Development of a Population Pharmacokinetic Model To Describe Azithromycin Whole-Blood and Plasma Concentrations over Time in Healthy Subjects

ABSTRACT Azithromycin (AZI), a broad-spectrum antibiotic, accumulates in polymorphonuclear cells and peripheral blood mononuclear cells. The distribution of AZI in proinflammatory cells may be important to the anti-inflammatory properties. Previous studies have described plasma AZI pharmacokinetics. The objective of this study was to describe the pharmacokinetics of AZI in whole blood (concentration in whole blood [ C b ]) and plasma (concentration in plasma [ C p ]) of healthy subjects. In this study, 12 subjects received AZI (500 mg once a day for 3 days). AZI C b and C p were quantified in serial samples collected up to 3 weeks after the last dose and analyzed using noncompartmental and compartmental methods. After the last dose, C b was greater than C p . Importantly, C b , but not C p , was quantifiable in all but one subject at 3 weeks. The blood area under the curve during a 24-h dosing interval (AUC 24 ) was ∼2-fold greater than the plasma AUC 24 , but simulations suggested that C b was not at steady state by day 3. Upon exploration of numerous models, an empirical 3-compartment model adequately described C p and C b , but C p was somewhat underestimated. Intercompartmental clearance (CL; likely representing cells) was lower than apparent oral CL (18 versus 118 liters/h). Plasma, peripheral, and cell compartmental volumes were 439 liters, 2,980 liters, and 3,084 liters, respectively. Interindividual variability in CL was low (26.2%), while the volume of distribution variability was high (107%). This is the first report to describe AZI C b in healthy subjects, the distribution parameters between C p and C b , and AZI retention in blood for up to 3 weeks following 3 daily doses. The model can be used to predict C b from C p for AZI under various dosing regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01026064.

Predicting Missing Links via Local Information

Missing link prediction of networks is of both theoretical interest and practical significance in modern science. In this paper, we empirically investigate a simple framework of link prediction on the basis of node similarity. We compare nine well-known local similarity measures on six real networks. The results indicate that the simplest measure, namely common neighbors, has the best overall performance, and the Adamic-Adar index performs the second best. A new similarity measure, motivated by the resource allocation process taking place on networks, is proposed and shown to have higher prediction accuracy than common neighbors. It is found that many links are assigned same scores if only the information of the nearest neighbors is used. We therefore design another new measure exploited information of the next nearest neighbors, which can remarkably enhance the prediction accuracy.Comment: For International Workshop: "The Physics Approach To Risk: Agent-Based Models and Networks", http://intern.sg.ethz.ch/cost-p10

The EC-Earth3 Earth system model for the Coupled Model Intercomparison Project 6

The Earth system model EC-Earth3 for contributions to CMIP6 is documented here, with its flexible coupling framework, major model configurations, a methodology for ensuring the simulations are comparable across different high-performance computing (HPC) systems, and with the physical performance of base configurations over the historical period. The variety of possible configurations and sub-models reflects the broad interests in the EC-Earth community. EC-Earth3 key performance metrics demonstrate physical behavior and biases well within the frame known from recent CMIP models. With improved physical and dynamic features, new Earth system model (ESM) components, community tools, and largely improved physical performance compared to the CMIP5 version, EC-Earth3 represents a clear step forward for the only European community ESM. We demonstrate here that EC-Earth3 is suited for a range of tasks in CMIP6 and beyond

The EC-Earth3 Earth system model for the Coupled Model Intercomparison Project 6

The Earth system model EC-Earth3 for contributions to CMIP6 is documented here, with its flexible coupling framework, major model configurations, a methodology for ensuring the simulations are comparable across different high-performance computing (HPC) systems, and with the physical performance of base configurations over the historical period. The variety of possible configurations and sub-models reflects the broad interests in the EC-Earth community. EC-Earth3 key performance metrics demonstrate physical behavior and biases well within the frame known from recent CMIP models. With improved physical and dynamic features, new Earth system model (ESM) components, community tools, and largely improved physical performance compared to the CMIP5 version, EC-Earth3 represents a clear step forward for the only European community ESM. We demonstrate here that EC-Earth3 is suited for a range of tasks in CMIP6 and beyond.Peer reviewe

Holocene Cyclic Records of Ice-Rafted Debris and Sea Ice Variations on the East Greenland and Northwest Iceland Margins

The dynamics of the Greenland Ice Sheet and drift of sea ice from the Arctic Ocean reaching Denmark Strait are poorly constrained. We present data on the provenance of Fe oxide detrital grains from two cores in the Denmark Strait area and compare the Fe grain source data with other environmental proxies in order to document the variations and potential periodicities in ice-rafted debris delivery during the Holocene. Based on their Fe grain geochemistry, the sediments can be traced to East Greenland sources and to more distal sites around the Arctic Basin. On the Holocene time scales of the two cores, sea ice biomarker (IP25) data, and quartz weight percent reveal positive associations with T°C and inverse associations with biogenic carbonate wt%. Trends in the data were obtained from Singular Spectrum Analysis (SSA), and residuals were tested for cyclicity. Trends on the environmental proxies explained between 15 and 90% of the variance. At both sites the primary Fe grain sources were from Greenland, but significant contributions were also noted from Banks Island and Svalbard. There is a prominent cyclicity of 800 yrs as well as other less prominent cycles for both Greenland and arctic sources. The Fe grain sources from Greenland and the circum-Arctic Ocean are in synchronization, suggesting that the forcings for these cycles are regional and not local ice sheet instabilities