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)

v. 1. Nicomachean ethics. Politics. The Athenian Constitution. Rhetoric. On Poetics.--v. 2. Logic.--v. 3. Physics. Metaphysics. On the soul. Short physical treaties.--v. 4. On the heavens. On generation and corruption. Meteorology. Biological treatises.

This article is part of a For-Discussion-Section of Methods of Information in Medicine about the paper "Biomedical Informatics: We Are What We Publish", written by Peter L. Elkin, Steven H. Brown, and Graham Wright. It is introduced by an editorial. This article contains the combined commentaries invited to independently comment on the Elkin et al. paper. In subsequent issues the discussion can continue through letters to the editor.

A substantial body of evidence suggests that autobiographical recollection and simulation of future happenings activate a shared neural network. Many of the neural regions implicated in this network are affected in patients with bipolar disorder , showing altered metabolic functioning and/or structural volume abnormalities. Studies of autobiographical recall in BD reveal overgeneralization, where autobiographical memory comprises primarily factual or repeated information as opposed to details specific in time and in place and definitive of re-experiencing. To date, no study has examined (...) whether these deficits extend to future event simulation. We examined the ability of patients with BD and controls to imagine positive, negative and neutral future events using a modified version of the Autobiographical Interview that allowed for separation of episodic and non-episodic details. Patients were selectively impaired in imagining future positive, negative, and neutral episodic details; simulation of non-episodic details was equivalent across groups. (shrink)

BackgroundIn the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort, participants underwent magnetic resonance imaging (MRI) of the brain, heart, and abdomen, that generated incidental findings (IFs). The approach to managing these unexpected results remain a complex issue. Our objectives were to describe the CAHHM policy for the management of IFs, to understand the impact of disclosing IFs to healthy research participants, and to reflect on the ethical obligations of researchers in future MRI studies.MethodsBetween 2013 and 2019, 8252 participants (...) (mean age 58 ± 9 years, 54% women) were recruited with a follow-up questionnaire administered to 909 participants (40% response rate) at 1-year. The CAHHM policy followed a restricted approach, whereby routine feedback on IFs was not provided. Only IFs of severe structural abnormalities were reported.ResultsSevere structural abnormalities occurred in 8.3% (95% confidence interval 7.7–8.9%) of participants, with the highest proportions found in the brain (4.2%) and abdomen (3.1%). The majority of participants (97%) informed of an IF reported no change in quality of life, with 3% of participants reporting that the knowledge of an IF negatively impacted their quality of life. Furthermore, 50% reported increased stress in learning about an IF, and in 95%, the discovery of an IF did not adversely impact his/her life insurance policy. Most participants (90%) would enrol in the study again and perceived the MRI scan to be beneficial, regardless of whether they were informed of IFs. While the implications of a restricted approach to IF management was perceived to be mostly positive, a degree of diagnostic misconception was present amongst participants, indicating the importance of a more thorough consent process to support participant autonomy.ConclusionThe management of IFs from research MRI scans remain a challenging issue, as participants may experience stress and a reduced quality of life when IFs are disclosed. The restricted approach to IF management in CAHHM demonstrated a fair fulfillment of the overarching ethical principles of respect for autonomy, concern for wellbeing, and justice. The approach outlined in the CAHHM policy may serve as a framework for future research studies.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/nct02220582. (shrink)

Cognitive science is currently a rapidly expanding area of research. Much is being written on it, but this collection is notable for its contributors who are extremely eminent and distinguished in the subject . The collection is well-balanced, since it includes the work of both philosophers and scientists . It will therefore appeal to all academics interested in the subject, irrespective of whether they have approached the subject from a philosophical or from a scientific point of view.

