We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls. Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents. Probands were more likely to carry an additional large copy-number variant when compared to matched controls. The clinical (...) features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease. © 2010 Nature America, Inc. All rights reserved. (shrink)

Avoiding whinges from various and potentially conflicting stakeholders is a major challenge for sustainable development and for the identification of sustainability scenarios or policies for biodiversity and ecosystem services. It turns out that independently complying with whinge thresholds and constraints of these stakeholders is not sufficient because dynamic ecological-economic interactions and uncertainties occur. Thus more demanding no whinge standards are needed. In this paper, we first argue that these new boundaries can be endogenously exhibited with the mathematical concepts of viability (...) kernel and viable controls. Second, it is shown how these no whinge kernels have components, such as harvesting of resources, that should remain within safe corridor while some other components, in particular biodiversity, have only lower conservation limits. Thus, using radar charts, we show how this no whinge kernels can take the shape of a tree that we name viability tree. These trees of viability capture the idea that the unbounded renewal potential of biodiversity combined with a bounded use of the different ecosystem services are crucial ingredients for the sustainability of socio-ecosystems and the design of no whinge policies reconciling the different stakeholders involved. (shrink)

© 2015, Springer-Verlag Berlin Heidelberg.Genetic studies have identified single nucleotide polymorphisms associated with the risk of prostate cancer. It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score and aggressiveness. Statistical analyses were used to compare the frequency (...) of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 was significantly and inversely associated with aggressive and high-grade disease in European men. Similar associations with aggressive and high-grade disease were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness. (shrink)

Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that (...) has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility. (shrink)

The format of this book is unusual, especially for a book about linguistics. The book is meant primarily as a research monograph aimed at linguists who have some background in formal semantics, e. g. Montague Grammar. However, I have two other audiences in mind. Linguists who have little or no experience of formal semantics, but who have worked through a basic mathematics for linguists course (e. g. using Wall, 1972, or Partee, 1978), should, perhaps with the help of a sympathetic (...) Montague gramma rian, be able to discover enough of how I have adapted some of the basic ideas in formal semantics to make the developments that I undertake in the rest of the book accessible. Logicians and computer scientists who know about model theoretic semantics and formal systems should be able to glean enough from Chapters I and II about linguistic concerns and techniques to be able to read the remainder of the book, again possibly with the help of a sympathetic Montague grammarian. However, readers should beware. Chapter II is not meant as a general introduction either to formal semantics or to linguistics and while much of the presentation there is going over ground that is already well covered in the literature, the particular formulation and the emphases are very much oriented to the developments to be undertaken later in the book. (shrink)

Humans are experts in cooperating with each other when trying to accomplish tasks they cannot achieve alone. Recent studies of joint action have shown that when performing tasks together people strongly rely on the neurocognitive mechanisms that they also use when performing actions individually, that is, they predict the consequences of their co‐actor’s behavior through internal action simulation. Context‐sensitive action monitoring and action selection processes, however, are relatively underrated but crucial ingredients of joint action. In the present paper, we try (...) to correct the somewhat simplified view on joint action by reviewing recent studies of joint action simulation, monitoring, and selection while emphasizing the intricate interrelationships between these processes. We complement our review by defining the contours of a neurologically plausible computational framework of joint action. (shrink)

Empirical ethics research is increasingly valued in bioethics and healthcare more generally, but there remain as yet under-researched areas such as pharmacy, despite the increasingly visible attempts by the profession to embrace additional roles beyond the supply of medicines. A descriptive and critical review of the extant empirical pharmacy ethics literature is provided here. A chronological change from quantitative to qualitative approaches is highlighted in this review, as well as differing theoretical approaches such as cognitive moral development and the four (...) principles of biomedical ethics. Research with pharmacy student cohorts is common, as is representation from American pharmacists. Many examples of ethical problems are identified, as well as commercial and legal influences on ethical understanding and decision making. In this paper, it is argued that as pharmacy seeks to develop additional roles with concomitant ethical responsibilities, a new prescription is needed for empirical ethics research in pharmacy—one that embraces an agenda of systematic research using a plurality of methodological and theoretical approaches to better explore this under-researched discipline. (shrink)

Live donor kidney transplantation is the best treatment option for most patients with late-stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. A consensus conference was held June 5-6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor (...) evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation. (shrink)

