Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 and X-linked CLDN2 through a two-stage genome-wide study. The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is (...) associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men. © 2012 Nature America, Inc. All rights reserved. (shrink)

This article explores aspects of the textual relationship between women and early modern London by examining three verbal ‘snapshots’ of the city in works either written by women or focusing on women in their urban environment. The first text, Isabella Whitney's ‘Wyll and Testament’ (1573), addresses London from a rural perspective, treating the city as a fickle male to whom she wants to hand back all his treasures. The poem constructs a vivid and ironic social topography, giving a glimpse of (...) the roles of men and women in the Tudor city. The second text is by Mary Carleton, the roguish Restoration figure who defended her apparently ‘counterfeit’ life in the prose of The Case of Madam Mary Carleton (1663). Carleton's London is a place of unwanted seduction and sexual intimidation, highlighting a gendered moral geography even while the memoir itself titillates the reader with the account of her bizarre experiences. Finally, in a coda to the discussions of Whitney and Carleton, early eighteenth-century London is viewed through Jonathan Swift's satirical mock-pastorals of squalid urban life, in which female identity, like the city itself, is a site of violence, disgust and deception. Together, these textual representations of women and early modern London indicate the complex interactions of gender, literature and the early modern city. The analysis of the texts also suggests the significance of the ironic voice as a quintessentially urban literary mode, the prevalence of the idea of woman as a commodified topographical site, and the function of metaphors of courtship or marriage as indicators of the paradoxical attractions of the city. (shrink)

Renowned moral philosopher Jonathan Glover confronts the brutal history of the twentieth century to unravel the mystery of why so many atrocities occurred. In a new preface, Glover brings the book through the post-September 11 era and into our own time—and asks whether humankind can "weaken the grip war has on us." _Praise for the first edition:_ “It is hard to imagine a more important book. Glover makes an overwhelming case for the need to understand our own inhumanity, and (...) reduce or eliminate the ways in which it can express itself—and he then begins the task himself. _Humanity _is_ _an extraordinary achievement.”—Peter Singer, Princeton University “This is an extraordinary book: brilliant, haunting and uniquely important. Almost 40 years ago a president read a best seller and avoided a holocaust. I like to think that some of the leaders and followers of tomorrow will read _Humanity._”_—_Steven Pinker, _New York Times Book Review_. (shrink)

A minimal essentialism (‘intrinsic biological essentialism’) about natural kinds is required to explain the projectability of human science terms. Human classifications that yield robust and ampliative projectable inferences refer to biological kinds. I articulate this argument with reference to an intrinsic essentialist account of HPC kinds. This account implies that human sciences (e.g., medicine, psychiatry) that aim to formulate predictive kind categories should classify biological kinds. Issues concerning psychiatric classification and pluralism are examined.

Jonathan Walkan challenges cognitive science's dominant model of mental representation and proposes a novel, well-devised alternative. The traditional view in the cognitive sciences uses a linguistic model of mental representation. That logic-based model of cognition informs and constrains both the classical tradition of artificial intelligence and modeling in the connectionist tradition. It falls short, however, when confronted by the frame problem---the lack of a principled way to determine which features of a representation must be updated when new information becomes (...) available. So far, proposed alternatives, including the imagistic model, have not resolved the problem. Waskan proposes the Intrinsic Cognitive Models hypothesis, according to which representational states can be concpetualized as the cognitive equivalent of scale models.Waskan argues further that the proposal that humans harbor and manipulate cognitive counterparts to scale models offers the only viable explanation for what most clearly differentiates humans from other creatures: the capacity to engage in truth-preserving manipulation of representations. The ICM hypothesis, he claims, can be distinguished from sentence-based accounts of truth preservation in a way that is fully compatible with what is known about the brain. (shrink)

This book explores the idea that much of our behaviour is controlled by automatic and intuitive mental processes, which shape and compete with our conscious thinking and decision making. Accessibly written, and assuming no prior knowledge of the field, the book will be fascinating reading for all those interested in human behaviour.

