Specific versus placebo effects in biofeedback: some brief back-to-basics considerations

Following the semantic complexities raised in earlier papers, this paper seeks to return to some of the more basic considerations arising from the preceding discussion. A critical part of the context of that discussion is the increasingly important issue of accountability. In this context, the citing of supportive studies is not enough; one must also be able to justify the logical relevance of those studies. The discussion therefore turns on the logic of treatment evaluation, which must be treated as objectively as possible. Also critical is the distinction between the question of whether an effect is present and the question of what the source of that question might be. In the quest for treatment evaluation, only the former question is important. However, this quest is one that is in the interest of researchers, clinicians, and consumers, for all of whom only the facts will do.     

Specific versus placebo effects in biofeedback training: A critical lay perspective

Recent interchanges on the question of how to evaluate biofeedback have been cast in terms of a researcher versus clinician dichotomy. This tends to make the arguments ad hominem and focuses attention on minutiae that are of limited general interest. Accordingly, one purpose of the present paper is to state the specific-effects approach to biofeedback evaluation from a critical lay, rather than a research, perspective. The logic of the specific-effects approach to treatment evaluation is first illustrated by a hypothetical example (the Minefield Parable), and it is then suggested that the approach is appropriate for the evaluation of any treatment, be it physical, psychological, or some complex combination. The other purpose of the paper is to further clarify the specific-effects position by responding to some difficulties that have been raised by critics of the position. Some of these difficulties are based on misrepresentations of the position, while others are genuine. However, even for the genuine difficulties, practical solutions are available. The paper concludes that the question of whether a particular class of treatments works is one that is properly raised by the intelligent consumer, and that, for the answer to that question, only the facts, based on adequately controlled clinical studies, will do.The preparation of this paper was supported by a grant from the National Science and Engineering Research Council of Canada. I am indebted to Hal Scher and Donna Shulhan for comments on an earlier draft.     

Specific versus placebo effects in biofeedback training: a critical lay perspective

Recent interchanges on the question of how to evaluate biofeedback have been cast in terms of a researcher versus clinician dichotomy. This tends to make the arguments ad hominem and focuses attention on minutiae that are of limited general interest. Accordingly, one purpose of the present paper is to state the specific-effects approach to biofeedback evaluation from a critical lay, rather than a research, perspective. The logic of the specific-effects approach to treatment evaluation is first illustrated by a hypothetical example (the Minefield Parable), and it is then suggested that the approach is appropriate for the evaluation of any treatment, be it physical, psychological, or some complex combination. The other purpose of the paper is to further clarify the specific-effects position by responding to some difficulties that have been raised by critics of the position. Some of these difficulties are based on misrepresentations of the position, while others are genuine. However, even for the genuine difficulties, practical solutions are available. The paper concludes that the question of whether a particular class of treatments works is one that is properly raised by the intelligent consumer, and that, for the answer to that question, only the facts, based on adequately controlled clinical studies, will do.     

Family refusal of emergency medical treatment in China: An investigation from legal,empirical and ethical perspectives

This paper is an analysis of the limits of family authority to refuse life saving treatment for a family member (in the Chinese medical context). Family consent has long been praised and practiced in many non-Western cultural settings such as China and Japan. In contrast, the controversy of family refusal remains less examined despite its prevalence in low-income and middle-income countries. In this paper, we investigate family refusal in medical emergencies through a combination of legal, empirical and ethical approaches, which is highly relevant to the ongoing discussion about the place of informed consent in non-Western cultures. We first provide an overview of the Chinese legislation concerning informed consent to show the significance of family values in the context of medical decision-making and demonstrate the lack of legal support to override family refusal. Next, we present the findings of a vignette question that investigated how 11,771 medical professionals and 2,944 patients in China responded to the family refusal of emergency treatment for an unconscious patient. In our analysis of these results, we employ ethical reasoning to question the legitimacy of family refusal of life-sustaining emergency treatment for temporarily incompetent patients. Last, we examine some practical obstacles encountered by medical professionals wishing to override family refusal to give context to the discussion.     

