This essay represents a serious but fictional obituary of a scientific concept called the Threshold Dose–Response Model, which has long dominated the fields of toxicology and the broader biomedical sciences. Recent evidence indicates that the Threshold Dose–Response Model has long outlived its utility to predict low‐dose effects. In fact, so poorly does this model predict low‐dose responses that the idea arose that it should receive a symbolic burial recounting its achievements and failings, hence this (...) obituary. BioEssays 29:686–688, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The use of transcranial Electrical Stimulation in the modulation of cognitive brain functions to improve neuropsychiatric conditions has extensively increased over the decades. tES techniques have also raised new challenges associated with study design, stimulation protocol, functional specificity, and dose-response relationship. In this paper, we addressed challenges through the emerging methodology to investigate the dose-response relationship of High Definition-transcranial Direct Current Stimulation, identifying the role of negative valence in tinnitus perception. In light of the neurofunctional testable (...) framework and tES application, hypotheses were formulated to measure clinical and surrogate endpoints. We posited that conscious pairing adequately pleasant stimuli with tinnitus perception results in correction of the loudness misperception and would be reinforced by concurrent active HD-tDCS on the left Dorsolateral Prefrontal Cortex. The dose-response relationship between HD-tDCS specificity and the loudness perception is also modeled. We conducted a double-blind, randomized crossover pilot study with six recruited tinnitus patients. Accrued data was utilized to design a well-controlled adaptive seamless Bayesian dose-response study. The sample size and optimum interims were anticipated for adaptive decision-making about efficacy, safety, and single session dose parameters. Furthermore, preliminary pilot study results were sufficient to show a significant difference within the longitudinally detected self-report tinnitus loudness between before and under positive emotion induction. This study demonstrated a research methodology used to improve emotion regulation in tinnitus patients. In the projected method, positive emotion induction is essential for promoting functional targeting under HD-tDCS anatomical specificity to indicate the efficacy and facilitate the dose-finding process. The continuous updating of prior knowledge about efficacy and dose during the exploratory stage adapts the anticipated dose-response model. Consequently, the effective dose range to make superiority neuromodulation in correcting loudness misperception of tinnitus will be redefined. Highly effective dose adapts the study to a standard randomized trial and transforms it into the confirmatory stage in which active HD-tDCS protocol is compared with a sham trial. Establishing the HD-tDCS intervention protocols relying on this novel method provides reliable evidence for regulatory agencies to approve or reject the efficacy and safety. Furthermore, this paper supports a technical report for designing multimodality data-driven complementary investigations in emotion regulation, including EEG-driven neuro markers, Stroop-driven attention biases, and neuroimaging-driven brain network dynamics. (shrink)

Many people argue that uncertain science—or controversial policies based on science—can be clarified primarily by greater attention to social/political values influencing the science and by greater attention to the vested interests involved. This paper argues that while such clarification is necessary, it is not a sufficient condition for achieving better science and policy; indeed its importance may be overemphasized. Using a case study involving the current, highly politicized controversy over the shape of dose‐response curves for biological effects of (...) ionizing radiation, the paper argues that the conflict could be significantly resolved through specific methodological improvements in the areas of metascience and philosophy of science. These improvements focus on taking account, respectively, of scale, data trimming, aggregation, measurability, and simplicity. (shrink)

Predictions about the health risks of low level radiation combine two sorts of measures. One estimates the amount and kinds of radiation released into the environment, and the other estimates the adverse health effects. A new field called health physics integrates and applies nuclear physics to cytology to supply both these estimates. It does so by first determining the kinds of effects different types of radiation produce in biological organisms, and second, by monitoring the extent of these effects produced by (...) given levels of exposure. This essay examines the interplay between evidential constraints and external, contextual interests and values in studying the biological hazards of radiation. By analyzing the debate over linear vs. quadratic dose response models, the essay focuses on problems of developing quantitative, rather than qualitative, estimates of the risks of increased cancer incidence in an exposed population. (shrink)

