Ethical Considerations for Enrolling "Invested Parties" in Large-Scale Clinical Studies: Insights from the RECOVER Initiative.

Research institutions often lack policies addressing the risks and benefits of enrolling "invested parties" such as investigators, research staff, and patient, caregiver, and community representatives (groups most affected by a disease or intervention) in studies where they have direct involvement. Invested parties may have both strong motivations to study the condition or intervention and to participate as study subjects. More guidance is needed to promote appropriate access to research participation and mitigate potential risks. This article addresses the gap in guidance by presenting an ethical framework and practical guidelines for the enrollment of invested parties. Drawing from experiences with the Researching COVID to Enhance Recovery (RECOVER) Initiative, a large multisite observational cohort study, we argue that invested parties should not be categorically excluded from enrollment in their own research studies if certain criteria are met and appropriate safeguards are in place. We underscore the need to balance inclusion with fairness, promote valid voluntary informed consent, ensure data privacy, protect scientific validity, and mitigate unique risks to invested parties as participants. Additionally, we recommend regular reporting and empirical assessment to evaluate the impact of enrolling invested parties on participants and study outcomes.

A scoping review of the legal and ethical challenges with the use of normothermic regional perfusion in controlled donation after circulatory determination of death from 2005 to 2023.

Use of normothermic regional perfusion (NRP) to enable organ reconditioning and assessment in donation after circulatory determination of death is controversial. We conducted a scoping review of peer-reviewed articles, news media, legal literature, and professional society position statements addressing ethical and/or legal issues in use of NRP in controlled donation after circulatory determination of death from January 1, 2005, to January 5, 2024. Thematic analysis, assessing the 4 principles of bioethics (autonomy, beneficence, nonmaleficence, and justice) and subthemes identified within each, was conducted for the 112 publications meeting inclusion criteria. More than 30 publications addressed the topic in each of 2022 and 2023, vs ≤6 per year previously. Nonmaleficence was the most frequently addressed bioethical principle (111/112 publications), and the most varied, with 14 subthemes. Attitudes toward NRP differed by type of NRP: of 72 publications discussing thoracoabdominal NRP, 22 (30.6%) were "In Favor," 39 (54.2%) were "Neutral," and 11 (15.3%) were "Against"; of 44 discussing abdominal NRP, 23 (52.3%) were "In Favor," 20 (45.5%) were "Neutral," and 1 (2.3%) was "Against." Attitudes differed by authors' country, degree, and affiliation, and by the clinical focus of the publishing journal. Overall, our review shows that the ethical and legal issues raised by NRP remain unresolved, and the debate centered on nonmaleficence.

Public attitudes to xenotransplantation: A national survey in the United States.

Xenotransplantation (XTx) presents a potential clinical alternative to the shortage of human organs for transplantation. Before clinical trials occur in the United States, public assessments are crucial to understand potential barriers to acceptance. The purpose of this study was to explore barriers and identify characteristics associated with attitudes toward XTx. A survey assessing demographic characteristics and attitudes toward XTx was distributed to a nationally representative sample of adults aged ≥18 years in the United States. Regression analysis was employed to identify characteristics associated with attitudes toward XTx. Between May 25 and June 14, 2023, 5008 respondents completed the survey. Importantly, half of the respondents expressed low or no knowledge of either transplantation or XTx. Approximately 40% expressed discomfort with receiving a pig organ for themselves or a loved one. Despite a lack of xenotransplant outcome data, 36% were open to experimental XTx if they needed a transplant. However, 57% rated lack of current evidence of success or fear of complications as top concerns. Regression models consistently associated being younger, female, not needing an organ, or being a member of a racial minority group with lower acceptance. This survey is the largest to date exploring public attitudes toward XTx. Despite overall acceptance, concerns persist. Increasing public acceptance is key as the field advances.

Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Research opportunities and ethical considerations for heart and lung xenotransplantation research: A report from the National Heart, Lung, and Blood Institute workshop.

Xenotransplantation offers the potential to meet the critical need for heart and lung transplantation presently constrained by the current human donor organ supply. Much was learned over the past decades regarding gene editing to prevent the immune activation and inflammation that cause early organ injury, and strategies for maintenance of immunosuppression to promote longer-term xenograft survival. However, many scientific questions remain regarding further requirements for genetic modification of donor organs, appropriate contexts for xenotransplantation research (including nonhuman primates, recently deceased humans, and living human recipients), and risk of xenozoonotic disease transmission. Related ethical questions include the appropriate selection of clinical trial participants, challenges with obtaining informed consent, animal rights and welfare considerations, and cost. Research involving recently deceased humans has also emerged as a potentially novel way to understand how xeno-organs will impact the human body. Clinical xenotransplantation and research involving decedents also raise ethical questions and will require consensus regarding regulatory oversight and protocol review. These considerations and the related opportunities for xenotransplantation research were discussed in a workshop sponsored by the National Heart, Lung, and Blood Institute, and are summarized in this meeting report.