How many words is a bilingual 2-year-old supposed to know or say in each of her languages? Speech and language therapists or researchers lack the tools to answer this question, because several factors have an impact on bilingual language skills: gender, amount of exposure, mode of acquisition, socio-economic status and the distance between L1 and L2. Unfortunately, these factors are usually studied separately, making it difficult to evaluate their weight on a unique measure of vocabulary. The present study measures the (...) contribution of the following factors to the vocabulary scores of bilingual toddlers: i) gender; ii) sibling ranking; iii) relative amount of exposure to each language; iv) mode of exposure; v) SES; vi) linguistic distance; vii) language spoken between parents. Close to the child’s second birthday, parents of 278 UK-based bilinguals completed successively: a 100-word version of the Oxford-CDI, the CDI in the child’s Additional Language, a family questionnaire, and the Language Exposure Questionnaire. Thirty-six British-English-AL pairs were considered, with languages contrasted on a second-language-learning scale : for example, Dutch and French are close to British-English, while Polish or Cantonese are more distant. Data from the corpus were included in two mixed-effect models, one with the English scores in comprehension as the dependent variable, and the other with production scores. The seven factors listed above were included as predictors. The amount of English exposure was the strongest predictor of comprehension scores = 9.35, p <.005, β = 0.02, t = 3.08, p <.005), followed by the language that parents speak between themselves = 14.94, p <.001, β = 1.37, t = 3.76, p <.0005), linguistic distance = 6.92, p <.01, β = -0.74, t = -2.66, p <.01) and age = 4.86, p <.05, β = 0.55, t = 2.17, p <.05). In production, gender = 13.57, p <.0005, β = -0.91, t = -03.72, p <.0005), amount of exposure to English = 13.57, p <.0005, β = -0.91, t = -03.72, p <.0005), the language that parents speak between themselves = 11.85, p <.005, β = 1.09, t = 3.41, p <.001), and the mother’s occupation = 4.51, p <.05, β = 0.63, t = 2.13, p <.05) were the significant predictors. The more English parents use to address one another, the more English words the child says and understands. This surprising result could be simply explained by the fact that parents who speak English together are also more likely to speak English to their child. The main results of this study is that linguistic distance is a powerful predictor of toddlers’ vocabulary in English, with children learning two close languages growing their vocabulary faster than those learning distant languages. (shrink)

The paper explores the role of good faith within the traditional theory of fiduciary duty in the lead-up of the Delaware Supreme Court’s Stone ex-rel. AmSouth Bancorporation v. Ritter decision. The enforcement of the director’s liability is discussed concerning the doctrinal controversies concerning inter alia, the reach of the exculpation statute passed after the Smith v Van Gorkon holding. The paper also analyzes the conditions that a Plaintiff must survive a motion to dismiss a claim of director liability; the (...) appropriate standard of review for alleged duty of liability breaches, and the role of good faith within the overall triad of traditional fiduciary responsibilities. Over a decade after this landmark case was decided, there is value in reconsidering whether the Stone judgment lived up to the promise of the Caremark holding and its reformulation of good faith as a judicial device for evaluating director liability in contexts that not do easily fit with the traditional doctrines of duty of care and loyalty. (shrink)

The purpose of the article is to reveal philosophical ideas in the mythology and folklore of the indigenous peoples of North America. An important question: "Can we assume that the spiritual culture of the American Indians contained philosophical knowledge?" remains relevant today. For example, European philosophy is defined by appeals to philosophers of the past, their texts. The philosophical tradition is characterized by rational argumentation and formulation of philosophical questions that differ from the questions of ordinary language. However, the problem (...) lies in the term "philosophy", which belongs to the so-called "philosophical untranslatability" and has many definitions. The question of whether philosophy is exclusively a phenomenon of European culture is still controversial. In the article, the concept of philosophy is used in a broad sense, which allows the analysis of the intellectual heritage of the culture of the indigenous people of North America for philosophical ideas. Theoretical basis of the study consists of primary sources, which are limited due to the "documentary horizon". It contains myths about the Twins, ritual rhetoric, examples of dream interpretation practices and the practical wisdom of tribal chiefs. The Chronicle of "Vallamolum", or "the Red List", testifies to the special idea of the Indians about history and their own historicity. Analysis of cosmogonical and cosmological ideas reveals the special features of the anthropological ideas of the North American Indians. Combined with the philosophical ideas of the Puritan philosophy of the settlers of New England, this analysis allows us to explore in more detail the processes of acculturation. The study uses critical literature from scholars and leading researchers of the wisdom and philosophy of Native Americans, such as Michael Yellow Bird, J. Baird Callicott, Henry Wadsworth Longfellow, Dennis H. McPherson, Lewis Henri Morgan, Thomas M. Norton-Smith, J. Douglas Rabb, Paul Radin, Jon Ewbank Manchip White. The views of early American philosophers: R. Williams, W. Penn, R. W. Emerson, on the problem of the relationship between the culture of settlers and the indigenous people of North America are noteworthy. Originality lies in the application of historical and philosophical methodology, identifying the features of philosophizing in the spiritual culture and worldview of the indigenous people of North America. Conclusions. In the conclusions, the obtained results complement the history of the origin and development of philosophical thought of the early American philosophy. (shrink)

In recent years there has been an increasing awareness that a comprehensive understanding of language, cognitive and affective processes, and social and interpersonal phenomena cannot be achieved without understanding the ways these processes are grounded in bodily states. The term ‘embodiment’ captures the common denominator of these developments, which come from several disciplinary perspectives ranging from neuroscience, cognitive science, social psychology, and affective sciences. For the first time, this volume brings together these varied developments under one umbrella and furnishes a (...) comprehensive overview of this intellectual movement in the cognitive-behavioral sciences. (shrink)

