Molecular basis for substrate recruitment to the PRMT5 methylosome.

PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. PRMT5 uses adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1, and COPR5) and show that it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable with other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosomal complexes. Furthermore, disruption of this site affects Sm spliceosome activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface impairs growth of MTAP-null tumor cells and is thus a site for development of therapeutic inhibitors of PRMT5.

Limitation of life sustaining therapy in disorders of consciousness: ethics and practice.

Clinical conversations surrounding the continuation or limitation of life-sustaining therapies (LLST) are both challenging and tragically necessary for patients with disorders of consciousness (DoC) following severe brain injury. Divergent cultural, philosophical and religious perspectives contribute to vast heterogeneity in clinical approaches to LLST-as reflected in regional differences and inter-clinician variability. Here we provide an ethical analysis of factors that inform LLST decisions among patients with DoC. We begin by introducing the clinical and ethical challenge and clarifying the distinction between withdrawing and withholding life-sustaining therapy. We then describe relevant factors that influence LLST decision-making including diagnostic and prognostic uncertainty, perception of pain, defining a 'good' outcome, and the role of clinicians. In concluding sections, we explore global variation in LLST practices as they pertain to patients with DoC and examine the impact of cultural and religious perspectives on approaches to LLST. Understanding and respecting the cultural and religious perspectives of patients and surrogates is essential to protecting patient autonomy and advancing goal-concordant care during critical moments of medical decision-making involving patients with DoC.

Immune to addiction: the ethical dimensions of vaccines against substance abuse.

Promising advances have been made in recent years for a unique class of immunotherapies that use vaccination to combat substance-use disorders. Although such vaccines are potentially useful for addictions, they raise a variety of ethical and social questions.

Disclosing Results of Tests for Covert Consciousness: A Framework for Ethical Translation.

The advent of neurotechnologies including advanced functional magnetic resonance imaging and electroencephalography to detect states of awareness not detectable by traditional bedside neurobehavioral techniques (i.e., covert consciousness) promises to transform neuroscience research and clinical practice for patients with brain injury. As these interventions progress from research tools into actionable, guideline-endorsed clinical tests, ethical guidance for clinicians on how to responsibly communicate the sensitive results they yield is crucial yet remains underdeveloped. Drawing on insights from empirical and theoretical neuroethics research and our clinical experience with advanced neurotechnologies to detect consciousness in behaviorally unresponsive patients, we critically evaluate ethical promises and perils associated with disclosing the results of clinical covert consciousness assessments and describe a semistructured approach to responsible data sharing to mitigate potential risks.

Equity in Clinical Care and Research Involving Persons with Disorders of Consciousness.

People with disorders of consciousness (DoC) are characteristically unable to synchronously participate in decision-making about clinical care or research. The inability to self-advocate exacerbates preexisting socioeconomic and geographic disparities, which include the wide variability observed across individuals, hospitals, and countries in access to acute care, expertise, and sophisticated diagnostic, prognostic, and therapeutic interventions. Concerns about equity for people with DoC are particularly notable when they lack a surrogate decision-maker (legally referred to as "unrepresented" or "unbefriended"). Decisions about both short-term and long-term life-sustaining treatment typically rely on neuroprognostication and individual patient preferences that carry additional ethical considerations for people with DoC, as even individuals with well thought out advance directives cannot anticipate every possible situation to guide such decisions. Further challenges exist with the inclusion of people with DoC in research because consent must be completed (in most circumstances) through a surrogate, which excludes those who are unrepresented and may discourage investigators from exploring questions related to this population. In this article, the Curing Coma Campaign Ethics Working Group reviews equity considerations in clinical care and research involving persons with DoC in the following domains: (1) access to acute care and expertise, (2) access to diagnostics and therapeutics, (3) neuroprognostication, (4) medical decision-making for unrepresented people, (5) end-of-life decision-making, (6) access to postacute rehabilitative care, (7) access to research, (8) inclusion of unrepresented people in research, and (9) remuneration and reciprocity for research participation. The goal of this discussion is to advance equitable, harmonized, guideline-directed, and goal-concordant care for people with DoC of all backgrounds worldwide, prioritizing the ethical standards of respect for autonomy, beneficence, and justice. Although the focus of this evaluation is on people with DoC, much of the discussion can be extrapolated to other critically ill persons worldwide.

