The FDA's new table of surrogate endpoints used for drug approvals is an important step forward for overseeing the use of biomarkers in clinical trials. Nevertheless, we present several ways in which the table can be improved.

Over the course of human life, health care decision‐making is often interdependent. In this article, we use “interdependence” to refer to patients’ engagement of nonclinicians—for example, family members or trusted friends—to reach health care decisions. Interdependence, we suggest, is common for patients in all stages of life, from early childhood to late adulthood. This view contrasts with the common bioethical assumption that medical decisions are either wholly independent or dependent and that independence or dependence is tightly coupled with a person's (...) decision‐making capacity. In this article, we array various approaches to decision‐making along a continuum of interdependence. An appreciation of this continuum can empower patients and elucidate ethical challenges that arise when people transition between different kinds of interdependence across the life span. (shrink)

BackgroundWhen conducting research with Indigenous populations consent should be sought from both individual participants and the local community. We aimed to search and summarise the literature about methods for seeking consent for research with Indigenous populations.MethodsA systematic literature search was conducted for articles that describe or evaluate the process of seeking informed consent for research with Indigenous participants. Guidelines for ethical research and for seeking consent with Indigenous people are also included in our review.ResultsOf 1447 articles found 1391 were excluded (...) ; 56 were relevant and included. Articles were categorised into original research that evaluated the consent process or publications detailing the process of seeking consent and guidelines for ethical research. Guidelines were categorised into international ; national and state/regional/local guidelines. In five studies based in Australia, Canada and The United States of America the consent process with Indigenous people was objectively evaluated. In 13 other studies interpreters, voice recording, videos, pictures, flipcharts and “plain language” forms were used to assist in seeking consent but these processes were not evaluated. Some Indigenous organisations provide examples of community-designed resources for seeking consent and describe methods of community engagement, but none are evaluated. International, national and local ethical guidelines stress the importance of upholding Indigenous values but fail to specify methods for engaging communities or obtaining individual consent. In the ‘Grey literature’ concerns about the consent process are identified but no solutions are offered.ConclusionConsultation with Indigenous communities is needed to determine how consent should be sought from the community and the individual, and how to evaluate this process. (shrink)

The rule of rescue describes the moral impulse to save identifiable lives in immediate danger at any expense. Think of the extremes taken to rescue a small child who has fallen down a well, a woman pinned beneath the rubble of an earthquake, or a submarine crew trapped on the ocean floor. No effort is deemed too great. Yet should this same moral instinct to rescue, regardless of cost, be applied in the emergency room, the hospital, or the community clinic? (...) -/- In health care, the desire to save lives at any cost must be reconciled with the reality of resource scarcity. As one example, the estimated cost for prophylactic Factor VIII to treat one patient with hemophilia for one year is $300,000. Costs of this magnitude have been accepted by public and private insurers in the developed world, even though, in principle, these sums could provide greater overall health benefit if allocated to pay for the unmet health care needs of many other patients. Looking forward, however, broad application of the rule of rescue will be increasingly untenable. But the moral instinct will remain: the desire to help those weakest among us, especially when their small numbers allow us to see them as unique individuals. What, then, is the ethical framework that can guide coverage and reimbursement decisions for orphan drugs into the future? (shrink)

The consent and community engagement process for research with Indigenous communities is rarely evaluated. Research protocols are not always collaborative, inclusive or culturally respectful. If participants do not trust or understand the research, selection bias may occur in recruitment, affecting study results potentially denying participants the opportunity to provide more knowledge and greater understanding about their community. Poorly informed consent can also harm the individual participant and the community as a whole. Invited by local Aboriginal community leaders of the Fitzroy (...) Valley, the Kimberley, Western Australia, The Picture Talk project explores the consent process for research. Focus groups of Aboriginal community members were conducted to establish preferences for methods of seeking individual consent. Transcripts were analysed through NVivo10 Qualitative software using grounded theory with inductive and deductive coding. Themes were synthesised with quotes highlighted. Focus groups with Aboriginal community members were facilitated by a Community Navigator as a cultural guide and interpreter and a researcher. Participants were recruited from all main language groups of the Fitzroy Valley – Gooniyandi, Walmajarri, Wangkatjungka, Bunuba and Nikinya. Participants were aged ≥18 years, with 5 female groups and one male group. Themes identified include: Reputation and trust is essential; The Community Navigator is key; Pictures give the words meaning – milli milli versus Pictures; Achieving consensus in circles; Signing for consent; and Research is needed in the Valley. Aboriginal communities of the Fitzroy Valley recommend that researchers collaborate with local leaders, develop trust and foster a good reputation in the community prior to research. Local Aboriginal researchers should be employed to provide cultural guidance throughout the research process and interpret local languages especially for elders. Pictures are preferred to written text to explain research information and most prefer to sign for consent. The Fitzroy Valley welcomes research when collaborative and for the benefit of the community. Future research could include exploring how to support young people, promote health screening and improve understanding of medical knowledge. (shrink)