A primer on choosing goals and indicators to evaluate ecological restoration success

We discuss aspects of one of the most important issues in ecological restoration: how to evaluate restoration success. This first requires clearly stated and justified restoration goals and targets; this may seem “obvious” but in our experience, this step is often elided. Indicators or proxy variables are the typical vehicle for monitoring; these must be justified in the context of goals and targets and ultimately compared against those to allow for an evaluation of outcome (e.g. success or failure). The monitoring phase is critical in that a project must consider how the monitoring frequency and overall design will allow the postrestoration trajectories of indicators to be analyzed. This allows for real‐time management adjustments—adaptive management (sensu lato)—to be implemented if the trajectories are diverging from the targets. However, as there may be large variation in early postrestoration stages or complicated (nonlinear) trajectory, caution is needed before committing to management adjustments. Ideally, there is not only a goal and target but also a model of the expected trajectory—that only can occur if there are sufficient data and enough knowledge about the ecosystem or site being restored. With so many possible decision points, we focus readers' attention on one critical step—how to choose indicators. We distinguish generalizable and specific indicators which can be qualitative, semiquantitative, or quantitative. The generalizable indicators can be used for meta‐analyses. There are many options of indicators but making them more uniform would help mutual comparisons among restoration projects.     

Mathematics, structuralism and biology

A new approach is gaining ground in biology, one that has much in common with the structuralist tradition in other fields. It is very much in the spirit of an earlier view of biology and indeed of science in general. It is also, though this is not generally recognized, in the spirit of twentieth century physics. As in modern physics, however, it is not a question of ignoring all the progress that has been made within the former paradigm. On the contrary, the aim is to use it as a basis for setting out in a somewhat different direction. Complex phenomena do not generally lend themselves to reductionist analyses which seek explanation only in terms of detailed mechanisms, but a proper scientific discussion of structure must make full use of what we have already learned - by whatever means - about the processes that underly the phenomena we are trying to understand.     

The argument from potential: a reappraisal

Several criticisms of the argument from potential are reported. It is noted that such criticisms are inspired by two similarly wrong interpretations of potentiality, one confusing it with possibility and another with probability. A brief analysis of the original Aristotelian context in which the concept emerged shows that potentiality cannot be thought of as indicating the provision of some empirical facts in the future, but must rather be referred to the inherent ontological structure of the being in question. It is then argued that such an Aristotelian concept can be useful to express the dynamic structure of the person, as it must be understood according to contemporary phenomenological personalism. In the light of this philosophical tradition, the embryo can be vieewed as a being already possessing the human nature and actively developing its potential for personhood: it also follows that human nature must not be understood as a static and predetermined essence, but rather as the principle of becoming and movement toward further achievements.     

Side by Side Battery Technologies with Lithium‐Ion Based Batteries

In recent years, the electrochemical power sources community has launched massive research programs, conferences, and workshops on the “post Li battery era.” However, in this report it is shown that the quest for post Li‐ion and Li battery technologies is incorrect in its essence. This is the outcome of a three day discussion on the future technologies that could provide an answer to a question that many ask these days: Which are the technologies that can be regarded as alternative to Li‐ion batteries? The answer to this question is a rather surprising one: Li‐ion battery technology will be here for many years to come, and therefore the use of “post Li‐ion” battery technologies would be misleading. However, there are applications with needs for which Li‐ion batteries will not be able to provide complete technological solutions, as well as lower cost and sustainability. In these specific cases, other battery technologies will play a key role. Here, the term “side‐by‐side technologies” is coined alongside a discussion of its meaning. The progress report does not cover the topic of Li‐metal battery technologies, but covers the technologies of sodium‐ion, multivalent, metal–air, and flow batteries.     

Polyclonal Tumors in the Mammalian Intestine: Are Interactions Among Multiple Initiated Clones Necessary for Tumor Initiation,Growth, and Progression?

Studies in both man and mouse indicate that the majority of familial intestinal tumors are polyclonal being composed of cells from at least two distinct progenitors. The formation of polyclonal tumors in the mouse can be explained by short-range interactions between multiple initiated clones within one or two crypt diameters of each other. These clonal interactions might be critical, if not necessary, for initiation, growth, progression, or all three stages of tumorigenesis. This view is diametrically opposed to the widely held view that intestinal tumors are monoclonal and progress by clonal expansion. The data supporting the latter are neither extensive nor definitive. In addition, the results from a recent study indicate that earlier studies of tumor clonality were heavily biased because lineage patches in the intestinal epithelium of humans resulting from X-inactivation are relatively large. Consequently, hundreds of tumors from familial and sporadic cases need to be analyzed to accurately assess tumor clonality. Investigators must keep an open mind regarding the clonality of tumors in the mammalian intestine as new experimental approaches are developed which will eventually provide a definitive answer to this fundamental question in the field of cancer biology.     