Jonathan Bennett here examines the second half of the Critique of Pure Reason, the Dialectic, where Kant is concerned with problems about substance, the nature ...

This chapter examines philosophical issues surrounding the classification of mental disorders by the Diagnostic and Statistical Manual of Mental Disorders (DSM). In particular, the chapter focuses on issues concerning the relative merits of descriptive versus theoretical approaches to psychiatric classification and whether the DSM should classify natural kinds. These issues are presented with reference to the history of the DSM, which has been published regularly by the American Psychiatric Association since 1952 and is currently in its fifth edition. While the (...) first two editions of the DSM adopted a theoretical (psychoanalytic) and etiological approach to classification, subsequent editions of the DSM have adopted an atheoretical and purely descriptive (“neo-Kraepelinian”) approach. It is argued that largest problem with the DSM at present—viz., its failure to provide valid diagnostic categories—is directly related to the purely descriptive methodology championed by the DSM since the third edition of the DSM. In light of this problem, the chapter discusses the prospects of a theoretical and causal approach to psychiatric classification and critically examines the assumption that the DSM should classify natural kinds. (shrink)

My central thesis is that presentism is incompatible with all of the main theories of persistence: endurance, exdurance and perdurance.

The last two decades have witnessed a crescendo of allegations that clinical translation is rife with waste and inefficiency. Patient advocates argue that excessively demanding regulations delay access to life‐saving drugs, research funders claim that too much basic science languishes in academic laboratories, journal editors allege that biased reporting squanders public investment in biomedical research, and drug companies (and their critics) argue that far too much is expended in pharmaceutical development.But how should stakeholders evaluate the efficiency of translation and proposed (...) reforms to drug development? Effective reforms require an accurate model of the systems they aspire to improve—their components, their proper functions, and their pathologies. However, there is currently no explicit and well‐developed model of translation for evaluating such criticisms.In what follows, we offer an explicit model of clinical translation. Many discussions of clinical translation and its pathologies presume that its main output is tangible: new drugs, vaccines, devices, and diagnostics. We disagree. We argue that the principal output of clinical translation is information—in particular, information about the coordinated set of materials, practices, and constraints needed to safely unlock the therapeutic or preventive activities of drugs, biologics, and diagnostics. To develop this information calls for a process far different from a simple linear progression of clinical trials; it requires exploratory sampling of many different elements in this set. Our model points to some limitations and liabilities of influential proposals for reforming research. It also reveals some underrecognized opportunities for improving the efficiency of clinical translation. (shrink)

How do our engagements with fictions and other products of the imagination compare to our experiences of the real world? Are the feelings we have about a novel's characters modelled on our thoughts about actual people? If it is wrong to feel pleasure over certain situations in real life, can it nonetheless be right to take pleasure in analogous scenarios represented in a fantasy or film? Should the desires we have for what goes on in a make-believe story cohere with (...) what we want to happen in the actual world? In Apt Imaginings, Jonathan Gilmore develops a new framework to pursue these questions, marshalling a wide range of research in aesthetics, the science of the emotions, moral philosophy, neuroscience, cognitive psychology, and film and literary theory. Gilmore argues that, while there is a substantial empirical continuity in our feelings across art and life, the norms that govern the appropriateness of those responses across the divide are discontinuous. In this view, the evaluative criteria that determine the fit, correctness, or rationality of our emotions and desires for what is internal to a fiction can be contrary to those that govern our affective attitudes toward analogous things in the real world. In short, it can be right to embrace within a story what one would condemn in real life. The theory Gilmore defends in this volume helps to explain our complex and sometimes conflicted attitudes toward works of the imagination; challenges the popular view that fictions serve to refine our moral sensibilities; and exposes a kind of autonomy of the imagination that can render our responses to art immune to standard real-world epistemic, practical, and affective kinds of criticism. (shrink)

Experimental manipulations are a key means to establish causal relationships in microbiology. However, challenges remain to establish the applicability of such experiments beyond the precise conditions in which they were conducted. Ecological information can help address these challenges by describing the extent to which an experimentally-determined mechanism can explain the natural phenomenon that it is purported to cause.

