More information would be required for a better understanding of the actual circumstances of serotonin syndrome (SS) occurrence in routine clinical practice.
The objective of the study was to analyze ...characteristics of SS French pharmacovigilance reports, especially involved drugs and nature of drug-drug interactions (DDIs).
We performed a retrospective analysis of SS registered in the French pharmacovigilance database between January 1, 1985 and May 27, 2013. Only cases whose clinical symptoms fulfilled Sternbach, Radomski, or Hunter SS diagnostic criteria were retained for the analysis.
Most of the 125 (84.0%) analyzed cases were associated with a recent change in a serotonergic drug (introduction, increasing the dose or overdose). Antidepressants were the most often involved serotonergic drugs, mostly serotonin reuptake inhibitors (SRIs, 42.1%) and to a lesser extent serotonin-noradrenalin reuptake inhibitors (9.1%, mainly venlafaxine), tricyclic antidepressants (8.6%, mainly clomipramine), and some monoamine oxidase inhibitors (6.2%, mainly moclobemide). Nonpsychotropic medications were also involved, generally opioids (14.8%, mainly tramadol). Most of the cases (59.2%) resulted from pharmacodynamic DDIs, most often involving SRIs + opioids (mostly paroxetine + tramadol). However, SS also occurred with a single serotonergic drug in a significant number of cases (40.8%), most often SRIs (mainly fluoxetine) or venlafaxine at usual doses. Lastly, a major pharmacokinetic DDI could have played a role in 1/5 (20.8%) of cases.
This is the first study about SS based on a large pharmacovigilance database and published in English. Our results reveal not only the frequent involvement of antidepressants and tramadol, the importance of DDIs (both pharmacodynamic and pharmacokinetic), but also the significant risk of SS even with a single serotonergic drug used at normal dose.
This work presents an original numerical model for a free surface flow interacting with a spring-block system. The formulation is based on the fictitious domain approach and a penalty method on ...viscosity to describe the rigid solid motion. The incompressible Navier-Stokes equations are solved in the whole domain and the free surface and the body contour are captured using a volume of fluid method. To describe the rigid body motion, a single degree of freedom model, able to represent translation or rotation, is embedded in the code. The discrete equations are written in a well-known finite volume framework over Cartesian grids. In such a context, the external spring and damping forces are represented as body forces in the solid region. The proposed strategy is tested in a sloshing damping system. The numerical results are compared with experimental data obtained within the present study. Finally, the method is used to simulate a wave energy converter system as an illustration of a rotational case.
The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity ...studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.
The reconstruction of geographic and demographic scenarios of dissemination for invasive pathogens of crops is a key step toward improving the management of emerging infectious diseases. Nowadays, ...the reconstruction of biological invasions typically uses the information of both genetic and historical information to test for different hypotheses of colonization. The Approximate Bayesian Computation framework and its recent Random Forest development (ABC‐RF) have been successfully used in evolutionary biology to decipher multiple histories of biological invasions. Yet, for some organisms, typically plant pathogens, historical data may not be reliable notably because of the difficulty to identify the organism and the delay between the introduction and the first mention. We investigated the history of the invasion of Africa by the fungal pathogen of banana Pseudocercospora fijiensis, by testing the historical hypothesis against other plausible hypotheses. We analyzed the genetic structure of eight populations from six eastern and western African countries, using 20 microsatellite markers and tested competing scenarios of population foundation using the ABC‐RF methodology. We do find evidence for an invasion front consistent with the historical hypothesis, but also for the existence of another front never mentioned in historical records. We question the historical introduction point of the disease on the continent. Crucially, our results illustrate that even if ABC‐RF inferences may sometimes fail to infer a single, well‐supported scenario of invasion, they can be helpful in rejecting unlikely scenarios, which can prove much useful to shed light on disease dissemination routes.
In this study, we illustrate that, in some cases, accepting not to use available historical data can be a fruitful way of reconsidering invasion processes using the model of the worldwide emergence of the fungal banana pathogen Pseudocercospora finjiensis. Using an ABC‐RF approach, we investigated the history of the invasion of Africa by P. fijiensis by testing the historical hypothesis against other plausible hypotheses. We do find evidence for an invasion front consistent with the historical hypothesis, but also for the existence of another front never mentioned in historical records and question the historical introduction point of the disease on the continent.
In this paper, the potential of a super-resolution technique is presented in the context of coastal wave forecasting. The method uses a neural network to predict a high-resolution spatial estimation ...of spectral wave parameters from a lower resolution numerical computation. In this particular example, one year of training data is sufficient to achieve satisfying accuracy for practical applications. The error of this method in reproducing the results of a high-resolution spectral model is an order of magnitude lower than the usual accuracy of spectral models. Simultaneously, it reduces the computation time by a factor of up to 50. Moreover, utilizing complementary training data of extreme events allows for a further improvement in accuracy. The study also shows that super-resolution is more accurate, albeit slower, than surrogate models, thus providing a trade-off solution between accuracy and speed. Overall, incorporation of the present approach into wave forecasting systems has the potential to rapidly generate “zoomed-in” areas of interest or to speed up ensemble forecasts without supplementary calculations at higher resolution.
