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)

In face of the multiple controversies surrounding the DSM process in general and the development of DSM-5 in particular, we have organized a discussion around what we consider six essential questions in further work on the DSM. The six questions involve: 1) the nature of a mental disorder; 2) the definition of mental disorder; 3) the issue of whether, in the current state of psychiatric science, DSM-5 should assume a cautious, conservative posture or an assertive, transformative posture; 4) the role (...) of pragmatic considerations in the construction of DSM-5; 5) the issue of utility of the DSM – whether DSM-III and IV have been designed more for clinicians or researchers, and how this conflict should be dealt with in the new manual; and 6) the possibility and advisability, given all the problems with DSM-III and IV, of designing a different diagnostic system. Part 1 of this article took up the first two questions. Part 2 took up the second two questions. Part 3 now deals with Questions 5 & 6. Question 5 confronts the issue of utility, whether the manual design of DSM-III and IV favors clinicians or researchers, and what that means for DSM-5. Our final question, Question 6, takes up a concluding issue, whether the acknowledged problems with the earlier DSMs warrants a significant overhaul of DSM-5 and future manuals. As in Parts 1 & 2 of this article, the general introduction, as well as the introductions and conclusions for the specific questions, are written by James Phillips, and the responses to commentaries are written by Allen Frances. (shrink)

Giordano Bruno (1548-1600), who died at the stake, is one of the best-known symbols of anti-establishment thought. The theme of this volume, which is offered as a collection of essays to honor the distinguished Bruno scholar Hilary Gatti, reflects her constant concern for the principles of cultural freedom and independent thinking. Several essays deal with Bruno himself, including an analysis of the Eroici furori, a study of his reception in relation to the group known as the Novatores, and discussions of (...) several important aspects of his stay in England. The authors and texts discussed here are linked by a relentless interest in the question of authority and originality, and they range from literary figures such as Alberti (1404-72), Vasari (1511-74) and the proponents of quantitative verse in sixteenth-century England to controversial philosophers who, like Bruno, were condemned by the Church, such as Tommaso Campanella (1568-1639) and Giulio Cesare Vanini (1585-1619). Taken together, these chapters show how much that was new and revolutionary in early modern culture came from its confrontation with the past. Martin McLaughlin is Agnelli-Serena Professor of Italian at Oxford. Elisabetta Tarantino is a Teaching Fellow in the Department of Italian at the University of Warwick. (shrink)

Checklists have been used to improve quality in many industries, including healthcare. The use of checklists, however, has not been extensively evaluated in clinical ethics consultation. This article seeks to fill this gap by exploring the efficacy of using a checklist in ethics consultation, as tested by an empirical investigation of the use of the checklist at a large academic medical system (Cleveland Clinic). The specific aims of this project are as follows: (1) to improve the quality of ethics consultations (...) by providing reminders to ethics consultants about process steps that are important for most patient-centered ethics consultations, (2) to create consistency in the ethics consultation process across the medical system, and (3) to establish an effective educational tool for trainers and trainees in clinical ethics consultation. The checklist was developed after a thorough literature review and an iterative process of revising and testing by a group of experienced ethics consultants. To pilot test the checklist, it was distributed to 46 ethics consultants. After a six-month pilot period in which ethics professionals used the checklist during their clinical activities, a survey was distributed to all of those who used the checklist. The 10-item survey examined consultants’ perceptions regarding the three aims listed above. Of the 25 survey respondents, 11 self-reported as experts in ethics consultation, nine perceived themselves to have mid-level expertise, and five self-reported as novices. The majority (68 percent) of all respondents, regardless of expertise, believed that the checklist could be a “helpful” or “very helpful” tool in the consultation process generally. Novices were more likely than experts to believe that the checklist would be useful in conducting consultations. The limitations of this study include: reduced generalizability given that this project was conducted at one medical system, utilized a small sample size, and used self-reported quality outcome measures. Despite these limitations, to the authors’ knowledge this is the first investigatation of the use of a checklist systematically to improve quality in ethics consultation. Importantly, our findings shed light on ways this checklist can be used to improve ethics consultation, including its use as an educational tool. The authors hope to test the checklist with consultants in other healthcare systems to explore its usefulness in different healthcare environments. (shrink)

