Showing papers by "University of Rennes published in 2017"

GW170817: observation of gravitational waves from a binary neutron star inspiral

Abstract: On August 17, 2017 at 12∶41:04 UTC the Advanced LIGO and Advanced Virgo gravitational-wave detectors made their first observation of a binary neutron star inspiral. The signal, GW170817, was detected with a combined signal-to-noise ratio of 32.4 and a false-alarm-rate estimate of less than one per 8.0×10^{4} years. We infer the component masses of the binary to be between 0.86 and 2.26 M_{⊙}, in agreement with masses of known neutron stars. Restricting the component spins to the range inferred in binary neutron stars, we find the component masses to be in the range 1.17-1.60 M_{⊙}, with the total mass of the system 2.74_{-0.01}^{+0.04}M_{⊙}. The source was localized within a sky region of 28 deg^{2} (90% probability) and had a luminosity distance of 40_{-14}^{+8} Mpc, the closest and most precisely localized gravitational-wave signal yet. The association with the γ-ray burst GRB 170817A, detected by Fermi-GBM 1.7 s after the coalescence, corroborates the hypothesis of a neutron star merger and provides the first direct evidence of a link between these mergers and short γ-ray bursts. Subsequent identification of transient counterparts across the electromagnetic spectrum in the same location further supports the interpretation of this event as a neutron star merger. This unprecedented joint gravitational and electromagnetic observation provides insight into astrophysics, dense matter, gravitation, and cosmology.

Gravitational Waves and Gamma-Rays from a Binary Neutron Star Merger: GW170817 and GRB 170817A

Abstract: On 2017 August 17, the gravitational-wave event GW170817 was observed by the Advanced LIGO and Virgo detectors, and the gamma-ray burst (GRB) GRB 170817A was observed independently by the Fermi Gamma-ray Burst Monitor, and the Anti-Coincidence Shield for the Spectrometer for the International Gamma-Ray Astrophysics Laboratory. The probability of the near-simultaneous temporal and spatial observation of GRB 170817A and GW170817 occurring by chance is $5.0\times {10}^{-8}$. We therefore confirm binary neutron star mergers as a progenitor of short GRBs. The association of GW170817 and GRB 170817A provides new insight into fundamental physics and the origin of short GRBs. We use the observed time delay of $(+1.74\pm 0.05)\,{\rm{s}}$ between GRB 170817A and GW170817 to: (i) constrain the difference between the speed of gravity and the speed of light to be between $-3\times {10}^{-15}$ and $+7\times {10}^{-16}$ times the speed of light, (ii) place new bounds on the violation of Lorentz invariance, (iii) present a new test of the equivalence principle by constraining the Shapiro delay between gravitational and electromagnetic radiation. We also use the time delay to constrain the size and bulk Lorentz factor of the region emitting the gamma-rays. GRB 170817A is the closest short GRB with a known distance, but is between 2 and 6 orders of magnitude less energetic than other bursts with measured redshift. A new generation of gamma-ray detectors, and subthreshold searches in existing detectors, will be essential to detect similar short bursts at greater distances. Finally, we predict a joint detection rate for the Fermi Gamma-ray Burst Monitor and the Advanced LIGO and Virgo detectors of 0.1–1.4 per year during the 2018–2019 observing run and 0.3–1.7 per year at design sensitivity.

GW170104: Observation of a 50-Solar-Mass Binary Black Hole Coalescence at Redshift 0.2

Abstract: We describe the observation of GW170104, a gravitational-wave signal produced by the coalescence of a pair of stellar-mass black holes. The signal was measured on January 4, 2017 at 10∶11:58.6 UTC by the twin advanced detectors of the Laser Interferometer Gravitational-Wave Observatory during their second observing run, with a network signal-to-noise ratio of 13 and a false alarm rate less than 1 in 70 000 years. The inferred component black hole masses are 31.2^(8.4) _(−6.0)M_⊙ and 19.4^(5.3)_( −5.9)M_⊙ (at the 90% credible level). The black hole spins are best constrained through measurement of the effective inspiral spin parameter, a mass-weighted combination of the spin components perpendicular to the orbital plane, χ_(eff) = −0.12^(0.21)_( −0.30). This result implies that spin configurations with both component spins positively aligned with the orbital angular momentum are disfavored. The source luminosity distance is 880^(450)_(−390) Mpc corresponding to a redshift of z = 0.18^(0.08)_( −0.07) . We constrain the magnitude of modifications to the gravitational-wave dispersion relation and perform null tests of general relativity. Assuming that gravitons are dispersed in vacuum like massive particles, we bound the graviton mass to m_g ≤ 7.7 × 10^(−23) eV/c^2. In all cases, we find that GW170104 is consistent with general relativity.

