While outcomes for children with T-cell acute lymphoblastic leukemia have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor T-ALLs as well as in a subset (...) of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.Leukemia advance online publication, 30 May 2017; doi:10.1038/leu.2017.136. (shrink)

This paper describes the change of emphasis that occurred in the teaching of ethics to small groups of clinical students. Although the original focus of the course was on the analysis of ethical dilemmas associated with individual patients known to the students, it soon became evident that there were, for the students themselves, more fundamental ethical dilemmas in their new role as clinical students. These included worries about how to respond when patients asked questions which their consultants had previously deceived (...) them about, worries about inflicting pain on patients, as with intravenous cannulation, and the role of the medical student in the clinical team. We emphasise the need to explore student experiences as part of the process of ethics teaching. (shrink)

BackgroundFor many decades, the debate on children’s competence to give informed consent in medical settings concentrated on ethical and legal aspects, with little empirical underpinnings. Recently, data from empirical research became available to advance the discussion. It was shown that children’s competence to consent to clinical research could be accurately assessed by the modified MacArthur Competence Assessment Tool for Clinical Research. Age limits for children to be deemed competent to decide on research participation have been studied: generally children of 11.2 (...) years and above were decision-making competent, while children of 9.6 years and younger were not. Age was pointed out to be the key determining factor in children’s competence. In this article we reflect on policy implications of these findings, considering legal, ethical, developmental and clinical perspectives.DiscussionAlthough assessment of children’s competence has a normative character, ethics, law and clinical practice can benefit from research data. The findings may help to do justice to the capacities children possess and challenges they may face when deciding about treatment and research options. We discuss advantages and drawbacks of standardized competence assessment in children on a case-by-case basis compared to application of a fixed age limit, and conclude that a selective implementation of case-by-case competence assessment in specific populations is preferable. We recommend the implementation of age limits based on empirical evidence. Furthermore, we elaborate on a suitable model for informed consent involving children and parents that would do justice to developmental aspects of children and the specific characteristics of the parent-child dyad.SummaryPrevious research outcomes showed that children’s medical decision-making capacities could be operationalized into a standardized assessment instrument. Recommendations for policies include a dual consent procedure, including both child as well as parents, for children from the age of 12 until they reach majority. For children between 10 and 12 years of age, and in case of children older than 12 years in special research populations of mentally compromised patients, we suggest a case-by-case assessment of children’s competence to consent. Since such a dual consent procedure is fundamentally different from a procedure of parental permission and child assent, and would imply a considerable shift regarding some current legislations, practical implications are elaborated. (shrink)

For decades, the discussion on children’s competence to consent to medical issues has concentrated around normative concerns, with little progress in clinical practices. Decision-making competence is an important condition in the informed consent model. In pediatrics, clinicians need to strike a proper balance in order to both protect children’s interests when they are not fully able to do so themselves and to respect their autonomy when they are. Children’s competence to consent, however, is currently not assessed in a standardized way. (...) Moreover, the correlation between competence to give informed consent and age in children has never been systematically investigated, nor do we know which factors exactly contribute to children’s competence. (shrink)

The assumption underlying this collection of essays is that recent developments in philosophy and fiction have brought them closer than they have been. Novelists' insights into the ambiguity of experience, and, at the same time, philosophy's trend towards concreteness in such areas as phenomenology, point to areas of rapprochement. What the novel can do, philosophically speaking, is to formulate "the initial stages of... metaphysical thinking," and "carry out an imaginative or emotional exploration of a system of thought." In his introduction, (...) Cruickshank suggests that the French novel has developed along these lines, in the generation which begins with Bernanos and continues through Robbe-Grillet. Most of these essays explore philosophical ideas in the novels without showing how radical developments in technique actually affect them. Martin Esslin takes this further step where he notes that because of Queneau's belief in the meaninglessness of the world, the artist has creative freedom. Queneau's linguistic innovations derive in large part from this principle. Only Geoffrey Hartman, in his discussion of Blanchot, takes this vexed question of the relation between philosophy and literature down its labyrinthine paths to the point where one becomes legitimately the embodiment of the other. While many of these essays are conventional literary criticism, the best of them interpret the title in its boldest sense, and show how philosophical intent can alter the very fabric of the novel, while, alternatively, the novelist can offer genuine insight into philosophical issues.—C. L. B. (shrink)

