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Challenges, triggers and initiators of climate policies and implications for policy formulation
(2020)
The combined effect of ultraviolet (UV) light soaking and self-assembled monolayer deposition on the work function (WF) of thin ZnO layers and on the efficiency of hole injection into the prototypical conjugated polymer poly(3-hexylthiophen-2,5-diyl) (P3HT) is systematically investigated. It is shown that the WF and injection efficiency depend strongly on the history of UV light exposure. Proper treatment of the ZnO layer enables ohmic hole injection into P3HT, demonstrating ZnO as a potential anode material for organic optoelectronic devices. The results also suggest that valid conclusions on the energy-level alignment at the ZnO/organic interfaces may only be drawn if the illumination history is precisely known and controlled. This is inherently problematic when comparing electronic data from ultraviolet photoelectron spectroscopy (UPS) measurements carried out under different or ill-defined illumination conditions.
Background:
Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn’s disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed.
Methods:
A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration–time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy.
Results:
For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110% and CV ≈80%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52–71%), being the highest for LBW-adjusted dosing.
Conclusion:
By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66% vs. 71%, respectively).
The termprocess modelis widely used, but rarely agreed upon. This paper proposes a framework for characterizing and building cognitive process models. Process models model not only inputs and outputs but also model the ongoing information transformations at a given level of abstraction. We argue that the following dimensions characterize process models: They have a scope that includes different levels of abstraction. They specify a hypothesized mental information transformation. They make predictions not only for the behavior of interest but also for processes. The models' predictions for the processes can be derived from the input, without reverse inference from the output data. Moreover, the presumed information transformation steps are not contradicting current knowledge of human cognitive capacities. Lastly, process models require a conceptual scope specifying levels of abstraction for the information entering the mind, the proposed mental events, and the behavior of interest. This framework can be used for refining models before testing them or after testing them empirically, and it does not rely on specific modeling paradigms. It can be a guideline for developing cognitive process models. Moreover, the framework can advance currently unresolved debates about which models belong to the category of process models.
In the comment on "Varves of the Dead Sea sedimentary record." Quaternary Science Reviews 215 (Ben Dor et al., 2019): 173-184. by R. Bookman, two recently published papers are suggested to prove that the interpretation of the laminated sedimentary sequence of the Dead Sea, deposited mostly during MIS2 and Holocene pluvials, as annual deposits (i.e., varves) is wrong. In the following response, we delineate several lines of evidence which coalesce to demonstrate that based on the vast majority of evidence, including some of the evidence provided in the comment itself, the interpretation of these sediments as varves is the more likely scientific conclusion. We further discuss the evidence brought up in the comment and its irrelevance and lack of robustness for addressing the question under discussion.