scholarly journals Informing Pharmacokinetic Models With Physiological Data: Oral Population Modeling of L-Serine in Humans

2021 ◽  
Vol 12 ◽  
Author(s):  
J. R. Bosley ◽  
Elias Björnson ◽  
Cheng Zhang ◽  
Hasan Turkez ◽  
Jens Nielsen ◽  
...  
Keyword(s):  
Central Compartment ◽  
Bound State ◽  
Physiological Data ◽  
Model Structure ◽  
Design Component ◽  
Human Dose ◽  
Improve Model ◽  
Prediction Confidence ◽  
Oral Agents ◽  
Set Up

To determine how to set optimal oral L-serine (serine) dose levels for a clinical trial, existing literature was surveyed. Data sufficient to set the dose was inadequate, and so an (n = 10) phase I-A calibration trial was performed, administering serine with and without other oral agents. We analyzed the trial and the literature data using pharmacokinetic (PK) modeling and statistical analysis. The therapeutic goal is to modulate specific serine-related metabolic pathways in the liver using the lowest possible dose which gives the desired effect since the upper bound was expected to be limited by toxicity. A standard PK approach, in which a common model structure was selected using a fit to data, yielded a model with a single central compartment corresponding to plasma, clearance from that compartment, and an endogenous source of serine. To improve conditioning, a parametric structure was changed to estimate ratios (bioavailability over volume, for example). Model fit quality was improved and the uncertainty in estimated parameters was reduced. Because of the particular interest in the fate of serine, the model was used to estimate whether serine is consumed in the gut, absorbed by the liver, or entered the blood in either a free state, or in a protein- or tissue-bound state that is not measured by our assay. The PK model structure was set up to represent relevant physiology, and this quantitative systems biology approach allowed a broader set of physiological data to be used to narrow parameter and prediction confidence intervals, and to better understand the biological meaning of the data. The model results allowed us to determine the optimal human dose for future trials, including a trial design component including IV and tracer studies. A key contribution is that we were able to use human physiological data from the literature to inform the PK model and to set reasonable bounds on parameters, and to improve model conditioning. Leveraging literature data produced a more predictive, useful model.

scholarly journals Informing Pharmacokinetic Models with Physiological Data: Oral Population Modeling of L-Serine in Humans

2019 ◽  
Author(s):  
J. R. Bosley ◽  
Elias Björnson ◽  
Cheng Zhang ◽  
Hasan Turkez ◽  
Jens Nielsen ◽  
...  
Keyword(s):  
Relevant Literature ◽  
Central Compartment ◽  
Bound State ◽  
Volume Of Distribution ◽  
Physiological Data ◽  
Model Structure ◽  
Design Component ◽  
Base Level ◽  
Human Dose ◽  
Oral Agents

AbstractTo determine how to set optimal oral L-serine (serine) dose levels for a clinical trial, existing literature was surveyed. Data sufficient to set the dose was inadequate, and so a (n=10) Phase I-A calibration trial was performed, administering serine with and without other oral agents. We analyzed the trial and the literature data using pharmacokinetic (PK) modeling and statistical analysis. The therapeutic goal is to modulate specific serine-related metabolic pathways in the liver using the lowest possible dose which gives the desired effect since the upper bound was expected to be limited by toxicity. In this paper, we first review relevant literature, describe the calibration trial and resulting data, and present the results of modeling from the trial. Serine is a non-essential amino acid that is nonetheless present at a base level in blood from both dietary sources and endogenous production. Serine is consumed by several pathways. A standard PK approach, in which a common model structure was selected using a fit to data, yielded a model with a single central compartment corresponding to plasma, clearance from that compartment, and an endogenous source of serine. The lack of intravenous data normally prevents independent determination of bioavailability and volume of distribution, however, under some assumptions about endogenous synthesis and use, values could be estimated. The model was poorly conditioned but did give consistent estimates. To improve conditioning, a parametric structure was changed to estimate ratios (bioavailability over volume, for example). Model fit quality was improved and the uncertainty in estimated parameters was reduced. Because of the particular interest in the fate of serine, the model was used to estimate whether serine is consumed in the gut, absorbed by the liver, or entered the blood in either a free state, or in a protein- or tissue-bound state that is not measured by our assay. The PK model structure was set up to represent relevant physiology, and this quantitative systems biology approach allowed a broader set of physiological data to be used to narrow parameter and prediction confidence intervals, and to better understand the biological meaning of the data. The model results allowed us to determine the optimal human dose for future trials, including a trial design component including IV and tracer studies. A key contribution is that we were able to use human physiological data from the literature to inform the PK model and to set reasonable bounds on parameters, and to improve model conditioning. Leveraging literature data produced a more predictive, useful model.

scholarly journals Spatio-Temporal Hydrological Model Structure and Parametrization Analysis