Current UK legislation is impacting upon the feasibility and cost-effectiveness of medical record-based research aimed at benefiting the NHS and the public heath. Whereas previous commentators have focused on the Data Protection Act 1998, the Health and Social Care Act 2001 is the key legislation for public health researchers wishing to access medical records without written consent. The Act requires researchers to apply to the Patient Information Advisory Group for permission to access medical records without written permission. We present a (...) case study of the work required to obtain the necessary permissions from PIAG in order to conduct a large scale public health research project. In our experience it took eight months to receive permission to access basic identifying information on individuals registered at general practices, and a decision on whether we could access clinical information in medical records without consent took 18 months. Such delays pose near insurmountable difficulties to grant funded research, and in our case £560 000 of public and charitable money was spent on research staff while a large part of their work was prohibited until the third year of a three year grant. We conclude by arguing that many of the current problems could be avoided by returning PIAG’s responsibilities to research ethics committees, and by allowing “opt-out” consent for many public health research projects. (shrink)

Current UK legislation is impacting upon the feasibility and cost-effectiveness of medical record-based research aimed at benefiting the NHS and the public heath. Whereas previous commentators have focused on the Data Protection Act 1998, the Health and Social Care Act 2001 is the key legislation for public health researchers wishing to access medical records without written consent. The Act requires researchers to apply to the Patient Information Advisory Group for permission to access medical records without written permission. We present a (...) case study of the work required to obtain the necessary permissions from PIAG in order to conduct a large scale public health research project. In our experience it took eight months to receive permission to access basic identifying information on individuals registered at general practices, and a decision on whether we could access clinical information in medical records without consent took 18 months. Such delays pose near insurmountable difficulties to grant funded research, and in our case £560 000 of public and charitable money was spent on research staff while a large part of their work was prohibited until the third year of a three year grant. We conclude by arguing that many of the current problems could be avoided by returning PIAG’s responsibilities to research ethics committees, and by allowing “opt-out” consent for many public health research projects. (shrink)

Social conditions of race and class continue to combine in ways that raise systemic questions about the adequacy and legitimacy of liberal, capitalist democracy in America. More radical alternatives, however, are still generally held to be irrelevant in the American context. The following is an effort to correct this widespread misrepresentation of socialism’s relevance to America generally, and to matters of race in particular. I consider the work of C.L.R. James who, fifty years ago, developed a class-oriented, explicitly Marxist theory (...) in which the aspirations and struggles of African-Americans were given a central place, both analytically and politically. (shrink)

In this consensus report by a diverse group of academics who conduct and/or are concerned about social and behavioral genomics (SBG) research, the authors recount the often‐ugly history of scientific attempts to understand the genetic contributions to human behaviors and social outcomes. They then describe what the current science—including genomewide association studies and polygenic indexes—can and cannot tell us, as well as its risks and potential benefits. They conclude with a discussion of responsible behavior in the context of SBG research. (...) SBG research that compares individuals within a group according to a “sensitive” phenotype requires extra attention to responsible conduct and to responsible communication about the research and its findings. SBG research (1) on sensitive phenotypes that (2) compares two or more groups defined by (a) race, (b) ethnicity, or (c) genetic ancestry (where genetic ancestry could easily be misunderstood as race or ethnicity) requires a compelling justification to be conducted, funded, or published. All authors agree that this justification at least requires a convincing argument that a study's design could yield scientifically valid results; some authors would additionally require the study to have a socially favorable risk‐benefit profile. (shrink)

Apart from the predictable end-of-the-century tendency to look backwards in time, it is not surprising that much commentary on contemporary American politics has taken on a reflective tone as we approach the end of the 20th century. Unresolved issues of race, class, and culture continue to raise fundamental questions about the legitimacy and functioning of modern liberalism. This is as true today as it was at the beginning of the century when the capitalist social order took on its characteristically modern (...) form in America. Thus, one finds increasing numbers of contemporary academics and activists struggling to understand from whence we have come so as to provide insight and guidance for the future. (shrink)

Psychiatry is rapidly adopting digital phenotyping and artificial intelligence/machine learning tools to study mental illness based on tracking participants’ locations, online activity, phone and text message usage, heart rate, sleep, physical activity, and more. Existing ethical frameworks for return of individual research results (IRRs) are inadequate to guide researchers for when, if, and how to return this unprecedented number of potentially sensitive results about each participant’s real-world behavior. To address this gap, we convened an interdisciplinary expert working group, supported by (...) a National Institute of Mental Health grant. Building on established guidelines and the emerging norm of returning results in participant-centered research, we present a novel framework specific to the ethical, legal, and social implications of returning IRRs in digital phenotyping research. Our framework offers researchers, clinicians, and Institutional Review Boards (IRBs) urgently needed guidance, and the principles developed here in the context of psychiatry will be readily adaptable to other therapeutic areas. (shrink)