Rita Bottino,1 Santosh Nagaraju,2 Vikas Satyananda,2 Hidetaka Hara,2 Martin Wijkstrom,2 Massimo Trucco,1 David KC Cooper2 1Institute of Cellular Therapeutics, Allegheny Health Network, 2Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA: Diabetes mellitus is increasing worldwide. Type 1 diabetes can be treated successfully by islet allotransplantation, the results of which are steadily improving. However, the number of islets that can be obtained from deceased human donors will never be sufficient to cure more than a very (...) small percentage of patients who might benefit from transplantation. Although there are some differences in glucose metabolism between pigs and humans, the use of pigs could provide an unlimited supply of islets, and the insulin produced would undoubtedly control glucose levels. Transplantation of islets into the portal vein results in islets residing in the liver; however, an early inflammatory response and rejection remain problematic, even when the recipient is receiving immunosuppressive therapy. In the long term, immunosuppressive drugs may exhibit toxicities to patients and specifically harm the islet cells. In contrast, encapsulation techniques provide islets with a physical barrier that prevents antibodies binding to the islet graft while still allowing insulin to be released into the recipient's circulation; in theory, patients receiving encapsulated grafts might not require exogenous immunosuppressive therapy. Nonhuman primates with encapsulated pig islet transplants have remained insulin-independent for several weeks, but long-term efficacy remains uncertain. Furthermore, techniques are now available to knock out genes from the pig and/or insert human genes, thus rendering the antigenic structure of pigs closer to that of humans, and providing protection from the human immune response. Islet transplantation from genetically engineered pigs has been followed by insulin independence in a small number of nonhuman primates for greater than 1 year. Neonatal islets have some advantages over adult islets in that they are easier to isolate and culture, and have the ability to proliferate during the first few months after transplantation. In 2009, the International Xenotransplantation Association set up a group to encourage and advise on clinical trials of pig islet xenotransplantation; this group's guidelines are discussed. Clinical trials of encapsulated pig islets are already under way. Keywords: diabetes, islets, pancreatic, pig, xenotransplantation. (shrink)

Do UK community pharmacists encounter the high drama dilemmas of the medical ethics literature or is a 'morality of the mundane' more appropriate? This paper presents the findings of a qualitative study that asked a sample of UK pharmacists to describe their ethical issues and to establish whether these were ethical dilemmas as understood philosophically or ethical problems of a more legal or emotional nature. It emerged that although many pharmacists referred to 'dilemmas', these were often problems involving a conflict (...) between an ethical value and a legal or procedural issue and often arose in the routine minutiae of dispensing prescriptions and selling medicines. Such ethical problems remained of concern for pharmacists and the commercial environment, corporate pharmacy ownership and pharmacists' subordination to doctors, all precipitated ethical problems. Law and ethics appeared to be understood synonymously but this may reflect a modernity that increasingly brackets out ethical experiences by encouraging reliance upon law and procedure. (shrink)

The key objectives of this book are to demonstrate the applicability of issues in the philosophy of science to problems in psychiatry and to show how the conceptual issues raised by psychiatry should be considered more closely by philosophers of science. These are worthy aims: the philosophy of psychiatry needs to draw more thoughtfully upon contemporary philosophical debates and stimulating interest within the philosophy of science is a good way to do this.Cooper's book succeeds for both of these desiderata. (...) The first five chapters discuss the central issues in the philosophy of psychiatry: whether mental illness is a disease/natural kind and what follows from this. There is a large literature on these questions, some of which …. (shrink)

Background: Increasing interest in empirical ethics has enhanced understanding of healthcare professionals’ ethical problems and attendant decision-making. A four-stage decision-making model involving ethical attention, reasoning, intention and action offers further insights into how more than reasoning alone may contribute to decision-making.Aims: To explore how the four-stage model can increase understanding of decision-making in healthcare and describe the decision-making of an under-researched professional group.Methods: 23 purposively sampled UK community pharmacists were asked, in semi-structured interviews, to describe ethical problems in their work (...) and how they were resolved. Framework analysis of transcribed interviews utilised the four decision-making stages, together with constant comparative methods and deviant-case analysis.Results: Pharmacists were often inattentive and constructed problems in legal terms. Ethical reasoning was limited, but examples of appeals to consequences, the golden rule, religious faith and common-sense experience emerged. Ethical intention was compromised by frequent concern about legal prosecution. Ethical inaction was common, typified by pharmacists’ failure to report healthcare professionals’ bad practices, and ethical passivity emerged to describe these negative examples of the four decision-making stages. Pharmacists occasionally described more ethically active decision-making, but this often involved ethical uncertainty.Discussion: The four decision-making stages are a useful tool in considering how healthcare professionals try to resolve ethical problems in practice. They reveal processes often ignored in normative theories, and their recognition and the emergence of ethical passivity indicates the complexity of decision-making in practice. Ethical passivity may be deleterious to patients’ welfare, and concerns emerge about improving pharmacists’ ethical training and promoting ethical awareness and responsibility. (shrink)

