Randomized controlled trial trial designs exist on an explanatory-pragmatic spectrum, depending on the degree to which a study aims to address a question of efficacy or effectiveness. As conceptualized by Schwartz and Lellouch in 1967, an explanatory approach to trial design emphasizes hypothesis testing about the mechanisms of action of treatments under ideal conditions, whereas a pragmatic approach emphasizes testing effectiveness of two or more available treatments in real-world conditions. Interest in, and the number of, pragmatic trials has grown substantially (...) in recent years, with increased recognition by funders and stakeholders worldwide of the need for credible evidence to inform clinical decision-making. This increase has been accompanied by the onset of learning healthcare systems, as well as an increasing focus on patient-oriented research. However, pragmatic trials have ethical challenges that have not yet been identified or adequately characterized. The present study aims to explore the views of key stakeholders with respect to ethical issues raised by the design and conduct of pragmatic trials. It is embedded within a large, four-year project that seeks to develop guidance for the ethical design and conduct of pragmatic trials. As a first step, this study will address important gaps in the current empirical literature with respect to identifying a comprehensive range of ethical issues arising from the design and conduct of pragmatic trials. By opening up a broad range of topics for consideration within our parallel ethical analysis, we will extend the current debate, which has largely emphasized issues of consent, to the range of ethical considerations that may flow from specific design choices. Semi-structured interviews with key stakeholders, across multiple jurisdictions, identified based on their known experience and/or expertise with pragmatic trials. We expect that the study outputs will be of interest to a wide range of knowledge users including trialists, ethicists, research ethics committees, journal editors, regulators, healthcare policymakers, research funders and patient groups. All publications will adhere to the Tri-Agency Open Access Policy on Publications. (shrink)

BackgroundCentral to ethically justified clinical trial design is the need for an informed consent process responsive to how potential subjects actually comprehend study participation, especially study goals, risks, and potential benefits. This will be particularly challenging when studying deep brain stimulation and whether it impedes symptom progression in Parkinson’s disease, since potential subjects will be Parkinson’s patients for whom deep brain stimulation will likely have therapeutic value in the future as their disease progresses.MethodAs part of an expanded informed consent process (...) for a pilot Phase I study of deep brain stimulation in early stage Parkinson’s disease, an ethics questionnaire composed of 13 open-ended questions was distributed to potential subjects. The questionnaire was designed to guide potential subjects in thinking about their potential participation.ResultsWhile the purpose of the study (safety and tolerability) was extensively presented during the informed consent process, in returned responses 70 percent focused on effectiveness and 91 percent included personal benefit as potential benefit from enrolling. However, 91 percent also indicated helping other Parkinson’s patients as motivation when considering whether or not to enroll.ConclusionsThis combination of responses highlights two issues to which investigators need to pay close attention in future trial designs: (1) how, and in what ways, informed consent processes reinforce potential subjects’ preconceived understandings of benefit, and (2) that potential subjects see themselves as part of a community of Parkinson’s sufferers with responsibilities extending beyond self-interest. More importantly, it invites speculation that a different paradigm for informed consent may be needed. (shrink)

The gelsolin gene family encodes a number of higher eukaryotic actin-binding proteins that are thought to function in the cytoplasm by severing, capping, nucleating or bundling actin filaments. Recent evidence, however, suggests that several members of the gelsolin family may have adopted unexpected nuclear functions including a role in regulating transcription. In particular, flightless I, supervillin and gelsolin itself have roles as coactivators for nuclear receptors, despite the fact that their divergence appears to predate the evolutionary appearance of nuclear receptors. (...) Flightless I has been shown to bind both actin and the actin-related BAF53a protein, which are subunits of SWI/SNF-like chromatin remodelling complexes. The primary sequences of some actin-related proteins such as BAF53a exhibit conservation of residues that, in actin itself, are known to interact with gelsolin-related proteins. In summary, there is a growing body of evidence supporting a biological role in the nucleus for actin, Arps and actin-binding proteins and, in particular, the gelsolin family of actin-binding proteins. (c) 2005 Wiley Periodicals, Inc. (shrink)

This scarce antiquarian book is a facsimile reprint of the original. Due to its age, it may contain imperfections such as marks, notations, marginalia and flawed pages. Because we believe this work is culturally important, we have made it available as part of our commitment for protecting, preserving, and promoting the world's literature in affordable, high quality, modern editions that are true to the original work.

