Medical Research Council

About: Medical Research Council is a government organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Malaria. The organization has 16430 authors who have published 19150 publications receiving 1475494 citations.

A guide to handling missing data in cost-effectiveness analysis conducted within randomised controlled trials.

Abstract: Missing data are a frequent problem in cost-effectiveness analysis (CEA) within a randomised controlled trial. Inappropriate methods to handle missing data can lead to misleading results and ultimately can affect the decision of whether an intervention is good value for money. This article provides practical guidance on how to handle missing data in within-trial CEAs following a principled approach: (i) the analysis should be based on a plausible assumption for the missing data mechanism, i.e. whether the probability that data are missing is independent of or dependent on the observed and/or unobserved values; (ii) the method chosen for the base-case should fit with the assumed mechanism; and (iii) sensitivity analysis should be conducted to explore to what extent the results change with the assumption made. This approach is implemented in three stages, which are described in detail: (1) descriptive analysis to inform the assumption on the missing data mechanism; (2) how to choose between alternative methods given their underlying assumptions; and (3) methods for sensitivity analysis. The case study illustrates how to apply this approach in practice, including software code. The article concludes with recommendations for practice and suggestions for future research.

Structure-function-rescue: the diverse nature of common p53 cancer mutants.

Abstract: The tumor suppressor protein p53 is inactivated by mutation in about half of all human cancers. Most mutations are located in the DNA-binding domain of the protein. It is, therefore, important to understand the structure of p53 and how it responds to mutation, so as to predict the phenotypic response and cancer prognosis. In this review, we present recent structural and systematic functional data that elucidate the molecular basis of how p53 is inactivated by different types of cancer mutation. Intriguingly, common cancer mutants exhibit a variety of distinct local structural changes, while the overall structural scaffold is largely preserved. The diverse structural and energetic response to mutation determines: (i) the folding state of a particular mutant under physiological conditions; (ii) its affinity for the various p53 target DNA sequences; and (iii) its protein-protein interactions both within the p53 tetramer and with a multitude of regulatory proteins. Further, the structural details of individual mutants provide the basis for the design of specific and generic drugs for cancer therapy purposes. In combination with studies on second-site suppressor mutations, it appears that some mutants are ideal rescue candidates, whereas for others simple pharmacological rescue by small molecule drugs may not be successful.

Physical activity and obesity prevention: a review of the current evidence

Abstract: Ecological data on temporal trends suggest that the rising prevalence of obesity is, at least in part, attributable to declining population energy expenditure. However, population-level data on trends in physical activity are scarce. In longitudinal cohort studies individuals who report higher levels of leisure-time physical activity tend to be less likely to gain weight, but studies vary in their conclusions because of issues of confounding, reverse causality and measurement error. The majority of studies suggest that low levels of activity are only weakly associated with future weight gain. Questions about dose-response can only be properly addressed by studies including objective measures of activity with known measurement error. The observational studies leave uncertainties about the direction of causality, as individuals who are overweight are less likely to stay active. Adjustment for confounding can diminish the impact of known confounders, but only randomisation can deal with issues of unmeasured confounding. Although there are a large number of clinical trials on the treatment of individuals with obesity or the prevention of weight regain among weight losers, the updated review of trials to prevent weight gain de novo only reveals six trials published since 2000 in adults and eleven in children. Not only are these trials relatively few in number but, for various methodological reasons, they are uncertain in their conclusions about whether increasing activity will be effective in preventing obesity. Whilst efforts should continue to enhance the evidence base it is wise, in the meantime, to stick to the consensus public health advice of advocating 45-60 min moderate intensity activity daily to prevent obesity.

Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia

Abstract: Understanding cancer pathogenesis requires knowledge of not only the specific contributory genetic mutations but also the cellular framework in which they arise and function. Here we explore the clonal evolution of a form of childhood precursor-B cell acute lymphoblastic leukemia that is characterized by a chromosomal translocation generating a TEL-AML1 fusion gene. We identify a cell compartment in leukemic children that can propagate leukemia when transplanted in mice. By studying a monochorionic twin pair, one preleukemic and one with frank leukemia, we establish the lineal relationship between these "cancer-propagating" cells and the preleukemic cell in which the TEL-AML1 fusion first arises or has functional impact. Analysis of TEL-AML1-transduced cord blood cells suggests that TEL-AML1 functions as a first-hit mutation by endowing this preleukemic cell with altered self-renewal and survival properties.