Comparative study of different methods for the prediction of drug-polymer solubility

YesIn this study, a comparison of different methods to predict drug−polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug−polymer solubility at 25 °C was predicted using the Flory−Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine−PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug−polymer solubility.The Irish Research Council and Eli Lilly S.A. through an Irish Research Council Enterprise Partnership Scholarship for C.M.B., in part by The Royal Society in the form of Industrial Fellowship awarded to G.A., and in part by a research grant from Science Foundation Ireland (SFI) under Grant Number SFI/12/RC/2275 (for A.M.H., L.T., K.P., and A.K.)

Historical Asbestos Measurements in Denmark-A National Database.

Objectives: Due to the long lag-time for health outcomes, historical asbestos exposure measurements are valuable to support assessments of associated occupational health effects, and also to assess time trends and effects of preventive measures. Methods: Different sources of stored data were collated, assessed and refined to create a harmonized database on historical asbestos fibre concentrations measured in specific work tasks and different industries. The final database contains 9236 asbestos measurements from Danish workplaces collected from 1971 to 1997. Results: The geometric mean of asbestos concentrations in different occupations and tasks ranged from 0.003 to 35 fibres cm(−3). Highest concentrations were registered during handling of asbestos products in the construction services during the period 1981–1997. Although all the measured asbestos exposures without the use of respiratory equipment by the worker in the period of 1971–1997 exceeded the current 8-h time-weighted average exposure limit of 0.1 fibres cm(−3), the majority of samples collected in the earlier period of 1971 to 1980 did not exceed the exposure limit of 2 fibres cm(−3), which was in place at the time. All exposure data obtained from 1980 and onwards were found to be one seventh of the mean fibre concentrations in the previous measurement period. The impact of time shows a clear exponentially decreasing trend-line. Conclusions: Despite limitations in coverage of different occupations and tasks associated with the inventoried historical asbestos measurements, the data are helpful to identify specific work scenarios within an industry, where relatively high asbestos exposure levels may still occur or have occurred from 1971 to 1997

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases

The chaos in calibrating crop models

Calibration, the estimation of model parameters based on fitting the model to experimental data, is among the first steps in many applications of system models and has an important impact on simulated values. Here we propose and illustrate a novel method of developing guidelines for calibration of system models. Our example is calibration of the phenology component of crop models. The approach is based on a multi-model study, where all teams are provided with the same data and asked to return simulations for the same conditions. All teams are asked to document in detail their calibration approach, including choices with respect to criteria for best parameters, choice of parameters to estimate and software. Based on an analysis of the advantages and disadvantages of the various choices, we propose calibration recommendations that cover a comprehensive list of decisions and that are based on actual practices.HighlightsWe propose a new approach to deriving calibration recommendations for system modelsApproach is based on analyzing calibration in multi-model simulation exercisesResulting recommendations are holistic and anchored in actual practiceWe apply the approach to calibration of crop models used to simulate phenologyRecommendations concern: objective function, parameters to estimate, software usedCompeting Interest StatementThe authors have declared no competing interest