Ethical Considerations in Neuroprognostication Following Acute Brain Injury.

Neuroprognostication following acute brain injury (ABI) is a complex process that involves integrating vast amounts of information to predict a patient's likely trajectory of neurologic recovery. In this setting, critically evaluating salient ethical questions is imperative, and the implications often inform high-stakes conversations about the continuation, limitation, or withdrawal of life-sustaining therapy. While neuroprognostication is central to these clinical "life-or-death" decisions, the ethical underpinnings of neuroprognostication itself have been underexplored for patients with ABI. In this article, we discuss the ethical challenges of individualized neuroprognostication including parsing and communicating its inherent uncertainty to surrogate decision-makers. We also explore the population-based ethical considerations that arise in the context of heterogenous prognostication practices. Finally, we examine the emergence of artificial intelligence-aided neuroprognostication, proposing an ethical framework relevant to both modern and longstanding prognostic tools.

Toward Uniform Insurer Coverage for Functional MRI Following Severe Brain Injury.

Functional magnetic resonance imaging (fMRI) now promises to improve diagnostic and prognostic accuracy for patients with disorders of consciousness, and accordingly has been endorsed by professional society guidelines, including those of the American Academy of Neurology, American College of Rehabilitation Medicine, National Institute on Disability, Independent Living, and Rehabilitation Research, and the European Academy of Neurology. Despite multiple professional society endorsements of fMRI in evaluating patients with disorders of consciousness following severe brain injury, insurers have yet to issue clear guidance regarding coverage of fMRI for this indication. Lack of insurer coverage may be a rate-limiting barrier to accessing this technique, which could uncover essential diagnostic and prognostic information for patients and their families. The emerging clinical and ethical case for harmonized insurer recognition and reimbursement of fMRI for vulnerable persons following severe brain injury with disorders of consciousness is explained and critically evaluated.

Ethics Along the Continuum of Research Involving Persons with Disorders of Consciousness.

Interest in disorders of consciousness (DoC) has grown substantially over the past decade and has illuminated the importance of improving understanding of DoC biology; care needs (use of monitoring, performance of interventions, and provision of emotional support); treatment options to promote recovery; and outcome prediction. Exploration of these topics requires awareness of numerous ethics considerations related to rights and resources. The Curing Coma Campaign Ethics Working Group used its expertise in neurocritical care, neuropalliative care, neuroethics, neuroscience, philosophy, and research to formulate an informal review of ethics considerations along the continuum of research involving persons with DoC related to the following: (1) study design; (2) comparison of risks versus benefits; (3) selection of inclusion and exclusion criteria; (4) screening, recruitment, and enrollment; (5) consent; (6) data protection; (7) disclosure of results to surrogates and/or legally authorized representatives; (8) translation of research into practice; (9) identification and management of conflicts of interest; (10) equity and resource availability; and (11) inclusion of minors with DoC in research. Awareness of these ethics considerations when planning and performing research involving persons with DoC will ensure that the participant rights are respected while maximizing the impact and meaningfulness of the research, interpretation of outcomes, and communication of results.

Measuring Consciousness in the Intensive Care Unit.

Early reemergence of consciousness predicts long-term functional recovery for patients with severe brain injury. However, tools to reliably detect consciousness in the intensive care unit are lacking. Transcranial magnetic stimulation electroencephalography has the potential to detect consciousness in the intensive care unit, predict recovery, and prevent premature withdrawal of life-sustaining therapy.

Neuroethics in the Era of Teleneurology.