GW170608: Observation of a 19 solar-mass binary black hole coalescence

Abstract: On 2017 June 8 at 02:01:16.49 UTC, a gravitational-wave (GW) signal from the merger of two stellar-mass black holes was observed by the two Advanced Laser Interferometer Gravitational-Wave Observatory detectors with a network signal-to-noise ratio of 13. This system is the lightest black hole binary so far observed, with component masses of ${12}_{-2}^{+7}\,{M}_{\odot }$ and ${7}_{-2}^{+2}\,{M}_{\odot }$ (90% credible intervals). These lie in the range of measured black hole masses in low-mass X-ray binaries, thus allowing us to compare black holes detected through GWs with electromagnetic observations. The source's luminosity distance is ${340}_{-140}^{+140}\,\mathrm{Mpc}$, corresponding to redshift ${0.07}_{-0.03}^{+0.03}$. We verify that the signal waveform is consistent with the predictions of general relativity.

Extremely efficient internal exciton dissociation through edge states in layered 2D perovskites

Abstract: Understanding and controlling charge and energy flow in state-of-the-art semiconductor quantum wells has enabled high-efficiency optoelectronic devices. Two-dimensional (2D) Ruddlesden-Popper perovskites are solution-processed quantum wells wherein the band gap can be tuned by varying the perovskite-layer thickness, which modulates the effective electron-hole confinement. We report that, counterintuitive to classical quantum-confined systems where photogenerated electrons and holes are strongly bound by Coulomb interactions or excitons, the photophysics of thin films made of Ruddlesden-Popper perovskites with a thickness exceeding two perovskite-crystal units (>1.3 nanometers) is dominated by lower-energy states associated with the local intrinsic electronic structure of the edges of the perovskite layers. These states provide a direct pathway for dissociating excitons into longer-lived free carriers that substantially improve the performance of optoelectronic devices.

Rapid transcriptional plasticity of duplicated gene clusters enables a clonally reproducing aphid to colonise diverse plant species

Abstract: The prevailing paradigm of host-parasite evolution is that arms races lead to increasing specialisation via genetic adaptation. Insect herbivores are no exception and the majority have evolved to colonise a small number of closely related host species. Remarkably, the green peach aphid, Myzus persicae, colonises plant species across 40 families and single M. persicae clonal lineages can colonise distantly related plants. This remarkable ability makes M. persicae a highly destructive pest of many important crop species. To investigate the exceptional phenotypic plasticity of M. persicae, we sequenced the M. persicae genome and assessed how one clonal lineage responds to host plant species of different families. We show that genetically identical individuals are able to colonise distantly related host species through the differential regulation of genes belonging to aphid-expanded gene families. Multigene clusters collectively upregulate in single aphids within two days upon host switch. Furthermore, we demonstrate the functional significance of this rapid transcriptional change using RNA interference (RNAi)-mediated knock-down of genes belonging to the cathepsin B gene family. Knock-down of cathepsin B genes reduced aphid fitness, but only on the host that induced upregulation of these genes. Previous research has focused on the role of genetic adaptation of parasites to their hosts. Here we show that the generalist aphid pest M. persicae is able to colonise diverse host plant species in the absence of genetic specialisation. This is achieved through rapid transcriptional plasticity of genes that have duplicated during aphid evolution.

Nanoplastic in the North Atlantic Subtropical Gyre.

Abstract: Plastics can be found in all ecosystems across the globe. This type of environmental pollution is important, even if its impact is not fully understood. The presence of small plastic particles at the micro- and nanoscales is of growing concern, but nanoplastic has not yet been observed in natural samples. In this study, we examined four size fractions (meso-, large micro-, small micro-, and nanoplastics) of debris collected in the North Atlantic subtropical gyre. To obtain the nanoplastic portion, we isolated the colloidal fraction of seawater. After ultrafiltration, the occurrence of nanoscale particles was demonstrated using dynamic light scattering experiments. The chemical fingerprint of the colloids was obtained by pyrolysis coupled with gas chromatography–mass spectrometry. We demonstrated that the signal was anthropogenic and attributed to a combination of plastics. The polymer composition varied among the size classes. At the micro- and nanoscales, polyvinyl chloride, polyethylene terephthalate, p...