Knowledge gaps in heart and lung donation after the circulatory determination of death: Report of a workshop of the National Heart, Lung, and Blood Institute.

In a workshop sponsored by the U.S. National Heart, Lung, and Blood Institute, experts identified current knowledge gaps and research opportunities in the scientific, conceptual, and ethical understanding of organ donation after the circulatory determination of death and its technologies. To minimize organ injury from warm ischemia and produce better recipient outcomes, innovative techniques to perfuse and oxygenate organs postmortem in situ, such as thoracoabdominal normothermic regional perfusion, are being implemented in several medical centers in the US and elsewhere. These technologies have improved organ outcomes but have raised ethical and legal questions. Re-establishing donor circulation postmortem can be viewed as invalidating the condition of permanent cessation of circulation on which the earlier death determination was made and clamping arch vessels to exclude brain circulation can be viewed as inducing brain death. Alternatively, TA-NRP can be viewed as localized in-situ organ perfusion, not whole-body resuscitation, that does not invalidate death determination. Further scientific, conceptual, and ethical studies, such as those identified in this workshop, can inform and help resolve controversies raised by this practice.

The American Society of Transplant Surgeons Consensus Statement on Normothermic Regional Perfusion.

On June 3, 2023, the American Society of Transplant Surgeons convened a meeting in San Diego, California to (1) develop a consensus statement with supporting data on the ethical tenets of thoracoabdominal normothermic regional perfusion (NRP) and abdominal NRP; (2) provide guidelines for the standards of practice that should govern thoracoabdominal NRP and abdominal NRP; and (3) develop and implement a central database for the collection of NRP donor and recipient data in the United States. National and international leaders in the fields of neuroscience, transplantation, critical care, NRP, Organ Procurement Organizations, transplant centers, and donor families participated. The conference was designed to focus on the controversial issues of neurological flow and function in donation after circulatory death donors during NRP and propose technical standards necessary to ensure that this procedure is performed safely and effectively. This article discusses major topics and conclusions addressed at the meeting.

Researching COVID to enhance recovery (RECOVER) tissue pathology study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. METHODS: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes. DISCUSSION: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.

Revisiting the Use of Ulysses Contracts in Xenotransplantation.

BACKGROUND: Xenotransplantation clinical trials may begin soon. A persistent risk of xenotransplantation, known for decades, is the possibility that a xenozoonotic infection could be transferred from a xenograft to its recipient and then to other human contacts. Because of this risk, guidelines and commentators have advocated for xenograft recipients to agree to either long-term or lifelong surveillance mechanisms. METHODS: For the past few decades, one solution that has been proposed to ensure that xenograft recipients will comply with surveillance protocols is the use of a heavily modified Ulysses contract, which we review. RESULTS: These contracts are most often used in psychiatry, and their application to xenotransplantation has been espoused several times with minimal criticism. CONCLUSIONS: In this article, we argue against the applicability of Ulysses contracts in xenotransplantation based upon (1) the telos of the advance directive that may not be applicable to this clinical context, (2) the suspect nature of enforcing Ulysses contracts in xenotransplantation, and (3) the ethical and regulatory hurdles that such enforcement would require. Although our focus is on the US regulatory landscape in preparation for clinical trials, there are applications globally.

Research involving the recently deceased: ethics questions that must be answered.

Research involving recently deceased humans that are physiologically maintained following declaration of death by neurologic criteria-or 'research involving the recently deceased'-can fill a translational research gap while reducing harm to animals and living human subjects. It also creates new challenges for honouring the donor's legacy, respecting the rights of donor loved ones, resource allocation and public health. As this research model gains traction, new empirical ethics questions must be answered to preserve public trust in all forms of tissue donation and in the practice of medicine while respecting the legacy of the deceased and the rights of donor loved ones. This article suggests several topics for immediate investigation to understand the attitudes and experiences of researchers, clinical collaborators, donor loved ones and the public to ensure research involving the recently deceased advances ethically.

Update on the ethical, legal and technical challenges of translating xenotransplantation.

This manuscript reports on a landmark symposium on the ethical, legal and technical challenges of xenotransplantation in the UK. King's College London, with endorsement from the British Transplantation Society (BTS), and the European Society of Organ Transplantation (ESOT), brought together a group of experts in xenotransplantation science, ethics and law to discuss the ethical, regulatory and technical challenges surrounding translating xenotransplantation into the clinical setting. The symposium was the first of its kind in the UK for 20 years. This paper summarises the content of the expert lectures showcasing the progress which has been made in xenotransplantation including-the history of xenotransplantation, advances in gene edited animals and progress towards clinical xenotransplantation. We then set out the ethical and legal issues still to be resolved. Finally, we report the themes of the roundtable discussion highlighting areas of consensus and controversy. While the detail of the legal discussion was directed towards the UK, the principles and summary reported here are intended to be applicable to any jurisdiction seeking to implement clinical xenotransplantation.