Biological wastewater treatment model building fits and misfits

The modeling of biological wastewater treatment processes has received much attention over the past ten years. Efforts are underway to develop a unified model for these processes which will greatly aid in the design and operation of wastewater treatment facilities. This paper presents a philosophical discussion of model building strategies augmented by a discussion of statistical problems associated with model parameter estimation and model discrimination. This discussion further illustrates with actual data, that goodness of fit is not a sufficient condition for model acceptance. Numerous rival models are examined to illustrate this point. In order to verify a model or to discriminate between rival models, they must be “Put in jeopardy.” If this attitude is not employed in model building efforts, important discrepancies in the proposed model may go undetected.     

Head-counting vs. heart-counting: an examination of the recent case of the conjoined twins from Malta

This paper reexamines the recent case of the conjoined twins from Malta. Survival was said to be possible only through separation, which would actually leave only one twin alive. The parents refused to allow the killing of one to save the other, but the court ruled that this would amount to the neglect of innocent life. The article questions the assumption that the case is indeed a struggle between two people. Further, it questions the assumption that a conjoined twin's natural interest and wish is separation. Historical evidence shows that many conjoined twins do not wish for separation, even when it becomes a question of survival.The article concludes with a critical evaluation of the tendency in contemporary society and particularly in bioethics to regard ethical challenges as rivalry between individuals competing for scarce resources.     

A direct advance on advance directives

Advance directives (ADs), which are also sometimes referred to as 'living wills', are statements made by a person that indicate what treatment she should not be given in the event that she is not competent to consent or refuse at the future moment in question. As such, ADs provide a way for patients to make decisions in advance about what treatments they do not want to receive, without doctors having to find proxy decision-makers or having recourse to the doctrine of necessity. While patients can request particular treatments in an AD, only refusals are binding. This paper will examine whether ADs safeguard the autonomy and best interests of the incompetent patient, and whether legislating for the use of ADs is justified, using the specific context of the legal situation in the United Kingdom to illustrate the debate. The issue of whether the law should permit ADs is itself dependent on the issue of whether ADs are ethically justified; thus we must answer a normative question in order to answer the legislative one. It emerges that ADs suffer from two major problems, one related to autonomy and one to consent. First, ADs' emphasis on precedent autonomy effectively sentences some people who want to live to death. Second, many ADs might not meet the standard criteria for informed refusal of treatment, because they fail on the crucial criterion of sufficient information. Ultimately, it transpires that ADs are typically only appropriate for patients who temporarily lose physical or mental capacity.     

On confidence bounds for the ratio of net differences in the "gold standard" design with reference, experimental, and placebo treatment

The three-arm clinical study including a placebo has been recommended to be the preferred study design for the comparison of an experimental treatment relative to a reference treatment. In a confirmatory three-arm study multiplicity issues arise that are not present in two-arm studies. In the past a successful demonstration of superiority of the reference over placebo has been regarded a prerequisite validation step for the demonstration of superiority of the experimental treatment over placebo. However, for an investigator this last comparison is the most critical one. In a clinical study the demonstration of superiority of the experimental treatment over placebo is a result of its own value and this should therefore not be made dependent on tests that are of higher priority in a hierarchical test procedure. This can be achieved through a symmetrical formulation of Fieller's method for constructing confidence intervals for ratio of the expected values from normally distributed variables. In the symmetrical formulation the different meanings of nominator and denominator disappear, and simultaneous statements for comparisons between the experimental treatment and placebo, reference treatment and placebo, and reference and experimental treatment can be made. This is accomplished by moving the discussion on confidence sets from the line of real numbers to the unit circle which allows representing confidence sectors always as connected sets, gives always simple geometrical interpretations, and is easy to be transformed back to the real numbers if the traditional calculations behave well. The proposed procedures provides additional insight in existing methods but does obviously not answer the clinical question whether or not the demonstration of superiority of the reference treatment over placebo is a necessary validation step for further comparisons.     

