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)

The possible integration of genomic sequencing (including whole‐genome and whole‐exome sequencing) into the three contexts addressed in this special report—state‐mandated screening programs, clinical care, and direct‐to‐consumer services—raises related but distinct legal issues. This essay will outline the legal issues surrounding the integration of genomic sequencing into state newborn screening programs, parental rights to refuse and access sequencing for their newborns in clinical and direct‐to‐consumer care, and privacy‐related legal issues attending the use of sequencing in newborns.

ABSTRACT Real-time graphical interval logic is a modal logic for reasoning about time in which the basic modality is the interval. The logic differs from other logics in that it has a natural intuitive graphical representation that resembles the timing diagrams drawn by system designers. We have developed an automted deduction system for the logic, which includes a theorem prover and a user interface. The theorem prover checks the validity of proofs in the logic and produces counterexamples to invalid proofs. (...) The user interface includes a graphical editor that enables the user to create graphical formulas on a workstation display, and a database and proof manager that tracks proof dependencies and allows graphical formulas to be stored and retrieved. In this paper we describe the logic, the automated deduction system, and an application to robotics. (shrink)

Part I: WHAT IS ETHICS? Plato: Socratic Morality: Crito. Suggestions for Further Reading. Part II: ETHICAL RELATIVISM VERSUS ETHICAL OBJECTIVISM. Herodotus: Custom is King. Thomas Aquinas: Objectivism: Natural Law. Ruth Benedict: A Defense of Ethical Relativism. Louis Pojman: A Critique of Ethical Relativism. Gilbert Harman: Moral Relativism Defended. Alan Gewirth: The Objective Status of Human Rights. Suggestions for Further Reading. Part III: MORALITY, SELF-INTEREST AND FUTURE SELVES. Plato: Why Be Moral? Richard Taylor: On the Socratic Dilemma. David Gauthier: Morality (...) and Advantage. Gregory Kavka: A Reconciliation Project. Derek Parfit: Later Selves and Moral Principles. Bernard Williams: Persons, Character, and Morality. Suggestions for Further Reading. Part IV: VALUE. Jeremy Bentham: Classical Hedonism. Robert Nozick: The Experience Machine. Richard Taylor: Value and the Origin of Right and Wrong. Friedrich Nietzsche: The Transvaluation of Values. Derek Parfit: What Makes Someone’s Life Go Best? Thomas Nagel: Value: The View from Nowhere. Suggestions for Further Reading. Part V: UTILITARIANISM AND CONSEQUENTIALISM. John Stuart Mill: Utilitarianism. J.J.C. Smart: Extreme and Restricted Utilitarianism. Kai Nielsen: Against Moral Conservatism. Bernard Williams: Against Utilitarianism. John Hospers: Rule-Utilitarianism. Robert Nozick: Side Constraints. Peter Singer: Famine, Affluence and Morality. Suggestions for Further Reading. Part VI: KANTIAN AND DEONTOLOGICAL SYSTEMS. Immanuel Kant: Foundation for the Metaphysic of Morals. W. D. Ross: What Makes Right Acts Right? Onora O’Neill: Kantian Formula of the End in Itself and World Hunger. Thomas Nagel: Moral Luck. Philippa Foot: Morality as a System of Hypothetical Imperatives. Judith Jarvis Thomson: Killing, Letting Die, and the Trolley Problem. Suggestions for Further Reading. Part VII: CONTRACTARIAN ETHICAL SYSTEMS. Thomas Hobbes: The Leviathan. David Gauthier: Why Contractarianism? John Rawls: Contractualism: Justice as Fairness. T.M. Scanlon: Contractualism and Utilitarianism. Suggestions for Further Reading. Part VIII: VIRTUE-BASED ETHICAL SYSTEMS. Aristotle: The Ethics of Virtue. Bernard Mayo: Virtue and the Moral Life. William Frankena: A Critique of Virtue-Based Ethics. Walter Schaller: Are Virtues No More than Dispositions to Obey Moral Rules? Alasdair MacIntyre: The Nature of the Virtues. Susan Wolf: Moral Saints. Louis P. Pojman: In Defense of Moral Saints. Suggestions for Further Reading. Part IX: THE FACT/VALUE PROBLEM: METAETHICS IN THE TWENTIETH CENTURY. David Hume: On Reason and the Emotions: The Fact/Value Distinction. G. E. Moore: Non-Naturalism. A. J. Ayer: Emotivism. R. M. Hare: Prescriptivism: The Structure of Ethics and Morals. Geoffrey Warnock: The Object of Morality. Suggestions for Further Reading. Part X: MORAL REALISM AND THE CHALLENGE OF SKEPTICISM. J.L. Mackie: The Subjectivity of Values. Jonathan Harrison: A Critique of Mackie’s Error Theory. Gilbert Harman: Moral Nihilism. Nicholas Sturgeon: Moral Explanations. Bernard Williams: Ethics and the Limits of Philosophy. Bruce Russell: Two Forms of Ethical Skepticism. Michael Smith: A Defense of Moral Realism. Suggestions for Further Reading. Part XI: RELIGION AND ETHICS. Plato: Morality and Religion. Immanuel Kant: God and Immortality as Necessary Postulates of Morality. George Mavrodes: Religious and the Queerness of Morality. Kai Nielson: Ethics Without God. Suggestions for Further Reading. Part XII: CONTEMPORARY CHALLENGES TO CLASSICAL ETHICAL THEORY. Part A. Sociobiology and the Question of Moral Responsibility. Charles Darwin: Ethics and the Descent of Man. E.O.Wilson: Sociobiology and Ethics. Michael Ruse: Evolution and Ethics: The Sociobiological Approach. Elliot Sober: Prospects for an Evolutionary Ethics. J.L. Mackie: The Law of the Jungle, Evolution and Morality. Suggestions for Further Readingon Sociobiology. Part B. The Challenge of Determinism to Moral Responsibility and Desert. Galen Strawson: The Impossibility of Moral Responsibility. Louis Pojman: Free Will, Determinism, and Moral Responsibility:A Response to Galen Strawson. Richard Taylor: A Libertarian Defense of Free Will and Responsibility. Suggestions for Further Reading on Moral Responsibility. Glossary of Ethical Terms. (shrink)

