games often exhibit characteristics similar to ancient and modern mythography, (2) that on the basis of these mythographical qualities, they may be considered as interactive mythology museums, and (3) that the incorporation of these features has potential for applications in education. As case studies, this article considers the popular games Age of Mythology, Smite, Immortals Fenyx Rising, God of War (and its sequel, God of War: Ragnarök), Apotheon, and Hades in light of their mythographical and museal properties. Finally, several future directions to further improve upon the educational potential of these games for both formal and informal learning are suggested. [ABSTRACT FROM AUTHOR]

Abstract The cytokine TNF drives inflammatory diseases, e.g., Crohn's disease. In a mouse model of TNF‐induced systemic inflammatory response syndrome (SIRS), severe impact on intestinal epithelial cells (IECs) is observed. Zinc confers complete protection in this model. We found that zinc no longer protects in animals which lack glucocorticoids (GCs), or express mutant versions of their receptor GR in IECs, nor in mice which lack gut microbiota. RNA‐seq studies in IECs showed that zinc caused reduction in expression of constitutive (STAT1‐induced) interferon‐stimulated response (ISRE) genes and interferon regulatory factor (IRF) genes. Since some of these genes are involved in TNF‐induced cell death in intestinal crypt Paneth cells, and since zinc has direct effects on the composition of the gut microbiota (such as several Staphylococcus species) and on TNF‐induced Paneth cell death, we postulate a new zinc‐related anti‐inflammatory mechanism. Zinc modulates the gut microbiota, causing less induction of ISRE/IRF genes in crypt cells, less TNF‐induced necroptosis in Paneth cells, and less fatal evasion of gut bacteria into the system.

Abstract Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease; however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARα is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARα in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARα levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARα agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARα function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point toward new therapeutic leads in sepsis.

Acute Myeloid Leukemia (AML) is a heterogeneous disease with limited treatment options and a high demand for novel targeted therapies. Since myeloid-related protein S100A9 is abundantly expressed in AML, we aimed to unravel the therapeutic impact and underlying mechanisms of targeting both intracellular and extracellular S100A9 protein in AML cell lines and primary patient samples. S100A9 silencing in AML cell lines resulted in increased apoptosis and reduced AML cell viability and proliferation. These therapeutic effects were associated with a decrease in mTOR and endoplasmic reticulum stress signaling. Comparable results on AML cell proliferation and mTOR signaling could be observed using the clinically available S100A9 inhibitor tasquinimod. Interestingly, while siRNA-mediated targeting of S100A9 affected both extracellular acidification and mitochondrial metabolism, tasquinimod only affected the mitochondrial function of AML cells. Finally, we found that S100A9-targeting approaches could significantly increase venetoclax sensitivity in AML cells, which was associated with a downregulation of BCL-2 and c-MYC in the combination group compared to single agent therapy. This study identifies S100A9 as a novel molecular target to treat AML and supports the therapeutic evaluation of tasquinimod in venetoclax-based regimens for AML patients. [ABSTRACT FROM AUTHOR]

Exposure to blue wavelength light stimulates alertness and performance by modulating a widespread set of task-dependent cortical and subcortical areas. How light affects the crosstalk between brain areas to trigger this stimulating effect is not established. Here we record the brain activity of 19 healthy young participants (24.05±2.63; 12 women) while they complete an auditory attentional task in darkness or under an active (blue-enriched) or a control (orange) light, in an ultra-high-field 7 Tesla MRI scanner. We test if light modulates the effective connectivity between an area of the posterior associative thalamus, encompassing the pulvinar, and the intraparietal sulcus (IPS), key areas in the regulation of attention. We find that only the blue-enriched light strengthens the connection from the posterior thalamus to the IPS. To the best of our knowledge, our results provide the first empirical data supporting that blue wavelength light affects ongoing non-visual cognitive activity by modulating task-dependent information flow from subcortical to cortical areas. The brain activity of 19 healthy young participants was recorded at 7 T MRI while performing an auditory oddball task under different light conditions. Only blue-enriched light strengthens subcortico-cortical connectivity (thalamus-to-IPS connection). [ABSTRACT FROM AUTHOR]

Abstract Sepsis is a highly lethal and urgent unmet medical need. It is the result of a complex interplay of several pathways, including inflammation, immune activation, hypoxia, and metabolic reprogramming. Specifically, the regulation and the impact of the latter have become better understood in which the highly catabolic status during sepsis and its similarity with starvation responses appear to be essential in the poor prognosis in sepsis. It seems logical that new interventions based on the recognition of new therapeutic targets in the key metabolic pathways should be developed and may have a good chance to penetrate to the bedside. In this review, we concentrate on the pathological changes in metabolism, observed during sepsis, and the presumed underlying mechanisms, with a focus on the level of the organism and the interplay between different organ systems.