On eight Sunday mornings between 15 January 1922 and 12 March 1922 Martin Buber delivered a series of lectures at the Frankfort Freies Jüdisches Lehrhaus, at the request of its director, Franz Rosenzweig. Entitled "Religion als Gegenwart", these lectures provided the stenographer’s copy from which Buber, in subsequent months, wrote his influential work, I and Thou. The present book publishes these lectures for the first time, without translation, and offers as well an historical analysis of the developments in Buber’s thinking (...) that surround the writing of I and Thou. The author provides a service in both regards. (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)

The well-established finding that siblings growing up in the same family turn out to be very different from one another has puzzled psychologists and behavior geneticists alike. In this theoretical note we describe the possible ontogeny and phylogeny of a sibling differentiation mechanism. We suggest that sibling competition for parental investment results in sibling differentiation on a number of characteristics, producing different developmental trajectories within families. Variations in developmental trajectories within families may have had fitness advantages in ancestral environments because(a) (...) sibling competition for extrafamilial resources would be reduced and(b) these variations would be suited to environments containing a variety of niches or to changing environments. Predictions derived from this model and an example of an application to attachment theory are presented. (shrink)

Synaesthesia is a condition in which one type of stimulation evokes the sensation of another, as when the hearing of a sound produces photisms, i.e. mental percepts of colours. R is a 20 year old colour blind subject who, in addition to the relatively common grapheme-colour synaesthesia, presents a rarely reported cross modal perception in which a variety of visual stimuli elicit aura-like percepts of colour. In R, photisms seem to be closely related to the affective valence of stimuli and (...) typically bring out a consistent pattern of emotional responses. The present case study suggests that colours might be an intrinsic category of the human brain. We developed an empirical methodology that allowed us to study the subject's otherwise inaccessible phenomenological experience. First, we found that R shows a Stroop effect elicited by photisms despite the fact that he does not show a regular Stroop with real colours. Secondly, by manipulating the colour context we confirmed that colours can alter R's emotional evaluation of the stimuli. Furthermore, we demonstrated that R's auras may actually lead to a partially inverted emotional spectrum where certain stimuli bring out emotional reactions opposite to the normal ones. These findings can only be accounted for by considering R's subjective colour experience or qualia. Therefore the present paper defends the view that qualia are a useful scientific concept that can be approached and studied by experimental methods. (shrink)

Synaesthesia is a condition in which one type of stimulation evokes the sensation of another, as when the hearing of a sound produces photisms, i.e. mental percepts of colours. R is a 20 year old colour blind subject who, in addition to the relatively common grapheme-colour synaesthesia, presents a rarely reported cross modal perception in which a variety of visual stimuli elicit aura-like percepts of colour. In R, photisms seem to be closely related to the affective valence of stimuli and (...) typically bring out a consistent pattern of emotional responses. The present case study suggests that colours might be an intrinsic category of the human brain. We developed an empirical methodology that allowed us to study the subject's otherwise inaccessible phenomenological experience. First, we found that R shows a Stroop effect (delayed response due to interference) elicited by photisms despite the fact that he does not show a regular Stroop with real colours. Secondly, by manipulating the colour context we confirmed that colours can alter R's emotional evaluation of the stimuli. Furthermore, we demonstrated that R's auras may actually lead to a partially inverted emotional spectrum where certain stimuli bring out emotional reactions opposite to the normal ones. These findings can only be accounted for by considering R's subjective colour experience or qualia. Therefore the present paper defends the view that qualia are a useful scientific concept that can be approached and studied by experimental methods. (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)

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)

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)