CHEAP LISTENING? – REFLECTIONS ON THE CONCEPT OF WRONGFUL DISABILITY1

This paper investigates the concept of wrongful disability. That concept suggests that parents are morally obligated to prevent the genetic transmission of certain conditions and so, if they do not, any resulting disability is 'wrongful'. In their book From Chance to Choice, Buchanan, Brock, Daniels and Wikler defend the concept of wrongful disability using the principle of avoidability via substitution. That principle is scrutinised here. It is argued that the idea of avoidability via substitution is both conceptually problematic and rather insensitive. Instead, it is suggested that the question of whether or not bringing a particular disability about is wrongful does not simply hinge on whether or not substitution takes place. Rather, it involves an evaluation of parental aspirations and responsibilities. It is argued that the desire need not be responsible for creating challenges for others that lie outside what is perceived to be an acceptable range provides a justification for termination of pregnancy on the grounds of projected disability that neither commits one to wrongful life claim, nor requires that one substitute a non-disabled child instead. The ramifications of such an approach are explored. The paper concludes by suggesting that the question of what is considered to be an acceptable range of human capability is an increasingly important one. It is argued that, when addressing that question, we should be acutely aware of the social context that may go some way to define what we consider to be an acceptable range.     

Ecosystems off track: rate‐induced critical transitions in ecological models

Theory suggests that gradual environmental change may erode the resilience of ecosystems and increase their susceptibility to critical transitions. This notion has received a lot of attention in ecology in recent decades. An important question receiving far less attention is whether ecosystems can cope with the rapid environmental changes currently imposed. The importance of this question was recently highlighted by model studies showing that elevated rates of change may trigger critical transitions, whereas slow environmental change would not. This paper aims to provide a mechanistic understanding of these rate‐induced critical transitions to facilitate identification of rate sensitive ecosystems. Analysis of rate sensitive ecological models is challenging, but we demonstrate how rate‐induced transitions in an elementary model can still be understood. Our analyses reveal that rate‐induced transitions 1) occur if the rate of environmental change is high compared to the response rate of ecosystems, 2) are driven by rates, rather than magnitudes, of change and 3) occur once a critical rate of change is exceeded. Disentangling rate‐induced transitions from classical transitions in observations would be challenging. However, common features of rate‐sensitive models suggest that ecosystems with coupled fast–slow dynamics, exhibiting repetitive catastrophic shifts or displaying periodic spatial patterns are more likely to be rate sensitive. Our findings are supported by experimental studies showing rate‐dependent outcomes. Rate sensitivity of models suggests that the common definition of ecological resilience is not suitable for a subset of real ecosystems and that formulating limits to magnitudes of change may not always safeguard against ecosystem degradation. Synthesis Understanding and predicting ecosystem response to environmental change is one of the key challenges in ecology. Model studies have suggested that slow, gradual environmental change beyond some critical threshold can trigger so‐called critical transitions and abrupt ecosystem degradation. An important question remains however whether ecosystems can cope with the ongoing rapid anthropogenic environmental changes to which they are currently imposed. In this study we demonstrate that in some ecological models elevated rates of change can trigger critical transitions even if slow environmental change of the same magnitude would not. Such rateinduced critical transitions in models suggest that concepts like resilience and planetary boundaries may not always be sufficient to explain and prevent ecosystem degradation.     

Male rhinoplasty

Rhinoplasty is one of the most complex and challenging operations in plastic surgery. This complexity is increased among male patients, because male patients tend to have relatively nonspecific complaints, are typically more demanding, and are regarded as being much less attentive during consultations. It is critical for the surgeon to verify that the male patient has realistic goals before he undergoes an operation, and the surgeon must confirm that the male patient has heard and understood all of the risks, benefits, and options. It is essential that masculine features be preserved for male rhinoplasty patients. Excessive dorsal reduction or tip refinement produces unsatisfactory results. A comprehensive discussion of proper evaluation of the male nose, surgical planning, intraoperative techniques, and postoperative treatment is presented. These tools should allow plastic surgeons to produce a balanced harmonious nose in relation to the rest of the face.     