2021 ◽  
Vol 9 (5) ◽  
pp. 467
Author(s):  
Mostafa Farrag ◽  
Gerald Corzo Perez ◽  
Dimitri Solomatine
Keyword(s):  
Hydrological Modeling ◽  
Model Building ◽  
Model Performance ◽  
Model Description ◽  
Generation Model ◽  
Model Structure ◽  
Runoff Generation ◽  
Spatial Sensitivity ◽  
Spatio Temporal ◽  
Set Up

Many grid-based spatial hydrological models suffer from the complexity of setting up a coherent spatial structure to calibrate such a complex, highly parameterized system. There are essential aspects of model-building to be taken into account: spatial resolution, the routing equation limitations, and calibration of spatial parameters, and their influence on modeling results, all are decisions that are often made without adequate analysis. In this research, an experimental analysis of grid discretization level, an analysis of processes integration, and the routing concepts are analyzed. The HBV-96 model is set up for each cell, and later on, cells are integrated into an interlinked modeling system (Hapi). The Jiboa River Basin in El Salvador is used as a case study. The first concept tested is the model structure temporal responses, which are highly linked to the runoff dynamics. By changing the runoff generation model description, we explore the responses to events. Two routing models are considered: Muskingum, which routes the runoff from each cell following the river network, and Maxbas, which routes the runoff directly to the outlet. The second concept is the spatial representation, where the model is built and tested for different spatial resolutions (500 m, 1 km, 2 km, and 4 km). The results show that the spatial sensitivity of the resolution is highly linked to the routing method, and it was found that routing sensitivity influenced the model performance more than the spatial discretization, and allowing for coarser discretization makes the model simpler and computationally faster. Slight performance improvement is gained by using different parameters’ values for each cell. It was found that the 2 km cell size corresponds to the least model error values. The proposed hydrological modeling codes have been published as open-source.

scholarly journals A Smart Contract-based Access Control Architecture for Telemedicine During Covid-19

2021 ◽  
Author(s):  
hideyat zerga ◽  
Asma AMRAOUI ◽  
badr BENMAMMAR
Keyword(s):  
Access Control ◽  
Fog Computing ◽  
Physiological Data ◽  
Public Health Issue ◽  
Global Public Health ◽  
Distributed Services ◽  
Patient Health ◽  
Set Up ◽  
Fundamental Requirement ◽  
Do So

Abstract In the fight against the COVID-19 epidemic that is currently a major global public health issue, social distancing has been imposed to prevent the massive transmission, thus doctors in hospitals have turned to telemedicine in order to be able to monitor their patient notably those suffering from chronic diseases. To do so, patients need to share their physiological data with doctors. In order to share this data safely, prevent malicious users from tampering with it and protect the privacy of patients, access control becomes a fundamental requirement. In order to set up a real-time (Internet of Thing) IoT enabled healthcare system (HS) scenario like telemedicine, Fog computing (FC) seems to be the best solution comparing to Cloud computing since it provides low latency, highly mobile and geo-distributed services and temporary storage. In this paper, the focus is on access control in the telemedicine systems. Our proposal is based, on one hand, the concept of Fog computing to ensure the distributed aspect needed in the monitoring of patient health remotely; and on the other hand Blockchain (BC) smart contracts, in order to provide a dynamic, optimized and self-adjusted access control.

scholarly journals Reproducing an extreme flood with uncertain post-event information

2016 ◽  
Author(s):  
Diana Fuentes-Andino ◽  
Keith Beven ◽  
Sven Halldin ◽  
Chong-Yu Xu ◽  
José-Eduardo Reynolds ◽  
...  
Keyword(s):  
Large Data ◽  
High Water ◽  
Rain Gauge ◽  
Estimation Methods ◽  
Event Data ◽  
Model Combination ◽  
Improve Model ◽  
Extreme Flood ◽  
The Times ◽  
Set Up

Abstract. Prevention and mitigation of floods require information on discharge and extent of inundation, commonly unavailable or uncertain, especially during extreme events. This study was initiated by the devastating flood in Tegucigalpa when Hurricane Mitch struck the city. In this study we hypothesised that it is possible to estimate, in a trustworthy way despite large data uncertainties, this extreme 1998 flood discharge and the extent of the inundations that followed, from a combination of models and post–event measured data. Post–event data collected in 2000 and 2001 were used to estimate discharge peaks, times of peaks and high water marks. These data were used in combination with rain data from two gauges to drive and constrain a combination of well–known models: TOPMODEL, Muskingum–Cunge–Todini routing, and the LISFLOOD–FP hydraulic model. Simulations were performed within the GLUE uncertainty–analysis framework. The model combination predicted peak discharge, times of peaks and more than 90 % of the observed high–water marks within the uncertainty bounds of the evaluation data. This allowed an inundation likelihood map to be produced. Observed high–water marks could not be reproduced at a few locations on the floodplain. These locations are useful to improve model set–up, model structure or post–event data–estimation methods. Rainfall data were of central importance in simulating the times of peak and results would be improved by a better spatial assessment of rainfall, e.g. from satellite data or a denser rain–gauge network. Our study demonstrated that it was possible, considering the uncertainty in the post–event data, to reasonable reproduce the extreme Mitch flood in Tegucigalpa in spite of no hydrometric gauging during the event.