Athens and Wittenberg explores how Luther and early Lutheranism did not neglect the classics of Greece and Rome, but continued to draw from the philosophy and poetry of antiquity in their quest to reform the church.

The Declaration of Independence states that all men are created equal in the United States, but that statement does not hold true for words. Some words carry more weight than others--they seem to work harder, get more done, and demand more respect. Political Keywords: Using Language that Uses Us looks at eight dominant words that are crucial to American political discourse, and how they have been employed during the last fifty years. Based on an analysis of eleven separate studies of (...) political language, Political Keywords helps readers to understand what these terms mean and how they are used. For example, the book tracks what politics now means to modern commentators, how schoolteacher impress certain values upon the nation's children by invoking the office of the president, and why an innocent word like government sometimes makes people so upset. It details how the people are referenced in political talk and how the media portray themselves. The book also considers the work done by political parties, political promises, and political consultants because, together, they shed special light on modern elections. Combining social science with subtle forms of cultural interpretation, Political Keywords: Using Language that Uses Us provides a fresh look at both American politics and American language. It is an ideal text for undergraduate and graduate courses in political communication, political language, political campaigns, media and politics, political psychology, public opinion, rhetorical criticism, contemporary public address, and presidential rhetoric. (shrink)

This paper investigates the effect of the countervailing forces within organizations of formal systems that direct employees toward ethical acts and informal systems that direct employees toward fraudulent behavior. We study the effect of these forces on deception, a key component of fraud. The results provide support for an interactive effect of these formal and informal systems. The effectiveness of formal systems is greater when there is a strong informal “push” to do wrong; conversely, in the absence of a strong (...) push to do wrong, the strength of formal systems has little impact on fraudulent behavior. These results help to explain why the implementation of formal systems within organizations has been met with mixed results and identifies when formal systems designed to promote ethical behavior will be most efficacious. (shrink)

This paper proposes a generalization of the Kripke semantics of intuitionistic logic IL appropriate for intuitionistic Łukasiewicz logic IŁL — a logic in the intersection between IL and (classical) Łukasiewicz logic. This generalised Kripke semantics is based on the poset sum construction, used in Bova and Montagna (Theoret Comput Sci 410(12):1143–1158, 2009) to show the decidability (and PSPACE completeness) of the quasiequational theory of commutative, integral and bounded GBL algebras. The main idea is that w \Vdash \sigma—which for IL is (...) a relation between worlds w and formulas \sigma, and can be seen as a function taking values in the booleans w \Vdash \sigma \in {B}—becomes a function taking values in the unit interval w \Vdash \sigma \in [0,1]. An appropriate monotonicity restriction (which we call sloping functions) needs to be put on such functions in order to ensure soundness and completeness of the semantics. (shrink)

The volume presents essays on the philosophical explanation of the relationship between body and soul in antiquity from the Presocratics to Galen. The title of the volume alludes to a phrase found in Plato, Aristotle and Plotinus, referring to aspects of living behaviour involving both body and soul, and is a commonplace in ancient philosophy, dealt with in very different ways by different authors.