In Computer Science stepwise refinement of algebraic specifications is a well-known formal methodology for rigorous program development. This paper illustrates how techniques from Algebraic Logic, in particular that of interpretation, understood as a multifunction that preserves and reflects logical consequence, capture a number of relevant transformations in the context of software design, reuse, and adaptation, difficult to deal with in classical approaches. Examples include data encapsulation and the decomposition of operations into atomic transactions. But if interpretations open such a new (...) research avenue in program refinement, (conceptual) tools are needed to reason about them. In this line, the paper’s main contribution is a study of the correspondence between logical interpretations and morphisms of a particular kind of coalgebras. This opens way to the use of coalgebraic constructions, such as simulation and bisimulation, in the study of interpretations between (abstract) logics. (shrink)

Nanomedicine is yielding new and improved treatments and diagnostics for a range of diseases and disorders. Nanomedicine applications incorporate materials and components with nanoscale dimensions where novel physiochemical properties emerge as a result of size-dependent phenomena and high surface-to-mass ratio. Nanotherapeutics and in vivo nanodiagnostics are a subset of nanomedicine products that enter the human body. These include drugs, biological products, implantable medical devices, and combination products that are designed to function in the body in ways unachievable at larger scales. (...) Nanotherapeutics andin vivonanodiagnostics incorporate materials that are engineered at the nanoscale to express novel properties that are medicinally useful. These nanomedicine applications can also contain nanomaterials that are biologically active, producing interactions that depend on biological triggers. Examples include nanoscale formulations of insoluble drugs to improve bioavailability and pharmacokinetics, drugs encapsulated in hollow nanoparticles with the ability to target and cross cellular and tissue membranes and to release their payload at a specific time or location, imaging agents that demonstrate novel optical properties to aid in locating micrometastases, and antimicrobial and drug-eluting components or coatings of implantable medical devices such as stents. (shrink)

The clinical ethicist met with Ms. H to clarify what information she wants and does not want to know. First, she wants to receive any treatment that could prolong her life, regardless of how the treatment affects her ability to engage in activities of daily living. Second, she wants to be included in the decision‐making process as much as possible, as long as clinicians use only “positive” language. Ms. H considers the words “dying,” “chemotherapy,” “radiation,” and “cancer” to be “bad (...) words.” For conversations in which these words cannot be avoided, she wants her clinicians to talk to her son. Her desired engagement includes hearing about risks, benefits, and alternatives to treatments if clinicians use only “positive” language. Finally, she says that she rarely sees doctors and that she is “very scared” of hospitals, despite exhibiting a comfortable demeanor.Should clinicians honor Ms. H's waiver of specified information and, if so, to what degree? (shrink)

In Neutrality and the Academic Ethic, distinguished philosopher Robert L. Simon explores the claim that universities can and should be politically neutral. He examines conceptual questions about the meaning of neutrality, distinguishes different conceptions of what neutrality involves, and considers in what sense, if any, institutional neutrality is both possible and desirable. In Part II, a collection of original and previously published essays provides different views on these and related issues.

Young men are more distressed by a partner’s sexual infidelity, whereas young women are more distressed by a partner’s emotional infidelity. The present research investigated (a) whether the sex difference in jealousy replicates in an older sample, and (b) whether younger people differ from older people in their selection of the more distressing infidelity scenario. We presented forced-choice dilemmas to 202 older people (mean age = 67 years) and to 234 younger people (mean age = 20 years). The sex difference (...) replicated in the older sample. In addition, older women were less likely than younger women to select a partner’s emotional infidelity as more distressing than a partner’s sexual infidelity. Discussion offers directions for future work on sex differences and age differences in jealousy. (shrink)

