Optimization of novel acyl pyrrolidine inhibitors of hepatitis C virus RNA-dependent RNA polymerase leading to a development candidate

Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.

Computational simulation methodologies for mechanobiological modelling: a cell-centred approach to neointima development in stents

The design of medical devices could be very much improved if robust tools were available for computational simulation of tissue response to the presence of the implant. Such tools require algorithms to simulate the response of tissues to mechanical and chemical stimuli. Available methodologies include those based on the principle of mechanical homeostasis, those which use continuum models to simulate biological constituents, and the cell-centred approach, which models cells as autonomous agents. In the latter approach, cell behaviour is governed by rules based on the state of the local environment around the cell; and informed by experiment. Tissue growth and differentiation requires simulating many of these cells together. In this paper, the methodology and applications of cell-centred techniques-with particular application to mechanobiology-are reviewed, and a cell-centred model of tissue formation in the lumen of an artery in response to the deployment of a stent is presented. The method is capable of capturing some of the most important aspects of restenosis, including nonlinear lesion growth with time. The approach taken in this paper provides a framework for simulating restenosis; the next step will be to couple it with more patient-specific geometries and quantitative parameter data.

Individual Differences in Children’s Paths to Arithmetical Development

Cross-sectional and longitudinal data consistently indicate that mathematical difficulties are more prevalent in older than in younger children (e.g. Department of Education, 2011). Children’s trajectories can take a variety of shapes such as linear, flat, curvilinear and uneven, and shape has been found to vary within children and across tasks (J Jordan et al. 2009). There has been an increase in the use of statistical methods which are specifically designed to study development, and this has greatly improved our understanding of children’s mathematical development. However, the effects of many cognitive and social variables (e.g. working memory and verbal ability) on mathematical development are unclear. It is likely that greater consistency between studies will be achieved by adopting a componential approach to study mathematics, rather than treating mathematics as a unitary concept.

An archaeological approach to the development of the late medieval peasant house

Archaeological excavation has provided an alternative source of evidence for the development of the late medieval peasant house. It is argued that whilst there was a significant change in building techniques in the decades around 1200 with the adoption of ground-set timbers, the most important factor which led to the survival of houses was a fall in real wages during the thirteenth century. This encouraged peasants to repair existing buildings, rather than replace them with new ones. Alternative traditions of building are also investigated. Stone construction was adopted in a number of areas of England, but in spite of the durability of the material, few medieval peasant buildings of this type have survived in use because of the failure to use lime mortar. Decisions about whether to invest in a building’s renovation will depend on the capital initially expended upon it. This interpretation is considered against the data from the fifteenth century and found to conform satisfactorily. Its implications are considered for the period between 1200 and 1350. Data collected from archaeological excavations combined with the results of dendrochronology on a growing number of closely dated standing buildings suggest that there was a significant ‘cull’ of houses in the period after 1350 as new dwellings were constructed.

Does childhood bullying lead to the development of psychotic symptoms? A meta-analysis and review of prospective studies

Purpose: Researchers have demonstrated associations between trauma and psychosis. Childhood trauma, in particular, appears to be an important determinant. Recently, bullying has become considered a traumatic experience in its own right. This review aims to analyse research with prospective designs, which will enable conclusions about whether or not bullying causes psychosis.

Methods: A systematic review of the literature was carried out independently by two reviewers. Eligibility and quality assessment criteria were applied. A meta-analysis and narrative synthesis were then completed.

Results: Ten studies met inclusion criteria. Four used data from the same large database, and were combined as one. The majority provided confirmation that bullying appears to cause later development of psychosis. A meta-analysis yielded an unadjusted odds ratio (OR) of 2.148 [95% confidence interval (CI) 1.140–4.044].

Conclusions: The studies reviewed here suggest that bullying does predict the later development of psychotic symptoms. What is lacking from the literature is adequate investigation into other potential mediating factors. The current review highlights the significant role of bullying within this complex interaction. Potential mediating variables are explored, including a dose–response effect for the severity and frequency of victimization. Suggestions for targeting intervention are also suggested alongside clinical implications and recommendations for future research.