When we hear about a transgression, we may consider whether the perpetrator’s individual circumstances make their transgression more understandable or excusable. Mitigating circumstances may reduce the severity of punishment that is deemed appropriate, both intuitively and legally. But importantly, in courts of public opinion and of law, mitigating information is typically presented only after information about a perpetrator’s transgression. We explore whether this sequence influences the force of mitigating evidence. Specifically, in two studies, we examined whether presenting evidence about a (...) perpetrator’s background before or after evidence of their violation influenced how severely U.S. participants punished perpetrators. In Study 1 (N = 132), evidence about the perpetrator’s mitigating circumstances reduced punishment only when it was presented before evidence about the perpetrator’s violation. Study 2 (N = 316) additionally revealed this moderating effect of presentation order across a variety of premeditated and impulsive violations. These findings are consistent with person-centered theories of punishment and with the Story Model of adjudication. (shrink)

Around the world, a growing number of communities are voicing their demands for authority in the governance of research involving them. Many such communities have experienced histories of exploitative, stigmatizing, intrusive research that failed to benefit them. To better understand what strategies communities are developing in order to have a say in research oversight, we conducted a scoping review of the international peer-reviewed and grey literature. Three primary strategies were identified: (1) guidelines; (2) community review boards; and (3) community advisory (...) boards. Guidelines include documents developed by, with, or for communities to outline ethical behavior or conduct in research with or within the community. Community review boards offer ethical review of research protocols, much like traditional research ethics boards, but are community led and focus on community interests. Community advisory boards consist of representatives from a given community and are developed to advise institutions or research teams on community-level ethical matters pertaining to research projects. Initiatives led by Indigenous communities far outnumbered others in the sample, reflecting the legacy of continuous Indigenous resistance to research as a tool of colonialism. In several cases, communities in marginalized neighbourhoods, where harmful and exploitative research practices have taken place, emphasized the significance of community-led governance grounded in shared geographical and social contexts. We discuss some of the beneficial and challenging features of each type of strategy and offer recommendations for stakeholders who wish to support community-led efforts in research ethics. (shrink)

Biomarkers can be powerful tools to guide diagnosis, treatment, and research. However, prudent use of biomarkers requires formal validation efforts. Although the data needed for biomarker validation has traditionally been hard to access, new research initiatives can ease this process.

Humans routinely modify their walking speed to adapt to functional goals and physical demands. However, damage to the central nervous system often results in abnormal modulation of walking speed and increased risk of falls. There is considerable interest in treatment modalities that can provide safe and salient training opportunities, feedback about walking performance, and that may augment less reliable sensory feedback within the CNS after injury or disease. Fully immersive virtual reality technologies show benefits in boosting training-related gains in walking (...) performance; however, they lack views of the real world that may limit functional carryover. Augmented reality and mixed reality head-mount displays provide partially immersive environments to extend the virtual reality benefits of interacting with virtual objects but within an unobstructed view of the real world. Despite this potential advantage, the feasibility of using MR-HMD visual feedback to promote goal-directed changes in overground walking speed remains unclear. Thus, we developed and evaluated a novel mixed reality application using the Microsoft HoloLens MR-HMD that provided real-time walking speed targets and augmented visual feedback during overground walking. We tested the application in a group of adults not living with disability and examined if they could use the targets and visual feedback to walk at 85%, 100%, and 115% of each individual’s self-selected speed. We examined whether individuals were able to meet each target gait speed and explored differences in accuracy across repeated trials and at the different speeds. Additionally, given the importance of task-specificity to therapeutic interventions, we examined if walking speed adjustment strategies were consistent with those observed during usual overground walking, and if walking with the MR-HMD resulted in increased variability in gait parameters. Overall, participants matched their overground walking speed to the target speed of the MR-HMD visual feedback conditions. The percent inaccuracy was approximately 5% across all speed matching conditions and remained consistent across walking trials after the first overall walking trial. Walking with the MR-HMD did not result in more variability in walking speed, however, we observed more variability in stride length and time when walking with feedback from the MR-HMD compared to walking without feedback. The findings offer support for mixed reality-based visual feedback as a method to provoke goal-specific changes in overground walking behavior. Further studies are necessary to determine the clinical safety and efficacy of this MR-HMD technology to provide extrinsic sensory feedback in combination with traditional treatments in rehabilitation. (shrink)