Information is usually supposed to be a prerequisite for people making decisions on whether or not to participate in a clinical trial. Previously conducted studies and research ethics scandals indicate that participants have sometimes lacked important pieces of information. Over the past few decades the quantity of information believed to be adequate has increased significantly, and in some instances a new maxim seems to be in place: the more information, the better the ethics in terms of respecting a participant’s autonomy. (...) The authors hypothesise that the dose-response curve from pharmacology or toxicology serves as a model to illustrate that a large amount of written information does not equal optimality. Using the curve as a pedagogical analogy when teaching ethics to students in clinical sciences, and also in engaging in dialogue with research institutions, may promote reflection on how to adjust information in relation to the preferences of individual participants, thereby transgressing the maxim that more information means better ethics. (shrink)

Many people argue that uncertain science -- or controversial policies based on science -- can be clarified primarily by greater attention to the social and ethical values influencing the science and the policy and by greater attention to the vested, economic interests involved. This paper argues that while such clarification is necessary, it is neither a sufficient condition, nor even the primary means, by which to achieve better science and better policy. Using a case study involving the current, highly politicized (...) controversy over the shape of dose-response curves for biological effects of ionizing radiation in both the protective action levels (PALS) and the International Commission on Radiological Protection (ICRP) environmental proposals, the paper argues that the conflict could be resolved largely through five specific methodological improvements in the areas of metascience and philosophy of science. (shrink)

Objective: A deep understanding of the relationship between a scarce drug's dose and clinical response is necessary to appropriately distribute a supply-constrained drug along these lines. Summary of key data: The vast majority of drug development and repurposing during the COVID-19 pandemic – an event that has made clear the ever-present scarcity in healthcare systems –has been ignorant of scarcity and dose optimisation's ability to help address it. Conclusions: Future pandemic clinical trials systems should obtain dose (...) optimisation data, as these appear necessary to enable appropriate scarce resource allocation according to societal values. (shrink)

Wardrope argues against my proposed non-consequentialist policy for the distribution of scarce influenza vaccine in the face of a pandemic. According to him, even if one accepts what he calls my deontological ethical theory, it does not follow that we are required to agree with my proposed randomised allocation of doses of vaccine by means of a lottery. He argues in particular that I fail to consider fully the prophylactic role of vaccination whereby it serves to protect from infection more (...) people than are vaccinated. He concludes that: ‘The benefits and burdens of vaccination are provided impartially and far more effectively by targeted vaccination than impartial lotteries.’ He has shown convincingly that this conclusion can be established in the case of his particular envisaged scenario. However, Wardrope gives no reason to suppose that, in the circumstances that we actually face, targeted vaccination would constitute impartial treatment of citizens in the UK. I readily agree with Wardrope that if it should treat its citizens justly and impartially, it does not necessarily follow that the state should distribute vaccinations of the basis of a lottery. That will be a reasonable thing to do only if certain assumptions are made. These assumptions will not always be reasonable. However, they are reasonable ones to make in the actual circumstances that currently apply. (shrink)

The goal of this paper is to present a succinct overview, from a clinician’s perspective, of the importance and implications of research on heart failure in African Americans. It first gives a brief outline of the rationale and results of the African-American Heart Failure Trial, which showed evidence for the effectiveness of fixed-dose combination of isosorbide dinitrate and hydralazine, marketed as BiDil, in this population. Finally, it underscores the necessity of treating African Americans with evidence-based medicine given that humanistic (...) physicians and other clinicians strive to provide holistic treatment to their patients.Most researchers and clinicians recognize the difficulty with utilizing race as a category for inclusion in trials. While race lacks any true biologic definition, it is potentially beneficial as a consideration in clinical studies, based on prior evidence of certain potential differences across self-identified racial/ethnic groups in morbidity and mortality and responses to medicine. Even though use of race as a classification is a problematic distinction, it should not be ignored. If clinical trials demonstrate significant improvement with targeted treatment in African Americans, clinicians should not withhold life-saving drugs that result from such studies. (shrink)

Nearly 30 years ago, Terry Horgan and Mark Timmons published a now- popular article that combines Hilary Putnam’s Twin Earth scenario with G.E. Moore’s open question argument in an effort to show that moral naturalism – the view that moral facts are at bottom ordinary, natural facts of some sort – is probably false. Responses to Horgan and Timmons’s “revised open question argument” have been legion, but surprisingly, no one has attempted to test the core assumption upon which the argument (...) is based; namely, that competent language users univocally treat natural kind-terms as rigid designators. Here, I present evidence that the intuitions of competent English speakers are not as univocal as Horgan and Timmons need them to be to ground their argument against moral naturalism. I also briefly sketch a way that the moral naturalist can respond even if competent language speakers do treat natural-kind terms in the way that Horgan and Timmons suggest. (shrink)