As scarcity of water is expected to intensify with global warming, unconventional water sources such as advective fogs may become essential. In numerous arid regions, nets are used to harvest such water droplets. However, many current fog nets are either not durable or expensive, and have poor performances for short time or low intensity fog events. With a dedicated test bench, we show here that a low-cost net with kirigami design offers a higher and faster fog collecting ability than the usual fibers nets. This kirigami fog net consists of a continuous network of strips where water quickly forms a stable film, accounting for its superior capture efficiency. We rationalize this mechanism with a simplified structure composed of disconnected strips whose optimization paves the way to the shaping of original fog nets such as the kirigami one. [ABSTRACT FROM AUTHOR]

The Spanish autonomous city of Melilla, located in northwest Africa, has one of the highest academic failure and abandonment rates in Europe. An effective way to improve this situation would be to improve students' digital competence. In order to do so, teachers must have competent digital skills themselves and also be able to teach them. To determine teachers' level of digital competence, the Spanish adaptation of the European Framework for Digital Competence of Educators was used to analyse the self-assessment responses of teachers in training at the Faculty of Education and Sport Sciences in Melilla, Spain. Several quantitative techniques were used to analyse data collected from a questionnaire based on the items in the framework. Indicators were given to each competence using a factor analysis to contrast differences between undergraduate and postgraduate students. Correlations between some of the students' characteristics and the competences were estimated using OLS. The results show students' self-assessment level of digital competence in different areas and differences between the bachelor's and master's programmes. Digital competence gaps were also detected in teacher training, especially in security. The conclusions highlight the need to improve digital security and facilitate a higher level of digital skills in line with the framework. Indeed, more hours of training in digital competence are required while taking into account the educational context and the technological, pedagogical and content knowledge needed to teach. Equally, the same skills must be developed by educators in order for them to transmit digital competence to their students and support them in educational centres. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to evaluate whether the use of citicoline oral solution could improve quality of life in patients with chronic open-angle glaucoma (OAG). Design: Randomized, double-masked, placebo-controlled, cross-over study was used. Patients were randomized to one of the two sequences: either citicoline 500 mg/day oral solution-placebo or placebo-citicoline 500 mg/day oral solution. Switch of treatments was done after 3 months; patients were then followed for other 6 months. Follow-up included 3-month, 6-month, and 9-month visits. Outcomes: The primary outcome was the mean change of "intra-patient" composite score of the Visual Function Questionnaire-25 (VFQ-25). after citicoline oral solution vs placebo at 6-month visit as compared with baseline. Methods: The trial was multicenter, conducted at 5 European Eye Clinics. OAG patients with bilateral visual field damage, a mean deviation (MD) ranging from − 5 to − 13 dB in the better eye, and controlled IOP were included. VFQ-25 and SF-36 questionnaires were administered at baseline and at 3-, 6-, and 9-month visits. A mixed effect model, with a random effect on the intercept, accounted for correlations among serial measurements on each subject. Results: The primary pre-specified outcome of the analysis reached statistical significance (p = 0.0413), showing greater improvement after citicoline oral solution. There was an increase in the composite score in both arms compared to baseline, but it was significant only for the placebo-citicoline arm (p = 0.0096, p = 0.0007, and p = 0.0006 for the three time-points compared to baseline). The effect of citicoline was stronger in patients with vision-related quality of life more affected by glaucoma at baseline. Conclusions: This is the first placebo-controlled clinical study evaluating the effect of a medical treatment aiming at improving vision-related quality of life in glaucomatous patients. [ABSTRACT FROM AUTHOR]