Metaphysical semantics is supposed to connect the nonfundamental to the fundamental in a distinctively “linguistic” way, explaining how nonfundamental truths can be grounded in fundamental facts , and so inducing a radically eliminative vision of the nonfundamental as mere talk. I wonder how the story goes when a single nonfundamental truth can be grounded in many different fundamental facts. For instance, the truth that Moore has hands can presumably be grounded in many different distributions of fields, arrangements of particles, vibrations (...) of strings, or whatnot. I am asking how metaphysical semantics can accommodate this sort of multiple realizability. (shrink)

Here I examine some recent attempts to provide a new way of thinking about the philosophy of time that question the central role of ‘presentness’ within the definition of presentism. The central concern raised by these critics turns on the intelligibility and theoretical usefulness of the term ‘is present’. My overarching aim is to at least challenge such concerns. I begin with arguments due to Deasy. Deasy develops a view that he calls ‘transientism’ and that he takes to be a (...) well-motivated version of presentism. I show that both this way of thinking about presentism and the argument supposedly motivating it all fail. I then move to an argument due to Correia and Rosenkrantz. Correia and Rosenkrantz purport to show that presentism can be salvaged without making recourse to the term ‘is present’. I demonstrate that their arguments fail. I then move on to a view, proposed and defended by Merricks, Tallant, and Zimmerman, and show that it has the wherewithal to meet the challenges raised by Williamson who, as noted above, raises genuine concerns about our capacity to define presentism. (shrink)

Federal policies on human subjects research have performed a near‐about face. In the 1970s, policies were motivated chiefly by a belief that subjects needed protection from the harms and risks of research. Now the driving concern is that patients, and the populations they represent, need access to the benefits of research.

abstract The most well‐known liberal‐egalitarian defence of cultural rights, provided by Will Kymlicka, presents culture as a primary good, and thus a resource that ought to be distributed according to some fair egalitarian criteria. Kymlicka relies on the intuition that inequalities between persons that are the result of brute luck rather than personal choice are unjust in making the case for various multicultural rights. This article makes two main claims. First, the standard luck egalitarian intuition on which Kymlicka's argument relies (...) cannot justify what he calls ‘polyethnic rights,’ in particular cultural and religious exemptions from generally applicable laws. Second, I argue that such exemptions are justifiable by appealing to the public value of fair equality of opportunity, properly construed. (shrink)

: Despite its mandate on minimizing harms in clinical trials, the Common Rule provides little guidance as to how IRBs should evaluate risk. The Common Rule and derivative commentaries tend to conceptualize risk review as an expert-based endeavor aimed at an objective and universal evaluation of possible harm; they also have tended to locate risk in the research activity itself rather than in the context of the research. These views of risk conflict with scholarship showing that risk evaluations are socially (...) determined even among experts, that the context of harms can influence how persons evaluate risks, and that forums that approach risk assessment as a technical endeavor bracket from discussion the numerous values that ground risk judgments. Possible reforms are proposed for clinical trial risk review that would render it more inclusive of the different types of risks encountered and more attuned to the priorities of trial subjects. (shrink)

Jonathan Dancy; I *—The Presidential Address: Why there is really No Such Thing as the Theory of Motivation, Proceedings of the Aristotelian Society, Volume 95.