Social evolution theory conventionally takes an externalist explanatory stance, treating observed cooperation as explanandum and the positive assortment of cooperative behaviour as explanans. We ask how the circumstances bringing about this positive assortment arose in the first place. Rather than merely push the explanatory problem back a step, we move from an externalist to an interactionist explanatory stance, in the spirit of Lewontin and the Niche Construction theorists. We develop a theory of ‘social niche construction’ in which we consider biological (...) entities to be both the subject and object of their own social evolution. Some important cases of the evolution of cooperation have the side-effect of causing changes in the hierarchical level at which the evolutionary process acts. This is because the traits that act to align the fitness interests of particles in a collective can also act to diminish the extent to which those particles are bearers of heritable fitness variance, while augmenting the extent to which collectives of such particles are bearers of heritable fitness variance. In this way, we can explain upward transitions in the hierarchical level at which the Darwinian machine operates in terms of particle-level selection, even though the outcome of the process is a collective-level selection regime. Our theory avoids the logical and metaphysical paradoxes faced by other attempts to explain evolutionary transitions. (shrink)

In her recent paper ‘The Epistemology of Propaganda’ Rachel McKinnon discusses what she refers to as ‘TERF propaganda’. We take issue with three points in her paper. The first is her rejection of the claim that ‘TERF’ is a misogynistic slur. The second is the examples she presents as commitments of so-called ‘TERFs’, in order to establish that radical (and gender critical) feminists rely on a flawed ideology. The third is her claim that standpoint epistemology can be used to establish (...) that such feminists are wrong to worry about a threat of male violence in relation to trans women. In Section 1 we argue that ‘TERF’ is not a merely descriptive term; that to the extent that McKinnon offers considerations in support of the claim that ‘TERF’ is not a slur, these considerations fail; and that ‘TERF’ is a slur according to several prominent accounts in the contemporary literature. In Section 2, we argue that McKinnon misrepresents the position of gender critical feminists, and in doing so fails to establish the claim that the ideology behind these positions is flawed. In Section 3 we argue that McKinnon’s criticism of Stanley fails, and one implication of this is that those she characterizes as ‘positively privileged’ cannot rely on the standpoint-relative knowledge of those she characterizes as ‘negatively privileged’. We also emphasize in this section McKinnon’s failure to understand and account for multiple axes of oppression, of which the cis/trans axis is only one. (shrink)

God’s 21st-century message is to coexist. To the universal God, it is ultra-blasphemous for humans to fail to tolerate and respect the loving, compassionate religions of others and to condone violence done in the name of any religion. This edition represents Spiritual Humans seeking tolerance, a virtue not found in most world religions. To be tolerant is to be fair and open-minded about the religious and political beliefs of others, and to disagree without attempting to suppress those not in agreement. (...) We are trying to provide Spiritual Humans and Others with a way to promote respect and tolerance so all can help God to bring more peace to our planet Earth, now troubled by religious strife. Thirty-one million or more North Americans are spiritual but not religious. The MeetingHouse feels that those in faiths with more traditional religions will see a common meeting ground for our mutual beliefs about God. (shrink)

Refugee concerns may be perceived as controversial or outside the business domain, yet some corporations publicly engage these issues in corporate social responsibility (CSR) initiatives. This article relies on institutional and constitutive approaches to CSR to explore why organizations might declare their engagement in refugee issues, and utilizes decoupling to explore the relationship between reported CSR policy and CSR activity. We utilize a mixed-method, content analysis approach to draw on Fortune Global 500 CSR reports between 2012 and 2019, a period (...) in which refugee activity increased around the world. Our research suggests that few corporations offer refugee programming and fewer still feature programs that are “coupled” with either CSR policies or impacts. We introduce a typology that depicts these corporations as reactionary, recurring, relevant, or revelatory, and offer constitutive implications for CSR programming in response to other emerging social issues. (shrink)

This paper uses the case of solo doctors to explore whether working in relative isolation from one’s peers may be detrimental to ethical decision-making. Drawing upon the relevance of communication and interaction for ethical decision-making in the ethical theories of Habermas, Mead and Gadamer, it is argued that doctors benefit from ethical discussion with their peers and that solo practice may make this more difficult. The paper identifies a paucity of empirical research related to solo practice and ethics but draws (...) upon more general medical ethics research and a study that identified ethical isolation among community pharmacists to support the theoretical claims made. The paper concludes by using the literary analogy of Soderberg’s Doctor Glas to illustrate the issues raised and how ethical decision-making in relative isolation may be problematical. (shrink)

This book is a collection of secondary essays on America's most important philosophic thinkers—statesmen, judges, writers, educators, and activists—from the colonial period to the present. Each essay is a comprehensive introduction to the thought of a noted American on the fundamental meaning of the American regime.