Melatonin: Pharmacology, Functions and Therapeutic Benefits

Abstract: Background: Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock. Methods: First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed. Results: The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects. Conclusion: This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects.

The ins and outs of microorganism–electrode electron transfer reactions

Abstract: Electron transfer between microorganisms and an electrode — even across long distances — enables the former to live by coupling to an electronic circuit. Such a system integrates biological metabolism with artificial electronics; studying these systems adds to our knowledge of charge transport in the chemical species involved, as well as, perhaps most importantly, to our knowledge of charge transport and chemistry at the cell–electrode interfaces. This understanding may lead to microbial electrochemical systems finding widespread application, particularly in the energy sector. Bioelectrochemical systems have already shown promise for electricity generation, as well as for the production of biochemical and chemical feedstocks, and with improvement are likely to give rise to viable applications. Electrodes colonized by microbial electrocatalysts can serve as useful components in the electrosynthesis of valuable chemical products. This Review outlines the mechanisms by which electrons are transferred between microorganisms and electrodes, and describes the challenges involved in designing robust and efficient systems.

Roseburia spp.: a marker of health?

Abstract: The genus Roseburia consists of obligate Gram-positive anaerobic bacteria that are slightly curved, rod-shaped and motile by means of multiple subterminal flagella. It includes five species: Roseburia intestinalis, R. hominis, R. inulinivorans, R. faecis and R. cecicola. Gut Roseburia spp. metabolize dietary components that stimulate their proliferation and metabolic activities. They are part of commensal bacteria producing short-chain fatty acids, especially butyrate, affecting colonic motility, immunity maintenance and anti-inflammatory properties. Modification in Roseburia spp. representation may affect various metabolic pathways and is associated with several diseases (including irritable bowel syndrome, obesity, Type 2 diabetes, nervous system conditions and allergies). Roseburia spp. could also serve as biomarkers for symptomatic pathologies (e.g., gallstone formation) or as probiotics for restoration of beneficial flora.

Defining epileptogenic networks: Contribution of SEEG and signal analysis

Abstract: Epileptogenic networks are defined by the brain regions involved in the production and propagation of epileptic activities. In this review we describe the historical, methodologic, and conceptual bases of this model in the analysis of electrophysiologic intracerebral recordings. In the context of epilepsy surgery, the determination of cerebral regions producing seizures (i.e., the “epileptogenic zone”) is a crucial objective. In contrast with a traditional focal vision of focal drug-resistant epilepsies, the concept of epileptogenic networks has been progressively introduced as a model better able to describe the complexity of seizure dynamics and realistically describe the distribution of epileptogenic anomalies in the brain. The concept of epileptogenic networks is historically linked to the development of the stereoelectroencephalography (SEEG) method and subsequent introduction of means of quantifying the recorded signals. Seizures, and preictal and interictal discharges produce clear patterns on SEEG. These patterns can be analyzed utilizing signal analysis methods that quantify high-frequency oscillations or changes in functional connectivity. Dramatic changes in SEEG brain connectivity can be described during seizure genesis and propagation within cortical and subcortical regions, associated with the production of different patterns of seizure semiology. The interictal state is characterized by networks generating abnormal activities (interictal spikes) and also by modified functional properties. The introduction of novel approaches to large-scale modeling of these networks offers new methods in the goal of better predicting the effects of epilepsy surgery. The epileptogenic network concept is a key factor in identifying the anatomic distribution of the epileptogenic process, which is particularly important in the context of epilepsy surgery. © 2017 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.