Nearly 30 years ago, Terry Horgan and Mark Timmons published a now- popular article that combines Hilary Putnam’s Twin Earth scenario with G.E. Moore’s open question argument in an effort to show that moral naturalism – the view that moral facts are at bottom ordinary, natural facts of some sort – is probably false. Responses to Horgan and Timmons’s “revised open question argument” have been legion, but surprisingly, no one has attempted to test the core assumption upon which the argument (...) is based; namely, that competent language users univocally treat natural kind-terms as rigid designators. Here, I present evidence that the intuitions of competent English speakers are not as univocal as Horgan and Timmons need them to be to ground their argument against moral naturalism. I also briefly sketch a way that the moral naturalist can respond even if competent language speakers do treat natural-kind terms in the way that Horgan and Timmons suggest. (shrink)

If scientists rely on assumptions rather than logic, empirical confirmation, and falsification, they are no longer doing science but ideology – which is, by definition, unethical. As a recent US National Academy of Sciences report put it, “bad science is always unethical.”1 This article discusses several ways in which toxicologists can fall into ideology – bad, therefore unethical, science. In part because of the increasing expense of pollution control, some toxicologists have been reexamining pollution dose-response curves that are (...) non-monotonic, that is, curves in which the direction of some response changes with increasing or decreasing dose.2 Ethanol is a classic example of a non-monotonic dose-response curve because moderate drinking is associated with lower risks of heart disease, whereas heavy drinking is associated with higher risks.3,4 If some low-dose pollutants exhibit adaptive or “beneficial effects,”5 this might suggest re-thinking pollution regulations which presuppose linear no-threshold (LNT) dose-response curves. (shrink)

This paper discusses theological responses in the Church of England to the South African War as reflected in sermons by theologians and church leaders and the limited amount of theological writing on the subject during the period. Three points emerge: first is the strong sense in which the mission was to civilise and Christianize. The fact that the war was being fought against a white enemy led to a characterisation of the Boer as uncivilised and primitive. Secondly, the British Empire (...) was not understood simply as a means of promoting the British interest across the world. Instead it was regarded as at least potentially a Christian Empire which embodied higher universal values. The emphasis was on humility and judgement, whereby moral absolutes were relativised by the vision of a more universal goal. This undoubtedly helped lessen the strength of some of the imperialist rhetoric. Finally, the higher values of self-sacrifice created a sense of moral seriousness: the universal values displayed in love for the community were prioritized over those of a narrow patriotism or individualism. Like the early days of the First World War, the Boer War functioned as an “antidote to anomie”. All in all, the strong dose of Platonism injected into Anglicanism in the nineteenth century meant that it functioned as a modest check on unfettered jingoism. A limited degree of prophetic critique – albeit deeply ambiguous, compromised and sometimes racist – remained the dominant theological discourse of Anglicanism, even at the highest point of imperialism. (shrink)

