The nuclear lamina binds the EBV genome during latency and regulates viral gene expression.

The Epstein Barr virus (EBV) infects almost 95% of the population worldwide. While typically asymptomatic, EBV latent infection is associated with several malignancies of epithelial and lymphoid origin in immunocompromised individuals. In latently infected cells, the EBV genome persists as a chromatinized episome that expresses a limited set of viral genes in different patterns, referred to as latency types, which coincide with varying stages of infection and various malignancies. We have previously demonstrated that latency types correlate with differences in the composition and structure of the EBV episome. Several cellular factors, including the nuclear lamina, regulate chromatin composition and architecture. While the interaction of the viral genome with the nuclear lamina has been studied in the context of EBV lytic reactivation, the role of the nuclear lamina in controlling EBV latency has not been investigated. Here, we report that the nuclear lamina is an essential epigenetic regulator of the EBV episome. We observed that in B cells, EBV infection affects the composition of the nuclear lamina by inducing the expression of lamin A/C, but only in EBV+ cells expressing the Type III latency program. Using ChIP-Seq, we determined that lamin B1 and lamin A/C bind the EBV genome, and their binding correlates with deposition of the histone repressive mark H3K9me2. By RNA-Seq, we observed that knock-out of lamin A/C in B cells alters EBV gene expression. Our data indicate that the interaction between lamins and the EBV episome contributes to the epigenetic control of viral gene expression during latency, suggesting a restrictive function of the nuclear lamina as part of the host response against viral DNA entry into the nucleus.

Limits on Parental Discretion in Medical Decision-Making: pediatric intervention principles converge.

Pediatric intervention principles help clinicians and health-care institutions determine appropriate responses when parents' medical decisions place children at risk. Several intervention principles have been proposed and defended in the pediatric ethics literature. These principles may appear to provide conflicting guidance, but much of that conflict is superficial. First, seemingly different pediatric intervention principles sometimes converge on the same guidance. Second, these principles often aim to solve different problems in pediatrics or to operate in different background conditions. The potential for convergence between intervention principles-or at least an absence of conflict between them-matters for both the theory and practice of pediatric ethics. This article builds on the recent work of a diverse group of pediatric ethicists tasked with identifying consensus guidelines for pediatric decision-making.

Clinical Ethics Fellowship Programs in the U.S. and Canada: A Descriptive Study of Program Characteristics and Practices.

To address the current lack of knowledge about clinical ethics fellowship programs (CEFPs), we surveyed all 36 programs in the U.S. and Canada. The number of CEFPs has grown exponentially over the last 40 years and far exceeds previous estimates. Commonalities among CEFPs include: 88.8% require an advanced degree or rarely accept applicants without one; 91.7% of programs do not restrict applicants to a specific background such as medicine or philosophy; and 88.9% of programs compensate fellows. CEFPs vary widely on numbers of fellows trained in the last 3 years (1-111), numbers of consultations performed by each fellow (0-450), and salaries paid ($0-$95,000). Less than half of programs meet CEFP standards established by ABPD. Nonpaying programs and larger programs tend to have lower admission standards and lower expectations for fellows. We hope these data will help inform CEFP standards that promote quality and consistency without stifling desirable diversity and innovation.

The Impact of a Study Trip to Auschwitz: Place-based Learning for Bioethics Education and Professional Identity Formation.

There are increasing calls for coverage of medicine during the Holocaust in medical school curricula. This article describes outcomes from a Holocaust and medicine educational program featuring a study trip to Poland, which focused on physician complicity during the Holocaust, as well as moral courage in health professionals who demonstrated various forms of resistance in the ghettos and concentration camps. The trip included tours of key sites in Krakow, Oswiecim, and the Auschwitz-Birkenau concentration camps, as well as meeting with survivors, lectures, reflective writings, and discussions. In-depth interviews and reflective writings were qualitatively analyzed. Resulting themes centered on greater understanding of the relationship between bioethics and the Holocaust, recognizing the need for moral courage and social awareness, deeper appreciation for the historical roles played by dehumanization and medical power and their contemporary manifestations, and the power of presence and experiential learning for bioethics education and professional identity formation. These findings evidence the significant impact of the experience and suggest broader adoption of pedagogies that include place-based and experiential learning coupled with critical reflection can amplify the impact of bioethics and humanism education as well as the process of professional identity formation of medical students.