Hyperbolically Embedded Subgroups and Rotating Families in Groups Acting on Hyperbolic Spaces

Abstract: We introduce and study the notions of hyperbolically embedded and very rotating families of subgroups. The former notion can be thought of as a generalization of peripheral structures of relative hyperbolicity groups, while the later one provides a natural framework for developing a geometric version of small cancellation theory. Examples of such families naturally occur in groups acting on hyperbolic spaces including hyperbolic and relatively hyperbolic groups, mapping class groups, $Out(F_n)$, and the Cremona group. Other examples can be found among groups acting geometrically on CAT(0) spaces, fundamental groups of graphs of groups, etc. Although our technique applies to a wide class of groups, it is capable of producing new results even for well-studied particular classes. For instance, we solve two open problems about mapping class groups, and obtain some results which are new even for relatively hyperbolic groups.

A state of the art review on viscosity of nanofluids

Abstract: A comprehensive review of research and development on rheological characteristics of nanofluids for their advanced heat transfer applications is performed and reported in this paper. It identifies the research anomaly and importance on this topic besides analysing rheology of nanofluids. Various classical and recently developed viscosity models for nanofluids are presented and discussed. Nanofluids are classified as metallic and nonmetallic types and research findings on this key property of available nanofluids are analyzed. Effects of several important factors such as concentration of nanoparticles and temperature on viscosity of each type of nanofluids have been explicitly reviewed. Results from various research groups and predictions from viscosity models are also compared and discussed in detail. Role and importance of the viscosity in connection with other thermal properties and parameters for their thermal management applications are highlighted. Furthermore, the research challenges and needs in this important area of nanofluids are also revealed.

Tunable White-Light Emission in Single-Cation-Templated Three-Layered 2D Perovskites (CH3CH2NH3)4Pb3Br10-xClx

Abstract: Two-dimensional (2D) hybrid halide perovskites come as a family (B)2(A)n−1PbnX3n+1 (B and A= cations; X= halide). These perovskites are promising semiconductors for solar cells and optoelectronic applications. Among the fascinating properties of these materials is white-light emission, which has been mostly observed in single-layered 2D lead bromide or chloride systems (n = 1), where the broad emission comes from the transient photoexcited states generated by self-trapped excitons (STEs) from structural distortion. Here we report a multilayered 2D perovskite (n = 3) exhibiting a tunable white-light emission. Ethylammonium (EA+) can stabilize the 2D perovskite structure in EA4Pb3Br10–xClx (x = 0, 2, 4, 6, 8, 9.5, and 10) with EA+ being both the A and B cations in this system. Because of the larger size of EA, these materials show a high distortion level in their inorganic structures, with EA4Pb3Cl10 having a much larger distortion than that of EA4Pb3Br10, which results in broadband white-light emission of ...

Surgical data science for next-generation interventions.

Abstract: Interventional healthcare will evolve from an artisanal craft based on the individual experiences, preferences and traditions of physicians into a discipline that relies on objective decision-making on the basis of large-scale data from heterogeneous sources.

FEELnc: a tool for long non-coding RNA annotation and its application to the dog transcriptome.

Abstract: Whole transcriptome sequencing (RNA-seq) has become a standard for cataloguing and monitoring RNA populations. One of the main bottlenecks, however, is to correctly identify the different classes of RNAs among the plethora of reconstructed transcripts, particularly those that will be translated (mRNAs) from the class of long non-coding RNAs (lncRNAs). Here, we present FEELnc (FlExible Extraction of LncRNAs), an alignment-free program that accurately annotates lncRNAs based on a Random Forest model trained with general features such as multi k-mer frequencies and relaxed open reading frames. Benchmarking versus five state-of-the-art tools shows that FEELnc achieves similar or better classification performance on GENCODE and NONCODE data sets. The program also provides specific modules that enable the user to fine-tune classification accuracy, to formalize the annotation of lncRNA classes and to identify lncRNAs even in the absence of a training set of non-coding RNAs. We used FEELnc on a real data set comprising 20 canine RNA-seq samples produced by the European LUPA consortium to substantially expand the canine genome annotation to include 10 374 novel lncRNAs and 58 640 mRNA transcripts. FEELnc moves beyond conventional coding potential classifiers by providing a standardized and complete solution for annotating lncRNAs and is freely available at https://github.com/tderrien/FEELnc.

