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 of 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.The preparation of this paper was supported by grants from the National Science and Engineering Research Council of Canada to both authors. We are indebted to Hal Scher 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.     

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.     

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.     

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.     

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.     

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.     

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.     

A hierarchical biology concept framework: a tool for course design

A typical undergraduate biology curriculum covers a very large number of concepts and details. We describe the development of a Biology Concept Framework (BCF) as a possible way to organize this material to enhance teaching and learning. Our BCF is hierarchical, places details in context, nests related concepts, and articulates concepts that are inherently obvious to experts but often difficult for novices to grasp. Our BCF is also cross-referenced, highlighting interconnections between concepts. We have found our BCF to be a versatile tool for design, evaluation, and revision of course goals and materials. There has been a call for creating Biology Concept Inventories, multiple-choice exams that test important biology concepts, analogous to those in physics, astronomy, and chemistry. We argue that the community of researchers and educators must first reach consensus about not only what concepts are important to test, but also how the concepts should be organized and how that organization might influence teaching and learning. We think that our BCF can serve as a catalyst for community-wide discussion on organizing the vast number of concepts in biology, as a model for others to formulate their own BCFs and as a contribution toward the creation of a comprehensive BCF.     

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.     

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.     

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.     

The value of grooming to female primates

Current socioecological models suggest that the structure of female-bonded primate groups is predicated on the need for coalitionary support in competitive interactions. Social grooming is thought to be the means by which females ensure support from other individuals, either by the direct exchange of grooming for aid or by using grooming as a means of strengthening social bonds. Since these relationships are valuable, they must be regularly serviced and must be repaired if they become damaged. We question this position and show that empirical evidence to support these theoretical arguments is lacking. We then go on to present a new framework in which the inconsistencies regarding grooming and relationship negotiation are interpreted in the context of individual decision-making processes. In this framework, primate groups represent biological markets in which individuals either trade grooming in a reciprocal manner for the direct benefits that grooming itself offers, or exchange it for tolerance by more powerful animals. A number of testable predictions are derived from this hypotheses. The need for socioecological studies to focus on the dynamics of individual relationships rather than using summary measures is emphasized since only a detailed knowledge of serial interaction will provide the key to understanding the complexities of individual decision-making processes.     

Expanding the proteome: disordered and alternatively folded proteins

Proteins provide much of the scaffolding for life, as well as undertaking a variety of essential catalytic reactions. These characteristic functions have led us to presuppose that proteins are in general functional only when well structured and correctly folded. As we begin to explore the repertoire of possible protein sequences inherent in the human and other genomes, two stark facts that belie this supposition become clear: firstly, the number of apparent open reading frames in the human genome is significantly smaller than appears to be necessary to code for all of the diverse proteins in higher organisms, and secondly that a significant proportion of the protein sequences that would be coded by the genome would not be expected to form stable three-dimensional (3D) structures. Clearly the genome must include coding for a multitude of alternative forms of proteins, some of which may be partly or fully disordered or incompletely structured in their functional states. At the same time as this likelihood was recognized, experimental studies also began to uncover examples of important protein molecules and domains that were incompletely structured or completely disordered in solution, yet remained perfectly functional. In the ensuing years, we have seen an explosion of experimental and genome-annotation studies that have mapped the extent of the intrinsic disorder phenomenon and explored the possible biological rationales for its widespread occurrence. Answers to the question 'why would a particular domain need to be unstructured?' are as varied as the systems where such domains are found. This review provides a survey of recent new directions in this field, and includes an evaluation of the role not only of intrinsically disordered proteins but also of partially structured and highly dynamic members of the disorder-order continuum.     

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.     

Identification of prolyl hydroxylation modifications in mammalian cell proteins

Prolyl hydroxylation is a PTM that plays an important role in the formation of collagen fibrils and in the oxygen‐dependent regulation of hypoxia inducible factor‐α (HIF‐α). While this modification has been well characterized in the context of these proteins, it remains unclear to what extent it occurs in the remaining mammalian proteome. We explored this question using MS to analyze cellular extracts subjected to various fractionation strategies. In one strategy, we employed the von Hippel Lindau tumor suppressor protein, which recognizes prolyl hydroxylated HIF‐α, as a scaffold for generating hydroxyproline capture reagents. We report novel sites of prolyl hydroxylation within five proteins: FK506‐binding protein 10, myosin heavy chain 10, hexokinase 2, pyruvate kinase, and C‐1 Tetrahydrofolate synthase. Furthermore, we show that identification of prolyl hydroxylation presents a significant technical challenge owing to widespread isobaric methionine oxidation, and that manual inspection of spectra of modified peptides in this context is critical for validation.     

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.     

Legal aspects of telepathology.

In some legal surroundings telepathology is considered a breach of registrational barriers. The recommendation of the G 8 states in Europe for required legislation in telemedicine suggests to recognise that the localization of the remote health care professional defines the site not only of licensure but also of liability. This approach must be considered helpful, since it can solve many problems brought about by the doubtful results of private international law and conventions like the European Union (EU) and Lugano Convention. Under today's conditions in private international law it must be considered essential to agree upon a choice of law and stipulate a court of jurisdiction when doing telepathology. However, the opposing aims of insuring the patients claims and avoiding jurisdictions that exceed the local expectations of the medical professional must be reconciled. Data protection and data security are other crucial topics that require attention. Generally speaking, the principles of minimum data exchange, anonymity, pseudonymity and cryptography must be established as a basis for all telepathology procedures. Only when personal data is needed, its use can be legitimated. Written consent of the patient is advised. To guarantee a cross-border security level the regulations of the EU-Data Protection Directive need to be transformed into national law. In practise, cross-border dataflow shall only take place where the security level can be maintained even within the other country. Finally, reimbursement questions must be answered to establish a sound economical basis for telepathology. The spatial distance between the participants may yield the question, whether the service has been rendered to an extent necessary and sufficient for reimbursement. If reimbursement takes place on a cross-border or cross-regional level, severe disturbances of the health systems can occur. Regulation schemes or treaties need therefore to be developed to avoid such disturbances and encompass mutual standards of care as well as methods to balance reimbursement.     

Training Nonhuman Primates to Cooperate With Scientific Procedures in Applied Biomedical Research

This report provides a brief overview of aspects of training nonhuman primates who have been, and continue to be, used in this laboratory. The research context involves applied behavioral studies in which animals are trained to perform complex operant behavioral sequences, often in their homecage environment. In such studies, animals have freedom to choose whether to engage in appetitively reinforced behavioral tests that employ neither food deprivation nor fluid management. This background of operant conditioning has provided an insight to, and a context for, animal training both as an adjunct to general laboratory management and as a way to expedite scientific procedures. Thus, training has potential implications for both well-being and scientific quality, although it must be considered an adjunct to the provision of socialization with conspecifics in high quality diverse housing systems and not as an alternative to such provision. The importance of discussion and consideration of alternative procedures cannot be overemphasized.