Properties come in clusters. It seems impossible, for instance, that a mass could float free, unattached to any other property. David Armstrong takes this as a reductio of the bundle theory and an argument for substrata, while Peter Simons and Arda Denkel reply by supplementing the bundle theory with accounts of property interdependencies. I argue against both views. Virtually all plausible ontologies turn out to be committed to the existence of free masses. I develop and defend the view that the (...) clustering of properties is a mere contingent truth, on grounds that properties can be subtracted one‐by‐one. This opens the door not just to the (unsupplemented) bundle theory, but also to any plausible account of the relation between objects and properties. (shrink)

This article makes four claims. First, that the analytic/Continental split in political theory stems from an unarticulated disagreement about human nature, with analytics believing we have an innate set of mostly compatible moral and political inclinations, and Continentals seeing such things as alterable products of historical contingency. Second, that we would do better to talk of Continental-political-theory versus Rawlsian-political-philosophy, given that the former avoids arguments over principles, whilst the latter leaves genuine analytic philosophy behind. Third, that Continentals suffer from a (...) lack of such arguments, even by their own lights, whilst Rawlsians suffer from inconsistencies within the thought-patterns on which their principles depend. Fourth, that there is an alternative method – ‘normative behaviourism’ – that at least tries to move beyond the problems of both approaches, whilst sharing an idea of ‘praxis’ with the first, and an idea of deriving-principles-from-existing-judgements with the second. (shrink)

Within the philosophy of time there has been a growing interest in positions that deny the reality of time. Those positions, whether motivated by arguments from physics or metaphysics, have a shared conclusion: time is not real. What has not been made wholly clear, however, is exactly what it entails to deny the reality of time. Time is unreal, sure. But what does that mean? There has been only one sustained attempt to spell out exactly what it would mean to (...) endorse a temporal error theory; a theory that denies the reality of time—Baron & Miller’s ‘What is temporal error theory?’. Despite the fact that their paper makes significant strides in spelling out what would be required of a temporal error theory, my claim in this paper is that their position must be rejected and replaced. As well as looking to reject Baron and Miller’s position, I also look to provide that replacement. (shrink)

Jonathan Bennett's analysis of the second half of Kant's Critique of Pure Reason, in which Kant concerns himself with topics such as substance, the nature of the self, the cosmos, freedom and the existence of God, continues to be an engaging and accessible exploration of Kant's major work. Presented in a fresh twenty-first-century series livery, and including a specially commissioned preface written by Karl Ameriks, illuminating its enduring importance and relevance to philosophical enquiry, this influential work has been revived (...) for a new generation of readers. (shrink)

Many commentators have expressed concern that large investments in biomedical research over the past two decades have not been translated effectively into clinical applications. In its Critical Path Report, the Food and Drug Administration characterized the problem as a “technological disconnect between discovery and the product development process,” and documented that the number of investigational new drugs submitted to the agency had declined “significantly” since 2000. Along a similar vein, another study found that only five of 101 basic science studies (...) showing significant therapeutic promise were successfully translated into clinical applications.This perceived translational lag is stimulating a shift toward human testing of study interventions earlier in the drug development process. One indication of this trend is a recent guidance encouraging sponsors to pursue human “exploratory” studies before embarking on phase I trials. (shrink)

This book provides the first systematic, book-length defence of natural law ideas in ethics, politics and jurisprudence since John Finnis's influential Natural Law and Natural Rights. Incorporating insights from recent work in ethical, legal and social theory, it presents a robust and original account of the natural law tradition, challenging common perceptions of natural law as a set of timeless standards imposed on humans from above. Natural law, Jonathan Crowe argues, is objective and normative, but nonetheless historically extended, socially (...) embodied and dependent on contingent facts about human nature. It reflects the ongoing human quest to work out how best to live flourishing lives, given the natures we have and the social environments we inhabit. The nature and purpose of law can only be adequately understood within this wider context of value. Timely, wide-ranging and clearly written, this volume will appeal to those working in law, philosophy and religious studies. (shrink)

Bioethics as a field has been fortunate that its values and concerns have mirrored the values and concerns of society. In light of the September 11th attacks, it is possible that we are witnessing the beginning of a transition in American culture, one fraught with implications for bioethics. The emphasis on autonomy and individual rights may come to be tempered by greater concern over the collective good. Increased emphasis on solidarity over autonomy could greatly alter public response to research abuses (...) aimed at defense from bioterrorism, to privacy of genetic information, and to control of private medical resources to protect the public health. (shrink)