The objective of this study was to assess the beliefs of parents of youth soccer players about Chronic Traumatic Encephalopathy, concussion, and retirement from sport decisions and compare them to those of concussion-specialized clinicians. An electronic survey was completed by parents of youth club soccer players and concussion-specialized clinicians located in a large U.S. urban center. Parents believed more strongly in the causal relationship between concussions and CTE, and between CTE and harm than did clinicians. Parents who themselves had participated (...) in sport at a high level had more conservative beliefs than other parents about the number of concussions after which an athlete should retire from contact or collision sport. Results are discussed in the context of ethical risk communication between clinicians and parents. This includes the importance of communicating information about CTE to parents and youth athletes in an understandable way so that they can make informed choices about contact and collision sport participation. Further research is encouraged to evaluate approaches of communicating evidence about CTE to a diverse population of families of youth athletes. (shrink)

The COVID-19 pandemic has been devastating for people living with dementia (PLWD) and their caregivers. While prior research has documented these effects, it has not delved into their specific causes or how they are modified by contextual variation in caregiving circumstances.

The online processing of both music and language involves making predictions about upcoming material, but the relationship between prediction in these two domains is not well understood. Electrophysiological methods for studying individual differences in prediction in language processing have opened the door to new questions. Specifically, we ask whether individuals with musical training predict upcoming linguistic material more strongly and/or more accurately than non-musicians. We propose two reasons why prediction in these two domains might be linked: Musicians may have greater (...) verbal short-term/working memory; music may specifically reward predictions based on hierarchical structure. We provide suggestions as to how to expand upon recent work on individual differences in language processing to test these hypotheses. (shrink)

Using medical advances to enhance human athletic, aesthetic, and cognitive performance, rather than to treat disease, has been controversial. Little is known about physicians? experiences, views, and attitudes in this regard. We surveyed a national sample of physicians to determine how often they prescribe enhancements, their views on using medicine for enhancement, and whether they would be willing to prescribe a series of potential interventions that might be considered enhancements. We find that many physicians occasionally prescribe enhancements, but doctors hold (...) nuanced and ambiguous views of these issues. Most express concerns about the potential effects of enhancements on social equity, yet many also believe specific enhancements that are safe and effective should be available but not covered by insurance. These apparently contradictory views might reflect inherent tensions between the values of equity and liberty, which could make crafting coherent social policies on medical enhancements challenging. [Supplementary materials are available for this article. Go to the publisher's online edition of American Journal of Bioethics for the following free supplemental resource(s): An additional table (Table 5) referred to on p. 5]. (shrink)

Cognitively engaging physical activity has been suggested to have superior effects on cognition compared to PA with low cognitive demands; however, there have been few studies directly comparing these different types of activities. The aim of this study is to compare the cognitive effects of a combined physically and cognitively engaging bout of PA to a physical or cognitive activity alone in children. Children were randomized in pairs to one of three 20-min conditions: a cognitive sedentary activity; a non-cognitively engaging (...) PA; and a cognitively engaging PA. Executive function was assessed using a modified Eriksen flanker task immediately before and 10–15 min following the experimental condition. Children ages 6–8 years were included in the study. A repeated measures ANOVA found no significant difference between groups with respect to scores on the flanker task. The results do not support the hypotheses that a cognitively engaging bout of PA enhances cognitive performance over non-cognitively engaging PA or sedentary activities. Possible explanations for our findings include overexertion during the acute bout of PA and depletion of positive affect prior to performing the post-intervention EF tasks. (shrink)