Modelling nitrogen transformations in surface flow wastewater treatment wetlands in Sweden

2001 ◽  
Vol 44 (11-12) ◽  
pp. 237-244 ◽  
Author(s):  
S. Kallner ◽  
H.B. Wittgren
Keyword(s):  
Wastewater Treatment ◽  
Model Performance ◽  
Surface Flow ◽  
Data Availability ◽  
Treatment Wetlands ◽  
Rate Coefficients ◽  
Rate Equations ◽  
Nitrogen Transformations ◽  
Improve Model ◽  
Set Up

The purpose of this study was to describe and compare the fate of nitrogen (N) in two Swedish wastewater treatment wetlands in the cities of Oxelösund and Hässleholm. Specifically, we wanted to see if a fairly simple model, developed with regard to common data availability, could satisfactorily describe the concentration dynamics at the outlet from the wetlands. A first-order area-based model, with two alternative expressions for temperature dependence, was set up to describe three major processes: ammonification, nitrification and denitrification. The N concentration dynamics at the outlet of the Oxelösund wetland was not satisfactorily described, R2(NH4+-N)=0.33 and R2(NO3--N)=0.10, while the modelled concentrations corresponded quite well with measured concentrations in the Hässleholm wetland, R2(NH4+-N)=0.83 and R2(NO3--N)=0.58. The NO3--N concentrations, in both wetlands, could be slightly better described when introducing a temperature coefficient as an additional free parameter. The explained variances reported above were achieved when the model was calibrated individually for the two wetlands, when the resulting (optimised) reaction rate coefficients for each of the three processes were quite different between the two wetlands. To improve model performance, the rate equations may have to be changed to include factors in addition to concentration and temperature, such as dissolved oxygen and hydraulic efficiency. It may also be important to include other processes, such as plant uptake/decay and ammonia volatilisation.

Design and construction of a three-span continuous box girder model

2021 ◽  
Author(s):  
Ao Wang ◽  
Xudong Jian ◽  
Ye Xia ◽  
Yafei Wang ◽  
Guoqiang Jing ◽  
...  
Keyword(s):  
Basic Structure ◽  
Scale Model ◽  
Model Structure ◽  
Model Design ◽  
Element Analysis ◽  
Box Girder ◽  
Static And Dynamic Characteristics ◽  
Girder Bridge ◽  
Set Up ◽  
Physical Quantities

<p>Scale model experiments have been widely used in short- and medium-span bridge research, including B- WIM technology and vehicle-bridge interaction mechanisms and applications. A high simulative scale model can be used to verify the relevant theories and technologies effectively. In this paper, a 1:20 scale model has been set up according to a 3×20m three-span continuous box girder bridge prototype. The physical quantities of the scale model have been derived by similitude law to guide the model design. Appropriate materials, such as PMMA and lead blocks, have been adopted to form the basic structure, whose arrangements are detailed. Finite element analysis (FEA) is applied to calculate and compare the static and dynamic characteristics between real bridge and model structure. One experiment case of a B-WIM test integrating influence surface and computer vision has been carried out to illustrate the model's validity. The constructed model can be a useful platform for future researches and provide a reference for practitioners.</p><p><br clear="none"/></p>

Investigating the Use of Smell in Vehicle-Driver Interaction

2016 ◽  
Author(s):  
Monica Bordegoni ◽  
Marina Carulli ◽  
Yuan Shi
Keyword(s):  
Experimental Testing ◽  
Psychological State ◽  
Physiological Data ◽  
Contributing Factors ◽  
Driver Assistance Systems ◽  
Cognitive Aspect ◽  
Olfactory Stimuli ◽  
Multisensory Environment ◽  
Set Up ◽  
Attention Level

