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Human cerebral organoids (HCOs) are model systems that enable researchers to investigate the human brain in ways that had previously been impossible. The emergence of HCOs was accompanied by both expert and layperson discussions concerning the possibility of these novel entities developing sentience or consciousness. Such concerns are reflected in deliberations about how to handle and regulate their use. This perspective article resulted from an international and interdisciplinary research retreat "Ethical, Legal and Social Aspects of Human Cerebral Organoids and their Governance in Germany, the United Kingdom and the United States", which took place in Tübingen, Germany, in August 2022. The retreat focused on whether HCO research requires new ethical and regulatory approaches. It addressed epistemic issues around the detection and theorisation of consciousness, ethical concerns around moral status and research conduct, difficulties for legislation and guidelines managing these entities, and public engagement., Competing Interests: JS is a member of Merck KGaA’s Ethics Advisory Panel and Stem Cell Research Oversight Committee; a member of IQVIA’s Ethics Advisory Panel; a member of Aspen Neurosciences Clinical Advisory Panel; and previously a member of a Merck Data Monitoring Committee and a consultant to Biogen. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pichl, Ranisch, Altinok, Antonakaki, Barnhart, Bassil, Boyd, Chinaia, Diner, Gaillard, Greely, Jowitt, Kreitmair, Lawrence, Lee, McKeown, Sachdev, Schicktanz, Sugarman, Trettenbach, Wiese, Wolff and Árnason.)

Cerebral organoid models in-of-themselves are considered as an alternative to research animal models. But their developmental and biological limitations currently inhibit the probability that organoids can fully replace animal models. Furthermore, these organoid limitations have, somewhat ironically, brought researchers back to the animal model via xenotransplantation, thus creating hybrids and chimeras. In addition to attempting to study and overcome cerebral organoid limitations, transplanting cerebral organoids into animal models brings an opportunity to observe behavioral changes in the animal itself. Traditional animal ethics frameworks, such as the well-known three Rs (reduce, refine, and replace), have previously addressed chimeras and xenotransplantation of tissue. But these frameworks have yet to completely assess the neural-chimeric possibilities. And while the three Rs framework was a historical landmark in animal ethics, there are identifiable gaps in the framework that require attention. The authors propose to utilize an expanded three Rs framework initially developed by David DeGrazia and Tom L. Beauchamp, known as the Six Principles (6Ps). This framework aims to expand upon the three Rs, fill in the gaps, and be a practical means for assessing animal ethical issues like that of neural-chimeras and cerebral organoid xenotransplantation. The scope of this 6Ps application will focus on two separate but recent studies, which were published in 2019 and 2020. First, they consider a study wherein cerebral organoids were grown from donors with Down syndrome and from neurotypical donors. After these organoids were grown and studied, they were then surgically implanted into mouse models to observe the physiological effects and any behavioral change in the chimera. Second, they consider a separate study wherein neurotypical human embryonic stem cell-derived cerebral organoids were grown and transplanted into mouse and macaque models. The aim was to observe if such a transplantation method would contribute to therapies for brain injury or stroke. The authors place both studies under the lens of the 6Ps framework, assess the relevant contexts of each case, and provide relevant normative conclusions. In this way, they demonstrate how the 6Ps could be applied in future cases of neural-chimeras and cerebral organoid xenotransplantation.

Ethical deliberations are unfolding for potentially controversial organoid-entities such as brain organoids and embryoids. Much of the ethical deliberation centers on the questionable moral status of such organoid-entities. However, while such work is important and appropriate, ethical deliberations may become too exclusively rooted in moral status and potentially overshadow other relevant moral dilemmas. The ethical discussion on organoid models can benefit from insights brought forth by both Judith Jarvis Thomson and Don Marquis in how they attempted to advance the abortion debate. To discuss other abortion ethical issues more fully, both Thomson and Marquis assumed differing moral status positions of the conceptus and followed lines of reasoning based on these moral status assumptions. We suggest a similar approach with controversial organoid-entities like brain organoids and embryoids. To avoid overshadowing or overlooking other relevant ethical issues, ethicists ought to first assume an organoid-entity moral status position (such as a high moral status or no moral status) and explore any possible arguments that may result from such a position. While we ought not to copy the content of Thomson and Marquis' arguments exactly for organoid-entities, it is worthwhile to translate their arguments' overarching structures. This paper explores the relevant insights of Thomson and Marquis, how they can be translated into the organoid ethics debate, and what possible lines of inquiry may be worth exploring based on particular moral status assumptions., (© 2022 John Wiley & Sons Ltd.)

