The 10 most recently published documents
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).
Sanctions are critical to the Security Council's efforts to fight terrorism. What is striking is that the Council's sanctions regimes are subject to detailed sets of rules and decision criteria. The scholarship on human rights in counterterrorism assumes that rights advocacy and court litigation have prompted this development. The article complements this literature by highlighting an unexplored internal driver of legal-regulatory decision-making and explores how mixed-motive interest constellations among Security Council members have affected the extent of committee regulations and the content of decisions taken by sanctions committees. Based on internal documents and diplomatic cables, a comparative analysis of the Iraq sanctions regime and the counterterrorism sanctions regime demonstrates that mixed-motive interest constellations among Security Council members provide incentives to elaborate rules to guide decision-making resulting in legal-regulatory sanctions governance, even if the human rights of targeted individuals are not at stake. For comparative leverage and to assess the limits of the proposed mechanism, the analysis is briefly extended to other sanctions regimes targeting individuals (Democratic Republic of the Congo and Sudan). The findings have implications for this essential tool of the Security Council to react to threats to peace as diverse as counterterrorism, nonproliferation, and internal armed conflict.
The article explores whether and to what extent expert recommendations affect decision-making within the Security Council and its North Korea and Iran sanctions regimes. The article first develops a rationalist theoretical argument to show why making many second-stage decisions, such as determining lists of items under export restrictions, subjects Security Council members to repeating coordination situations. Expert recommendations may provide focal point solutions to coordination problems, even when interests diverge and preferences remain stable. Empirically, the article first explores whether expert recommendations affected decision-making on commodity sanctions imposed on North Korea. Council members heavily relied on recommended export trigger lists as focal points, solving a divisive conflict among great powers. Second, the article explores whether expert recommendations affected the designation of sanctions violators in the Iran sanctions regime. Council members designated individuals and entities following expert recommendations as focal points, despite conflicting interests among great powers. The article concludes that expert recommendations are an additional means of influence in Security Council decision-making and seem relevant for second-stage decision-making among great powers in other international organisations.
Phase transitions in molecular crystals are often determined by intermolecular interactions. The cage complex of [Co(C12H30N8)](3+) . 3 NO3- is reported to undergo a disorder-order phase transition at T-c1 approximate to 133 K upon cooling. Temperature-dependent neutron and synchrotron diffraction experiments revealed satellite reflections in addition to main reflections in the diffraction patterns below T-c1. The modulation wave vector varies as function of temperature and locks in at T-c3 approximate to 98 K. Here, we demonstrate that the crystal symmetry lowers from hexagonal to monoclinic in the incommensurately modulated phases in T-c1<T<T-c3. Distinctive levels of competitions: trade-off between longer N-H...O and shorter C-H...O hydrogen bonds; steric constraints to dense C-H...O bonds give rise to pronounced modulation of the basic structure. Severely frustrated crystal packing in the incommensurate phase is precursor to optimal balance of intermolecular interactions in the lock-in phase.
Leo Baeck
(2023)
Leo Baeck gilt als bedeutendster Repräsentant des deutschen Judentums in der ersten Hälfte des 20. Jahrhunderts und als Spiritus rector von dessen liberaler Richtung. Er entwickelte seinen Ansatz zu einer jüdischen Theologie in kritischer Auseinandersetzung mit dem zeitgenössischen Protestantismus. Als jüdischer Religionsphilosoph steht Baeck in einer Reihe mit Hermann Cohen (1842–1918), Franz Rosenzweig (1886–1929) und Martin Buber (1878–1965).
Background: The worldwide prevalence of diabetes has been increasing in recent years, with a projected prevalence of 700 million patients by 2045, leading to economic burdens on societies. Type 2 diabetes mellitus (T2DM), representing more than 95% of all diabetes cases, is a multifactorial metabolic disorder characterized by insulin resistance leading to an imbalance between insulin requirements and supply. Overweight and obesity are the main risk factors for developing type 2 diabetes mellitus. The lifestyle modification of following a healthy diet and physical activity are the primary successful treatment and prevention methods for type 2 diabetes mellitus. Problems may exist with patients not achieving recommended levels of physical activity. Electrical muscle stimulation (EMS) is an increasingly popular training method and has become in the focus of research in recent years. It involves the external application of an electric field to muscles, which can lead to muscle contraction. Positive effects of EMS training have been found in healthy individuals as well as in various patient groups. New EMS devices offer a wide range of mobile applications for whole-body electrical muscle stimulation (WB-EMS) training, e.g., the intensification of dynamic low-intensity endurance exercises through WB-EMS. This dissertation project aims to investigate whether WB-EMS is suitable for intensifying low-intensive dynamic exercises such as walking and Nordic walking.
