Pharmacokinetic-pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients.

AIM: To characterize ticagrelor exposure-response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using non-linear mixed effects modelling and simulation. METHODS: Platelet function data were integrated with plasma concentration data of ticagrelor and its active metabolite AR-C1249010XX in a population pharmacokinetic and pharmacodynamic (PK/PD) model, based on two clinical studies. In the ONSET/OFFSET study, PK and platelet function were assessed in 123 CAD patients receiving placebo, ticagrelor (180 mg followed by 90 mg twice daily) or clopidogrel (600 mg followed by 75 mg once daily). In the PEGASUS-TIMI 54 platelet function substudy, PK and platelet function were assessed during maintenance dosing in 180 prior MI patients receiving placebo, ticagrelor 60 mg or ticagrelor 90 mg twice daily. RESULTS: Platelet inhibition by ticagrelor was described by a sigmoidal Emax model. On average, half maximal inhibition was reached at ticagrelor concentrations of 116 (RSE: 5.3%) nmol/L. Simulations showed that near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At simulated lower doses, platelet inhibition is overall reduced, more variable between patients, and show greater peak-to-trough variability. Ticagrelor antiplatelet response was similar between the studied patient populations. CONCLUSIONS: In patients with stable CAD or a history of MI, near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At modeled doses below 60mg, the response is overall reduced, more variable between patients, and patients will display greater peak-to-trough variability

Antisense Therapy Attenuates Phospholamban p.(Arg14del) Cardiomyopathy in Mice and Reverses Protein Aggregation

Inherited cardiomyopathy caused by the p.(Arg14del) pathogenic variant of the phospholamban (PLN) gene is characterized by intracardiomyocyte PLN aggregation and can lead to severe dilated cardiomyopathy. We recently reported that pre-emptive depletion of PLN attenuated heart failure (HF) in several cardiomyopathy models. Here, we investigated if administration of a Pln-targeting antisense oligonucleotide (ASO) could halt or reverse disease progression in mice with advanced PLN-R14del cardiomyopathy. To this aim, homozygous PLN-R14del (PLN-R14 (Δ/Δ)) mice received PLN-ASO injections starting at 5 or 6 weeks of age, in the presence of moderate or severe HF, respectively. Mice were monitored for another 4 months with echocardiographic analyses at several timepoints, after which cardiac tissues were examined for pathological remodeling. We found that vehicle-treated PLN-R14 (Δ/Δ) mice continued to develop severe HF, and reached a humane endpoint at 8.1 ± 0.5 weeks of age. Both early and late PLN-ASO administration halted further cardiac remodeling and dysfunction shortly after treatment start, resulting in a life span extension to at least 22 weeks of age. Earlier treatment initiation halted disease development sooner, resulting in better heart function and less remodeling at the study endpoint. PLN-ASO treatment almost completely eliminated PLN aggregates, and normalized levels of autophagic proteins. In conclusion, these findings indicate that PLN-ASO therapy may have beneficial outcomes in PLN-R14del cardiomyopathy when administered after disease onset. Although existing tissue damage was not reversed, further cardiomyopathy progression was stopped, and PLN aggregates were resolved

Equine Mesenchymal Stromal Cells retain a pericyte-like phenotype

Mesenchymal Stem/Stromal Cells (MSCs) have been used in human and equine regenerative medicine, and interest in exploiting their potential has increased dramatically over the years. Despite significant effort to characterize equine MSCs, the actual origin of these cells and how much of their native phenotype is maintained in culture have not been determined. In this study, we investigated the relationship between MSCs, derived from adipose tissue (AT) and bone marrow (BM), and pericytes in the horse. Both pericyte (CD146, NG2 and αSMA) and MSC (CD29, CD90 and CD73) markers were detected in equine adipose tissue and co-localized around blood vessels. Importantly, as assessed by flow cytometry, both pericyte (CD146, NG2 and αSMA) and MSC (CD29, CD44, CD90 and CD105) markers were present in a majority (≥90%) of cells in cultures of AT- and BM-MSCs, however, levels of pericyte markers were variable within each of those populations. Moreover, the expression of pericyte markers was maintained for at least 8 passages in both AT- and BM-MSCs. Hematopoietic (CD45) and endothelial (CD144) markers were also detected at low levels in MSCs by qPCR. Finally, in co-culture experiments, AT-MSCs closely associated with networks produced by endothelial cells, resembling the natural perivascular location of pericytes in vivo. Our results indicate that equine MSCs originate from perivascular cells and, moreover, maintain a pericyte-like phenotype in culture. Therefore, we suggest that, in addition to classical MSC markers, pericyte markers such as CD146 could also be used when assessing and characterising equine MSCs.</p

The adaptiveness in stock markets: testing the stylized facts in the DAX 30

© 2017, Springer-Verlag Berlin Heidelberg. By testing a simple asset pricing model of heterogeneous agents to characterize the power-law behavior of the DAX 30 from 1975 to 2007, we provide supporting evidence on empirical findings that investors and fund managers use combinations of fixed and switching strategies based on fundamental and technical analysis when making investment decisions. A mechanism analysis based on the calibrated model provides a behavioral insight into the explanatory power of rational switching behavior of investors on the volatility clustering and long range dependence in return volatility

Employment Protection and Parental Child Care

I examine if employment protection affects parental childcare. I find that a softer employment protection has a substantial effect on how parents use and divide paid childcare between them. The identification relies on a reform that made it easier for employers in Sweden to dismiss workers in small firms. I estimate that a softer employment protection reduces the total days of parental childcare in targeted firms, measured as total days of parental leave or temporary parental leave. Both a sorting effect and a behavioral effect can explain the reduced childcare. I also find evidence of a redistribution effect of paid parental childcare within households if only one partner was affected by the reform. I interpret the redistribution effect as a way of evading an external cost on the child

Empirical Validation of Simulated Models through the GSL-div: An Illustrative Application

A major concern about the use of simulation models regards their relationship with the empirical data. The identification of a suitable indicator quantifying the distance between the model and the data would help and guide model selection and output validation. This paper proposes the use of a new criterion, called GSL-div and developed in Lamperti (2015), to assess the degree of similarity between the dynamics observed in the data and those generated by the numerical simulation of models. As an illustrative application, this approach is used to distinguish between different versions of the well known asset pricing model with heterogeneous beliefs proposed in Brock and Hommes (1998). Once the discrimination ability of the GSL-div is proved, model's dynamics are directly compared with actual data coming from two major stock market indexes (EuroSTOXX 50 for Europe and CSI 300 for China). Results show that the model, once calibrated, is fairly able to track the evolution of both the two indexes, even though a better fit is reported for the Chinese stock market. However, I also find that many different combinations of traders behavioural rules are compatible with the same observed dynamics. Within this heterogeneity, an emerging common trait is found: to be empirically valid, the model has to account for a strong trend following component, which might either come from a unique trend type that heavily extrapolates information from past observations or the combinations of different types with milder, or even opposite, attitudes towards the trend