Chewing khat during pregnancy adversely affects maternal and fetal health, but available studies are scarce and inconsistent, and it is difficult to conclude the relationship between khat consumption and perinatal outcomes. We aimed to investigate the available studies on the effect of khat use during pregnancy on perinatal and maternal outcomes. For this meta-analysis, we conducted a thorough search of articles published in PubMed, Embase, Scopus, and Web of Science up to the date this search was undertaken (03.01.2022). We used random effect model with the Mantel–Haenszel method to calculate the pooled odds ratio and mean difference. We found that khat use during pregnancy was significantly associated with increased odds of low birth weight (OR:2.51; 95% CI: 1.60 to 3.94), congenital anomalies (OR:3.17; 95% CI: 1.30 to 7.73), premature rupture of membrane (OR: 1.99; 95% CI: 1.59 to 2.50), perinatal mortality (OR: 1.95; 95% CI: 1.26 to 3.03), and lower APGAR scores at the fifth minute (MD: −1.7; 95% CI: −2.32 to −1.07). Also, increased odds for developing maternal psychological stress and anemia were reported in women using khat during pregnancy. There were no statistically significant differences in stillbirth and preterm birth between women using khat during pregnancy and their counterparts. Since prenatal khat use is associated with adverse perinatal and maternal outcomes, we strongly recommend equitable and easily accessible health services through the implementation of integrated addiction treatment with maternity services to address khat use during pregnancy and encourage the practice of healthy behavior of women. [ABSTRACT FROM AUTHOR]

Magnetocapillary interactions between particles allow to self-assemble floating crystals along liquid interfaces. For a fixed number of particles, different states possessing different symmetrical features, known as metastable states, coexist. In this paper, we demonstrate how to trigger the transition from one state to another, either by rearranging the crystal, or by controlling its growth. First, we show that externally controlled magnetic fields can squeeze the entire crystal to induce structural modifications, that upon relaxation can lead to a modified state. Second, we propose localized laser-induced thermocapillary flows that can be used to guide new particles towards an existing crystal in a desired direction, thus favoring a particular resulting state. The control of the formation of metastable states is a key ingredient to functionalize such assemblies, paving the way to self-assembled microrobots. [ABSTRACT FROM AUTHOR]

The Schlieren method intends to reveal the elevation of a refractive fluid–fluid interface. The method is based on a comparison of images of a single pattern placed at the bottom of the container. Accurate measurements can be obtained with a simple and low-cost optical setup. However, it is restricted to weak interface deformations, weak slopes and weak paraxial angles. To overcome these limitations, we propose an enhanced optical setup that uses a bitelecentric objective and a double pattern. Thanks to this new setup, we avoid geometrical approximations and we extend the method to moderate/large deformations. Moreover, the proposed method does not depend on the liquid depth and could be used in various applications. [ABSTRACT FROM AUTHOR]

Information storage is a key element of autonomous, out-of-equilibrium dynamics, especially for biological and synthetic active matter. In synthetic active matter however, the implementation of internal memory in self-propelled systems is often absent, limiting our understanding of memory-driven dynamics. Recently, a system comprised of a droplet generating its guiding wavefield appeared as a prime candidate for such investigations. Indeed, the wavefield, propelling the droplet, encodes information about the droplet trajectory and the amount of information can be controlled by a single scalar experimental parameter. In this work, we show numerically and experimentally that the accumulation of information in the wavefield induces the loss of time correlations, where the dynamics can then be described by a memory-less process. We rationalize the resulting statistical behavior by defining an effective temperature for the particle dynamics where the wavefield acts as a thermostat of large dimensions, and by evidencing a minimization principle of the generated wavefield. Memory and information storage play an important role in biological systems, however challenging to implement in synthetic active matter. The authors show that the wave field, propelling the particle, acts as a memory repository, and an excess of memory leads to a memory-less particle dynamics. [ABSTRACT FROM AUTHOR]

