In vivo "real-time" monitoring of glucose in the brain with an amperometric enzyme-based biosensor based on gold coated tungsten (W-Au) microelectrodes

Biosensors based on Pt or Pt/Ir based needle-type microelectrodes have been successfully employed for continuous in vivo real-time brain biomonitoring of biomarkers such as glutamate and glucose. However, when implanted, these biosensors often bend, thereby damaging its surface and degrading its bioanalytical properties. In addition, downscaling of Pt and Pt/Ir needle-type biosensors, to improve the spatial resolution and decrease tissue damage, is technically challenging. In that sense, we investigated whether the use of a material with low malleability, tungsten (W), coated with a highly conductive material, gold (Au) could be as an alternative for conventional needle-type based biosensors. Therefore, we developed implantable needle-type (50 tim 0) gold coated tungsten (W-Au) amperometric microbiosensors. First, we evaluated electrochemically, the ability of W-Au microelectrodes (50 tim 0) to continuously monitor changes in H2O2. After, we functionalized, using a layer-by-layer assembly, the surface of W-Au microelectrodes. First with permselective membrane(s) (Nafion and Nafion-PPD) and after with an enzymatic hydrogel, containing an enzyme selective for glucose (glucose oxidase). Both the enzyme loading and the applied potential were optimized and the performance of functionalized W-Au microelectrodes and fully assembled biosensors was evaluated electrochemically. Additionally, the surface of bare and functionalized microelectrodes was also characterized by imaging techniques (scanning electron microscopy). In vivo experiments revealed that, W-Au based glucose biosensors, were able to accurately monitor, in real-time, changes in brain glucose in response to relevant pharmacological challenges. (C) 2018 Elsevier B.V. All rights reserved

U.S. IOOS coastal and ocean modeling testbed: Evaluation of tide, wave, and hurricane surge response sensitivities to mesh resolution and friction in the Gulf of Mexico: IOOS TESTBED-RESOLUTION AND FRICTION

This paper investigates model response sensitivities to mesh resolution, topographical details, bottom friction formulations, the interaction of wind waves and circulation, and nonlinear advection on tidal and hurricane surge and wave processes at the basin, shelf, wetland, and coastal channel scales within the Gulf of Mexico. Tides in the Gulf of Mexico are modestly energetic processes, whereas hurricane surge and waves are highly energetic. The unstructured-mesh, coupled wind-wave and circulation modeling system, SWAN+ ADCIRC, is implemented to generate modeled tidal harmonic constituents and hurricane waves and surge for a Hurricane Ike (2008) hindcast. In the open ocean, mesh resolution requirements are less stringent in achieving accurate tidal signals or matching hurricane surge and wave responses; however, coarser resolution or the absence of intertidal zones decreases accuracy along protected nearshore and inland coastal areas due to improper conveyance and/or lateral attenuation. Bottom friction formulations are shown to have little impact on tidal signal accuracy, but hurricane surge is much more sensitive, especially in shelf waters, where development of a strong shore-parallel current is essential to the development of Ike's geostrophic setup. The spatial and temporal contributions of wave radiation stress gradients and nonlinear advection were charted for Ike. Nonlinear advection improves model performance by capturing an additional 10―20 cm of geostrophic setup and increasing resonant cross-shelf waves by 30―40 cm. Wave radiation stress gradients improve performance at coastal stations by adding an extra 20―40 cm to water levels

Hindcast and validation of Hurricane Ike (2008) waves, forerunner, and storm surge: HINDCAST AND VALIDATION OF HURRICANE IKE

[1] Hurricane Ike (2008) made landfall near Galveston, Texas, as a moderate intensity storm. Its large wind field in conjunction with the Louisiana‐Texas coastline's broad shelf and large scale concave geometry generated waves and surge that impacted over 1000 km of coastline. Ike's complex and varied wave and surge response physics included: the capture of surge by the protruding Mississippi River Delta; the strong influence of wave radiation stress gradients on the Delta adjacent to the shelf break; the development of strong wind driven shore‐parallel currents and the associated geostrophic setup; the forced early rise of water in coastal bays and lakes facilitating inland surge penetration; the propagation of a free wave along the southern Texas shelf; shore‐normal peak wind‐driven surge; and resonant and reflected long waves across a wide continental shelf. Preexisting and rapidly deployed instrumentation provided the most comprehensive hurricane response data of any previous hurricane. More than 94 wave parameter time histories, 523 water level time histories, and 206 high water marks were collected throughout the Gulf in deep water, along the nearshore, and up to 65 km inland. Ike's highly varied physics were simulated using SWAN + ADCIRC, a tightly coupled wave and circulation model, on SL18TX33, a new unstructured mesh of the Gulf of Mexico, Caribbean Sea, and western Atlantic Ocean with high resolution of the Gulf's coastal floodplain from Alabama to the Texas‐Mexico border. A comprehensive validation was made of the model's ability to capture the varied physics in the system