__Improving Education Together _offers a step-by-step guide to Labor-Management-Community (LMC) collaboration, an intervention that has successfully improved student outcomes in a wide variety of school districts across the country._ The authors illustrate how a culture of collaboration between labor, management, and community stakeholders can be built using readily available tools for needs assessment, root-cause analysis, team norms, brainstorming, consensus-building, and long-term planning. _Improving Education Together _offers detailed examples of how districts across the country—including Massachusetts, Maryland, and Illinois—have successfully implemented the (...) LMC approach, along with resources and strategies employed and lessons learned from obstacles and setbacks encountered along the way. Timely, useful, and accessible, this guide will appeal to a broad audience of school leaders, board members, and community leaders eager to learn more about how to collectively lead and manage school district change that is sustainable and results in improved teaching and learning. (shrink)

Koonin argues that CRISPR-Cas systems present the best-known case in point for Lamarckian evolution because they satisfy his proposed criteria for the specific inheritance of acquired adaptive characteristics. We see two interrelated issues with Koonin’s characterization of CRISPR-Cas systems as Lamarckian. First, at times he appears to confuse an account of the CRISPR-Cas system with an account of the mechanism it employs. We argue there is no evidence for the CRISPR-Cas system being “Lamarckian” in any sense. Second, it is unclear (...) whether the mechanism is more “Lamarckian” than many other forms of genetic change already well-characterized in Darwinian terms. We present three conceptually distinct senses in which the mechanism of IAC may be considered Lamarckian and argue that only the strongest sense of goal-directed IAC would be difficult to accommodate in a Darwinian account. As the CRISPR-Cas mechanism does not qualify as “Lamarckian” in this strong sense, we argue there is no conceptual value in calling it “Lamarckian”. Finally, we suggest that CRISPR-Cas systems do hold the potential for genuinely non-Darwinian, directed evolution in a way that Koonin did not discuss, involving their potential use as a human gene-editing tool. (shrink)

Le sens du nom grec de φύσις, et celui de la physique aristotélicienne, sont au cœur de la compréhension heideggerienne de la métaphysique, qu’il s’agisse, dans les années 1920, de refonder celle-ci en retrouvant ses possibilités initiales, ou, à la fin des années 1930, de l’assumer pour pouvoir la dépasser, puis de la laisser. De part et d’autre du tournant, la φύσις, dans sa surabondance et dans son dépliement, permet en effet de rendre compte de l’émergence de deux domaines, ceux (...) de la physique et de la métaphysique. Toutefois, la plurivocité diachronique et synchronique de φύσις, telle qu’elle est mise en lumière en 1929-1930, se trouve ensuite comprise de manière plus radicale. Il ne s’agit plus de repérer l’évolution du sens de φύσις et la coexistence de significations contemporaines, mais de mettre au jour le télescopage, dans la pensée aristotélicienne, de deux significations qui diffèrent de manière historiale. (shrink)

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) (...) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer. (shrink)

Dans cet article, nous présentons une étude de faisabilité sur l’annotation des passages entre guillemets, phénomènes linguistiques polyphoniques qui résistent souvent à une lecture univoque et à un schéma d’annotation simplificateur. La faisabilité de l’annotation a été testée à travers une étude inter-annotateurs qui a montré, avec un accord pour 80% des annotations effectuées, que des valeurs stables (dénomination, citation, autonymie, commentaires modalisants) pouvaient être postulées. Les cas de désaccord, en partie inévitables face à la complexité du phénomène, peuvent être (...) en partie réduits par un repérage systématique des marques formelles (marques typo-dispositionnelles, éléments du lexique et formules syntaxiques) et un inventaire détaillé des contextes d’emploi pour chaque valeur. Certaines valeurs demeurant ambiguës, il convient toutefois de prévoir dans l’annotation des cas de cumul de valeurs (le passage entre guillemets cumule plusieurs valeurs compatibles) ou d’ambiguïtés (plusieurs interprétations différentes sont possibles) en cas de désaccord des annotateurs. (shrink)

Dans un format concis et accessible, la sociologue Anne Revillard propose d’initier un public, averti ou non, aux enjeux relatifs à l’emploi des personnes handicapées. En six chapitres, l’ouvrage dresse le constat d’une population en situation de handicap doublement marginalisée et propose une recension critique des dispositifs d’action publique pour l’emploi des personnes handicapées. Le lecteur appréciera la bibliographie fournie de cet ouvrage qui recense aussi bien les travaux français qu...