Summary
Background
Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification.
Objectives
To describe ...the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype–genotype correlations.
Methods
We performed a 4‐year, large, prospective, multicentric, collaborative dermatological and genetic study.
Results
Forty‐five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype–genotype correlation was determined.
Conclusions
A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.
What's already known about this topic?
Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological input.
Dermatological findings remain essential to diagnose CFCS and to differentiate it from other RASopathies that it resembles phenotypically, specifically Noonan syndrome (NS) and Costello syndrome (CS).
What does this study add?
Scarcity or absence of eyebrows, association of ulerythema ophryogenes and palmoplantar keratoderma, diffuse keratosis pilaris and multiple melanocytic naevi appeared pertinent manifestations in assisting the positive diagnosis of CFCS and differentiating it from CS and NS.
Oral acitretin could be highly beneficial for therapeutic management of PPHK.
No significant dermatological phenotype–genotype correlation in the presence or absence of BRAF mutation could be determined.
Linked Comment: Moss. Br J Dermatol 2019; 180:21.
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•ITER data model design and implementation.•Experiment data archiving design.•Experimental data archiving over HDF5 files.
ITER’s CODAC archiving system currently manages three different sets of ...data: DAN, SDN and PON, that correspond with the three networks: Data Archiving Network, Synchronous Data Network, and Plan Operational Network. In this sense, ITER’s CODAC data archiving system has been implemented to manage a wide variety of complex types of data and to support multidimensionality, dynamic resolution, metadata embedded types with header and footer sections, or user defined composition of types. This work describes ITER archiving data model, how it is able to fulfill ITER data requirements and keys of its implementation.
The sustained growth of the offshore wind sector is leading to the construction of offshore wind farms in highly seismic regions of the world. Hence, a large proportion of the potential sites may be ...exposed to liquefaction risk. Monopiles are directly affected by this phenomenon given their preference as a support system for offshore wind turbines over other foundation types. This paper includes a comprehensive study of the lateral response of monopiles against the combined action of earthquake induced liquefaction and environmental loading using centrifuge modelling. The experimental setup was designed to compare the amount of excess pore pressure generated within the soil adjacent to the monopile with and without operational wind/wave loading. The results revealed higher accumulation of excess pore pressure in the non-laterally loaded case, and significant differences in the amount of excess pore pressure recorded in the windward and leeward sides of the monopile in the laterally loaded scenario. In addition, the study provides data on the rotation experienced by monopile supported offshore wind turbines in liquefiable soils.
Lipid amidases of therapeutic relevance include acid ceramidase (AC), N-acylethanolamine-hydrolyzing acid amidase, and fatty acid amide hydrolase (FAAH). Although fluorogenic substrates have been ...developed for the three enzymes and high-throughput methods for screening have been reported, a platform for the specific detection of these enzyme activities in intact cells is lacking. In this article, we report on the coumarinic 1-deoxydihydroceramide RBM1-151, a 1-deoxy derivative and vinilog of RBM14-C12, as a novel substrate of amidases. This compound is hydrolyzed by AC (appKm = 7.0 μM; appVmax = 99.3 nM/min), N-acylethanolamine-hydrolyzing acid amidase (appKm = 0.73 μM; appVmax = 0.24 nM/min), and FAAH (appKm = 3.6 μM; appVmax = 7.6 nM/min) but not by other ceramidases. We provide proof of concept that the use of RBM1-151 in combination with reported irreversible inhibitors of AC and FAAH allows the determination in parallel of the three amidase activities in single experiments in intact cells.
Glutamate (Glu) is the cornerstone of nitrogen assimilation and photorespiration in illuminated leaves. Despite this crucial role, our knowledge of the flux to Glu de novo synthesis is rather ...limited. Here, we used isotopic labelling with (CO2)-C-13 and C-13-NMR analyses to examine the labelling pattern and the appearance of multi-labelled species of Glu molecules to trace the origin of C-atoms found in Glu. We also compared this with C-13-labelling patterns in Ala and Asp, which reflect citrate (and thus Glu) precursors, that is, pyruvate and oxaloacetate. Glu appeared to be less C-13-labelled than Asp and Ala, showing that the Glu pool was mostly formed by 'old' carbon atoms. There were modest differences in intramolecular C-13-C-13 couplings between Glu C-2 and Asp C-3, showing that oxaloacetate metabolism to Glu biosynthesis did not involve C-atom redistribution by the Krebs cycle. The apparent carbon allocation increased with carbon net photosynthesis. However, when expressed relative to CO2 fixation, it was clearly higher at low CO2 while it did not change in 2% O-2, as compared to standard conditions. We conclude that Glu production from current photosynthetic carbon represents a small flux that is controlled by the gaseous environment, typically upregulated at low CO2.
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