Is the medicalization of poverty a rational and humane response to an intractable problem, or just the latest in a long series of ineffective and costly attempts to address the problem? Considerable ink has been spilled on the dispute, with each side marshalling heart-rending anecdotes to help make their case — along with the obligatory statistics and regression analyses. Rather than add more verbiage to that dispute, this article sketches out a framework for understanding the phenomenon of medicalization, along (...) with a description of the demand-side and supply-side factors that have brought us to this pass. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Response to Øivind Varkøy, “The Concept of ‘Bildung’”Frederik PioThe process of Bildung has to do with something that “becomes.” The dimension of moving and developing makes the Bildung-metaphor of ‘the journey’ come into focus in Øivind Varkøy’s paper. As Varkøy states in his article, in relation to the Bildung concept one can see that “[the] relation between what is known in everyday life and what is new, unknown, (...) and strange, can in a sense be regarded as the meaning and intention of the concept.”This tension between that which is known and that which is unknown is handled by means of the metaphor of the journey. The journey is about leaving one’s homeground behind. The homeground is all that which is known. Then there is a venture into something not yet known. And then finally the individual returns home, enriched with a new experience, as a deeper and more encompassing human being. This is the blueprint of ‘the journey.’Thus the metaphor of the journey tells us that the crucial Bildung-factor is connected with a transgression of all that is familiar and well-known. So an experience is conducive to a process of Bildung to the extent that a transgression [End Page 97] occurs. That is as a movement that takes place beyond that in our ordinary lives which is all too well-known. Varkøy puts it this way:To have an experience is to be stricken, shaken, and affected. In this way, an experience is something which exceeds all boundaries, it notifies the arrival of something new and unknown. The subject is jerked out of its usual pattern and meets something that makes it look at itself with new eyes, experience its own subjectivity from unfamiliar quarters. Such experiences, such journeys, mean that we come into contact with important sides and dimensions of our way of being human.This translates into an educational context where a focus is on subject content “which enable[s] the students ‘to make journeys’... so that students can thereby not only emerge as educated music educationalists, but also as cultured (bilded) people.”All this belongs to the dimension of freedom. But as mentioned by Varkøy, Bildung is also about that which is authoritative and un-free. Thus Varkøy mentions Jon Fosse who found that “Norwegian schools certainly need a dose of Harold Bloom” and his book The Western Canon.So we have a tension between freedom (the journey into the unknown) and that which is un-free: the score we all have to settle with a great tradition that was there long before we arrived here and broke the surface of existence. In continuation of this I sense that Varkøy is touching upon a theme that tells us this: Today a process of Bildung should neither reject the tradition (to become anti-traditional). Nor should a process of Bildung become something that is just blindly reproducing the tradition and its values. So, it is not about being either anti-traditional or completely traditional, but about a quality which could be termed un-traditional. Varkøy says it like this:It is true to say... that the concept of Bildung’s cultural heritage perspective does not nescessarily mean a one-sided backwards glance focusing upon old masterworks... but also that it can to a considerable extent open up for focusing on the new and unknown.”So the Bildung concept contains simultaneously a directedness towards the past and a tradition which is authoritative, coupled with a directedness towards the future: and all that which is new and unknown, the open horizon of existence. It is in the light of this double directedness that Varkøy questions whether “the concept ‘cultural heritage’ should be considered, as something static or as something which is continually moving and developing.”So the past and our cultural heritage and the masterworks our cultural heritage is based upon, do not belong to bygone days. They do not belong to a finished [End Page 98] past. On the contrary, it is all still with us. That is how I read Varkøy. And this reading has a tremenduous resemblence to... (shrink)

The case of Ashley X involved a young girl with profound and permanent developmental disability who underwent growth attenuation using high-dose estrogen, a hysterectomy, and surgical removal of her breast buds. Many individuals and groups have been critical of the decisions made by Ashley's parents, physicians, and the hospital ethics committee that supported the decision. While some of the opposition has been grounded in distorted facts and misunderstandings, others have raised important concerns. The purpose of this paper is to (...) provide a brief review of the case and the issues it raised, then address 25 distinct substantive arguments that have been proposed as reasons that Ashley's treatment might be unethical. We conclude that while some important concerns have been raised, the weight of these concerns is not sufficient to consider the interventions used in Ashley's case to be contrary to her best interests, nor are they sufficient to preclude similar use of these interventions in the future for carefully selected patients who might also benefit from them. (shrink)

The case of Ashley X involved a young girl with profound and permanent developmental disability who underwent growth attenuation using high-dose estrogen, a hysterectomy, and surgical removal of her breast buds. Many individuals and groups have been critical of the decisions made by Ashley's parents, physicians, and the hospital ethics committee that supported the decision. While some of the opposition has been grounded in distorted facts and misunderstandings, others have raised important concerns. The purpose of this paper is to (...) provide a brief review of the case and the issues it raised, then address 25 distinct substantive arguments that have been proposed as reasons that Ashley's treatment might be unethical. We conclude that while some important concerns have been raised, the weight of these concerns is not sufficient to consider the interventions used in Ashley's case to be contrary to her best interests, nor are they sufficient to preclude similar use of these interventions in the future for carefully selected patients who might also benefit from them. (shrink)

