Telomere-to-telomere assembly of a complete human X chromosome.

After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist1,2. Here we present a human genome assembly that surpasses the continuity of GRCh382, along with a gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome3, we reconstructed the centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis ampliconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes.

Ethical considerations for psychedelic-assisted therapy in military clinical settings.

Psychedelic treatments, particularly 3,4-methylenedioxymethamphetamine (MDMA)-assisted and psilocybin-assisted therapies, have recently seen renewed interest in their clinical potential to treat various mental health conditions. Clinical trials for both MDMA-assisted and psilocybin-assisted therapies have shown to be highly efficacious for post-traumatic stress disorder and major depression. Recent research trials for psychedelic-assisted therapies (PAT) have demonstrated that although they are resource-intensive, their effects are rapid-acting, durable and cost-effective. These results have generated enthusiasm among researchers seeking to investigate psychedelic therapies in active-duty service members of the US military, particularly those with treatment refractory mental health conditions. At the same time, psychedelics remain in early stages of clinical investigation, have not yet achieved regulatory approval for general clinical use and may confer unique psychological and neurobiological effects that could raise novel ethical considerations when treating active-duty service members. Should psychedelics achieve regulatory approval, military relevant considerations may include issues of access to these treatments, appropriate procedures for informed consent, confidentiality standards, and possible unanticipated mental health risks and other psychological sequelae. A service member's deployability, as well as their ability to return to full military duty following PAT, may also be of unique concern. The authors argue that MDMA-assisted therapy currently represents a promising treatment that should be more rapidly investigated as a clinical therapy for service members while still taking a measured approach that accounts for the many military-specific uncertainties that remain.

Should Providers Advocate for Their Patients?

AbstractThis piece discusses several ways in which providers may advocate for patients and their families that go beyond what providers usually do to help their patients. A much more expanded view of advocacy is suggested. Real cases illustrating all interventions suggested are presented, and each is paradigmatic of numerous others. Categories of possible options suggested for expanded advocacy include (1) providers enhancing patients' outcomes when standard treatments have failed, (2) providers taking measures outside those they usually take to benefit patients to a greater extent, and (3) providers sacrificing their own needs more than they customarily do to help their patients still further. The suggested interventions are practical and can be implemented immediately. Taken together, the interventions proposed are also aspirational.

New Ways to Help Patients Worst Off.

AbstractThis introduction to The Journal of Clinical Ethics highlights and expands four articles within this issue that propose somewhat new and radical innovations to help and further the interests of patients and families worst off. One article urges us to enable historically marginalized groups to participate more than they have in research; a second urges us to allocate limited resources that can be divided, such as vaccines and even ventilators, in a different way; a third urges us to help families find greater meaning when their loved ones are dying; and a fourth urges us to treat patients who illegally use drugs as caringly as is possible, though there may be limits to what providers can do. This piece also addresses the importance of providers bonding with patients, recognizing that some providers may be better at eliciting patients' trust than others, and thus the importance of connecting these patients with these providers since this may be the sole way these patients can optimally respond and do well. Finally, providers taking time away from their patients to oppose and reduce social stigma is considered.

When, If Ever, Should Care Providers Neither Contact Families of Suicidal Patients to Gain More Information Nor Hospitalize Patients?

AbstractIn this piece I discuss when care providers should not contact suicidal patients' families to get collateral information from them or hospitalize patients over their objections. I suggest that when these patients are chronically suicidal, overriding these wants may be best in the short run but increase their net risk in the longer run. I also discuss in this regard how contacted families may become overprotective and how hospitalization can be traumatic. I present an alternative approach that can increase these patients' safety over the longer run and relate three practical approaches care providers may find useful: explaining their decisions to patients, monitoring their own fear, and instilling hope.

Questions Care Providers Should Ask When They Have Ethical Discretion.

AbstractSince some care providers give colleagues' interests priority over patients' and families', they are at risk of imposing their bias on patients without knowing this. In this piece I discuss how the risk increases when care providers have greater discretion and how they can best avoid this risk. I discuss identifying these situations, assessing them, and then, based on what they have concluded, intervening and use their having inadequate resources, their seeing what patients want as futile, and their making decisions regarding surrogate decision makers as paradigmatic examples. As "remedies," I suggest that care providers share with patients their rationales, validate adaptive aspects of difficult behaviors, self-disclose, and sometimes even go beyond their usual clinical practices.