The US neutrino community gathered at the Workshop on the Intermediate Neutrino Program at Brookhaven National Laboratory February 4-6, 2015 to explore opportunities in neutrino physics over the next five to ten years. Scientists from particle, astroparticle and nuclear physics participated in the workshop. The workshop examined promising opportunities for neutrino physics in the intermediate term, including possible new small to mid-scale experiments, US contributions to large experiments, upgrades to existing experiments, R&D plans and theory. The workshop was organized into (...) two sets of parallel working group sessions, divided by physics topics and technology. Physics working groups covered topics on Sterile Neutrinos, Neutrino Mixing, Neutrino Interactions, Neutrino Properties and Astrophysical Neutrinos. Technology sessions were organized into Theory, Short-Baseline Accelerator Neutrinos, Reactor Neutrinos, Detector R&D and Source, Cyclotron and Meson Decay at Rest sessions.This report summarizes discussion and conclusions from the workshop. (shrink)

Objective: To examine changes in patients’ desired control of the deep brain stimulator and perception of global life control throughout DBS.Methods: A consecutive cohort of 52 patients with Parkinson’s disease was recruited to participate in a prospective longitudinal study over three assessment points. Semi-structured interviews assessing participants’ desire for stimulation control and perception of global control were conducted at all three points. Qualitative data were coded using content analysis. Visual analog scales were embedded in the interviews to quantify participants’ perceptions (...) of control over time.Results: Participants reported significant increases in their perception of global control over time and significant declines in their desired control of the stimulation. These changes were unrelated to improvements in motor symptoms. Improvements in global control were negatively correlated with a decline in desired stimulation control. Qualitative data indicate that participants have changed, nuanced levels of desired control over their stimulators. Increased global life control following DBS may be attributed to increased control over PD symptoms, increased ability to engage in valued activities, and increased overall self-regulation, while other domains related to global control remained unaffected by DBS.Conclusions: There are few empirical data documenting patients’ desire for stimulation control throughout neuromodulation and how stimulation control is related to other aspects of control despite the growing application of neuromodulation devices to treat a variety of disorders. Our data highlight distinctions in different types of control and have implications for the development of patient-controlled neurostimulation devices. (shrink)

Peter Abelard (1079–1142 ce) was the most wide‐ranging philosopher of the twelfth century. He quickly established himself as a leading teacher of logic in and near Paris shortly after 1100. After his affair with Heloise, and his subsequent castration, Abelard became a monk, but he returned to teaching in the Paris schools until 1140, when his work was condemned by a Church Council at Sens. His logical writings were based around discussion of the “Old Logic”: Porphyry's Isagoge, aristotle'S Categories and (...) On Interpretation and boethius'S textbook on topical inference. They comprise a freestanding Dialectica (“Logic”; probably c.1116), a set of commentaries (known as the Logica [Ingredientibus], c. 1119) and a later (c. 1125) commentary on the Isagoge (Logica Nostrorum Petititoni Sociorum or Glossulae). In a work Abelard called his Theologia, issued in three main versions (between 1120 and c.1134), he attempted a logical analysis of trinitarian relations and explored the philosophical problems surrounding God's claims to omnipotence and omniscience. The Collationes (“Debates,” also known as “Dialogue between a Christian, a Philosopher and a Jew”; probably c.1130) present a rational investigation into the nature of the highest good, in which the Christian and the Philosopher (who seems to be modeled on a philosopher of pagan antiquity) are remarkably in agreement. The unfinished Scito teipsum (“Know thyself,” also known as the “Ethics”; c.1138) analyses moral action. (shrink)

The regulation of narcotic medications used in narcotic addiction treatment is unique in medical therapeutics. Physicians who want to use narcotics for this indication must obtain a separate annual registration from the Drug Enforcement Administration. Annual registration is contingent on compliance with both the DEA's security regulations as well as treatment regulations jointly promulgated by the Food and Drug Administration and the National Institute on Drug Abuse.During the last decade, a number of events have occurred that persuaded NIDA that it (...) is time to reevaluate the current method by which the Department of Health and Human Services regulates methadone treatment. As a result of research during the past twenty years, we have learned about the effective components of methadone treatment. In comparison to other available treatment modalities for opioid addiction, methadone treatment is uniquely effective when administered by well-trained medical staffs. (shrink)