In 2011 the European Society for the Study of Tourette Syndrome (ESSTS) published its first European clinical guidelines for the treatment of Tourette Syndrome (TS) with part IV on deep brain stimulation (DBS). Here, we present a revised version of these guidelines with updated recommendations based on the current literature covering the last decade as well as a survey among ESSTS experts. Currently, data from the International Tourette DBS Registry and Database, two meta-analyses, and eight randomized controlled trials (RCTs) are available. Interpretation of outcomes is limited by small sample sizes and short follow-up periods. Compared to open uncontrolled case studies, RCTs report less favorable outcomes with conflicting results. This could be related to several different aspects including methodological issues, but also substantial placebo effects. These guidelines, therefore, not only present currently available data from open and controlled studies, but also include expert knowledge. Although the overall database has increased in size since 2011, definite conclusions regarding the efficacy and tolerability of DBS in TS are still open to debate. Therefore, we continue to consider DBS for TS as an experimental treatment that should be used only in carefully selected, severely affected and otherwise treatment-resistant patients. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We examined whether the non-HLA susceptibility locus ERBB3/IKZF4 influences progression of type 1 diabetes stage specifically according to sex. Methods: SNPs of ERBB3 (rs2292239 T/G) and IKZF4 (rs1701704 G/T) were screened by allelic discrimination quantitative PCR assay in first-degree relatives of type 1 diabetes patients who had developed at least one circulating autoantibody. The effect of ERBB3/IKZF4 genotypes and sex, on the progression of single autoantibody positivity to multiple autoantibody positivity and from multiple autoantibody positivity to diabetes, was studied by Kaplan–Meier analysis and multivariate Cox regression. Results: In the cohort of autoantibody-positive first-degree relatives, the risk allele frequencies for ERBB3 rs2292239 (T) and IKZF4 rs1701704 (G) were increased. There was a significant male excess at the stage of multiple autoantibody positivity (p = 0.021). In Kaplan–Meier survival analysis, progression from single to multiple antibody positivity was delayed in female participants with genotype ERBB3 GG (p = 0.018, vs ERBB3 TG+TT) or IKZF4 TT (p = 0.023, vs IKZF4 GT+GG), but not in male participants. In multivariate Cox regression models, the interaction effects between female sex and ERBB3 GG (p = 0.012; HR = 0.305 [95% CI 0.120, 0.773]) or between female sex and IKZF4 TT (p = 0.011; HR = 0.329 [95% CI 0.140, 0.777]) emerged as potential determinants of delayed progression to multiple autoantibodies. The progression from multiple autoantibody positivity to type 1 diabetes appeared not to be influenced by ERBB3/IKZF4. Conclusions/interpretation: In siblings and offspring of type 1 diabetes patients, polymorphism in region ERBB3/IKZF4 may affect disease progression at the level of epitope spreading in female individuals. Our findings suggest that interaction between sex and ERBB3/IKZF4 may contribute to the post-pubertal male excess in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Introduction: Given the relatively small number of patients with haemophilia A, head-to-head comparisons between recombinant FVIII (rFVIII) products are difficult to conduct. This study compared the efficacy and consumption of rVIII-SingleChain (lonoctocog alfa, AFSTYLA®) with rAHF-PFM (octocog alfa, Advate®) and rFVIIIFc (efmoroctocog alfa, Elocta®), for the prophylaxis and treatment of bleeding episodes in previously treated adolescents/adults with severe haemophilia A, through a matching-adjusted indirect comparison (MAIC). Methods: A systematic literature review identified published clinical trials for rAHF-PFM and rFVIIIFc. Individual patient data for rVIII-SingleChain were used to match baseline patient characteristics to those from published trials, using an approach similar to propensity score weighting. After matching, annualized bleeding rates (ABR), percentage of patients with zero bleeds, and rFVIII consumption were compared across trial populations. Results: Published data were identified from two rAHF-PFM trials and one rFVIIIFc trial. rVIII-SingleChain had similar ABR (risk ratio [RR]: 0.74 [0.16; 3.48]; RR: 1.18 [0.85; 1.65]) and percentage of patients with zero bleeds (odds ratio [OR]: 1.34 [0.56; 3.22]; OR: 0.78 [0.47; 1.31]) versus rAHF-PFM and rFVIIIFc, respectively. Annual rVIII-SingleChain consumption was significantly lower than rAHF-PFM (mean difference: − 1507.66 IU/kg/year [− 2011.71; − 1003.61]) and equivalent to rFVIIIFc (RR: 0.96 [0.62; 1.49]). Conclusion: Although limited to published information for comparator trials, these results suggest that with an annualized rFVIII consumption comparable to rFVIIIFc, but significantly lower than rAHF-PFM, routine prophylaxis with rVIII-SingleChain is able to maintain a similar ABR and percentage of patients with zero bleeds, attesting to the long-acting nature of rVIII-SingleChain. Plain Language Summary: It is difficult to directly compare different recombinant FVIII products in head-to-head studies because there are few patients with haemophilia A. This study aimed to indirectly compare the efficacy and consumption of different recombinant FVIII products in the prophylactic treatment of haemophilia A using published clinical data. A proven method for performing indirect comparisons of products is referred to as a matching-adjusted indirect comparison. Using this approach, we were able to compare rVIII-SingleChain with two other recombinant FVIII products (rAHF-PFM and rFVIIIFc). Our results suggest that annual FVIII consumption with rVIII-SingleChain is comparable to rFVIIIFc, but is significantly lower than rAHF-PFM, while maintaining a similar bleeding rate. These results highlight the long-acting nature of the product. [ABSTRACT FROM AUTHOR]