Patients with Invisible Pain: How Might We See This Pain and Help These Patients More?

AbstractIn this piece I discuss two ways in which providers may become able to treat patients better. The first is for them to encourage all medical parties, including medical students, to always speak up. The second is to take initiatives to learn of pain that patients feel but neither show nor spontaneously report. They may refer to this pain as invisible pain, often bitterly, in that others not seeing their pain judge them wrongly and harshly. Providers, once seeing this pain, are encouraged to then take additional measures to try to alleviate it. Clinical examples provided to illustrate the range of treatments providers may add are post-traumatic stress disorders, problems involving substance use, and hoarding disorders. Similar concerns regarding people who are deaf and hard of hearing are also addressed.

When Should Providers Defer versus Impose Their Views?

AbstractThis piece discusses perhaps the most agonizing ethical decision ethics consultants and other providers encounter. This is the extent to which providers should defer decisions to patients or to their proxy decision makers as opposed to imposing their own views as to what they think is ethically right. It discusses the most difficult issues these providers may encounter, especially when they wish to depart from authoritative bodies' standards or guidelines, and it presents initial steps providers may take to help patients and their families work together to resolve these dilemmas more harmoniously. It highlights how providers may inadvertently impose flawed biases on patients and families. Finally, it discusses how providers should take initiative with both parties to offer to help appeal when these avenues already exist and seek to establish the appellate procedures when they are absent.

Seeing the Invisible.

This article focuses on three different ways that we may demean people by seeing them as less than they are, and describes ways we may best avoid doing this. More specifically, I explain how we may not see the physical and emotional issues that plague patients and others. This may be because they choose not to disclose their difficulties to us. We may also err when we see only one aspect of who and how others are. These challenges pose ethical quandaries that involve equity, improved communication with patients, and subjecting ethical principles to empirical study before we adopt them. I explore the means to do these.

Beyond the Basics: More Ways that Ethics Consultants Can Help Patients.

The primary task of ethics consultants is to work with patients-and sometimes also their families-to discern and then meet patients' and families' needs and wants to the extent possible. That is primarily a cognitive endeavor. Yet the feelings of patients and ethics consultants may determine what they can work together to accomplish. This article considers their feelings. It looks at sources of distrust and their hoped-for resolution, specific means to enhance patients' decision making in their relationship with ethics consultants, and a new, highly different approach that may enhance their relationships more than most commonly used ways of relating.

Should Ethics Consultants Make their Findings Transparent? How Important Is "Intimacy" between Patients and Careproviders?

A recently enacted law permits patients to see their electronic medical record (EMR) immediately after their careprovider writes in it. In this article I discuss a proposal that authors make in this issue of The Journal of Clinical Ethics, that ethics consultants (ECs) keep their notes in a separate section of the EMR that patients cannot access when their ethics notes may be troubling to patients, to avoid unduly harming them. I discuss this concern and three more widely applicable clinical goals: to help patients feel safe; to gain patients' trust; and to provide hope to patients, when possible. These goals apply to careproviders and ECs who seek to help patients and families resolve ethical conflicts. I explain why these goals are singularly important and how careproviders may pursue them, using as an example informing patients about temporal framing to help them find hope.

When Should Careproviders Deviate from Consensus?

Consensus documents may be extremely helpful. They may, however, also do harm. They may, for example, suggest interventions that are less than optimal, especially when they apply to patients whose situations are at the "outer margins" of their applicability. Yet, even in these instances, clinicians and ethics consultants may still feel pressure to comply with a guideline. Then, we may not do what we think is best for our particular patient because we fear departing from a guideline. In this article I discuss the risks of departing from guidelines and suggest what we can do to overcome those possible risks. I suggest that while guidelines may help, we should continue to put, above all else, tailoring our interventions to our patients' individual needs and wants. With our patients, together, we should decide what to do, notwithstanding what the most applicable guidelines propose.

People with Differences of Sexual Development: Can We Do Better?

This article discusses how careproviders of all types can help people with differences of sexual development (DSD): people with ambiguous genitalia, who used to be referred to as intersexed. Careproviders may be in a unique position to benefit these people by offering to discuss difficult issues that concern them, even when the discussions are brief. Specific interventions include learning about people with DSD, whether through the literature or in the clinic; treating them with optimal respect; raising difficult topics such as sex, fertility, and social stigma; encouraging them and helping them to meet others with DSD; and sharing the strengths that we can see that they have. We have come far, but have a long way to go.

