Moxidectin is a frontrunner drug candidate in the treatment of strongyloidiasis. A dose of 8 mg is recommended to treat this indication, which shows a reasonably good efficacy and tolerability ...profile. Yet, owing to the unique life cycle of Strongyloides stercoralis (S. stercoralis) that entails internal autoinfection, a curative treatment would be desirable. Population‐based pharmacometric modeling that would help to identify an ideal dosing strategy are yet lacking. The aims of this study were to (i) explore the exposure‐efficacy response relationship of moxidectin in treating S. stercoralis and (ii) evaluate whether moxidectin treatment outcomes in terms of cure rates at baseline as compared to post‐treatment could be optimized. Our pharmacodynamic model suggests high predictive power (area under the concentration time curve‐receiver operating characteristic AUC‐ROC 0.817) in the probability of being cured by linking an exposure metric (i.e., AUC0‐24 or maximum concentration Cmax) to baseline infection intensity. Pharmacometric simulations indicate that with a minimum dose of 4 mg a maximum cure rate of ~ 95% is established in the low infection intensity group (larvae per gram LPG ≥0.4–1), whereas in the moderate‐to‐high intensity group (LPG >1) the cure rate plateaus at ~ 87%, following an 8 mg dose. To enhance efficacy further, studies using repeated dosing based on the duration of the autoinfection cycle, for example a two‐dose regimen 3 weeks apart should be considered. Simulations revealed similar Cmax in both treatment courses of a two‐dose regimen; hence safety should not be a concern. Collectively, our results provide evidence‐based guidance for enhanced dosing strategies and should be considered when designing future treatment strategies.
This paper argues that personal and group migration (as a subset of mobility) was a central feature of Linearbandkeramik (c. 5500-4900 cal BC) life, and not confined to short-term events along the ...agricultural frontier. The first part summarises the data currently available on individual migration (mostly interpreted as female exogamy) and the migration of households or groups of households. It is noted that in current models, migratory behaviour is often seen as pertaining to lower-status groups or that it constitutes a crisis response. In the second part of the paper, I outline the evidence, both isotopic and archaeological, for migration as a constant behaviour and show where this has opened up avenues for new research, notably concerning the use of non-loess areas. In turn, narratives suggesting an increase in hierarchical differences throughout the LBK as a whole are challenged. It is argued that migration was an accepted social strategy that could be used to gain status, and counteracted the creation of hereditary and durable social stratification in established settlement sites. Seeing migration as a constant in LBK life can thus lead to a reinterpretation of other aspects of this early farming society.
Dengue fever is a severe, widespread, and neglected disease with more than 2 million diagnosed infections per year. The dengue virus NS2B/NS3 protease (PR) represents a prime target for rational drug ...design. At the moment, there are no clinical PR inhibitors (PIs) available. We have identified diaryl (thio)ethers as candidates for a novel class of PIs. Here, we report the selective and noncompetitive inhibition of the serotype 2 and 3 dengue virus PR in vitro and in cells by benzothiazole derivatives exhibiting 50% inhibitory concentrations (IC50s) in the low-micromolar range. Inhibition of replication of DENV serotypes 1 to 3 was specific, since all substances influenced neither hepatitis C virus (HCV) nor HIV-1 replication. Molecular docking suggests binding at a specific allosteric binding site. In addition to the in vitro assays, a cell-based PR assay was developed to test these substances in a replication-independent way. The new compounds inhibited the DENV PR with IC50s in the low-micromolar or submicromolar range in cells. Furthermore, these novel PIs inhibit viral replication at submicromolar concentrations.
In this article, we critically review recurrent tropes, implicit frameworks, and unexplained concepts in current research on the process of “Neolithisation” in the western part of southern Norway. ...Two models are on offer, as also seen elsewhere in the European research: either 1) the transition to agriculture is rapid and substantially carried by migrants, or 2) the Late Neolithic transition builds on a long history of local adaptation. After outlining these models, we scrutinise especially west Norwegian evidence, pointing out ambiguities and limitations in the material which mean that neither of the two models fit. In the final section, we consider which new questions could be asked to move beyond the current, somewhat polarised debate: Who are the actors of the transition, how are boundaries between groups created, and can the acknowledgement of the complexity of the process of ‘migration’ result in new narratives? Addressing these questions remains a fundamental challenge for archaeological migration studies as a whole.
Community differentiation is a fundamental topic of the social sciences, and its prehistoric origins in Europe are typically assumed to lie among the complex, densely populated societies that ...developed millennia after their Neolithic predecessors. Here we present the earliest, statistically significant evidence for such differentiation among the first farmers of Neolithic Europe. By using strontium isotopic data from more than 300 early Neolithic human skeletons, we find significantly less variance in geographic signatures among males than we find among females, and less variance among burials with ground stone adzes than burials without such adzes. From this, in context with other available evidence, we infer differential land use in early Neolithic central Europe within a patrilocal kinship system.
The fifth millennium is characterized by far-flung contacts and a veritable flood of innovations. While its beginning is still strongly reminiscent of a broadly Linearbandkeramik way of life, at its ...end we find new, inter-regionally valid forms of symbolism, representation and ritual behaviour, changes in the settlement system, in architecture and in routine life. Yet, these inter-regional tendencies are paired with a profusion of increasingly small-scale archaeological cultures, many of them defined through pottery only. This tension between large-scale interaction and more local developments remains ill understood, largely because inter-regional comparisons are lacking. Contributors in this volume provide up-to-date regional overviews of the main developments in the fifth millennium and discuss, amongst others, in how far ceramically-defined 'cultures' can be seen as spatially coherent social groups with their own way of life and worldview, and how processes of innovation can be understood. Case studies range from the Neolithisation of the Netherlands, hunter-gatherer - farmer fusions in the Polish Lowlands, to the Italian Neolithic. Amongst others, they cover the circulation of stone disc-rings in western Europe, the formation of post-LBK societies in central Europe and the reliability of pottery as an indicator for social transformations.
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