X‐chromosome inactivation ensures dosage compensation between the sexes in mammals by randomly choosing one out of the two X chromosomes in females for inactivation. This process imposes a plethora of questions: How do cells count their X chromosome number and ensure that exactly one stays active? How do they randomly choose one of two identical X chromosomes for inactivation? And how do they stably maintain this state of monoallelic expression? Here, different regulatory concepts and their plausibility are evaluated in the (...) context of theoretical studies that have investigated threshold behavior, ultrasensitivity, and bistability through mathematical modeling. It is discussed how a twofold difference between a single and a double dose of X‐linked genes might be converted to an all‐or‐nothing response and how mutually exclusive expression can be initiated and maintained. Finally, candidate factors that might mediate the proposed regulatory principles are reviewed. (shrink)

Half of the 33.2 million people living with HIV today are women. Yet, responses to the epidemic are not adequately meeting the needs of women. This article critically evaluates how prevention of mother-to-child transmission (PMTCT) programs, the principal framework under which women's health is currently addressed in the global response to AIDS, have tended to focus on the prevention of HIV transmission from HIV-positive women to their infants. This paper concludes that more than ten years after their inception, PMTCT (...) programs still do not successfully ensure the adequate treatment, care and support of HIV-infected women. Of particular concern is the continued widespread use of single-dose nevirapine despite World Health Organization recommendations to employ more effective combination therapies that do not potentially jeopardize women's future treatment outcomes. In response, the article calls for a more comprehensive approach that places women's health needs at the centre of AIDS responses. This is critical in settings where the pandemic is generalized and there is a push to greatly expand PMTCT programs, as a more effective and equitable way of meeting the needs of women in the context of HIV. Without such a comprehensive approach, women will continue to be impacted disproportionately by the pandemic, and current strategies for prevention, including PMTCT, and treatment will not be as effective and responsive as they need to be. (shrink)

Acerca de la imagen de tapa: Ritmos Primarios, la Subversión del Alma, de Hugo Aveta, 2013.

Acerca de la imagen de tapa: El Negro Matapacos, por Caiozzama. Noviembre 2019, Santiago de Chile.

In his comments, Daniel Nicholls succeeds in saying more than a few things that I had scarcely realized about the ways in which I write and, therefore, of what I tend to take for granted. He sees in what I write a capacity ‘to utilize the “obvious” whilst at the same time saying something about it.’ Not every philosopher would take that as a compliment. Many philosophers and philosophies have quite other pretensions – to transcend the illusions of common thought (...) and perception towards a higher plane of metaphysical philosophy – or of physics and mathematics. I find that Nicholls’s remark both compliments and complements my work, however. The use of everyday language and example to disturb that everyday world to ‘bring it into high relief’ as Nicholls puts it – is a significant part of philosophical method. To juxtapose the esoteric language of metaphysics (being-in-itself, being-for-itself, being-for-others) with the everyday (what there is, living for oneself, living for others) is to haunt the everyday with a metaphysical imagination even as it reveals what metaphysics had erased from the coinage of common words. (I am thinking, of course, of Derrida’s remarks about Anatole France’s satirical view of philosophical language as coinage from which all marking has been erased). (shrink)

In this article I argue that Part II of the Family LawAct 1996 gives expression to a new form ofresponsibility. I begin by suggesting thatresponsible behaviour has shifted from prohibiting orrequiring particular actions: we now exhibitresponsibility by our attitude towards our actions. I then examine where this new conception ofresponsibility has come from. Through an examinationof the work of post-liberal theorists, principallyMichael Sandel, I argue that a changing view ofpersonhood within post-liberal theory has led to aquestioning of the possibility of (...) choice, and that theabsence of choice necessitates a shift in thedefinition of responsible behaviour. If we are createdby our decisions then we cannot be held to account forour decisions, but only for the care we have takenover them. Responsibility is therefore measured notby our level of self-control but by our level ofself-awareness. Finally I examine the consequences ofthis shift in the meaning of responsibility. Withinthis framework autonomy is illusory thereforedecisions do not need to be respected. This explainswhy the implementation of Part II of the Family LawAct 1996 has been called into question. Within thisframework responsibility is relative therefore itextends indefinitely. This enables the Family Law Actto be uniquely intrusive and judgmental: everydivorcing couple, on being held up to scrutiny, isfound lacking. (shrink)