Hurricane Gustav (2008) Waves and Storm Surge: Hindcast, Synoptic Analysis, and Validation in Southern Louisiana

Hurricane Gustav (2008) made landfall in southern Louisiana on 1 September 2008 with its eye never closer than 75 km to New Orleans, but its waves and storm surge threatened to flood the city. Easterly tropical-storm-strength winds impacted the region east of the Mississippi River for 12-15 h, allowing for early surge to develop up to 3.5 m there and enter the river and the city's navigation canals. During landfall, winds shifted from easterly to southerly, resulting in late surge development and propagation over more than 70 km of marshes on the river's west bank, over more than 40 km of Caernarvon marsh on the east bank, and into Lake Pontchartrain to the north. Wind waves with estimated significant heights of 15 m developed in the deep Gulf of Mexico but were reduced in size once they reached the continental shelf. The barrier islands further dissipated the waves, and locally generated seas existed behind these effective breaking zones. The hardening and innovative deployment of gauges since Hurricane Katrina (2005) resulted in a wealth of measured data for Gustav. A total of 39 wind wave time histories, 362 water level time histories, and 82 high water marks were available to describe the event. Computational models-including a structured-mesh deepwater wave model (WAM) and a nearshore steady-state wave (STWAVE) model, as well as an unstructured-mesh "simulating waves nearshore'' (SWAN) wave model and an advanced circulation (ADCIRC) model-resolve the region with unprecedented levels of detail, with an unstructured mesh spacing of 100-200 m in the wave-breaking zones and 20-50 m in the small-scale channels. Data-assimilated winds were applied using NOAA's Hurricane Research Division Wind Analysis System (H*Wind) and Interactive Objective Kinematic Analysis (IOKA) procedures. Wave and surge computations from these models are validated comprehensively at the measurement locations ranging from the deep Gulf of Mexico and along the coast to the rivers and floodplains of southern Louisiana and are described and quantified within the context of the evolution of the storm

U.S. IOOS coastal and ocean modeling testbed : inter-model evaluation of tides, waves, and hurricane surge in the Gulf of Mexico

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Journal of Geophysical Research: Oceans 118 (2013): 5129–5172, doi:10.1002/jgrc.20376.A Gulf of Mexico performance evaluation and comparison of coastal circulation and wave models was executed through harmonic analyses of tidal simulations, hindcasts of Hurricane Ike (2008) and Rita (2005), and a benchmarking study. Three unstructured coastal circulation models (ADCIRC, FVCOM, and SELFE) validated with similar skill on a new common Gulf scale mesh (ULLR) with identical frictional parameterization and forcing for the tidal validation and hurricane hindcasts. Coupled circulation and wave models, SWAN+ADCIRC and WWMII+SELFE, along with FVCOM loosely coupled with SWAN, also validated with similar skill. NOAA's official operational forecast storm surge model (SLOSH) was implemented on local and Gulf scale meshes with the same wind stress and pressure forcing used by the unstructured models for hindcasts of Ike and Rita. SLOSH's local meshes failed to capture regional processes such as Ike's forerunner and the results from the Gulf scale mesh further suggest shortcomings may be due to a combination of poor mesh resolution, missing internal physics such as tides and nonlinear advection, and SLOSH's internal frictional parameterization. In addition, these models were benchmarked to assess and compare execution speed and scalability for a prototypical operational simulation. It was apparent that a higher number of computational cores are needed for the unstructured models to meet similar operational implementation requirements to SLOSH, and that some of them could benefit from improved parallelization and faster execution speed.This project was supported by NOAA via the U.S. IOOS Office (award: NA10NOS0120063 and NA11NOS0120141

Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins

In the pharmaceutical industry, improving the early detection of drug-induced hepatotoxicity is essential as it is one of the most important reasons for attrition of candidate drugs during the later stages of drug development. The first objective of this study was to better characterize different cellular models (i.e., HepG2, HepaRG cells, and fresh primary human hepatocytes) at the gene expression level and analyze their metabolic cytochrome P450 capabilities. The cellular models were exposed to three different CYP450 inducers; beta-naphthoflavone (BNF), phenobarbital (PB), and rifampicin (RIF). HepG2 cells responded very weakly to the different inducers at the gene expression level, and this translated generally into low CYP450 activities in the induced cells compared with the control cells. On the contrary, HepaRG cells and the three human donors were inducible after exposure to BNF, PB, and RIF according to gene expression responses and CYP450 activities. Consequently, HepaRG cells could be used in screening as a substitute and/or in complement to primary hepatocytes for CYP induction studies. The second objective was to investigate the predictivity of the different cellular models to detect hepatotoxins (16 hepatotoxic and 5 nonhepatotoxic compounds). Specificity was 100% with the different cellular models tested. Cryopreserved human hepatocytes gave the highest sensitivity, ranging from 31% to 44% (depending on the donor), followed by lower sensitivity (13%) for HepaRG and HepG2 cells (6.3%). Overall, none of the models under study gave desirable sensitivities (80–100%). Consequently, a high metabolic capacity and CYP inducibility in cell lines does not necessarily correlate with a high sensitivity for the detection of hepatotoxic drugs. Further investigations are necessary to compare different cellular models and determine those that are best suited for the detection of hepatotoxic compounds