Granular multiparticle ensembles are of interest from fundamental statistical viewpoints as well as for the understanding of collective processes in industry and in nature. Extraction of physical data from optical observations of three-dimensional (3D) granular ensembles poses considerable problems. Particle-based tracking is possible only at low volume fractions, not in clusters. We apply shadow-based and feature-tracking methods to analyze the dynamics of granular gases in a container with vibrating side walls under microgravity. In order to validate the reliability of these optical analysis methods, we perform numerical simulations of ensembles similar to the experiment. The simulation output is graphically rendered to mimic the experimentally obtained images. We validate the output of the optical analysis methods on the basis of this ground truth information. This approach provides insight in two interconnected problems: the confirmation of the accuracy of the simulations and the test of the applicability of the visual analysis. The proposed approach can be used for further investigations of dynamical properties of such media, including the granular Leidenfrost effect, granular cooling, and gas-clustering transitions. [ABSTRACT FROM AUTHOR]

Kinetic equations model distributions of particles in position-velocity phase space. Often, one is interested in studying the long-time behavior of particles in high-collisional regimes in which an approximate (advection)-diffusion model holds. In this paper we consider the diffusive scaling. Classical particle-based techniques suffer from a strict time-step restriction in this limit, to maintain stability. Asymptotic-preserving schemes avoid this problem, but introduce an additional time discretization error, possibly resulting in an unacceptably large bias for larger time steps. Here, we present and analyze a multilevel Monte Carlo scheme that reduces this bias by combining estimates using a hierarchy of different time step sizes. We demonstrate how to correlate trajectories from this scheme, using different time steps. We also present a strategy for selecting the levels in the multilevel scheme. Our approach significantly reduces the computation required to perform accurate simulations of the considered kinetic equations, compared to classical Monte Carlo approaches. [ABSTRACT FROM AUTHOR]

The dynamics of a triangular magnetocapillary swimmer is studied using the lattice Boltzmann method. We extend on our previous work, which deals with the self-assembly and a specific type of the swimmer motion characterized by the swimmer's maximum velocity centred around the particle's inverse viscous time. Here, we identify additional regimes of motion. First, modifying the ratio of surface tension and magnetic forces allows to study the swimmer propagation in the regime of significantly lower frequencies mainly defined by the strength of the magnetocapillary potential. Second, introducing a constant magnetic contribution in each of the particles in addition to their magnetic moment induced by external fields leads to another regime characterized by strong in-plane swimmer reorientations that resemble experimental observations. [ABSTRACT FROM AUTHOR]

A generic method is introduced to visualize in a "Gaussian-like way," and onto ℝ 2 , results of Gaussian or non-Gaussian–based clustering. The key point is to explicitly force a visualization based on a spherical Gaussian mixture to inherit from the within cluster overlap that is present in the initial clustering mixture. The result is a particularly user-friendly drawing of the clusters, providing any practitioner with an overview of the potentially complex clustering result. An entropic measure provides information about the quality of the drawn overlap compared with the true one in the initial space. The proposed method is illustrated on four real data sets of different types (categorical, mixed, functional, and network) and is implemented on the r package ClusVis. [ABSTRACT FROM AUTHOR]

Aegagropiles are round-shaped conglomerations of Posidonia oceanica debris commonly found along the coasts of the Mediterranean Sea. This study presents a detailed description of the composition of aegagropiles in terms of their internal organisation in different layers (and the orientation of the fibres in these layers), the proportion of constituent elements (fibres and minerals) and the histological (by way of microscopic observations) nature of all of these aegagropiles elements. The aim of this work is to take a detailed interest in the structure of the aegagropiles of Posidonia oceanica and to determine the process that forms them. Aegagropiles are an assemblage of two types of debris from the P. oceanica meadow: (1) plant-based: fibres more or less degraded from P. oceanica shoots (leaves and rhizomes) and (2) mineral particles such as silicates and biotic Ca-carbonate debris. On the basis of structural and compositional observations, we proposed an elucidation of the cycle in several phases: initiation of a "roll" by aggregation of litter fibres and sand in the ripple marks, growth, breakdown of the roll into small balls (microbial and mechanical degradation) and export of aegagropiles down (into the abyss) or on to the beaches. Calculations estimate that considering its density of 0.2 g/cm3, an aegagropile represents the accumulation of fibres from approximately 25 shoots of P. oceanica. [ABSTRACT FROM AUTHOR]