Threshold effects in genetic toxicity: perspective of chemicals regulation in Germany

In the regulation of chemical substances, it is generally agreed that there are no thresholds for genotoxic effects of chemicals, i.e. , that there are no doses without genotoxic effects. When classifying and labelling chemicals, dangerous properties of chemicals are to be identified. In this context, in general, the mode of action (threshold or not) is not considered for genotoxic substances. In the process of quantitative risk assessment, however, determination of the type of dose-effect relationships is decisive for the outcome and the type of risk management. The presence of a threshold must be justified specifically in each individual case. Inter alia, the following aspects may be discussed in this respect: aneugenic activity, indirect modes of action, extremely steep dose-effect relationships in combination with strong toxicity, specific toxicokinetic conditions which may lead to 'metabolic protection' prior to an attack of DNA. In the practice of the regulation of chemical substances with respect to their genotoxic effects, the discussion of thresholds has played a minor role. For notified new substances, there are, in general, no data available that would allow a reasonable discussion. Concerning substances out of the European programme on existing substances, so far 29 have been assessed in our institute with respect to genetic toxicity. Eight out of these have shown considerable evidence for genotoxicity. For two of them, a possible threshold is discussed: one substance is an aneugen, the other one is metabolised to an endogenic compound with genotoxic potential. In the practice of risk assessment of genotoxic substances, the discussion of the mode of action for genotoxicity is frequently associated with the evaluation of potential carcinogenic effects. Here, tissue-specific genotoxic effects in target organs for carcinogenicity are to be discussed. Moreover, the contribution of genotoxicity to the multifactorial process of tumour development should be assessed.     

Toward an understanding of the role of DNA adduct conformation in defining mutagenic mechanism based on studies of the major adduct (formed at N(2)-dG) of the potent environmental carcinogen, benzo[a]pyrene

The process of carcinogenesis is initiated by mutagenesis, which often involves replication past damaged DNA. One question - what exactly is a DNA polymerase seeing when it incorrectly copies a damaged DNA base (e.g., inserting dATP opposite a dG adduct)? - has not been answered in any case. Herein, we reflect on this question, principally by considering the mutagenicity of one activated form of benzo[a]pyrene, (+)-anti-B[a]PDE, and its major adduct [+ta]-B[a]P-N(2)-dG. In previous work, [+ta]-B[a]P-N(2)-dG was shown to be capable of inducing>95% G-->T mutations in one sequence context (5'-TGC), and approximately 95% G-->A mutations in another (5'-AGA). This raises the question - how can a single chemical entity induce different mutations depending upon DNA sequence context? Our current working hypothesis is that adduct conformational complexity causes adduct mutational complexity, where DNA sequence context can affect the former, thereby influencing the latter. Evidence supporting this hypothesis was discussed recently (Seo et al., Mutation Res. [in press]). Assuming this hypothesis is correct (at least in some cases), one goal is to consider what these mutagenic conformations might be. Based on molecular modeling studies, 16 possible conformations for [+ta]-B[a]P-N(2)-dG are proposed. A correlation between molecular modeling and mutagenesis work suggests a hypothesis (Hypothesis 3): a base displaced conformation with the dG moiety of the adduct in the major vs. minor groove gives G-->T vs. G-->A mutations, respectively. (Hypothesis 4, which is a generalized version of Hypothesis 3, is also proposed, and can potentially rationalize aspects of both [+ta]-B[a]P-N(2)-dG and AP-site mutagenesis, as well as the so-called "A-rule".) Finally, there is a discussion of how conformational complexity might explain some unusual mutagenesis results that suggest [+ta]-B[a]P-N(2)-dG can become trapped in different conformations, and why we think it makes sense to interpret adduct mutagenesis results by modeling ds-DNA (at least in some cases), even though the mutagenic event must occur at a ss/ds-DNA junction in the presence of a DNA polymerase.     

Ethical concerns regarding commercialization of deep brain stimulation for obsessive compulsive disorder

The United States Food and Drug Administration's recent approval of the commercial use of Deep Brain Stimulation (DBS) as a treatment for Obsessive Compulsive Disorder (OCD) will be discussed within the context of the existing USA regulatory framework. The purpose will be to illustrate the current lack of regulation and oversight of the DBS market, which has resulted in the violation of basic ethical norms. The discussion will focus on: 1) the lack of available evidence on procedural safety and efficacy, 2) the numerous conflicts of interest held by research investigators, and 3) the ambiguity of both aforementioned categories due to an inherent lack of transparency in the research. It is argued that in order to address these issues, ethical analyses of DBS for psychiatric disorders must include the role of the industry forces that have become the primary impetus for this research. As such, DBS for OCD serves as an important case example in studies of neurotechnology and innovative surgery.