Direct Remaining Useful Life Estimation Based on Support Vector Regression

Abstract: Prognostics is a major activity in the field of prognostics and health management It aims at increasing the reliability and safety of systems while reducing the maintenance cost by providing an estimate of the current health status and remaining useful life (RUL) Classical RUL estimation techniques are usually composed of different steps: estimations of a health indicator, degradation states, a failure threshold, and finally the RUL In this work, a procedure that is able to estimate the RUL of equipment directly from sensor values without the need for estimating degradation states or a failure threshold is developed A direct relation between sensor values or health indicators is modeled using a support vector regression Using this procedure, the RUL can be estimated at any time instant of the degradation process In addition, an offline wrapper variable selection is applied before training the prediction model This step has a positive impact on the accuracy of the prediction while reducing the computational time compared to existing indirect RUL prediction methods To assess the performance of the proposed approach, the Turbofan dataset, widely considered in the literature, is used Experimental results show that the performance of the proposed method is competitive with other existing approaches

Upper Limits on the Stochastic Gravitational-Wave Background from Advanced LIGO's First Observing Run

Abstract: A wide variety of astrophysical and cosmological sources are expected to contribute to a stochastic gravitational-wave background. Following the observations of GW150914 and GW151226, the rate and mass of coalescing binary black holes appear to be greater than many previous expectations. As a result, the stochastic background from unresolved compact binary coalescences is expected to be particularly loud. We perform a search for the isotropic stochastic gravitational-wave background using data from Advanced Laser Interferometer Gravitational Wave Observatory’s (aLIGO) first observing run. The data display no evidence of a stochastic gravitational-wave signal. We constrain the dimensionless energy density of gravitational waves to be Ω 0 < 1.7 × 10 − 7 with 95% confidence, assuming a flat energy density spectrum in the most sensitive part of the LIGO band (20–86 Hz). This is a factor of ∼ 33 times more sensitive than previous measurements. We also constrain arbitrary power-law spectra. Finally, we investigate the implications of this search for the background of binary black holes using an astrophysical model for the background.

FDR-controlled metabolite annotation for high-resolution imaging mass spectrometry

Abstract: High-mass-resolution imaging mass spectrometry promises to localize hundreds of metabolites in tissues, cell cultures, and agar plates with cellular resolution, but it is hampered by the lack of bioinformatics tools for automated metabolite identification. We report pySM, a framework for false discovery rate (FDR)-controlled metabolite annotation at the level of the molecular sum formula, for high-mass-resolution imaging mass spectrometry (https://github.com/alexandrovteam/pySM). We introduce a metabolite-signal match score and a target-decoy FDR estimate for spatial metabolomics.

Targeting RET in patients with RET-rearranged lung cancers: Results from the global, multicenter RET registry

Abstract: Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

Standing on the Shoulders of Dwarfs: the Kepler Asteroseismic LEGACY Sample. II.Radii, Masses, and Ages

Abstract: We use asteroseismic data from the Kepler satellite to determine fundamental stellar properties of the 66 main-sequence targets observed for at least one full year by the mission. We distributed tens of individual oscillation frequencies extracted from the time series of each star among seven modelling teams who applied different methods to determine radii, masses, and ages for all stars in the sample. Comparisons among the different results reveal a good level of agreement in all stellar properties, which is remarkable considering the variety of codes, input physics and analysis methods employed by the different teams. Average uncertainties are of the order of ~2% in radius, ~4% in mass, and 10% in age, making this the best-characterised sample of main-sequence stars available to date. We test the accuracy of the determined stellar properties by comparing them to the Sun, angular diameter measurements, Gaia parallaxes, and binary evolution, finding excellent agreement in all cases and further confirming the robustness of asteroseismically-determined physical parameters of stars when individual frequencies of oscillation are available. Baptised as the Kepler dwarfs LEGACY sample, these stars are the solar-like oscillators with the best asteroseismic properties available for at least another decade. All data used in this analysis and the resulting stellar parameters are made publicly available for the community.

Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.