Conscientious Objection to Aggressive Interventions for Patients in a Vegetative State.

Some physicians refuse to perform life-sustaining interventions, such as tracheostomy, on patients who are very likely to remain permanently unconscious. To explain their refusal, these clinicians often invoke the language of "futility", but this can be inaccurate and can mask problematic forms of clinical power. This paper explores whether such refusals should instead be framed as conscientious objections. We contend that the refusal to provide interventions for patients very likely to remain permanently unconscious meets widely recognized ethical standards for the exercise of conscience. We conclude that conscientious objection to tracheostomy and other life-sustaining interventions on such patients can be ethical because it does not necessarily constitute a form of invidious discrimination. Furthermore, when a physician frames their refusal as conscientious objection, it makes transparent the value-laden nature of their objection and can better facilitate patient access to the requested treatment.

It's Worth What You Can Sell It for: A Survey of Employment and Compensation Models for Clinical Ethicists.

This article reports results of a survey about employment and compensation models for clinical ethics consultants working in the United States and discusses the relevance of these results for the professionalization of clinical ethics. This project uses self-reported data from healthcare ethics consultants to estimate compensation across different employment models. The average full-time annualized salary of respondents with a clinical doctorate is $188,310.08 (SD=$88,556.67), $146,134.85 (SD=$55,485.63) for those with a non-clinical doctorate, and $113,625.00 (SD=$35,872.96) for those with a masters as their highest degree. Pay differences across degree level and type were statistically significant (F = 3.43; p < .05). In a multivariate model, there is an average increase of $2,707.84 for every additional year of experience, controlling for having a clinical doctorate (ß=0.454; p < .01). Our results also show high variability in the backgrounds and experiences of healthcare ethics consultants and a wide variety of employment models. The significant variation in employment and compensation models is likely to pose a challenge for the professionalization of healthcare ethics consultation.

The PRR14 heterochromatin tether encodes modular domains that mediate and regulate nuclear lamina targeting.

A large fraction of epigenetically silent heterochromatin is anchored to the nuclear periphery via 'tethering proteins' that function to bridge heterochromatin and the nuclear membrane or nuclear lamina. We previously identified a human tethering protein, PRR14, that binds heterochromatin through an N-terminal domain, but the mechanism and regulation of nuclear lamina association remained to be investigated. Here we identify an evolutionarily conserved PRR14 nuclear lamina binding domain (LBD) that is both necessary and sufficient for positioning of PRR14 at the nuclear lamina. We show that PRR14 associates dynamically with the nuclear lamina, and provide evidence that such dynamics are regulated through phosphorylation and dephosphorylation of the LBD. Furthermore, we identify a PP2A phosphatase recognition motif within the evolutionarily conserved C-terminal Tantalus domain of PRR14. Disruption of this motif affects PRR14 localization to the nuclear lamina. The overall findings demonstrate a heterochromatin anchoring mechanism whereby the PRR14 tether simultaneously binds heterochromatin and the nuclear lamina through two separable modular domains. Our findings also describe an optimal PRR14 LBD fragment that could be used for efficient targeting of fusion proteins to the nuclear lamina.

The capacity to designate a surrogate is distinct from decisional capacity: normative and empirical considerations.