This scarce antiquarian book is a facsimile reprint of the original. Due to its age, it may contain imperfections such as marks, notations, marginalia and flawed pages. Because we believe this work is culturally important, we have made it available as part of our commitment for protecting, preserving, and promoting the world's literature in affordable, high quality, modern editions that are true to the original work.

ObjectivesTo describe reporting of informed consent in pragmatic trials, justifications for waivers of consent and reporting of alternative approaches to standard written consent. To identify factors associated with (1) not reporting and (2) not obtaining consent.MethodsSurvey of primary trial reports, published 2014–2019, identified using an electronic search filter for pragmatic trials implemented in MEDLINE, and registered in ClinicalTrials.gov.ResultsAmong 1988 trials, 132 (6.6%) did not include a statement about participant consent, 1691 (85.0%) reported consent had been obtained, 139 (7.0%) reported a (...) waiver and 26 (1.3%) reported consent for one aspect (eg, data collection) but a waiver for another (eg, intervention). Of the 165 trials reporting a waiver, 76 (46.1%) provided a justification. Few (53, 2.9%) explicitly reported use of alternative approaches to consent. In multivariable logistic regression analyses, lower journal impact factor (p=0.001) and cluster randomisation (p<0.0001) were significantly associated with not reporting on consent, while trial recency, cluster randomisation, higher-income country settings, health services research and explicit labelling as pragmatic were significantly associated with not obtaining consent (all p<0.0001).DiscussionNot obtaining consent seems to be increasing and is associated with the use of cluster randomisation and pragmatic aims, but neither cluster randomisation nor pragmatism are currently accepted justifications for waivers of consent. Rather than considering either standard written informed consent or waivers of consent, researchers and research ethics committees could consider alternative consent approaches that may facilitate the conduct of pragmatic trials while preserving patient autonomy and the public’s trust in research. (shrink)

BackgroundIt is commonly reported by editors that it has become harder to recruit reviewers for peer review and that this is because individuals are being asked to review too often and are experiencing reviewer fatigue. However, evidence supporting these arguments is largely anecdotal.Main bodyWe examine responses of individuals to review invitations for six journals in ecology and evolution. The proportion of invitations that lead to a submitted review has been decreasing steadily over 13 years (2003–2015) for four of the six (...) journals examined, with a cumulative effect that has been quite substantial (average decline from 56% of review invitations generating a review in 2003 to just 37% in 2015). The likelihood that an invitee agrees to review declines significantly with the number of invitations they receive in a year. However, the average number of invitations being sent to prospective reviewers and the proportion of individuals being invited more than once per year has not changed much over these 13 years, despite substantial increases in the total number of review invitations being sent by these journals—the reviewer base has expanded concomitant with this growth in review requests.ConclusionsThe proportion of review invitations that lead to a review being submitted has been declining steadily for four of the six journals examined here, but reviewer fatigue is not likely the primary explanation for this decline. (shrink)

Despite the accumulation of substantial cognitive science research relevant to education, there remains confusion and controversy in the application of research to educational practice. In support of a more systematic approach, we describe the Knowledge-Learning-Instruction (KLI) framework. KLI promotes the emergence of instructional principles of high potential for generality, while explicitly identifying constraints of and opportunities for detailed analysis of the knowledge students may acquire in courses. Drawing on research across domains of science, math, and language learning, we illustrate the (...) analyses of knowledge, learning, and instructional events that the KLI framework affords. We present a set of three coordinated taxonomies of knowledge, learning, and instruction. For example, we identify three broad classes of learning events (LEs): (a) memory and fluency processes, (b) induction and refinement processes, and (c) understanding and sense-making processes, and we show how these can lead to different knowledge changes and constraints on optimal instructional choices. (shrink)