Abstract: Background Psoriasis is an immune-mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. Several randomised controlled trials (RCTs) have compared the efficacy of the different systemic treatments in psoriasis against placebo. However, the relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head to head, which is why we chose to conduct a network meta-analysis. Objectives To compare the efficacy and safety of conventional systemic agents (acitretin, ciclosporin, fumaric acid esters, methotrexate), small molecules (apremilast, tofacitinib, ponesimod), anti-TNF alpha (etanercept, infliximab, adalimumab, certolizumab), anti-IL12/23 (ustekinumab), anti-IL17 (secukinumab, ixekizumab, brodalumab), anti-IL23 (guselkumab, tildrakizumab), and other biologics (alefacept, itolizumab) for patients with moderate to severe psoriasis and to provide a ranking of these treatments according to their efficacy and safety. Search methods We searched the following databases to December 2016: the Cochrane Skin Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS. We also searched five trials registers and the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) reports. We checked the reference lists of included and excluded studies for further references to relevant RCTs. We searched the trial results databases of a number of pharmaceutical companies and handsearched the conference proceedings of a number of dermatology meetings. Selection criteria Randomised controlled trials (RCTs) of systemic and biological treatments in adults (over 18 years of age) with moderate to severe plaque psoriasis or psoriatic arthritis whose skin had been clinically diagnosed with moderate to severe psoriasis, at any stage of treatment, in comparison to placebo or another active agent. Data collection and analysis Three groups of two review authors independently undertook study selection, data extraction, 'Risk of bias' assessment, and analyses. We synthesised the data using pair-wise and network meta-analysis (NMA) to compare the treatments of interest and rank them according to their effectiveness (as measured by the Psoriasis Area and Severity Index score (PASI) 90) and acceptability (the inverse of serious adverse effects). We assessed the certainty of the body of evidence from the NMA for the two primary outcomes, according to GRADE; we evaluated evidence as either very low, low, moderate, or high. We contacted study authors when data were unclear or missing. Main results We included 109 studies in our review (39,882 randomised participants, 68% men, all recruited from a hospital). The overall average age was 44 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most of these studies were placebo controlled (67%), 23% were head-to-head studies, and 10% were multi-armed studies with both an active comparator and placebo. We have assessed all treatments listed in the objectives (19 in total). In all, 86 trials were multicentric trials (two to 231 centres). All of the trials included in this review were limited to the induction phase (assessment at less than 24 weeks after randomisation); in fact, all trials included in the network meta-analysis were measured between 12 and 16 weeks after randomisation. We assessed the majority of studies (48/109) as being at high risk of bias; 38 were assessed as at an unclear risk, and 23, low risk. Network meta-analysis at class level showed that all of the interventions (conventional systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in terms of reaching PASI 90. In terms of reaching PASI 90, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents. Small molecules were associated with a higher chance of reaching PASI 90 compared to conventional systemic agents. At drug level, in terms of reaching PASI 90, all of the anti-IL17 agents and guselkumab (an anti-IL23 drug) were significantly more effective than the anti-TNF alpha agents infliximab, adalimumab, and etanercept, but not certolizumab. Ustekinumab was superior to etanercept. No clear difference was shown between infliximab, adalimumab, and etanercept. Only one trial assessed the efficacy of infliximab in this network; thus, these results have to be interpreted with caution. Tofacitinib was significantly superior to methotrexate, and no clear difference was shown between any of the other small molecules versus conventional treatments. Network meta-analysis also showed that ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab outperformed other drugs when compared to placebo in terms of reaching PASI 90: the most effective drug was ixekizumab (risk ratio (RR) 32.45, 95% confidence interval (CI) 23.61 to 44.60; Surface Under the Cumulative Ranking (SUCRA) = 94.3; high-certainty evidence), followed by secukinumab (RR 26.55, 95% CI 20.32 to 34.69; SUCRA = 86.5; high-certainty evidence), brodalumab (RR 25.45, 95% CI 18.74 to 34.57; SUCRA = 84.3; moderate-certainty evidence), guselkumab (RR 21.03, 95% CI 14.56 to 30.38; SUCRA = 77; moderate-certainty evidence), certolizumab (RR 24.58, 95% CI 3.46 to 174.73; SUCRA = 75.7; moderate-certainty evidence), and ustekinumab (RR 19.91, 95% CI 15.11 to 26.23; SUCRA = 72.6; high-certainty evidence). We found no significant difference between all of the interventions and the placebo regarding the risk of serious adverse effects (SAEs): the relative ranking strongly suggested that methotrexate was associated with the best safety profile regarding all of the SAEs (RR 0.23, 95% CI 0.05 to 0.99; SUCRA = 90.7; moderate-certainty evidence), followed by ciclosporin (RR 0.23, 95% CI 0.01 to 5.10; SUCRA = 78.2; very low-certainty evidence), certolizumab (RR 0.49, 95% CI 0.10 to 2.36; SUCRA = 70.9; moderate-certainty evidence), infliximab (RR 0.56, 95% CI 0.10 to 3.00; SUCRA = 64.4; very low-certainty evidence), alefacept (RR 0.72, 95% CI 0.34 to 1.55; SUCRA = 62.6; low-certainty evidence), and fumaric acid esters (RR 0.77, 95% CI 0.30 to 1.99; SUCRA = 57.7; very low-certainty evidence). Major adverse cardiac events, serious infections, or malignancies were reported in both the placebo and intervention groups. Nevertheless, the SAEs analyses were based on a very low number of events with low to very low certainty for just over half of the treatment estimates in total, moderate for the others. Thus, the results have to be considered with caution. Considering both efficacy (PASI 90 outcome) and acceptability (SAEs outcome), highly effective treatments also had more SAEs compared to the other treatments, and ustekinumab, infliximab, and certolizumab appeared to have the better trade-off between efficacy and acceptability. Regarding the other efficacy outcomes, PASI 75 and Physician Global Assessment (PGA) 0/1, the results were very similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for a third of the interventions. Authors' conclusions Our review shows that compared to placebo, the biologics ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab are the best choices for achieving PASI 90 in people with moderate to severe psoriasis on the basis of moderate- to high-certainty evidence. At class level, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents, too. This NMA evidence is limited to induction therapy (outcomes were measured between 12 to 16 weeks after randomisation) and is not sufficiently relevant for a chronic disease. Moreover, low numbers of studies were found for some of the interventions, and the young age (mean age of 44 years) and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice. Another major concern is that short-term trials provide scanty and sometimes poorly reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. Indeed, we found no significant difference in the assessed interventions and placebo in terms of SAEs. Methotrexate appeared to have the best safety profile, but as the evidence was of very low to moderate quality, we cannot be sure of the ranking. In order to provide long-term information on the safety of the treatments included in this review, it will be necessary to evaluate non-randomised studies and postmarketing reports released from regulatory agencies as well. In terms of future research, randomised trials comparing directly active agents are necessary once high-quality evidence of benefit against placebo is established, including head-to-head trials amongst and between conventional systemic and small molecules, and between biological agents (anti-IL17 versus anti-IL23, anti-IL23 versus anti-IL12/23, anti-TNF alpha versus anti-IL12/23). Future trials should also undertake systematic subgroup analyses (e.g. assessing biological-naive patients, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, outcome measure harmonisation is needed in psoriasis trials, and researchers should look at the medium- and long-term benefit and safety of the interventions and the comparative safety of different agents.