The capacity to designate a surrogate (CDS) is not simply another kind of medical decision-making capacity (DMC). A patient with DMC can express a preference, understand information relevant to that choice, appreciate the significance of that information for their clinical condition, and reason about their choice in light of their goals and values. In contrast, a patient can possess the CDS even if they cannot appreciate their condition or reason about the relative risks and benefits of their options. Patients who lack DMC for many or most kinds of medical choices may nonetheless possess the CDS, particularly since the complex means-ends reasoning required by DMC is one of the first capacities to be lost in progressive cognitive diseases (eg, Alzheimer's disease). That is, patients with significant cognitive decline or mental illness may still understand what a surrogate does, express a preference about a potential surrogate, and be able to provide some kind of justification for that selection. Moreover, there are many legitimate and relevant rationales for surrogate selection that are inconsistent with the reasoning criterion of DMC. Unfortunately, many patients are prevented from designating a surrogate if they are judged to lack DMC. When such patients possess the CDS, this practice is ethically wrong, legally dubious and imposes avoidable burdens on healthcare institutions.

Practising what we preach: clinical ethicists' professional perspectives and personal use of advance directives.

The field of clinical bioethics strongly advocates for the use of advance directives to promote patient autonomy, particularly at the end of life. This paper reports a study of clinical bioethicists' perceptions of the professional consensus about advance directives, as well as their personal advance care planning practices. We find that clinical bioethicists are often sceptical about the value of advance directives, and their personal choices about advance directives often deviate from what clinical ethicists acknowledge to be their profession's recommendations. Moreover, our respondents identified a pluralistic set of justifications for completing treatment directives and designating surrogates, even while the consensus view focuses on patient autonomy. Our results suggest important revisions to academic discussion and public-facing advocacy about advance care planning.

Three Kinds of Decision-Making Capacity for Refusing Medical Interventions.

According to a standard account of patient decision-making capacity (DMC), patients can provide ethically valid consent or refusal only if they are able to understand and appreciate their medical condition and can comparatively evaluate all offered treatment options. We argue instead that some patient refusals can be capacitated, and therefore ethically authoritative, without meeting the strict criteria of this standard account-what we call comparative DMC. We describe how patients may possess burdens-based DMC for refusal if they have an overriding objection to at least one burden associated with each treatment option or goals-based DMC for refusal if they have an overriding goal that is inconsistent with treatment. The overridingness of a patient's objections to burdens, or of their commitment to a goal, can justify the moral authority of their refusal, even when a patient lacks some of the cognitive capacities that standard accounts of DMC involve.

On Triggering and Being Triggered: Civil Society and Building Brave Spaces in Medical Education.

IssueHow educators should respond to student reports of intense emotional reactions to curricular content-i.e., being triggered-invites intense debate. There are claims of insensitivity on one side and calls to "toughen up" on the other. These polemics aside, such instances sometimes represent a true dilemma, particularly within medical education where engaging highly sensitive content is essential to future patient care and where managing one's own emotions is a core competency. Parsing this convoluted and emotional debate into these domains illustrates how medical educators can simultaneously legitimize the lived experiences of students, engage in honest dialogue, and maintain a shared commitment to education. Evidence: While substantial energy has been spent debating the legitimacy of students' emotional reactions, the discourse lacks a clear conceptual framework and we often end up talking past each other. The concept of brave spaces offers an important alternative where sensitive subject matter can be engaged with civility. Implications: This paper offers a model for building brave spaces within medical education by clarifying the rights and responsibilities of both teachers and learners in each of three intersecting domains: intrapersonal, interpersonal, and civic. This model is exemplified in a case where students reported being triggered by course content. By parsing this case across the three domains, we can clarify how responses are multifaceted and we can simultaneously avoid indictment of another's lived experiences while preserving the pedagogical integrity of the curriculum.

Guidance and Intervention Principles in Pediatrics: The Need for Pluralism.