Distinctive aspects of a culture are often reflected in the meaning and usage of words in the language spoken by bearers of that culture. Keywords such as душа (soul) in Russian, hati (heart) in Indonesian and Malay, and gezellig (convivial/cosy/fun) in Dutch are held to be especially culturally revealing, and scholars have identified a number of such keywords using careful linguistic analyses (Peeters, 2020b; Wierzbicka, 1990). Because keywords are expected to have different statistical properties than related words in other languages, (...) we argue that a quantitative comparison of word usage across languages can help to identify cultural keywords. To support this claim, we describe a computational method that compares word frequencies across languages, and apply it to both linguistic corpora and word association data. The method identifies culturally specific words that range from “obvious” examples, such as Amsterdam in Dutch, to non‐obvious yet independently proposed examples, such as hati (heart) in Indonesian. We show in addition that linguistic corpora and word association data provide converging evidence about culturally specific words. Our results therefore show how computational analyses and behavioral experiments can supplement the methods previously used by linguists to identify culturally salient words across languages. (shrink)

This book provides a comprehensive analysis of the ethical philosophy of John Stuart Mill, whose works shaped classical liberalism and utilitarianism. It explores Mill's thoughts on topics such as individual autonomy, rights, justice, and happiness, and how his ideas have influenced modern ethical thinking. This work has been selected by scholars as being culturally important, and is part of the knowledge base of civilization as we know it. This work is in the "public domain in the United States of (...) America, and possibly other nations. Within the United States, you may freely copy and distribute this work, as no entity (individual or corporate) has a copyright on the body of the work. Scholars believe, and we concur, that this work is important enough to be preserved, reproduced, and made generally available to the public. We appreciate your support of the preservation process, and thank you for being an important part of keeping this knowledge alive and relevant. (shrink)

Institutional review boards are almost universally considered to be overworked and understaffed. They also require substantial commitments of time and resources from their members. Although some surveys report average IRB memberships of 15 people or more, federal regulations require only five. We present data on IRB meetings at eight of the top 25 academic medical centers in the United States funded by the National Institutes of Health. These data indicate substantial contributions from primary reviewers and chairs during protocol discussions but (...) little from other members, which implies that it may be possible for smaller IRBs to accomplish the same tasks with no reduction in the quality of review. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Dracula and Carmilla:Monsters and the MindBenson Saler and Charles A. ZieglerFollowing the publication of Bram Stoker's Dracula in 1897, vampire narratives proliferated in Britain and the United States.1 While many twentieth century short stories, novels, plays, and films in both countries depart from Dracula in various ways, it is our impression that that workand its close derivatives retain pride of place in the popular imagination. Yet Dracula was (...) but one of several well-known vampire stories published in English during the nineteenth century, and scholars deem certain of the other tales to be of literary merit.In noting that, we raise this question: What is it about the plot and the characterization of vampires in Dracula that make it the most famous example of vampires in English fiction? Why, in particular, has it been more influential than Le Fanu's Carmilla which preceded it in time and is of equal or perhaps greater literary distinction?2 We address that question, and by doing so we hope to gain some insight into the attraction and persistence of vampire tales across time and cultures.We begin by sketching our approach to conceptualizing the category "vampire." Nina Auerbach, a Professor of English at the University of Pennsylvania, writes that "There is no such creature as 'The Vampire'; there are only vampires."3 That declaration is in keeping with her demonstration that in nineteenth and twentieth century British and American vampire novels, short stories, plays, and films, vampires vary greatly in behavior, in apparent motivation, and in cultural significance. Different social orders and different culturally supported sensibilities [End Page 218] and sensitivities, she persuasively argues, find expression in different sorts of vampires.We deem Auerbach's literary nominalism preferable to an essentialism that would govern vampiric class inclusion by insisting on some conjunction of necessary features or conditions. At the same time, however, we think that there is a better way of allowing for differences in conceptualizing vampires and in understanding their multi-faceted significance in British and American imaginings of the last two centuries. That way combines the recognition of family resemblances with insights derived from prototype theory in the cognitive sciences.A family resemblance approach can be quite liberal in what it includes as instantiations of the category "vampire." It can encompass not only such familiar (albeit different) figures as Ruthven, Varney, Carmilla, Dracula, and Lestat, but also others, including so-called "psychic vampires," who flourish not by sucking blood but by draining vitality, will, and even experience from their victims. Some may ask, does this not create a category that is so promiscuous in what it includes as to render the category analytically useless? No, we reply, once you couple family resemblance with insights from prototype theory.Prototype theory, narrowly described, attempts to account for "prototype effects." These "effects" are differences in the judgments that people render about how well different instances of a category exemplify the category. Thus, for instance, some people may judge apples and oranges to be clearer or better exemplars of the category "fruit" than olives. Similarly, some may judge robins and sparrows to be clearer or better exemplars of the category "bird" than penguins. Judgments can be explicitly given, or they can be inferred from the order of examples that people give or from their responses to lists of examples furnished by others. Prototype theorists call the adjudged clearest or "best" examples of categories "prototypes" or "the most prototypical exemplars."4 This approach celebrates centrality and periphery rather than essence and boundary in conceptualizing categories.5 It allows that some instantiations of a category may be deemed more central to the category than others. Thus in the case of vampires, Dracula is more central to the category than, say, the shape-shifting space alien who extracts salt from victims in an episode of Star Trek, First Generation. Auerbach recognizes that centrality when she refers to "Dracula's dominance in our century" (p. 111). We contend, moreover, that while Sheridan Le Fanu's vampire Carmilla is more prototypical—that is, an adjudged better exemplar of the category—than vampiric space aliens [End Page 219] and legions of psychic vampires, she is less... (shrink)