Search for Post-merger Gravitational Waves from the Remnant of the Binary Neutron Star Merger GW170817

Abstract: The first observation of a binary neutron star (NS) coalescence by the Advanced LIGO and Advanced Virgo gravitational-wave (GW) detectors offers an unprecedented opportunity to study matter under the most extreme conditions. After such a merger, a compact remnant is left over whose nature depends primarily on the masses of the inspiraling objects and on the equation of state of nuclear matter. This could be either a black hole (BH) or an NS, with the latter being either long-lived or too massive for stability implying delayed collapse to a BH. Here, we present a search for GWs from the remnant of the binary NS merger GW170817 using data from Advanced LIGO and Advanced Virgo. We search for short- (lesssim1 s) and intermediate-duration (lesssim500 s) signals, which include GW emission from a hypermassive NS or supramassive NS, respectively. We find no signal from the post-merger remnant. Our derived strain upper limits are more than an order of magnitude larger than those predicted by most models. For short signals, our best upper limit on the root sum square of the GW strain emitted from 1–4 kHz is ${h}_{\mathrm{rss}}^{50 \% }=2.1\times {10}^{-22}\,{\mathrm{Hz}}^{-1/2}$ at 50% detection efficiency. For intermediate-duration signals, our best upper limit at 50% detection efficiency is ${h}_{\mathrm{rss}}^{50 \% }=8.4\times {10}^{-22}\,{\mathrm{Hz}}^{-1/2}$ for a millisecond magnetar model, and ${h}_{\mathrm{rss}}^{50 \% }=5.9\times {10}^{-22}\,{\mathrm{Hz}}^{-1/2}$ for a bar-mode model. These results indicate that post-merger emission from a similar event may be detectable when advanced detectors reach design sensitivity or with next-generation detectors.

