Experimentally-calibrated population of models predicts and explains inter-subject variability in cardiac cellular\ud electrophysiology

Cellular and ionic causes of variability in the electrophysiological activity of hearts from individuals of the same species are unknown. However, improved understanding of this variability is key to enable prediction of the response of specific hearts to disease and therapies. Limitations of current mathematical modeling and experimental techniques hamper our ability to provide insight into variability. Here we describe a methodology to unravel the ionic determinants of inter-subject variability exhibited in experimental recordings, based on the construction and calibration of populations of models. We illustrate the methodology through its application to rabbit Purkinje preparations, due to their importance in arrhythmias and safety pharmacology assessment. We consider a set of equations describing the biophysical processes underlying rabbit Purkinje electrophysiology and we construct a population of over 10,000 models by randomly assigning specific parameter values corresponding to ionic current conductances and kinetics. We calibrate the model population by closely comparing simulation output and experimental recordings at three pacing frequencies. We show that 213 of the 10,000 candidate models are fully consistent with the experimental dataset. Ionic properties in the 213 models cover a wide range of values, including differences up to ±100% in several conductances. Partial correlation analysis shows that particular combinations of ionic properties determine the precise shape, amplitude and rate dependence of specific action potentials. Finally, we demonstrate that the population of models calibrated using data obtained under physiological conditions quantitatively predicts the action potential duration prolongation caused by exposure to four concentrations of the potassium channel blocker dofetilide

Adsorption of cesium on different types of activated carbon

The optimal conditions to remove radiocesium from water by adsorption on activated carbon (AC) were investigated. Two commercial ACs were compared to ACs prepared by steam activation of brewers’ spent grain. The influence of pH and loading AC with Prussian Blue were studied. 134Cs, measured by gamma-ray spectroscopy, served as a tracer for the Cs concentration. Column experiments showed that a neutral to acidic pH enhanced adsorption compared to high pH. Norit GAC 1240 had the highest adsorption capacity, 8.5 µg Cs g-1 AC for a column filtration. Sequential columns of Norit GAC 1240 removed 28.1 ± 2.8 % of Cs per column.JRC.D.4-Standards for Nuclear Safety, Security and Safeguard

Intercomparison of 99mTc, 18F and 111In activity measurements with radionuclide calibrators in Belgian hospitals

This study presents current status of performance of radiopharmaceutical activity measurements using radionuclide calibrators in Belgium. An intercomparison exercise was performed among 15 hospitals to test the accuracy of 99mTc, 18F and 111In activity measurements by means of radionuclide calibrators. Four sessions were held in different geographical regions between December 2013 and February 2015. The data set includes measurements from 38 calibrators, yielding 36 calibrations for 99mTc and 111In, and 21 calibrations for 18F. For each radionuclide, 3 ml of stock solution was measured in two clinical geometries: a 10 ml glass vial and a 10 ml syringe. The initial activity was typically 100 MBq for 99mTc, 15 MBq for 111In and 115 MBq for 18F. The reference value for the massic activity of the radioactive solutions was determined by means of primary and secondary standardisation techniques at the radionuclide metrology laboratory of the JRC. The overall results of the intercomparison were satisfactory for 99mTc and 18F, since most radionuclide calibrators (>70%) were accurate within ±5% of the reference value. Nevertheless, some devices underestimated the activity by 10–20%. Conversely, 111In measurements were strongly affected by source geometry effects and this had a negative impact on the accuracy of the measurements, in particular for the syringe sample. Large overestimations (up to 72%) were observed, even when taking into account the corrections and uncertainties supplied by the manufacturers for container effects. The results of this exercise encourage the hospitals to perform corrective actions to improve the calibration of their devices where needed.JRC.G.2-Standards for Nuclear Safety, Security and Safeguard

Intercomparison of radionuclide calibrators in Belgian hospitals

The SCK•CEN conducted a proficiency test of the capacity of Belgian hospitals to determine activity of Tc-99m, In-111 and F-18 in vials and syringes using radionuclide calibrators. The reference values were provided by the European Commissions Joint Research Centre in Geel. The results are presented and discussed. I key result is that calibration factors for syringes with In-111 need to be improved.JRC.D.4-Standards for Nuclear Safety, Security and Safeguard

Application of semiparametric mixed models and simultaneous confidence bands in a cardiovascular safety experiment with longitudinal data

Several pharmacological studies involve experiments aimed at testing for a difference between experimental groups wherein the data are longitudinal in nature, frequently with long sequences per subject. Oftentimes, treatment effect, if present, is not constant over time. In such situations, imposing a parametric mean structure can be too complicated and/or restrictive. A more flexible approach is to model the mean using a semiparametric smooth function, estimated using, for example, penalized smoothing splines. We formulate a series of models exhibiting how the group-specific mean profiles could possibly differ. Once an appropriate model is chosen, interest lies in identifying specific time points where the groups differ. For this purpose, we propose the use of simultaneous confidence bands around the fitted models wherein the bands take into account within and between-subject variability, as well as variability arising from smoothing.status: publishe

Tutorial in Biostatistics Analysis of cross-over designs with serial correlation within periods using semiparametric mixed models

status: publishe

Is decay constant?

Some authors have raised doubt about the invariability of decay constants, which would invalidate the exponential-decay law and the foundation on which the common measurement system for radioactivity is based. Claims were made about a new interaction – the fifth force – by which neutrinos could affect decay constants, thus predicting changes in decay rates in correlation with the variations of the solar neutrino flux. Their argument is based on the observation of permille-sized annual modulations in particular decay rate measurements, as well as transient oscillations at frequencies near 11 year-1 and 12.7 year-1 which they speculatively associate with dynamics of the solar interior. In this work, 12 data sets of precise long-term decay rate measurements have been investigated for the presence of systematic modulations at frequencies between 0.08 and 20 year-1. Besides small annual effects, no common oscillations could be observed among alpha, beta minus, beta plus or EC decaying nuclides. The amplitudes of fitted oscillations to residuals from exponential decay do not exceed 3 times their standard uncertainty, which varies from 0.00023% to 0.023%. This contradicts the assertion that 'neutrino-induced' beta decay provides information about the deep solar interior.JRC.G.2-Standards for Nuclear Safety, Security and Safeguard