The purpose of this article was to validate the published artificial intelligence facilities management outsourcing relationships system by real business cases in the working environment. The research aims to inspire the modern FM professionals in different industries with some challenging and innovative concepts about FM outsourcing relationships between facilities owners and service providers. First, it will briefly introduce the theory of the FM outsourcing relationships system on how it can help the FM seniors and strategists to design their FM daily (...) strategies wisely and make their business more effective and productive. Second, it will also introduce what the research is practically doing in the stage of case study for test and verification. It is concluded that FM outsourcing categorization may help to define the appropriate relationships. This further detailed outcome generated from the AI can be considered a solid reference to define and explain the existing outsourcing relationships between the stakeholders and the service providers to assign an outsourcing category to the FM relationship between the client and service provider based on the learnt rules. (shrink)

The last three decades have witnessed a heated debate of the merits of intelligent design (ID) as a way to understand a number of observable natural phenomena. The present dispute has its roots in a much older discussion: that of natural theology, which has always had as its goal the discernment of design(s) attributable to God in the natural world. Despite its ongoing relevance, natural theology does not have a coherent scholarly history. Turning Points in Natural Theology from Bacon to (...) Darwin deftly fills that gap, analysing the argument of design during the period from Francis Bacon (1561-1626) to Charles Darwin (1809-82), with a specific focus on those moments at which the rhetorical terms changed significantly. (shrink)

Introduction.--Biographical notes.--General analysis of knowledge and the act.--Perceptual and manipulatory phases of the act.--Cosmology.--Value and the act.--Supplementary essays.

Background: Low rates of participation of adolescents and young adults (AYAs) in clinical oncology trials may contribute to poorer outcomes. Factors that influence the decision of AYAs to participate in health research and whether these factors are different from those that affect the participation of parents of children with cancer. Methods: This is a secondary analysis of data from validated questionnaires provided to adolescents (>12 years old) diagnosed with cancer and parents of children with cancer at 3 sites in Canada (...) (Halifax, Vancouver, and Montreal) and 2 in the United States (Atlanta, GA, and Memphis, TN). Respondents reported their own research participation and cited factors that would influence their own decision to participate in, or to provide parental authorization for their child to participate in health research. Results: Completed questionnaire rates for AYAs and parents were 86 (46.5%) of 185 and 409 (65.2%) of 627, respectively. AYAs (n = 86 [67%]) and parents (n = 409 [85%]) cited that they would participate in research because it would help others. AYAs perceived pressure by their family and friends (16%) and their physician (19%). Having too much to think about at the time of accrual was an impediment to both groups (36% AYAs and 47% parents). The main deterrent for AYAs was that research would take up too much time (45%). Nonwhite parents (7 of 56 [12.5%]) were more apt to decline than white parents (12 of 32 [3.7%]; P < .01). Conclusions: AYAs identified time commitment and having too much to think about as significant impediments to research participation. Addressing these barriers by minimizing time requirements and further supporting decision-making may improve informed consent and impact on enrollment in trials. (shrink)