The three important target articles make a strong case for regarding racism as a public health crisis. Each calls for advocacy by the bi...

In a recent paper in this journal, Dagsvik derives the class of independent random utility representations that are “equivalent” to the independence-from-irrelevant-alternatives assumption by Luce. In this short note, we clarify the relations between this paper by Dagsvik, and a paper in Lindberg’s 2012 thesis.

_341_ _Objectives: _In patients with multivessel disease both the detection of the culprit lesion and the exact allocation are important preconditions for sufficient treatment and improved outcome. In a vessel based approach the combination of quantitative coronary angiography and fractional flow reserve measured by a pressure wire should be advantageous compared to myocardial SPECT, as morphological and functional information is delivered simultaneously. Therefore our aim was to evaluate MS in the detection and allocation of hemodynamically significant stenoses obtained by the (...) combined gold standard QCA plus FFR in patients with multivessel disease. _Methods: _FFR and QCA of 95 vessels in 80 patients have been evaluated. Hemodynamically significant target lesions were defined as intermediate stenoses between 50 and 75% with an FFR. (shrink)

In the business world, one of the key challenges is how to survive in ever changing business environments and outperforming the competitors, while keeping the operational cost at minimum and profits at maximum level. In other words, this can be described as the problem of improving operational efficiency and reducing cost. Over the past few years due to global financial challenges, it has become even more important to improve the operational efficiency and reduce costs to survive through these tough conditions. (...) Like other successful implementations of Lean philosophy, especially in automobile, aerospace, steel and healthcare, it can be applied in cable manufacturing to achieve competitive, sustainable and profitable processes. The main focus of Lean philosophy is to create value for the stakeholders and end customers by reducing the non-value added activities or waste, and laying a strong foundation towards sustainable growth, by focusing on continuous process improvement. The overall philosophy provides a focused approach for continuous process improvement and the targeting of a variety of tools and methods to bring improvements. This paper presents case studies for Lean scheduling of manufacturing processes and exemplify how Lean scheduling processes allow organisations to maintain the continuous improvement philosophy. This paper also addresses the key elements of rescheduling processes i.e. how to schedule and when to schedule. Further, the paper will exemplify key benefits of Lean scheduling and how the Cable industry could benefit from the proposed approach. (shrink)

Physicians working in the world of competitive sports face unique ethical challenges, many of which center around conflicts of interest. Team-employed physicians have obligations to act in the club's best interest while caring for the individual athlete. As such, they must balance issues like protecting versus sharing health information, as well as issues regarding autonomous informed consent versus paternalistic decision making in determining whether an athlete may compete safely. Moreover, the physician has to deal with an athlete's decisions about performance (...) enhancement and return to play, pursuit of which may not be in the athlete's long-term best interests but may benefit the athlete and team in the short term. These difficult tasks are complicated by the lack of evidence-based standards in a field influenced by the lure of financial gains for multiple parties involved. In this article, we review ethical issues in sports medicine with specific attention paid to American professional football. (shrink)

This project investigates critical issues and events related to Trek Therapeutics experience as a public benefit corporation. We will present and discuss how Trek differentiates itself in an industry where the attention is on high prices supporting high investor returns. Trek’s benefit corporation status helped it garner favorable attention in some respects, but has also presented challenges, particularly when it comes to attracting new capital.

The Covid‐19 pandemic has concentrated bioethics attention on the “lifeboat ethics” of rationing and fair allocation of scarce medical resources, such as testing, intensive care unit beds, and ventilators. This focus drives ethics resources away from persistent and systemic problems—in particular, the structural injustices that give rise to health disparities affecting disadvantaged communities of color. Bioethics, long allied with academic medicine and highly attentive to individual decision‐making, has largely neglected its responsibility to address these difficult “upstream” issues. It is time (...) to broaden our teaching, research, and practice to match the breadth of the field in order to help address these significant societal inequities and unmet health needs. (shrink)