The accelerating integration of telehealth technologies in neurology practice has transformed traditional interactions between neurologists and patients, allied clinicians and society. Despite the immense promise of these technologies to improve systems of neurological care, the infusion of telehealth technologies into neurology practice introduces a host of unique ethical challenges. Proactive consideration of the ethical dimensions of teleneurology and of the impact of these innovations on the field of neurology more generally can help to ensure responsible development and deployment across stages of implementation. Toward these ends, this article explores key ethical dimensions of teleneurology practice and policy, presents a normative framework for their consideration, and calls attention to underexplored questions ripe for further study at this evolving nexus of teleneurology and neuroethics. To promote successful and ethically resilient development of teleneurology across diverse contexts, clinicians, organizational leaders, and information technology specialists should work closely with neuroethicists with the common goal of identifying and rigorously assessing the trajectories and potential limits of teleneurology systems.

Neuroethics across the Disorders of Consciousness Care Continuum.

This review provides an ethical analysis of disorders of consciousness (DoC) along the care continuum, from preinjury to injury, acute care to subacute care and early rehabilitation, and finally transitioning to chronic rehabilitation and societal reintegration. We provide an actionable, chronological assessment of ethical issues related to DoC care. This expands upon established ethics literature, which focuses almost exclusively on the clinical encounter for DoC. Our goal is to broaden the aperture of ethical analysis to address how social and environmental conditions predispose some persons to brain injury, and how such conditions might also pose barriers to meaningful societal reintegration after recovery.

The neuroethics of disorders of consciousness: a brief history of evolving ideas.

Neuroethical questions raised by recent advances in the diagnosis and treatment of disorders of consciousness are rapidly expanding, increasingly relevant and yet underexplored. The aim of this thematic review is to provide a clinically applicable framework for understanding the current taxonomy of disorders of consciousness and to propose an approach to identifying and critically evaluating actionable neuroethical issues that are frequently encountered in research and clinical care for this vulnerable population. Increased awareness of these issues and clarity about opportunities for optimizing ethically responsible care in this domain are especially timely given recent surges in critically ill patients with prolonged disorders of consciousness associated with coronavirus disease 2019 around the world. We begin with an overview of the field of neuroethics: what it is, its history and evolution in the context of biomedical ethics at large. We then explore nomenclature used in disorders of consciousness, covering categories proposed by the American Academy of Neurology, the American Congress of Rehabilitation Medicine and the National Institute on Disability, Independent Living and Rehabilitation Research, including definitions of terms such as coma, the vegetative state, unresponsive wakefulness syndrome, minimally conscious state, covert consciousness and the confusional state. We discuss why these definitions matter, and why there has been such evolution in this nosology over the years, from Jennett and Plum in 1972 to the Multi-Society Task Force in 1994, the Aspen Working Group in 2002 and the 2018 American and 2020 European Disorders of Consciousness guidelines. We then move to a discussion of clinical aspects of disorders of consciousness, the natural history of recovery and ethical issues that arise within the context of caring for people with disorders of consciousness. We conclude with a discussion of key challenges associated with assessing residual consciousness in disorders of consciousness, potential solutions and future directions, including integration of crucial disability rights perspectives.

Ethics Priorities of the Curing Coma Campaign: An Empirical Survey.

BACKGROUND: The Curing Coma Campaign (CCC) is a multidisciplinary global initiative focused on evaluation, diagnosis, treatment, research, and prognostication for patients who are comatose due to any etiology. To support this mission, the CCC Ethics Working Group conducted a survey of CCC collaborators to identify the ethics priorities of the CCC and the variability in priorities based on country of practice. METHODS: An electronic survey on the ethics priorities for the CCC was developed using rank-choice questions and distributed between May and July 2021 to a listserv of the 164 collaborators of the CCC. The median rank for each topic and subtopic was determined. Comparisons were made on the basis of country of practice. RESULTS: The survey was completed by 93 respondents (57% response rate); 67% practiced in the United States. On the basis of respondent ranking of each topic, the prioritization of ethics topics across respondents was as follows: (1) clinical care, (2) diagnostic definitions, (3) clinical research, (4) implementation/innovation, (5) family, (6) data management, (7) public engagement/perceptions, and (8) equity. Respondents who practiced in the United States were particularly concerned about public engagement, the distinction between clinical care and research, disclosure of results from clinical research to families, the definition of "personhood," and the distinction between the self-fulfilling prophecy/nihilism and medical futility. Respondents who practiced in other countries were particularly concerned about diagnostic modalities for clinical care, investigational drugs/devices for clinical research, translation of research into practice, and the definition of "minimally conscious state." CONCLUSIONS: Collaborators of the CCC considered clinical care, diagnostic definitions, and clinical research the top ethics priorities of the CCC. These priorities should be considered as the CCC explores ways to improve evaluation, diagnosis, treatment, research, and prognostication of patients with coma and associated disorders of consciousness. There is some variability in ethics priorities based on country of practice.