Introduction Currently, The nature and scope of Clinical Ethics Protocols in Madrid are not well understood.Objectives The main objective is to describe the features of ‘guideline/recommendation’ type CEPs that have been or are being developed by existing Clinical Ethics Committees in Madrid. Secondary objectives include characterisation of those CECs that have been the most prolific in reference to CEP creation and implementation and identification of any trends in future CEP development.Methods We collected CEPs produced and in process by CECs accredited (...) in the public hospitals in Madrid, Spain, from 1996 to 2008.Results CECs developed 30 CEPs, with 10 more in process. The most common topic is refusal of treatment . If CEPs addressing terminal illness, Do-Not-Resuscitate orders and advance directives are placed into a separate ‘ethical problems at the end of life’ category, this CEP subject emerges as the most common . There is a relationship between the age of the CEC and the development of CEPs . CECs now seem to be more likely to engage in CEP development.Conclusions The CECs in Madrid, Spain, have developed a significant number of CEPs and there is a trend towards continued development. The most frequent topics are ethical problems at the end of life and refusal of treatment by the patient. (shrink)

BackgroundPreprint usage is growing rapidly in the life sciences; however, questions remain on the relative quality of preprints when compared to published articles. An objective dimension of quality that is readily measurable is completeness of reporting, as transparency can improve the reader’s ability to independently interpret data and reproduce findings.MethodsIn this observational study, we initially compared independent samples of articles published in bioRxiv and in PubMed-indexed journals in 2016 using a quality of reporting questionnaire. After that, we performed paired comparisons (...) between preprints from bioRxiv to their own peer-reviewed versions in journals.ResultsPeer-reviewed articles had, on average, higher quality of reporting than preprints, although the difference was small, with absolute differences of 5.0% [95% CI 1.4, 8.6] and 4.7% [95% CI 2.4, 7.0] of reported items in the independent samples and paired sample comparison, respectively. There were larger differences favoring peer-reviewed articles in subjective ratings of how clearly titles and abstracts presented the main findings and how easy it was to locate relevant reporting information. Changes in reporting from preprints to peer-reviewed versions did not correlate with the impact factor of the publication venue or with the time lag from bioRxiv to journal publication.ConclusionsOur results suggest that, on average, publication in a peer-reviewed journal is associated with improvement in quality of reporting. They also show that quality of reporting in preprints in the life sciences is within a similar range as that of peer-reviewed articles, albeit slightly lower on average, supporting the idea that preprints should be considered valid scientific contributions. (shrink)

A high percent of oxidative energy metabolism is needed to support brain growth during infancy. Unhealthy diets and limited nutrition, as well as other environmental insults, can compromise these essential developmental processes. In particular, iron deficiency anemia has been found to undermine both normal brain growth and neurobehavioral development. Even moderate ID may affect neural maturation because when iron is limited, it is prioritized first to red blood cells over the brain. A primate model was used to investigate the neural (...) effects of a transient ID and if deficits would persist after iron treatment. The large size and postnatal growth of the monkey brain makes the findings relevant to the metabolic and iron needs of human infants, and initiating treatment upon diagnosis of anemia reflects clinical practice. Specifically, this analysis determined whether brain maturation would still be compromised at 1 year of age if an anemic infant was treated promptly once diagnosed. The hematology and iron status of 41 infant rhesus monkeys was screened at 2-month intervals. Fifteen became ID; 12 met clinical criteria for anemia and were administered iron dextran and B vitamins for 1–2 months. MRI scans were acquired at 1 year. The volumetric and diffusion tensor imaging measures from the ID infants were compared with monkeys who remained continuously iron sufficient. A prior history of ID was associated with smaller total brain volumes, driven primarily by significantly less total gray matter and smaller GM volumes in several cortical regions. At the macrostructual level, the effect on white matter volumes was not as overt. However, DTI analyses of WM microstructure indicated two later-maturating anterior tracts were negatively affected. The findings reaffirm the importance of iron for normal brain development. Given that brain differences were still evident even after iron treatment and following recovery of iron-dependent hematological indices, the results highlight the importance of early detection and preemptive supplementation to limit the neural consequences of ID. (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)