Methods: Two independent studies were conducted. The first study aimed to investigate the reliability of exercise parameters during the 10-meter Incremental Shuttle Walk Test (10MISWT) using superimposed WB-EMS (research question 1, sub-question a) and the difference in exercise intensity compared to conventional walking (CON-W, research question 1, sub-question b). The second study aimed to compare differences in exercise parameters between superimposed WB-EMS (WB-EMS-W) and conventional walking (CON-W), as well as between superimposed WB-EMS (WB-EMS-NW) and conventional Nordic walking (CON-NW) on a treadmill (research question 2). Both studies took place in participant groups of healthy, moderately active men aged 35-70 years. During all measurements, the Easy Motion Skin® WB-EMS low frequency stimulation device with adjustable intensities for eight muscle groups was used. The current intensity was individually adjusted for each participant at each trial to ensure safety, avoiding pain and muscle cramps. In study 1, thirteen individuals were included for each sub question. A randomized cross-over design with three measurement appointments used was to avoid confounding factors such as delayed onset muscle soreness. The 10MISWT was performed until the participants no longer met the criteria of the test and recording five outcome measures: peak oxygen uptake (VO2peak), relative VO2peak (rel.VO2peak), maximum walk distance (MWD), blood lactate concentration, and the rate of perceived exertion (RPE).
Eleven participants were included in study 2. A randomized cross-over design in a study with four measurement appointments was used to avoid confounding factors. A treadmill test protocol at constant velocity (6.5 m/s) was developed to compare exercise intensities. Oxygen uptake (VO2), relative VO2 (rel.VO2) blood lactate, and the RPE were used as outcome variables. Test-retest reliability between measurements was determined using a compilation of absolute and relative measures of reliability. Outcome measures in study 2 were studied using multifactorial analyses of variances.
Results: Reliability analysis showed good reliability for VO2peak, rel.VO2peak, MWD and RPE with no statistically significant difference for WB-EMS-W during 10WISWT. However, differences compared to conventional walking in outcome variables were not found. The analysis of the treadmill tests showed significant effects for the factors CON/WB-EMS and W/NW for the outcome variables VO2, rel.VO2 and lactate, with both factors leading to higher results. However, the difference in VO2 and relative VO2 is within the range of biological variability of ± 12%. The factor combination EMS∗W/NW is statistically non-significant for all three variables. WB-EMS resulted in the higher RPE values, RPE differences for W/NW and EMS∗W/NW were not significant.
Discussion: The present project found good reliability for measuring VO2peak, rel. VO2peak, MWD and RPE during 10MISWT during WB-EMS-W, confirming prior research of the test. The test appears technically limited rather than physiologically in healthy, moderately active men. However, it is unsuitable for investigating differences in exercise intensities using WB-EMS-W compared to CON-W due to different perceptions of current intensity between exercise and rest. A treadmill test with constant walking speed was conducted to adjust individual maximum tolerable current intensity for the second part of the project. The treadmill test showed a significant increase in metabolic demands during WB-EMS-W and WB-EMS-NW by an increased VO2 and blood lactate concentration. However, the clinical relevance of these findings remains debatable. The study also found that WB-EMS superimposed exercises are perceived as more strenuous than conventional exercise. While in parts comparable studies lead to higher results for VO2, our results are in line with those of other studies using the same frequency. Due to the minor clinical relevance the use of WB-EMS as exercise intensification tool during walking and Nordic walking is limited. High device cost should be considered. Habituation to WB-EMS could increase current intensity tolerance and VO2 and make it a meaningful method in the treatment of T2DM. Recent figures show that WB-EMS is used in obese people to achieve health and weight goals. The supposed benefit should be further investigated scientifically.
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.
Aldehyde oxidases (AOXs) are a small group of enzymes belonging to the larger family of molybdo-flavoenzymes, along with the well-characterized xanthine oxidoreductase. The two major types of reactions that are catalyzed by AOXs are the hydroxylation of heterocycles and the oxidation of aldehydes to their corresponding carboxylic acids. Different animal species have different complements of AOX genes. The two extremes are represented in humans and rodents; whereas the human genome contains a single active gene (AOX1), those of rodents, such as mice, are endowed with four genes (Aox1-4), clustering on the same chromosome, each encoding a functionally distinct AOX enzyme. It still remains enigmatic why some species have numerous AOX enzymes, whereas others harbor only one functional enzyme. At present, little is known about the physiological relevance of AOX enzymes in humans and their additional forms in other mammals. These enzymes are expressed in the liver and play an important role in the metabolisms of drugs and other xenobiotics. In this review, we discuss the expression, tissue-specific roles, and substrate specificities of the different mammalian AOX enzymes and highlight insights into their physiological roles.