RECENT attempts to explain and justify Aristotle's principle of non-contradiction have focused to a great extent on the dialectical dimension of Aristotle's account. For example, T. Irwin maintains that Aristotle justifies the PNC by arguing that there is a sub-set of dialectical opinions which no one can rationally give up. J. Lear supports the importance of the dialectical dimension by summarizing Aristotle's defense of the PNC as follows: The opponent of the PNC tries to argue dialectically that one should not (...) accept it. "Aristotle's point is that there is no conceptual space in which such a rational discussion can occur." By appealing to the limits of rationally, externally, expressible discourse as the basis of the PNC, Irwin and Lear fail to take seriously the more explicitly psychological and metaphysical bases of the PNC. C. Kirwan, and most recently, R. Smith also either argue against or ignore the role of the psychological and metaphysical bases. Smith goes so far as to argue that common axioms like the PNC are simply empty statement schemata of universal validity, i.e., general verbal forms or patterns which no one can deny with intelligibility. (shrink)

We describe the ethics consultation service (ECS) at the Cleveland Clinic and report on its activities over a 24-month period in which 478 consultations were performed. To our knowledge, this is the largest case series of ethics consultations reported to date. Established more than 25 years ago, the ECS at the Cleveland Clinic is staffed by multiple consultants with advanced training in bioethics. Several of these ethicists work closely with specialized clinical units and research departments, where they participate in multidisciplinary (...) meetings and provide specialized assistance. This combination of historical experience, large numbers of consultation requests, and specialized clinical ethicists suggests that the experience at the Cleveland Clinic may be helpful to ethicists and others who may be considering how to structure and sustain a vibrant ECS. Our results highlight the diversity of activities performed by a high-volume ECS at a tertiary care facility. Our hope in sharing the inner workings of the ECS at the Cleveland Clinic is to promote dialogue on common practices and approaches across medical institutions that support ethics consultation. (shrink)

It is generally accepted that appropriate documentation of activities and recommendations of ethics consultants in patients’ medical records is critical. Despite this acceptance, the bioethics literature is largely devoid of guidance on key elements of an ethics chart note, the degree of specificity that it should contain, and its stylistic tenor. We aim to provide guidance for a variety of persons engaged in clinical ethics consultation: new and seasoned ethics committee members who are new to ethics consultation, students and trainees (...) in clinical ethics, and those who have significant experience with ethics consultation so that they can reflect on their practice. Toward the goal of promoting quality charting practices in ethics consultations, we propose recommendations on a broad array of questions concerning clinical ethics consultation chart notes, including whether and when to write a chart note, and practical considerations for the tenor, purpose, and content of a chart note. Our broader aim is to promote discussion about good charting practices in clinical ethics, with the hope of contributing to clear standards of excellence in clinical ethics consultation. (shrink)

In this paper, we describe the use of legal ontologies as a basis to improve IT support for professional judges. As opposed to most legal ontologies designed so far, which are mostly based on dogmatic and normative knowledge, we emphasize the importance of professional knowledge and experience as an important pillar for constructing the ontology. We describe an intelligent FAQ system for junior judges that intensively use the ontology.

Because men are overrepresented within positions of power, men are perceived as the default in academia. Androcentric bias emerges whereby research by men and/or dominated by men is perceived as higher quality and gains more attention. We examined if these androcentric biases materialize within fields that study bias. How do individuals in close contact with psychology view psychology research outlets with titles including the words women, gender, sex, or feminism or contain the words men or masculinity versus psychology journals that (...) publish other-specialized research, and do these perceptions differ in the general public? While the men-related journal was less meritorious than its other-specialty journal, evidence emerged supporting androcentric bias such that the men-related journal was more favorable than the other sex/gender-related journals. Further, undergraduate men taking psychology classes rated sex/gender-related versus other-specialty journals as less favorable, were less likely to recommend subscription, and rated the journals as lower quality. Low endorsement of feminist ideology was associated with less support for sex/gender-related journals versus matched other-specialty journals. Decreased subscription recommendations for sex/gender-related journals were mediated by decreased favorability and quality beliefs, especially for men and those low in feminist ideology. However, we found possible androcentric-interest within the public sphere. The public reach of articles published in sex/gender-related was greater than other-specialty journals. The consequences of these differential perceptions for students versus the public and the impact on women’s advancement in social science and psychological science are discussed. (shrink)