The regulation of narcotic medications used in narcotic addiction treatment is unique in medical therapeutics. Physicians who want to use narcotics for this indication must obtain a separate annual registration from the Drug Enforcement Administration. Annual registration is contingent on compliance with both the DEA's security regulations as well as treatment regulations jointly promulgated by the Food and Drug Administration and the National Institute on Drug Abuse.During the last decade, a number of events have occurred that persuaded NIDA that it (...) is time to reevaluate the current method by which the Department of Health and Human Services regulates methadone treatment. As a result of research during the past twenty years, we have learned about the effective components of methadone treatment. In comparison to other available treatment modalities for opioid addiction, methadone treatment is uniquely effective when administered by well-trained medical staffs. (shrink)

Since its founding in 1943, Medievalia et Humanistica has won worldwide recognition as the first scholarly publication in America to devote itself entirely to medieval and Renaissance studies. Since 1970, a new series, sponsored by the Modern Language Association of America and edited by an international board of distinguished scholars and critics, has published interdisciplinary articles. In yearly hardbound volumes, the new series publishes significant scholarship, criticism, and reviews treating all facets of medieval and Renaissance culture: history, art, literature, music, (...) science, law, economics, and philosophy. (shrink)

We propose a naturalistic version of the “guesser–knower” paradigm in which the experimental subject has an opportunity to choose which individual to follow to a hidden food source. This design allows nonhumans to display the attribution of knowledge to another conspecific, rather than a human, in a naturalistic context (finding food), and it is readily adapted to different species.

The purpose of this study was to evaluate, revise, and extend the Informed Consent Ontology (ICO) for expressing clinical permissions, including reuse of residual clinical biospecimens and health data. This study followed a formative evaluation design and used a bottom-up modeling approach. Data were collected from the literature on US federal regulations and a study of clinical consent forms. Eleven federal regulations and fifteen permission-sentences from clinical consent forms were iteratively modeled to identify entities and their relationships, followed by community (...) reflection and negotiation based on a series of predetermined evaluation questions. ICO included fifty-two classes and twelve object properties necessary when modeling, demonstrating appropriateness of extending ICO for the clinical domain. Twenty-six additional classes were imported into ICO from other ontologies, and twelve new classes were recommended for development. This work addresses a critical gap in formally representing permissions clinical permissions, including reuse of residual clinical biospecimens and health data. It makes missing content available to the OBO Foundry, enabling use alongside other widely-adopted biomedical ontologies. ICO serves as a machine-interpretable and interoperable tool for responsible reuse of residual clinical biospecimens and health data at scale. (shrink)

The essays in this collection honor Professor Ellis Sandoz, Hermann Moyse Jr. Distinguished Professor of Political Science, Louisiana State University, and founding director of the Eric Voegelin Institute for American Renaissance Studies, an institute located at Louisiana State University and devoted to research and publication in the fields of political philosophy, constitutional law, and Voegelin studies. Without the tireless leadership—both academic and economic—of Ellis Sandoz, who was one of Eric Voegelin’s early students and his first American doctoral candidate at the (...) University of Munich, the thirty-four volumes of _The Collected Works of Eric Voegelin _would never have neared completion within only twenty years of Voegelin’s death. The authors of the essays, some of the most respected scholars in the field of political philosophy, hail from Austria, Canada, the Czech Republic, Germany, Ireland, and the United States. They have known Sandoz in a variety of ways: as former students, as beneficiaries of his work on constitutionalism, as fellow participants in the publication of _The Collected Works of Eric Voegelin_, as philosophical colleagues, as participating members of the Eric Voegelin Society, and finally as friends. The essays, each written especially for this volume, are grouped into the disciplines of philosophy, literature, and politics and range widely across these subjects, exploring writers as diverse as Xenophon, Natsume Soseki, Freud, and George Santayana and topics ranging from the leadership style of François Mitterrand and the Velvet Revolution to the nature of the Law and of the Political. _Philosophy, Literature, and Politics _is a fitting tribute to a man whose life’s work has been formed by commitment to the philosophical enterprise and by a conviction in Eric Voegelin’s contribution to that enterprise. The seventeen essays in this collection will be of particular interest to scholars of politics, comparative government, Japanese studies, political philosophy, and literary criticism. (shrink)