Objective: To present the ethical issues, moral arguments, and reasons found in the ethical literature on organoid models., Design: In this systematic review of reasons in ethical literature, we selected sources based on predefined criteria: (1) The publication mentions moral reasons or arguments directly relating to the creation and/or use of organoid models in biomedical research; (2) These moral reasons and arguments are significantly addressed, not as mere passing mentions, or comprise a large portion of the body of work; (3) The publication is peer-reviewed and published in an academic article, book, national-level report, working paper, or Ph.D. thesis; (4) The publications collected are in English., Analysis: Each article was read in-depth for identifiable moral reasons, arguments, and concerns. These were then inductively classified and synthesized to create broader categories of reasons, and eventually an overarching conceptual scheme was created., Results: A total of twenty-three sources were included and analyzed out of an initial 266 collected sources. Five themes of ethical issues and arguments were found: Animal Experimentation; Clinical Applications and Experiments; Commercialization and Consent; Organoid Ontology and Moral Status; and Research Ethics and Research Integrity. These themes are then further broken down into sub-themes and topics. Given the extensive nature of the topics found, we will focus on describing the topics that comprised of more in-depth reasons and arguments rather than few, passing mentions or concerns., Conclusions: The ethics of organoids requires further deliberation in multiple areas, as much of the discussions are not presented as in-depth arguments. Such sentiments are also echoed throughout the organoid ethics literature., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Research with cerebral organoids is beginning to make significant progress in understanding the etiology of autism spectrum disorder (ASD). Brain organoid models can be grown from the cells of donors with ASD. Researchers can explore the genetic, developmental, and other factors that may give rise to the varieties of autism. Researchers could study all of these factors together with brain organoids grown from cells originating from ASD individuals. This makes brain organoids unique from other forms of ASD research. They are like a multi-tool, one with significant versatility for the scope of ASD research and clinical applications. There is hope that brain organoids could one day be used for precision medicine, like developing tailored ASD drug treatments., Main Body: Brain organoid researchers often incorporate the medical model of disability when researching the origins of ASD, especially when the research has the specific aim of potentially finding tailored clinical treatments for ASD individuals. The neurodiversity movement-a developmental disability movement and paradigm that understands autism as a form of natural human diversity-will potentially disagree with approaches or aims of cerebral organoid research on ASD. Neurodiversity advocates incorporate a social model of disability into their movement, which focuses more on the social, attitudinal, and environmental barriers rather than biophysical or psychological deficits. Therefore, a potential conflict may arise between these perspectives on how to proceed with cerebral organoid research regarding neurodevelopmental conditions, especially ASD., Conclusions: Here, we present these perspectives and give at least three initial recommendations to achieve a more holistic and inclusive approach to cerebral organoid research on ASD. These three initial starting points can build bridges between researchers and the neurodiversity movement. First, neurodiverse individuals should be included as co-creators in both the scientific process and research communication. Second, clinicians and neurodiverse communities should have open and respectful communication. Finally, we suggest a continual reconceptualization of illness, impairment, disability, behavior, and person.

Background and Objectives: The Patient-centered Medical Home (PCMH) concept, essential functions of primary care, and an appropriate primary care workforce have been shown to improve health outcomes and reduce health care costs. This paper describes a curriculum that uses the PCMH and related health policy concepts as the foundation for didactic, clinical, and self-directed elements. The PCMH-focused curriculum improved overall student clerkship ratings and maintained student performance on the National Board of Medical Education subject exam.

The results are disappointing, providing little support for the validity of the case-passing decisions based on this simple approach to scoring and standard setting. The case-passing decisions predicted what the case author intended for about only 73% or 74% of the students on average and, with agreement expected by chance removed, predicted what the case author intended for about only 25% of the students. Even with the use of the optimal pass/fail cutoffs and the dropping of students with ambiguous borderline global ratings, the case-passing decisions failed to agree with the case authors' global ratings for 15% to 30% of the students. The findings might be dismissed as simply due to low reliabilities of passing decisions and global ratings based on a single case. Although this concern would apply to intercase reliabilities, which would be subject to case specificity, the appropriate reliabilities here would seem to be intracase (i.e., intrarater), which should be fairly high (if they could be computed). Nevertheless, it seems reasonable to expect much better agreement between results of case scoring and of standard setting developed by the case author and the case author's global ratings of performance on that case, given that the case author might recall the checklist, assign a weight to each item, and so forth. Also, case-passing decisions would possibly agree more with global ratings of live or videotaped performances than with ratings of written summaries of performance; however, that question remains a challenge for further research. In conclusion, the study provides only weak evidence, at best, for the validity of the scoring and standard setting commonly used with SP assessment. The results do not undermine claims about the realism of the SP approach, however, nor do they call into question the standardization afforded by this method of assessing clinical competence. The results do raise serious concerns about this simple approach to scoring and standard setting for SP-based assessments and suggest that we should focus more on the observation and evaluation of actual student performance on SP cases in the development of valid scoring and standard setting.

In a dog model of myocardial ischemia, i.v. injection of [67Cu]Cu(PTSM) leads to an excellent linear correlation for both the heart and kidney between regional tissue radiocopper concentration and regional blood flow measured by radioactive micropheres. The 62Cu-labeled complex may serve as a generator-produced position-emitting perfusion tracer for these organs.