The United Kingdom has many bodies that play their part in carrying out the work of national ethics committees, but its nearest equivalent of a U.S. presidential bioethics commission is the Nuffield Council on Bioethics, established in 1991. The Council is charged with examining ethical questions raised by developments in biological and medical research, publishing reports, and making representations to appropriate bodies in order to respond to or anticipate public concern. It is a nongovernment organization with no defined or guaranteed (...) channels of influence. It has no authority merely by virtue of the position it holds. Rather, it has established relational authority based on its reputation. Unlike the U.S. bioethics commission, it is not part of executive government, nor is it constituted to contribute to the legislative branch, as does the French Comité Consultatif National d'Ethique. Its nongovernmental status notwithstanding, the Nuffield Council's work affects the U.K. government and the British public, and the Council has achieved international recognition for its reports. I was the chairperson from 2012 to 2017 and draw on my experience in this piece to consider three key audiences: governments, publics, and the international community. (shrink)

The Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products recently issued documents encouraging sponsors to consider microdose testing before launching Phase I trials, and many commentators predict that such methodologies will be applied more routinely in drug development. However, exploratory testing has provoked several ethical criticisms. Skeptics question the value and validity of microdose trials, and whether they present a reasonable balance of risks and benefits for subjects. Another major criticism is that such studies (...) serve mainly commercial ends. The present article explores these and other ethical concerns for studies conducted in the oncology setting. It concludes that microdosing is not inconsistent with prevailing practices in Phase I research, and that in principle, such studies could strengthen the ethical basis for Phase I trials by providing them better evidentiary justification. (shrink)

There is a well-developed literature on trust. Distrust, on the other hand, has gathered far less attention in the philosophical literature. A recent exception to that trend in the philosophical literature is Hawley who develops a unified account of both trust and distrust. My aim in this paper is to present arguments against her account of trust and distrust, though then to also suggest a patch.

According to the parent analogy, as a caretaker’s goodness, ability and intelligence increase, the likelihood that the caretaker will make arrangements for the attainment of future goods that are unnoticed or underappreciated by their dependents also increases. Consequently, if this analogy accurately represents our relationship to God, then we should expect to find many instances of inscrutable evil in the world. This argument in support of skeptical theism has recently been criticized by Dougherty. I argue that Dougherty’s argument is incomplete, (...) for there are two plausible ways of construing the parent analogy’s conclusion. I supplement Dougherty’s case by offering a new argument against the parent analogy based on failed expectations concerning the amount of inscrutable evils encountered in the world. Consequently, there remains a significant empirical hurdle for skeptical theism to overcome if it is to maintain its status as a defeater for our reliability when tracking gratuitous evils. (shrink)

There is a well-developed literature on trust. Distrust, on the other hand, has gathered far less attention in the philosophical literature. A recent exception to that trend in the philosophical literature is Hawley who develops a unified account of both trust and distrust. My aim in this paper is to present arguments against her account of trust and distrust, though then to also suggest a patch.

Matching bias in conditional reasoning consists of a tendency to select as relevant cases whose lexical content matches that referred to in the conditional statement, regardless of the presence of negatives. Evans demonstrated that use of explicit rather than implicit negative cases markedly reduced the matching bias effect on the conditional truth table task. In apparent contrast, recent studies of explicit negation on the Wason selection task have failed to find evidence of logical facilitation. Experiment 1 of the present study (...) strongly replicated the Evans findings and extended them to three forms of conditional statement. Experiments 2 and 3 showed further that the use of explicit negatives removed completely the matching bias effect on the Wason selection task. However, consistent with other recent studies, this elimination of bias didnotlead to facilitation of correct responding. The findings are interpreted as providing evidence that matching bias reflects a linguistically cued relevance effect. (shrink)

"To some people, life is very simple . . . no shadings and grays, all blacks and whites. . . . Now, others of us find that good, bad, right, wrong, are many-sided, complex things. We try to see every side; but the more we see, the less sure we are." —Sir John Talbot, The Wolf Man (Universal Pictures, 1941).