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This article assesses the distance between the laws of stochastic differential equations with multiplicative Lévy noise on path space in terms of their characteristics. The notion of transportation distance on the set of Lévy kernels introduced by Kosenkova and Kulik yields a natural and statistically tractable upper bound on the noise sensitivity. This extends recent results for the additive case in terms of coupling distances to the multiplicative case. The strength of this notion is shown in a statistical implementation for simulations and the example of a benchmark time series in paleoclimate.
This article assesses the distance between the laws of stochastic differential equations with multiplicative Levy noise on path space in terms of their characteristics. The notion of transportation distance on the set of Levy kernels introduced by Kosenkova and Kulik yields a natural and statistically tractable upper bound on the noise sensitivity. This extends recent results for the additive case in terms of coupling distances to the multiplicative case. The strength of this notion is shown in a statistical implementation for simulations and the example of a benchmark time series in paleoclimate.
Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK-PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK-PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN-MER might be favorable over LZD-MER due to an unfavorable antagonistic interaction between LZD and MER.
As a potentially toxic agent on nervous system and bone, the safety of aluminium exposure from adjuvants in vaccines and subcutaneous immune therapy (SCIT) products has to be continuously reevaluated, especially regarding concomitant administrations. For this purpose, knowledge on absorption and disposition of aluminium in plasma and tissues is essential. Pharmacokinetic data after vaccination in humans, however, are not available, and for methodological and ethical reasons difficult to obtain. To overcome these limitations, we discuss the possibility of an in vitro-in silico approach combining a toxicokinetic model for aluminium disposition with biorelevant kinetic absorption parameters from adjuvants. We critically review available kinetic aluminium-26 data for model building and, on the basis of a reparameterized toxicokinetic model (Nolte et al., 2001), we identify main modelling gaps. The potential of in vitro dissolution experiments for the prediction of intramuscular absorption kinetics of aluminium after vaccination is explored. It becomes apparent that there is need for detailed in vitro dissolution and in vivo absorption data to establish an in vitro-in vivo correlation (IVIVC) for aluminium adjuvants. We conclude that a combination of new experimental data and further refinement of the Nolte model has the potential to fill a gap in aluminium risk assessment. (C) 2017 Elsevier Inc. All rights reserved.
Towards the right Hamiltonians for singular perturbations via regularization and extension theory
(1996)
Towards the assimilation of tree-ring-width records using ensemble Kalman filtering techniques
(2016)
This paper investigates the applicability of the Vaganov–Shashkin–Lite (VSL) forward model for tree-ring-width chronologies as observation operator within a proxy data assimilation (DA) setting. Based on the principle of limiting factors, VSL combines temperature and moisture time series in a nonlinear fashion to obtain simulated TRW chronologies. When used as observation operator, this modelling approach implies three compounding, challenging features: (1) time averaging, (2) “switching recording” of 2 variables and (3) bounded response windows leading to “thresholded response”. We generate pseudo-TRW observations from a chaotic 2-scale dynamical system, used as a cartoon of the atmosphere-land system, and attempt to assimilate them via ensemble Kalman filtering techniques. Results within our simplified setting reveal that VSL’s nonlinearities may lead to considerable loss of assimilation skill, as compared to the utilization of a time-averaged (TA) linear observation operator. In order to understand this undesired effect, we embed VSL’s formulation into the framework of fuzzy logic (FL) theory, which thereby exposes multiple representations of the principle of limiting factors. DA experiments employing three alternative growth rate functions disclose a strong link between the lack of smoothness of the growth rate function and the loss of optimality in the estimate of the TA state. Accordingly, VSL’s performance as observation operator can be enhanced by resorting to smoother FL representations of the principle of limiting factors. This finding fosters new interpretations of tree-ring-growth limitation processes.