In much the same way that genomic technologies are changing the complexion of biomedical research, the issues they generate are changing the agenda of IRBs and research ethics. Many of the biggest challenges facing traditional research ethics today — privacy and confidentiality of research subjects; ownership, control, and sharing of research data; return of results and incidental findings; the relevance of group interests and harms; the scope of informed consent; and the relative importance of the therapeutic misconception — have become (...) important policy issues over the last 20 years because of the ways they have been magnified by genomic research efforts. Research that examines the ethical, legal, and social implications of human genomics research has become a burgeoning international field of scholarship over the last 20 years, thanks in part to its support first by the genome research funding bodies in the U.S. and then by national science agencies in other countries. (shrink)

In the course of an immune response, antibodies undergo affinity maturation in order to increase their efficiency in neutralizing foreign invaders. Affinity maturation occurs by the introduction of multiple point mutations in the variable region gene that encodes the antigen binding site. This somatic hypermutation is restricted to immunoglobulin genes and occurs at very high rates. The precise molecular basis of this process remains obscure. However, recent studies using a variety of in vivo and in vitro systems have revealed important (...) regulatory regions, base motifs that are preferred targets of mutation and evidence that transcription may play an active role in hypermutation. BioEssays 20:227–234, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

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.

Psychological contracts represent perceived reciprocal obligations between an employer and an employee. Most research has focused on employee or employer rights (the entitlement side of the obligation equation). We examine the responsibilities inherent in psychological contracts. After reviewing the moral aspect of psychological contracts, we use the issue of tenure as a discussion point for this topic.

The power of the application of bioinformatics across multiple publicly available transcriptomic data sets was explored. Using 19 human and mouse circadian transcriptomic data sets, we found that NR1D1 and NR1D2 which encode heme‐responsive nuclear receptors are the most rhythmic transcripts across sleep conditions and tissues suggesting that they are at the core of circadian rhythm generation. Analyzes of human transcriptomic data show that a core set of transcripts related to processes including immune function, glucocorticoid signalling, and lipid metabolism is (...) rhythmically expressed independently of the sleep‐wake cycle. We also identify key transcripts associated with transcription and translation that are disrupted by sleep manipulations, and through network analysis identify putative mechanisms underlying the adverse health outcomes associated with sleep disruption, such as diabetes and cancer. Comparative bioinformatics applied to existing and future data sets will be a powerful tool for the identification of core circadian‐ and sleep‐dependent molecules. (shrink)

The fusion of law and equity in common law systems was a crucial moment in the development of the modern law. In this volume leading scholars assess the significance of the fusion of law and equity from comparative, doctrinal, historical and theoretical perspectives.

Bioethics needs an expanded moral vision. It is now time for bioethics to take full account of the problems of health disparities and structural injustice that are made newly urgent by the COVID-19 pandemic and the effects of climate change. Nancy M. P. King, Gail E. Henderson, and Larry R. Churchill make the case for a more social understanding and application of justice, a deeper humility in assessing expertise in bioethics consulting, a broader and more relevant research agenda, and (...) greater appreciation of the profound health implications of global warming. (shrink)

Many of our concepts are introduced to us via, and seem only to be constrained by, roughand-ready explanations and some sample paradigm positive and negative applications. This happens even in informal logic and mathematics. Yet in some cases, the concepts in question – although only informally and vaguely characterized – in fact have, or appear to have, entirely determinate extensions. Here’s one familiar example. When we start learning computability theory, we are introduced to the idea of an algorithmically computable function (...) (from numbers to numbers) – i.e. one whose value for any given input can be determined by a step-by-step calculating procedure, where each step is fully determined by some antecedently given finite set of calculating rules. We are told that we are to abstract from practical considerations of how many steps will be needed and how much ink will be spilt in the process, so long as everything remains finite. We are also told that each step is to be ‘small’ and the rules governing it must be ‘simple’, available to a cognitively limited calculating agent: for we want an algorithmic procedure, step-by-minimal-step, to be idiot-proof. For a classic elucidation of this kind, see e.g. Rogers (1967, pp. 1–5). Church’s Thesis, in one form, then claims this informally explicated concept in fact has a perfectly precise extension, the set of recursive functions. Church’s Thesis can be supported in a quasi-empirical way, by the failure of our searches for counterexamples. It can be supported too in a more principled way, by the observation that different appealing ways of sharpening up the informal chararacterization of algorithmic computability end up specifying the same set of recursive functions. But such considerations fall short of a demonstration of the Thesis. So is there a different argumentative strategy we could use, one that could lead to a proof? Sometimes it is claimed that there just can’t be, because you can never really prove results involving an informal concept like algorithmic computability.. (shrink)