Pharmacokinetics-based Chronotherapy

Dosing time-dependency of pharmacokinetics (or chronopharmacokinetics) has been long recognized. Studies in recent years have revealed that diurnal rhythmicity in expression of drug-metabolizing enzymes and transporters (DMETs) are key factors determining chronopharmacokinetics. In this article, we briefly summarize current knowledge with respect to circadian mechanisms of DMETs and discuss how rhythmic DMETs are translated to drug chronoeffects. More importantly, we present our perspectives on pharmacokinetics-based chronotherapy.

Probability of detection, localization, and sizing: The evolution of reliability metrics in Structural Health Monitoring

The successful implementation of Structural Health Monitoring (SHM) systems is confined to the capability of evaluating their performance, reliability, and durability. Although there are many SHM techniques capable of detecting, locating and quantifying damage in several types of structures, their certification process is still limited. Despite the effort of academia and industry in defining methodologies for the performance assessment of such systems in recent years, many challenges remain to be solved. Methodologies used in Non-Destructive Evaluation (NDE) have been taken as a starting point to develop the required metrics for SHM, such as Probability of Detection (POD) curves. However, the transposition of such methodologies to SHM is anything but straightforward because additional factors should be considered. The time dependency of the data, the larger amount of variability sources and the complexity of the structures to be monitored exacerbate/aggravate the existing challenges, suggesting that much work has still to be done in SHM. The article focuses on the current challenges and barriers preventing the development of proper reliability metrics for SHM, analyzing the main differences with respect to POD methodologies for NDE. It was found that the development of POD curves for SHM systems requires a higher level of statistical expertise and their use in the literature is still limited to few studies. Finally, the discussion extends beyond POD curves towards new metrics such as Probability of Localization (POL) and Probability of Sizing (POS) curves, reflecting the diagnosis paradigm of SHM.

Software Reliability Modeling Incorporating Fault Detection and Fault Correction Processes with Testing Coverage and Fault Amount Dependency

This paper presents a general testing coverage software reliability modeling framework that covers imperfect debugging and considers not only fault detection processes (FDP) but also fault correction processes (FCP). Numerous software reliability growth models have evaluated the reliability of software over the last few decades, but most of them attached importance to modeling the fault detection process rather than modeling the fault correction process. Previous studies analyzed the time dependency between the fault detection and correction processes and modeled the fault correction process as a delayed detection process with a random or deterministic time delay. We study the quantitative dependency between dual processes from the viewpoint of fault amount dependency instead of time dependency, then propose a generalized modeling framework along with imperfect debugging and testing coverage. New models are derived by adopting different testing coverage functions. We compared the performance of these proposed models with existing models under the context of two kinds of failure data, one of which only includes observations of faults detected, and the other includes not only fault detection but also fault correction data. Different parameter estimation methods and performance comparison criteria are presented according to the characteristics of different kinds of datasets. No matter what kind of data, the comparison results reveal that the proposed models generally give improved descriptive and predictive performance than existing models.

Reconsidering the shi…(de) construction in spoken Mandarin

This paper revisits the use of the shi…de construction, based on the analysis of structures with predicative adjectives in a 500,000-character corpus of spoken Mandarin assembled from transcripts of a popular Chinese chat show. Overall, de was omitted more than 40% of the time with a predicative adjective, a significantly higher rate than that found in previous studies. The data reveal a number of factors that may all play a role in determining the likelihood of de omission or retention: the time dependency of the adjective, the particular intensifier chosen to modify the adjective, the discourse function of the utterance and the presence of certain markers of epistemic modality. The findings also lend support to the hypothesis that shi is grammaticalizing to a bound morpheme in some so-called ‘conventionalised forms’ involving epistemic and evidentiality markers.

Time-dependence of Heterogeneous Ice Nucleation by Ambient Aerosols: Laboratory Observations and a Formulation for Models

The time dependence of ice-nucleating particle (INP) activity is known to exist, yet for simplicity it is often omitted in atmospheric models as an approximation. Hitherto only limited experimental work has been done to quantify this time dependency, for which published data are especially scarce regarding ambient aerosol samples and longer time scales. In this study, the time dependence of INP activity is quantified experimentally for ambient environmental samples. The experimental approach includes a series of hybrid experiments with alternating constant cooling and isothermal experiments using a recently developed cold-stage setup called the Lund University Cold-Stage (LUCS). This approach of observing ambient aerosol samples provides the optimum realism for representing their time dependence in any model. Six ambient aerosol samples were collected representing aerosol conditions likely influenced by these types of INPs: marine, mineral dust, continental pristine, continental polluted, combustion-related and rural continental aerosol. Active INP concentrations were seen to be augmented by about 40 % to 100 % (or 70 % to 200 %), depending on the sample, over 2 (or 10) hours. This degree of time dependence observed was comparable to that seen in previous published works. Our observations show that the minority of active ice nuclei (IN) with strong time dependency on hourly time scales display only weak time dependence on short time scales of a few minutes. A general tendency was observed for the natural time scale of the freezing to dilate increasingly with time. The fractional freezing rate was observed to steadily declines exponentially with the order of magnitude (logarithm) of the time since the start of isothermal conditions. A representation of time dependence for incorporation into schemes of heterogeneous ice nucleation that currently omit time dependence is proposed.