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This paper describes the developing theory and underlying processes of the microscale obstacle-resolving model MITRAS version 2. MITRAS calculates wind, temperature, humidity, and precipitation fields, as well as transport within the obstacle layer using Reynolds averaging. It explicitly resolves obstacles, including buildings and overhanging obstacles, to consider their aerodynamic and thermodynamic effects. Buildings are represented by impermeable grid cells at the building positions so that the wind speed vanishes in these grid cells. Wall functions are used to calculate appropriate turbulent fluxes. Most exchange processes at the obstacle surfaces are considered in MITRAS, including turbulent and radiative processes, in order to obtain an accurate surface temperature. MITRAS is also able to simulate the effect of wind turbines. They are parameterized using the actuator-disk concept to account for the reduction in wind speed. The turbulence generation in the wake of a wind turbine is parameterized by adding an additional part to the turbulence mechanical production term in the turbulent kinetic energy equation. Effects of trees are considered explicitly, including the wind speed reduction, turbulence production, and dissipation due to drag forces from plant foliage elements, as well as the radiation absorption and shading. The paper provides not only documentation of the model dynamics and numerical framework but also a solid foundation for future microscale model extensions.Published by Copernicus Publications on behalf of the European Geosciences Union.

Keywordscholesteryl ester transfer protein, concentration-effect relationship, first in man, pharmacodynamics, pharmacokinetics ---------------------------------------------------------------------- WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesterol esters from the cardioprotective high density lipoprotein cholesterol (HDL-C) to the proatherogenic low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C) leading to lower concentrations of HDL-C but raising the concentrations of proatherogenic LDL-C and VLDL-C. • Inhibition of CETP is considered a potential approach to treat dyslipidaemia.• Phase III studies demonstrating no benefit in regard to the defined clinical end points with the CETP inhibitor torcetrapib challenged the future perspectives of CETP inhibitors as potential therapeutic agents although it has been recently discussed whether potential off-target effects of torcetrapib could have contributed to the failure of this CETP inhibitor.• It has been suggested in recent publications to continue studying other CETP inhibitors for their potential to improve plasma lipid profiles and reduce cardiovascular risk. Currently, several compounds are being investigated in preclinical or clinical studies. WHAT THIS STUDY ADDS• This study provides information on the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of a potential new treatment for dyslipidaemia.• Data from a first in man study with the new CETP inhibitor BAY 60-5521 are presented that demonstrate that BAY 60-5521 is clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL-C could be demonstrated. AIMSTo determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). METHODSThe first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n = 28) or were treated with a placebo (n = 10). RESULTSIn all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relativ...

Abstract. This paper describes the developing theory and the underlying processes of the microscale obstacle resolving model MITRAS Version 2. MITRAS calculates wind, temperature, humidity and precipitation fields as well as transport within the obstacles layer using Reynolds averaging. It explicitly resolves obstacles, including buildings and overhanging obstacles, to consider their aerodynamic and thermodynamic effects. Buildings are represented by impermeable grid cells at the building positions so that the wind speed vanishes and zero turbulent kinetic energy is assumed in these grid cells. Wall functions are 15 used to calculate appropriate turbulent fluxes. Most exchange processes at the obstacle surfaces are considered in MITRAS, including convective and radiative processes in order to obtain an accurate surface temperature. MITRAS is also able to simulate the effect of wind turbines. They are parameterized using the actuator-disk concept to account for the reduction in wind speed. The turbulence generation in the wake of a wind turbine is parameterized by adding an additional part to the turbulence mechanical production term in the turbulent kinetic energy equation. Effects of trees are considered explicitly, 20 including the wind speed reduction, turbulence production, and dissipation due to drag forces from plant foliage elements as well as the radiation absorption and shading. The paper is providing not only a documentation of the model dynamics and numerical framework but also a solid foundation for future microscale model extensions.

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