Seven "Between-the-Lines" Questions All Ethics Consultants Should Continue to Ask.

Clinical ethics consultants (CECs) must know key moral principles and have adequate psychosocial skills. This is, though, not enough. They must also have and hone "between-the-lines" skills that will change over time. This article discusses seven of these skills that CECs need before, during, and after consultations. They have in common the unusual primary goal of maximizing CECs' ability to bond with the patients and families with whom they consult. A focus on relationships, rather than on ethical outcomes, may paradoxically enhance the possibility of achieving an ethical outcome.

Caring for Transgender Adolescents.

This introductory article presents some subtle and, perhaps, controversial aspects of providing care to adolescents who identify as transgender. I will describe (1) how praise from careproviders can benefit parents who have difficulty accepting the gender identity of their child that was not assigned at birth; (2) how adolescents who identify as transgender may follow the internet advice of peers on how to "con" careproviders; (3) how it may be difficult for careproviders to decide whether to further patients' felt needs and to protect them, paternalistically, from making an irreversible decision they may later regret; and (4) how careproviders can benefit adolescents by taking the initiative to discuss sex and how to say "no." I emphasize how careproviders who see these patients, even when they have no special expertise in this area, may be able to enhance patients' equality in every respect, even when they otherwise might not choose to do so.

Can Careproviders Still Bond with Patients after They Are Turned Down for a Treatment They Need?

After COVID-19 first began to spread in the United States, dentists developed new guidelines that limited whom they could treat under these emergency conditions. Patients who faced greater limits to accessing treatment included children. Using a case of a child who was not able to access treatment, I discuss how careproviders might best seek to maintain their emotional bonding with patients and their loved ones, even if they must turn them down for an intervention. I also address whether and when to give patients and their loved ones warning that access to treatment could be limited, using illness caused by COVID-19 as an example of how careproviders may better anticipate patients' needs at all times. Finally, I discuss careproviders' needs. I suggest that medical professionals' culture should make it as easy as possible for them to acknowledge their feelings of vulnerability, so that they may better determine, in times of disaster, whether they should treat or triage patients. Careproviders who triage may choose to share with patients and loved ones that they also feel pain when they deny patients an intervention.

Remembering Al Jonsen.

The author, editor-in-chief of The Journal of Clinical Ethics, recalls the contributions of Albert R. Jonsen, PhD, one of the founding members of the editorial board of the journal.

Beyond Determining Decision-Making Capacity.

One of the most important and difficult tasks in medicine is to determine when patients have the capacity to make decisions for themselves. This determination may determine a patient's life or death. This article presents criteria and approaches now used to make this assessment and discusses how these approaches are presently applied in five common disorders that can serve as paradigms for approaches in other disorders. I propose that since there are new diagnoses and treatments, reconsidering our current practices is warranted. The possibilities that clinicians can nudge patients to make better choices for themselves and, above all, that clinicians can maintain and maximize positive patient/careprovider relationships during and after these assessments, are emphasized.

Sweetening the "Sweet Spot" of Dementia.

Alzheimer's disease is singularly tragic in that it may rob patients of much or all of their personal identity. Some persons fear this outcome so much that they talk of wanting to find the "sweet spot," a time midway in the course of ever-increasing dementia, during which they are able to foresee a possible loss of identity in sufficient time to end their life before they lose the capacity to choose to do so, and before further devastation occurs. This article presents the belief of some experts that patients always retain a basic, core underlying awareness. Practical approaches that careproviders and caregivers can take to maximize patients' quality of life are discussed. The possibility that patients and loved ones can find meaning in last months and years of life is emphasized.

Ethical Issues Posed by Face Transplants.

A face transplant is as challenging a surgical procedure as any patient can undergo. In this introduction I present the medical aspects of this surgery, the profound ethical issues it raises, and optimal interventions that clinicians can pursue to help these patients and their loved ones. I then discuss how to help other kinds of patients and loved ones who confront similar stresses. I end by presenting a goal that author Sharrona Pearl puts forth after she studied many face transplant patients. The efforts she urges should maximize our capacity to see face transplant patients-and anyone-as they are, as opposed to how they look.