Multiple surgical targets for treating obsessive-compulsive disorder with deep brain stimulation (DBS) have been proposed. However, different targets may modulate the same neural network responsible for clinical improvement. We analyzed data from four cohorts of patients (N = 50) that underwent DBS to the anterior limb of the internal capsule (ALIC), the nucleus accumbens or the subthalamic nucleus (STN). The same fiber bundle was associated with optimal clinical response in cohorts targeting either structure. This bundle connected frontal regions to the STN. When informing the tract target based on the first cohort, clinical improvements in the second could be significantly predicted, and vice versa. To further confirm results, clinical improvements in eight patients from a third center and six patients from a fourth center were significantly predicted based on their stimulation overlap with this tract. Our results show that connectivity-derived models may inform clinical improvements across DBS targets, surgeons and centers. The identified tract target is openly available in atlas form. Li et al. analyzed structural connectivity of deep brain stimulation electrodes in 50 patients suffering from obsessive-compulsive disorder operated at four centers. Connectivity to a specific tract within the anterior limb of the internal capsule was associated with optimal treatment response across cohorts, surgeons and centers. [ABSTRACT FROM AUTHOR]

When tiny soft ferromagnetic particles are placed along a liquid interface and exposed to a vertical magnetic field, the balance between capillary attraction and magnetic repulsion leads to self-organization into well-defined patterns. Here, we demonstrate experimentally that precessing magnetic fields induce metachronal waves on the periphery of these assemblies, similar to the ones observed in ciliates and some arthropods. The outermost layer of particles behaves like an array of cilia or legs whose sequential movement causes a net and controllable locomotion. This bioinspired many-particle swimming strategy is effective even at low Reynolds number, using only spatially uniform fields to generate the waves. The assembly and manipulation of synthetic microswimmers often exploits parallels with living systems. Here, the authors show precessing magnetic fields induce rotation and translation in large self-assembled rafts of magnetic beads thanks to metachronal waves and in analogy with ciliates swimmers [ABSTRACT FROM AUTHOR]

Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and sleep symptoms in Parkinson's disease (PD). However, the long-term effects of STN-DBS on sleep and its relationship with QoL outcome are unclear. Methods: In this prospective, observational, multicenter study including 73 PD patients undergoing bilateral STN-DBS, we examined PDSleep Scale (PDSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD-motor examination, -activities of daily living, and -complications (SCOPA-A, -B, -C), and levodopa-equivalent daily dose (LEDD) preoperatively, at 5 and 24 months follow-up. Longitudinal changes were analyzed with Friedman-tests or repeated-measures ANOVA, when parametric tests were applicable, and Bonferroni-correction for multiple comparisons. Post-hoc, visits were compared with Wilcoxon signed-rank/t-tests. The magnitude of clinical responses was investigated using effect size. Results: Significant beneficial effects of STN-DBS were observed for PDSS, PDQ-8, SCOPA-A, -B, and -C. All outcomes improved significantly at 5 months with subsequent decrements in gains at 24 months follow-up which were significant for PDSS, PDQ-8, and SCOPA-B. Comparing baseline and 24 months follow-up, we observed significant improvements of PDSS (small effect), SCOPA-A (moderate effect), -C, and LEDD (large effects). PDSS and PDQ-8 improvements correlated significantly at 5 and 24 months follow-up. Conclusions: In this multicenter study with a 24 months follow-up, we report significant sustained improvements after bilateral STN-DBS using a PD-specific sleep scale and a significant relationship between sleep and QoL improvements. This highlights the importance of sleep in holistic assessments of DBS outcomes. [ABSTRACT FROM AUTHOR]

Although already some mesoporous (2–50 nm) sol–gel TiO2 synthesis strategies exist, no pore size control beyond the 12 nm range is possible without using specialized organic structure-directing agents synthetized via controlled anionic/radical polymerizations. Here, we present the use of reversible addition–fragmentation chain transfer (RAFT) polymerization as a straightforward and industrial applicable alternative to the existing controlled polymerization methods for structure-directing agent synthesis. Poly(N,N-dimethylacrylamide)-block-polystyrene (PDMA-b-PS) block copolymer, synthesized via RAFT, was chosen as structure-directing agent for the formation of the mesoporous TiO2. Crack-free thin layers TiO2 with tunable pores from 8 to 45 nm could be acquired. For the first time, in a detailed and systematic approach, the influence of the block size and dispersity of the block copolymer is experimentally screened for their influence on the final meso-TiO2 layers. As expected, the mesoporous TiO2 pore sizes showed a clear correlation to the polystyrene block size and the dispersity of the PDMA-b-PS block copolymer. Surprisingly, the dispersity of the polymer was shown not to be affecting the standard deviation of the pores. As a consequence, RAFT could be seen as a viable alternative to the aforementioned controlled polymerization reactions for the synthesis of structure-directing agents enabling the formation of mesoporous pore size-controlled TiO2. To examine the photocatalytic activity of the mesoporous TiO2 thin layers, the degradation of acetaldehyde, a known indoor pollutant, was studied. Even after 3 years of aging, the TiO2 thin layer retained most of its activity. [ABSTRACT FROM AUTHOR]