The thymus is a unique primary lymphoid organ that supports the production of self‐tolerant T‐cells essential for adaptive immunity. Intrathymic microenvironments are microanatomically compartmentalised, forming defined cortical, and medullary regions each differentially supporting critical aspects of thymus‐dependent T‐cell maturation. Importantly, the specific functional properties of thymic cortical and medullary compartments are defined by highly specialised thymic epithelial cells (TEC). For example, in the medulla heterogenous medullary TEC (mTEC) contribute to the enforcement of central tolerance by supporting deletion of autoreactive T‐cell (...) clones, thereby counterbalancing the potential for random T‐cell receptor generation to contribute to autoimmune disease. Recent advances have further shed light on the pathways and mechanisms that control heterogeneous mTEC development and how differential mTEC functionality contributes to control self‐tolerant T‐cell development. Here we discuss recent findings in relation to mTEC development and highlight examples of how mTEC diversity contribute to thymus medulla function. (shrink)

There is a growing trend of refusal of blood transfusions from COVID-19 vaccinated donors. We highlight three cases where parents have refused blood transfusions from COVID-19 vaccinated donors on behalf of their children in the setting of congenital cardiac surgery. These families have also requested accommodations such as explicit identification of blood from COVID-19 vaccinated donors, directed donation from a COVID19 unvaccinated family member, or use of a non-standard blood supplier. We address the ethical challenges posed by these issues. We (...) describe the current screening and safety processes for standard blood donation and explore the importance of donor anonymity and challenges with directed donation and non-standard blood suppliers. We present an ethical framework using the Best Interest Standard, the Zone of Parental Discretion, and the Harm Principle when considering these refusals. Finally, we provide recommendations for how to approach these requests as they potentially become more commonplace in pediatrics. (shrink)

Un joueur de jeux vidéo sur deux est une joueuse. À l’écran cependant, la présence des femmes et leur représentation ne vont pas de soi. L’entretien analyse le dernier opus d’Assassin’s Creed, une saga dont chaque titre se déroule dans un contexte historique précis. Le premier jeu de la série (2007) imposait d’incarner un avatar masculin ; le huitième permettait d’incarner un personnage féminin, mais doté de caractéristiques autres que son homologue masculin ; le quatorzième proposait d’incarner un ou une (...) hoplite, tous deux égaux dans le combat. Mais sur le plan du genre, le dernier titre en date, Valhalla (2020), va plus loin. Le joueur, en ouverture, incarne Eivor, un enfant dont le sexe est indéterminé. À l’âge adulte, il doit choisir : jouer Eivor au féminin, au masculin, ou laisser le système décider. Le genre ainsi n’est pas subi mais choisi, et est modifiable en cours de partie. S’agit-il vraiment d’une révolution? Les frontières du genre ne sont-elles pas simplement repoussées? Et comment, si c’est le cas, pourrait-on les dépasser enfin? (shrink)

The growing block view of time holds that the past and present are real whilst the future is unreal; as future events become present and real, they are added on to the growing block of reality. Surprisingly, given the recent interest in this view, there is very little literature on its origins. This paper explores those origins, and advances two theses. First, I show that although C. D. Broad’s Scientific Thought provides the first defence of the growing block theory, the (...) theory receives its first articulation in Samuel Alexander’s Space, Time, and Deity. Further, Alexander’s account of deity inclines towards the growing block view. Second, I argue that Broad shifted towards the growing block theory as a result of his newfound conviction that time has a direction. By way of tying these theses together, I argue that Broad’s views on the direction of time – and possibly even his growing block theory – are sourced in Alexander. (shrink)