Affective Man-Machine Interface: Unveiling human emotions through biosignals

As is known for centuries, humans exhibit an electrical profile. This profile is altered through various psychological and physiological processes, which can be measured through biosignals; e.g., electromyography (EMG) and electrodermal activity (EDA). These biosignals can reveal our emotions and, as such, can serve as an advanced man-machine interface (MMI) for empathic consumer products. However, such a MMI requires the correct classification of biosignals to emotion classes. This chapter starts with an introduction on biosignals for emotion detection. Next, a state-of-the-art review is presented on automatic emotion classification. Moreover, guidelines are presented for affective MMI. Subsequently, a research is presented that explores the use of EDA and three facial EMG signals to determine neutral, positive, negative, and mixed emotions, using recordings of 21 people. A range of techniques is tested, which resulted in a generic framework for automated emotion classification with up to 61.31% correct classification of the four emotion classes, without the need of personal profiles. Among various other directives for future research, the results emphasize the need for parallel processing of multiple biosignals

The Impact of a Standardized Pre-visit Laboratory Testing Panel in the Internal Medicine Outpatient Clinic: a Controlled “On-Off” Trial

Background: In several settings, a shorter time to diagnosis has been shown to lead to improved clinical outcomes. The implementation of a rapid laboratory testing allows for a pre-visit testing in the outpatient clinic, meaning that test results are available during the first outpatient visit. Objective: To determine whether the pre-visit laboratory testing leads to a shorter time to diagnosis in the general internal medicine outpatient clinic. Design: An “on-off” trial, allocating subjects to one of two treatment arms in consecutive alternating blocks. Participants: All new referrals to the internal medicine outpatient clinic of a university hospital were included, excluding second opinions. A total of 595 patients were eligible; one person declined to participate, leaving data from 594 patients for analysis. Intervention: In the intervention group, patients had a standardized pre-visit laboratory testing before the first visit. Main Measures: The primary outcome was the time to diagnosis. Secondary outcomes were the correctness of the preliminary diagnosis on the first day, health care utilization, and patient and physician satisfaction. Key Results: There was no difference in time to diagnosis between the two groups (median 35 days vs 35 days; hazard ratio 1.03 [0.87–1.22]; p =.71). The pre-visit testing group had higher proportions of both correct preliminary diagnoses on day 1 (24% vs 14%; p =.003) and diagnostic workups being completed on day 1 (10% vs 3%; p <.001). The intervention group had more laboratory tests done (50.0 [interquartile range (IQR) 39.0–69.0] vs 43.0 [IQR 31.0–68.5]; p <.001). Otherwise, there were no differences between the groups. Conclusions: Pre-visit testing did not lead to a shorter overall time to diagnosis. However, a greater proportion of patients had a correct diagnosis on the first day. Further studies should focus on customizing pre-visit laboratory panels, to improve their efficacy. Trial Registration: NL500

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Report from the EPAA workshop: In vitro ADME in safety testing used by EPAA industry sectors

AbstractThere are now numerous in vitro and in silico ADME alternatives to in vivo assays but how do different industries incorporate them into their decision tree approaches for risk assessment, bearing in mind that the chemicals tested are intended for widely varying purposes? The extent of the use of animal tests is mainly driven by regulations or by the lack of a suitable in vitro model. Therefore, what considerations are needed for alternative models and how can they be improved so that they can be used as part of the risk assessment process? To address these issues, the European Partnership for Alternative Approaches to Animal Testing (EPAA) working group on prioritisation, promotion and implementation of the 3Rs research held a workshop in November, 2008 in Duesseldorf, Germany. Participants included different industry sectors such as pharmaceuticals, cosmetics, industrial- and agro-chemicals. This report describes the outcome of the discussions and recommendations (a) to reduce the number of animals used for determining the ADME properties of chemicals and (b) for considerations and actions regarding in vitro and in silico assays. These included: standardisation and promotion of in vitro assays so that they may become accepted by regulators; increased availability of industry in vivo kinetic data for a central database to increase the power of in silico predictions; expansion of the applicability domains of in vitro and in silico tools (which are not necessarily more applicable or even exclusive to one particular sector) and continued collaborations between regulators, academia and industry. A recommended immediate course of action was to establish an expert panel of users, developers and regulators to define the testing scope of models for different chemical classes. It was agreed by all participants that improvement and harmonization of alternative approaches is needed for all sectors and this will most effectively be achieved by stakeholders from different sectors sharing data