Every year approximately more than one million people die on world’s road. Human factors are the largest contributing factors to the traffic crashes and fatality, and recent researches have identified drivers’ cognitive aspect as the major cause of human errors in 80% of crash events. Thus, the development of countermeasures to manage drivers’ cognitive aspect is an important challenge to address. Driver-Assistance Systems have been developed and integrated into vehicles to acquire data about the environment and the driver, and to communicate information to the driver, usually via the senses of vision and hearing. Unfortunately, these senses are already subjected to high demands, and the visual and auditory stimuli can be underestimate or considered as annoying. However, other sensory channels could be used to elicit the drivers’ cognitive aspect. In particular, smell can impact on various aspects of humans’ psychological state, such as people’s attention level, and can induce activation states in people. The research presented in this paper aims at investigating whether olfactory stimuli, instead of auditory ones, can be used to influence the cognitive aspect of the drivers. For this purpose, an experimental framework has been set up and experimental testing sessions have been performed. The experimental framework is a multisensory environment consisting of an active stereo-projector and a screen used for displaying a video that reproduces a very monotonous car trip, a seating-buck for simulating the car environment, a wearable Olfactory Display, in-ear earphones and the BioGraph Infiniti system for acquiring the subjects’ physiological data. The analysis of the data collected in the testing sessions shows that, in comparison to the relaxation state, olfactory stimuli are effective in increasing subjects’ attention level more than the auditory ones.

scholarly journals Computer-based Monitoring and Data Analysis in Anaesthesia and Intensive Care

1982 ◽  
Vol 10 (3) ◽  
pp. 223-228 ◽  
Author(s):  
Garry D. Phillips ◽  
Phillip J. Gordon ◽  
Michael J. Cousins
Keyword(s):  
Intensive Care ◽  
Software Package ◽  
Computer Time ◽  
Physiological Data ◽  
Operating Theatres ◽  
Computer Based ◽  
Set Up ◽  
The Cost ◽  
Further Development

A computer with a software package for physiological monitoring at the bedside has been set up, modified and used in a Department of Anaesthesia and Intensive Care over the last three and a half years. Many difficulties have been experienced in implementing a useful computer-based program for monitoring physiological data. The cost of further development to overcome these difficulties could not be justified, and demands for computer time to allow storage and analysis of other data was increasing. A decision was therefore made to eliminate the monitoring role of the computer, and it is now used for storage and analysis of administrative and clinical data from the Intensive Care Unit, Operating Theatres and Pain Management Unit.

The role of increasing vertical resolution on the detection and attribution of North Atlantic storms

2020 ◽  
Author(s):  
Erin Walker ◽  
Daniel Mitchell ◽  
William Seviour ◽  
Paul Valdes ◽  
Mat Collins
Keyword(s):  
North Atlantic ◽  
Storm Track ◽  
Storm Tracks ◽  
Vertical Resolution ◽  
The North ◽  
Detection And Attribution ◽  
Regional Impacts ◽  
Improve Model ◽  
Set Up

&lt;p&gt;Accurately determining extratropical cyclone paths is key in determining regional impacts associated with precipitation and wind. It is known that the stratosphere plays an important role in atmospheric dynamics and can extend its influence down to the surface. Despite this, many attribution studies have not included a stratosphere in their experiments. We believe that not considering the stratosphere could affect the results of these experiments, so the role it has on North Atlantic storm tracks is analysed using an idealised, atmospheric only model named Isca. With the aim of identifying clear implications of including the stratosphere in storm track analysis in the North Atlantic basin, a large ensemble formed of 4 separate experiments is set up for the winter of 2013/2014. The four experiments are as follows; 1) no vertical layers in the stratosphere, 2) vertical levels extended to the upper stratosphere, 3) doubling of vertical levels throughout the atmosphere, and finally, 4) an increase of vertical levels at the tropopause. We expect that including the stratosphere, in addition to increasing vertical resolution, will help improve model representation of storm tracks and their intensities during the 2013/2014 winter. The results of this study hope to highlight how the inclusion of the stratosphere and increased vertical resolution can lead to the improvement in modelling storm track statistics, which in turn will help to make more reliable attribution statements in the future.&lt;/p&gt;

Advances towards a new measurement of the 1S–2S transition of positroniumThis paper was presented at the International Conference on Precision Physics of Simple Atomic Systems, held at École de Physique, les Houches, France, 30 May – 4 June, 2010.

2011 ◽  
Vol 89 (1) ◽  
pp. 29-35 ◽  
Author(s):  
P. Crivelli ◽  
C. L. Cesar ◽  
U. Gendotti
Keyword(s):  
Experimental Technique ◽  
Laser System ◽  
Bound State ◽  
Atomic Systems ◽  
International Conference ◽  
Technological Advances ◽  
Set Up ◽  
Current Accuracy

In this paper, a new experiment is presented to measure the 1S–2S transition of positronium, the bound state of an electron and a positron. The goal is to improve the current accuracy by a factor of 5 to reach a precision of the order of 0.6 ppb, to check recent QED calculations. This accuracy is challenging, but it seems well within reach in view of the technological advances that have occurred during the last two decades. We will present the details of the experimental set-up, the advances in the production of positronium, the developments of the laser system, and as well our new experimental technique for the detection of Ps in the 2S state.

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