Institutional review board delays may hinder the successful completion of federally funded research in the U.S. military. When this happens, time-sensitive, mission-relevant questions go unanswered. Research participants face unnecessary burdens and risks if delays squeeze recruitment timelines, resulting in inadequate sample sizes for definitive analyses. More broadly, military members are exposed to untested or undertested interventions, implemented by well-intentioned leaders who bypass the research process altogether. To illustrate, we offer two case examples. We posit that IRB delays often appear in (...) the service of managing institutional risk, rather than protecting research participants. Regulators may see more risk associated with moving quickly than risk related to delay, choosing to err on the side of bureaucracy. The authors of this article, all of whom are military-funded researchers, government stakeholders, and/or human subject protection experts, offer feasible recommendations to improv... (shrink)

PURPOSE: There is an increasing demand for researchers to provide research results to participants. Our aim was to define an appropriate process for this, based on needs and attitudes of participants. METHODS: A multicenter survey in five sites in the United States and Canada was offered to parents of children with cancer and adolescents with cancer. Respondents indicated their preferred mode of communication of research results with respect to implications; timing, provider, and content of the results; reasons for and against (...) providing results; and barriers to providing results. RESULTS: Four hundred nine parents (including 19 of deceased children) and 86 adolescents responded. Most parents (n = 385; 94.2%) felt that they had a strong right to research results. For positive results, most wanted a letter or e-mail summary (n = 238; 58.2%) or a phone call followed by a letter (n = 100; 24.4%). If the results were negative, phone call (n = 136; 33.3%) or personal visits (n = 150; 36.7%) were preferred. Parents wanted the summary to include long-term sequelae and suggestions for participants (n = 341; 83.4%), effect on future treatments (n = 341; 83.4%), and subsequent research steps (n = 284; 69.5%). Understanding the researcher was a main concern about receiving results (n = 145; 35.5%). Parents felt that results provide information to support quality of life (n = 315; 77%) and raise public awareness of research (n = 282; 68.9%). Adolescents identified similar preferences. CONCLUSION: Parents of children with cancer and adolescents with cancer feel strongly that they have a right to be offered research results and have specific preferences of how and what information should be communicated. (shrink)

PURPOSE: The offer to return research results to participants is increasingly recognized as an ethical obligation, although few researchers routinely return results. We examined the needs and attitudes of parents of children with cancer and of adolescents with cancer to the return of research results. METHODS: Seven experts in research ethics scored content validity on parent and adolescent questionnaires previously developed through focus group and phone interviews. The questionnaires were revised and provided to 30 parents and 10 adolescents in a (...) tertiary care oncology setting. RESULTS: The content validity index for individual questions and the overall questionnaires scored as 0.86 for both questionnaires. All 30 parents and 10 adolescents who agreed to participate returned questionnaires. The majority (>95%) indicated that they had a strong or very strong right to receive results. Letter or e-mail was a satisfactory means to return results described as good or neutral (66% parents, 100% adolescents) but more participants wished face-to-face disclosure of results with negative implications (50% parents, 60% adolescents). Very few wanted results disseminated through a Web site. The majority acknowledged the need for peer-review before disclosure (60% of adolescents and parents) but did not want "to be the last to know." CONCLUSIONS: Our data suggest that pediatric oncology patients and parents of children with cancer strongly feel that they have a right to research results, and that they wish to receive these in a timely manner. (shrink)

Social anxiety disorder has been widely recognised as one of the most commonly diagnosed mental disorders. Individuals with social anxiety disorder experience difficulties during social interactions that are essential in the regular functioning of daily routines; perpetually motivating research into the aetiology, maintenance and treatment methods. Traditionally, social and clinical neuroscience studies incorporated protocols testing one participant at a time. However, it has been recently suggested that such protocols are unable to directly assess social interaction performance, which can be revealed (...) by testing multiple individuals simultaneously. The principle of two-person neuroscience highlights the interpersonal aspect of social interactions that observes behaviour and brain activity from both constituents of the interaction, rather than analysing on an individual level or an individual observation of a social situation. Therefore, two-person neuroscience could be a promising direction for assessment and intervention of the social anxiety disorder. In this paper, we propose a novel paradigm which integrates two-person neuroscience in a neurofeedback protocol. Neurofeedback and interbrain synchrony, a branch of two-person neuroscience, are discussed in their own capacities for their relationship with social anxiety disorder and relevance to the paradigm. The newly proposed paradigm sets out to assess the social interaction performance using interbrain synchrony between interacting individuals, and to employ a multi-user neurofeedback protocol for intervention of the social anxiety. (shrink)