Enhanced migration of engrafted retinal progenitor cells into the host retina via disruption of glial barriers.

Purpose: Migration and integration remain critical challenges for stem cell replacement therapy. Glial barriers play an important role in preventing cell migration and integration. The purpose of this study was to investigate the effect and mechanisms of chondroitinase ABC on the migration of murine retinal progenitor cells (mRPCs) transplanted into the subretinal space of B6 mice. Methods: mRPCs were harvested from the neural retinas of P1 enhanced green fluorescent protein (GFP) B6 mice. Two µl containing 2 × 105 expanded RPCs alone or combined with chondroitinase ABC in suspension were injected into the subretinal space of the recipient B6 mice. Immunohistochemistry was performed on the recipient B6 retinas to evaluate the glial barrier formation and migration of the mRPCs. Western blotting was also used to check the expression of the glial barriers. Results: Glial fibrillary acidic protein (GFAP) and vimentin could be seen around the transplanted mRPCs in the B6 mice. Formation of glial barriers prevented the migration of donor cells into the retinal layers. Chondroitinase ABC promoted the migration and survival rates of the engrafted retinal progenitor cells in the retinal layers of recipient B6 mice. Injection induced upregulation of GFAP, chondroitin, and CD44 expression. Chondroitinase ABC disrupted the glial barriers. The CD44 around the mRPCs was much lower in the chondroitinase group. However, the CD44 in the retinal layers was considerably higher in the chondroitinase group. With the employment of chondroitinase ABC, more cells migrated into the outer nuclear layer or inner nuclear layer. The chondroitin and CD44 expression decreased 3 weeks after transplantation in the chondroitinase ABC group. Conclusions: Chondroitinase ABC degraded glial barriers and enhanced the migration of transplanted mouse retinal progenitor cells. Chondroitinase ABC may also have induced activation of the CD44 signaling pathway to exert the effect.

Brain-Computer Interfaces in Neurorecovery and Neurorehabilitation.

Recent advances in brain-computer interface technology to restore and rehabilitate neurologic function aim to enable persons with disabling neurologic conditions to communicate, interact with the environment, and achieve other key activities of daily living and personal goals. Here we evaluate the principles, benefits, challenges, and future directions of brain-computer interfaces in the context of neurorehabilitation. We then explore the clinical translation of these technologies and propose an approach to facilitate implementation of brain-computer interfaces for persons with neurologic disease.

Creutzfeldt-Jakob disease in a man with COVID-19: SARS-CoV-2-accelerated neurodegeneration?

We describe a man whose first manifestations of Creutzfeldt-Jakob disease occurred in tandem with symptomatic onset of coronavirus disease 2019 (COVID-19). Drawing from recent data on prion disease pathogenesis and immune responses to SARS-CoV-2, we hypothesize that the cascade of systemic inflammatory mediators in response to the virus accelerated the pathogenesis of our patient's prion disease. This hypothesis introduces the potential relationship between immune responses to the novel coronavirus and the hastening of preclinical or manifest neurodegenerative disorders. The global prevalence of both COVID-19 and neurodegenerative disorders adds urgency to the study of this potential relationship.

Undocumented injustice? Medical repatriation and the ends of health care.

The authors review the history and motivations behind medical repatriation, the transfer of undocumented patients in need of subacute care to their country of origin. They argue that involuntary medical repatriation violates the ethical duties of health care providers.