Echo-Doppler estimation of left ventricular filling pressure: results of the multicentre EACVI Euro-Filling study.

Abstract: Aims The present Euro-Filling report aimed at comparing the diagnostic accuracy of the 2009 and 2016 echocardiographic grading algorithms for predicting invasively measured left ventricular filling pressure (LVFP). Method and results A total of 159 patients who underwent simultaneous evaluation of echo estimates of LVFP and invasive measurements of LV end-diastolic pressure (LVEDP) were enrolled at nine EACVI centres. Thirty-nine (25%) patients had a reduced LV ejection fraction (<50%), 77 (64%) were in NYHA ≥ II, and 85 (53%) had coronary artery disease. Sixty-four (40%) patients had elevated LVEDP (≥15 mmHg). Taken individually, all echocardiographic Doppler estimates of LVFP (E/A, E/e', left atrial volume, tricuspid regurgitation jet velocity) were marginally correlated with LVEDP. By using the 2016 recommendations, 65% of patients with normal non-invasive estimate of LVFP had normal LVEDP, while 79% of those with elevated non-invasive LVFP had elevated invasive LVEDP. By using 2009 recommendations, 68% of the patients with normal non-invasive LVFP had normal LVEDP, while 55% of those with elevated non-invasive LVFP had elevated LVEDP. The 2016 recommendations (sensitivity 75%, specificity 74%, positive predictive value 39%, negative predictive value 93%, AUC 0.78) identified slightly better patients with elevated invasive LVEDP (≥ 15 mmHg) as compared with the 2009 recommendations (sensitivity 43%, specificity 75%, positive predictive value 49%, negative predictive value 71%, AUC 0.68). Conclusion The present Euro-Filling study demonstrates that the new 2016 recommendations for assessing LVFP non-invasively are fairly reliable and clinically useful, as well as superior to the 2009 recommendations in estimating invasive LVEDP.

Elemental properties, hydrology, and biology interact to shape concentration-discharge curves for carbon, nutrients, sediment, and major ions

Abstract: To investigate the prevalence and cause of concentration-discharge (C-Q) relationships for carbon, nutrients, major ions, and particulates, we analyzed 40 years of water quality data from 293 monitoring stations in France. Catchments drained diverse landscapes and ranged from 50 to 110,000 km2, together covering nearly half of France. To test for differences during low and high flows, we calculated independent C-Q slopes above and below the median discharge. We found that 84% of all catchment-element combinations were chemodynamic for at least half of the hydrograph and 60% of combinations showed non-linear C-Q curves. Only two or three of the nine possible C-Q modalities were manifest for each parameter, and these modalities were stable through time, suggesting that intrinsic and extrinsic elemental properties (e.g. solubility, reactivity, and source dynamics) set basic C-Q templates for each parameter, which are secondarily influenced by biological activity during low flows, and the interaction between hydrology and catchment characteristics at high flows. Several patterns challenged current C-Q views, including low-flow chemostasis for TSS in 66% of catchments, low-flow biological mediation of NO3- in 71% of catchments, and positive C-Q for dissolved organic carbon independent of catchment size in 80% of catchments. Efforts to reduce nutrient loading decreased phosphorus concentration and altered C-Q curves, but NO3- continued to increase. While C-Q segmentation requires more data than a single analysis, the prevalence of non-linear C-Q slopes demonstrates the potential information loss associated with linear or monotonic analysis of C-Q relationships, and conversely, the value of long-term monitoring. This article is protected by copyright. All rights reserved.

Model Evaluation of Continuous Data Pharmacometric Models: Metrics and Graphics.

Abstract: This article represents the first in a series of tutorials on model evaluation in nonlinear mixed effect models (NLMEMs), from the International Society of Pharmacometrics (ISoP) Model Evaluation Group. Numerous tools are available for evaluation of NLMEM, with a particular emphasis on visual assessment. This first basic tutorial focuses on presenting graphical evaluation tools of NLMEM for continuous data. It illustrates graphs for correct or misspecified models, discusses their pros and cons, and recalls the definition of metrics used.