Modelling PK/QT relationships from Phase I dose‐escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations

In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose‐escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose‐concentration and concentration‐QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug–drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose‐escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision‐making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd.     

Advertising ‘Happy’ Children: The Settler Family,Happiness and the Indigenous Child Removal System

We analyse 4300 advertisements of children featured in the Today's Child column, a daily written by Helen Allen in The Toronto Telegram and The Toronto Star from 1964 to 1982, to understand how the Canadian public became accepting of the adoption of Indigenous children. While children of all ethnic backgrounds were featured, the Indigenous children who were displayed were part of a larger system of child removal, known as the ‘Sixties Scoop’. We demonstrate the ways Indigenous children are described with a specific form of happiness that is conjoined with colonial conceptions of the family and nation.     

Making Implementation More Democratic through Action Implementation Research

Public administration scholars often associate increased publicparticipation in policy implementation with the advancementof democratic values. Likewise, scholars engaged in the variousforms of action research (AR) promote their efforts as a meansto democratizing the research process or contributing to improvedsocial outcomes. Despite these common interests in participationand democracy, there have been few attempts to apply AR methodsto policy implementation problems. Drawing on Matland's conflict-ambiguitymatrix, we develop a framework for matching particular AR methodsto specific policy implementation contexts.     

Seducing Leadership: Stories of Leadership Development

This article argues that leadership development is a process of seduction. Drawing on some stories of leadership development from my experience as participant, observer and teacher I show the ways in which certain sorts of highly valued leadership teaching contain seductive elements, including sweeping audiences off their feet and, in some contexts, forestalling critique about the content that is offered. The article also considers the extent to which seduction is a gendered performance. I conclude that, while gender and power are defining elements and constraints in how seductive pedagogical relations are constructed, there are opportunities for experimentation and display that potentially subvert gendered stereotypes. Seeing the seduction in leadership can help us understand leadership and leadership teaching better, and can open the way to doing it differently — to experimentation and innovation.     

Is DNA cut out for a long life?

Much attention has been focused on the DNA repair hypothesis of aging. Studies in mammals that seek to test the validity of this model are complicated by both the functional redundancy and the essential nature of genes involved in the repair process. Compared to mammals, the study of DNA repair and aging in yeast has considerably fewer complicating factors. In this Perspective, I discuss results presented in this month's issue of Aging Cell that address whether the types of DNA damage repaired by the base excision repair pathway cause aging in yeast.     

Empirically supported ethical research practice: the costs and benefits of research from the participants' view

Researchers and institutional review boards are routinely called upon to evaluate the cost-benefit status of proposed research protocols that involve human participants. Often these assessments are based on subjective judgments in the absence of empirical data. This reliance on subjective judgments is of particular concern for studies involving clinical samples where unfounded assumptions may adversely affect research progress or clinical outcomes. The Reactions to Research Participation Questionnaire (RRPQ) was designed to address this shortcoming and to help promote ethical decision making about research practice. The present study describes development of the RRPQ and presents a series of exploratory and confirmatory analyses investigating its structure. Based on these findings, a revised version of the instrument and suggestions for future research are presented. This approach provides a foundation for scientifically informed protection of human subjects.     

The trouble with foster care: the impact of stressful 'events' on foster carers

Summary The article draws on the first stages of a large-scale longitudinalstudy into foster care with 'looked after' children. It usesdata supplied by 950 foster carers in response to a postal questionnairedesigned to document the proportions who had experienced oneor more of six potentially stressful 'events': breakdowns ordisruptions, allegations, relationship with birth parents, familytensions, 'tug of love' cases, and other disagreements withsocial services. The article uses carers' comments to describetheir reaction to the 'events'. It then examines the relationshipbetween the 'events' and measures of carer stress, satisfactionwith fostering, and intentions to continue fostering. Overall,two-thirds of the sample had experienced one or more of these'events' and these were associated with a measure of mentalill-health and with attitudes towards continuing fostering.     

Some aspects of inflation and published accounts

Company accounts are at present drafted in an uneasy compromise between different objectives. It is not yet generally appreciated that no single figure or set of figures can sum up the whole financial state of an enterprise. The basic tools of financial management are short and long-run cash projections and the reports of actual flows which monitor these. The problem in drafting annual accounts so that they will help shareholders and others to make decisions is that financial reality requires a look into the future and this in turn calls for subjective judgement. But the more realistic are the accounts in this sense, the less susceptible are they to objective audit. Inflation adds a further level of distortion, but the effects of this can be brought out in a relatively simple way by making corrections based on movements in a general index of prices. Although there are considerable practical difficulties it seems likely that a more fundamental improvement would be the introduction of a ‘current value’ or modified ‘replacement cost’ approach to ordinary accounting in addition to (but not in place of) the general index inflation correction.