Heart failure (HF) remains a main cause of mortality worldwide. Risk stratification of patients with systolic chronic HF is critical to identify those who may benefit from advanced HF therapies. The aim of this study is to identify plasmatic proteins that could predict the early death (within 3 years) of HF patients with reduced ejection fraction hospitalized in CHRU de Lille. The subproteome targeted by an aptamer-based technology, the Slow Off-rate Modified Aptamer (SOMA) scan assay of 1310 proteins, was profiled in blood samples from 168 HF patients, and 203 proteins were significantly modulated between patients who died of cardiovascular death and patients who were alive after 3 years of HF evaluation (Wilcoxon test, FDR 5%). A molecular network was built using these 203 proteins, and the resulting network contained 2281 molecules assigned to 34 clusters annotated to biological pathways by Gene Ontology. This network model highlighted extracellular matrix organization as the main mechanism involved in early death in HF patients. In parallel, an adaptive Least Absolute Shrinkage and Selection Operator (LASSO) was performed on these 203 proteins, and six proteins were selected as candidates to predict early death in HF patients: complement C3, cathepsin S and F107B were decreased and MAPK5, MMP1 and MMP7 increased in patients who died of cardiovascular causes compared with patients living 3 years after HF evaluation. This proteomic signature of 6 circulating plasma proteins allows the identification of systolic HF patients with a risk of early death. [ABSTRACT FROM AUTHOR]

Background: Adverse outcomes for infants born with left congenital diaphragmatic hernia (CDH) have been correlated with fetal imaging findings.Objective: We sought to corroborate these correlations in a high-risk cohort and describe a predictive mortality algorithm combining multiple imaging biomarkers for use in prenatal counseling.Materials and Methods: We reviewed fetal MRI examinations at our institution from 2004 to 2016 demonstrating left-side CDH. MRI findings, hospital course and outcomes were recorded and analyzed using bivariate and multivariable analysis. We generated a receiver operating curve (ROC) to determine a cut-off relation for mortality. Finally, we created a predictive mortality calculator.Results: Of 41 fetuses included in this high-risk cohort, 41% survived. Per bivariate analysis, observed-to-expected total fetal lung volume (P=0.007), intrathoracic position of the stomach (P=0.049), and extracorporeal membrane oxygenation (ECMO) requirement (P<0.001) were significantly associated with infant mortality. Youden J statistic optimized the ROC for mortality at 24% observed-to-expected total fetal lung volume (sensitivity 64%, specificity 82%, area under the curve 0.72). On multivariable analysis, observed-to-expected total fetal lung volume ± 24% was predictive of mortality (adjusted odds ratio, 95% confidence interval: 0.09 [0.02, 0.55]; P=0.008). We derived a novel mortality prediction calculator from this analysis.Conclusion: In this high-risk cohort, decreased observed-to-expected total fetal lung volume and stomach herniation were significantly associated with mortality. The novel predictive mortality calculator utilizes information from fetal MR imaging and provides prognostic information for health care providers. Creation of similar predictive tools by other institutions, using their distinct populations, might prove useful in family counseling, especially where there are discordant imaging findings. [ABSTRACT FROM AUTHOR]