Two core questions in pediatric ethics concern when and how physicians are ethically permitted to intervene in parental treatment decisions (intervention principles), and the goals or values that should direct physicians' and parents' decisions about the care of children (guidance principles). Lainie Friedman Ross argues in this issue of The Journal of Clinical Ethics that constrained parental autonomy (CPA) simultaneously answers both questions: physicians should intervene when parental treatment preferences fail to protect a child's basic needs or primary goods, and both physicians and parents should be guided by a commitment to protect a child's basic needs and primary goods. In contrast, we argue that no principle-neither Ross's CPA, nor the best interest standard or the harm threshold-can serve as both an intervention principle and a guidance principle. First, there are as many correct intervention principles as there are different kinds of interventions, since different kinds of interventions can be justified under different conditions. Second, physicians and parents have different guidance principles, because the decisions physicians and parents make for a child should be informed by different values and balanced by different (potentially) conflicting commitments.

Reasons to Amplify the Role of Parental Permission in Pediatric Treatment.

Two new documents from the Committee on Bioethics of the American Academy of Pediatrics (AAP) expand the terrain for parental decision making, suggesting that pediatricians may override only those parental requests that cross a harm threshold. These new documents introduce a broader set of considerations in favor of parental authority in pediatric care than previous AAP documents have embraced. While we find this to be a positive move, we argue that the 2016 AAP positions actually understate the importance of informed and voluntary parental involvement in pediatric decision making. This article provides a more expansive account of the value of parental permission. In particular, we suggest that an expansive role for parental permission may (1) reveal facts and values relevant to their child's treatment, (2) encourage resistance to suboptimal default practices, (3) improve adherence to treatment, (4) nurture children's autonomy, and (5) promote the interests of other family members.

When Respecting Autonomy Is Harmful: A Clinically Useful Approach to the Nocebo Effect.

Nocebo effects occur when an adverse effect on the patient arises from the patient's own negative expectations. In accordance with informed consent, providers often disclose information that results in unintended adverse outcomes for the patient. While this may adhere to the principle of autonomy, it violates the doctrine of "primum non nocere," given that side-effect disclosure may cause those side effects. In this article we build off previous work, particularly by Wells and Kaptchuk ( 2012 ) and by Cohen ( 2013 ), to suggest ethical guidelines that permit nondisclosure in the case when a nocebo effect is likely to occur on of the basis of nonmaleficence. We accept that that autonomy vis-à-vis informed consent must be forestalled, but salvage much of its role by elaborating a practical clinical approach to postencounter follow-up. In doing so, we reconcile a clinically practicable process of determining conditions of disclosure with long-standing ethical commitments to patients.

Differentiated squamous intraepithelial neoplasia associated with squamous cell carcinoma of the anal canal.

AIMS: Differentiated squamous intraepithelial neoplasia (DSIN) has been described in several sites, including the upper aerodigestive tract and vulva, so this study investigated whether it also occurred in the anal canal. METHODS AND RESULTS: All cases of squamous cell carcinoma (SCC) involving the anal canal diagnosed between 2009 and 2015 at our institution were reviewed. Eighty-six cases were included, and 13 (15%) showed features consistent with DSIN: 10 were 'pure' DSIN, and three were 'mixed' DSIN and squamous intraepithelial lesion. DSIN was characterized by atypical keratinocytes limited to the basal/parabasal layers, acanthosis, and a 'cobblestone' appearance. Among specimens with pure DSIN, the surface was flat in eight cases. In five cases, the DSIN was extensive, and associated with deeply invasive SCC requiring radical surgical resection. Immunohistochemically, the epithelia showing changes consistent with DSIN were p16-negative, whereas the invasive component was p16-positive in 12 cases. Both Ki67 and p53 showed strong nuclear positivity in the basal/parabasal layers of DSIN. CONCLUSIONS: Invasive SCC associated with DSIN often presents at an advanced stage of disease, requiring radical surgical treatment. The neoplastic changes in DSIN are limited to the basal/parabasal layers, which may account for the negative diagnoses by anal cytopathology and late clinical diagnosis. The recognition of anal DSIN is important in order to avoid underdiagnosis in superficial biopsies.