Challenges Unique to Transgender Persons in US Correctional Settings: a Scoping Review.

US correctional facilities operate under a binary interpretation of gender, which can yield inherent risks and conflicts for incarcerated transgender people. We conducted a scoping literature review on challenges unique to transgender individuals within US correctional settings. Online databases were searched to identify papers that addressed the challenges of incarcerated transgender adults age 18 + within US correctional institutions. A concurrent analysis of legal literature was reviewed with key policy recommendations extracted. A total of 33 papers (21 scientific studies and 12 legal analyses) met criteria for inclusion. Of the 21 scientific studies, the majority of papers (n = 14) focused on transgender women and most (n = 13) utilized qualitative methods. Emerging themes revealed challenges in key domains of violence, health, healthcare access, housing, and a pervasive culture of transphobia. Legal analyses supported policy changes such as implementing case-by-case housing classification systems, providing all forms of gender-affirming care, and safeguarding gender expression. Transgender persons face distinct obstacles while incarcerated in US correctional facilities and are in need of expanded protections. Working in tandem with efforts to decarcerate and reduce criminal legal involvement, widespread institutional policy change, such as redefining housing assignment policies, ensuring gender-affirming healthcare, and expanding transgender-specific competency trainings for correctional staff, is necessary.

Examining the Ethics and Impacts of Laws Restricting Transgender Youth-Athlete Participation.

As of this writing, twenty-one states have passed laws barring transgender youth-athletes from competing on public-school sports teams in accordance with their gender identity. Proponents of these regulations claim that transgender females in particular have inherent physiological advantages that threaten a "level playing field" for their cisgender competitors. Existing evidence is limited but does not support these restrictions. Gathering more robust data will require allowing transgender youth to compete (rather than preemptively barring them), but even if trans females are shown to retain some advantage, this would not have greater moral significance than the many other "fair" physical and economic advantages found across sports. These regulations deprive transgender youth, an exceptionally vulnerable population, from the vast physical, mental, and social benefits of sports. While we advocate for transgender inclusion under our current, gender-segregated model of sport, we propose changes to the overarching structure that would promote a more inclusive and fairer athletic environment.

Thoracoabdominal normothermic regional perfusion in donation after circulatory death does not restore brain blood flow.

Use of thoracoabdominal normothermic regional perfusion (TA-NRP) during donation after circulatory death (DCD) is an important advance in organ donation. Prior to establishing TA-NRP, the brachiocephalic, left carotid, and left subclavian arteries are ligated, thereby eliminating anterograde brain blood flow via the carotid and vertebral arteries. While theoretical concerns have been voiced that TA-NRP after DCD may restore brain blood flow via collaterals, there have been no studies to confirm or refute this possibility. We evaluated brain blood flow using intraoperative transcranial Doppler (TCD) in two DCD TA-NRP cases. Pre-extubation, anterior and posterior circulation brain blood flow waveforms were present in both cases, similar to the waveforms detected in a control patient on mechanical circulatory support undergoing cardiothoracic surgery. Following declaration of death and initiation of TA-NRP, no brain blood flow was detected in either case. Additionally, there was absence of brainstem reflexes, no response to noxious stimuli and no respiratory effort. These TCD results demonstrate that DCD with TA-NRP did not restore brain blood flow.

Extracorporeal cardiopulmonary resuscitation dissemination and integration with organ preservation in the USA: ethical and logistical considerations.

Use of extracorporeal membrane oxygenation (ECMO) in cardiopulmonary resuscitation, termed eCPR, offers the prospect of improving survival with good neurological function after cardiac arrest. After death, ECMO can also be used for enhanced preservation of abdominal and thoracic organs, designated normothermic regional perfusion (NRP), before organ recovery for transplantation. To optimize resuscitation and transplantation outcomes, healthcare networks in Portugal and Italy have developed cardiac arrest protocols that integrate use of eCPR with NRP. Similar dissemination of eCPR and its integration with NRP in the USA raise novel ethical issues due to a non-nationalized health system and an opt-in framework for organ donation, as well as other legal and cultural factors. Nonetheless, eCPR investigations are ongoing, and both eCPR and NRP are selectively employed in clinical practice. This paper delineates the most pressing relevant ethical considerations and proposes recommendations for implementation of protocols that aim to promote public trust and reduce conflicts of interest. Transparent policies should rely on protocols that separate lifesaving from organ preservation considerations; robust, centralized eCPR data to inform equitable and evidence-based allocations; uniform practices concerning clinical decision-making and resource utilization; and partnership with community stakeholders, allowing patients to make decisions about emergency care that align with their values. Proactively addressing these ethical and logistical challenges could enable eCPR dissemination and integration with NRP protocols in the USA, with the potential to maximize lives saved through both improved resuscitation with good neurological outcomes and increased organ donation opportunities when resuscitation is unsuccessful or not in accordance with individuals' wishes.