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Purpose: Trending the pediatric-adjusted shock index (SIPA) after admission has been described for children suffering severe blunt injuries (i.e., injury severity score (ISS) ≥ 15). We propose that following SIPA in children with moderate blunt injuries, as defined by ISS 10-14, has similar utility.Methods: The trauma registry at a single institution was queried over a 7 year period. Patients were included if they were between 4 and 16 years old at the time of admission, sustained a blunt injury with an ISS 10-14, and were admitted less than 12 h after their injury (n = 501). Each patient's SIPA was then calculated at 0, 12, 24, 36, and 48 h (h) after admission and then categorized as elevated or normal at each time frame based on previously reported values. Trends in outcome variables as a function of time from admission for patients with an abnormal SIPA to normalize as well as patients with a normal admission SIPA to abnormal were analyzed.Results: In patients with a normal SIPA at arrival, elevation within the first 24 h of admission correlated with increased length of stay (LOS). Increased transfusion requirement, incidence of infectious complications, and need for in-patient rehabilitation were also seen in analyzed sub-groups. An elevated SIPA at arrival with increased length of time to normalize SIPA correlated with increased length of stay LOS in the entire cohort and in those without head injury, but not in patients with a head injury. No deaths occurred within the study cohort.Conclusions: Patients with an ISS 10-14 and a normal SIPA at time of arrival who then have an elevated SIPA in the first 24 h of admission are at increased risk for morbidity including longer LOS and infectious complications. Similarly, time to normalize an elevated admission SIPA appears to directly correlate with LOS in patients without head injuries. No correlations with markers for morbidity could be identified in patients with a head injury and an elevated SIPA at arrival. This may be due to small sample size, as there were no relations to severity of head injury as measured by head abbreviated injury scale (head AIS) and the outcome variables reported. This is an area of ongoing analysis. This study extends the previously reported utility of following SIPA after admission into milder blunt injuries. [ABSTRACT FROM AUTHOR]

The discovery of intrinsically photosensitive retinal ganglion cells (ipRGCs) marked a major shift in our understanding of how light information is processed by the mammalian brain. These ipRGCs influence multiple functions not directly related to image formation such as circadian resetting and entrainment, pupil constriction, enhancement of alertness, as well as the modulation of cognition. More recently, it was demonstrated that ipRGCs may also contribute to basic visual functions. The impact of ipRGCs on visual function, independently of image forming photoreceptors, remains difficult to isolate, however, particularly in humans. We previously showed that exposure to intense monochromatic blue light (465 nm) induced non-conscious light perception in a forced choice task in three rare totally visually blind individuals without detectable rod and cone function, but who retained non-image-forming responses to light, very likely via ipRGCs. The neural foundation of such light perception in the absence of conscious vision is unknown, however. In this study, we characterized the brain activity of these three participants using electroencephalography (EEG), and demonstrate that unconsciously perceived light triggers an early and reliable transient desynchronization (i.e. decreased power) of the alpha EEG rhythm (8–14 Hz) over the occipital cortex. These results provide compelling insight into how ipRGC may contribute to transient changes in ongoing brain activity. They suggest that occipital alpha rhythm synchrony, which is typically linked to the visual system, is modulated by ipRGCs photoreception; a process that may contribute to the non-conscious light perception in those blind individuals. [ABSTRACT FROM AUTHOR]

In the study of microscopic flows, self-propulsion has been particularly topical in recent years, with the rise of miniature artificial swimmers as a new tool for flow control, low Reynolds number mixing, micromanipulation or even drug delivery. It is possible to take advantage of interfacial physics to propel these microrobots, as demonstrated by recent experiments using the proximity of an interface, or the interface itself, to generate propulsion at low Reynolds number. This paper discusses how a nearby interface can provide the symmetry breaking necessary for propulsion. An overview of recent experiments illustrates how forces at the interface can be used to generate locomotion. Surface swimmers ranging from the microscopic scale to typically the capillary length are covered. Two systems are then discussed in greater detail. The first is composed of floating ferromagnetic spheres that assemble through capillarity into swimming structures. Two previously studied configurations, triangular and collinear, are discussed and contrasted. A new interpretation for the triangular swimmer is presented. Then, the non-monotonic influence of surface tension and viscosity is evidenced in the collinear case. Finally, a new system is introduced. It is a magnetically powered, centimeter-sized piece that swims similarly to water striders. [ABSTRACT FROM AUTHOR]

Inbred mouse strains derived from the species Mus spretus have been very informative in the study of certain gene polymorphisms in inflammation and infection. Based on our interest in sepsis, we used SPRET/EiJ mice and mapped several critical loci that are linked to sensitivity to cytokine-induced inflammation and endotoxemia. These studies were based on prominent phenotypes that have never been observed in strains derived from Mus musculus and we mapped them at a resolution that enables us to draw conclusions on the mechanisms. Now that the genome of SPRET/EiJ has been sequenced, and other tools have become available, it is time to revisit this strain and emphasize its advantages and disadvantages as a research tool and a discovery platform. [ABSTRACT FROM AUTHOR]